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Slide 1 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders
Slide 2 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest
Slide 3 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder
Slide 4 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem.
Slide 5 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder
Slide 6 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon)
Slide 7 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder?
Slide 8 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc.
Slide 9 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control
Slide 10 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…]
Slide 11 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt
Slide 12 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems
Slide 13 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment
Slide 14 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia
Slide 15 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery
Slide 16 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No.
Slide 17 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No. Belmaker RH and Agam G, NEJM 2008, 358:55-68 iproniazid (1957) imipramine (1959) The monoamine hypothesis (1965) Joseph Schildkraut
Slide 18 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No. Belmaker RH and Agam G, NEJM 2008, 358:55-68 iproniazid (1957) imipramine (1959) The monoamine hypothesis (1965) Joseph Schildkraut Question: Do antidepressants have additional actions besides inhibition of reuptake transporters? “…the Zoloft cartoon” from: http://gifsoup.com/webroot/animatedgifs/50426_o.gif; chemical inbalance
Slide 19 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No. Belmaker RH and Agam G, NEJM 2008, 358:55-68 iproniazid (1957) imipramine (1959) The monoamine hypothesis (1965) Joseph Schildkraut Question: Do antidepressants have additional actions besides inhibition of reuptake transporters? “…the Zoloft cartoon” from: http://gifsoup.com/webroot/animatedgifs/50426_o.gif; chemical inbalance Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. J Neurosci. 2000 Dec 15;20(24):9104-10 Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Science. 2003 Aug 8;301(5634):805-9. Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Haenisch B, Bönisch H. Pharmacol Ther. 2011 Mar;129(3):352-68. Epub 2010 Dec 13. Review. Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices. Hennings EC, Kiss JP, De Oliveira K, Toth PT, Vizi ES. J Neurochem. 1999 Sep;73(3):1043-50. Block of an ether-a-go-go-like K(+) channel by imipramine rescues egl-2 excitation defects in Caenorhabditis elegans. Weinshenker D, Wei A, Salkoff L, Thomas JH. J Neurosci. 1999 Nov 15;19(22):9831-40. photo from: http://www.sciencedaily.com/releases/2006/11/061121082449.htm
Slide 20 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No. Belmaker RH and Agam G, NEJM 2008, 358:55-68 iproniazid (1957) imipramine (1959) The monoamine hypothesis (1965) Joseph Schildkraut Question: Do antidepressants have additional actions besides inhibition of reuptake transporters? “…the Zoloft cartoon” from: http://gifsoup.com/webroot/animatedgifs/50426_o.gif; chemical inbalance Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. J Neurosci. 2000 Dec 15;20(24):9104-10 Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Science. 2003 Aug 8;301(5634):805-9. Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Haenisch B, Bönisch H. Pharmacol Ther. 2011 Mar;129(3):352-68. Epub 2010 Dec 13. Review. Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices. Hennings EC, Kiss JP, De Oliveira K, Toth PT, Vizi ES. J Neurochem. 1999 Sep;73(3):1043-50. Block of an ether-a-go-go-like K(+) channel by imipramine rescues egl-2 excitation defects in Caenorhabditis elegans. Weinshenker D, Wei A, Salkoff L, Thomas JH. J Neurosci. 1999 Nov 15;19(22):9831-40. photo from: http://www.sciencedaily.com/releases/2006/11/061121082449.htm Subsequent hypotheses about MDD altered glutamatergic transmission ↓’d GABAergic transmission monoamine-Ach imbalance disruption of endogenous opioid signalling neurosteroid deficiencies thyroxine abnormalities cytokine-mediated x-talk betw immune system & CNS circadian abnormalities (specific brain structure/circuit dysfxns…) as summarized in Belmaker RH and Agam G, NEJM 2008, 358:55-68
Slide 21 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No. Belmaker RH and Agam G, NEJM 2008, 358:55-68 iproniazid (1957) imipramine (1959) The monoamine hypothesis (1965) Joseph Schildkraut Question: Do antidepressants have additional actions besides inhibition of reuptake transporters? “…the Zoloft cartoon” from: http://gifsoup.com/webroot/animatedgifs/50426_o.gif; chemical inbalance Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. J Neurosci. 2000 Dec 15;20(24):9104-10 Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Science. 2003 Aug 8;301(5634):805-9. Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Haenisch B, Bönisch H. Pharmacol Ther. 2011 Mar;129(3):352-68. Epub 2010 Dec 13. Review. Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices. Hennings EC, Kiss JP, De Oliveira K, Toth PT, Vizi ES. J Neurochem. 1999 Sep;73(3):1043-50. Block of an ether-a-go-go-like K(+) channel by imipramine rescues egl-2 excitation defects in Caenorhabditis elegans. Weinshenker D, Wei A, Salkoff L, Thomas JH. J Neurosci. 1999 Nov 15;19(22):9831-40. photo from: http://www.sciencedaily.com/releases/2006/11/061121082449.htm Subsequent hypotheses about MDD altered glutamatergic transmission ↓’d GABAergic transmission monoamine-Ach imbalance disruption of endogenous opioid signalling neurosteroid deficiencies thyroxine abnormalities cytokine-mediated x-talk betw immune system & CNS circadian abnormalities (specific brain structure/circuit dysfxns…) as summarized in Belmaker RH and Agam G, NEJM 2008, 358:55-68 MDD tx options selective serotonin reuptake inhibitors (SSRIs) fluoxetine (PROZAC), 20-80 mg/d citalopram (CELEXA), 20-40 mg/d escitalopram (LEXAPRO), 10-20 mg/d sertraline (ZOLOFT), 50-200 mg/d paroxetine (PAXIL), 20-50 mg/d serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine XR (EFFEXOR XR), 37.5-225 mg/d desvenlafaxine (PRISTIQ) duloxetine (CYMBALTA), 30-120 mg/d others bupropion SR, XL (WELLBUTRIN) 100-200 mg BID (SR) 150-450 mg/d (XL) mirtazapine (REMERON), 15-45 mg/d trazodone, 50-200mg/noc (for sleep) nefazodone tricyclic antidepressants (TCADs) amitriptyline  nortriptyline imipramine  desipramine monoamine oxidase inhibitors (MAO-Is) typically, non-selective & irreversible MAO-A (NE, EPI, 5HT, DA) MAO-B (trace amines, DA) why we “wash-out” 5HT syndrome HTNsive crisis selegiline (EMSAM) [additional] augmenting agents Li+ T3, 25 mcg/d buspirone (BuSPAR), 5-30 mg BID atypical antipsychotics
Slide 22 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No. Belmaker RH and Agam G, NEJM 2008, 358:55-68 iproniazid (1957) imipramine (1959) The monoamine hypothesis (1965) Joseph Schildkraut Question: Do antidepressants have additional actions besides inhibition of reuptake transporters? “…the Zoloft cartoon” from: http://gifsoup.com/webroot/animatedgifs/50426_o.gif; chemical inbalance Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. J Neurosci. 2000 Dec 15;20(24):9104-10 Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Science. 2003 Aug 8;301(5634):805-9. Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Haenisch B, Bönisch H. Pharmacol Ther. 2011 Mar;129(3):352-68. Epub 2010 Dec 13. Review. Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices. Hennings EC, Kiss JP, De Oliveira K, Toth PT, Vizi ES. J Neurochem. 1999 Sep;73(3):1043-50. Block of an ether-a-go-go-like K(+) channel by imipramine rescues egl-2 excitation defects in Caenorhabditis elegans. Weinshenker D, Wei A, Salkoff L, Thomas JH. J Neurosci. 1999 Nov 15;19(22):9831-40. photo from: http://www.sciencedaily.com/releases/2006/11/061121082449.htm Subsequent hypotheses about MDD altered glutamatergic transmission ↓’d GABAergic transmission monoamine-Ach imbalance disruption of endogenous opioid signalling neurosteroid deficiencies thyroxine abnormalities cytokine-mediated x-talk betw immune system & CNS circadian abnormalities (specific brain structure/circuit dysfxns…) as summarized in Belmaker RH and Agam G, NEJM 2008, 358:55-68 MDD tx options selective serotonin reuptake inhibitors (SSRIs) fluoxetine (PROZAC), 20-80 mg/d citalopram (CELEXA), 20-40 mg/d escitalopram (LEXAPRO), 10-20 mg/d sertraline (ZOLOFT), 50-200 mg/d paroxetine (PAXIL), 20-50 mg/d serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine XR (EFFEXOR XR), 37.5-225 mg/d desvenlafaxine (PRISTIQ) duloxetine (CYMBALTA), 30-120 mg/d others bupropion SR, XL (WELLBUTRIN) 100-200 mg BID (SR) 150-450 mg/d (XL) mirtazapine (REMERON), 15-45 mg/d trazodone, 50-200mg/noc (for sleep) nefazodone tricyclic antidepressants (TCADs) amitriptyline  nortriptyline imipramine  desipramine monoamine oxidase inhibitors (MAO-Is) typically, non-selective & irreversible MAO-A (NE, EPI, 5HT, DA) MAO-B (trace amines, DA) why we “wash-out” 5HT syndrome HTNsive crisis selegiline (EMSAM) [additional] augmenting agents Li+ T3, 25 mcg/d buspirone (BuSPAR), 5-30 mg BID atypical antipsychotics Sequenced Treatment Alternatives for the Relief of Depression (STAR*D) major NIMH-funded study (PI: A. John Rush) w/ 14 regional centers & 41 clinical sites initial enrollment of 4,041 patients aim: which tx algorithms work best after an initial failure to remit non-psychotic depression w/ an antidepressant? http://www.clinicaltrials.gov/ct/show/NCT00021528?order=1
Slide 23 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No. Belmaker RH and Agam G, NEJM 2008, 358:55-68 iproniazid (1957) imipramine (1959) The monoamine hypothesis (1965) Joseph Schildkraut Question: Do antidepressants have additional actions besides inhibition of reuptake transporters? “…the Zoloft cartoon” from: http://gifsoup.com/webroot/animatedgifs/50426_o.gif; chemical inbalance Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. J Neurosci. 2000 Dec 15;20(24):9104-10 Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Science. 2003 Aug 8;301(5634):805-9. Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Haenisch B, Bönisch H. Pharmacol Ther. 2011 Mar;129(3):352-68. Epub 2010 Dec 13. Review. Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices. Hennings EC, Kiss JP, De Oliveira K, Toth PT, Vizi ES. J Neurochem. 1999 Sep;73(3):1043-50. Block of an ether-a-go-go-like K(+) channel by imipramine rescues egl-2 excitation defects in Caenorhabditis elegans. Weinshenker D, Wei A, Salkoff L, Thomas JH. J Neurosci. 1999 Nov 15;19(22):9831-40. photo from: http://www.sciencedaily.com/releases/2006/11/061121082449.htm Subsequent hypotheses about MDD altered glutamatergic transmission ↓’d GABAergic transmission monoamine-Ach imbalance disruption of endogenous opioid signalling neurosteroid deficiencies thyroxine abnormalities cytokine-mediated x-talk betw immune system & CNS circadian abnormalities (specific brain structure/circuit dysfxns…) as summarized in Belmaker RH and Agam G, NEJM 2008, 358:55-68 MDD tx options selective serotonin reuptake inhibitors (SSRIs) fluoxetine (PROZAC), 20-80 mg/d citalopram (CELEXA), 20-40 mg/d escitalopram (LEXAPRO), 10-20 mg/d sertraline (ZOLOFT), 50-200 mg/d paroxetine (PAXIL), 20-50 mg/d serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine XR (EFFEXOR XR), 37.5-225 mg/d desvenlafaxine (PRISTIQ) duloxetine (CYMBALTA), 30-120 mg/d others bupropion SR, XL (WELLBUTRIN) 100-200 mg BID (SR) 150-450 mg/d (XL) mirtazapine (REMERON), 15-45 mg/d trazodone, 50-200mg/noc (for sleep) nefazodone tricyclic antidepressants (TCADs) amitriptyline  nortriptyline imipramine  desipramine monoamine oxidase inhibitors (MAO-Is) typically, non-selective & irreversible MAO-A (NE, EPI, 5HT, DA) MAO-B (trace amines, DA) why we “wash-out” 5HT syndrome HTNsive crisis selegiline (EMSAM) [additional] augmenting agents Li+ T3, 25 mcg/d buspirone (BuSPAR), 5-30 mg BID atypical antipsychotics Sequenced Treatment Alternatives for the Relief of Depression (STAR*D) major NIMH-funded study (PI: A. John Rush) w/ 14 regional centers & 41 clinical sites initial enrollment of 4,041 patients aim: which tx algorithms work best after an initial failure to remit non-psychotic depression w/ an antidepressant? http://www.clinicaltrials.gov/ct/show/NCT00021528?order=1 Trivedi MH et al, Am J Psychiatry. 2006 Jan;163(1):28-40 47% response rate on citalopram (by *QIDS-SR, 50% ↓ in sxs) Sequenced Treatment Alternatives for the Relief of Depression (STAR*D), n = 2,876 (qualifying pts) 33% remission rate on citalopram (by QIDS-SR, score <5) Rx choice: according to side effects (SE’s), comorbid condn’s / risks (GMC & Ψ), ?FmRxHx 6-8wk trials each (preferable) augmentation v. switch? *QIDS-SR = Quick Inventory of Depressive Symptomatology, Self-Report (range 0-27) http://www.ids-qids.org/
Slide 24 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No. Belmaker RH and Agam G, NEJM 2008, 358:55-68 iproniazid (1957) imipramine (1959) The monoamine hypothesis (1965) Joseph Schildkraut Question: Do antidepressants have additional actions besides inhibition of reuptake transporters? “…the Zoloft cartoon” from: http://gifsoup.com/webroot/animatedgifs/50426_o.gif; chemical inbalance Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. J Neurosci. 2000 Dec 15;20(24):9104-10 Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Science. 2003 Aug 8;301(5634):805-9. Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Haenisch B, Bönisch H. Pharmacol Ther. 2011 Mar;129(3):352-68. Epub 2010 Dec 13. Review. Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices. Hennings EC, Kiss JP, De Oliveira K, Toth PT, Vizi ES. J Neurochem. 1999 Sep;73(3):1043-50. Block of an ether-a-go-go-like K(+) channel by imipramine rescues egl-2 excitation defects in Caenorhabditis elegans. Weinshenker D, Wei A, Salkoff L, Thomas JH. J Neurosci. 1999 Nov 15;19(22):9831-40. photo from: http://www.sciencedaily.com/releases/2006/11/061121082449.htm Subsequent hypotheses about MDD altered glutamatergic transmission ↓’d GABAergic transmission monoamine-Ach imbalance disruption of endogenous opioid signalling neurosteroid deficiencies thyroxine abnormalities cytokine-mediated x-talk betw immune system & CNS circadian abnormalities (specific brain structure/circuit dysfxns…) as summarized in Belmaker RH and Agam G, NEJM 2008, 358:55-68 MDD tx options selective serotonin reuptake inhibitors (SSRIs) fluoxetine (PROZAC), 20-80 mg/d citalopram (CELEXA), 20-40 mg/d escitalopram (LEXAPRO), 10-20 mg/d sertraline (ZOLOFT), 50-200 mg/d paroxetine (PAXIL), 20-50 mg/d serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine XR (EFFEXOR XR), 37.5-225 mg/d desvenlafaxine (PRISTIQ) duloxetine (CYMBALTA), 30-120 mg/d others bupropion SR, XL (WELLBUTRIN) 100-200 mg BID (SR) 150-450 mg/d (XL) mirtazapine (REMERON), 15-45 mg/d trazodone, 50-200mg/noc (for sleep) nefazodone tricyclic antidepressants (TCADs) amitriptyline  nortriptyline imipramine  desipramine monoamine oxidase inhibitors (MAO-Is) typically, non-selective & irreversible MAO-A (NE, EPI, 5HT, DA) MAO-B (trace amines, DA) why we “wash-out” 5HT syndrome HTNsive crisis selegiline (EMSAM) [additional] augmenting agents Li+ T3, 25 mcg/d buspirone (BuSPAR), 5-30 mg BID atypical antipsychotics Sequenced Treatment Alternatives for the Relief of Depression (STAR*D) major NIMH-funded study (PI: A. John Rush) w/ 14 regional centers & 41 clinical sites initial enrollment of 4,041 patients aim: which tx algorithms work best after an initial failure to remit non-psychotic depression w/ an antidepressant? http://www.clinicaltrials.gov/ct/show/NCT00021528?order=1 Trivedi MH et al, Am J Psychiatry. 2006 Jan;163(1):28-40 47% response rate on citalopram (by *QIDS-SR, 50% ↓ in sxs) Sequenced Treatment Alternatives for the Relief of Depression (STAR*D), n = 2,876 (qualifying pts) 33% remission rate on citalopram (by QIDS-SR, score <5) Rx choice: according to side effects (SE’s), comorbid condn’s / risks (GMC & Ψ), ?FmRxHx 6-8wk trials each (preferable) augmentation v. switch? *QIDS-SR = Quick Inventory of Depressive Symptomatology, Self-Report (range 0-27) http://www.ids-qids.org/ MDD tx options Ψtherapy cognitive bx therapy (CBT) interpersonal therapy (IPT) psychodynamic therapy interventional Ψ electroconvulsive therapy (ECT) transcranial magnetic stimulation (TMS) vagal nerve stimulation (VNS) deep brain stimulation (DBS) other lightbox therapy (mostly for MDD w/ seasonal features)
Slide 25 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No. Belmaker RH and Agam G, NEJM 2008, 358:55-68 iproniazid (1957) imipramine (1959) The monoamine hypothesis (1965) Joseph Schildkraut Question: Do antidepressants have additional actions besides inhibition of reuptake transporters? “…the Zoloft cartoon” from: http://gifsoup.com/webroot/animatedgifs/50426_o.gif; chemical inbalance Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. J Neurosci. 2000 Dec 15;20(24):9104-10 Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Science. 2003 Aug 8;301(5634):805-9. Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Haenisch B, Bönisch H. Pharmacol Ther. 2011 Mar;129(3):352-68. Epub 2010 Dec 13. Review. Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices. Hennings EC, Kiss JP, De Oliveira K, Toth PT, Vizi ES. J Neurochem. 1999 Sep;73(3):1043-50. Block of an ether-a-go-go-like K(+) channel by imipramine rescues egl-2 excitation defects in Caenorhabditis elegans. Weinshenker D, Wei A, Salkoff L, Thomas JH. J Neurosci. 1999 Nov 15;19(22):9831-40. photo from: http://www.sciencedaily.com/releases/2006/11/061121082449.htm Subsequent hypotheses about MDD altered glutamatergic transmission ↓’d GABAergic transmission monoamine-Ach imbalance disruption of endogenous opioid signalling neurosteroid deficiencies thyroxine abnormalities cytokine-mediated x-talk betw immune system & CNS circadian abnormalities (specific brain structure/circuit dysfxns…) as summarized in Belmaker RH and Agam G, NEJM 2008, 358:55-68 MDD tx options selective serotonin reuptake inhibitors (SSRIs) fluoxetine (PROZAC), 20-80 mg/d citalopram (CELEXA), 20-40 mg/d escitalopram (LEXAPRO), 10-20 mg/d sertraline (ZOLOFT), 50-200 mg/d paroxetine (PAXIL), 20-50 mg/d serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine XR (EFFEXOR XR), 37.5-225 mg/d desvenlafaxine (PRISTIQ) duloxetine (CYMBALTA), 30-120 mg/d others bupropion SR, XL (WELLBUTRIN) 100-200 mg BID (SR) 150-450 mg/d (XL) mirtazapine (REMERON), 15-45 mg/d trazodone, 50-200mg/noc (for sleep) nefazodone tricyclic antidepressants (TCADs) amitriptyline  nortriptyline imipramine  desipramine monoamine oxidase inhibitors (MAO-Is) typically, non-selective & irreversible MAO-A (NE, EPI, 5HT, DA) MAO-B (trace amines, DA) why we “wash-out” 5HT syndrome HTNsive crisis selegiline (EMSAM) [additional] augmenting agents Li+ T3, 25 mcg/d buspirone (BuSPAR), 5-30 mg BID atypical antipsychotics Sequenced Treatment Alternatives for the Relief of Depression (STAR*D) major NIMH-funded study (PI: A. John Rush) w/ 14 regional centers & 41 clinical sites initial enrollment of 4,041 patients aim: which tx algorithms work best after an initial failure to remit non-psychotic depression w/ an antidepressant? http://www.clinicaltrials.gov/ct/show/NCT00021528?order=1 Trivedi MH et al, Am J Psychiatry. 2006 Jan;163(1):28-40 47% response rate on citalopram (by *QIDS-SR, 50% ↓ in sxs) Sequenced Treatment Alternatives for the Relief of Depression (STAR*D), n = 2,876 (qualifying pts) 33% remission rate on citalopram (by QIDS-SR, score <5) Rx choice: according to side effects (SE’s), comorbid condn’s / risks (GMC & Ψ), ?FmRxHx 6-8wk trials each (preferable) augmentation v. switch? *QIDS-SR = Quick Inventory of Depressive Symptomatology, Self-Report (range 0-27) http://www.ids-qids.org/ MDD tx options Ψtherapy cognitive bx therapy (CBT) interpersonal therapy (IPT) psychodynamic therapy interventional Ψ electroconvulsive therapy (ECT) transcranial magnetic stimulation (TMS) vagal nerve stimulation (VNS) deep brain stimulation (DBS) other lightbox therapy (mostly for MDD w/ seasonal features) Major Depressive D/O (MDD) NATURAL HISTORY (Frank E and Thase ME, 1999 & DSM-5) recovery usually begins: w/in 3mos for two in five indivs w/in 1y for four in five indivs risk of subsequent episodes (w/in 3y) increases w/ n: ≥50% if n=1 ≥70% if n=2 ≥90% if n=3 dz course does not typically change as one ages 5-10% will eventually be dx’d w/ bipolar disorder (BD) more likely w/: onset of ‘MDD’ in adolescence a family history of BD ‘mixed features’ 6% lifetime SUI risk (Davies S et al, 2001); up to 15% w/ severe MDD
Slide 26 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No. Belmaker RH and Agam G, NEJM 2008, 358:55-68 iproniazid (1957) imipramine (1959) The monoamine hypothesis (1965) Joseph Schildkraut Question: Do antidepressants have additional actions besides inhibition of reuptake transporters? “…the Zoloft cartoon” from: http://gifsoup.com/webroot/animatedgifs/50426_o.gif; chemical inbalance Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. J Neurosci. 2000 Dec 15;20(24):9104-10 Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Science. 2003 Aug 8;301(5634):805-9. Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Haenisch B, Bönisch H. Pharmacol Ther. 2011 Mar;129(3):352-68. Epub 2010 Dec 13. Review. Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices. Hennings EC, Kiss JP, De Oliveira K, Toth PT, Vizi ES. J Neurochem. 1999 Sep;73(3):1043-50. Block of an ether-a-go-go-like K(+) channel by imipramine rescues egl-2 excitation defects in Caenorhabditis elegans. Weinshenker D, Wei A, Salkoff L, Thomas JH. J Neurosci. 1999 Nov 15;19(22):9831-40. photo from: http://www.sciencedaily.com/releases/2006/11/061121082449.htm Subsequent hypotheses about MDD altered glutamatergic transmission ↓’d GABAergic transmission monoamine-Ach imbalance disruption of endogenous opioid signalling neurosteroid deficiencies thyroxine abnormalities cytokine-mediated x-talk betw immune system & CNS circadian abnormalities (specific brain structure/circuit dysfxns…) as summarized in Belmaker RH and Agam G, NEJM 2008, 358:55-68 MDD tx options selective serotonin reuptake inhibitors (SSRIs) fluoxetine (PROZAC), 20-80 mg/d citalopram (CELEXA), 20-40 mg/d escitalopram (LEXAPRO), 10-20 mg/d sertraline (ZOLOFT), 50-200 mg/d paroxetine (PAXIL), 20-50 mg/d serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine XR (EFFEXOR XR), 37.5-225 mg/d desvenlafaxine (PRISTIQ) duloxetine (CYMBALTA), 30-120 mg/d others bupropion SR, XL (WELLBUTRIN) 100-200 mg BID (SR) 150-450 mg/d (XL) mirtazapine (REMERON), 15-45 mg/d trazodone, 50-200mg/noc (for sleep) nefazodone tricyclic antidepressants (TCADs) amitriptyline  nortriptyline imipramine  desipramine monoamine oxidase inhibitors (MAO-Is) typically, non-selective & irreversible MAO-A (NE, EPI, 5HT, DA) MAO-B (trace amines, DA) why we “wash-out” 5HT syndrome HTNsive crisis selegiline (EMSAM) [additional] augmenting agents Li+ T3, 25 mcg/d buspirone (BuSPAR), 5-30 mg BID atypical antipsychotics Sequenced Treatment Alternatives for the Relief of Depression (STAR*D) major NIMH-funded study (PI: A. John Rush) w/ 14 regional centers & 41 clinical sites initial enrollment of 4,041 patients aim: which tx algorithms work best after an initial failure to remit non-psychotic depression w/ an antidepressant? http://www.clinicaltrials.gov/ct/show/NCT00021528?order=1 Trivedi MH et al, Am J Psychiatry. 2006 Jan;163(1):28-40 47% response rate on citalopram (by *QIDS-SR, 50% ↓ in sxs) Sequenced Treatment Alternatives for the Relief of Depression (STAR*D), n = 2,876 (qualifying pts) 33% remission rate on citalopram (by QIDS-SR, score <5) Rx choice: according to side effects (SE’s), comorbid condn’s / risks (GMC & Ψ), ?FmRxHx 6-8wk trials each (preferable) augmentation v. switch? *QIDS-SR = Quick Inventory of Depressive Symptomatology, Self-Report (range 0-27) http://www.ids-qids.org/ MDD tx options Ψtherapy cognitive bx therapy (CBT) interpersonal therapy (IPT) psychodynamic therapy interventional Ψ electroconvulsive therapy (ECT) transcranial magnetic stimulation (TMS) vagal nerve stimulation (VNS) deep brain stimulation (DBS) other lightbox therapy (mostly for MDD w/ seasonal features) Major Depressive D/O (MDD) NATURAL HISTORY (Frank E and Thase ME, 1999 & DSM-5) recovery usually begins: w/in 3mos for two in five indivs w/in 1y for four in five indivs risk of subsequent episodes (w/in 3y) increases w/ n: ≥50% if n=1 ≥70% if n=2 ≥90% if n=3 dz course does not typically change as one ages 5-10% will eventually be dx’d w/ bipolar disorder (BD) more likely w/: onset of ‘MDD’ in adolescence a family history of BD ‘mixed features’ 6% lifetime SUI risk (Davies S et al, 2001); up to 15% w/ severe MDD Persistent depressive disorder (dysthymia) 2y of depressed mood (1y in children/adolescents) most of the day, more days than not, plus 2 of the following: appetite disturbance (↓ or ↑) veg sleep disturbance (↓ or ↑) veg ↓energy E ↓esteem E poor [ ] C hopeless H never sx-free for more than 2mos at a time overlapping dx of MDD is now allowed there has never been mania, hypomania, or cyclothymia MDD specifiers can also be used for dysthymia additionally: early onset (before age 21) late onset (at age 21 or older) w/ pure dysthymic syndrome from DSM-5 w/ persistent MDE w/ intermittent MDE’s, w/ current episode w/ intermittent MDE’s, w/o current episode --these last 3 are essentially a co-dx of MDD, but captured within the specifier…
Slide 27 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No. Belmaker RH and Agam G, NEJM 2008, 358:55-68 iproniazid (1957) imipramine (1959) The monoamine hypothesis (1965) Joseph Schildkraut Question: Do antidepressants have additional actions besides inhibition of reuptake transporters? “…the Zoloft cartoon” from: http://gifsoup.com/webroot/animatedgifs/50426_o.gif; chemical inbalance Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. J Neurosci. 2000 Dec 15;20(24):9104-10 Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Science. 2003 Aug 8;301(5634):805-9. Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Haenisch B, Bönisch H. Pharmacol Ther. 2011 Mar;129(3):352-68. Epub 2010 Dec 13. Review. Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices. Hennings EC, Kiss JP, De Oliveira K, Toth PT, Vizi ES. J Neurochem. 1999 Sep;73(3):1043-50. Block of an ether-a-go-go-like K(+) channel by imipramine rescues egl-2 excitation defects in Caenorhabditis elegans. Weinshenker D, Wei A, Salkoff L, Thomas JH. J Neurosci. 1999 Nov 15;19(22):9831-40. photo from: http://www.sciencedaily.com/releases/2006/11/061121082449.htm Subsequent hypotheses about MDD altered glutamatergic transmission ↓’d GABAergic transmission monoamine-Ach imbalance disruption of endogenous opioid signalling neurosteroid deficiencies thyroxine abnormalities cytokine-mediated x-talk betw immune system & CNS circadian abnormalities (specific brain structure/circuit dysfxns…) as summarized in Belmaker RH and Agam G, NEJM 2008, 358:55-68 MDD tx options selective serotonin reuptake inhibitors (SSRIs) fluoxetine (PROZAC), 20-80 mg/d citalopram (CELEXA), 20-40 mg/d escitalopram (LEXAPRO), 10-20 mg/d sertraline (ZOLOFT), 50-200 mg/d paroxetine (PAXIL), 20-50 mg/d serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine XR (EFFEXOR XR), 37.5-225 mg/d desvenlafaxine (PRISTIQ) duloxetine (CYMBALTA), 30-120 mg/d others bupropion SR, XL (WELLBUTRIN) 100-200 mg BID (SR) 150-450 mg/d (XL) mirtazapine (REMERON), 15-45 mg/d trazodone, 50-200mg/noc (for sleep) nefazodone tricyclic antidepressants (TCADs) amitriptyline  nortriptyline imipramine  desipramine monoamine oxidase inhibitors (MAO-Is) typically, non-selective & irreversible MAO-A (NE, EPI, 5HT, DA) MAO-B (trace amines, DA) why we “wash-out” 5HT syndrome HTNsive crisis selegiline (EMSAM) [additional] augmenting agents Li+ T3, 25 mcg/d buspirone (BuSPAR), 5-30 mg BID atypical antipsychotics Sequenced Treatment Alternatives for the Relief of Depression (STAR*D) major NIMH-funded study (PI: A. John Rush) w/ 14 regional centers & 41 clinical sites initial enrollment of 4,041 patients aim: which tx algorithms work best after an initial failure to remit non-psychotic depression w/ an antidepressant? http://www.clinicaltrials.gov/ct/show/NCT00021528?order=1 Trivedi MH et al, Am J Psychiatry. 2006 Jan;163(1):28-40 47% response rate on citalopram (by *QIDS-SR, 50% ↓ in sxs) Sequenced Treatment Alternatives for the Relief of Depression (STAR*D), n = 2,876 (qualifying pts) 33% remission rate on citalopram (by QIDS-SR, score <5) Rx choice: according to side effects (SE’s), comorbid condn’s / risks (GMC & Ψ), ?FmRxHx 6-8wk trials each (preferable) augmentation v. switch? *QIDS-SR = Quick Inventory of Depressive Symptomatology, Self-Report (range 0-27) http://www.ids-qids.org/ MDD tx options Ψtherapy cognitive bx therapy (CBT) interpersonal therapy (IPT) psychodynamic therapy interventional Ψ electroconvulsive therapy (ECT) transcranial magnetic stimulation (TMS) vagal nerve stimulation (VNS) deep brain stimulation (DBS) other lightbox therapy (mostly for MDD w/ seasonal features) Major Depressive D/O (MDD) NATURAL HISTORY (Frank E and Thase ME, 1999 & DSM-5) recovery usually begins: w/in 3mos for two in five indivs w/in 1y for four in five indivs risk of subsequent episodes (w/in 3y) increases w/ n: ≥50% if n=1 ≥70% if n=2 ≥90% if n=3 dz course does not typically change as one ages 5-10% will eventually be dx’d w/ bipolar disorder (BD) more likely w/: onset of ‘MDD’ in adolescence a family history of BD ‘mixed features’ 6% lifetime SUI risk (Davies S et al, 2001); up to 15% w/ severe MDD Persistent depressive disorder (dysthymia) 2y of depressed mood (1y in children/adolescents) most of the day, more days than not, plus 2 of the following: appetite disturbance (↓ or ↑) veg sleep disturbance (↓ or ↑) veg ↓energy E ↓esteem E poor [ ] C hopeless H never sx-free for more than 2mos at a time overlapping dx of MDD is now allowed there has never been mania, hypomania, or cyclothymia MDD specifiers can also be used for dysthymia additionally: early onset (before age 21) late onset (at age 21 or older) w/ pure dysthymic syndrome from DSM-5 w/ persistent MDE w/ intermittent MDE’s, w/ current episode w/ intermittent MDE’s, w/o current episode --these last 3 are essentially a co-dx of MDD, but captured within the specifier… Persistent depressive disorder (dysthymia) may be more treatment-resistant (TxR) than straightforward MDD EPIDEMIOLOGY lifetime prevalence = 6% 12-mo prevalence = 0.5%, compared w/ 1.5% for MDD high comorbidity w/ personality d/o’s (particularly clusters B, C) From Sadock & Sadock & DSM-5
Slide 28 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No. Belmaker RH and Agam G, NEJM 2008, 358:55-68 iproniazid (1957) imipramine (1959) The monoamine hypothesis (1965) Joseph Schildkraut Question: Do antidepressants have additional actions besides inhibition of reuptake transporters? “…the Zoloft cartoon” from: http://gifsoup.com/webroot/animatedgifs/50426_o.gif; chemical inbalance Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. J Neurosci. 2000 Dec 15;20(24):9104-10 Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Science. 2003 Aug 8;301(5634):805-9. Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Haenisch B, Bönisch H. Pharmacol Ther. 2011 Mar;129(3):352-68. Epub 2010 Dec 13. Review. Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices. Hennings EC, Kiss JP, De Oliveira K, Toth PT, Vizi ES. J Neurochem. 1999 Sep;73(3):1043-50. Block of an ether-a-go-go-like K(+) channel by imipramine rescues egl-2 excitation defects in Caenorhabditis elegans. Weinshenker D, Wei A, Salkoff L, Thomas JH. J Neurosci. 1999 Nov 15;19(22):9831-40. photo from: http://www.sciencedaily.com/releases/2006/11/061121082449.htm Subsequent hypotheses about MDD altered glutamatergic transmission ↓’d GABAergic transmission monoamine-Ach imbalance disruption of endogenous opioid signalling neurosteroid deficiencies thyroxine abnormalities cytokine-mediated x-talk betw immune system & CNS circadian abnormalities (specific brain structure/circuit dysfxns…) as summarized in Belmaker RH and Agam G, NEJM 2008, 358:55-68 MDD tx options selective serotonin reuptake inhibitors (SSRIs) fluoxetine (PROZAC), 20-80 mg/d citalopram (CELEXA), 20-40 mg/d escitalopram (LEXAPRO), 10-20 mg/d sertraline (ZOLOFT), 50-200 mg/d paroxetine (PAXIL), 20-50 mg/d serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine XR (EFFEXOR XR), 37.5-225 mg/d desvenlafaxine (PRISTIQ) duloxetine (CYMBALTA), 30-120 mg/d others bupropion SR, XL (WELLBUTRIN) 100-200 mg BID (SR) 150-450 mg/d (XL) mirtazapine (REMERON), 15-45 mg/d trazodone, 50-200mg/noc (for sleep) nefazodone tricyclic antidepressants (TCADs) amitriptyline  nortriptyline imipramine  desipramine monoamine oxidase inhibitors (MAO-Is) typically, non-selective & irreversible MAO-A (NE, EPI, 5HT, DA) MAO-B (trace amines, DA) why we “wash-out” 5HT syndrome HTNsive crisis selegiline (EMSAM) [additional] augmenting agents Li+ T3, 25 mcg/d buspirone (BuSPAR), 5-30 mg BID atypical antipsychotics Sequenced Treatment Alternatives for the Relief of Depression (STAR*D) major NIMH-funded study (PI: A. John Rush) w/ 14 regional centers & 41 clinical sites initial enrollment of 4,041 patients aim: which tx algorithms work best after an initial failure to remit non-psychotic depression w/ an antidepressant? http://www.clinicaltrials.gov/ct/show/NCT00021528?order=1 Trivedi MH et al, Am J Psychiatry. 2006 Jan;163(1):28-40 47% response rate on citalopram (by *QIDS-SR, 50% ↓ in sxs) Sequenced Treatment Alternatives for the Relief of Depression (STAR*D), n = 2,876 (qualifying pts) 33% remission rate on citalopram (by QIDS-SR, score <5) Rx choice: according to side effects (SE’s), comorbid condn’s / risks (GMC & Ψ), ?FmRxHx 6-8wk trials each (preferable) augmentation v. switch? *QIDS-SR = Quick Inventory of Depressive Symptomatology, Self-Report (range 0-27) http://www.ids-qids.org/ MDD tx options Ψtherapy cognitive bx therapy (CBT) interpersonal therapy (IPT) psychodynamic therapy interventional Ψ electroconvulsive therapy (ECT) transcranial magnetic stimulation (TMS) vagal nerve stimulation (VNS) deep brain stimulation (DBS) other lightbox therapy (mostly for MDD w/ seasonal features) Major Depressive D/O (MDD) NATURAL HISTORY (Frank E and Thase ME, 1999 & DSM-5) recovery usually begins: w/in 3mos for two in five indivs w/in 1y for four in five indivs risk of subsequent episodes (w/in 3y) increases w/ n: ≥50% if n=1 ≥70% if n=2 ≥90% if n=3 dz course does not typically change as one ages 5-10% will eventually be dx’d w/ bipolar disorder (BD) more likely w/: onset of ‘MDD’ in adolescence a family history of BD ‘mixed features’ 6% lifetime SUI risk (Davies S et al, 2001); up to 15% w/ severe MDD Persistent depressive disorder (dysthymia) 2y of depressed mood (1y in children/adolescents) most of the day, more days than not, plus 2 of the following: appetite disturbance (↓ or ↑) veg sleep disturbance (↓ or ↑) veg ↓energy E ↓esteem E poor [ ] C hopeless H never sx-free for more than 2mos at a time overlapping dx of MDD is now allowed there has never been mania, hypomania, or cyclothymia MDD specifiers can also be used for dysthymia additionally: early onset (before age 21) late onset (at age 21 or older) w/ pure dysthymic syndrome from DSM-5 w/ persistent MDE w/ intermittent MDE’s, w/ current episode w/ intermittent MDE’s, w/o current episode --these last 3 are essentially a co-dx of MDD, but captured within the specifier… Persistent depressive disorder (dysthymia) may be more treatment-resistant (TxR) than straightforward MDD EPIDEMIOLOGY lifetime prevalence = 6% 12-mo prevalence = 0.5%, compared w/ 1.5% for MDD high comorbidity w/ personality d/o’s (particularly clusters B, C) From Sadock & Sadock & DSM-5 Case 1. 36yo F presenting w/ 3mos of ↓mood. She reports getting only ~4h of sleep/noc b/c of regular early AM awakenings. She feels drained everyday, all day long. She’s gained about 10 lbs in the last 2mos. What else would you like to ask? How would you work-up this patient? In the meantime, what would you dx and what would be your tentative tx plan? She returns 1mo later and reports that her mood continues to spiral downward. Now, she adds that she’s starting to think more morbid thoughts and that maybe it wouldn’t be such a bad thing if she weren’t around anymore. What would you ask now? How would you revise your tx plan? The pt’s sxs are finally stabilized and she returns at a later date w/ her sxs in remission x 1mo. “Doctor, I’m feeling so much better now. Do you think I can stop my psych Rxs?” How would you answer?
Slide 29 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No. Belmaker RH and Agam G, NEJM 2008, 358:55-68 iproniazid (1957) imipramine (1959) The monoamine hypothesis (1965) Joseph Schildkraut Question: Do antidepressants have additional actions besides inhibition of reuptake transporters? “…the Zoloft cartoon” from: http://gifsoup.com/webroot/animatedgifs/50426_o.gif; chemical inbalance Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. J Neurosci. 2000 Dec 15;20(24):9104-10 Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Science. 2003 Aug 8;301(5634):805-9. Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Haenisch B, Bönisch H. Pharmacol Ther. 2011 Mar;129(3):352-68. Epub 2010 Dec 13. Review. Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices. Hennings EC, Kiss JP, De Oliveira K, Toth PT, Vizi ES. J Neurochem. 1999 Sep;73(3):1043-50. Block of an ether-a-go-go-like K(+) channel by imipramine rescues egl-2 excitation defects in Caenorhabditis elegans. Weinshenker D, Wei A, Salkoff L, Thomas JH. J Neurosci. 1999 Nov 15;19(22):9831-40. photo from: http://www.sciencedaily.com/releases/2006/11/061121082449.htm Subsequent hypotheses about MDD altered glutamatergic transmission ↓’d GABAergic transmission monoamine-Ach imbalance disruption of endogenous opioid signalling neurosteroid deficiencies thyroxine abnormalities cytokine-mediated x-talk betw immune system & CNS circadian abnormalities (specific brain structure/circuit dysfxns…) as summarized in Belmaker RH and Agam G, NEJM 2008, 358:55-68 MDD tx options selective serotonin reuptake inhibitors (SSRIs) fluoxetine (PROZAC), 20-80 mg/d citalopram (CELEXA), 20-40 mg/d escitalopram (LEXAPRO), 10-20 mg/d sertraline (ZOLOFT), 50-200 mg/d paroxetine (PAXIL), 20-50 mg/d serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine XR (EFFEXOR XR), 37.5-225 mg/d desvenlafaxine (PRISTIQ) duloxetine (CYMBALTA), 30-120 mg/d others bupropion SR, XL (WELLBUTRIN) 100-200 mg BID (SR) 150-450 mg/d (XL) mirtazapine (REMERON), 15-45 mg/d trazodone, 50-200mg/noc (for sleep) nefazodone tricyclic antidepressants (TCADs) amitriptyline  nortriptyline imipramine  desipramine monoamine oxidase inhibitors (MAO-Is) typically, non-selective & irreversible MAO-A (NE, EPI, 5HT, DA) MAO-B (trace amines, DA) why we “wash-out” 5HT syndrome HTNsive crisis selegiline (EMSAM) [additional] augmenting agents Li+ T3, 25 mcg/d buspirone (BuSPAR), 5-30 mg BID atypical antipsychotics Sequenced Treatment Alternatives for the Relief of Depression (STAR*D) major NIMH-funded study (PI: A. John Rush) w/ 14 regional centers & 41 clinical sites initial enrollment of 4,041 patients aim: which tx algorithms work best after an initial failure to remit non-psychotic depression w/ an antidepressant? http://www.clinicaltrials.gov/ct/show/NCT00021528?order=1 Trivedi MH et al, Am J Psychiatry. 2006 Jan;163(1):28-40 47% response rate on citalopram (by *QIDS-SR, 50% ↓ in sxs) Sequenced Treatment Alternatives for the Relief of Depression (STAR*D), n = 2,876 (qualifying pts) 33% remission rate on citalopram (by QIDS-SR, score <5) Rx choice: according to side effects (SE’s), comorbid condn’s / risks (GMC & Ψ), ?FmRxHx 6-8wk trials each (preferable) augmentation v. switch? *QIDS-SR = Quick Inventory of Depressive Symptomatology, Self-Report (range 0-27) http://www.ids-qids.org/ MDD tx options Ψtherapy cognitive bx therapy (CBT) interpersonal therapy (IPT) psychodynamic therapy interventional Ψ electroconvulsive therapy (ECT) transcranial magnetic stimulation (TMS) vagal nerve stimulation (VNS) deep brain stimulation (DBS) other lightbox therapy (mostly for MDD w/ seasonal features) Major Depressive D/O (MDD) NATURAL HISTORY (Frank E and Thase ME, 1999 & DSM-5) recovery usually begins: w/in 3mos for two in five indivs w/in 1y for four in five indivs risk of subsequent episodes (w/in 3y) increases w/ n: ≥50% if n=1 ≥70% if n=2 ≥90% if n=3 dz course does not typically change as one ages 5-10% will eventually be dx’d w/ bipolar disorder (BD) more likely w/: onset of ‘MDD’ in adolescence a family history of BD ‘mixed features’ 6% lifetime SUI risk (Davies S et al, 2001); up to 15% w/ severe MDD Persistent depressive disorder (dysthymia) 2y of depressed mood (1y in children/adolescents) most of the day, more days than not, plus 2 of the following: appetite disturbance (↓ or ↑) veg sleep disturbance (↓ or ↑) veg ↓energy E ↓esteem E poor [ ] C hopeless H never sx-free for more than 2mos at a time overlapping dx of MDD is now allowed there has never been mania, hypomania, or cyclothymia MDD specifiers can also be used for dysthymia additionally: early onset (before age 21) late onset (at age 21 or older) w/ pure dysthymic syndrome from DSM-5 w/ persistent MDE w/ intermittent MDE’s, w/ current episode w/ intermittent MDE’s, w/o current episode --these last 3 are essentially a co-dx of MDD, but captured within the specifier… Persistent depressive disorder (dysthymia) may be more treatment-resistant (TxR) than straightforward MDD EPIDEMIOLOGY lifetime prevalence = 6% 12-mo prevalence = 0.5%, compared w/ 1.5% for MDD high comorbidity w/ personality d/o’s (particularly clusters B, C) From Sadock & Sadock & DSM-5 Case 1. 36yo F presenting w/ 3mos of ↓mood. She reports getting only ~4h of sleep/noc b/c of regular early AM awakenings. She feels drained everyday, all day long. She’s gained about 10 lbs in the last 2mos. What else would you like to ask? How would you work-up this patient? In the meantime, what would you dx and what would be your tentative tx plan? She returns 1mo later and reports that her mood continues to spiral downward. Now, she adds that she’s starting to think more morbid thoughts and that maybe it wouldn’t be such a bad thing if she weren’t around anymore. What would you ask now? How would you revise your tx plan? The pt’s sxs are finally stabilized and she returns at a later date w/ her sxs in remission x 1mo. “Doctor, I’m feeling so much better now. Do you think I can stop my psych Rxs?” How would you answer? Premenstrual dysphoric d/o Criterion A. In most menstrual cycles, ≥5 sxs in the final week before onset of menses, w/ improvement w/in a few days after onset of menses, and near-absent in the week post-menses Criterion B. ≥1 (or more) sx of marked: 1. lability (e.g., mood swings, suddenly sad, increased rejection sensitivity) 2. irritability /anger / increase in interpersonal conflicts 3. anxiety / tension / keyed-up feeling/edginess Criterion C. ≥1 (or more) sx to reach a total of 5 in combation w/ previous list: 1. anhedonia 2. [ ] impairment 3. anergia 4. significant appetite change (including specific food cravings) 5. sleep disturbance (↑ or ↓) 6. feeling overwhelmed or out of control 7. px sxs (e.g., breast tenderness/swelling, arthralgias/myalgias, bloating, wt gain) Special notes. Can’t just be menstrual exacerbation of MDD or other Axis I or II dx; must have confirmation by prospective daily rating scales during at least 2 sx-ic cycles (provisional dx allowed beforehand)
Slide 30 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No. Belmaker RH and Agam G, NEJM 2008, 358:55-68 iproniazid (1957) imipramine (1959) The monoamine hypothesis (1965) Joseph Schildkraut Question: Do antidepressants have additional actions besides inhibition of reuptake transporters? “…the Zoloft cartoon” from: http://gifsoup.com/webroot/animatedgifs/50426_o.gif; chemical inbalance Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. J Neurosci. 2000 Dec 15;20(24):9104-10 Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Science. 2003 Aug 8;301(5634):805-9. Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Haenisch B, Bönisch H. Pharmacol Ther. 2011 Mar;129(3):352-68. Epub 2010 Dec 13. Review. Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices. Hennings EC, Kiss JP, De Oliveira K, Toth PT, Vizi ES. J Neurochem. 1999 Sep;73(3):1043-50. Block of an ether-a-go-go-like K(+) channel by imipramine rescues egl-2 excitation defects in Caenorhabditis elegans. Weinshenker D, Wei A, Salkoff L, Thomas JH. J Neurosci. 1999 Nov 15;19(22):9831-40. photo from: http://www.sciencedaily.com/releases/2006/11/061121082449.htm Subsequent hypotheses about MDD altered glutamatergic transmission ↓’d GABAergic transmission monoamine-Ach imbalance disruption of endogenous opioid signalling neurosteroid deficiencies thyroxine abnormalities cytokine-mediated x-talk betw immune system & CNS circadian abnormalities (specific brain structure/circuit dysfxns…) as summarized in Belmaker RH and Agam G, NEJM 2008, 358:55-68 MDD tx options selective serotonin reuptake inhibitors (SSRIs) fluoxetine (PROZAC), 20-80 mg/d citalopram (CELEXA), 20-40 mg/d escitalopram (LEXAPRO), 10-20 mg/d sertraline (ZOLOFT), 50-200 mg/d paroxetine (PAXIL), 20-50 mg/d serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine XR (EFFEXOR XR), 37.5-225 mg/d desvenlafaxine (PRISTIQ) duloxetine (CYMBALTA), 30-120 mg/d others bupropion SR, XL (WELLBUTRIN) 100-200 mg BID (SR) 150-450 mg/d (XL) mirtazapine (REMERON), 15-45 mg/d trazodone, 50-200mg/noc (for sleep) nefazodone tricyclic antidepressants (TCADs) amitriptyline  nortriptyline imipramine  desipramine monoamine oxidase inhibitors (MAO-Is) typically, non-selective & irreversible MAO-A (NE, EPI, 5HT, DA) MAO-B (trace amines, DA) why we “wash-out” 5HT syndrome HTNsive crisis selegiline (EMSAM) [additional] augmenting agents Li+ T3, 25 mcg/d buspirone (BuSPAR), 5-30 mg BID atypical antipsychotics Sequenced Treatment Alternatives for the Relief of Depression (STAR*D) major NIMH-funded study (PI: A. John Rush) w/ 14 regional centers & 41 clinical sites initial enrollment of 4,041 patients aim: which tx algorithms work best after an initial failure to remit non-psychotic depression w/ an antidepressant? http://www.clinicaltrials.gov/ct/show/NCT00021528?order=1 Trivedi MH et al, Am J Psychiatry. 2006 Jan;163(1):28-40 47% response rate on citalopram (by *QIDS-SR, 50% ↓ in sxs) Sequenced Treatment Alternatives for the Relief of Depression (STAR*D), n = 2,876 (qualifying pts) 33% remission rate on citalopram (by QIDS-SR, score <5) Rx choice: according to side effects (SE’s), comorbid condn’s / risks (GMC & Ψ), ?FmRxHx 6-8wk trials each (preferable) augmentation v. switch? *QIDS-SR = Quick Inventory of Depressive Symptomatology, Self-Report (range 0-27) http://www.ids-qids.org/ MDD tx options Ψtherapy cognitive bx therapy (CBT) interpersonal therapy (IPT) psychodynamic therapy interventional Ψ electroconvulsive therapy (ECT) transcranial magnetic stimulation (TMS) vagal nerve stimulation (VNS) deep brain stimulation (DBS) other lightbox therapy (mostly for MDD w/ seasonal features) Major Depressive D/O (MDD) NATURAL HISTORY (Frank E and Thase ME, 1999 & DSM-5) recovery usually begins: w/in 3mos for two in five indivs w/in 1y for four in five indivs risk of subsequent episodes (w/in 3y) increases w/ n: ≥50% if n=1 ≥70% if n=2 ≥90% if n=3 dz course does not typically change as one ages 5-10% will eventually be dx’d w/ bipolar disorder (BD) more likely w/: onset of ‘MDD’ in adolescence a family history of BD ‘mixed features’ 6% lifetime SUI risk (Davies S et al, 2001); up to 15% w/ severe MDD Persistent depressive disorder (dysthymia) 2y of depressed mood (1y in children/adolescents) most of the day, more days than not, plus 2 of the following: appetite disturbance (↓ or ↑) veg sleep disturbance (↓ or ↑) veg ↓energy E ↓esteem E poor [ ] C hopeless H never sx-free for more than 2mos at a time overlapping dx of MDD is now allowed there has never been mania, hypomania, or cyclothymia MDD specifiers can also be used for dysthymia additionally: early onset (before age 21) late onset (at age 21 or older) w/ pure dysthymic syndrome from DSM-5 w/ persistent MDE w/ intermittent MDE’s, w/ current episode w/ intermittent MDE’s, w/o current episode --these last 3 are essentially a co-dx of MDD, but captured within the specifier… Persistent depressive disorder (dysthymia) may be more treatment-resistant (TxR) than straightforward MDD EPIDEMIOLOGY lifetime prevalence = 6% 12-mo prevalence = 0.5%, compared w/ 1.5% for MDD high comorbidity w/ personality d/o’s (particularly clusters B, C) From Sadock & Sadock & DSM-5 Case 1. 36yo F presenting w/ 3mos of ↓mood. She reports getting only ~4h of sleep/noc b/c of regular early AM awakenings. She feels drained everyday, all day long. She’s gained about 10 lbs in the last 2mos. What else would you like to ask? How would you work-up this patient? In the meantime, what would you dx and what would be your tentative tx plan? She returns 1mo later and reports that her mood continues to spiral downward. Now, she adds that she’s starting to think more morbid thoughts and that maybe it wouldn’t be such a bad thing if she weren’t around anymore. What would you ask now? How would you revise your tx plan? The pt’s sxs are finally stabilized and she returns at a later date w/ her sxs in remission x 1mo. “Doctor, I’m feeling so much better now. Do you think I can stop my psych Rxs?” How would you answer? Premenstrual dysphoric d/o Criterion A. In most menstrual cycles, ≥5 sxs in the final week before onset of menses, w/ improvement w/in a few days after onset of menses, and near-absent in the week post-menses Criterion B. ≥1 (or more) sx of marked: 1. lability (e.g., mood swings, suddenly sad, increased rejection sensitivity) 2. irritability /anger / increase in interpersonal conflicts 3. anxiety / tension / keyed-up feeling/edginess Criterion C. ≥1 (or more) sx to reach a total of 5 in combation w/ previous list: 1. anhedonia 2. [ ] impairment 3. anergia 4. significant appetite change (including specific food cravings) 5. sleep disturbance (↑ or ↓) 6. feeling overwhelmed or out of control 7. px sxs (e.g., breast tenderness/swelling, arthralgias/myalgias, bloating, wt gain) Special notes. Can’t just be menstrual exacerbation of MDD or other Axis I or II dx; must have confirmation by prospective daily rating scales during at least 2 sx-ic cycles (provisional dx allowed beforehand) Premenstrual dysphoric d/o (M)ood (labile &/or irritable &/or anxious) Sleep Interest Body Energy Concentration Appetite Out of control Treatment: SSRI daily luteal phase only (i.e., day 14 of cycle  menses) some data suggest
Slide 31 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No. Belmaker RH and Agam G, NEJM 2008, 358:55-68 iproniazid (1957) imipramine (1959) The monoamine hypothesis (1965) Joseph Schildkraut Question: Do antidepressants have additional actions besides inhibition of reuptake transporters? “…the Zoloft cartoon” from: http://gifsoup.com/webroot/animatedgifs/50426_o.gif; chemical inbalance Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. J Neurosci. 2000 Dec 15;20(24):9104-10 Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Science. 2003 Aug 8;301(5634):805-9. Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Haenisch B, Bönisch H. Pharmacol Ther. 2011 Mar;129(3):352-68. Epub 2010 Dec 13. Review. Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices. Hennings EC, Kiss JP, De Oliveira K, Toth PT, Vizi ES. J Neurochem. 1999 Sep;73(3):1043-50. Block of an ether-a-go-go-like K(+) channel by imipramine rescues egl-2 excitation defects in Caenorhabditis elegans. Weinshenker D, Wei A, Salkoff L, Thomas JH. J Neurosci. 1999 Nov 15;19(22):9831-40. photo from: http://www.sciencedaily.com/releases/2006/11/061121082449.htm Subsequent hypotheses about MDD altered glutamatergic transmission ↓’d GABAergic transmission monoamine-Ach imbalance disruption of endogenous opioid signalling neurosteroid deficiencies thyroxine abnormalities cytokine-mediated x-talk betw immune system & CNS circadian abnormalities (specific brain structure/circuit dysfxns…) as summarized in Belmaker RH and Agam G, NEJM 2008, 358:55-68 MDD tx options selective serotonin reuptake inhibitors (SSRIs) fluoxetine (PROZAC), 20-80 mg/d citalopram (CELEXA), 20-40 mg/d escitalopram (LEXAPRO), 10-20 mg/d sertraline (ZOLOFT), 50-200 mg/d paroxetine (PAXIL), 20-50 mg/d serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine XR (EFFEXOR XR), 37.5-225 mg/d desvenlafaxine (PRISTIQ) duloxetine (CYMBALTA), 30-120 mg/d others bupropion SR, XL (WELLBUTRIN) 100-200 mg BID (SR) 150-450 mg/d (XL) mirtazapine (REMERON), 15-45 mg/d trazodone, 50-200mg/noc (for sleep) nefazodone tricyclic antidepressants (TCADs) amitriptyline  nortriptyline imipramine  desipramine monoamine oxidase inhibitors (MAO-Is) typically, non-selective & irreversible MAO-A (NE, EPI, 5HT, DA) MAO-B (trace amines, DA) why we “wash-out” 5HT syndrome HTNsive crisis selegiline (EMSAM) [additional] augmenting agents Li+ T3, 25 mcg/d buspirone (BuSPAR), 5-30 mg BID atypical antipsychotics Sequenced Treatment Alternatives for the Relief of Depression (STAR*D) major NIMH-funded study (PI: A. John Rush) w/ 14 regional centers & 41 clinical sites initial enrollment of 4,041 patients aim: which tx algorithms work best after an initial failure to remit non-psychotic depression w/ an antidepressant? http://www.clinicaltrials.gov/ct/show/NCT00021528?order=1 Trivedi MH et al, Am J Psychiatry. 2006 Jan;163(1):28-40 47% response rate on citalopram (by *QIDS-SR, 50% ↓ in sxs) Sequenced Treatment Alternatives for the Relief of Depression (STAR*D), n = 2,876 (qualifying pts) 33% remission rate on citalopram (by QIDS-SR, score <5) Rx choice: according to side effects (SE’s), comorbid condn’s / risks (GMC & Ψ), ?FmRxHx 6-8wk trials each (preferable) augmentation v. switch? *QIDS-SR = Quick Inventory of Depressive Symptomatology, Self-Report (range 0-27) http://www.ids-qids.org/ MDD tx options Ψtherapy cognitive bx therapy (CBT) interpersonal therapy (IPT) psychodynamic therapy interventional Ψ electroconvulsive therapy (ECT) transcranial magnetic stimulation (TMS) vagal nerve stimulation (VNS) deep brain stimulation (DBS) other lightbox therapy (mostly for MDD w/ seasonal features) Major Depressive D/O (MDD) NATURAL HISTORY (Frank E and Thase ME, 1999 & DSM-5) recovery usually begins: w/in 3mos for two in five indivs w/in 1y for four in five indivs risk of subsequent episodes (w/in 3y) increases w/ n: ≥50% if n=1 ≥70% if n=2 ≥90% if n=3 dz course does not typically change as one ages 5-10% will eventually be dx’d w/ bipolar disorder (BD) more likely w/: onset of ‘MDD’ in adolescence a family history of BD ‘mixed features’ 6% lifetime SUI risk (Davies S et al, 2001); up to 15% w/ severe MDD Persistent depressive disorder (dysthymia) 2y of depressed mood (1y in children/adolescents) most of the day, more days than not, plus 2 of the following: appetite disturbance (↓ or ↑) veg sleep disturbance (↓ or ↑) veg ↓energy E ↓esteem E poor [ ] C hopeless H never sx-free for more than 2mos at a time overlapping dx of MDD is now allowed there has never been mania, hypomania, or cyclothymia MDD specifiers can also be used for dysthymia additionally: early onset (before age 21) late onset (at age 21 or older) w/ pure dysthymic syndrome from DSM-5 w/ persistent MDE w/ intermittent MDE’s, w/ current episode w/ intermittent MDE’s, w/o current episode --these last 3 are essentially a co-dx of MDD, but captured within the specifier… Persistent depressive disorder (dysthymia) may be more treatment-resistant (TxR) than straightforward MDD EPIDEMIOLOGY lifetime prevalence = 6% 12-mo prevalence = 0.5%, compared w/ 1.5% for MDD high comorbidity w/ personality d/o’s (particularly clusters B, C) From Sadock & Sadock & DSM-5 Case 1. 36yo F presenting w/ 3mos of ↓mood. She reports getting only ~4h of sleep/noc b/c of regular early AM awakenings. She feels drained everyday, all day long. She’s gained about 10 lbs in the last 2mos. What else would you like to ask? How would you work-up this patient? In the meantime, what would you dx and what would be your tentative tx plan? She returns 1mo later and reports that her mood continues to spiral downward. Now, she adds that she’s starting to think more morbid thoughts and that maybe it wouldn’t be such a bad thing if she weren’t around anymore. What would you ask now? How would you revise your tx plan? The pt’s sxs are finally stabilized and she returns at a later date w/ her sxs in remission x 1mo. “Doctor, I’m feeling so much better now. Do you think I can stop my psych Rxs?” How would you answer? Premenstrual dysphoric d/o Criterion A. In most menstrual cycles, ≥5 sxs in the final week before onset of menses, w/ improvement w/in a few days after onset of menses, and near-absent in the week post-menses Criterion B. ≥1 (or more) sx of marked: 1. lability (e.g., mood swings, suddenly sad, increased rejection sensitivity) 2. irritability /anger / increase in interpersonal conflicts 3. anxiety / tension / keyed-up feeling/edginess Criterion C. ≥1 (or more) sx to reach a total of 5 in combation w/ previous list: 1. anhedonia 2. [ ] impairment 3. anergia 4. significant appetite change (including specific food cravings) 5. sleep disturbance (↑ or ↓) 6. feeling overwhelmed or out of control 7. px sxs (e.g., breast tenderness/swelling, arthralgias/myalgias, bloating, wt gain) Special notes. Can’t just be menstrual exacerbation of MDD or other Axis I or II dx; must have confirmation by prospective daily rating scales during at least 2 sx-ic cycles (provisional dx allowed beforehand) Premenstrual dysphoric d/o (M)ood (labile &/or irritable &/or anxious) Sleep Interest Body Energy Concentration Appetite Out of control Treatment: SSRI daily luteal phase only (i.e., day 14 of cycle  menses) some data suggest
Slide 32 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No. Belmaker RH and Agam G, NEJM 2008, 358:55-68 iproniazid (1957) imipramine (1959) The monoamine hypothesis (1965) Joseph Schildkraut Question: Do antidepressants have additional actions besides inhibition of reuptake transporters? “…the Zoloft cartoon” from: http://gifsoup.com/webroot/animatedgifs/50426_o.gif; chemical inbalance Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. J Neurosci. 2000 Dec 15;20(24):9104-10 Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Science. 2003 Aug 8;301(5634):805-9. Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Haenisch B, Bönisch H. Pharmacol Ther. 2011 Mar;129(3):352-68. Epub 2010 Dec 13. Review. Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices. Hennings EC, Kiss JP, De Oliveira K, Toth PT, Vizi ES. J Neurochem. 1999 Sep;73(3):1043-50. Block of an ether-a-go-go-like K(+) channel by imipramine rescues egl-2 excitation defects in Caenorhabditis elegans. Weinshenker D, Wei A, Salkoff L, Thomas JH. J Neurosci. 1999 Nov 15;19(22):9831-40. photo from: http://www.sciencedaily.com/releases/2006/11/061121082449.htm Subsequent hypotheses about MDD altered glutamatergic transmission ↓’d GABAergic transmission monoamine-Ach imbalance disruption of endogenous opioid signalling neurosteroid deficiencies thyroxine abnormalities cytokine-mediated x-talk betw immune system & CNS circadian abnormalities (specific brain structure/circuit dysfxns…) as summarized in Belmaker RH and Agam G, NEJM 2008, 358:55-68 MDD tx options selective serotonin reuptake inhibitors (SSRIs) fluoxetine (PROZAC), 20-80 mg/d citalopram (CELEXA), 20-40 mg/d escitalopram (LEXAPRO), 10-20 mg/d sertraline (ZOLOFT), 50-200 mg/d paroxetine (PAXIL), 20-50 mg/d serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine XR (EFFEXOR XR), 37.5-225 mg/d desvenlafaxine (PRISTIQ) duloxetine (CYMBALTA), 30-120 mg/d others bupropion SR, XL (WELLBUTRIN) 100-200 mg BID (SR) 150-450 mg/d (XL) mirtazapine (REMERON), 15-45 mg/d trazodone, 50-200mg/noc (for sleep) nefazodone tricyclic antidepressants (TCADs) amitriptyline  nortriptyline imipramine  desipramine monoamine oxidase inhibitors (MAO-Is) typically, non-selective & irreversible MAO-A (NE, EPI, 5HT, DA) MAO-B (trace amines, DA) why we “wash-out” 5HT syndrome HTNsive crisis selegiline (EMSAM) [additional] augmenting agents Li+ T3, 25 mcg/d buspirone (BuSPAR), 5-30 mg BID atypical antipsychotics Sequenced Treatment Alternatives for the Relief of Depression (STAR*D) major NIMH-funded study (PI: A. John Rush) w/ 14 regional centers & 41 clinical sites initial enrollment of 4,041 patients aim: which tx algorithms work best after an initial failure to remit non-psychotic depression w/ an antidepressant? http://www.clinicaltrials.gov/ct/show/NCT00021528?order=1 Trivedi MH et al, Am J Psychiatry. 2006 Jan;163(1):28-40 47% response rate on citalopram (by *QIDS-SR, 50% ↓ in sxs) Sequenced Treatment Alternatives for the Relief of Depression (STAR*D), n = 2,876 (qualifying pts) 33% remission rate on citalopram (by QIDS-SR, score <5) Rx choice: according to side effects (SE’s), comorbid condn’s / risks (GMC & Ψ), ?FmRxHx 6-8wk trials each (preferable) augmentation v. switch? *QIDS-SR = Quick Inventory of Depressive Symptomatology, Self-Report (range 0-27) http://www.ids-qids.org/ MDD tx options Ψtherapy cognitive bx therapy (CBT) interpersonal therapy (IPT) psychodynamic therapy interventional Ψ electroconvulsive therapy (ECT) transcranial magnetic stimulation (TMS) vagal nerve stimulation (VNS) deep brain stimulation (DBS) other lightbox therapy (mostly for MDD w/ seasonal features) Major Depressive D/O (MDD) NATURAL HISTORY (Frank E and Thase ME, 1999 & DSM-5) recovery usually begins: w/in 3mos for two in five indivs w/in 1y for four in five indivs risk of subsequent episodes (w/in 3y) increases w/ n: ≥50% if n=1 ≥70% if n=2 ≥90% if n=3 dz course does not typically change as one ages 5-10% will eventually be dx’d w/ bipolar disorder (BD) more likely w/: onset of ‘MDD’ in adolescence a family history of BD ‘mixed features’ 6% lifetime SUI risk (Davies S et al, 2001); up to 15% w/ severe MDD Persistent depressive disorder (dysthymia) 2y of depressed mood (1y in children/adolescents) most of the day, more days than not, plus 2 of the following: appetite disturbance (↓ or ↑) veg sleep disturbance (↓ or ↑) veg ↓energy E ↓esteem E poor [ ] C hopeless H never sx-free for more than 2mos at a time overlapping dx of MDD is now allowed there has never been mania, hypomania, or cyclothymia MDD specifiers can also be used for dysthymia additionally: early onset (before age 21) late onset (at age 21 or older) w/ pure dysthymic syndrome from DSM-5 w/ persistent MDE w/ intermittent MDE’s, w/ current episode w/ intermittent MDE’s, w/o current episode --these last 3 are essentially a co-dx of MDD, but captured within the specifier… Persistent depressive disorder (dysthymia) may be more treatment-resistant (TxR) than straightforward MDD EPIDEMIOLOGY lifetime prevalence = 6% 12-mo prevalence = 0.5%, compared w/ 1.5% for MDD high comorbidity w/ personality d/o’s (particularly clusters B, C) From Sadock & Sadock & DSM-5 Case 1. 36yo F presenting w/ 3mos of ↓mood. She reports getting only ~4h of sleep/noc b/c of regular early AM awakenings. She feels drained everyday, all day long. She’s gained about 10 lbs in the last 2mos. What else would you like to ask? How would you work-up this patient? In the meantime, what would you dx and what would be your tentative tx plan? She returns 1mo later and reports that her mood continues to spiral downward. Now, she adds that she’s starting to think more morbid thoughts and that maybe it wouldn’t be such a bad thing if she weren’t around anymore. What would you ask now? How would you revise your tx plan? The pt’s sxs are finally stabilized and she returns at a later date w/ her sxs in remission x 1mo. “Doctor, I’m feeling so much better now. Do you think I can stop my psych Rxs?” How would you answer? Premenstrual dysphoric d/o Criterion A. In most menstrual cycles, ≥5 sxs in the final week before onset of menses, w/ improvement w/in a few days after onset of menses, and near-absent in the week post-menses Criterion B. ≥1 (or more) sx of marked: 1. lability (e.g., mood swings, suddenly sad, increased rejection sensitivity) 2. irritability /anger / increase in interpersonal conflicts 3. anxiety / tension / keyed-up feeling/edginess Criterion C. ≥1 (or more) sx to reach a total of 5 in combation w/ previous list: 1. anhedonia 2. [ ] impairment 3. anergia 4. significant appetite change (including specific food cravings) 5. sleep disturbance (↑ or ↓) 6. feeling overwhelmed or out of control 7. px sxs (e.g., breast tenderness/swelling, arthralgias/myalgias, bloating, wt gain) Special notes. Can’t just be menstrual exacerbation of MDD or other Axis I or II dx; must have confirmation by prospective daily rating scales during at least 2 sx-ic cycles (provisional dx allowed beforehand) Premenstrual dysphoric d/o (M)ood (labile &/or irritable &/or anxious) Sleep Interest Body Energy Concentration Appetite Out of control Treatment: SSRI daily luteal phase only (i.e., day 14 of cycle  menses) some data suggest
Slide 33 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No. Belmaker RH and Agam G, NEJM 2008, 358:55-68 iproniazid (1957) imipramine (1959) The monoamine hypothesis (1965) Joseph Schildkraut Question: Do antidepressants have additional actions besides inhibition of reuptake transporters? “…the Zoloft cartoon” from: http://gifsoup.com/webroot/animatedgifs/50426_o.gif; chemical inbalance Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. J Neurosci. 2000 Dec 15;20(24):9104-10 Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Science. 2003 Aug 8;301(5634):805-9. Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Haenisch B, Bönisch H. Pharmacol Ther. 2011 Mar;129(3):352-68. Epub 2010 Dec 13. Review. Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices. Hennings EC, Kiss JP, De Oliveira K, Toth PT, Vizi ES. J Neurochem. 1999 Sep;73(3):1043-50. Block of an ether-a-go-go-like K(+) channel by imipramine rescues egl-2 excitation defects in Caenorhabditis elegans. Weinshenker D, Wei A, Salkoff L, Thomas JH. J Neurosci. 1999 Nov 15;19(22):9831-40. photo from: http://www.sciencedaily.com/releases/2006/11/061121082449.htm Subsequent hypotheses about MDD altered glutamatergic transmission ↓’d GABAergic transmission monoamine-Ach imbalance disruption of endogenous opioid signalling neurosteroid deficiencies thyroxine abnormalities cytokine-mediated x-talk betw immune system & CNS circadian abnormalities (specific brain structure/circuit dysfxns…) as summarized in Belmaker RH and Agam G, NEJM 2008, 358:55-68 MDD tx options selective serotonin reuptake inhibitors (SSRIs) fluoxetine (PROZAC), 20-80 mg/d citalopram (CELEXA), 20-40 mg/d escitalopram (LEXAPRO), 10-20 mg/d sertraline (ZOLOFT), 50-200 mg/d paroxetine (PAXIL), 20-50 mg/d serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine XR (EFFEXOR XR), 37.5-225 mg/d desvenlafaxine (PRISTIQ) duloxetine (CYMBALTA), 30-120 mg/d others bupropion SR, XL (WELLBUTRIN) 100-200 mg BID (SR) 150-450 mg/d (XL) mirtazapine (REMERON), 15-45 mg/d trazodone, 50-200mg/noc (for sleep) nefazodone tricyclic antidepressants (TCADs) amitriptyline  nortriptyline imipramine  desipramine monoamine oxidase inhibitors (MAO-Is) typically, non-selective & irreversible MAO-A (NE, EPI, 5HT, DA) MAO-B (trace amines, DA) why we “wash-out” 5HT syndrome HTNsive crisis selegiline (EMSAM) [additional] augmenting agents Li+ T3, 25 mcg/d buspirone (BuSPAR), 5-30 mg BID atypical antipsychotics Sequenced Treatment Alternatives for the Relief of Depression (STAR*D) major NIMH-funded study (PI: A. John Rush) w/ 14 regional centers & 41 clinical sites initial enrollment of 4,041 patients aim: which tx algorithms work best after an initial failure to remit non-psychotic depression w/ an antidepressant? http://www.clinicaltrials.gov/ct/show/NCT00021528?order=1 Trivedi MH et al, Am J Psychiatry. 2006 Jan;163(1):28-40 47% response rate on citalopram (by *QIDS-SR, 50% ↓ in sxs) Sequenced Treatment Alternatives for the Relief of Depression (STAR*D), n = 2,876 (qualifying pts) 33% remission rate on citalopram (by QIDS-SR, score <5) Rx choice: according to side effects (SE’s), comorbid condn’s / risks (GMC & Ψ), ?FmRxHx 6-8wk trials each (preferable) augmentation v. switch? *QIDS-SR = Quick Inventory of Depressive Symptomatology, Self-Report (range 0-27) http://www.ids-qids.org/ MDD tx options Ψtherapy cognitive bx therapy (CBT) interpersonal therapy (IPT) psychodynamic therapy interventional Ψ electroconvulsive therapy (ECT) transcranial magnetic stimulation (TMS) vagal nerve stimulation (VNS) deep brain stimulation (DBS) other lightbox therapy (mostly for MDD w/ seasonal features) Major Depressive D/O (MDD) NATURAL HISTORY (Frank E and Thase ME, 1999 & DSM-5) recovery usually begins: w/in 3mos for two in five indivs w/in 1y for four in five indivs risk of subsequent episodes (w/in 3y) increases w/ n: ≥50% if n=1 ≥70% if n=2 ≥90% if n=3 dz course does not typically change as one ages 5-10% will eventually be dx’d w/ bipolar disorder (BD) more likely w/: onset of ‘MDD’ in adolescence a family history of BD ‘mixed features’ 6% lifetime SUI risk (Davies S et al, 2001); up to 15% w/ severe MDD Persistent depressive disorder (dysthymia) 2y of depressed mood (1y in children/adolescents) most of the day, more days than not, plus 2 of the following: appetite disturbance (↓ or ↑) veg sleep disturbance (↓ or ↑) veg ↓energy E ↓esteem E poor [ ] C hopeless H never sx-free for more than 2mos at a time overlapping dx of MDD is now allowed there has never been mania, hypomania, or cyclothymia MDD specifiers can also be used for dysthymia additionally: early onset (before age 21) late onset (at age 21 or older) w/ pure dysthymic syndrome from DSM-5 w/ persistent MDE w/ intermittent MDE’s, w/ current episode w/ intermittent MDE’s, w/o current episode --these last 3 are essentially a co-dx of MDD, but captured within the specifier… Persistent depressive disorder (dysthymia) may be more treatment-resistant (TxR) than straightforward MDD EPIDEMIOLOGY lifetime prevalence = 6% 12-mo prevalence = 0.5%, compared w/ 1.5% for MDD high comorbidity w/ personality d/o’s (particularly clusters B, C) From Sadock & Sadock & DSM-5 Case 1. 36yo F presenting w/ 3mos of ↓mood. She reports getting only ~4h of sleep/noc b/c of regular early AM awakenings. She feels drained everyday, all day long. She’s gained about 10 lbs in the last 2mos. What else would you like to ask? How would you work-up this patient? In the meantime, what would you dx and what would be your tentative tx plan? She returns 1mo later and reports that her mood continues to spiral downward. Now, she adds that she’s starting to think more morbid thoughts and that maybe it wouldn’t be such a bad thing if she weren’t around anymore. What would you ask now? How would you revise your tx plan? The pt’s sxs are finally stabilized and she returns at a later date w/ her sxs in remission x 1mo. “Doctor, I’m feeling so much better now. Do you think I can stop my psych Rxs?” How would you answer? Premenstrual dysphoric d/o Criterion A. In most menstrual cycles, ≥5 sxs in the final week before onset of menses, w/ improvement w/in a few days after onset of menses, and near-absent in the week post-menses Criterion B. ≥1 (or more) sx of marked: 1. lability (e.g., mood swings, suddenly sad, increased rejection sensitivity) 2. irritability /anger / increase in interpersonal conflicts 3. anxiety / tension / keyed-up feeling/edginess Criterion C. ≥1 (or more) sx to reach a total of 5 in combation w/ previous list: 1. anhedonia 2. [ ] impairment 3. anergia 4. significant appetite change (including specific food cravings) 5. sleep disturbance (↑ or ↓) 6. feeling overwhelmed or out of control 7. px sxs (e.g., breast tenderness/swelling, arthralgias/myalgias, bloating, wt gain) Special notes. Can’t just be menstrual exacerbation of MDD or other Axis I or II dx; must have confirmation by prospective daily rating scales during at least 2 sx-ic cycles (provisional dx allowed beforehand) Premenstrual dysphoric d/o (M)ood (labile &/or irritable &/or anxious) Sleep Interest Body Energy Concentration Appetite Out of control Treatment: SSRI daily luteal phase only (i.e., day 14 of cycle  menses) some data suggest
Slide 34 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No. Belmaker RH and Agam G, NEJM 2008, 358:55-68 iproniazid (1957) imipramine (1959) The monoamine hypothesis (1965) Joseph Schildkraut Question: Do antidepressants have additional actions besides inhibition of reuptake transporters? “…the Zoloft cartoon” from: http://gifsoup.com/webroot/animatedgifs/50426_o.gif; chemical inbalance Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. J Neurosci. 2000 Dec 15;20(24):9104-10 Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Science. 2003 Aug 8;301(5634):805-9. Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Haenisch B, Bönisch H. Pharmacol Ther. 2011 Mar;129(3):352-68. Epub 2010 Dec 13. Review. Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices. Hennings EC, Kiss JP, De Oliveira K, Toth PT, Vizi ES. J Neurochem. 1999 Sep;73(3):1043-50. Block of an ether-a-go-go-like K(+) channel by imipramine rescues egl-2 excitation defects in Caenorhabditis elegans. Weinshenker D, Wei A, Salkoff L, Thomas JH. J Neurosci. 1999 Nov 15;19(22):9831-40. photo from: http://www.sciencedaily.com/releases/2006/11/061121082449.htm Subsequent hypotheses about MDD altered glutamatergic transmission ↓’d GABAergic transmission monoamine-Ach imbalance disruption of endogenous opioid signalling neurosteroid deficiencies thyroxine abnormalities cytokine-mediated x-talk betw immune system & CNS circadian abnormalities (specific brain structure/circuit dysfxns…) as summarized in Belmaker RH and Agam G, NEJM 2008, 358:55-68 MDD tx options selective serotonin reuptake inhibitors (SSRIs) fluoxetine (PROZAC), 20-80 mg/d citalopram (CELEXA), 20-40 mg/d escitalopram (LEXAPRO), 10-20 mg/d sertraline (ZOLOFT), 50-200 mg/d paroxetine (PAXIL), 20-50 mg/d serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine XR (EFFEXOR XR), 37.5-225 mg/d desvenlafaxine (PRISTIQ) duloxetine (CYMBALTA), 30-120 mg/d others bupropion SR, XL (WELLBUTRIN) 100-200 mg BID (SR) 150-450 mg/d (XL) mirtazapine (REMERON), 15-45 mg/d trazodone, 50-200mg/noc (for sleep) nefazodone tricyclic antidepressants (TCADs) amitriptyline  nortriptyline imipramine  desipramine monoamine oxidase inhibitors (MAO-Is) typically, non-selective & irreversible MAO-A (NE, EPI, 5HT, DA) MAO-B (trace amines, DA) why we “wash-out” 5HT syndrome HTNsive crisis selegiline (EMSAM) [additional] augmenting agents Li+ T3, 25 mcg/d buspirone (BuSPAR), 5-30 mg BID atypical antipsychotics Sequenced Treatment Alternatives for the Relief of Depression (STAR*D) major NIMH-funded study (PI: A. John Rush) w/ 14 regional centers & 41 clinical sites initial enrollment of 4,041 patients aim: which tx algorithms work best after an initial failure to remit non-psychotic depression w/ an antidepressant? http://www.clinicaltrials.gov/ct/show/NCT00021528?order=1 Trivedi MH et al, Am J Psychiatry. 2006 Jan;163(1):28-40 47% response rate on citalopram (by *QIDS-SR, 50% ↓ in sxs) Sequenced Treatment Alternatives for the Relief of Depression (STAR*D), n = 2,876 (qualifying pts) 33% remission rate on citalopram (by QIDS-SR, score <5) Rx choice: according to side effects (SE’s), comorbid condn’s / risks (GMC & Ψ), ?FmRxHx 6-8wk trials each (preferable) augmentation v. switch? *QIDS-SR = Quick Inventory of Depressive Symptomatology, Self-Report (range 0-27) http://www.ids-qids.org/ MDD tx options Ψtherapy cognitive bx therapy (CBT) interpersonal therapy (IPT) psychodynamic therapy interventional Ψ electroconvulsive therapy (ECT) transcranial magnetic stimulation (TMS) vagal nerve stimulation (VNS) deep brain stimulation (DBS) other lightbox therapy (mostly for MDD w/ seasonal features) Major Depressive D/O (MDD) NATURAL HISTORY (Frank E and Thase ME, 1999 & DSM-5) recovery usually begins: w/in 3mos for two in five indivs w/in 1y for four in five indivs risk of subsequent episodes (w/in 3y) increases w/ n: ≥50% if n=1 ≥70% if n=2 ≥90% if n=3 dz course does not typically change as one ages 5-10% will eventually be dx’d w/ bipolar disorder (BD) more likely w/: onset of ‘MDD’ in adolescence a family history of BD ‘mixed features’ 6% lifetime SUI risk (Davies S et al, 2001); up to 15% w/ severe MDD Persistent depressive disorder (dysthymia) 2y of depressed mood (1y in children/adolescents) most of the day, more days than not, plus 2 of the following: appetite disturbance (↓ or ↑) veg sleep disturbance (↓ or ↑) veg ↓energy E ↓esteem E poor [ ] C hopeless H never sx-free for more than 2mos at a time overlapping dx of MDD is now allowed there has never been mania, hypomania, or cyclothymia MDD specifiers can also be used for dysthymia additionally: early onset (before age 21) late onset (at age 21 or older) w/ pure dysthymic syndrome from DSM-5 w/ persistent MDE w/ intermittent MDE’s, w/ current episode w/ intermittent MDE’s, w/o current episode --these last 3 are essentially a co-dx of MDD, but captured within the specifier… Persistent depressive disorder (dysthymia) may be more treatment-resistant (TxR) than straightforward MDD EPIDEMIOLOGY lifetime prevalence = 6% 12-mo prevalence = 0.5%, compared w/ 1.5% for MDD high comorbidity w/ personality d/o’s (particularly clusters B, C) From Sadock & Sadock & DSM-5 Case 1. 36yo F presenting w/ 3mos of ↓mood. She reports getting only ~4h of sleep/noc b/c of regular early AM awakenings. She feels drained everyday, all day long. She’s gained about 10 lbs in the last 2mos. What else would you like to ask? How would you work-up this patient? In the meantime, what would you dx and what would be your tentative tx plan? She returns 1mo later and reports that her mood continues to spiral downward. Now, she adds that she’s starting to think more morbid thoughts and that maybe it wouldn’t be such a bad thing if she weren’t around anymore. What would you ask now? How would you revise your tx plan? The pt’s sxs are finally stabilized and she returns at a later date w/ her sxs in remission x 1mo. “Doctor, I’m feeling so much better now. Do you think I can stop my psych Rxs?” How would you answer? Premenstrual dysphoric d/o Criterion A. In most menstrual cycles, ≥5 sxs in the final week before onset of menses, w/ improvement w/in a few days after onset of menses, and near-absent in the week post-menses Criterion B. ≥1 (or more) sx of marked: 1. lability (e.g., mood swings, suddenly sad, increased rejection sensitivity) 2. irritability /anger / increase in interpersonal conflicts 3. anxiety / tension / keyed-up feeling/edginess Criterion C. ≥1 (or more) sx to reach a total of 5 in combation w/ previous list: 1. anhedonia 2. [ ] impairment 3. anergia 4. significant appetite change (including specific food cravings) 5. sleep disturbance (↑ or ↓) 6. feeling overwhelmed or out of control 7. px sxs (e.g., breast tenderness/swelling, arthralgias/myalgias, bloating, wt gain) Special notes. Can’t just be menstrual exacerbation of MDD or other Axis I or II dx; must have confirmation by prospective daily rating scales during at least 2 sx-ic cycles (provisional dx allowed beforehand) Premenstrual dysphoric d/o (M)ood (labile &/or irritable &/or anxious) Sleep Interest Body Energy Concentration Appetite Out of control Treatment: SSRI daily luteal phase only (i.e., day 14 of cycle  menses) some data suggest
Slide 35 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No. Belmaker RH and Agam G, NEJM 2008, 358:55-68 iproniazid (1957) imipramine (1959) The monoamine hypothesis (1965) Joseph Schildkraut Question: Do antidepressants have additional actions besides inhibition of reuptake transporters? “…the Zoloft cartoon” from: http://gifsoup.com/webroot/animatedgifs/50426_o.gif; chemical inbalance Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. J Neurosci. 2000 Dec 15;20(24):9104-10 Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Science. 2003 Aug 8;301(5634):805-9. Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Haenisch B, Bönisch H. Pharmacol Ther. 2011 Mar;129(3):352-68. Epub 2010 Dec 13. Review. Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices. Hennings EC, Kiss JP, De Oliveira K, Toth PT, Vizi ES. J Neurochem. 1999 Sep;73(3):1043-50. Block of an ether-a-go-go-like K(+) channel by imipramine rescues egl-2 excitation defects in Caenorhabditis elegans. Weinshenker D, Wei A, Salkoff L, Thomas JH. J Neurosci. 1999 Nov 15;19(22):9831-40. photo from: http://www.sciencedaily.com/releases/2006/11/061121082449.htm Subsequent hypotheses about MDD altered glutamatergic transmission ↓’d GABAergic transmission monoamine-Ach imbalance disruption of endogenous opioid signalling neurosteroid deficiencies thyroxine abnormalities cytokine-mediated x-talk betw immune system & CNS circadian abnormalities (specific brain structure/circuit dysfxns…) as summarized in Belmaker RH and Agam G, NEJM 2008, 358:55-68 MDD tx options selective serotonin reuptake inhibitors (SSRIs) fluoxetine (PROZAC), 20-80 mg/d citalopram (CELEXA), 20-40 mg/d escitalopram (LEXAPRO), 10-20 mg/d sertraline (ZOLOFT), 50-200 mg/d paroxetine (PAXIL), 20-50 mg/d serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine XR (EFFEXOR XR), 37.5-225 mg/d desvenlafaxine (PRISTIQ) duloxetine (CYMBALTA), 30-120 mg/d others bupropion SR, XL (WELLBUTRIN) 100-200 mg BID (SR) 150-450 mg/d (XL) mirtazapine (REMERON), 15-45 mg/d trazodone, 50-200mg/noc (for sleep) nefazodone tricyclic antidepressants (TCADs) amitriptyline  nortriptyline imipramine  desipramine monoamine oxidase inhibitors (MAO-Is) typically, non-selective & irreversible MAO-A (NE, EPI, 5HT, DA) MAO-B (trace amines, DA) why we “wash-out” 5HT syndrome HTNsive crisis selegiline (EMSAM) [additional] augmenting agents Li+ T3, 25 mcg/d buspirone (BuSPAR), 5-30 mg BID atypical antipsychotics Sequenced Treatment Alternatives for the Relief of Depression (STAR*D) major NIMH-funded study (PI: A. John Rush) w/ 14 regional centers & 41 clinical sites initial enrollment of 4,041 patients aim: which tx algorithms work best after an initial failure to remit non-psychotic depression w/ an antidepressant? http://www.clinicaltrials.gov/ct/show/NCT00021528?order=1 Trivedi MH et al, Am J Psychiatry. 2006 Jan;163(1):28-40 47% response rate on citalopram (by *QIDS-SR, 50% ↓ in sxs) Sequenced Treatment Alternatives for the Relief of Depression (STAR*D), n = 2,876 (qualifying pts) 33% remission rate on citalopram (by QIDS-SR, score <5) Rx choice: according to side effects (SE’s), comorbid condn’s / risks (GMC & Ψ), ?FmRxHx 6-8wk trials each (preferable) augmentation v. switch? *QIDS-SR = Quick Inventory of Depressive Symptomatology, Self-Report (range 0-27) http://www.ids-qids.org/ MDD tx options Ψtherapy cognitive bx therapy (CBT) interpersonal therapy (IPT) psychodynamic therapy interventional Ψ electroconvulsive therapy (ECT) transcranial magnetic stimulation (TMS) vagal nerve stimulation (VNS) deep brain stimulation (DBS) other lightbox therapy (mostly for MDD w/ seasonal features) Major Depressive D/O (MDD) NATURAL HISTORY (Frank E and Thase ME, 1999 & DSM-5) recovery usually begins: w/in 3mos for two in five indivs w/in 1y for four in five indivs risk of subsequent episodes (w/in 3y) increases w/ n: ≥50% if n=1 ≥70% if n=2 ≥90% if n=3 dz course does not typically change as one ages 5-10% will eventually be dx’d w/ bipolar disorder (BD) more likely w/: onset of ‘MDD’ in adolescence a family history of BD ‘mixed features’ 6% lifetime SUI risk (Davies S et al, 2001); up to 15% w/ severe MDD Persistent depressive disorder (dysthymia) 2y of depressed mood (1y in children/adolescents) most of the day, more days than not, plus 2 of the following: appetite disturbance (↓ or ↑) veg sleep disturbance (↓ or ↑) veg ↓energy E ↓esteem E poor [ ] C hopeless H never sx-free for more than 2mos at a time overlapping dx of MDD is now allowed there has never been mania, hypomania, or cyclothymia MDD specifiers can also be used for dysthymia additionally: early onset (before age 21) late onset (at age 21 or older) w/ pure dysthymic syndrome from DSM-5 w/ persistent MDE w/ intermittent MDE’s, w/ current episode w/ intermittent MDE’s, w/o current episode --these last 3 are essentially a co-dx of MDD, but captured within the specifier… Persistent depressive disorder (dysthymia) may be more treatment-resistant (TxR) than straightforward MDD EPIDEMIOLOGY lifetime prevalence = 6% 12-mo prevalence = 0.5%, compared w/ 1.5% for MDD high comorbidity w/ personality d/o’s (particularly clusters B, C) From Sadock & Sadock & DSM-5 Case 1. 36yo F presenting w/ 3mos of ↓mood. She reports getting only ~4h of sleep/noc b/c of regular early AM awakenings. She feels drained everyday, all day long. She’s gained about 10 lbs in the last 2mos. What else would you like to ask? How would you work-up this patient? In the meantime, what would you dx and what would be your tentative tx plan? She returns 1mo later and reports that her mood continues to spiral downward. Now, she adds that she’s starting to think more morbid thoughts and that maybe it wouldn’t be such a bad thing if she weren’t around anymore. What would you ask now? How would you revise your tx plan? The pt’s sxs are finally stabilized and she returns at a later date w/ her sxs in remission x 1mo. “Doctor, I’m feeling so much better now. Do you think I can stop my psych Rxs?” How would you answer? Premenstrual dysphoric d/o Criterion A. In most menstrual cycles, ≥5 sxs in the final week before onset of menses, w/ improvement w/in a few days after onset of menses, and near-absent in the week post-menses Criterion B. ≥1 (or more) sx of marked: 1. lability (e.g., mood swings, suddenly sad, increased rejection sensitivity) 2. irritability /anger / increase in interpersonal conflicts 3. anxiety / tension / keyed-up feeling/edginess Criterion C. ≥1 (or more) sx to reach a total of 5 in combation w/ previous list: 1. anhedonia 2. [ ] impairment 3. anergia 4. significant appetite change (including specific food cravings) 5. sleep disturbance (↑ or ↓) 6. feeling overwhelmed or out of control 7. px sxs (e.g., breast tenderness/swelling, arthralgias/myalgias, bloating, wt gain) Special notes. Can’t just be menstrual exacerbation of MDD or other Axis I or II dx; must have confirmation by prospective daily rating scales during at least 2 sx-ic cycles (provisional dx allowed beforehand) Premenstrual dysphoric d/o (M)ood (labile &/or irritable &/or anxious) Sleep Interest Body Energy Concentration Appetite Out of control Treatment: SSRI daily luteal phase only (i.e., day 14 of cycle  menses) some data suggest
Slide 36 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No. Belmaker RH and Agam G, NEJM 2008, 358:55-68 iproniazid (1957) imipramine (1959) The monoamine hypothesis (1965) Joseph Schildkraut Question: Do antidepressants have additional actions besides inhibition of reuptake transporters? “…the Zoloft cartoon” from: http://gifsoup.com/webroot/animatedgifs/50426_o.gif; chemical inbalance Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. J Neurosci. 2000 Dec 15;20(24):9104-10 Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Science. 2003 Aug 8;301(5634):805-9. Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Haenisch B, Bönisch H. Pharmacol Ther. 2011 Mar;129(3):352-68. Epub 2010 Dec 13. Review. Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices. Hennings EC, Kiss JP, De Oliveira K, Toth PT, Vizi ES. J Neurochem. 1999 Sep;73(3):1043-50. Block of an ether-a-go-go-like K(+) channel by imipramine rescues egl-2 excitation defects in Caenorhabditis elegans. Weinshenker D, Wei A, Salkoff L, Thomas JH. J Neurosci. 1999 Nov 15;19(22):9831-40. photo from: http://www.sciencedaily.com/releases/2006/11/061121082449.htm Subsequent hypotheses about MDD altered glutamatergic transmission ↓’d GABAergic transmission monoamine-Ach imbalance disruption of endogenous opioid signalling neurosteroid deficiencies thyroxine abnormalities cytokine-mediated x-talk betw immune system & CNS circadian abnormalities (specific brain structure/circuit dysfxns…) as summarized in Belmaker RH and Agam G, NEJM 2008, 358:55-68 MDD tx options selective serotonin reuptake inhibitors (SSRIs) fluoxetine (PROZAC), 20-80 mg/d citalopram (CELEXA), 20-40 mg/d escitalopram (LEXAPRO), 10-20 mg/d sertraline (ZOLOFT), 50-200 mg/d paroxetine (PAXIL), 20-50 mg/d serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine XR (EFFEXOR XR), 37.5-225 mg/d desvenlafaxine (PRISTIQ) duloxetine (CYMBALTA), 30-120 mg/d others bupropion SR, XL (WELLBUTRIN) 100-200 mg BID (SR) 150-450 mg/d (XL) mirtazapine (REMERON), 15-45 mg/d trazodone, 50-200mg/noc (for sleep) nefazodone tricyclic antidepressants (TCADs) amitriptyline  nortriptyline imipramine  desipramine monoamine oxidase inhibitors (MAO-Is) typically, non-selective & irreversible MAO-A (NE, EPI, 5HT, DA) MAO-B (trace amines, DA) why we “wash-out” 5HT syndrome HTNsive crisis selegiline (EMSAM) [additional] augmenting agents Li+ T3, 25 mcg/d buspirone (BuSPAR), 5-30 mg BID atypical antipsychotics Sequenced Treatment Alternatives for the Relief of Depression (STAR*D) major NIMH-funded study (PI: A. John Rush) w/ 14 regional centers & 41 clinical sites initial enrollment of 4,041 patients aim: which tx algorithms work best after an initial failure to remit non-psychotic depression w/ an antidepressant? http://www.clinicaltrials.gov/ct/show/NCT00021528?order=1 Trivedi MH et al, Am J Psychiatry. 2006 Jan;163(1):28-40 47% response rate on citalopram (by *QIDS-SR, 50% ↓ in sxs) Sequenced Treatment Alternatives for the Relief of Depression (STAR*D), n = 2,876 (qualifying pts) 33% remission rate on citalopram (by QIDS-SR, score <5) Rx choice: according to side effects (SE’s), comorbid condn’s / risks (GMC & Ψ), ?FmRxHx 6-8wk trials each (preferable) augmentation v. switch? *QIDS-SR = Quick Inventory of Depressive Symptomatology, Self-Report (range 0-27) http://www.ids-qids.org/ MDD tx options Ψtherapy cognitive bx therapy (CBT) interpersonal therapy (IPT) psychodynamic therapy interventional Ψ electroconvulsive therapy (ECT) transcranial magnetic stimulation (TMS) vagal nerve stimulation (VNS) deep brain stimulation (DBS) other lightbox therapy (mostly for MDD w/ seasonal features) Major Depressive D/O (MDD) NATURAL HISTORY (Frank E and Thase ME, 1999 & DSM-5) recovery usually begins: w/in 3mos for two in five indivs w/in 1y for four in five indivs risk of subsequent episodes (w/in 3y) increases w/ n: ≥50% if n=1 ≥70% if n=2 ≥90% if n=3 dz course does not typically change as one ages 5-10% will eventually be dx’d w/ bipolar disorder (BD) more likely w/: onset of ‘MDD’ in adolescence a family history of BD ‘mixed features’ 6% lifetime SUI risk (Davies S et al, 2001); up to 15% w/ severe MDD Persistent depressive disorder (dysthymia) 2y of depressed mood (1y in children/adolescents) most of the day, more days than not, plus 2 of the following: appetite disturbance (↓ or ↑) veg sleep disturbance (↓ or ↑) veg ↓energy E ↓esteem E poor [ ] C hopeless H never sx-free for more than 2mos at a time overlapping dx of MDD is now allowed there has never been mania, hypomania, or cyclothymia MDD specifiers can also be used for dysthymia additionally: early onset (before age 21) late onset (at age 21 or older) w/ pure dysthymic syndrome from DSM-5 w/ persistent MDE w/ intermittent MDE’s, w/ current episode w/ intermittent MDE’s, w/o current episode --these last 3 are essentially a co-dx of MDD, but captured within the specifier… Persistent depressive disorder (dysthymia) may be more treatment-resistant (TxR) than straightforward MDD EPIDEMIOLOGY lifetime prevalence = 6% 12-mo prevalence = 0.5%, compared w/ 1.5% for MDD high comorbidity w/ personality d/o’s (particularly clusters B, C) From Sadock & Sadock & DSM-5 Case 1. 36yo F presenting w/ 3mos of ↓mood. She reports getting only ~4h of sleep/noc b/c of regular early AM awakenings. She feels drained everyday, all day long. She’s gained about 10 lbs in the last 2mos. What else would you like to ask? How would you work-up this patient? In the meantime, what would you dx and what would be your tentative tx plan? She returns 1mo later and reports that her mood continues to spiral downward. Now, she adds that she’s starting to think more morbid thoughts and that maybe it wouldn’t be such a bad thing if she weren’t around anymore. What would you ask now? How would you revise your tx plan? The pt’s sxs are finally stabilized and she returns at a later date w/ her sxs in remission x 1mo. “Doctor, I’m feeling so much better now. Do you think I can stop my psych Rxs?” How would you answer? Premenstrual dysphoric d/o Criterion A. In most menstrual cycles, ≥5 sxs in the final week before onset of menses, w/ improvement w/in a few days after onset of menses, and near-absent in the week post-menses Criterion B. ≥1 (or more) sx of marked: 1. lability (e.g., mood swings, suddenly sad, increased rejection sensitivity) 2. irritability /anger / increase in interpersonal conflicts 3. anxiety / tension / keyed-up feeling/edginess Criterion C. ≥1 (or more) sx to reach a total of 5 in combation w/ previous list: 1. anhedonia 2. [ ] impairment 3. anergia 4. significant appetite change (including specific food cravings) 5. sleep disturbance (↑ or ↓) 6. feeling overwhelmed or out of control 7. px sxs (e.g., breast tenderness/swelling, arthralgias/myalgias, bloating, wt gain) Special notes. Can’t just be menstrual exacerbation of MDD or other Axis I or II dx; must have confirmation by prospective daily rating scales during at least 2 sx-ic cycles (provisional dx allowed beforehand) Premenstrual dysphoric d/o (M)ood (labile &/or irritable &/or anxious) Sleep Interest Body Energy Concentration Appetite Out of control Treatment: SSRI daily luteal phase only (i.e., day 14 of cycle  menses) some data suggest
Slide 37 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No. Belmaker RH and Agam G, NEJM 2008, 358:55-68 iproniazid (1957) imipramine (1959) The monoamine hypothesis (1965) Joseph Schildkraut Question: Do antidepressants have additional actions besides inhibition of reuptake transporters? “…the Zoloft cartoon” from: http://gifsoup.com/webroot/animatedgifs/50426_o.gif; chemical inbalance Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. J Neurosci. 2000 Dec 15;20(24):9104-10 Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Science. 2003 Aug 8;301(5634):805-9. Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Haenisch B, Bönisch H. Pharmacol Ther. 2011 Mar;129(3):352-68. Epub 2010 Dec 13. Review. Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices. Hennings EC, Kiss JP, De Oliveira K, Toth PT, Vizi ES. J Neurochem. 1999 Sep;73(3):1043-50. Block of an ether-a-go-go-like K(+) channel by imipramine rescues egl-2 excitation defects in Caenorhabditis elegans. Weinshenker D, Wei A, Salkoff L, Thomas JH. J Neurosci. 1999 Nov 15;19(22):9831-40. photo from: http://www.sciencedaily.com/releases/2006/11/061121082449.htm Subsequent hypotheses about MDD altered glutamatergic transmission ↓’d GABAergic transmission monoamine-Ach imbalance disruption of endogenous opioid signalling neurosteroid deficiencies thyroxine abnormalities cytokine-mediated x-talk betw immune system & CNS circadian abnormalities (specific brain structure/circuit dysfxns…) as summarized in Belmaker RH and Agam G, NEJM 2008, 358:55-68 MDD tx options selective serotonin reuptake inhibitors (SSRIs) fluoxetine (PROZAC), 20-80 mg/d citalopram (CELEXA), 20-40 mg/d escitalopram (LEXAPRO), 10-20 mg/d sertraline (ZOLOFT), 50-200 mg/d paroxetine (PAXIL), 20-50 mg/d serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine XR (EFFEXOR XR), 37.5-225 mg/d desvenlafaxine (PRISTIQ) duloxetine (CYMBALTA), 30-120 mg/d others bupropion SR, XL (WELLBUTRIN) 100-200 mg BID (SR) 150-450 mg/d (XL) mirtazapine (REMERON), 15-45 mg/d trazodone, 50-200mg/noc (for sleep) nefazodone tricyclic antidepressants (TCADs) amitriptyline  nortriptyline imipramine  desipramine monoamine oxidase inhibitors (MAO-Is) typically, non-selective & irreversible MAO-A (NE, EPI, 5HT, DA) MAO-B (trace amines, DA) why we “wash-out” 5HT syndrome HTNsive crisis selegiline (EMSAM) [additional] augmenting agents Li+ T3, 25 mcg/d buspirone (BuSPAR), 5-30 mg BID atypical antipsychotics Sequenced Treatment Alternatives for the Relief of Depression (STAR*D) major NIMH-funded study (PI: A. John Rush) w/ 14 regional centers & 41 clinical sites initial enrollment of 4,041 patients aim: which tx algorithms work best after an initial failure to remit non-psychotic depression w/ an antidepressant? http://www.clinicaltrials.gov/ct/show/NCT00021528?order=1 Trivedi MH et al, Am J Psychiatry. 2006 Jan;163(1):28-40 47% response rate on citalopram (by *QIDS-SR, 50% ↓ in sxs) Sequenced Treatment Alternatives for the Relief of Depression (STAR*D), n = 2,876 (qualifying pts) 33% remission rate on citalopram (by QIDS-SR, score <5) Rx choice: according to side effects (SE’s), comorbid condn’s / risks (GMC & Ψ), ?FmRxHx 6-8wk trials each (preferable) augmentation v. switch? *QIDS-SR = Quick Inventory of Depressive Symptomatology, Self-Report (range 0-27) http://www.ids-qids.org/ MDD tx options Ψtherapy cognitive bx therapy (CBT) interpersonal therapy (IPT) psychodynamic therapy interventional Ψ electroconvulsive therapy (ECT) transcranial magnetic stimulation (TMS) vagal nerve stimulation (VNS) deep brain stimulation (DBS) other lightbox therapy (mostly for MDD w/ seasonal features) Major Depressive D/O (MDD) NATURAL HISTORY (Frank E and Thase ME, 1999 & DSM-5) recovery usually begins: w/in 3mos for two in five indivs w/in 1y for four in five indivs risk of subsequent episodes (w/in 3y) increases w/ n: ≥50% if n=1 ≥70% if n=2 ≥90% if n=3 dz course does not typically change as one ages 5-10% will eventually be dx’d w/ bipolar disorder (BD) more likely w/: onset of ‘MDD’ in adolescence a family history of BD ‘mixed features’ 6% lifetime SUI risk (Davies S et al, 2001); up to 15% w/ severe MDD Persistent depressive disorder (dysthymia) 2y of depressed mood (1y in children/adolescents) most of the day, more days than not, plus 2 of the following: appetite disturbance (↓ or ↑) veg sleep disturbance (↓ or ↑) veg ↓energy E ↓esteem E poor [ ] C hopeless H never sx-free for more than 2mos at a time overlapping dx of MDD is now allowed there has never been mania, hypomania, or cyclothymia MDD specifiers can also be used for dysthymia additionally: early onset (before age 21) late onset (at age 21 or older) w/ pure dysthymic syndrome from DSM-5 w/ persistent MDE w/ intermittent MDE’s, w/ current episode w/ intermittent MDE’s, w/o current episode --these last 3 are essentially a co-dx of MDD, but captured within the specifier… Persistent depressive disorder (dysthymia) may be more treatment-resistant (TxR) than straightforward MDD EPIDEMIOLOGY lifetime prevalence = 6% 12-mo prevalence = 0.5%, compared w/ 1.5% for MDD high comorbidity w/ personality d/o’s (particularly clusters B, C) From Sadock & Sadock & DSM-5 Case 1. 36yo F presenting w/ 3mos of ↓mood. She reports getting only ~4h of sleep/noc b/c of regular early AM awakenings. She feels drained everyday, all day long. She’s gained about 10 lbs in the last 2mos. What else would you like to ask? How would you work-up this patient? In the meantime, what would you dx and what would be your tentative tx plan? She returns 1mo later and reports that her mood continues to spiral downward. Now, she adds that she’s starting to think more morbid thoughts and that maybe it wouldn’t be such a bad thing if she weren’t around anymore. What would you ask now? How would you revise your tx plan? The pt’s sxs are finally stabilized and she returns at a later date w/ her sxs in remission x 1mo. “Doctor, I’m feeling so much better now. Do you think I can stop my psych Rxs?” How would you answer? Premenstrual dysphoric d/o Criterion A. In most menstrual cycles, ≥5 sxs in the final week before onset of menses, w/ improvement w/in a few days after onset of menses, and near-absent in the week post-menses Criterion B. ≥1 (or more) sx of marked: 1. lability (e.g., mood swings, suddenly sad, increased rejection sensitivity) 2. irritability /anger / increase in interpersonal conflicts 3. anxiety / tension / keyed-up feeling/edginess Criterion C. ≥1 (or more) sx to reach a total of 5 in combation w/ previous list: 1. anhedonia 2. [ ] impairment 3. anergia 4. significant appetite change (including specific food cravings) 5. sleep disturbance (↑ or ↓) 6. feeling overwhelmed or out of control 7. px sxs (e.g., breast tenderness/swelling, arthralgias/myalgias, bloating, wt gain) Special notes. Can’t just be menstrual exacerbation of MDD or other Axis I or II dx; must have confirmation by prospective daily rating scales during at least 2 sx-ic cycles (provisional dx allowed beforehand) Premenstrual dysphoric d/o (M)ood (labile &/or irritable &/or anxious) Sleep Interest Body Energy Concentration Appetite Out of control Treatment: SSRI daily luteal phase only (i.e., day 14 of cycle  menses) some data suggest
Slide 38 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No. Belmaker RH and Agam G, NEJM 2008, 358:55-68 iproniazid (1957) imipramine (1959) The monoamine hypothesis (1965) Joseph Schildkraut Question: Do antidepressants have additional actions besides inhibition of reuptake transporters? “…the Zoloft cartoon” from: http://gifsoup.com/webroot/animatedgifs/50426_o.gif; chemical inbalance Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. J Neurosci. 2000 Dec 15;20(24):9104-10 Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Science. 2003 Aug 8;301(5634):805-9. Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Haenisch B, Bönisch H. Pharmacol Ther. 2011 Mar;129(3):352-68. Epub 2010 Dec 13. Review. Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices. Hennings EC, Kiss JP, De Oliveira K, Toth PT, Vizi ES. J Neurochem. 1999 Sep;73(3):1043-50. Block of an ether-a-go-go-like K(+) channel by imipramine rescues egl-2 excitation defects in Caenorhabditis elegans. Weinshenker D, Wei A, Salkoff L, Thomas JH. J Neurosci. 1999 Nov 15;19(22):9831-40. photo from: http://www.sciencedaily.com/releases/2006/11/061121082449.htm Subsequent hypotheses about MDD altered glutamatergic transmission ↓’d GABAergic transmission monoamine-Ach imbalance disruption of endogenous opioid signalling neurosteroid deficiencies thyroxine abnormalities cytokine-mediated x-talk betw immune system & CNS circadian abnormalities (specific brain structure/circuit dysfxns…) as summarized in Belmaker RH and Agam G, NEJM 2008, 358:55-68 MDD tx options selective serotonin reuptake inhibitors (SSRIs) fluoxetine (PROZAC), 20-80 mg/d citalopram (CELEXA), 20-40 mg/d escitalopram (LEXAPRO), 10-20 mg/d sertraline (ZOLOFT), 50-200 mg/d paroxetine (PAXIL), 20-50 mg/d serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine XR (EFFEXOR XR), 37.5-225 mg/d desvenlafaxine (PRISTIQ) duloxetine (CYMBALTA), 30-120 mg/d others bupropion SR, XL (WELLBUTRIN) 100-200 mg BID (SR) 150-450 mg/d (XL) mirtazapine (REMERON), 15-45 mg/d trazodone, 50-200mg/noc (for sleep) nefazodone tricyclic antidepressants (TCADs) amitriptyline  nortriptyline imipramine  desipramine monoamine oxidase inhibitors (MAO-Is) typically, non-selective & irreversible MAO-A (NE, EPI, 5HT, DA) MAO-B (trace amines, DA) why we “wash-out” 5HT syndrome HTNsive crisis selegiline (EMSAM) [additional] augmenting agents Li+ T3, 25 mcg/d buspirone (BuSPAR), 5-30 mg BID atypical antipsychotics Sequenced Treatment Alternatives for the Relief of Depression (STAR*D) major NIMH-funded study (PI: A. John Rush) w/ 14 regional centers & 41 clinical sites initial enrollment of 4,041 patients aim: which tx algorithms work best after an initial failure to remit non-psychotic depression w/ an antidepressant? http://www.clinicaltrials.gov/ct/show/NCT00021528?order=1 Trivedi MH et al, Am J Psychiatry. 2006 Jan;163(1):28-40 47% response rate on citalopram (by *QIDS-SR, 50% ↓ in sxs) Sequenced Treatment Alternatives for the Relief of Depression (STAR*D), n = 2,876 (qualifying pts) 33% remission rate on citalopram (by QIDS-SR, score <5) Rx choice: according to side effects (SE’s), comorbid condn’s / risks (GMC & Ψ), ?FmRxHx 6-8wk trials each (preferable) augmentation v. switch? *QIDS-SR = Quick Inventory of Depressive Symptomatology, Self-Report (range 0-27) http://www.ids-qids.org/ MDD tx options Ψtherapy cognitive bx therapy (CBT) interpersonal therapy (IPT) psychodynamic therapy interventional Ψ electroconvulsive therapy (ECT) transcranial magnetic stimulation (TMS) vagal nerve stimulation (VNS) deep brain stimulation (DBS) other lightbox therapy (mostly for MDD w/ seasonal features) Major Depressive D/O (MDD) NATURAL HISTORY (Frank E and Thase ME, 1999 & DSM-5) recovery usually begins: w/in 3mos for two in five indivs w/in 1y for four in five indivs risk of subsequent episodes (w/in 3y) increases w/ n: ≥50% if n=1 ≥70% if n=2 ≥90% if n=3 dz course does not typically change as one ages 5-10% will eventually be dx’d w/ bipolar disorder (BD) more likely w/: onset of ‘MDD’ in adolescence a family history of BD ‘mixed features’ 6% lifetime SUI risk (Davies S et al, 2001); up to 15% w/ severe MDD Persistent depressive disorder (dysthymia) 2y of depressed mood (1y in children/adolescents) most of the day, more days than not, plus 2 of the following: appetite disturbance (↓ or ↑) veg sleep disturbance (↓ or ↑) veg ↓energy E ↓esteem E poor [ ] C hopeless H never sx-free for more than 2mos at a time overlapping dx of MDD is now allowed there has never been mania, hypomania, or cyclothymia MDD specifiers can also be used for dysthymia additionally: early onset (before age 21) late onset (at age 21 or older) w/ pure dysthymic syndrome from DSM-5 w/ persistent MDE w/ intermittent MDE’s, w/ current episode w/ intermittent MDE’s, w/o current episode --these last 3 are essentially a co-dx of MDD, but captured within the specifier… Persistent depressive disorder (dysthymia) may be more treatment-resistant (TxR) than straightforward MDD EPIDEMIOLOGY lifetime prevalence = 6% 12-mo prevalence = 0.5%, compared w/ 1.5% for MDD high comorbidity w/ personality d/o’s (particularly clusters B, C) From Sadock & Sadock & DSM-5 Case 1. 36yo F presenting w/ 3mos of ↓mood. She reports getting only ~4h of sleep/noc b/c of regular early AM awakenings. She feels drained everyday, all day long. She’s gained about 10 lbs in the last 2mos. What else would you like to ask? How would you work-up this patient? In the meantime, what would you dx and what would be your tentative tx plan? She returns 1mo later and reports that her mood continues to spiral downward. Now, she adds that she’s starting to think more morbid thoughts and that maybe it wouldn’t be such a bad thing if she weren’t around anymore. What would you ask now? How would you revise your tx plan? The pt’s sxs are finally stabilized and she returns at a later date w/ her sxs in remission x 1mo. “Doctor, I’m feeling so much better now. Do you think I can stop my psych Rxs?” How would you answer? Premenstrual dysphoric d/o Criterion A. In most menstrual cycles, ≥5 sxs in the final week before onset of menses, w/ improvement w/in a few days after onset of menses, and near-absent in the week post-menses Criterion B. ≥1 (or more) sx of marked: 1. lability (e.g., mood swings, suddenly sad, increased rejection sensitivity) 2. irritability /anger / increase in interpersonal conflicts 3. anxiety / tension / keyed-up feeling/edginess Criterion C. ≥1 (or more) sx to reach a total of 5 in combation w/ previous list: 1. anhedonia 2. [ ] impairment 3. anergia 4. significant appetite change (including specific food cravings) 5. sleep disturbance (↑ or ↓) 6. feeling overwhelmed or out of control 7. px sxs (e.g., breast tenderness/swelling, arthralgias/myalgias, bloating, wt gain) Special notes. Can’t just be menstrual exacerbation of MDD or other Axis I or II dx; must have confirmation by prospective daily rating scales during at least 2 sx-ic cycles (provisional dx allowed beforehand) Premenstrual dysphoric d/o (M)ood (labile &/or irritable &/or anxious) Sleep Interest Body Energy Concentration Appetite Out of control Treatment: SSRI daily luteal phase only (i.e., day 14 of cycle  menses) some data suggest
Slide 39 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No. Belmaker RH and Agam G, NEJM 2008, 358:55-68 iproniazid (1957) imipramine (1959) The monoamine hypothesis (1965) Joseph Schildkraut Question: Do antidepressants have additional actions besides inhibition of reuptake transporters? “…the Zoloft cartoon” from: http://gifsoup.com/webroot/animatedgifs/50426_o.gif; chemical inbalance Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. J Neurosci. 2000 Dec 15;20(24):9104-10 Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Science. 2003 Aug 8;301(5634):805-9. Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Haenisch B, Bönisch H. Pharmacol Ther. 2011 Mar;129(3):352-68. Epub 2010 Dec 13. Review. Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices. Hennings EC, Kiss JP, De Oliveira K, Toth PT, Vizi ES. J Neurochem. 1999 Sep;73(3):1043-50. Block of an ether-a-go-go-like K(+) channel by imipramine rescues egl-2 excitation defects in Caenorhabditis elegans. Weinshenker D, Wei A, Salkoff L, Thomas JH. J Neurosci. 1999 Nov 15;19(22):9831-40. photo from: http://www.sciencedaily.com/releases/2006/11/061121082449.htm Subsequent hypotheses about MDD altered glutamatergic transmission ↓’d GABAergic transmission monoamine-Ach imbalance disruption of endogenous opioid signalling neurosteroid deficiencies thyroxine abnormalities cytokine-mediated x-talk betw immune system & CNS circadian abnormalities (specific brain structure/circuit dysfxns…) as summarized in Belmaker RH and Agam G, NEJM 2008, 358:55-68 MDD tx options selective serotonin reuptake inhibitors (SSRIs) fluoxetine (PROZAC), 20-80 mg/d citalopram (CELEXA), 20-40 mg/d escitalopram (LEXAPRO), 10-20 mg/d sertraline (ZOLOFT), 50-200 mg/d paroxetine (PAXIL), 20-50 mg/d serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine XR (EFFEXOR XR), 37.5-225 mg/d desvenlafaxine (PRISTIQ) duloxetine (CYMBALTA), 30-120 mg/d others bupropion SR, XL (WELLBUTRIN) 100-200 mg BID (SR) 150-450 mg/d (XL) mirtazapine (REMERON), 15-45 mg/d trazodone, 50-200mg/noc (for sleep) nefazodone tricyclic antidepressants (TCADs) amitriptyline  nortriptyline imipramine  desipramine monoamine oxidase inhibitors (MAO-Is) typically, non-selective & irreversible MAO-A (NE, EPI, 5HT, DA) MAO-B (trace amines, DA) why we “wash-out” 5HT syndrome HTNsive crisis selegiline (EMSAM) [additional] augmenting agents Li+ T3, 25 mcg/d buspirone (BuSPAR), 5-30 mg BID atypical antipsychotics Sequenced Treatment Alternatives for the Relief of Depression (STAR*D) major NIMH-funded study (PI: A. John Rush) w/ 14 regional centers & 41 clinical sites initial enrollment of 4,041 patients aim: which tx algorithms work best after an initial failure to remit non-psychotic depression w/ an antidepressant? http://www.clinicaltrials.gov/ct/show/NCT00021528?order=1 Trivedi MH et al, Am J Psychiatry. 2006 Jan;163(1):28-40 47% response rate on citalopram (by *QIDS-SR, 50% ↓ in sxs) Sequenced Treatment Alternatives for the Relief of Depression (STAR*D), n = 2,876 (qualifying pts) 33% remission rate on citalopram (by QIDS-SR, score <5) Rx choice: according to side effects (SE’s), comorbid condn’s / risks (GMC & Ψ), ?FmRxHx 6-8wk trials each (preferable) augmentation v. switch? *QIDS-SR = Quick Inventory of Depressive Symptomatology, Self-Report (range 0-27) http://www.ids-qids.org/ MDD tx options Ψtherapy cognitive bx therapy (CBT) interpersonal therapy (IPT) psychodynamic therapy interventional Ψ electroconvulsive therapy (ECT) transcranial magnetic stimulation (TMS) vagal nerve stimulation (VNS) deep brain stimulation (DBS) other lightbox therapy (mostly for MDD w/ seasonal features) Major Depressive D/O (MDD) NATURAL HISTORY (Frank E and Thase ME, 1999 & DSM-5) recovery usually begins: w/in 3mos for two in five indivs w/in 1y for four in five indivs risk of subsequent episodes (w/in 3y) increases w/ n: ≥50% if n=1 ≥70% if n=2 ≥90% if n=3 dz course does not typically change as one ages 5-10% will eventually be dx’d w/ bipolar disorder (BD) more likely w/: onset of ‘MDD’ in adolescence a family history of BD ‘mixed features’ 6% lifetime SUI risk (Davies S et al, 2001); up to 15% w/ severe MDD Persistent depressive disorder (dysthymia) 2y of depressed mood (1y in children/adolescents) most of the day, more days than not, plus 2 of the following: appetite disturbance (↓ or ↑) veg sleep disturbance (↓ or ↑) veg ↓energy E ↓esteem E poor [ ] C hopeless H never sx-free for more than 2mos at a time overlapping dx of MDD is now allowed there has never been mania, hypomania, or cyclothymia MDD specifiers can also be used for dysthymia additionally: early onset (before age 21) late onset (at age 21 or older) w/ pure dysthymic syndrome from DSM-5 w/ persistent MDE w/ intermittent MDE’s, w/ current episode w/ intermittent MDE’s, w/o current episode --these last 3 are essentially a co-dx of MDD, but captured within the specifier… Persistent depressive disorder (dysthymia) may be more treatment-resistant (TxR) than straightforward MDD EPIDEMIOLOGY lifetime prevalence = 6% 12-mo prevalence = 0.5%, compared w/ 1.5% for MDD high comorbidity w/ personality d/o’s (particularly clusters B, C) From Sadock & Sadock & DSM-5 Case 1. 36yo F presenting w/ 3mos of ↓mood. She reports getting only ~4h of sleep/noc b/c of regular early AM awakenings. She feels drained everyday, all day long. She’s gained about 10 lbs in the last 2mos. What else would you like to ask? How would you work-up this patient? In the meantime, what would you dx and what would be your tentative tx plan? She returns 1mo later and reports that her mood continues to spiral downward. Now, she adds that she’s starting to think more morbid thoughts and that maybe it wouldn’t be such a bad thing if she weren’t around anymore. What would you ask now? How would you revise your tx plan? The pt’s sxs are finally stabilized and she returns at a later date w/ her sxs in remission x 1mo. “Doctor, I’m feeling so much better now. Do you think I can stop my psych Rxs?” How would you answer? Premenstrual dysphoric d/o Criterion A. In most menstrual cycles, ≥5 sxs in the final week before onset of menses, w/ improvement w/in a few days after onset of menses, and near-absent in the week post-menses Criterion B. ≥1 (or more) sx of marked: 1. lability (e.g., mood swings, suddenly sad, increased rejection sensitivity) 2. irritability /anger / increase in interpersonal conflicts 3. anxiety / tension / keyed-up feeling/edginess Criterion C. ≥1 (or more) sx to reach a total of 5 in combation w/ previous list: 1. anhedonia 2. [ ] impairment 3. anergia 4. significant appetite change (including specific food cravings) 5. sleep disturbance (↑ or ↓) 6. feeling overwhelmed or out of control 7. px sxs (e.g., breast tenderness/swelling, arthralgias/myalgias, bloating, wt gain) Special notes. Can’t just be menstrual exacerbation of MDD or other Axis I or II dx; must have confirmation by prospective daily rating scales during at least 2 sx-ic cycles (provisional dx allowed beforehand) Premenstrual dysphoric d/o (M)ood (labile &/or irritable &/or anxious) Sleep Interest Body Energy Concentration Appetite Out of control Treatment: SSRI daily luteal phase only (i.e., day 14 of cycle  menses) some data suggest
Slide 40 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No. Belmaker RH and Agam G, NEJM 2008, 358:55-68 iproniazid (1957) imipramine (1959) The monoamine hypothesis (1965) Joseph Schildkraut Question: Do antidepressants have additional actions besides inhibition of reuptake transporters? “…the Zoloft cartoon” from: http://gifsoup.com/webroot/animatedgifs/50426_o.gif; chemical inbalance Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. J Neurosci. 2000 Dec 15;20(24):9104-10 Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Science. 2003 Aug 8;301(5634):805-9. Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Haenisch B, Bönisch H. Pharmacol Ther. 2011 Mar;129(3):352-68. Epub 2010 Dec 13. Review. Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices. Hennings EC, Kiss JP, De Oliveira K, Toth PT, Vizi ES. J Neurochem. 1999 Sep;73(3):1043-50. Block of an ether-a-go-go-like K(+) channel by imipramine rescues egl-2 excitation defects in Caenorhabditis elegans. Weinshenker D, Wei A, Salkoff L, Thomas JH. J Neurosci. 1999 Nov 15;19(22):9831-40. photo from: http://www.sciencedaily.com/releases/2006/11/061121082449.htm Subsequent hypotheses about MDD altered glutamatergic transmission ↓’d GABAergic transmission monoamine-Ach imbalance disruption of endogenous opioid signalling neurosteroid deficiencies thyroxine abnormalities cytokine-mediated x-talk betw immune system & CNS circadian abnormalities (specific brain structure/circuit dysfxns…) as summarized in Belmaker RH and Agam G, NEJM 2008, 358:55-68 MDD tx options selective serotonin reuptake inhibitors (SSRIs) fluoxetine (PROZAC), 20-80 mg/d citalopram (CELEXA), 20-40 mg/d escitalopram (LEXAPRO), 10-20 mg/d sertraline (ZOLOFT), 50-200 mg/d paroxetine (PAXIL), 20-50 mg/d serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine XR (EFFEXOR XR), 37.5-225 mg/d desvenlafaxine (PRISTIQ) duloxetine (CYMBALTA), 30-120 mg/d others bupropion SR, XL (WELLBUTRIN) 100-200 mg BID (SR) 150-450 mg/d (XL) mirtazapine (REMERON), 15-45 mg/d trazodone, 50-200mg/noc (for sleep) nefazodone tricyclic antidepressants (TCADs) amitriptyline  nortriptyline imipramine  desipramine monoamine oxidase inhibitors (MAO-Is) typically, non-selective & irreversible MAO-A (NE, EPI, 5HT, DA) MAO-B (trace amines, DA) why we “wash-out” 5HT syndrome HTNsive crisis selegiline (EMSAM) [additional] augmenting agents Li+ T3, 25 mcg/d buspirone (BuSPAR), 5-30 mg BID atypical antipsychotics Sequenced Treatment Alternatives for the Relief of Depression (STAR*D) major NIMH-funded study (PI: A. John Rush) w/ 14 regional centers & 41 clinical sites initial enrollment of 4,041 patients aim: which tx algorithms work best after an initial failure to remit non-psychotic depression w/ an antidepressant? http://www.clinicaltrials.gov/ct/show/NCT00021528?order=1 Trivedi MH et al, Am J Psychiatry. 2006 Jan;163(1):28-40 47% response rate on citalopram (by *QIDS-SR, 50% ↓ in sxs) Sequenced Treatment Alternatives for the Relief of Depression (STAR*D), n = 2,876 (qualifying pts) 33% remission rate on citalopram (by QIDS-SR, score <5) Rx choice: according to side effects (SE’s), comorbid condn’s / risks (GMC & Ψ), ?FmRxHx 6-8wk trials each (preferable) augmentation v. switch? *QIDS-SR = Quick Inventory of Depressive Symptomatology, Self-Report (range 0-27) http://www.ids-qids.org/ MDD tx options Ψtherapy cognitive bx therapy (CBT) interpersonal therapy (IPT) psychodynamic therapy interventional Ψ electroconvulsive therapy (ECT) transcranial magnetic stimulation (TMS) vagal nerve stimulation (VNS) deep brain stimulation (DBS) other lightbox therapy (mostly for MDD w/ seasonal features) Major Depressive D/O (MDD) NATURAL HISTORY (Frank E and Thase ME, 1999 & DSM-5) recovery usually begins: w/in 3mos for two in five indivs w/in 1y for four in five indivs risk of subsequent episodes (w/in 3y) increases w/ n: ≥50% if n=1 ≥70% if n=2 ≥90% if n=3 dz course does not typically change as one ages 5-10% will eventually be dx’d w/ bipolar disorder (BD) more likely w/: onset of ‘MDD’ in adolescence a family history of BD ‘mixed features’ 6% lifetime SUI risk (Davies S et al, 2001); up to 15% w/ severe MDD Persistent depressive disorder (dysthymia) 2y of depressed mood (1y in children/adolescents) most of the day, more days than not, plus 2 of the following: appetite disturbance (↓ or ↑) veg sleep disturbance (↓ or ↑) veg ↓energy E ↓esteem E poor [ ] C hopeless H never sx-free for more than 2mos at a time overlapping dx of MDD is now allowed there has never been mania, hypomania, or cyclothymia MDD specifiers can also be used for dysthymia additionally: early onset (before age 21) late onset (at age 21 or older) w/ pure dysthymic syndrome from DSM-5 w/ persistent MDE w/ intermittent MDE’s, w/ current episode w/ intermittent MDE’s, w/o current episode --these last 3 are essentially a co-dx of MDD, but captured within the specifier… Persistent depressive disorder (dysthymia) may be more treatment-resistant (TxR) than straightforward MDD EPIDEMIOLOGY lifetime prevalence = 6% 12-mo prevalence = 0.5%, compared w/ 1.5% for MDD high comorbidity w/ personality d/o’s (particularly clusters B, C) From Sadock & Sadock & DSM-5 Case 1. 36yo F presenting w/ 3mos of ↓mood. She reports getting only ~4h of sleep/noc b/c of regular early AM awakenings. She feels drained everyday, all day long. She’s gained about 10 lbs in the last 2mos. What else would you like to ask? How would you work-up this patient? In the meantime, what would you dx and what would be your tentative tx plan? She returns 1mo later and reports that her mood continues to spiral downward. Now, she adds that she’s starting to think more morbid thoughts and that maybe it wouldn’t be such a bad thing if she weren’t around anymore. What would you ask now? How would you revise your tx plan? The pt’s sxs are finally stabilized and she returns at a later date w/ her sxs in remission x 1mo. “Doctor, I’m feeling so much better now. Do you think I can stop my psych Rxs?” How would you answer? Premenstrual dysphoric d/o Criterion A. In most menstrual cycles, ≥5 sxs in the final week before onset of menses, w/ improvement w/in a few days after onset of menses, and near-absent in the week post-menses Criterion B. ≥1 (or more) sx of marked: 1. lability (e.g., mood swings, suddenly sad, increased rejection sensitivity) 2. irritability /anger / increase in interpersonal conflicts 3. anxiety / tension / keyed-up feeling/edginess Criterion C. ≥1 (or more) sx to reach a total of 5 in combation w/ previous list: 1. anhedonia 2. [ ] impairment 3. anergia 4. significant appetite change (including specific food cravings) 5. sleep disturbance (↑ or ↓) 6. feeling overwhelmed or out of control 7. px sxs (e.g., breast tenderness/swelling, arthralgias/myalgias, bloating, wt gain) Special notes. Can’t just be menstrual exacerbation of MDD or other Axis I or II dx; must have confirmation by prospective daily rating scales during at least 2 sx-ic cycles (provisional dx allowed beforehand) Premenstrual dysphoric d/o (M)ood (labile &/or irritable &/or anxious) Sleep Interest Body Energy Concentration Appetite Out of control Treatment: SSRI daily luteal phase only (i.e., day 14 of cycle  menses) some data suggest
Slide 41 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No. Belmaker RH and Agam G, NEJM 2008, 358:55-68 iproniazid (1957) imipramine (1959) The monoamine hypothesis (1965) Joseph Schildkraut Question: Do antidepressants have additional actions besides inhibition of reuptake transporters? “…the Zoloft cartoon” from: http://gifsoup.com/webroot/animatedgifs/50426_o.gif; chemical inbalance Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. J Neurosci. 2000 Dec 15;20(24):9104-10 Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Science. 2003 Aug 8;301(5634):805-9. Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Haenisch B, Bönisch H. Pharmacol Ther. 2011 Mar;129(3):352-68. Epub 2010 Dec 13. Review. Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices. Hennings EC, Kiss JP, De Oliveira K, Toth PT, Vizi ES. J Neurochem. 1999 Sep;73(3):1043-50. Block of an ether-a-go-go-like K(+) channel by imipramine rescues egl-2 excitation defects in Caenorhabditis elegans. Weinshenker D, Wei A, Salkoff L, Thomas JH. J Neurosci. 1999 Nov 15;19(22):9831-40. photo from: http://www.sciencedaily.com/releases/2006/11/061121082449.htm Subsequent hypotheses about MDD altered glutamatergic transmission ↓’d GABAergic transmission monoamine-Ach imbalance disruption of endogenous opioid signalling neurosteroid deficiencies thyroxine abnormalities cytokine-mediated x-talk betw immune system & CNS circadian abnormalities (specific brain structure/circuit dysfxns…) as summarized in Belmaker RH and Agam G, NEJM 2008, 358:55-68 MDD tx options selective serotonin reuptake inhibitors (SSRIs) fluoxetine (PROZAC), 20-80 mg/d citalopram (CELEXA), 20-40 mg/d escitalopram (LEXAPRO), 10-20 mg/d sertraline (ZOLOFT), 50-200 mg/d paroxetine (PAXIL), 20-50 mg/d serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine XR (EFFEXOR XR), 37.5-225 mg/d desvenlafaxine (PRISTIQ) duloxetine (CYMBALTA), 30-120 mg/d others bupropion SR, XL (WELLBUTRIN) 100-200 mg BID (SR) 150-450 mg/d (XL) mirtazapine (REMERON), 15-45 mg/d trazodone, 50-200mg/noc (for sleep) nefazodone tricyclic antidepressants (TCADs) amitriptyline  nortriptyline imipramine  desipramine monoamine oxidase inhibitors (MAO-Is) typically, non-selective & irreversible MAO-A (NE, EPI, 5HT, DA) MAO-B (trace amines, DA) why we “wash-out” 5HT syndrome HTNsive crisis selegiline (EMSAM) [additional] augmenting agents Li+ T3, 25 mcg/d buspirone (BuSPAR), 5-30 mg BID atypical antipsychotics Sequenced Treatment Alternatives for the Relief of Depression (STAR*D) major NIMH-funded study (PI: A. John Rush) w/ 14 regional centers & 41 clinical sites initial enrollment of 4,041 patients aim: which tx algorithms work best after an initial failure to remit non-psychotic depression w/ an antidepressant? http://www.clinicaltrials.gov/ct/show/NCT00021528?order=1 Trivedi MH et al, Am J Psychiatry. 2006 Jan;163(1):28-40 47% response rate on citalopram (by *QIDS-SR, 50% ↓ in sxs) Sequenced Treatment Alternatives for the Relief of Depression (STAR*D), n = 2,876 (qualifying pts) 33% remission rate on citalopram (by QIDS-SR, score <5) Rx choice: according to side effects (SE’s), comorbid condn’s / risks (GMC & Ψ), ?FmRxHx 6-8wk trials each (preferable) augmentation v. switch? *QIDS-SR = Quick Inventory of Depressive Symptomatology, Self-Report (range 0-27) http://www.ids-qids.org/ MDD tx options Ψtherapy cognitive bx therapy (CBT) interpersonal therapy (IPT) psychodynamic therapy interventional Ψ electroconvulsive therapy (ECT) transcranial magnetic stimulation (TMS) vagal nerve stimulation (VNS) deep brain stimulation (DBS) other lightbox therapy (mostly for MDD w/ seasonal features) Major Depressive D/O (MDD) NATURAL HISTORY (Frank E and Thase ME, 1999 & DSM-5) recovery usually begins: w/in 3mos for two in five indivs w/in 1y for four in five indivs risk of subsequent episodes (w/in 3y) increases w/ n: ≥50% if n=1 ≥70% if n=2 ≥90% if n=3 dz course does not typically change as one ages 5-10% will eventually be dx’d w/ bipolar disorder (BD) more likely w/: onset of ‘MDD’ in adolescence a family history of BD ‘mixed features’ 6% lifetime SUI risk (Davies S et al, 2001); up to 15% w/ severe MDD Persistent depressive disorder (dysthymia) 2y of depressed mood (1y in children/adolescents) most of the day, more days than not, plus 2 of the following: appetite disturbance (↓ or ↑) veg sleep disturbance (↓ or ↑) veg ↓energy E ↓esteem E poor [ ] C hopeless H never sx-free for more than 2mos at a time overlapping dx of MDD is now allowed there has never been mania, hypomania, or cyclothymia MDD specifiers can also be used for dysthymia additionally: early onset (before age 21) late onset (at age 21 or older) w/ pure dysthymic syndrome from DSM-5 w/ persistent MDE w/ intermittent MDE’s, w/ current episode w/ intermittent MDE’s, w/o current episode --these last 3 are essentially a co-dx of MDD, but captured within the specifier… Persistent depressive disorder (dysthymia) may be more treatment-resistant (TxR) than straightforward MDD EPIDEMIOLOGY lifetime prevalence = 6% 12-mo prevalence = 0.5%, compared w/ 1.5% for MDD high comorbidity w/ personality d/o’s (particularly clusters B, C) From Sadock & Sadock & DSM-5 Case 1. 36yo F presenting w/ 3mos of ↓mood. She reports getting only ~4h of sleep/noc b/c of regular early AM awakenings. She feels drained everyday, all day long. She’s gained about 10 lbs in the last 2mos. What else would you like to ask? How would you work-up this patient? In the meantime, what would you dx and what would be your tentative tx plan? She returns 1mo later and reports that her mood continues to spiral downward. Now, she adds that she’s starting to think more morbid thoughts and that maybe it wouldn’t be such a bad thing if she weren’t around anymore. What would you ask now? How would you revise your tx plan? The pt’s sxs are finally stabilized and she returns at a later date w/ her sxs in remission x 1mo. “Doctor, I’m feeling so much better now. Do you think I can stop my psych Rxs?” How would you answer? Premenstrual dysphoric d/o Criterion A. In most menstrual cycles, ≥5 sxs in the final week before onset of menses, w/ improvement w/in a few days after onset of menses, and near-absent in the week post-menses Criterion B. ≥1 (or more) sx of marked: 1. lability (e.g., mood swings, suddenly sad, increased rejection sensitivity) 2. irritability /anger / increase in interpersonal conflicts 3. anxiety / tension / keyed-up feeling/edginess Criterion C. ≥1 (or more) sx to reach a total of 5 in combation w/ previous list: 1. anhedonia 2. [ ] impairment 3. anergia 4. significant appetite change (including specific food cravings) 5. sleep disturbance (↑ or ↓) 6. feeling overwhelmed or out of control 7. px sxs (e.g., breast tenderness/swelling, arthralgias/myalgias, bloating, wt gain) Special notes. Can’t just be menstrual exacerbation of MDD or other Axis I or II dx; must have confirmation by prospective daily rating scales during at least 2 sx-ic cycles (provisional dx allowed beforehand) Premenstrual dysphoric d/o (M)ood (labile &/or irritable &/or anxious) Sleep Interest Body Energy Concentration Appetite Out of control Treatment: SSRI daily luteal phase only (i.e., day 14 of cycle  menses) some data suggest
Slide 42 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No. Belmaker RH and Agam G, NEJM 2008, 358:55-68 iproniazid (1957) imipramine (1959) The monoamine hypothesis (1965) Joseph Schildkraut Question: Do antidepressants have additional actions besides inhibition of reuptake transporters? “…the Zoloft cartoon” from: http://gifsoup.com/webroot/animatedgifs/50426_o.gif; chemical inbalance Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. J Neurosci. 2000 Dec 15;20(24):9104-10 Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Science. 2003 Aug 8;301(5634):805-9. Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Haenisch B, Bönisch H. Pharmacol Ther. 2011 Mar;129(3):352-68. Epub 2010 Dec 13. Review. Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices. Hennings EC, Kiss JP, De Oliveira K, Toth PT, Vizi ES. J Neurochem. 1999 Sep;73(3):1043-50. Block of an ether-a-go-go-like K(+) channel by imipramine rescues egl-2 excitation defects in Caenorhabditis elegans. Weinshenker D, Wei A, Salkoff L, Thomas JH. J Neurosci. 1999 Nov 15;19(22):9831-40. photo from: http://www.sciencedaily.com/releases/2006/11/061121082449.htm Subsequent hypotheses about MDD altered glutamatergic transmission ↓’d GABAergic transmission monoamine-Ach imbalance disruption of endogenous opioid signalling neurosteroid deficiencies thyroxine abnormalities cytokine-mediated x-talk betw immune system & CNS circadian abnormalities (specific brain structure/circuit dysfxns…) as summarized in Belmaker RH and Agam G, NEJM 2008, 358:55-68 MDD tx options selective serotonin reuptake inhibitors (SSRIs) fluoxetine (PROZAC), 20-80 mg/d citalopram (CELEXA), 20-40 mg/d escitalopram (LEXAPRO), 10-20 mg/d sertraline (ZOLOFT), 50-200 mg/d paroxetine (PAXIL), 20-50 mg/d serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine XR (EFFEXOR XR), 37.5-225 mg/d desvenlafaxine (PRISTIQ) duloxetine (CYMBALTA), 30-120 mg/d others bupropion SR, XL (WELLBUTRIN) 100-200 mg BID (SR) 150-450 mg/d (XL) mirtazapine (REMERON), 15-45 mg/d trazodone, 50-200mg/noc (for sleep) nefazodone tricyclic antidepressants (TCADs) amitriptyline  nortriptyline imipramine  desipramine monoamine oxidase inhibitors (MAO-Is) typically, non-selective & irreversible MAO-A (NE, EPI, 5HT, DA) MAO-B (trace amines, DA) why we “wash-out” 5HT syndrome HTNsive crisis selegiline (EMSAM) [additional] augmenting agents Li+ T3, 25 mcg/d buspirone (BuSPAR), 5-30 mg BID atypical antipsychotics Sequenced Treatment Alternatives for the Relief of Depression (STAR*D) major NIMH-funded study (PI: A. John Rush) w/ 14 regional centers & 41 clinical sites initial enrollment of 4,041 patients aim: which tx algorithms work best after an initial failure to remit non-psychotic depression w/ an antidepressant? http://www.clinicaltrials.gov/ct/show/NCT00021528?order=1 Trivedi MH et al, Am J Psychiatry. 2006 Jan;163(1):28-40 47% response rate on citalopram (by *QIDS-SR, 50% ↓ in sxs) Sequenced Treatment Alternatives for the Relief of Depression (STAR*D), n = 2,876 (qualifying pts) 33% remission rate on citalopram (by QIDS-SR, score <5) Rx choice: according to side effects (SE’s), comorbid condn’s / risks (GMC & Ψ), ?FmRxHx 6-8wk trials each (preferable) augmentation v. switch? *QIDS-SR = Quick Inventory of Depressive Symptomatology, Self-Report (range 0-27) http://www.ids-qids.org/ MDD tx options Ψtherapy cognitive bx therapy (CBT) interpersonal therapy (IPT) psychodynamic therapy interventional Ψ electroconvulsive therapy (ECT) transcranial magnetic stimulation (TMS) vagal nerve stimulation (VNS) deep brain stimulation (DBS) other lightbox therapy (mostly for MDD w/ seasonal features) Major Depressive D/O (MDD) NATURAL HISTORY (Frank E and Thase ME, 1999 & DSM-5) recovery usually begins: w/in 3mos for two in five indivs w/in 1y for four in five indivs risk of subsequent episodes (w/in 3y) increases w/ n: ≥50% if n=1 ≥70% if n=2 ≥90% if n=3 dz course does not typically change as one ages 5-10% will eventually be dx’d w/ bipolar disorder (BD) more likely w/: onset of ‘MDD’ in adolescence a family history of BD ‘mixed features’ 6% lifetime SUI risk (Davies S et al, 2001); up to 15% w/ severe MDD Persistent depressive disorder (dysthymia) 2y of depressed mood (1y in children/adolescents) most of the day, more days than not, plus 2 of the following: appetite disturbance (↓ or ↑) veg sleep disturbance (↓ or ↑) veg ↓energy E ↓esteem E poor [ ] C hopeless H never sx-free for more than 2mos at a time overlapping dx of MDD is now allowed there has never been mania, hypomania, or cyclothymia MDD specifiers can also be used for dysthymia additionally: early onset (before age 21) late onset (at age 21 or older) w/ pure dysthymic syndrome from DSM-5 w/ persistent MDE w/ intermittent MDE’s, w/ current episode w/ intermittent MDE’s, w/o current episode --these last 3 are essentially a co-dx of MDD, but captured within the specifier… Persistent depressive disorder (dysthymia) may be more treatment-resistant (TxR) than straightforward MDD EPIDEMIOLOGY lifetime prevalence = 6% 12-mo prevalence = 0.5%, compared w/ 1.5% for MDD high comorbidity w/ personality d/o’s (particularly clusters B, C) From Sadock & Sadock & DSM-5 Case 1. 36yo F presenting w/ 3mos of ↓mood. She reports getting only ~4h of sleep/noc b/c of regular early AM awakenings. She feels drained everyday, all day long. She’s gained about 10 lbs in the last 2mos. What else would you like to ask? How would you work-up this patient? In the meantime, what would you dx and what would be your tentative tx plan? She returns 1mo later and reports that her mood continues to spiral downward. Now, she adds that she’s starting to think more morbid thoughts and that maybe it wouldn’t be such a bad thing if she weren’t around anymore. What would you ask now? How would you revise your tx plan? The pt’s sxs are finally stabilized and she returns at a later date w/ her sxs in remission x 1mo. “Doctor, I’m feeling so much better now. Do you think I can stop my psych Rxs?” How would you answer? Premenstrual dysphoric d/o Criterion A. In most menstrual cycles, ≥5 sxs in the final week before onset of menses, w/ improvement w/in a few days after onset of menses, and near-absent in the week post-menses Criterion B. ≥1 (or more) sx of marked: 1. lability (e.g., mood swings, suddenly sad, increased rejection sensitivity) 2. irritability /anger / increase in interpersonal conflicts 3. anxiety / tension / keyed-up feeling/edginess Criterion C. ≥1 (or more) sx to reach a total of 5 in combation w/ previous list: 1. anhedonia 2. [ ] impairment 3. anergia 4. significant appetite change (including specific food cravings) 5. sleep disturbance (↑ or ↓) 6. feeling overwhelmed or out of control 7. px sxs (e.g., breast tenderness/swelling, arthralgias/myalgias, bloating, wt gain) Special notes. Can’t just be menstrual exacerbation of MDD or other Axis I or II dx; must have confirmation by prospective daily rating scales during at least 2 sx-ic cycles (provisional dx allowed beforehand) Premenstrual dysphoric d/o (M)ood (labile &/or irritable &/or anxious) Sleep Interest Body Energy Concentration Appetite Out of control Treatment: SSRI daily luteal phase only (i.e., day 14 of cycle  menses) some data suggest
Slide 43 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No. Belmaker RH and Agam G, NEJM 2008, 358:55-68 iproniazid (1957) imipramine (1959) The monoamine hypothesis (1965) Joseph Schildkraut Question: Do antidepressants have additional actions besides inhibition of reuptake transporters? “…the Zoloft cartoon” from: http://gifsoup.com/webroot/animatedgifs/50426_o.gif; chemical inbalance Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. J Neurosci. 2000 Dec 15;20(24):9104-10 Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Science. 2003 Aug 8;301(5634):805-9. Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Haenisch B, Bönisch H. Pharmacol Ther. 2011 Mar;129(3):352-68. Epub 2010 Dec 13. Review. Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices. Hennings EC, Kiss JP, De Oliveira K, Toth PT, Vizi ES. J Neurochem. 1999 Sep;73(3):1043-50. Block of an ether-a-go-go-like K(+) channel by imipramine rescues egl-2 excitation defects in Caenorhabditis elegans. Weinshenker D, Wei A, Salkoff L, Thomas JH. J Neurosci. 1999 Nov 15;19(22):9831-40. photo from: http://www.sciencedaily.com/releases/2006/11/061121082449.htm Subsequent hypotheses about MDD altered glutamatergic transmission ↓’d GABAergic transmission monoamine-Ach imbalance disruption of endogenous opioid signalling neurosteroid deficiencies thyroxine abnormalities cytokine-mediated x-talk betw immune system & CNS circadian abnormalities (specific brain structure/circuit dysfxns…) as summarized in Belmaker RH and Agam G, NEJM 2008, 358:55-68 MDD tx options selective serotonin reuptake inhibitors (SSRIs) fluoxetine (PROZAC), 20-80 mg/d citalopram (CELEXA), 20-40 mg/d escitalopram (LEXAPRO), 10-20 mg/d sertraline (ZOLOFT), 50-200 mg/d paroxetine (PAXIL), 20-50 mg/d serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine XR (EFFEXOR XR), 37.5-225 mg/d desvenlafaxine (PRISTIQ) duloxetine (CYMBALTA), 30-120 mg/d others bupropion SR, XL (WELLBUTRIN) 100-200 mg BID (SR) 150-450 mg/d (XL) mirtazapine (REMERON), 15-45 mg/d trazodone, 50-200mg/noc (for sleep) nefazodone tricyclic antidepressants (TCADs) amitriptyline  nortriptyline imipramine  desipramine monoamine oxidase inhibitors (MAO-Is) typically, non-selective & irreversible MAO-A (NE, EPI, 5HT, DA) MAO-B (trace amines, DA) why we “wash-out” 5HT syndrome HTNsive crisis selegiline (EMSAM) [additional] augmenting agents Li+ T3, 25 mcg/d buspirone (BuSPAR), 5-30 mg BID atypical antipsychotics Sequenced Treatment Alternatives for the Relief of Depression (STAR*D) major NIMH-funded study (PI: A. John Rush) w/ 14 regional centers & 41 clinical sites initial enrollment of 4,041 patients aim: which tx algorithms work best after an initial failure to remit non-psychotic depression w/ an antidepressant? http://www.clinicaltrials.gov/ct/show/NCT00021528?order=1 Trivedi MH et al, Am J Psychiatry. 2006 Jan;163(1):28-40 47% response rate on citalopram (by *QIDS-SR, 50% ↓ in sxs) Sequenced Treatment Alternatives for the Relief of Depression (STAR*D), n = 2,876 (qualifying pts) 33% remission rate on citalopram (by QIDS-SR, score <5) Rx choice: according to side effects (SE’s), comorbid condn’s / risks (GMC & Ψ), ?FmRxHx 6-8wk trials each (preferable) augmentation v. switch? *QIDS-SR = Quick Inventory of Depressive Symptomatology, Self-Report (range 0-27) http://www.ids-qids.org/ MDD tx options Ψtherapy cognitive bx therapy (CBT) interpersonal therapy (IPT) psychodynamic therapy interventional Ψ electroconvulsive therapy (ECT) transcranial magnetic stimulation (TMS) vagal nerve stimulation (VNS) deep brain stimulation (DBS) other lightbox therapy (mostly for MDD w/ seasonal features) Major Depressive D/O (MDD) NATURAL HISTORY (Frank E and Thase ME, 1999 & DSM-5) recovery usually begins: w/in 3mos for two in five indivs w/in 1y for four in five indivs risk of subsequent episodes (w/in 3y) increases w/ n: ≥50% if n=1 ≥70% if n=2 ≥90% if n=3 dz course does not typically change as one ages 5-10% will eventually be dx’d w/ bipolar disorder (BD) more likely w/: onset of ‘MDD’ in adolescence a family history of BD ‘mixed features’ 6% lifetime SUI risk (Davies S et al, 2001); up to 15% w/ severe MDD Persistent depressive disorder (dysthymia) 2y of depressed mood (1y in children/adolescents) most of the day, more days than not, plus 2 of the following: appetite disturbance (↓ or ↑) veg sleep disturbance (↓ or ↑) veg ↓energy E ↓esteem E poor [ ] C hopeless H never sx-free for more than 2mos at a time overlapping dx of MDD is now allowed there has never been mania, hypomania, or cyclothymia MDD specifiers can also be used for dysthymia additionally: early onset (before age 21) late onset (at age 21 or older) w/ pure dysthymic syndrome from DSM-5 w/ persistent MDE w/ intermittent MDE’s, w/ current episode w/ intermittent MDE’s, w/o current episode --these last 3 are essentially a co-dx of MDD, but captured within the specifier… Persistent depressive disorder (dysthymia) may be more treatment-resistant (TxR) than straightforward MDD EPIDEMIOLOGY lifetime prevalence = 6% 12-mo prevalence = 0.5%, compared w/ 1.5% for MDD high comorbidity w/ personality d/o’s (particularly clusters B, C) From Sadock & Sadock & DSM-5 Case 1. 36yo F presenting w/ 3mos of ↓mood. She reports getting only ~4h of sleep/noc b/c of regular early AM awakenings. She feels drained everyday, all day long. She’s gained about 10 lbs in the last 2mos. What else would you like to ask? How would you work-up this patient? In the meantime, what would you dx and what would be your tentative tx plan? She returns 1mo later and reports that her mood continues to spiral downward. Now, she adds that she’s starting to think more morbid thoughts and that maybe it wouldn’t be such a bad thing if she weren’t around anymore. What would you ask now? How would you revise your tx plan? The pt’s sxs are finally stabilized and she returns at a later date w/ her sxs in remission x 1mo. “Doctor, I’m feeling so much better now. Do you think I can stop my psych Rxs?” How would you answer? Premenstrual dysphoric d/o Criterion A. In most menstrual cycles, ≥5 sxs in the final week before onset of menses, w/ improvement w/in a few days after onset of menses, and near-absent in the week post-menses Criterion B. ≥1 (or more) sx of marked: 1. lability (e.g., mood swings, suddenly sad, increased rejection sensitivity) 2. irritability /anger / increase in interpersonal conflicts 3. anxiety / tension / keyed-up feeling/edginess Criterion C. ≥1 (or more) sx to reach a total of 5 in combation w/ previous list: 1. anhedonia 2. [ ] impairment 3. anergia 4. significant appetite change (including specific food cravings) 5. sleep disturbance (↑ or ↓) 6. feeling overwhelmed or out of control 7. px sxs (e.g., breast tenderness/swelling, arthralgias/myalgias, bloating, wt gain) Special notes. Can’t just be menstrual exacerbation of MDD or other Axis I or II dx; must have confirmation by prospective daily rating scales during at least 2 sx-ic cycles (provisional dx allowed beforehand) Premenstrual dysphoric d/o (M)ood (labile &/or irritable &/or anxious) Sleep Interest Body Energy Concentration Appetite Out of control Treatment: SSRI daily luteal phase only (i.e., day 14 of cycle  menses) some data suggest
Slide 44 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No. Belmaker RH and Agam G, NEJM 2008, 358:55-68 iproniazid (1957) imipramine (1959) The monoamine hypothesis (1965) Joseph Schildkraut Question: Do antidepressants have additional actions besides inhibition of reuptake transporters? “…the Zoloft cartoon” from: http://gifsoup.com/webroot/animatedgifs/50426_o.gif; chemical inbalance Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. J Neurosci. 2000 Dec 15;20(24):9104-10 Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Science. 2003 Aug 8;301(5634):805-9. Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Haenisch B, Bönisch H. Pharmacol Ther. 2011 Mar;129(3):352-68. Epub 2010 Dec 13. Review. Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices. Hennings EC, Kiss JP, De Oliveira K, Toth PT, Vizi ES. J Neurochem. 1999 Sep;73(3):1043-50. Block of an ether-a-go-go-like K(+) channel by imipramine rescues egl-2 excitation defects in Caenorhabditis elegans. Weinshenker D, Wei A, Salkoff L, Thomas JH. J Neurosci. 1999 Nov 15;19(22):9831-40. photo from: http://www.sciencedaily.com/releases/2006/11/061121082449.htm Subsequent hypotheses about MDD altered glutamatergic transmission ↓’d GABAergic transmission monoamine-Ach imbalance disruption of endogenous opioid signalling neurosteroid deficiencies thyroxine abnormalities cytokine-mediated x-talk betw immune system & CNS circadian abnormalities (specific brain structure/circuit dysfxns…) as summarized in Belmaker RH and Agam G, NEJM 2008, 358:55-68 MDD tx options selective serotonin reuptake inhibitors (SSRIs) fluoxetine (PROZAC), 20-80 mg/d citalopram (CELEXA), 20-40 mg/d escitalopram (LEXAPRO), 10-20 mg/d sertraline (ZOLOFT), 50-200 mg/d paroxetine (PAXIL), 20-50 mg/d serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine XR (EFFEXOR XR), 37.5-225 mg/d desvenlafaxine (PRISTIQ) duloxetine (CYMBALTA), 30-120 mg/d others bupropion SR, XL (WELLBUTRIN) 100-200 mg BID (SR) 150-450 mg/d (XL) mirtazapine (REMERON), 15-45 mg/d trazodone, 50-200mg/noc (for sleep) nefazodone tricyclic antidepressants (TCADs) amitriptyline  nortriptyline imipramine  desipramine monoamine oxidase inhibitors (MAO-Is) typically, non-selective & irreversible MAO-A (NE, EPI, 5HT, DA) MAO-B (trace amines, DA) why we “wash-out” 5HT syndrome HTNsive crisis selegiline (EMSAM) [additional] augmenting agents Li+ T3, 25 mcg/d buspirone (BuSPAR), 5-30 mg BID atypical antipsychotics Sequenced Treatment Alternatives for the Relief of Depression (STAR*D) major NIMH-funded study (PI: A. John Rush) w/ 14 regional centers & 41 clinical sites initial enrollment of 4,041 patients aim: which tx algorithms work best after an initial failure to remit non-psychotic depression w/ an antidepressant? http://www.clinicaltrials.gov/ct/show/NCT00021528?order=1 Trivedi MH et al, Am J Psychiatry. 2006 Jan;163(1):28-40 47% response rate on citalopram (by *QIDS-SR, 50% ↓ in sxs) Sequenced Treatment Alternatives for the Relief of Depression (STAR*D), n = 2,876 (qualifying pts) 33% remission rate on citalopram (by QIDS-SR, score <5) Rx choice: according to side effects (SE’s), comorbid condn’s / risks (GMC & Ψ), ?FmRxHx 6-8wk trials each (preferable) augmentation v. switch? *QIDS-SR = Quick Inventory of Depressive Symptomatology, Self-Report (range 0-27) http://www.ids-qids.org/ MDD tx options Ψtherapy cognitive bx therapy (CBT) interpersonal therapy (IPT) psychodynamic therapy interventional Ψ electroconvulsive therapy (ECT) transcranial magnetic stimulation (TMS) vagal nerve stimulation (VNS) deep brain stimulation (DBS) other lightbox therapy (mostly for MDD w/ seasonal features) Major Depressive D/O (MDD) NATURAL HISTORY (Frank E and Thase ME, 1999 & DSM-5) recovery usually begins: w/in 3mos for two in five indivs w/in 1y for four in five indivs risk of subsequent episodes (w/in 3y) increases w/ n: ≥50% if n=1 ≥70% if n=2 ≥90% if n=3 dz course does not typically change as one ages 5-10% will eventually be dx’d w/ bipolar disorder (BD) more likely w/: onset of ‘MDD’ in adolescence a family history of BD ‘mixed features’ 6% lifetime SUI risk (Davies S et al, 2001); up to 15% w/ severe MDD Persistent depressive disorder (dysthymia) 2y of depressed mood (1y in children/adolescents) most of the day, more days than not, plus 2 of the following: appetite disturbance (↓ or ↑) veg sleep disturbance (↓ or ↑) veg ↓energy E ↓esteem E poor [ ] C hopeless H never sx-free for more than 2mos at a time overlapping dx of MDD is now allowed there has never been mania, hypomania, or cyclothymia MDD specifiers can also be used for dysthymia additionally: early onset (before age 21) late onset (at age 21 or older) w/ pure dysthymic syndrome from DSM-5 w/ persistent MDE w/ intermittent MDE’s, w/ current episode w/ intermittent MDE’s, w/o current episode --these last 3 are essentially a co-dx of MDD, but captured within the specifier… Persistent depressive disorder (dysthymia) may be more treatment-resistant (TxR) than straightforward MDD EPIDEMIOLOGY lifetime prevalence = 6% 12-mo prevalence = 0.5%, compared w/ 1.5% for MDD high comorbidity w/ personality d/o’s (particularly clusters B, C) From Sadock & Sadock & DSM-5 Case 1. 36yo F presenting w/ 3mos of ↓mood. She reports getting only ~4h of sleep/noc b/c of regular early AM awakenings. She feels drained everyday, all day long. She’s gained about 10 lbs in the last 2mos. What else would you like to ask? How would you work-up this patient? In the meantime, what would you dx and what would be your tentative tx plan? She returns 1mo later and reports that her mood continues to spiral downward. Now, she adds that she’s starting to think more morbid thoughts and that maybe it wouldn’t be such a bad thing if she weren’t around anymore. What would you ask now? How would you revise your tx plan? The pt’s sxs are finally stabilized and she returns at a later date w/ her sxs in remission x 1mo. “Doctor, I’m feeling so much better now. Do you think I can stop my psych Rxs?” How would you answer? Premenstrual dysphoric d/o Criterion A. In most menstrual cycles, ≥5 sxs in the final week before onset of menses, w/ improvement w/in a few days after onset of menses, and near-absent in the week post-menses Criterion B. ≥1 (or more) sx of marked: 1. lability (e.g., mood swings, suddenly sad, increased rejection sensitivity) 2. irritability /anger / increase in interpersonal conflicts 3. anxiety / tension / keyed-up feeling/edginess Criterion C. ≥1 (or more) sx to reach a total of 5 in combation w/ previous list: 1. anhedonia 2. [ ] impairment 3. anergia 4. significant appetite change (including specific food cravings) 5. sleep disturbance (↑ or ↓) 6. feeling overwhelmed or out of control 7. px sxs (e.g., breast tenderness/swelling, arthralgias/myalgias, bloating, wt gain) Special notes. Can’t just be menstrual exacerbation of MDD or other Axis I or II dx; must have confirmation by prospective daily rating scales during at least 2 sx-ic cycles (provisional dx allowed beforehand) Premenstrual dysphoric d/o (M)ood (labile &/or irritable &/or anxious) Sleep Interest Body Energy Concentration Appetite Out of control Treatment: SSRI daily luteal phase only (i.e., day 14 of cycle  menses) some data suggest
Slide 45 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No. Belmaker RH and Agam G, NEJM 2008, 358:55-68 iproniazid (1957) imipramine (1959) The monoamine hypothesis (1965) Joseph Schildkraut Question: Do antidepressants have additional actions besides inhibition of reuptake transporters? “…the Zoloft cartoon” from: http://gifsoup.com/webroot/animatedgifs/50426_o.gif; chemical inbalance Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. J Neurosci. 2000 Dec 15;20(24):9104-10 Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Science. 2003 Aug 8;301(5634):805-9. Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Haenisch B, Bönisch H. Pharmacol Ther. 2011 Mar;129(3):352-68. Epub 2010 Dec 13. Review. Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices. Hennings EC, Kiss JP, De Oliveira K, Toth PT, Vizi ES. J Neurochem. 1999 Sep;73(3):1043-50. Block of an ether-a-go-go-like K(+) channel by imipramine rescues egl-2 excitation defects in Caenorhabditis elegans. Weinshenker D, Wei A, Salkoff L, Thomas JH. J Neurosci. 1999 Nov 15;19(22):9831-40. photo from: http://www.sciencedaily.com/releases/2006/11/061121082449.htm Subsequent hypotheses about MDD altered glutamatergic transmission ↓’d GABAergic transmission monoamine-Ach imbalance disruption of endogenous opioid signalling neurosteroid deficiencies thyroxine abnormalities cytokine-mediated x-talk betw immune system & CNS circadian abnormalities (specific brain structure/circuit dysfxns…) as summarized in Belmaker RH and Agam G, NEJM 2008, 358:55-68 MDD tx options selective serotonin reuptake inhibitors (SSRIs) fluoxetine (PROZAC), 20-80 mg/d citalopram (CELEXA), 20-40 mg/d escitalopram (LEXAPRO), 10-20 mg/d sertraline (ZOLOFT), 50-200 mg/d paroxetine (PAXIL), 20-50 mg/d serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine XR (EFFEXOR XR), 37.5-225 mg/d desvenlafaxine (PRISTIQ) duloxetine (CYMBALTA), 30-120 mg/d others bupropion SR, XL (WELLBUTRIN) 100-200 mg BID (SR) 150-450 mg/d (XL) mirtazapine (REMERON), 15-45 mg/d trazodone, 50-200mg/noc (for sleep) nefazodone tricyclic antidepressants (TCADs) amitriptyline  nortriptyline imipramine  desipramine monoamine oxidase inhibitors (MAO-Is) typically, non-selective & irreversible MAO-A (NE, EPI, 5HT, DA) MAO-B (trace amines, DA) why we “wash-out” 5HT syndrome HTNsive crisis selegiline (EMSAM) [additional] augmenting agents Li+ T3, 25 mcg/d buspirone (BuSPAR), 5-30 mg BID atypical antipsychotics Sequenced Treatment Alternatives for the Relief of Depression (STAR*D) major NIMH-funded study (PI: A. John Rush) w/ 14 regional centers & 41 clinical sites initial enrollment of 4,041 patients aim: which tx algorithms work best after an initial failure to remit non-psychotic depression w/ an antidepressant? http://www.clinicaltrials.gov/ct/show/NCT00021528?order=1 Trivedi MH et al, Am J Psychiatry. 2006 Jan;163(1):28-40 47% response rate on citalopram (by *QIDS-SR, 50% ↓ in sxs) Sequenced Treatment Alternatives for the Relief of Depression (STAR*D), n = 2,876 (qualifying pts) 33% remission rate on citalopram (by QIDS-SR, score <5) Rx choice: according to side effects (SE’s), comorbid condn’s / risks (GMC & Ψ), ?FmRxHx 6-8wk trials each (preferable) augmentation v. switch? *QIDS-SR = Quick Inventory of Depressive Symptomatology, Self-Report (range 0-27) http://www.ids-qids.org/ MDD tx options Ψtherapy cognitive bx therapy (CBT) interpersonal therapy (IPT) psychodynamic therapy interventional Ψ electroconvulsive therapy (ECT) transcranial magnetic stimulation (TMS) vagal nerve stimulation (VNS) deep brain stimulation (DBS) other lightbox therapy (mostly for MDD w/ seasonal features) Major Depressive D/O (MDD) NATURAL HISTORY (Frank E and Thase ME, 1999 & DSM-5) recovery usually begins: w/in 3mos for two in five indivs w/in 1y for four in five indivs risk of subsequent episodes (w/in 3y) increases w/ n: ≥50% if n=1 ≥70% if n=2 ≥90% if n=3 dz course does not typically change as one ages 5-10% will eventually be dx’d w/ bipolar disorder (BD) more likely w/: onset of ‘MDD’ in adolescence a family history of BD ‘mixed features’ 6% lifetime SUI risk (Davies S et al, 2001); up to 15% w/ severe MDD Persistent depressive disorder (dysthymia) 2y of depressed mood (1y in children/adolescents) most of the day, more days than not, plus 2 of the following: appetite disturbance (↓ or ↑) veg sleep disturbance (↓ or ↑) veg ↓energy E ↓esteem E poor [ ] C hopeless H never sx-free for more than 2mos at a time overlapping dx of MDD is now allowed there has never been mania, hypomania, or cyclothymia MDD specifiers can also be used for dysthymia additionally: early onset (before age 21) late onset (at age 21 or older) w/ pure dysthymic syndrome from DSM-5 w/ persistent MDE w/ intermittent MDE’s, w/ current episode w/ intermittent MDE’s, w/o current episode --these last 3 are essentially a co-dx of MDD, but captured within the specifier… Persistent depressive disorder (dysthymia) may be more treatment-resistant (TxR) than straightforward MDD EPIDEMIOLOGY lifetime prevalence = 6% 12-mo prevalence = 0.5%, compared w/ 1.5% for MDD high comorbidity w/ personality d/o’s (particularly clusters B, C) From Sadock & Sadock & DSM-5 Case 1. 36yo F presenting w/ 3mos of ↓mood. She reports getting only ~4h of sleep/noc b/c of regular early AM awakenings. She feels drained everyday, all day long. She’s gained about 10 lbs in the last 2mos. What else would you like to ask? How would you work-up this patient? In the meantime, what would you dx and what would be your tentative tx plan? She returns 1mo later and reports that her mood continues to spiral downward. Now, she adds that she’s starting to think more morbid thoughts and that maybe it wouldn’t be such a bad thing if she weren’t around anymore. What would you ask now? How would you revise your tx plan? The pt’s sxs are finally stabilized and she returns at a later date w/ her sxs in remission x 1mo. “Doctor, I’m feeling so much better now. Do you think I can stop my psych Rxs?” How would you answer? Premenstrual dysphoric d/o Criterion A. In most menstrual cycles, ≥5 sxs in the final week before onset of menses, w/ improvement w/in a few days after onset of menses, and near-absent in the week post-menses Criterion B. ≥1 (or more) sx of marked: 1. lability (e.g., mood swings, suddenly sad, increased rejection sensitivity) 2. irritability /anger / increase in interpersonal conflicts 3. anxiety / tension / keyed-up feeling/edginess Criterion C. ≥1 (or more) sx to reach a total of 5 in combation w/ previous list: 1. anhedonia 2. [ ] impairment 3. anergia 4. significant appetite change (including specific food cravings) 5. sleep disturbance (↑ or ↓) 6. feeling overwhelmed or out of control 7. px sxs (e.g., breast tenderness/swelling, arthralgias/myalgias, bloating, wt gain) Special notes. Can’t just be menstrual exacerbation of MDD or other Axis I or II dx; must have confirmation by prospective daily rating scales during at least 2 sx-ic cycles (provisional dx allowed beforehand) Premenstrual dysphoric d/o (M)ood (labile &/or irritable &/or anxious) Sleep Interest Body Energy Concentration Appetite Out of control Treatment: SSRI daily luteal phase only (i.e., day 14 of cycle  menses) some data suggest successful in tx’ing mixed episodes, BD indivs w/ comorbid substance issues Areas of concern: Li+ ↔ renal; interaction w/ NSAIDs VPA ↔ liver; VPA in young ♀  polycystic ovarian syndrome (PCOS) Teratogenicity Li+  Ebstein’s anomaly (1st trimester) hazard ratio 10-20, but AR still 1:1000 VPA  neural tube defects AR 10% OTHER NOTES: CBZ: auto-induction, agranulocytosis Lamictal: Stevens-Johnson syndrome (SJS), interaxn w/ oral contraceptives (OCPs), interaxn w/ VPA
Slide 46 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No. Belmaker RH and Agam G, NEJM 2008, 358:55-68 iproniazid (1957) imipramine (1959) The monoamine hypothesis (1965) Joseph Schildkraut Question: Do antidepressants have additional actions besides inhibition of reuptake transporters? “…the Zoloft cartoon” from: http://gifsoup.com/webroot/animatedgifs/50426_o.gif; chemical inbalance Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. J Neurosci. 2000 Dec 15;20(24):9104-10 Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Science. 2003 Aug 8;301(5634):805-9. Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Haenisch B, Bönisch H. Pharmacol Ther. 2011 Mar;129(3):352-68. Epub 2010 Dec 13. Review. Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices. Hennings EC, Kiss JP, De Oliveira K, Toth PT, Vizi ES. J Neurochem. 1999 Sep;73(3):1043-50. Block of an ether-a-go-go-like K(+) channel by imipramine rescues egl-2 excitation defects in Caenorhabditis elegans. Weinshenker D, Wei A, Salkoff L, Thomas JH. J Neurosci. 1999 Nov 15;19(22):9831-40. photo from: http://www.sciencedaily.com/releases/2006/11/061121082449.htm Subsequent hypotheses about MDD altered glutamatergic transmission ↓’d GABAergic transmission monoamine-Ach imbalance disruption of endogenous opioid signalling neurosteroid deficiencies thyroxine abnormalities cytokine-mediated x-talk betw immune system & CNS circadian abnormalities (specific brain structure/circuit dysfxns…) as summarized in Belmaker RH and Agam G, NEJM 2008, 358:55-68 MDD tx options selective serotonin reuptake inhibitors (SSRIs) fluoxetine (PROZAC), 20-80 mg/d citalopram (CELEXA), 20-40 mg/d escitalopram (LEXAPRO), 10-20 mg/d sertraline (ZOLOFT), 50-200 mg/d paroxetine (PAXIL), 20-50 mg/d serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine XR (EFFEXOR XR), 37.5-225 mg/d desvenlafaxine (PRISTIQ) duloxetine (CYMBALTA), 30-120 mg/d others bupropion SR, XL (WELLBUTRIN) 100-200 mg BID (SR) 150-450 mg/d (XL) mirtazapine (REMERON), 15-45 mg/d trazodone, 50-200mg/noc (for sleep) nefazodone tricyclic antidepressants (TCADs) amitriptyline  nortriptyline imipramine  desipramine monoamine oxidase inhibitors (MAO-Is) typically, non-selective & irreversible MAO-A (NE, EPI, 5HT, DA) MAO-B (trace amines, DA) why we “wash-out” 5HT syndrome HTNsive crisis selegiline (EMSAM) [additional] augmenting agents Li+ T3, 25 mcg/d buspirone (BuSPAR), 5-30 mg BID atypical antipsychotics Sequenced Treatment Alternatives for the Relief of Depression (STAR*D) major NIMH-funded study (PI: A. John Rush) w/ 14 regional centers & 41 clinical sites initial enrollment of 4,041 patients aim: which tx algorithms work best after an initial failure to remit non-psychotic depression w/ an antidepressant? http://www.clinicaltrials.gov/ct/show/NCT00021528?order=1 Trivedi MH et al, Am J Psychiatry. 2006 Jan;163(1):28-40 47% response rate on citalopram (by *QIDS-SR, 50% ↓ in sxs) Sequenced Treatment Alternatives for the Relief of Depression (STAR*D), n = 2,876 (qualifying pts) 33% remission rate on citalopram (by QIDS-SR, score <5) Rx choice: according to side effects (SE’s), comorbid condn’s / risks (GMC & Ψ), ?FmRxHx 6-8wk trials each (preferable) augmentation v. switch? *QIDS-SR = Quick Inventory of Depressive Symptomatology, Self-Report (range 0-27) http://www.ids-qids.org/ MDD tx options Ψtherapy cognitive bx therapy (CBT) interpersonal therapy (IPT) psychodynamic therapy interventional Ψ electroconvulsive therapy (ECT) transcranial magnetic stimulation (TMS) vagal nerve stimulation (VNS) deep brain stimulation (DBS) other lightbox therapy (mostly for MDD w/ seasonal features) Major Depressive D/O (MDD) NATURAL HISTORY (Frank E and Thase ME, 1999 & DSM-5) recovery usually begins: w/in 3mos for two in five indivs w/in 1y for four in five indivs risk of subsequent episodes (w/in 3y) increases w/ n: ≥50% if n=1 ≥70% if n=2 ≥90% if n=3 dz course does not typically change as one ages 5-10% will eventually be dx’d w/ bipolar disorder (BD) more likely w/: onset of ‘MDD’ in adolescence a family history of BD ‘mixed features’ 6% lifetime SUI risk (Davies S et al, 2001); up to 15% w/ severe MDD Persistent depressive disorder (dysthymia) 2y of depressed mood (1y in children/adolescents) most of the day, more days than not, plus 2 of the following: appetite disturbance (↓ or ↑) veg sleep disturbance (↓ or ↑) veg ↓energy E ↓esteem E poor [ ] C hopeless H never sx-free for more than 2mos at a time overlapping dx of MDD is now allowed there has never been mania, hypomania, or cyclothymia MDD specifiers can also be used for dysthymia additionally: early onset (before age 21) late onset (at age 21 or older) w/ pure dysthymic syndrome from DSM-5 w/ persistent MDE w/ intermittent MDE’s, w/ current episode w/ intermittent MDE’s, w/o current episode --these last 3 are essentially a co-dx of MDD, but captured within the specifier… Persistent depressive disorder (dysthymia) may be more treatment-resistant (TxR) than straightforward MDD EPIDEMIOLOGY lifetime prevalence = 6% 12-mo prevalence = 0.5%, compared w/ 1.5% for MDD high comorbidity w/ personality d/o’s (particularly clusters B, C) From Sadock & Sadock & DSM-5 Case 1. 36yo F presenting w/ 3mos of ↓mood. She reports getting only ~4h of sleep/noc b/c of regular early AM awakenings. She feels drained everyday, all day long. She’s gained about 10 lbs in the last 2mos. What else would you like to ask? How would you work-up this patient? In the meantime, what would you dx and what would be your tentative tx plan? She returns 1mo later and reports that her mood continues to spiral downward. Now, she adds that she’s starting to think more morbid thoughts and that maybe it wouldn’t be such a bad thing if she weren’t around anymore. What would you ask now? How would you revise your tx plan? The pt’s sxs are finally stabilized and she returns at a later date w/ her sxs in remission x 1mo. “Doctor, I’m feeling so much better now. Do you think I can stop my psych Rxs?” How would you answer? Premenstrual dysphoric d/o Criterion A. In most menstrual cycles, ≥5 sxs in the final week before onset of menses, w/ improvement w/in a few days after onset of menses, and near-absent in the week post-menses Criterion B. ≥1 (or more) sx of marked: 1. lability (e.g., mood swings, suddenly sad, increased rejection sensitivity) 2. irritability /anger / increase in interpersonal conflicts 3. anxiety / tension / keyed-up feeling/edginess Criterion C. ≥1 (or more) sx to reach a total of 5 in combation w/ previous list: 1. anhedonia 2. [ ] impairment 3. anergia 4. significant appetite change (including specific food cravings) 5. sleep disturbance (↑ or ↓) 6. feeling overwhelmed or out of control 7. px sxs (e.g., breast tenderness/swelling, arthralgias/myalgias, bloating, wt gain) Special notes. Can’t just be menstrual exacerbation of MDD or other Axis I or II dx; must have confirmation by prospective daily rating scales during at least 2 sx-ic cycles (provisional dx allowed beforehand) Premenstrual dysphoric d/o (M)ood (labile &/or irritable &/or anxious) Sleep Interest Body Energy Concentration Appetite Out of control Treatment: SSRI daily luteal phase only (i.e., day 14 of cycle  menses) some data suggest successful in tx’ing mixed episodes, BD indivs w/ comorbid substance issues Areas of concern: Li+ ↔ renal; interaction w/ NSAIDs VPA ↔ liver; VPA in young ♀  polycystic ovarian syndrome (PCOS) Teratogenicity Li+  Ebstein’s anomaly (1st trimester) hazard ratio 10-20, but AR still 1:1000 VPA  neural tube defects AR 10% OTHER NOTES: CBZ: auto-induction, agranulocytosis Lamictal: Stevens-Johnson syndrome (SJS), interaxn w/ oral contraceptives (OCPs), interaxn w/ VPA Bipolar Disorder (BD) – treatment (cont’d) How many agents to use? combination tx often helpful in acute stabilization antipsychotics REQ’D when there are psychotic features to mood episode Adjuncts benzos --Don’t forget about ECT… Manic switch w/… reuptake blockers Lamictal, too! (van der Loos ML et al, 2009)
Slide 47 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No. Belmaker RH and Agam G, NEJM 2008, 358:55-68 iproniazid (1957) imipramine (1959) The monoamine hypothesis (1965) Joseph Schildkraut Question: Do antidepressants have additional actions besides inhibition of reuptake transporters? “…the Zoloft cartoon” from: http://gifsoup.com/webroot/animatedgifs/50426_o.gif; chemical inbalance Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. J Neurosci. 2000 Dec 15;20(24):9104-10 Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Science. 2003 Aug 8;301(5634):805-9. Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Haenisch B, Bönisch H. Pharmacol Ther. 2011 Mar;129(3):352-68. Epub 2010 Dec 13. Review. Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices. Hennings EC, Kiss JP, De Oliveira K, Toth PT, Vizi ES. J Neurochem. 1999 Sep;73(3):1043-50. Block of an ether-a-go-go-like K(+) channel by imipramine rescues egl-2 excitation defects in Caenorhabditis elegans. Weinshenker D, Wei A, Salkoff L, Thomas JH. J Neurosci. 1999 Nov 15;19(22):9831-40. photo from: http://www.sciencedaily.com/releases/2006/11/061121082449.htm Subsequent hypotheses about MDD altered glutamatergic transmission ↓’d GABAergic transmission monoamine-Ach imbalance disruption of endogenous opioid signalling neurosteroid deficiencies thyroxine abnormalities cytokine-mediated x-talk betw immune system & CNS circadian abnormalities (specific brain structure/circuit dysfxns…) as summarized in Belmaker RH and Agam G, NEJM 2008, 358:55-68 MDD tx options selective serotonin reuptake inhibitors (SSRIs) fluoxetine (PROZAC), 20-80 mg/d citalopram (CELEXA), 20-40 mg/d escitalopram (LEXAPRO), 10-20 mg/d sertraline (ZOLOFT), 50-200 mg/d paroxetine (PAXIL), 20-50 mg/d serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine XR (EFFEXOR XR), 37.5-225 mg/d desvenlafaxine (PRISTIQ) duloxetine (CYMBALTA), 30-120 mg/d others bupropion SR, XL (WELLBUTRIN) 100-200 mg BID (SR) 150-450 mg/d (XL) mirtazapine (REMERON), 15-45 mg/d trazodone, 50-200mg/noc (for sleep) nefazodone tricyclic antidepressants (TCADs) amitriptyline  nortriptyline imipramine  desipramine monoamine oxidase inhibitors (MAO-Is) typically, non-selective & irreversible MAO-A (NE, EPI, 5HT, DA) MAO-B (trace amines, DA) why we “wash-out” 5HT syndrome HTNsive crisis selegiline (EMSAM) [additional] augmenting agents Li+ T3, 25 mcg/d buspirone (BuSPAR), 5-30 mg BID atypical antipsychotics Sequenced Treatment Alternatives for the Relief of Depression (STAR*D) major NIMH-funded study (PI: A. John Rush) w/ 14 regional centers & 41 clinical sites initial enrollment of 4,041 patients aim: which tx algorithms work best after an initial failure to remit non-psychotic depression w/ an antidepressant? http://www.clinicaltrials.gov/ct/show/NCT00021528?order=1 Trivedi MH et al, Am J Psychiatry. 2006 Jan;163(1):28-40 47% response rate on citalopram (by *QIDS-SR, 50% ↓ in sxs) Sequenced Treatment Alternatives for the Relief of Depression (STAR*D), n = 2,876 (qualifying pts) 33% remission rate on citalopram (by QIDS-SR, score <5) Rx choice: according to side effects (SE’s), comorbid condn’s / risks (GMC & Ψ), ?FmRxHx 6-8wk trials each (preferable) augmentation v. switch? *QIDS-SR = Quick Inventory of Depressive Symptomatology, Self-Report (range 0-27) http://www.ids-qids.org/ MDD tx options Ψtherapy cognitive bx therapy (CBT) interpersonal therapy (IPT) psychodynamic therapy interventional Ψ electroconvulsive therapy (ECT) transcranial magnetic stimulation (TMS) vagal nerve stimulation (VNS) deep brain stimulation (DBS) other lightbox therapy (mostly for MDD w/ seasonal features) Major Depressive D/O (MDD) NATURAL HISTORY (Frank E and Thase ME, 1999 & DSM-5) recovery usually begins: w/in 3mos for two in five indivs w/in 1y for four in five indivs risk of subsequent episodes (w/in 3y) increases w/ n: ≥50% if n=1 ≥70% if n=2 ≥90% if n=3 dz course does not typically change as one ages 5-10% will eventually be dx’d w/ bipolar disorder (BD) more likely w/: onset of ‘MDD’ in adolescence a family history of BD ‘mixed features’ 6% lifetime SUI risk (Davies S et al, 2001); up to 15% w/ severe MDD Persistent depressive disorder (dysthymia) 2y of depressed mood (1y in children/adolescents) most of the day, more days than not, plus 2 of the following: appetite disturbance (↓ or ↑) veg sleep disturbance (↓ or ↑) veg ↓energy E ↓esteem E poor [ ] C hopeless H never sx-free for more than 2mos at a time overlapping dx of MDD is now allowed there has never been mania, hypomania, or cyclothymia MDD specifiers can also be used for dysthymia additionally: early onset (before age 21) late onset (at age 21 or older) w/ pure dysthymic syndrome from DSM-5 w/ persistent MDE w/ intermittent MDE’s, w/ current episode w/ intermittent MDE’s, w/o current episode --these last 3 are essentially a co-dx of MDD, but captured within the specifier… Persistent depressive disorder (dysthymia) may be more treatment-resistant (TxR) than straightforward MDD EPIDEMIOLOGY lifetime prevalence = 6% 12-mo prevalence = 0.5%, compared w/ 1.5% for MDD high comorbidity w/ personality d/o’s (particularly clusters B, C) From Sadock & Sadock & DSM-5 Case 1. 36yo F presenting w/ 3mos of ↓mood. She reports getting only ~4h of sleep/noc b/c of regular early AM awakenings. She feels drained everyday, all day long. She’s gained about 10 lbs in the last 2mos. What else would you like to ask? How would you work-up this patient? In the meantime, what would you dx and what would be your tentative tx plan? She returns 1mo later and reports that her mood continues to spiral downward. Now, she adds that she’s starting to think more morbid thoughts and that maybe it wouldn’t be such a bad thing if she weren’t around anymore. What would you ask now? How would you revise your tx plan? The pt’s sxs are finally stabilized and she returns at a later date w/ her sxs in remission x 1mo. “Doctor, I’m feeling so much better now. Do you think I can stop my psych Rxs?” How would you answer? Premenstrual dysphoric d/o Criterion A. In most menstrual cycles, ≥5 sxs in the final week before onset of menses, w/ improvement w/in a few days after onset of menses, and near-absent in the week post-menses Criterion B. ≥1 (or more) sx of marked: 1. lability (e.g., mood swings, suddenly sad, increased rejection sensitivity) 2. irritability /anger / increase in interpersonal conflicts 3. anxiety / tension / keyed-up feeling/edginess Criterion C. ≥1 (or more) sx to reach a total of 5 in combation w/ previous list: 1. anhedonia 2. [ ] impairment 3. anergia 4. significant appetite change (including specific food cravings) 5. sleep disturbance (↑ or ↓) 6. feeling overwhelmed or out of control 7. px sxs (e.g., breast tenderness/swelling, arthralgias/myalgias, bloating, wt gain) Special notes. Can’t just be menstrual exacerbation of MDD or other Axis I or II dx; must have confirmation by prospective daily rating scales during at least 2 sx-ic cycles (provisional dx allowed beforehand) Premenstrual dysphoric d/o (M)ood (labile &/or irritable &/or anxious) Sleep Interest Body Energy Concentration Appetite Out of control Treatment: SSRI daily luteal phase only (i.e., day 14 of cycle  menses) some data suggest successful in tx’ing mixed episodes, BD indivs w/ comorbid substance issues Areas of concern: Li+ ↔ renal; interaction w/ NSAIDs VPA ↔ liver; VPA in young ♀  polycystic ovarian syndrome (PCOS) Teratogenicity Li+  Ebstein’s anomaly (1st trimester) hazard ratio 10-20, but AR still 1:1000 VPA  neural tube defects AR 10% OTHER NOTES: CBZ: auto-induction, agranulocytosis Lamictal: Stevens-Johnson syndrome (SJS), interaxn w/ oral contraceptives (OCPs), interaxn w/ VPA Bipolar Disorder (BD) – treatment (cont’d) How many agents to use? combination tx often helpful in acute stabilization antipsychotics REQ’D when there are psychotic features to mood episode Adjuncts benzos --Don’t forget about ECT… Manic switch w/… reuptake blockers Lamictal, too! (van der Loos ML et al, 2009) Bipolar Disorder (BD) – natural history 60% of manic episodes immediately precede an MDE MDE’s usually significantly outnumber hypomanic and manic episodes ~10% of BD II’s  BD I episodes tend to increase in frequency/duration w/ age re: suicide… 35% lifetime prevalence of at least one SUI attempt in bipolar 15% suicide completion rate (may be an overestimate) 15x the risk of the general population (for completions) perhaps ¼ of all suicides in the population >lethality of SUI attempts in BD II (than BD I) adapated, in part,from DSM-5
Slide 48 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No. Belmaker RH and Agam G, NEJM 2008, 358:55-68 iproniazid (1957) imipramine (1959) The monoamine hypothesis (1965) Joseph Schildkraut Question: Do antidepressants have additional actions besides inhibition of reuptake transporters? “…the Zoloft cartoon” from: http://gifsoup.com/webroot/animatedgifs/50426_o.gif; chemical inbalance Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. J Neurosci. 2000 Dec 15;20(24):9104-10 Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Science. 2003 Aug 8;301(5634):805-9. Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Haenisch B, Bönisch H. Pharmacol Ther. 2011 Mar;129(3):352-68. Epub 2010 Dec 13. Review. Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices. Hennings EC, Kiss JP, De Oliveira K, Toth PT, Vizi ES. J Neurochem. 1999 Sep;73(3):1043-50. Block of an ether-a-go-go-like K(+) channel by imipramine rescues egl-2 excitation defects in Caenorhabditis elegans. Weinshenker D, Wei A, Salkoff L, Thomas JH. J Neurosci. 1999 Nov 15;19(22):9831-40. photo from: http://www.sciencedaily.com/releases/2006/11/061121082449.htm Subsequent hypotheses about MDD altered glutamatergic transmission ↓’d GABAergic transmission monoamine-Ach imbalance disruption of endogenous opioid signalling neurosteroid deficiencies thyroxine abnormalities cytokine-mediated x-talk betw immune system & CNS circadian abnormalities (specific brain structure/circuit dysfxns…) as summarized in Belmaker RH and Agam G, NEJM 2008, 358:55-68 MDD tx options selective serotonin reuptake inhibitors (SSRIs) fluoxetine (PROZAC), 20-80 mg/d citalopram (CELEXA), 20-40 mg/d escitalopram (LEXAPRO), 10-20 mg/d sertraline (ZOLOFT), 50-200 mg/d paroxetine (PAXIL), 20-50 mg/d serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine XR (EFFEXOR XR), 37.5-225 mg/d desvenlafaxine (PRISTIQ) duloxetine (CYMBALTA), 30-120 mg/d others bupropion SR, XL (WELLBUTRIN) 100-200 mg BID (SR) 150-450 mg/d (XL) mirtazapine (REMERON), 15-45 mg/d trazodone, 50-200mg/noc (for sleep) nefazodone tricyclic antidepressants (TCADs) amitriptyline  nortriptyline imipramine  desipramine monoamine oxidase inhibitors (MAO-Is) typically, non-selective & irreversible MAO-A (NE, EPI, 5HT, DA) MAO-B (trace amines, DA) why we “wash-out” 5HT syndrome HTNsive crisis selegiline (EMSAM) [additional] augmenting agents Li+ T3, 25 mcg/d buspirone (BuSPAR), 5-30 mg BID atypical antipsychotics Sequenced Treatment Alternatives for the Relief of Depression (STAR*D) major NIMH-funded study (PI: A. John Rush) w/ 14 regional centers & 41 clinical sites initial enrollment of 4,041 patients aim: which tx algorithms work best after an initial failure to remit non-psychotic depression w/ an antidepressant? http://www.clinicaltrials.gov/ct/show/NCT00021528?order=1 Trivedi MH et al, Am J Psychiatry. 2006 Jan;163(1):28-40 47% response rate on citalopram (by *QIDS-SR, 50% ↓ in sxs) Sequenced Treatment Alternatives for the Relief of Depression (STAR*D), n = 2,876 (qualifying pts) 33% remission rate on citalopram (by QIDS-SR, score <5) Rx choice: according to side effects (SE’s), comorbid condn’s / risks (GMC & Ψ), ?FmRxHx 6-8wk trials each (preferable) augmentation v. switch? *QIDS-SR = Quick Inventory of Depressive Symptomatology, Self-Report (range 0-27) http://www.ids-qids.org/ MDD tx options Ψtherapy cognitive bx therapy (CBT) interpersonal therapy (IPT) psychodynamic therapy interventional Ψ electroconvulsive therapy (ECT) transcranial magnetic stimulation (TMS) vagal nerve stimulation (VNS) deep brain stimulation (DBS) other lightbox therapy (mostly for MDD w/ seasonal features) Major Depressive D/O (MDD) NATURAL HISTORY (Frank E and Thase ME, 1999 & DSM-5) recovery usually begins: w/in 3mos for two in five indivs w/in 1y for four in five indivs risk of subsequent episodes (w/in 3y) increases w/ n: ≥50% if n=1 ≥70% if n=2 ≥90% if n=3 dz course does not typically change as one ages 5-10% will eventually be dx’d w/ bipolar disorder (BD) more likely w/: onset of ‘MDD’ in adolescence a family history of BD ‘mixed features’ 6% lifetime SUI risk (Davies S et al, 2001); up to 15% w/ severe MDD Persistent depressive disorder (dysthymia) 2y of depressed mood (1y in children/adolescents) most of the day, more days than not, plus 2 of the following: appetite disturbance (↓ or ↑) veg sleep disturbance (↓ or ↑) veg ↓energy E ↓esteem E poor [ ] C hopeless H never sx-free for more than 2mos at a time overlapping dx of MDD is now allowed there has never been mania, hypomania, or cyclothymia MDD specifiers can also be used for dysthymia additionally: early onset (before age 21) late onset (at age 21 or older) w/ pure dysthymic syndrome from DSM-5 w/ persistent MDE w/ intermittent MDE’s, w/ current episode w/ intermittent MDE’s, w/o current episode --these last 3 are essentially a co-dx of MDD, but captured within the specifier… Persistent depressive disorder (dysthymia) may be more treatment-resistant (TxR) than straightforward MDD EPIDEMIOLOGY lifetime prevalence = 6% 12-mo prevalence = 0.5%, compared w/ 1.5% for MDD high comorbidity w/ personality d/o’s (particularly clusters B, C) From Sadock & Sadock & DSM-5 Case 1. 36yo F presenting w/ 3mos of ↓mood. She reports getting only ~4h of sleep/noc b/c of regular early AM awakenings. She feels drained everyday, all day long. She’s gained about 10 lbs in the last 2mos. What else would you like to ask? How would you work-up this patient? In the meantime, what would you dx and what would be your tentative tx plan? She returns 1mo later and reports that her mood continues to spiral downward. Now, she adds that she’s starting to think more morbid thoughts and that maybe it wouldn’t be such a bad thing if she weren’t around anymore. What would you ask now? How would you revise your tx plan? The pt’s sxs are finally stabilized and she returns at a later date w/ her sxs in remission x 1mo. “Doctor, I’m feeling so much better now. Do you think I can stop my psych Rxs?” How would you answer? Premenstrual dysphoric d/o Criterion A. In most menstrual cycles, ≥5 sxs in the final week before onset of menses, w/ improvement w/in a few days after onset of menses, and near-absent in the week post-menses Criterion B. ≥1 (or more) sx of marked: 1. lability (e.g., mood swings, suddenly sad, increased rejection sensitivity) 2. irritability /anger / increase in interpersonal conflicts 3. anxiety / tension / keyed-up feeling/edginess Criterion C. ≥1 (or more) sx to reach a total of 5 in combation w/ previous list: 1. anhedonia 2. [ ] impairment 3. anergia 4. significant appetite change (including specific food cravings) 5. sleep disturbance (↑ or ↓) 6. feeling overwhelmed or out of control 7. px sxs (e.g., breast tenderness/swelling, arthralgias/myalgias, bloating, wt gain) Special notes. Can’t just be menstrual exacerbation of MDD or other Axis I or II dx; must have confirmation by prospective daily rating scales during at least 2 sx-ic cycles (provisional dx allowed beforehand) Premenstrual dysphoric d/o (M)ood (labile &/or irritable &/or anxious) Sleep Interest Body Energy Concentration Appetite Out of control Treatment: SSRI daily luteal phase only (i.e., day 14 of cycle  menses) some data suggest successful in tx’ing mixed episodes, BD indivs w/ comorbid substance issues Areas of concern: Li+ ↔ renal; interaction w/ NSAIDs VPA ↔ liver; VPA in young ♀  polycystic ovarian syndrome (PCOS) Teratogenicity Li+  Ebstein’s anomaly (1st trimester) hazard ratio 10-20, but AR still 1:1000 VPA  neural tube defects AR 10% OTHER NOTES: CBZ: auto-induction, agranulocytosis Lamictal: Stevens-Johnson syndrome (SJS), interaxn w/ oral contraceptives (OCPs), interaxn w/ VPA Bipolar Disorder (BD) – treatment (cont’d) How many agents to use? combination tx often helpful in acute stabilization antipsychotics REQ’D when there are psychotic features to mood episode Adjuncts benzos --Don’t forget about ECT… Manic switch w/… reuptake blockers Lamictal, too! (van der Loos ML et al, 2009) Bipolar Disorder (BD) – natural history 60% of manic episodes immediately precede an MDE MDE’s usually significantly outnumber hypomanic and manic episodes ~10% of BD II’s  BD I episodes tend to increase in frequency/duration w/ age re: suicide… 35% lifetime prevalence of at least one SUI attempt in bipolar 15% suicide completion rate (may be an overestimate) 15x the risk of the general population (for completions) perhaps ¼ of all suicides in the population >lethality of SUI attempts in BD II (than BD I) adapated, in part,from DSM-5 Cyclothymic D/O 2y of fluctuating mood (1y in children, adolescents) hypomanic symptoms (but NOT episodes) dysthymic symptoms (but no MDEs) ≥ half the time & (no more than 2mos sx-free) EXCLUSIONS no manic/hypomanic episodes no depressive episodes
Slide 49 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No. Belmaker RH and Agam G, NEJM 2008, 358:55-68 iproniazid (1957) imipramine (1959) The monoamine hypothesis (1965) Joseph Schildkraut Question: Do antidepressants have additional actions besides inhibition of reuptake transporters? “…the Zoloft cartoon” from: http://gifsoup.com/webroot/animatedgifs/50426_o.gif; chemical inbalance Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. J Neurosci. 2000 Dec 15;20(24):9104-10 Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Science. 2003 Aug 8;301(5634):805-9. Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Haenisch B, Bönisch H. Pharmacol Ther. 2011 Mar;129(3):352-68. Epub 2010 Dec 13. Review. Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices. Hennings EC, Kiss JP, De Oliveira K, Toth PT, Vizi ES. J Neurochem. 1999 Sep;73(3):1043-50. Block of an ether-a-go-go-like K(+) channel by imipramine rescues egl-2 excitation defects in Caenorhabditis elegans. Weinshenker D, Wei A, Salkoff L, Thomas JH. J Neurosci. 1999 Nov 15;19(22):9831-40. photo from: http://www.sciencedaily.com/releases/2006/11/061121082449.htm Subsequent hypotheses about MDD altered glutamatergic transmission ↓’d GABAergic transmission monoamine-Ach imbalance disruption of endogenous opioid signalling neurosteroid deficiencies thyroxine abnormalities cytokine-mediated x-talk betw immune system & CNS circadian abnormalities (specific brain structure/circuit dysfxns…) as summarized in Belmaker RH and Agam G, NEJM 2008, 358:55-68 MDD tx options selective serotonin reuptake inhibitors (SSRIs) fluoxetine (PROZAC), 20-80 mg/d citalopram (CELEXA), 20-40 mg/d escitalopram (LEXAPRO), 10-20 mg/d sertraline (ZOLOFT), 50-200 mg/d paroxetine (PAXIL), 20-50 mg/d serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine XR (EFFEXOR XR), 37.5-225 mg/d desvenlafaxine (PRISTIQ) duloxetine (CYMBALTA), 30-120 mg/d others bupropion SR, XL (WELLBUTRIN) 100-200 mg BID (SR) 150-450 mg/d (XL) mirtazapine (REMERON), 15-45 mg/d trazodone, 50-200mg/noc (for sleep) nefazodone tricyclic antidepressants (TCADs) amitriptyline  nortriptyline imipramine  desipramine monoamine oxidase inhibitors (MAO-Is) typically, non-selective & irreversible MAO-A (NE, EPI, 5HT, DA) MAO-B (trace amines, DA) why we “wash-out” 5HT syndrome HTNsive crisis selegiline (EMSAM) [additional] augmenting agents Li+ T3, 25 mcg/d buspirone (BuSPAR), 5-30 mg BID atypical antipsychotics Sequenced Treatment Alternatives for the Relief of Depression (STAR*D) major NIMH-funded study (PI: A. John Rush) w/ 14 regional centers & 41 clinical sites initial enrollment of 4,041 patients aim: which tx algorithms work best after an initial failure to remit non-psychotic depression w/ an antidepressant? http://www.clinicaltrials.gov/ct/show/NCT00021528?order=1 Trivedi MH et al, Am J Psychiatry. 2006 Jan;163(1):28-40 47% response rate on citalopram (by *QIDS-SR, 50% ↓ in sxs) Sequenced Treatment Alternatives for the Relief of Depression (STAR*D), n = 2,876 (qualifying pts) 33% remission rate on citalopram (by QIDS-SR, score <5) Rx choice: according to side effects (SE’s), comorbid condn’s / risks (GMC & Ψ), ?FmRxHx 6-8wk trials each (preferable) augmentation v. switch? *QIDS-SR = Quick Inventory of Depressive Symptomatology, Self-Report (range 0-27) http://www.ids-qids.org/ MDD tx options Ψtherapy cognitive bx therapy (CBT) interpersonal therapy (IPT) psychodynamic therapy interventional Ψ electroconvulsive therapy (ECT) transcranial magnetic stimulation (TMS) vagal nerve stimulation (VNS) deep brain stimulation (DBS) other lightbox therapy (mostly for MDD w/ seasonal features) Major Depressive D/O (MDD) NATURAL HISTORY (Frank E and Thase ME, 1999 & DSM-5) recovery usually begins: w/in 3mos for two in five indivs w/in 1y for four in five indivs risk of subsequent episodes (w/in 3y) increases w/ n: ≥50% if n=1 ≥70% if n=2 ≥90% if n=3 dz course does not typically change as one ages 5-10% will eventually be dx’d w/ bipolar disorder (BD) more likely w/: onset of ‘MDD’ in adolescence a family history of BD ‘mixed features’ 6% lifetime SUI risk (Davies S et al, 2001); up to 15% w/ severe MDD Persistent depressive disorder (dysthymia) 2y of depressed mood (1y in children/adolescents) most of the day, more days than not, plus 2 of the following: appetite disturbance (↓ or ↑) veg sleep disturbance (↓ or ↑) veg ↓energy E ↓esteem E poor [ ] C hopeless H never sx-free for more than 2mos at a time overlapping dx of MDD is now allowed there has never been mania, hypomania, or cyclothymia MDD specifiers can also be used for dysthymia additionally: early onset (before age 21) late onset (at age 21 or older) w/ pure dysthymic syndrome from DSM-5 w/ persistent MDE w/ intermittent MDE’s, w/ current episode w/ intermittent MDE’s, w/o current episode --these last 3 are essentially a co-dx of MDD, but captured within the specifier… Persistent depressive disorder (dysthymia) may be more treatment-resistant (TxR) than straightforward MDD EPIDEMIOLOGY lifetime prevalence = 6% 12-mo prevalence = 0.5%, compared w/ 1.5% for MDD high comorbidity w/ personality d/o’s (particularly clusters B, C) From Sadock & Sadock & DSM-5 Case 1. 36yo F presenting w/ 3mos of ↓mood. She reports getting only ~4h of sleep/noc b/c of regular early AM awakenings. She feels drained everyday, all day long. She’s gained about 10 lbs in the last 2mos. What else would you like to ask? How would you work-up this patient? In the meantime, what would you dx and what would be your tentative tx plan? She returns 1mo later and reports that her mood continues to spiral downward. Now, she adds that she’s starting to think more morbid thoughts and that maybe it wouldn’t be such a bad thing if she weren’t around anymore. What would you ask now? How would you revise your tx plan? The pt’s sxs are finally stabilized and she returns at a later date w/ her sxs in remission x 1mo. “Doctor, I’m feeling so much better now. Do you think I can stop my psych Rxs?” How would you answer? Premenstrual dysphoric d/o Criterion A. In most menstrual cycles, ≥5 sxs in the final week before onset of menses, w/ improvement w/in a few days after onset of menses, and near-absent in the week post-menses Criterion B. ≥1 (or more) sx of marked: 1. lability (e.g., mood swings, suddenly sad, increased rejection sensitivity) 2. irritability /anger / increase in interpersonal conflicts 3. anxiety / tension / keyed-up feeling/edginess Criterion C. ≥1 (or more) sx to reach a total of 5 in combation w/ previous list: 1. anhedonia 2. [ ] impairment 3. anergia 4. significant appetite change (including specific food cravings) 5. sleep disturbance (↑ or ↓) 6. feeling overwhelmed or out of control 7. px sxs (e.g., breast tenderness/swelling, arthralgias/myalgias, bloating, wt gain) Special notes. Can’t just be menstrual exacerbation of MDD or other Axis I or II dx; must have confirmation by prospective daily rating scales during at least 2 sx-ic cycles (provisional dx allowed beforehand) Premenstrual dysphoric d/o (M)ood (labile &/or irritable &/or anxious) Sleep Interest Body Energy Concentration Appetite Out of control Treatment: SSRI daily luteal phase only (i.e., day 14 of cycle  menses) some data suggest successful in tx’ing mixed episodes, BD indivs w/ comorbid substance issues Areas of concern: Li+ ↔ renal; interaction w/ NSAIDs VPA ↔ liver; VPA in young ♀  polycystic ovarian syndrome (PCOS) Teratogenicity Li+  Ebstein’s anomaly (1st trimester) hazard ratio 10-20, but AR still 1:1000 VPA  neural tube defects AR 10% OTHER NOTES: CBZ: auto-induction, agranulocytosis Lamictal: Stevens-Johnson syndrome (SJS), interaxn w/ oral contraceptives (OCPs), interaxn w/ VPA Bipolar Disorder (BD) – treatment (cont’d) How many agents to use? combination tx often helpful in acute stabilization antipsychotics REQ’D when there are psychotic features to mood episode Adjuncts benzos --Don’t forget about ECT… Manic switch w/… reuptake blockers Lamictal, too! (van der Loos ML et al, 2009) Bipolar Disorder (BD) – natural history 60% of manic episodes immediately precede an MDE MDE’s usually significantly outnumber hypomanic and manic episodes ~10% of BD II’s  BD I episodes tend to increase in frequency/duration w/ age re: suicide… 35% lifetime prevalence of at least one SUI attempt in bipolar 15% suicide completion rate (may be an overestimate) 15x the risk of the general population (for completions) perhaps ¼ of all suicides in the population >lethality of SUI attempts in BD II (than BD I) adapated, in part,from DSM-5 Cyclothymic D/O 2y of fluctuating mood (1y in children, adolescents) hypomanic symptoms (but NOT episodes) dysthymic symptoms (but no MDEs) ≥ half the time & (no more than 2mos sx-free) EXCLUSIONS no manic/hypomanic episodes no depressive episodes Differential diagnosis
Slide 50 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No. Belmaker RH and Agam G, NEJM 2008, 358:55-68 iproniazid (1957) imipramine (1959) The monoamine hypothesis (1965) Joseph Schildkraut Question: Do antidepressants have additional actions besides inhibition of reuptake transporters? “…the Zoloft cartoon” from: http://gifsoup.com/webroot/animatedgifs/50426_o.gif; chemical inbalance Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. J Neurosci. 2000 Dec 15;20(24):9104-10 Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Science. 2003 Aug 8;301(5634):805-9. Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Haenisch B, Bönisch H. Pharmacol Ther. 2011 Mar;129(3):352-68. Epub 2010 Dec 13. Review. Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices. Hennings EC, Kiss JP, De Oliveira K, Toth PT, Vizi ES. J Neurochem. 1999 Sep;73(3):1043-50. Block of an ether-a-go-go-like K(+) channel by imipramine rescues egl-2 excitation defects in Caenorhabditis elegans. Weinshenker D, Wei A, Salkoff L, Thomas JH. J Neurosci. 1999 Nov 15;19(22):9831-40. photo from: http://www.sciencedaily.com/releases/2006/11/061121082449.htm Subsequent hypotheses about MDD altered glutamatergic transmission ↓’d GABAergic transmission monoamine-Ach imbalance disruption of endogenous opioid signalling neurosteroid deficiencies thyroxine abnormalities cytokine-mediated x-talk betw immune system & CNS circadian abnormalities (specific brain structure/circuit dysfxns…) as summarized in Belmaker RH and Agam G, NEJM 2008, 358:55-68 MDD tx options selective serotonin reuptake inhibitors (SSRIs) fluoxetine (PROZAC), 20-80 mg/d citalopram (CELEXA), 20-40 mg/d escitalopram (LEXAPRO), 10-20 mg/d sertraline (ZOLOFT), 50-200 mg/d paroxetine (PAXIL), 20-50 mg/d serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine XR (EFFEXOR XR), 37.5-225 mg/d desvenlafaxine (PRISTIQ) duloxetine (CYMBALTA), 30-120 mg/d others bupropion SR, XL (WELLBUTRIN) 100-200 mg BID (SR) 150-450 mg/d (XL) mirtazapine (REMERON), 15-45 mg/d trazodone, 50-200mg/noc (for sleep) nefazodone tricyclic antidepressants (TCADs) amitriptyline  nortriptyline imipramine  desipramine monoamine oxidase inhibitors (MAO-Is) typically, non-selective & irreversible MAO-A (NE, EPI, 5HT, DA) MAO-B (trace amines, DA) why we “wash-out” 5HT syndrome HTNsive crisis selegiline (EMSAM) [additional] augmenting agents Li+ T3, 25 mcg/d buspirone (BuSPAR), 5-30 mg BID atypical antipsychotics Sequenced Treatment Alternatives for the Relief of Depression (STAR*D) major NIMH-funded study (PI: A. John Rush) w/ 14 regional centers & 41 clinical sites initial enrollment of 4,041 patients aim: which tx algorithms work best after an initial failure to remit non-psychotic depression w/ an antidepressant? http://www.clinicaltrials.gov/ct/show/NCT00021528?order=1 Trivedi MH et al, Am J Psychiatry. 2006 Jan;163(1):28-40 47% response rate on citalopram (by *QIDS-SR, 50% ↓ in sxs) Sequenced Treatment Alternatives for the Relief of Depression (STAR*D), n = 2,876 (qualifying pts) 33% remission rate on citalopram (by QIDS-SR, score <5) Rx choice: according to side effects (SE’s), comorbid condn’s / risks (GMC & Ψ), ?FmRxHx 6-8wk trials each (preferable) augmentation v. switch? *QIDS-SR = Quick Inventory of Depressive Symptomatology, Self-Report (range 0-27) http://www.ids-qids.org/ MDD tx options Ψtherapy cognitive bx therapy (CBT) interpersonal therapy (IPT) psychodynamic therapy interventional Ψ electroconvulsive therapy (ECT) transcranial magnetic stimulation (TMS) vagal nerve stimulation (VNS) deep brain stimulation (DBS) other lightbox therapy (mostly for MDD w/ seasonal features) Major Depressive D/O (MDD) NATURAL HISTORY (Frank E and Thase ME, 1999 & DSM-5) recovery usually begins: w/in 3mos for two in five indivs w/in 1y for four in five indivs risk of subsequent episodes (w/in 3y) increases w/ n: ≥50% if n=1 ≥70% if n=2 ≥90% if n=3 dz course does not typically change as one ages 5-10% will eventually be dx’d w/ bipolar disorder (BD) more likely w/: onset of ‘MDD’ in adolescence a family history of BD ‘mixed features’ 6% lifetime SUI risk (Davies S et al, 2001); up to 15% w/ severe MDD Persistent depressive disorder (dysthymia) 2y of depressed mood (1y in children/adolescents) most of the day, more days than not, plus 2 of the following: appetite disturbance (↓ or ↑) veg sleep disturbance (↓ or ↑) veg ↓energy E ↓esteem E poor [ ] C hopeless H never sx-free for more than 2mos at a time overlapping dx of MDD is now allowed there has never been mania, hypomania, or cyclothymia MDD specifiers can also be used for dysthymia additionally: early onset (before age 21) late onset (at age 21 or older) w/ pure dysthymic syndrome from DSM-5 w/ persistent MDE w/ intermittent MDE’s, w/ current episode w/ intermittent MDE’s, w/o current episode --these last 3 are essentially a co-dx of MDD, but captured within the specifier… Persistent depressive disorder (dysthymia) may be more treatment-resistant (TxR) than straightforward MDD EPIDEMIOLOGY lifetime prevalence = 6% 12-mo prevalence = 0.5%, compared w/ 1.5% for MDD high comorbidity w/ personality d/o’s (particularly clusters B, C) From Sadock & Sadock & DSM-5 Case 1. 36yo F presenting w/ 3mos of ↓mood. She reports getting only ~4h of sleep/noc b/c of regular early AM awakenings. She feels drained everyday, all day long. She’s gained about 10 lbs in the last 2mos. What else would you like to ask? How would you work-up this patient? In the meantime, what would you dx and what would be your tentative tx plan? She returns 1mo later and reports that her mood continues to spiral downward. Now, she adds that she’s starting to think more morbid thoughts and that maybe it wouldn’t be such a bad thing if she weren’t around anymore. What would you ask now? How would you revise your tx plan? The pt’s sxs are finally stabilized and she returns at a later date w/ her sxs in remission x 1mo. “Doctor, I’m feeling so much better now. Do you think I can stop my psych Rxs?” How would you answer? Premenstrual dysphoric d/o Criterion A. In most menstrual cycles, ≥5 sxs in the final week before onset of menses, w/ improvement w/in a few days after onset of menses, and near-absent in the week post-menses Criterion B. ≥1 (or more) sx of marked: 1. lability (e.g., mood swings, suddenly sad, increased rejection sensitivity) 2. irritability /anger / increase in interpersonal conflicts 3. anxiety / tension / keyed-up feeling/edginess Criterion C. ≥1 (or more) sx to reach a total of 5 in combation w/ previous list: 1. anhedonia 2. [ ] impairment 3. anergia 4. significant appetite change (including specific food cravings) 5. sleep disturbance (↑ or ↓) 6. feeling overwhelmed or out of control 7. px sxs (e.g., breast tenderness/swelling, arthralgias/myalgias, bloating, wt gain) Special notes. Can’t just be menstrual exacerbation of MDD or other Axis I or II dx; must have confirmation by prospective daily rating scales during at least 2 sx-ic cycles (provisional dx allowed beforehand) Premenstrual dysphoric d/o (M)ood (labile &/or irritable &/or anxious) Sleep Interest Body Energy Concentration Appetite Out of control Treatment: SSRI daily luteal phase only (i.e., day 14 of cycle  menses) some data suggest successful in tx’ing mixed episodes, BD indivs w/ comorbid substance issues Areas of concern: Li+ ↔ renal; interaction w/ NSAIDs VPA ↔ liver; VPA in young ♀  polycystic ovarian syndrome (PCOS) Teratogenicity Li+  Ebstein’s anomaly (1st trimester) hazard ratio 10-20, but AR still 1:1000 VPA  neural tube defects AR 10% OTHER NOTES: CBZ: auto-induction, agranulocytosis Lamictal: Stevens-Johnson syndrome (SJS), interaxn w/ oral contraceptives (OCPs), interaxn w/ VPA Bipolar Disorder (BD) – treatment (cont’d) How many agents to use? combination tx often helpful in acute stabilization antipsychotics REQ’D when there are psychotic features to mood episode Adjuncts benzos --Don’t forget about ECT… Manic switch w/… reuptake blockers Lamictal, too! (van der Loos ML et al, 2009) Bipolar Disorder (BD) – natural history 60% of manic episodes immediately precede an MDE MDE’s usually significantly outnumber hypomanic and manic episodes ~10% of BD II’s  BD I episodes tend to increase in frequency/duration w/ age re: suicide… 35% lifetime prevalence of at least one SUI attempt in bipolar 15% suicide completion rate (may be an overestimate) 15x the risk of the general population (for completions) perhaps ¼ of all suicides in the population >lethality of SUI attempts in BD II (than BD I) adapated, in part,from DSM-5 Cyclothymic D/O 2y of fluctuating mood (1y in children, adolescents) hypomanic symptoms (but NOT episodes) dysthymic symptoms (but no MDEs) ≥ half the time & (no more than 2mos sx-free) EXCLUSIONS no manic/hypomanic episodes no depressive episodes Differential diagnosis Phenocopies and gray areas… Anxiety D/O’s (esp. GAD, PTSD) Schizoaffective D/O Delirium Dementia Personality D/O’s Substance/Medication-induced Depressive D/O Depressive D/O d/t Another Medical Condition Other Specified Depressive D/O Unspecified Depressive D/O Substance/Medication-induced Bipolar and Related D/O Bipolar and Related D/O d/t Another Medical Condition Other Specified Bipolar and Related D/O Unspecified Bipolar and Related D/O
Slide 51 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No. Belmaker RH and Agam G, NEJM 2008, 358:55-68 iproniazid (1957) imipramine (1959) The monoamine hypothesis (1965) Joseph Schildkraut Question: Do antidepressants have additional actions besides inhibition of reuptake transporters? “…the Zoloft cartoon” from: http://gifsoup.com/webroot/animatedgifs/50426_o.gif; chemical inbalance Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. J Neurosci. 2000 Dec 15;20(24):9104-10 Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Science. 2003 Aug 8;301(5634):805-9. Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Haenisch B, Bönisch H. Pharmacol Ther. 2011 Mar;129(3):352-68. Epub 2010 Dec 13. Review. Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices. Hennings EC, Kiss JP, De Oliveira K, Toth PT, Vizi ES. J Neurochem. 1999 Sep;73(3):1043-50. Block of an ether-a-go-go-like K(+) channel by imipramine rescues egl-2 excitation defects in Caenorhabditis elegans. Weinshenker D, Wei A, Salkoff L, Thomas JH. J Neurosci. 1999 Nov 15;19(22):9831-40. photo from: http://www.sciencedaily.com/releases/2006/11/061121082449.htm Subsequent hypotheses about MDD altered glutamatergic transmission ↓’d GABAergic transmission monoamine-Ach imbalance disruption of endogenous opioid signalling neurosteroid deficiencies thyroxine abnormalities cytokine-mediated x-talk betw immune system & CNS circadian abnormalities (specific brain structure/circuit dysfxns…) as summarized in Belmaker RH and Agam G, NEJM 2008, 358:55-68 MDD tx options selective serotonin reuptake inhibitors (SSRIs) fluoxetine (PROZAC), 20-80 mg/d citalopram (CELEXA), 20-40 mg/d escitalopram (LEXAPRO), 10-20 mg/d sertraline (ZOLOFT), 50-200 mg/d paroxetine (PAXIL), 20-50 mg/d serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine XR (EFFEXOR XR), 37.5-225 mg/d desvenlafaxine (PRISTIQ) duloxetine (CYMBALTA), 30-120 mg/d others bupropion SR, XL (WELLBUTRIN) 100-200 mg BID (SR) 150-450 mg/d (XL) mirtazapine (REMERON), 15-45 mg/d trazodone, 50-200mg/noc (for sleep) nefazodone tricyclic antidepressants (TCADs) amitriptyline  nortriptyline imipramine  desipramine monoamine oxidase inhibitors (MAO-Is) typically, non-selective & irreversible MAO-A (NE, EPI, 5HT, DA) MAO-B (trace amines, DA) why we “wash-out” 5HT syndrome HTNsive crisis selegiline (EMSAM) [additional] augmenting agents Li+ T3, 25 mcg/d buspirone (BuSPAR), 5-30 mg BID atypical antipsychotics Sequenced Treatment Alternatives for the Relief of Depression (STAR*D) major NIMH-funded study (PI: A. John Rush) w/ 14 regional centers & 41 clinical sites initial enrollment of 4,041 patients aim: which tx algorithms work best after an initial failure to remit non-psychotic depression w/ an antidepressant? http://www.clinicaltrials.gov/ct/show/NCT00021528?order=1 Trivedi MH et al, Am J Psychiatry. 2006 Jan;163(1):28-40 47% response rate on citalopram (by *QIDS-SR, 50% ↓ in sxs) Sequenced Treatment Alternatives for the Relief of Depression (STAR*D), n = 2,876 (qualifying pts) 33% remission rate on citalopram (by QIDS-SR, score <5) Rx choice: according to side effects (SE’s), comorbid condn’s / risks (GMC & Ψ), ?FmRxHx 6-8wk trials each (preferable) augmentation v. switch? *QIDS-SR = Quick Inventory of Depressive Symptomatology, Self-Report (range 0-27) http://www.ids-qids.org/ MDD tx options Ψtherapy cognitive bx therapy (CBT) interpersonal therapy (IPT) psychodynamic therapy interventional Ψ electroconvulsive therapy (ECT) transcranial magnetic stimulation (TMS) vagal nerve stimulation (VNS) deep brain stimulation (DBS) other lightbox therapy (mostly for MDD w/ seasonal features) Major Depressive D/O (MDD) NATURAL HISTORY (Frank E and Thase ME, 1999 & DSM-5) recovery usually begins: w/in 3mos for two in five indivs w/in 1y for four in five indivs risk of subsequent episodes (w/in 3y) increases w/ n: ≥50% if n=1 ≥70% if n=2 ≥90% if n=3 dz course does not typically change as one ages 5-10% will eventually be dx’d w/ bipolar disorder (BD) more likely w/: onset of ‘MDD’ in adolescence a family history of BD ‘mixed features’ 6% lifetime SUI risk (Davies S et al, 2001); up to 15% w/ severe MDD Persistent depressive disorder (dysthymia) 2y of depressed mood (1y in children/adolescents) most of the day, more days than not, plus 2 of the following: appetite disturbance (↓ or ↑) veg sleep disturbance (↓ or ↑) veg ↓energy E ↓esteem E poor [ ] C hopeless H never sx-free for more than 2mos at a time overlapping dx of MDD is now allowed there has never been mania, hypomania, or cyclothymia MDD specifiers can also be used for dysthymia additionally: early onset (before age 21) late onset (at age 21 or older) w/ pure dysthymic syndrome from DSM-5 w/ persistent MDE w/ intermittent MDE’s, w/ current episode w/ intermittent MDE’s, w/o current episode --these last 3 are essentially a co-dx of MDD, but captured within the specifier… Persistent depressive disorder (dysthymia) may be more treatment-resistant (TxR) than straightforward MDD EPIDEMIOLOGY lifetime prevalence = 6% 12-mo prevalence = 0.5%, compared w/ 1.5% for MDD high comorbidity w/ personality d/o’s (particularly clusters B, C) From Sadock & Sadock & DSM-5 Case 1. 36yo F presenting w/ 3mos of ↓mood. She reports getting only ~4h of sleep/noc b/c of regular early AM awakenings. She feels drained everyday, all day long. She’s gained about 10 lbs in the last 2mos. What else would you like to ask? How would you work-up this patient? In the meantime, what would you dx and what would be your tentative tx plan? She returns 1mo later and reports that her mood continues to spiral downward. Now, she adds that she’s starting to think more morbid thoughts and that maybe it wouldn’t be such a bad thing if she weren’t around anymore. What would you ask now? How would you revise your tx plan? The pt’s sxs are finally stabilized and she returns at a later date w/ her sxs in remission x 1mo. “Doctor, I’m feeling so much better now. Do you think I can stop my psych Rxs?” How would you answer? Premenstrual dysphoric d/o Criterion A. In most menstrual cycles, ≥5 sxs in the final week before onset of menses, w/ improvement w/in a few days after onset of menses, and near-absent in the week post-menses Criterion B. ≥1 (or more) sx of marked: 1. lability (e.g., mood swings, suddenly sad, increased rejection sensitivity) 2. irritability /anger / increase in interpersonal conflicts 3. anxiety / tension / keyed-up feeling/edginess Criterion C. ≥1 (or more) sx to reach a total of 5 in combation w/ previous list: 1. anhedonia 2. [ ] impairment 3. anergia 4. significant appetite change (including specific food cravings) 5. sleep disturbance (↑ or ↓) 6. feeling overwhelmed or out of control 7. px sxs (e.g., breast tenderness/swelling, arthralgias/myalgias, bloating, wt gain) Special notes. Can’t just be menstrual exacerbation of MDD or other Axis I or II dx; must have confirmation by prospective daily rating scales during at least 2 sx-ic cycles (provisional dx allowed beforehand) Premenstrual dysphoric d/o (M)ood (labile &/or irritable &/or anxious) Sleep Interest Body Energy Concentration Appetite Out of control Treatment: SSRI daily luteal phase only (i.e., day 14 of cycle  menses) some data suggest successful in tx’ing mixed episodes, BD indivs w/ comorbid substance issues Areas of concern: Li+ ↔ renal; interaction w/ NSAIDs VPA ↔ liver; VPA in young ♀  polycystic ovarian syndrome (PCOS) Teratogenicity Li+  Ebstein’s anomaly (1st trimester) hazard ratio 10-20, but AR still 1:1000 VPA  neural tube defects AR 10% OTHER NOTES: CBZ: auto-induction, agranulocytosis Lamictal: Stevens-Johnson syndrome (SJS), interaxn w/ oral contraceptives (OCPs), interaxn w/ VPA Bipolar Disorder (BD) – treatment (cont’d) How many agents to use? combination tx often helpful in acute stabilization antipsychotics REQ’D when there are psychotic features to mood episode Adjuncts benzos --Don’t forget about ECT… Manic switch w/… reuptake blockers Lamictal, too! (van der Loos ML et al, 2009) Bipolar Disorder (BD) – natural history 60% of manic episodes immediately precede an MDE MDE’s usually significantly outnumber hypomanic and manic episodes ~10% of BD II’s  BD I episodes tend to increase in frequency/duration w/ age re: suicide… 35% lifetime prevalence of at least one SUI attempt in bipolar 15% suicide completion rate (may be an overestimate) 15x the risk of the general population (for completions) perhaps ¼ of all suicides in the population >lethality of SUI attempts in BD II (than BD I) adapated, in part,from DSM-5 Cyclothymic D/O 2y of fluctuating mood (1y in children, adolescents) hypomanic symptoms (but NOT episodes) dysthymic symptoms (but no MDEs) ≥ half the time & (no more than 2mos sx-free) EXCLUSIONS no manic/hypomanic episodes no depressive episodes Differential diagnosis Phenocopies and gray areas… Anxiety D/O’s (esp. GAD, PTSD) Schizoaffective D/O Delirium Dementia Personality D/O’s Substance/Medication-induced Depressive D/O Depressive D/O d/t Another Medical Condition Other Specified Depressive D/O Unspecified Depressive D/O Substance/Medication-induced Bipolar and Related D/O Bipolar and Related D/O d/t Another Medical Condition Other Specified Bipolar and Related D/O Unspecified Bipolar and Related D/O Depressive, Bipolar & Related D/O d/t a Another Medical Condition Endocrine (e.g., thyroid, hypothalamic-pituitary-adrenal/HPA) Neurologic (e.g., multiple sclerosis, CVA, brain tumor, Parkinson’s, Alzheimer’s/other dementia, Huntington’s, seizure d/o) Neoplastic (e.g., pancreas) TBI Autoimmune (e.g., neuropsychiatric systemic lupus erythematosus / NPSLE) Hematologic (e.g., acute intermittent porphyria / AIP) typically: anx/depr >> s/t Ψosis, mania (rare) acute abdominal pain, muscle weakness port wine-colored urine (porphobilinogen) transient damage to nerve cells Nutritional (e.g., B12) Infectious (e.g., HIV, Syphilis)
Slide 52 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No. Belmaker RH and Agam G, NEJM 2008, 358:55-68 iproniazid (1957) imipramine (1959) The monoamine hypothesis (1965) Joseph Schildkraut Question: Do antidepressants have additional actions besides inhibition of reuptake transporters? “…the Zoloft cartoon” from: http://gifsoup.com/webroot/animatedgifs/50426_o.gif; chemical inbalance Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. J Neurosci. 2000 Dec 15;20(24):9104-10 Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Science. 2003 Aug 8;301(5634):805-9. Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Haenisch B, Bönisch H. Pharmacol Ther. 2011 Mar;129(3):352-68. Epub 2010 Dec 13. Review. Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices. Hennings EC, Kiss JP, De Oliveira K, Toth PT, Vizi ES. J Neurochem. 1999 Sep;73(3):1043-50. Block of an ether-a-go-go-like K(+) channel by imipramine rescues egl-2 excitation defects in Caenorhabditis elegans. Weinshenker D, Wei A, Salkoff L, Thomas JH. J Neurosci. 1999 Nov 15;19(22):9831-40. photo from: http://www.sciencedaily.com/releases/2006/11/061121082449.htm Subsequent hypotheses about MDD altered glutamatergic transmission ↓’d GABAergic transmission monoamine-Ach imbalance disruption of endogenous opioid signalling neurosteroid deficiencies thyroxine abnormalities cytokine-mediated x-talk betw immune system & CNS circadian abnormalities (specific brain structure/circuit dysfxns…) as summarized in Belmaker RH and Agam G, NEJM 2008, 358:55-68 MDD tx options selective serotonin reuptake inhibitors (SSRIs) fluoxetine (PROZAC), 20-80 mg/d citalopram (CELEXA), 20-40 mg/d escitalopram (LEXAPRO), 10-20 mg/d sertraline (ZOLOFT), 50-200 mg/d paroxetine (PAXIL), 20-50 mg/d serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine XR (EFFEXOR XR), 37.5-225 mg/d desvenlafaxine (PRISTIQ) duloxetine (CYMBALTA), 30-120 mg/d others bupropion SR, XL (WELLBUTRIN) 100-200 mg BID (SR) 150-450 mg/d (XL) mirtazapine (REMERON), 15-45 mg/d trazodone, 50-200mg/noc (for sleep) nefazodone tricyclic antidepressants (TCADs) amitriptyline  nortriptyline imipramine  desipramine monoamine oxidase inhibitors (MAO-Is) typically, non-selective & irreversible MAO-A (NE, EPI, 5HT, DA) MAO-B (trace amines, DA) why we “wash-out” 5HT syndrome HTNsive crisis selegiline (EMSAM) [additional] augmenting agents Li+ T3, 25 mcg/d buspirone (BuSPAR), 5-30 mg BID atypical antipsychotics Sequenced Treatment Alternatives for the Relief of Depression (STAR*D) major NIMH-funded study (PI: A. John Rush) w/ 14 regional centers & 41 clinical sites initial enrollment of 4,041 patients aim: which tx algorithms work best after an initial failure to remit non-psychotic depression w/ an antidepressant? http://www.clinicaltrials.gov/ct/show/NCT00021528?order=1 Trivedi MH et al, Am J Psychiatry. 2006 Jan;163(1):28-40 47% response rate on citalopram (by *QIDS-SR, 50% ↓ in sxs) Sequenced Treatment Alternatives for the Relief of Depression (STAR*D), n = 2,876 (qualifying pts) 33% remission rate on citalopram (by QIDS-SR, score <5) Rx choice: according to side effects (SE’s), comorbid condn’s / risks (GMC & Ψ), ?FmRxHx 6-8wk trials each (preferable) augmentation v. switch? *QIDS-SR = Quick Inventory of Depressive Symptomatology, Self-Report (range 0-27) http://www.ids-qids.org/ MDD tx options Ψtherapy cognitive bx therapy (CBT) interpersonal therapy (IPT) psychodynamic therapy interventional Ψ electroconvulsive therapy (ECT) transcranial magnetic stimulation (TMS) vagal nerve stimulation (VNS) deep brain stimulation (DBS) other lightbox therapy (mostly for MDD w/ seasonal features) Major Depressive D/O (MDD) NATURAL HISTORY (Frank E and Thase ME, 1999 & DSM-5) recovery usually begins: w/in 3mos for two in five indivs w/in 1y for four in five indivs risk of subsequent episodes (w/in 3y) increases w/ n: ≥50% if n=1 ≥70% if n=2 ≥90% if n=3 dz course does not typically change as one ages 5-10% will eventually be dx’d w/ bipolar disorder (BD) more likely w/: onset of ‘MDD’ in adolescence a family history of BD ‘mixed features’ 6% lifetime SUI risk (Davies S et al, 2001); up to 15% w/ severe MDD Persistent depressive disorder (dysthymia) 2y of depressed mood (1y in children/adolescents) most of the day, more days than not, plus 2 of the following: appetite disturbance (↓ or ↑) veg sleep disturbance (↓ or ↑) veg ↓energy E ↓esteem E poor [ ] C hopeless H never sx-free for more than 2mos at a time overlapping dx of MDD is now allowed there has never been mania, hypomania, or cyclothymia MDD specifiers can also be used for dysthymia additionally: early onset (before age 21) late onset (at age 21 or older) w/ pure dysthymic syndrome from DSM-5 w/ persistent MDE w/ intermittent MDE’s, w/ current episode w/ intermittent MDE’s, w/o current episode --these last 3 are essentially a co-dx of MDD, but captured within the specifier… Persistent depressive disorder (dysthymia) may be more treatment-resistant (TxR) than straightforward MDD EPIDEMIOLOGY lifetime prevalence = 6% 12-mo prevalence = 0.5%, compared w/ 1.5% for MDD high comorbidity w/ personality d/o’s (particularly clusters B, C) From Sadock & Sadock & DSM-5 Case 1. 36yo F presenting w/ 3mos of ↓mood. She reports getting only ~4h of sleep/noc b/c of regular early AM awakenings. She feels drained everyday, all day long. She’s gained about 10 lbs in the last 2mos. What else would you like to ask? How would you work-up this patient? In the meantime, what would you dx and what would be your tentative tx plan? She returns 1mo later and reports that her mood continues to spiral downward. Now, she adds that she’s starting to think more morbid thoughts and that maybe it wouldn’t be such a bad thing if she weren’t around anymore. What would you ask now? How would you revise your tx plan? The pt’s sxs are finally stabilized and she returns at a later date w/ her sxs in remission x 1mo. “Doctor, I’m feeling so much better now. Do you think I can stop my psych Rxs?” How would you answer? Premenstrual dysphoric d/o Criterion A. In most menstrual cycles, ≥5 sxs in the final week before onset of menses, w/ improvement w/in a few days after onset of menses, and near-absent in the week post-menses Criterion B. ≥1 (or more) sx of marked: 1. lability (e.g., mood swings, suddenly sad, increased rejection sensitivity) 2. irritability /anger / increase in interpersonal conflicts 3. anxiety / tension / keyed-up feeling/edginess Criterion C. ≥1 (or more) sx to reach a total of 5 in combation w/ previous list: 1. anhedonia 2. [ ] impairment 3. anergia 4. significant appetite change (including specific food cravings) 5. sleep disturbance (↑ or ↓) 6. feeling overwhelmed or out of control 7. px sxs (e.g., breast tenderness/swelling, arthralgias/myalgias, bloating, wt gain) Special notes. Can’t just be menstrual exacerbation of MDD or other Axis I or II dx; must have confirmation by prospective daily rating scales during at least 2 sx-ic cycles (provisional dx allowed beforehand) Premenstrual dysphoric d/o (M)ood (labile &/or irritable &/or anxious) Sleep Interest Body Energy Concentration Appetite Out of control Treatment: SSRI daily luteal phase only (i.e., day 14 of cycle  menses) some data suggest successful in tx’ing mixed episodes, BD indivs w/ comorbid substance issues Areas of concern: Li+ ↔ renal; interaction w/ NSAIDs VPA ↔ liver; VPA in young ♀  polycystic ovarian syndrome (PCOS) Teratogenicity Li+  Ebstein’s anomaly (1st trimester) hazard ratio 10-20, but AR still 1:1000 VPA  neural tube defects AR 10% OTHER NOTES: CBZ: auto-induction, agranulocytosis Lamictal: Stevens-Johnson syndrome (SJS), interaxn w/ oral contraceptives (OCPs), interaxn w/ VPA Bipolar Disorder (BD) – treatment (cont’d) How many agents to use? combination tx often helpful in acute stabilization antipsychotics REQ’D when there are psychotic features to mood episode Adjuncts benzos --Don’t forget about ECT… Manic switch w/… reuptake blockers Lamictal, too! (van der Loos ML et al, 2009) Bipolar Disorder (BD) – natural history 60% of manic episodes immediately precede an MDE MDE’s usually significantly outnumber hypomanic and manic episodes ~10% of BD II’s  BD I episodes tend to increase in frequency/duration w/ age re: suicide… 35% lifetime prevalence of at least one SUI attempt in bipolar 15% suicide completion rate (may be an overestimate) 15x the risk of the general population (for completions) perhaps ¼ of all suicides in the population >lethality of SUI attempts in BD II (than BD I) adapated, in part,from DSM-5 Cyclothymic D/O 2y of fluctuating mood (1y in children, adolescents) hypomanic symptoms (but NOT episodes) dysthymic symptoms (but no MDEs) ≥ half the time & (no more than 2mos sx-free) EXCLUSIONS no manic/hypomanic episodes no depressive episodes Differential diagnosis Phenocopies and gray areas… Anxiety D/O’s (esp. GAD, PTSD) Schizoaffective D/O Delirium Dementia Personality D/O’s Substance/Medication-induced Depressive D/O Depressive D/O d/t Another Medical Condition Other Specified Depressive D/O Unspecified Depressive D/O Substance/Medication-induced Bipolar and Related D/O Bipolar and Related D/O d/t Another Medical Condition Other Specified Bipolar and Related D/O Unspecified Bipolar and Related D/O Depressive, Bipolar & Related D/O d/t a Another Medical Condition Endocrine (e.g., thyroid, hypothalamic-pituitary-adrenal/HPA) Neurologic (e.g., multiple sclerosis, CVA, brain tumor, Parkinson’s, Alzheimer’s/other dementia, Huntington’s, seizure d/o) Neoplastic (e.g., pancreas) TBI Autoimmune (e.g., neuropsychiatric systemic lupus erythematosus / NPSLE) Hematologic (e.g., acute intermittent porphyria / AIP) typically: anx/depr >> s/t Ψosis, mania (rare) acute abdominal pain, muscle weakness port wine-colored urine (porphobilinogen) transient damage to nerve cells Nutritional (e.g., B12) Infectious (e.g., HIV, Syphilis) Substance/Medication-induced Depressive, Bipolar & Related D/O ILLICITS can be from intoxication or withdrawal phases EtOH – typically depressive stimulants – typically manic/hypomanic --good to ask about sxs during windows of sobriety (ideally, ≥6mos) high substance comorbidity rates w/ endogenous Axis I Ψ d/o’s, though (esp. BD I) Prescription Rxs steroids IFN-α2b, RBV (HCV tx) β-blockers antidepressants α-TB drugs
Slide 53 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No. Belmaker RH and Agam G, NEJM 2008, 358:55-68 iproniazid (1957) imipramine (1959) The monoamine hypothesis (1965) Joseph Schildkraut Question: Do antidepressants have additional actions besides inhibition of reuptake transporters? “…the Zoloft cartoon” from: http://gifsoup.com/webroot/animatedgifs/50426_o.gif; chemical inbalance Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. J Neurosci. 2000 Dec 15;20(24):9104-10 Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Science. 2003 Aug 8;301(5634):805-9. Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Haenisch B, Bönisch H. Pharmacol Ther. 2011 Mar;129(3):352-68. Epub 2010 Dec 13. Review. Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices. Hennings EC, Kiss JP, De Oliveira K, Toth PT, Vizi ES. J Neurochem. 1999 Sep;73(3):1043-50. Block of an ether-a-go-go-like K(+) channel by imipramine rescues egl-2 excitation defects in Caenorhabditis elegans. Weinshenker D, Wei A, Salkoff L, Thomas JH. J Neurosci. 1999 Nov 15;19(22):9831-40. photo from: http://www.sciencedaily.com/releases/2006/11/061121082449.htm Subsequent hypotheses about MDD altered glutamatergic transmission ↓’d GABAergic transmission monoamine-Ach imbalance disruption of endogenous opioid signalling neurosteroid deficiencies thyroxine abnormalities cytokine-mediated x-talk betw immune system & CNS circadian abnormalities (specific brain structure/circuit dysfxns…) as summarized in Belmaker RH and Agam G, NEJM 2008, 358:55-68 MDD tx options selective serotonin reuptake inhibitors (SSRIs) fluoxetine (PROZAC), 20-80 mg/d citalopram (CELEXA), 20-40 mg/d escitalopram (LEXAPRO), 10-20 mg/d sertraline (ZOLOFT), 50-200 mg/d paroxetine (PAXIL), 20-50 mg/d serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine XR (EFFEXOR XR), 37.5-225 mg/d desvenlafaxine (PRISTIQ) duloxetine (CYMBALTA), 30-120 mg/d others bupropion SR, XL (WELLBUTRIN) 100-200 mg BID (SR) 150-450 mg/d (XL) mirtazapine (REMERON), 15-45 mg/d trazodone, 50-200mg/noc (for sleep) nefazodone tricyclic antidepressants (TCADs) amitriptyline  nortriptyline imipramine  desipramine monoamine oxidase inhibitors (MAO-Is) typically, non-selective & irreversible MAO-A (NE, EPI, 5HT, DA) MAO-B (trace amines, DA) why we “wash-out” 5HT syndrome HTNsive crisis selegiline (EMSAM) [additional] augmenting agents Li+ T3, 25 mcg/d buspirone (BuSPAR), 5-30 mg BID atypical antipsychotics Sequenced Treatment Alternatives for the Relief of Depression (STAR*D) major NIMH-funded study (PI: A. John Rush) w/ 14 regional centers & 41 clinical sites initial enrollment of 4,041 patients aim: which tx algorithms work best after an initial failure to remit non-psychotic depression w/ an antidepressant? http://www.clinicaltrials.gov/ct/show/NCT00021528?order=1 Trivedi MH et al, Am J Psychiatry. 2006 Jan;163(1):28-40 47% response rate on citalopram (by *QIDS-SR, 50% ↓ in sxs) Sequenced Treatment Alternatives for the Relief of Depression (STAR*D), n = 2,876 (qualifying pts) 33% remission rate on citalopram (by QIDS-SR, score <5) Rx choice: according to side effects (SE’s), comorbid condn’s / risks (GMC & Ψ), ?FmRxHx 6-8wk trials each (preferable) augmentation v. switch? *QIDS-SR = Quick Inventory of Depressive Symptomatology, Self-Report (range 0-27) http://www.ids-qids.org/ MDD tx options Ψtherapy cognitive bx therapy (CBT) interpersonal therapy (IPT) psychodynamic therapy interventional Ψ electroconvulsive therapy (ECT) transcranial magnetic stimulation (TMS) vagal nerve stimulation (VNS) deep brain stimulation (DBS) other lightbox therapy (mostly for MDD w/ seasonal features) Major Depressive D/O (MDD) NATURAL HISTORY (Frank E and Thase ME, 1999 & DSM-5) recovery usually begins: w/in 3mos for two in five indivs w/in 1y for four in five indivs risk of subsequent episodes (w/in 3y) increases w/ n: ≥50% if n=1 ≥70% if n=2 ≥90% if n=3 dz course does not typically change as one ages 5-10% will eventually be dx’d w/ bipolar disorder (BD) more likely w/: onset of ‘MDD’ in adolescence a family history of BD ‘mixed features’ 6% lifetime SUI risk (Davies S et al, 2001); up to 15% w/ severe MDD Persistent depressive disorder (dysthymia) 2y of depressed mood (1y in children/adolescents) most of the day, more days than not, plus 2 of the following: appetite disturbance (↓ or ↑) veg sleep disturbance (↓ or ↑) veg ↓energy E ↓esteem E poor [ ] C hopeless H never sx-free for more than 2mos at a time overlapping dx of MDD is now allowed there has never been mania, hypomania, or cyclothymia MDD specifiers can also be used for dysthymia additionally: early onset (before age 21) late onset (at age 21 or older) w/ pure dysthymic syndrome from DSM-5 w/ persistent MDE w/ intermittent MDE’s, w/ current episode w/ intermittent MDE’s, w/o current episode --these last 3 are essentially a co-dx of MDD, but captured within the specifier… Persistent depressive disorder (dysthymia) may be more treatment-resistant (TxR) than straightforward MDD EPIDEMIOLOGY lifetime prevalence = 6% 12-mo prevalence = 0.5%, compared w/ 1.5% for MDD high comorbidity w/ personality d/o’s (particularly clusters B, C) From Sadock & Sadock & DSM-5 Case 1. 36yo F presenting w/ 3mos of ↓mood. She reports getting only ~4h of sleep/noc b/c of regular early AM awakenings. She feels drained everyday, all day long. She’s gained about 10 lbs in the last 2mos. What else would you like to ask? How would you work-up this patient? In the meantime, what would you dx and what would be your tentative tx plan? She returns 1mo later and reports that her mood continues to spiral downward. Now, she adds that she’s starting to think more morbid thoughts and that maybe it wouldn’t be such a bad thing if she weren’t around anymore. What would you ask now? How would you revise your tx plan? The pt’s sxs are finally stabilized and she returns at a later date w/ her sxs in remission x 1mo. “Doctor, I’m feeling so much better now. Do you think I can stop my psych Rxs?” How would you answer? Premenstrual dysphoric d/o Criterion A. In most menstrual cycles, ≥5 sxs in the final week before onset of menses, w/ improvement w/in a few days after onset of menses, and near-absent in the week post-menses Criterion B. ≥1 (or more) sx of marked: 1. lability (e.g., mood swings, suddenly sad, increased rejection sensitivity) 2. irritability /anger / increase in interpersonal conflicts 3. anxiety / tension / keyed-up feeling/edginess Criterion C. ≥1 (or more) sx to reach a total of 5 in combation w/ previous list: 1. anhedonia 2. [ ] impairment 3. anergia 4. significant appetite change (including specific food cravings) 5. sleep disturbance (↑ or ↓) 6. feeling overwhelmed or out of control 7. px sxs (e.g., breast tenderness/swelling, arthralgias/myalgias, bloating, wt gain) Special notes. Can’t just be menstrual exacerbation of MDD or other Axis I or II dx; must have confirmation by prospective daily rating scales during at least 2 sx-ic cycles (provisional dx allowed beforehand) Premenstrual dysphoric d/o (M)ood (labile &/or irritable &/or anxious) Sleep Interest Body Energy Concentration Appetite Out of control Treatment: SSRI daily luteal phase only (i.e., day 14 of cycle  menses) some data suggest successful in tx’ing mixed episodes, BD indivs w/ comorbid substance issues Areas of concern: Li+ ↔ renal; interaction w/ NSAIDs VPA ↔ liver; VPA in young ♀  polycystic ovarian syndrome (PCOS) Teratogenicity Li+  Ebstein’s anomaly (1st trimester) hazard ratio 10-20, but AR still 1:1000 VPA  neural tube defects AR 10% OTHER NOTES: CBZ: auto-induction, agranulocytosis Lamictal: Stevens-Johnson syndrome (SJS), interaxn w/ oral contraceptives (OCPs), interaxn w/ VPA Bipolar Disorder (BD) – treatment (cont’d) How many agents to use? combination tx often helpful in acute stabilization antipsychotics REQ’D when there are psychotic features to mood episode Adjuncts benzos --Don’t forget about ECT… Manic switch w/… reuptake blockers Lamictal, too! (van der Loos ML et al, 2009) Bipolar Disorder (BD) – natural history 60% of manic episodes immediately precede an MDE MDE’s usually significantly outnumber hypomanic and manic episodes ~10% of BD II’s  BD I episodes tend to increase in frequency/duration w/ age re: suicide… 35% lifetime prevalence of at least one SUI attempt in bipolar 15% suicide completion rate (may be an overestimate) 15x the risk of the general population (for completions) perhaps ¼ of all suicides in the population >lethality of SUI attempts in BD II (than BD I) adapated, in part,from DSM-5 Cyclothymic D/O 2y of fluctuating mood (1y in children, adolescents) hypomanic symptoms (but NOT episodes) dysthymic symptoms (but no MDEs) ≥ half the time & (no more than 2mos sx-free) EXCLUSIONS no manic/hypomanic episodes no depressive episodes Differential diagnosis Phenocopies and gray areas… Anxiety D/O’s (esp. GAD, PTSD) Schizoaffective D/O Delirium Dementia Personality D/O’s Substance/Medication-induced Depressive D/O Depressive D/O d/t Another Medical Condition Other Specified Depressive D/O Unspecified Depressive D/O Substance/Medication-induced Bipolar and Related D/O Bipolar and Related D/O d/t Another Medical Condition Other Specified Bipolar and Related D/O Unspecified Bipolar and Related D/O Depressive, Bipolar & Related D/O d/t a Another Medical Condition Endocrine (e.g., thyroid, hypothalamic-pituitary-adrenal/HPA) Neurologic (e.g., multiple sclerosis, CVA, brain tumor, Parkinson’s, Alzheimer’s/other dementia, Huntington’s, seizure d/o) Neoplastic (e.g., pancreas) TBI Autoimmune (e.g., neuropsychiatric systemic lupus erythematosus / NPSLE) Hematologic (e.g., acute intermittent porphyria / AIP) typically: anx/depr >> s/t Ψosis, mania (rare) acute abdominal pain, muscle weakness port wine-colored urine (porphobilinogen) transient damage to nerve cells Nutritional (e.g., B12) Infectious (e.g., HIV, Syphilis) Substance/Medication-induced Depressive, Bipolar & Related D/O ILLICITS can be from intoxication or withdrawal phases EtOH – typically depressive stimulants – typically manic/hypomanic --good to ask about sxs during windows of sobriety (ideally, ≥6mos) high substance comorbidity rates w/ endogenous Axis I Ψ d/o’s, though (esp. BD I) Prescription Rxs steroids IFN-α2b, RBV (HCV tx) β-blockers antidepressants α-TB drugs Other Specified / Unspecified v. Adjustment D/O (e.g., w/ depressed mood, w/ mixed anxiety & depressed mood) What is Adjustment D/O? develops in response to a stressor (w/in 3mos) terminates w/in 6mos of the end of the original precipitating stressor clinically significant b/c: there is marked distress out of proportion to the severity of the stressor or there is significant impairment Intended, in DSM-5, to be < of a residual dx and to be thought of as more in the same spectrum as Acute Stress D/O (ASD) and PTSD, but: not necessarily w/ as severe a stressor as in ASD or PTSD not necessarily w/ as severe a sx response as in ASD or PTSD
Slide 54 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No. Belmaker RH and Agam G, NEJM 2008, 358:55-68 iproniazid (1957) imipramine (1959) The monoamine hypothesis (1965) Joseph Schildkraut Question: Do antidepressants have additional actions besides inhibition of reuptake transporters? “…the Zoloft cartoon” from: http://gifsoup.com/webroot/animatedgifs/50426_o.gif; chemical inbalance Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. J Neurosci. 2000 Dec 15;20(24):9104-10 Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Science. 2003 Aug 8;301(5634):805-9. Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Haenisch B, Bönisch H. Pharmacol Ther. 2011 Mar;129(3):352-68. Epub 2010 Dec 13. Review. Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices. Hennings EC, Kiss JP, De Oliveira K, Toth PT, Vizi ES. J Neurochem. 1999 Sep;73(3):1043-50. Block of an ether-a-go-go-like K(+) channel by imipramine rescues egl-2 excitation defects in Caenorhabditis elegans. Weinshenker D, Wei A, Salkoff L, Thomas JH. J Neurosci. 1999 Nov 15;19(22):9831-40. photo from: http://www.sciencedaily.com/releases/2006/11/061121082449.htm Subsequent hypotheses about MDD altered glutamatergic transmission ↓’d GABAergic transmission monoamine-Ach imbalance disruption of endogenous opioid signalling neurosteroid deficiencies thyroxine abnormalities cytokine-mediated x-talk betw immune system & CNS circadian abnormalities (specific brain structure/circuit dysfxns…) as summarized in Belmaker RH and Agam G, NEJM 2008, 358:55-68 MDD tx options selective serotonin reuptake inhibitors (SSRIs) fluoxetine (PROZAC), 20-80 mg/d citalopram (CELEXA), 20-40 mg/d escitalopram (LEXAPRO), 10-20 mg/d sertraline (ZOLOFT), 50-200 mg/d paroxetine (PAXIL), 20-50 mg/d serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine XR (EFFEXOR XR), 37.5-225 mg/d desvenlafaxine (PRISTIQ) duloxetine (CYMBALTA), 30-120 mg/d others bupropion SR, XL (WELLBUTRIN) 100-200 mg BID (SR) 150-450 mg/d (XL) mirtazapine (REMERON), 15-45 mg/d trazodone, 50-200mg/noc (for sleep) nefazodone tricyclic antidepressants (TCADs) amitriptyline  nortriptyline imipramine  desipramine monoamine oxidase inhibitors (MAO-Is) typically, non-selective & irreversible MAO-A (NE, EPI, 5HT, DA) MAO-B (trace amines, DA) why we “wash-out” 5HT syndrome HTNsive crisis selegiline (EMSAM) [additional] augmenting agents Li+ T3, 25 mcg/d buspirone (BuSPAR), 5-30 mg BID atypical antipsychotics Sequenced Treatment Alternatives for the Relief of Depression (STAR*D) major NIMH-funded study (PI: A. John Rush) w/ 14 regional centers & 41 clinical sites initial enrollment of 4,041 patients aim: which tx algorithms work best after an initial failure to remit non-psychotic depression w/ an antidepressant? http://www.clinicaltrials.gov/ct/show/NCT00021528?order=1 Trivedi MH et al, Am J Psychiatry. 2006 Jan;163(1):28-40 47% response rate on citalopram (by *QIDS-SR, 50% ↓ in sxs) Sequenced Treatment Alternatives for the Relief of Depression (STAR*D), n = 2,876 (qualifying pts) 33% remission rate on citalopram (by QIDS-SR, score <5) Rx choice: according to side effects (SE’s), comorbid condn’s / risks (GMC & Ψ), ?FmRxHx 6-8wk trials each (preferable) augmentation v. switch? *QIDS-SR = Quick Inventory of Depressive Symptomatology, Self-Report (range 0-27) http://www.ids-qids.org/ MDD tx options Ψtherapy cognitive bx therapy (CBT) interpersonal therapy (IPT) psychodynamic therapy interventional Ψ electroconvulsive therapy (ECT) transcranial magnetic stimulation (TMS) vagal nerve stimulation (VNS) deep brain stimulation (DBS) other lightbox therapy (mostly for MDD w/ seasonal features) Major Depressive D/O (MDD) NATURAL HISTORY (Frank E and Thase ME, 1999 & DSM-5) recovery usually begins: w/in 3mos for two in five indivs w/in 1y for four in five indivs risk of subsequent episodes (w/in 3y) increases w/ n: ≥50% if n=1 ≥70% if n=2 ≥90% if n=3 dz course does not typically change as one ages 5-10% will eventually be dx’d w/ bipolar disorder (BD) more likely w/: onset of ‘MDD’ in adolescence a family history of BD ‘mixed features’ 6% lifetime SUI risk (Davies S et al, 2001); up to 15% w/ severe MDD Persistent depressive disorder (dysthymia) 2y of depressed mood (1y in children/adolescents) most of the day, more days than not, plus 2 of the following: appetite disturbance (↓ or ↑) veg sleep disturbance (↓ or ↑) veg ↓energy E ↓esteem E poor [ ] C hopeless H never sx-free for more than 2mos at a time overlapping dx of MDD is now allowed there has never been mania, hypomania, or cyclothymia MDD specifiers can also be used for dysthymia additionally: early onset (before age 21) late onset (at age 21 or older) w/ pure dysthymic syndrome from DSM-5 w/ persistent MDE w/ intermittent MDE’s, w/ current episode w/ intermittent MDE’s, w/o current episode --these last 3 are essentially a co-dx of MDD, but captured within the specifier… Persistent depressive disorder (dysthymia) may be more treatment-resistant (TxR) than straightforward MDD EPIDEMIOLOGY lifetime prevalence = 6% 12-mo prevalence = 0.5%, compared w/ 1.5% for MDD high comorbidity w/ personality d/o’s (particularly clusters B, C) From Sadock & Sadock & DSM-5 Case 1. 36yo F presenting w/ 3mos of ↓mood. She reports getting only ~4h of sleep/noc b/c of regular early AM awakenings. She feels drained everyday, all day long. She’s gained about 10 lbs in the last 2mos. What else would you like to ask? How would you work-up this patient? In the meantime, what would you dx and what would be your tentative tx plan? She returns 1mo later and reports that her mood continues to spiral downward. Now, she adds that she’s starting to think more morbid thoughts and that maybe it wouldn’t be such a bad thing if she weren’t around anymore. What would you ask now? How would you revise your tx plan? The pt’s sxs are finally stabilized and she returns at a later date w/ her sxs in remission x 1mo. “Doctor, I’m feeling so much better now. Do you think I can stop my psych Rxs?” How would you answer? Premenstrual dysphoric d/o Criterion A. In most menstrual cycles, ≥5 sxs in the final week before onset of menses, w/ improvement w/in a few days after onset of menses, and near-absent in the week post-menses Criterion B. ≥1 (or more) sx of marked: 1. lability (e.g., mood swings, suddenly sad, increased rejection sensitivity) 2. irritability /anger / increase in interpersonal conflicts 3. anxiety / tension / keyed-up feeling/edginess Criterion C. ≥1 (or more) sx to reach a total of 5 in combation w/ previous list: 1. anhedonia 2. [ ] impairment 3. anergia 4. significant appetite change (including specific food cravings) 5. sleep disturbance (↑ or ↓) 6. feeling overwhelmed or out of control 7. px sxs (e.g., breast tenderness/swelling, arthralgias/myalgias, bloating, wt gain) Special notes. Can’t just be menstrual exacerbation of MDD or other Axis I or II dx; must have confirmation by prospective daily rating scales during at least 2 sx-ic cycles (provisional dx allowed beforehand) Premenstrual dysphoric d/o (M)ood (labile &/or irritable &/or anxious) Sleep Interest Body Energy Concentration Appetite Out of control Treatment: SSRI daily luteal phase only (i.e., day 14 of cycle  menses) some data suggest successful in tx’ing mixed episodes, BD indivs w/ comorbid substance issues Areas of concern: Li+ ↔ renal; interaction w/ NSAIDs VPA ↔ liver; VPA in young ♀  polycystic ovarian syndrome (PCOS) Teratogenicity Li+  Ebstein’s anomaly (1st trimester) hazard ratio 10-20, but AR still 1:1000 VPA  neural tube defects AR 10% OTHER NOTES: CBZ: auto-induction, agranulocytosis Lamictal: Stevens-Johnson syndrome (SJS), interaxn w/ oral contraceptives (OCPs), interaxn w/ VPA Bipolar Disorder (BD) – treatment (cont’d) How many agents to use? combination tx often helpful in acute stabilization antipsychotics REQ’D when there are psychotic features to mood episode Adjuncts benzos --Don’t forget about ECT… Manic switch w/… reuptake blockers Lamictal, too! (van der Loos ML et al, 2009) Bipolar Disorder (BD) – natural history 60% of manic episodes immediately precede an MDE MDE’s usually significantly outnumber hypomanic and manic episodes ~10% of BD II’s  BD I episodes tend to increase in frequency/duration w/ age re: suicide… 35% lifetime prevalence of at least one SUI attempt in bipolar 15% suicide completion rate (may be an overestimate) 15x the risk of the general population (for completions) perhaps ¼ of all suicides in the population >lethality of SUI attempts in BD II (than BD I) adapated, in part,from DSM-5 Cyclothymic D/O 2y of fluctuating mood (1y in children, adolescents) hypomanic symptoms (but NOT episodes) dysthymic symptoms (but no MDEs) ≥ half the time & (no more than 2mos sx-free) EXCLUSIONS no manic/hypomanic episodes no depressive episodes Differential diagnosis Phenocopies and gray areas… Anxiety D/O’s (esp. GAD, PTSD) Schizoaffective D/O Delirium Dementia Personality D/O’s Substance/Medication-induced Depressive D/O Depressive D/O d/t Another Medical Condition Other Specified Depressive D/O Unspecified Depressive D/O Substance/Medication-induced Bipolar and Related D/O Bipolar and Related D/O d/t Another Medical Condition Other Specified Bipolar and Related D/O Unspecified Bipolar and Related D/O Depressive, Bipolar & Related D/O d/t a Another Medical Condition Endocrine (e.g., thyroid, hypothalamic-pituitary-adrenal/HPA) Neurologic (e.g., multiple sclerosis, CVA, brain tumor, Parkinson’s, Alzheimer’s/other dementia, Huntington’s, seizure d/o) Neoplastic (e.g., pancreas) TBI Autoimmune (e.g., neuropsychiatric systemic lupus erythematosus / NPSLE) Hematologic (e.g., acute intermittent porphyria / AIP) typically: anx/depr >> s/t Ψosis, mania (rare) acute abdominal pain, muscle weakness port wine-colored urine (porphobilinogen) transient damage to nerve cells Nutritional (e.g., B12) Infectious (e.g., HIV, Syphilis) Substance/Medication-induced Depressive, Bipolar & Related D/O ILLICITS can be from intoxication or withdrawal phases EtOH – typically depressive stimulants – typically manic/hypomanic --good to ask about sxs during windows of sobriety (ideally, ≥6mos) high substance comorbidity rates w/ endogenous Axis I Ψ d/o’s, though (esp. BD I) Prescription Rxs steroids IFN-α2b, RBV (HCV tx) β-blockers antidepressants α-TB drugs Other Specified / Unspecified v. Adjustment D/O (e.g., w/ depressed mood, w/ mixed anxiety & depressed mood) What is Adjustment D/O? develops in response to a stressor (w/in 3mos) terminates w/in 6mos of the end of the original precipitating stressor clinically significant b/c: there is marked distress out of proportion to the severity of the stressor or there is significant impairment Intended, in DSM-5, to be < of a residual dx and to be thought of as more in the same spectrum as Acute Stress D/O (ASD) and PTSD, but: not necessarily w/ as severe a stressor as in ASD or PTSD not necessarily w/ as severe a sx response as in ASD or PTSD Mood D/O’s lab w/u CBC Chem panel TSH B12 U-tox U-preg (dep on demographics) RPR HIV-1,2 ELISA (lower threshold for BD patients…)
Slide 55 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No. Belmaker RH and Agam G, NEJM 2008, 358:55-68 iproniazid (1957) imipramine (1959) The monoamine hypothesis (1965) Joseph Schildkraut Question: Do antidepressants have additional actions besides inhibition of reuptake transporters? “…the Zoloft cartoon” from: http://gifsoup.com/webroot/animatedgifs/50426_o.gif; chemical inbalance Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. J Neurosci. 2000 Dec 15;20(24):9104-10 Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Science. 2003 Aug 8;301(5634):805-9. Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Haenisch B, Bönisch H. Pharmacol Ther. 2011 Mar;129(3):352-68. Epub 2010 Dec 13. Review. Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices. Hennings EC, Kiss JP, De Oliveira K, Toth PT, Vizi ES. J Neurochem. 1999 Sep;73(3):1043-50. Block of an ether-a-go-go-like K(+) channel by imipramine rescues egl-2 excitation defects in Caenorhabditis elegans. Weinshenker D, Wei A, Salkoff L, Thomas JH. J Neurosci. 1999 Nov 15;19(22):9831-40. photo from: http://www.sciencedaily.com/releases/2006/11/061121082449.htm Subsequent hypotheses about MDD altered glutamatergic transmission ↓’d GABAergic transmission monoamine-Ach imbalance disruption of endogenous opioid signalling neurosteroid deficiencies thyroxine abnormalities cytokine-mediated x-talk betw immune system & CNS circadian abnormalities (specific brain structure/circuit dysfxns…) as summarized in Belmaker RH and Agam G, NEJM 2008, 358:55-68 MDD tx options selective serotonin reuptake inhibitors (SSRIs) fluoxetine (PROZAC), 20-80 mg/d citalopram (CELEXA), 20-40 mg/d escitalopram (LEXAPRO), 10-20 mg/d sertraline (ZOLOFT), 50-200 mg/d paroxetine (PAXIL), 20-50 mg/d serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine XR (EFFEXOR XR), 37.5-225 mg/d desvenlafaxine (PRISTIQ) duloxetine (CYMBALTA), 30-120 mg/d others bupropion SR, XL (WELLBUTRIN) 100-200 mg BID (SR) 150-450 mg/d (XL) mirtazapine (REMERON), 15-45 mg/d trazodone, 50-200mg/noc (for sleep) nefazodone tricyclic antidepressants (TCADs) amitriptyline  nortriptyline imipramine  desipramine monoamine oxidase inhibitors (MAO-Is) typically, non-selective & irreversible MAO-A (NE, EPI, 5HT, DA) MAO-B (trace amines, DA) why we “wash-out” 5HT syndrome HTNsive crisis selegiline (EMSAM) [additional] augmenting agents Li+ T3, 25 mcg/d buspirone (BuSPAR), 5-30 mg BID atypical antipsychotics Sequenced Treatment Alternatives for the Relief of Depression (STAR*D) major NIMH-funded study (PI: A. John Rush) w/ 14 regional centers & 41 clinical sites initial enrollment of 4,041 patients aim: which tx algorithms work best after an initial failure to remit non-psychotic depression w/ an antidepressant? http://www.clinicaltrials.gov/ct/show/NCT00021528?order=1 Trivedi MH et al, Am J Psychiatry. 2006 Jan;163(1):28-40 47% response rate on citalopram (by *QIDS-SR, 50% ↓ in sxs) Sequenced Treatment Alternatives for the Relief of Depression (STAR*D), n = 2,876 (qualifying pts) 33% remission rate on citalopram (by QIDS-SR, score <5) Rx choice: according to side effects (SE’s), comorbid condn’s / risks (GMC & Ψ), ?FmRxHx 6-8wk trials each (preferable) augmentation v. switch? *QIDS-SR = Quick Inventory of Depressive Symptomatology, Self-Report (range 0-27) http://www.ids-qids.org/ MDD tx options Ψtherapy cognitive bx therapy (CBT) interpersonal therapy (IPT) psychodynamic therapy interventional Ψ electroconvulsive therapy (ECT) transcranial magnetic stimulation (TMS) vagal nerve stimulation (VNS) deep brain stimulation (DBS) other lightbox therapy (mostly for MDD w/ seasonal features) Major Depressive D/O (MDD) NATURAL HISTORY (Frank E and Thase ME, 1999 & DSM-5) recovery usually begins: w/in 3mos for two in five indivs w/in 1y for four in five indivs risk of subsequent episodes (w/in 3y) increases w/ n: ≥50% if n=1 ≥70% if n=2 ≥90% if n=3 dz course does not typically change as one ages 5-10% will eventually be dx’d w/ bipolar disorder (BD) more likely w/: onset of ‘MDD’ in adolescence a family history of BD ‘mixed features’ 6% lifetime SUI risk (Davies S et al, 2001); up to 15% w/ severe MDD Persistent depressive disorder (dysthymia) 2y of depressed mood (1y in children/adolescents) most of the day, more days than not, plus 2 of the following: appetite disturbance (↓ or ↑) veg sleep disturbance (↓ or ↑) veg ↓energy E ↓esteem E poor [ ] C hopeless H never sx-free for more than 2mos at a time overlapping dx of MDD is now allowed there has never been mania, hypomania, or cyclothymia MDD specifiers can also be used for dysthymia additionally: early onset (before age 21) late onset (at age 21 or older) w/ pure dysthymic syndrome from DSM-5 w/ persistent MDE w/ intermittent MDE’s, w/ current episode w/ intermittent MDE’s, w/o current episode --these last 3 are essentially a co-dx of MDD, but captured within the specifier… Persistent depressive disorder (dysthymia) may be more treatment-resistant (TxR) than straightforward MDD EPIDEMIOLOGY lifetime prevalence = 6% 12-mo prevalence = 0.5%, compared w/ 1.5% for MDD high comorbidity w/ personality d/o’s (particularly clusters B, C) From Sadock & Sadock & DSM-5 Case 1. 36yo F presenting w/ 3mos of ↓mood. She reports getting only ~4h of sleep/noc b/c of regular early AM awakenings. She feels drained everyday, all day long. She’s gained about 10 lbs in the last 2mos. What else would you like to ask? How would you work-up this patient? In the meantime, what would you dx and what would be your tentative tx plan? She returns 1mo later and reports that her mood continues to spiral downward. Now, she adds that she’s starting to think more morbid thoughts and that maybe it wouldn’t be such a bad thing if she weren’t around anymore. What would you ask now? How would you revise your tx plan? The pt’s sxs are finally stabilized and she returns at a later date w/ her sxs in remission x 1mo. “Doctor, I’m feeling so much better now. Do you think I can stop my psych Rxs?” How would you answer? Premenstrual dysphoric d/o Criterion A. In most menstrual cycles, ≥5 sxs in the final week before onset of menses, w/ improvement w/in a few days after onset of menses, and near-absent in the week post-menses Criterion B. ≥1 (or more) sx of marked: 1. lability (e.g., mood swings, suddenly sad, increased rejection sensitivity) 2. irritability /anger / increase in interpersonal conflicts 3. anxiety / tension / keyed-up feeling/edginess Criterion C. ≥1 (or more) sx to reach a total of 5 in combation w/ previous list: 1. anhedonia 2. [ ] impairment 3. anergia 4. significant appetite change (including specific food cravings) 5. sleep disturbance (↑ or ↓) 6. feeling overwhelmed or out of control 7. px sxs (e.g., breast tenderness/swelling, arthralgias/myalgias, bloating, wt gain) Special notes. Can’t just be menstrual exacerbation of MDD or other Axis I or II dx; must have confirmation by prospective daily rating scales during at least 2 sx-ic cycles (provisional dx allowed beforehand) Premenstrual dysphoric d/o (M)ood (labile &/or irritable &/or anxious) Sleep Interest Body Energy Concentration Appetite Out of control Treatment: SSRI daily luteal phase only (i.e., day 14 of cycle  menses) some data suggest successful in tx’ing mixed episodes, BD indivs w/ comorbid substance issues Areas of concern: Li+ ↔ renal; interaction w/ NSAIDs VPA ↔ liver; VPA in young ♀  polycystic ovarian syndrome (PCOS) Teratogenicity Li+  Ebstein’s anomaly (1st trimester) hazard ratio 10-20, but AR still 1:1000 VPA  neural tube defects AR 10% OTHER NOTES: CBZ: auto-induction, agranulocytosis Lamictal: Stevens-Johnson syndrome (SJS), interaxn w/ oral contraceptives (OCPs), interaxn w/ VPA Bipolar Disorder (BD) – treatment (cont’d) How many agents to use? combination tx often helpful in acute stabilization antipsychotics REQ’D when there are psychotic features to mood episode Adjuncts benzos --Don’t forget about ECT… Manic switch w/… reuptake blockers Lamictal, too! (van der Loos ML et al, 2009) Bipolar Disorder (BD) – natural history 60% of manic episodes immediately precede an MDE MDE’s usually significantly outnumber hypomanic and manic episodes ~10% of BD II’s  BD I episodes tend to increase in frequency/duration w/ age re: suicide… 35% lifetime prevalence of at least one SUI attempt in bipolar 15% suicide completion rate (may be an overestimate) 15x the risk of the general population (for completions) perhaps ¼ of all suicides in the population >lethality of SUI attempts in BD II (than BD I) adapated, in part,from DSM-5 Cyclothymic D/O 2y of fluctuating mood (1y in children, adolescents) hypomanic symptoms (but NOT episodes) dysthymic symptoms (but no MDEs) ≥ half the time & (no more than 2mos sx-free) EXCLUSIONS no manic/hypomanic episodes no depressive episodes Differential diagnosis Phenocopies and gray areas… Anxiety D/O’s (esp. GAD, PTSD) Schizoaffective D/O Delirium Dementia Personality D/O’s Substance/Medication-induced Depressive D/O Depressive D/O d/t Another Medical Condition Other Specified Depressive D/O Unspecified Depressive D/O Substance/Medication-induced Bipolar and Related D/O Bipolar and Related D/O d/t Another Medical Condition Other Specified Bipolar and Related D/O Unspecified Bipolar and Related D/O Depressive, Bipolar & Related D/O d/t a Another Medical Condition Endocrine (e.g., thyroid, hypothalamic-pituitary-adrenal/HPA) Neurologic (e.g., multiple sclerosis, CVA, brain tumor, Parkinson’s, Alzheimer’s/other dementia, Huntington’s, seizure d/o) Neoplastic (e.g., pancreas) TBI Autoimmune (e.g., neuropsychiatric systemic lupus erythematosus / NPSLE) Hematologic (e.g., acute intermittent porphyria / AIP) typically: anx/depr >> s/t Ψosis, mania (rare) acute abdominal pain, muscle weakness port wine-colored urine (porphobilinogen) transient damage to nerve cells Nutritional (e.g., B12) Infectious (e.g., HIV, Syphilis) Substance/Medication-induced Depressive, Bipolar & Related D/O ILLICITS can be from intoxication or withdrawal phases EtOH – typically depressive stimulants – typically manic/hypomanic --good to ask about sxs during windows of sobriety (ideally, ≥6mos) high substance comorbidity rates w/ endogenous Axis I Ψ d/o’s, though (esp. BD I) Prescription Rxs steroids IFN-α2b, RBV (HCV tx) β-blockers antidepressants α-TB drugs Other Specified / Unspecified v. Adjustment D/O (e.g., w/ depressed mood, w/ mixed anxiety & depressed mood) What is Adjustment D/O? develops in response to a stressor (w/in 3mos) terminates w/in 6mos of the end of the original precipitating stressor clinically significant b/c: there is marked distress out of proportion to the severity of the stressor or there is significant impairment Intended, in DSM-5, to be < of a residual dx and to be thought of as more in the same spectrum as Acute Stress D/O (ASD) and PTSD, but: not necessarily w/ as severe a stressor as in ASD or PTSD not necessarily w/ as severe a sx response as in ASD or PTSD Mood D/O’s lab w/u CBC Chem panel TSH B12 U-tox U-preg (dep on demographics) RPR HIV-1,2 ELISA (lower threshold for BD patients…) Summary – cont’d Diagnostic building blocks (not counting mixed feature possibilities…)
Slide 56 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No. Belmaker RH and Agam G, NEJM 2008, 358:55-68 iproniazid (1957) imipramine (1959) The monoamine hypothesis (1965) Joseph Schildkraut Question: Do antidepressants have additional actions besides inhibition of reuptake transporters? “…the Zoloft cartoon” from: http://gifsoup.com/webroot/animatedgifs/50426_o.gif; chemical inbalance Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. J Neurosci. 2000 Dec 15;20(24):9104-10 Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Science. 2003 Aug 8;301(5634):805-9. Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Haenisch B, Bönisch H. Pharmacol Ther. 2011 Mar;129(3):352-68. Epub 2010 Dec 13. Review. Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices. Hennings EC, Kiss JP, De Oliveira K, Toth PT, Vizi ES. J Neurochem. 1999 Sep;73(3):1043-50. Block of an ether-a-go-go-like K(+) channel by imipramine rescues egl-2 excitation defects in Caenorhabditis elegans. Weinshenker D, Wei A, Salkoff L, Thomas JH. J Neurosci. 1999 Nov 15;19(22):9831-40. photo from: http://www.sciencedaily.com/releases/2006/11/061121082449.htm Subsequent hypotheses about MDD altered glutamatergic transmission ↓’d GABAergic transmission monoamine-Ach imbalance disruption of endogenous opioid signalling neurosteroid deficiencies thyroxine abnormalities cytokine-mediated x-talk betw immune system & CNS circadian abnormalities (specific brain structure/circuit dysfxns…) as summarized in Belmaker RH and Agam G, NEJM 2008, 358:55-68 MDD tx options selective serotonin reuptake inhibitors (SSRIs) fluoxetine (PROZAC), 20-80 mg/d citalopram (CELEXA), 20-40 mg/d escitalopram (LEXAPRO), 10-20 mg/d sertraline (ZOLOFT), 50-200 mg/d paroxetine (PAXIL), 20-50 mg/d serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine XR (EFFEXOR XR), 37.5-225 mg/d desvenlafaxine (PRISTIQ) duloxetine (CYMBALTA), 30-120 mg/d others bupropion SR, XL (WELLBUTRIN) 100-200 mg BID (SR) 150-450 mg/d (XL) mirtazapine (REMERON), 15-45 mg/d trazodone, 50-200mg/noc (for sleep) nefazodone tricyclic antidepressants (TCADs) amitriptyline  nortriptyline imipramine  desipramine monoamine oxidase inhibitors (MAO-Is) typically, non-selective & irreversible MAO-A (NE, EPI, 5HT, DA) MAO-B (trace amines, DA) why we “wash-out” 5HT syndrome HTNsive crisis selegiline (EMSAM) [additional] augmenting agents Li+ T3, 25 mcg/d buspirone (BuSPAR), 5-30 mg BID atypical antipsychotics Sequenced Treatment Alternatives for the Relief of Depression (STAR*D) major NIMH-funded study (PI: A. John Rush) w/ 14 regional centers & 41 clinical sites initial enrollment of 4,041 patients aim: which tx algorithms work best after an initial failure to remit non-psychotic depression w/ an antidepressant? http://www.clinicaltrials.gov/ct/show/NCT00021528?order=1 Trivedi MH et al, Am J Psychiatry. 2006 Jan;163(1):28-40 47% response rate on citalopram (by *QIDS-SR, 50% ↓ in sxs) Sequenced Treatment Alternatives for the Relief of Depression (STAR*D), n = 2,876 (qualifying pts) 33% remission rate on citalopram (by QIDS-SR, score <5) Rx choice: according to side effects (SE’s), comorbid condn’s / risks (GMC & Ψ), ?FmRxHx 6-8wk trials each (preferable) augmentation v. switch? *QIDS-SR = Quick Inventory of Depressive Symptomatology, Self-Report (range 0-27) http://www.ids-qids.org/ MDD tx options Ψtherapy cognitive bx therapy (CBT) interpersonal therapy (IPT) psychodynamic therapy interventional Ψ electroconvulsive therapy (ECT) transcranial magnetic stimulation (TMS) vagal nerve stimulation (VNS) deep brain stimulation (DBS) other lightbox therapy (mostly for MDD w/ seasonal features) Major Depressive D/O (MDD) NATURAL HISTORY (Frank E and Thase ME, 1999 & DSM-5) recovery usually begins: w/in 3mos for two in five indivs w/in 1y for four in five indivs risk of subsequent episodes (w/in 3y) increases w/ n: ≥50% if n=1 ≥70% if n=2 ≥90% if n=3 dz course does not typically change as one ages 5-10% will eventually be dx’d w/ bipolar disorder (BD) more likely w/: onset of ‘MDD’ in adolescence a family history of BD ‘mixed features’ 6% lifetime SUI risk (Davies S et al, 2001); up to 15% w/ severe MDD Persistent depressive disorder (dysthymia) 2y of depressed mood (1y in children/adolescents) most of the day, more days than not, plus 2 of the following: appetite disturbance (↓ or ↑) veg sleep disturbance (↓ or ↑) veg ↓energy E ↓esteem E poor [ ] C hopeless H never sx-free for more than 2mos at a time overlapping dx of MDD is now allowed there has never been mania, hypomania, or cyclothymia MDD specifiers can also be used for dysthymia additionally: early onset (before age 21) late onset (at age 21 or older) w/ pure dysthymic syndrome from DSM-5 w/ persistent MDE w/ intermittent MDE’s, w/ current episode w/ intermittent MDE’s, w/o current episode --these last 3 are essentially a co-dx of MDD, but captured within the specifier… Persistent depressive disorder (dysthymia) may be more treatment-resistant (TxR) than straightforward MDD EPIDEMIOLOGY lifetime prevalence = 6% 12-mo prevalence = 0.5%, compared w/ 1.5% for MDD high comorbidity w/ personality d/o’s (particularly clusters B, C) From Sadock & Sadock & DSM-5 Case 1. 36yo F presenting w/ 3mos of ↓mood. She reports getting only ~4h of sleep/noc b/c of regular early AM awakenings. She feels drained everyday, all day long. She’s gained about 10 lbs in the last 2mos. What else would you like to ask? How would you work-up this patient? In the meantime, what would you dx and what would be your tentative tx plan? She returns 1mo later and reports that her mood continues to spiral downward. Now, she adds that she’s starting to think more morbid thoughts and that maybe it wouldn’t be such a bad thing if she weren’t around anymore. What would you ask now? How would you revise your tx plan? The pt’s sxs are finally stabilized and she returns at a later date w/ her sxs in remission x 1mo. “Doctor, I’m feeling so much better now. Do you think I can stop my psych Rxs?” How would you answer? Premenstrual dysphoric d/o Criterion A. In most menstrual cycles, ≥5 sxs in the final week before onset of menses, w/ improvement w/in a few days after onset of menses, and near-absent in the week post-menses Criterion B. ≥1 (or more) sx of marked: 1. lability (e.g., mood swings, suddenly sad, increased rejection sensitivity) 2. irritability /anger / increase in interpersonal conflicts 3. anxiety / tension / keyed-up feeling/edginess Criterion C. ≥1 (or more) sx to reach a total of 5 in combation w/ previous list: 1. anhedonia 2. [ ] impairment 3. anergia 4. significant appetite change (including specific food cravings) 5. sleep disturbance (↑ or ↓) 6. feeling overwhelmed or out of control 7. px sxs (e.g., breast tenderness/swelling, arthralgias/myalgias, bloating, wt gain) Special notes. Can’t just be menstrual exacerbation of MDD or other Axis I or II dx; must have confirmation by prospective daily rating scales during at least 2 sx-ic cycles (provisional dx allowed beforehand) Premenstrual dysphoric d/o (M)ood (labile &/or irritable &/or anxious) Sleep Interest Body Energy Concentration Appetite Out of control Treatment: SSRI daily luteal phase only (i.e., day 14 of cycle  menses) some data suggest successful in tx’ing mixed episodes, BD indivs w/ comorbid substance issues Areas of concern: Li+ ↔ renal; interaction w/ NSAIDs VPA ↔ liver; VPA in young ♀  polycystic ovarian syndrome (PCOS) Teratogenicity Li+  Ebstein’s anomaly (1st trimester) hazard ratio 10-20, but AR still 1:1000 VPA  neural tube defects AR 10% OTHER NOTES: CBZ: auto-induction, agranulocytosis Lamictal: Stevens-Johnson syndrome (SJS), interaxn w/ oral contraceptives (OCPs), interaxn w/ VPA Bipolar Disorder (BD) – treatment (cont’d) How many agents to use? combination tx often helpful in acute stabilization antipsychotics REQ’D when there are psychotic features to mood episode Adjuncts benzos --Don’t forget about ECT… Manic switch w/… reuptake blockers Lamictal, too! (van der Loos ML et al, 2009) Bipolar Disorder (BD) – natural history 60% of manic episodes immediately precede an MDE MDE’s usually significantly outnumber hypomanic and manic episodes ~10% of BD II’s  BD I episodes tend to increase in frequency/duration w/ age re: suicide… 35% lifetime prevalence of at least one SUI attempt in bipolar 15% suicide completion rate (may be an overestimate) 15x the risk of the general population (for completions) perhaps ¼ of all suicides in the population >lethality of SUI attempts in BD II (than BD I) adapated, in part,from DSM-5 Cyclothymic D/O 2y of fluctuating mood (1y in children, adolescents) hypomanic symptoms (but NOT episodes) dysthymic symptoms (but no MDEs) ≥ half the time & (no more than 2mos sx-free) EXCLUSIONS no manic/hypomanic episodes no depressive episodes Differential diagnosis Phenocopies and gray areas… Anxiety D/O’s (esp. GAD, PTSD) Schizoaffective D/O Delirium Dementia Personality D/O’s Substance/Medication-induced Depressive D/O Depressive D/O d/t Another Medical Condition Other Specified Depressive D/O Unspecified Depressive D/O Substance/Medication-induced Bipolar and Related D/O Bipolar and Related D/O d/t Another Medical Condition Other Specified Bipolar and Related D/O Unspecified Bipolar and Related D/O Depressive, Bipolar & Related D/O d/t a Another Medical Condition Endocrine (e.g., thyroid, hypothalamic-pituitary-adrenal/HPA) Neurologic (e.g., multiple sclerosis, CVA, brain tumor, Parkinson’s, Alzheimer’s/other dementia, Huntington’s, seizure d/o) Neoplastic (e.g., pancreas) TBI Autoimmune (e.g., neuropsychiatric systemic lupus erythematosus / NPSLE) Hematologic (e.g., acute intermittent porphyria / AIP) typically: anx/depr >> s/t Ψosis, mania (rare) acute abdominal pain, muscle weakness port wine-colored urine (porphobilinogen) transient damage to nerve cells Nutritional (e.g., B12) Infectious (e.g., HIV, Syphilis) Substance/Medication-induced Depressive, Bipolar & Related D/O ILLICITS can be from intoxication or withdrawal phases EtOH – typically depressive stimulants – typically manic/hypomanic --good to ask about sxs during windows of sobriety (ideally, ≥6mos) high substance comorbidity rates w/ endogenous Axis I Ψ d/o’s, though (esp. BD I) Prescription Rxs steroids IFN-α2b, RBV (HCV tx) β-blockers antidepressants α-TB drugs Other Specified / Unspecified v. Adjustment D/O (e.g., w/ depressed mood, w/ mixed anxiety & depressed mood) What is Adjustment D/O? develops in response to a stressor (w/in 3mos) terminates w/in 6mos of the end of the original precipitating stressor clinically significant b/c: there is marked distress out of proportion to the severity of the stressor or there is significant impairment Intended, in DSM-5, to be < of a residual dx and to be thought of as more in the same spectrum as Acute Stress D/O (ASD) and PTSD, but: not necessarily w/ as severe a stressor as in ASD or PTSD not necessarily w/ as severe a sx response as in ASD or PTSD Mood D/O’s lab w/u CBC Chem panel TSH B12 U-tox U-preg (dep on demographics) RPR HIV-1,2 ELISA (lower threshold for BD patients…) Summary – cont’d Diagnostic building blocks (not counting mixed feature possibilities…) Summary – cont’d Mood D/O’s are Ψ conditions where emotional dysregulation is the primary issue. Mood d/o’s can be endogenous, due to substances/medication, or due to another medical condition. There are additional phenocopies which should always be in your Ddx, including Anxiety D/O’s, Schizoaffective D/O, Personality D/O’s, Delirium, and Mild/Major Neurocognitive D/O’s. The monoamine hypothesis of depression is only a preliminary framework for conceptualizing Mood d/o’s and their tx, and requires significant theoretical revision. Mood D/O’s, like other Ψ conditions in the DSM, are best conceived as syndromes rather than as unitary or homogeneous medical conditions. A little less than ½ of tx-naïve pts will respond to their first antidepressant; only 1/3 will remit without further intervention. Non-pharmacologic approaches to treating Mood D/O’s include psychotherapy and interventional procedures (e.g., ECT).
Slide 57 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No. Belmaker RH and Agam G, NEJM 2008, 358:55-68 iproniazid (1957) imipramine (1959) The monoamine hypothesis (1965) Joseph Schildkraut Question: Do antidepressants have additional actions besides inhibition of reuptake transporters? “…the Zoloft cartoon” from: http://gifsoup.com/webroot/animatedgifs/50426_o.gif; chemical inbalance Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. J Neurosci. 2000 Dec 15;20(24):9104-10 Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Science. 2003 Aug 8;301(5634):805-9. Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Haenisch B, Bönisch H. Pharmacol Ther. 2011 Mar;129(3):352-68. Epub 2010 Dec 13. Review. Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices. Hennings EC, Kiss JP, De Oliveira K, Toth PT, Vizi ES. J Neurochem. 1999 Sep;73(3):1043-50. Block of an ether-a-go-go-like K(+) channel by imipramine rescues egl-2 excitation defects in Caenorhabditis elegans. Weinshenker D, Wei A, Salkoff L, Thomas JH. J Neurosci. 1999 Nov 15;19(22):9831-40. photo from: http://www.sciencedaily.com/releases/2006/11/061121082449.htm Subsequent hypotheses about MDD altered glutamatergic transmission ↓’d GABAergic transmission monoamine-Ach imbalance disruption of endogenous opioid signalling neurosteroid deficiencies thyroxine abnormalities cytokine-mediated x-talk betw immune system & CNS circadian abnormalities (specific brain structure/circuit dysfxns…) as summarized in Belmaker RH and Agam G, NEJM 2008, 358:55-68 MDD tx options selective serotonin reuptake inhibitors (SSRIs) fluoxetine (PROZAC), 20-80 mg/d citalopram (CELEXA), 20-40 mg/d escitalopram (LEXAPRO), 10-20 mg/d sertraline (ZOLOFT), 50-200 mg/d paroxetine (PAXIL), 20-50 mg/d serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine XR (EFFEXOR XR), 37.5-225 mg/d desvenlafaxine (PRISTIQ) duloxetine (CYMBALTA), 30-120 mg/d others bupropion SR, XL (WELLBUTRIN) 100-200 mg BID (SR) 150-450 mg/d (XL) mirtazapine (REMERON), 15-45 mg/d trazodone, 50-200mg/noc (for sleep) nefazodone tricyclic antidepressants (TCADs) amitriptyline  nortriptyline imipramine  desipramine monoamine oxidase inhibitors (MAO-Is) typically, non-selective & irreversible MAO-A (NE, EPI, 5HT, DA) MAO-B (trace amines, DA) why we “wash-out” 5HT syndrome HTNsive crisis selegiline (EMSAM) [additional] augmenting agents Li+ T3, 25 mcg/d buspirone (BuSPAR), 5-30 mg BID atypical antipsychotics Sequenced Treatment Alternatives for the Relief of Depression (STAR*D) major NIMH-funded study (PI: A. John Rush) w/ 14 regional centers & 41 clinical sites initial enrollment of 4,041 patients aim: which tx algorithms work best after an initial failure to remit non-psychotic depression w/ an antidepressant? http://www.clinicaltrials.gov/ct/show/NCT00021528?order=1 Trivedi MH et al, Am J Psychiatry. 2006 Jan;163(1):28-40 47% response rate on citalopram (by *QIDS-SR, 50% ↓ in sxs) Sequenced Treatment Alternatives for the Relief of Depression (STAR*D), n = 2,876 (qualifying pts) 33% remission rate on citalopram (by QIDS-SR, score <5) Rx choice: according to side effects (SE’s), comorbid condn’s / risks (GMC & Ψ), ?FmRxHx 6-8wk trials each (preferable) augmentation v. switch? *QIDS-SR = Quick Inventory of Depressive Symptomatology, Self-Report (range 0-27) http://www.ids-qids.org/ MDD tx options Ψtherapy cognitive bx therapy (CBT) interpersonal therapy (IPT) psychodynamic therapy interventional Ψ electroconvulsive therapy (ECT) transcranial magnetic stimulation (TMS) vagal nerve stimulation (VNS) deep brain stimulation (DBS) other lightbox therapy (mostly for MDD w/ seasonal features) Major Depressive D/O (MDD) NATURAL HISTORY (Frank E and Thase ME, 1999 & DSM-5) recovery usually begins: w/in 3mos for two in five indivs w/in 1y for four in five indivs risk of subsequent episodes (w/in 3y) increases w/ n: ≥50% if n=1 ≥70% if n=2 ≥90% if n=3 dz course does not typically change as one ages 5-10% will eventually be dx’d w/ bipolar disorder (BD) more likely w/: onset of ‘MDD’ in adolescence a family history of BD ‘mixed features’ 6% lifetime SUI risk (Davies S et al, 2001); up to 15% w/ severe MDD Persistent depressive disorder (dysthymia) 2y of depressed mood (1y in children/adolescents) most of the day, more days than not, plus 2 of the following: appetite disturbance (↓ or ↑) veg sleep disturbance (↓ or ↑) veg ↓energy E ↓esteem E poor [ ] C hopeless H never sx-free for more than 2mos at a time overlapping dx of MDD is now allowed there has never been mania, hypomania, or cyclothymia MDD specifiers can also be used for dysthymia additionally: early onset (before age 21) late onset (at age 21 or older) w/ pure dysthymic syndrome from DSM-5 w/ persistent MDE w/ intermittent MDE’s, w/ current episode w/ intermittent MDE’s, w/o current episode --these last 3 are essentially a co-dx of MDD, but captured within the specifier… Persistent depressive disorder (dysthymia) may be more treatment-resistant (TxR) than straightforward MDD EPIDEMIOLOGY lifetime prevalence = 6% 12-mo prevalence = 0.5%, compared w/ 1.5% for MDD high comorbidity w/ personality d/o’s (particularly clusters B, C) From Sadock & Sadock & DSM-5 Case 1. 36yo F presenting w/ 3mos of ↓mood. She reports getting only ~4h of sleep/noc b/c of regular early AM awakenings. She feels drained everyday, all day long. She’s gained about 10 lbs in the last 2mos. What else would you like to ask? How would you work-up this patient? In the meantime, what would you dx and what would be your tentative tx plan? She returns 1mo later and reports that her mood continues to spiral downward. Now, she adds that she’s starting to think more morbid thoughts and that maybe it wouldn’t be such a bad thing if she weren’t around anymore. What would you ask now? How would you revise your tx plan? The pt’s sxs are finally stabilized and she returns at a later date w/ her sxs in remission x 1mo. “Doctor, I’m feeling so much better now. Do you think I can stop my psych Rxs?” How would you answer? Premenstrual dysphoric d/o Criterion A. In most menstrual cycles, ≥5 sxs in the final week before onset of menses, w/ improvement w/in a few days after onset of menses, and near-absent in the week post-menses Criterion B. ≥1 (or more) sx of marked: 1. lability (e.g., mood swings, suddenly sad, increased rejection sensitivity) 2. irritability /anger / increase in interpersonal conflicts 3. anxiety / tension / keyed-up feeling/edginess Criterion C. ≥1 (or more) sx to reach a total of 5 in combation w/ previous list: 1. anhedonia 2. [ ] impairment 3. anergia 4. significant appetite change (including specific food cravings) 5. sleep disturbance (↑ or ↓) 6. feeling overwhelmed or out of control 7. px sxs (e.g., breast tenderness/swelling, arthralgias/myalgias, bloating, wt gain) Special notes. Can’t just be menstrual exacerbation of MDD or other Axis I or II dx; must have confirmation by prospective daily rating scales during at least 2 sx-ic cycles (provisional dx allowed beforehand) Premenstrual dysphoric d/o (M)ood (labile &/or irritable &/or anxious) Sleep Interest Body Energy Concentration Appetite Out of control Treatment: SSRI daily luteal phase only (i.e., day 14 of cycle  menses) some data suggest successful in tx’ing mixed episodes, BD indivs w/ comorbid substance issues Areas of concern: Li+ ↔ renal; interaction w/ NSAIDs VPA ↔ liver; VPA in young ♀  polycystic ovarian syndrome (PCOS) Teratogenicity Li+  Ebstein’s anomaly (1st trimester) hazard ratio 10-20, but AR still 1:1000 VPA  neural tube defects AR 10% OTHER NOTES: CBZ: auto-induction, agranulocytosis Lamictal: Stevens-Johnson syndrome (SJS), interaxn w/ oral contraceptives (OCPs), interaxn w/ VPA Bipolar Disorder (BD) – treatment (cont’d) How many agents to use? combination tx often helpful in acute stabilization antipsychotics REQ’D when there are psychotic features to mood episode Adjuncts benzos --Don’t forget about ECT… Manic switch w/… reuptake blockers Lamictal, too! (van der Loos ML et al, 2009) Bipolar Disorder (BD) – natural history 60% of manic episodes immediately precede an MDE MDE’s usually significantly outnumber hypomanic and manic episodes ~10% of BD II’s  BD I episodes tend to increase in frequency/duration w/ age re: suicide… 35% lifetime prevalence of at least one SUI attempt in bipolar 15% suicide completion rate (may be an overestimate) 15x the risk of the general population (for completions) perhaps ¼ of all suicides in the population >lethality of SUI attempts in BD II (than BD I) adapated, in part,from DSM-5 Cyclothymic D/O 2y of fluctuating mood (1y in children, adolescents) hypomanic symptoms (but NOT episodes) dysthymic symptoms (but no MDEs) ≥ half the time & (no more than 2mos sx-free) EXCLUSIONS no manic/hypomanic episodes no depressive episodes Differential diagnosis Phenocopies and gray areas… Anxiety D/O’s (esp. GAD, PTSD) Schizoaffective D/O Delirium Dementia Personality D/O’s Substance/Medication-induced Depressive D/O Depressive D/O d/t Another Medical Condition Other Specified Depressive D/O Unspecified Depressive D/O Substance/Medication-induced Bipolar and Related D/O Bipolar and Related D/O d/t Another Medical Condition Other Specified Bipolar and Related D/O Unspecified Bipolar and Related D/O Depressive, Bipolar & Related D/O d/t a Another Medical Condition Endocrine (e.g., thyroid, hypothalamic-pituitary-adrenal/HPA) Neurologic (e.g., multiple sclerosis, CVA, brain tumor, Parkinson’s, Alzheimer’s/other dementia, Huntington’s, seizure d/o) Neoplastic (e.g., pancreas) TBI Autoimmune (e.g., neuropsychiatric systemic lupus erythematosus / NPSLE) Hematologic (e.g., acute intermittent porphyria / AIP) typically: anx/depr >> s/t Ψosis, mania (rare) acute abdominal pain, muscle weakness port wine-colored urine (porphobilinogen) transient damage to nerve cells Nutritional (e.g., B12) Infectious (e.g., HIV, Syphilis) Substance/Medication-induced Depressive, Bipolar & Related D/O ILLICITS can be from intoxication or withdrawal phases EtOH – typically depressive stimulants – typically manic/hypomanic --good to ask about sxs during windows of sobriety (ideally, ≥6mos) high substance comorbidity rates w/ endogenous Axis I Ψ d/o’s, though (esp. BD I) Prescription Rxs steroids IFN-α2b, RBV (HCV tx) β-blockers antidepressants α-TB drugs Other Specified / Unspecified v. Adjustment D/O (e.g., w/ depressed mood, w/ mixed anxiety & depressed mood) What is Adjustment D/O? develops in response to a stressor (w/in 3mos) terminates w/in 6mos of the end of the original precipitating stressor clinically significant b/c: there is marked distress out of proportion to the severity of the stressor or there is significant impairment Intended, in DSM-5, to be < of a residual dx and to be thought of as more in the same spectrum as Acute Stress D/O (ASD) and PTSD, but: not necessarily w/ as severe a stressor as in ASD or PTSD not necessarily w/ as severe a sx response as in ASD or PTSD Mood D/O’s lab w/u CBC Chem panel TSH B12 U-tox U-preg (dep on demographics) RPR HIV-1,2 ELISA (lower threshold for BD patients…) Summary – cont’d Diagnostic building blocks (not counting mixed feature possibilities…) Summary – cont’d Mood D/O’s are Ψ conditions where emotional dysregulation is the primary issue. Mood d/o’s can be endogenous, due to substances/medication, or due to another medical condition. There are additional phenocopies which should always be in your Ddx, including Anxiety D/O’s, Schizoaffective D/O, Personality D/O’s, Delirium, and Mild/Major Neurocognitive D/O’s. The monoamine hypothesis of depression is only a preliminary framework for conceptualizing Mood d/o’s and their tx, and requires significant theoretical revision. Mood D/O’s, like other Ψ conditions in the DSM, are best conceived as syndromes rather than as unitary or homogeneous medical conditions. A little less than ½ of tx-naïve pts will respond to their first antidepressant; only 1/3 will remit without further intervention. Non-pharmacologic approaches to treating Mood D/O’s include psychotherapy and interventional procedures (e.g., ECT). Additional case presentations
Slide 58 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No. Belmaker RH and Agam G, NEJM 2008, 358:55-68 iproniazid (1957) imipramine (1959) The monoamine hypothesis (1965) Joseph Schildkraut Question: Do antidepressants have additional actions besides inhibition of reuptake transporters? “…the Zoloft cartoon” from: http://gifsoup.com/webroot/animatedgifs/50426_o.gif; chemical inbalance Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. J Neurosci. 2000 Dec 15;20(24):9104-10 Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Science. 2003 Aug 8;301(5634):805-9. Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Haenisch B, Bönisch H. Pharmacol Ther. 2011 Mar;129(3):352-68. Epub 2010 Dec 13. Review. Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices. Hennings EC, Kiss JP, De Oliveira K, Toth PT, Vizi ES. J Neurochem. 1999 Sep;73(3):1043-50. Block of an ether-a-go-go-like K(+) channel by imipramine rescues egl-2 excitation defects in Caenorhabditis elegans. Weinshenker D, Wei A, Salkoff L, Thomas JH. J Neurosci. 1999 Nov 15;19(22):9831-40. photo from: http://www.sciencedaily.com/releases/2006/11/061121082449.htm Subsequent hypotheses about MDD altered glutamatergic transmission ↓’d GABAergic transmission monoamine-Ach imbalance disruption of endogenous opioid signalling neurosteroid deficiencies thyroxine abnormalities cytokine-mediated x-talk betw immune system & CNS circadian abnormalities (specific brain structure/circuit dysfxns…) as summarized in Belmaker RH and Agam G, NEJM 2008, 358:55-68 MDD tx options selective serotonin reuptake inhibitors (SSRIs) fluoxetine (PROZAC), 20-80 mg/d citalopram (CELEXA), 20-40 mg/d escitalopram (LEXAPRO), 10-20 mg/d sertraline (ZOLOFT), 50-200 mg/d paroxetine (PAXIL), 20-50 mg/d serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine XR (EFFEXOR XR), 37.5-225 mg/d desvenlafaxine (PRISTIQ) duloxetine (CYMBALTA), 30-120 mg/d others bupropion SR, XL (WELLBUTRIN) 100-200 mg BID (SR) 150-450 mg/d (XL) mirtazapine (REMERON), 15-45 mg/d trazodone, 50-200mg/noc (for sleep) nefazodone tricyclic antidepressants (TCADs) amitriptyline  nortriptyline imipramine  desipramine monoamine oxidase inhibitors (MAO-Is) typically, non-selective & irreversible MAO-A (NE, EPI, 5HT, DA) MAO-B (trace amines, DA) why we “wash-out” 5HT syndrome HTNsive crisis selegiline (EMSAM) [additional] augmenting agents Li+ T3, 25 mcg/d buspirone (BuSPAR), 5-30 mg BID atypical antipsychotics Sequenced Treatment Alternatives for the Relief of Depression (STAR*D) major NIMH-funded study (PI: A. John Rush) w/ 14 regional centers & 41 clinical sites initial enrollment of 4,041 patients aim: which tx algorithms work best after an initial failure to remit non-psychotic depression w/ an antidepressant? http://www.clinicaltrials.gov/ct/show/NCT00021528?order=1 Trivedi MH et al, Am J Psychiatry. 2006 Jan;163(1):28-40 47% response rate on citalopram (by *QIDS-SR, 50% ↓ in sxs) Sequenced Treatment Alternatives for the Relief of Depression (STAR*D), n = 2,876 (qualifying pts) 33% remission rate on citalopram (by QIDS-SR, score <5) Rx choice: according to side effects (SE’s), comorbid condn’s / risks (GMC & Ψ), ?FmRxHx 6-8wk trials each (preferable) augmentation v. switch? *QIDS-SR = Quick Inventory of Depressive Symptomatology, Self-Report (range 0-27) http://www.ids-qids.org/ MDD tx options Ψtherapy cognitive bx therapy (CBT) interpersonal therapy (IPT) psychodynamic therapy interventional Ψ electroconvulsive therapy (ECT) transcranial magnetic stimulation (TMS) vagal nerve stimulation (VNS) deep brain stimulation (DBS) other lightbox therapy (mostly for MDD w/ seasonal features) Major Depressive D/O (MDD) NATURAL HISTORY (Frank E and Thase ME, 1999 & DSM-5) recovery usually begins: w/in 3mos for two in five indivs w/in 1y for four in five indivs risk of subsequent episodes (w/in 3y) increases w/ n: ≥50% if n=1 ≥70% if n=2 ≥90% if n=3 dz course does not typically change as one ages 5-10% will eventually be dx’d w/ bipolar disorder (BD) more likely w/: onset of ‘MDD’ in adolescence a family history of BD ‘mixed features’ 6% lifetime SUI risk (Davies S et al, 2001); up to 15% w/ severe MDD Persistent depressive disorder (dysthymia) 2y of depressed mood (1y in children/adolescents) most of the day, more days than not, plus 2 of the following: appetite disturbance (↓ or ↑) veg sleep disturbance (↓ or ↑) veg ↓energy E ↓esteem E poor [ ] C hopeless H never sx-free for more than 2mos at a time overlapping dx of MDD is now allowed there has never been mania, hypomania, or cyclothymia MDD specifiers can also be used for dysthymia additionally: early onset (before age 21) late onset (at age 21 or older) w/ pure dysthymic syndrome from DSM-5 w/ persistent MDE w/ intermittent MDE’s, w/ current episode w/ intermittent MDE’s, w/o current episode --these last 3 are essentially a co-dx of MDD, but captured within the specifier… Persistent depressive disorder (dysthymia) may be more treatment-resistant (TxR) than straightforward MDD EPIDEMIOLOGY lifetime prevalence = 6% 12-mo prevalence = 0.5%, compared w/ 1.5% for MDD high comorbidity w/ personality d/o’s (particularly clusters B, C) From Sadock & Sadock & DSM-5 Case 1. 36yo F presenting w/ 3mos of ↓mood. She reports getting only ~4h of sleep/noc b/c of regular early AM awakenings. She feels drained everyday, all day long. She’s gained about 10 lbs in the last 2mos. What else would you like to ask? How would you work-up this patient? In the meantime, what would you dx and what would be your tentative tx plan? She returns 1mo later and reports that her mood continues to spiral downward. Now, she adds that she’s starting to think more morbid thoughts and that maybe it wouldn’t be such a bad thing if she weren’t around anymore. What would you ask now? How would you revise your tx plan? The pt’s sxs are finally stabilized and she returns at a later date w/ her sxs in remission x 1mo. “Doctor, I’m feeling so much better now. Do you think I can stop my psych Rxs?” How would you answer? Premenstrual dysphoric d/o Criterion A. In most menstrual cycles, ≥5 sxs in the final week before onset of menses, w/ improvement w/in a few days after onset of menses, and near-absent in the week post-menses Criterion B. ≥1 (or more) sx of marked: 1. lability (e.g., mood swings, suddenly sad, increased rejection sensitivity) 2. irritability /anger / increase in interpersonal conflicts 3. anxiety / tension / keyed-up feeling/edginess Criterion C. ≥1 (or more) sx to reach a total of 5 in combation w/ previous list: 1. anhedonia 2. [ ] impairment 3. anergia 4. significant appetite change (including specific food cravings) 5. sleep disturbance (↑ or ↓) 6. feeling overwhelmed or out of control 7. px sxs (e.g., breast tenderness/swelling, arthralgias/myalgias, bloating, wt gain) Special notes. Can’t just be menstrual exacerbation of MDD or other Axis I or II dx; must have confirmation by prospective daily rating scales during at least 2 sx-ic cycles (provisional dx allowed beforehand) Premenstrual dysphoric d/o (M)ood (labile &/or irritable &/or anxious) Sleep Interest Body Energy Concentration Appetite Out of control Treatment: SSRI daily luteal phase only (i.e., day 14 of cycle  menses) some data suggest successful in tx’ing mixed episodes, BD indivs w/ comorbid substance issues Areas of concern: Li+ ↔ renal; interaction w/ NSAIDs VPA ↔ liver; VPA in young ♀  polycystic ovarian syndrome (PCOS) Teratogenicity Li+  Ebstein’s anomaly (1st trimester) hazard ratio 10-20, but AR still 1:1000 VPA  neural tube defects AR 10% OTHER NOTES: CBZ: auto-induction, agranulocytosis Lamictal: Stevens-Johnson syndrome (SJS), interaxn w/ oral contraceptives (OCPs), interaxn w/ VPA Bipolar Disorder (BD) – treatment (cont’d) How many agents to use? combination tx often helpful in acute stabilization antipsychotics REQ’D when there are psychotic features to mood episode Adjuncts benzos --Don’t forget about ECT… Manic switch w/… reuptake blockers Lamictal, too! (van der Loos ML et al, 2009) Bipolar Disorder (BD) – natural history 60% of manic episodes immediately precede an MDE MDE’s usually significantly outnumber hypomanic and manic episodes ~10% of BD II’s  BD I episodes tend to increase in frequency/duration w/ age re: suicide… 35% lifetime prevalence of at least one SUI attempt in bipolar 15% suicide completion rate (may be an overestimate) 15x the risk of the general population (for completions) perhaps ¼ of all suicides in the population >lethality of SUI attempts in BD II (than BD I) adapated, in part,from DSM-5 Cyclothymic D/O 2y of fluctuating mood (1y in children, adolescents) hypomanic symptoms (but NOT episodes) dysthymic symptoms (but no MDEs) ≥ half the time & (no more than 2mos sx-free) EXCLUSIONS no manic/hypomanic episodes no depressive episodes Differential diagnosis Phenocopies and gray areas… Anxiety D/O’s (esp. GAD, PTSD) Schizoaffective D/O Delirium Dementia Personality D/O’s Substance/Medication-induced Depressive D/O Depressive D/O d/t Another Medical Condition Other Specified Depressive D/O Unspecified Depressive D/O Substance/Medication-induced Bipolar and Related D/O Bipolar and Related D/O d/t Another Medical Condition Other Specified Bipolar and Related D/O Unspecified Bipolar and Related D/O Depressive, Bipolar & Related D/O d/t a Another Medical Condition Endocrine (e.g., thyroid, hypothalamic-pituitary-adrenal/HPA) Neurologic (e.g., multiple sclerosis, CVA, brain tumor, Parkinson’s, Alzheimer’s/other dementia, Huntington’s, seizure d/o) Neoplastic (e.g., pancreas) TBI Autoimmune (e.g., neuropsychiatric systemic lupus erythematosus / NPSLE) Hematologic (e.g., acute intermittent porphyria / AIP) typically: anx/depr >> s/t Ψosis, mania (rare) acute abdominal pain, muscle weakness port wine-colored urine (porphobilinogen) transient damage to nerve cells Nutritional (e.g., B12) Infectious (e.g., HIV, Syphilis) Substance/Medication-induced Depressive, Bipolar & Related D/O ILLICITS can be from intoxication or withdrawal phases EtOH – typically depressive stimulants – typically manic/hypomanic --good to ask about sxs during windows of sobriety (ideally, ≥6mos) high substance comorbidity rates w/ endogenous Axis I Ψ d/o’s, though (esp. BD I) Prescription Rxs steroids IFN-α2b, RBV (HCV tx) β-blockers antidepressants α-TB drugs Other Specified / Unspecified v. Adjustment D/O (e.g., w/ depressed mood, w/ mixed anxiety & depressed mood) What is Adjustment D/O? develops in response to a stressor (w/in 3mos) terminates w/in 6mos of the end of the original precipitating stressor clinically significant b/c: there is marked distress out of proportion to the severity of the stressor or there is significant impairment Intended, in DSM-5, to be < of a residual dx and to be thought of as more in the same spectrum as Acute Stress D/O (ASD) and PTSD, but: not necessarily w/ as severe a stressor as in ASD or PTSD not necessarily w/ as severe a sx response as in ASD or PTSD Mood D/O’s lab w/u CBC Chem panel TSH B12 U-tox U-preg (dep on demographics) RPR HIV-1,2 ELISA (lower threshold for BD patients…) Summary – cont’d Diagnostic building blocks (not counting mixed feature possibilities…) Summary – cont’d Mood D/O’s are Ψ conditions where emotional dysregulation is the primary issue. Mood d/o’s can be endogenous, due to substances/medication, or due to another medical condition. There are additional phenocopies which should always be in your Ddx, including Anxiety D/O’s, Schizoaffective D/O, Personality D/O’s, Delirium, and Mild/Major Neurocognitive D/O’s. The monoamine hypothesis of depression is only a preliminary framework for conceptualizing Mood d/o’s and their tx, and requires significant theoretical revision. Mood D/O’s, like other Ψ conditions in the DSM, are best conceived as syndromes rather than as unitary or homogeneous medical conditions. A little less than ½ of tx-naïve pts will respond to their first antidepressant; only 1/3 will remit without further intervention. Non-pharmacologic approaches to treating Mood D/O’s include psychotherapy and interventional procedures (e.g., ECT). Additional case presentations Case 2. 18yo M high school student who was BIB his parents to the ER after ingesting a bottle of 50 Tylenol pills. Recently, he has been isolating himself to his room more, sitting- out dinners with the family, and has been overheard at home talking about what a horrible “sinner” he is. He has shown increasing despondence and mood lability. He is well-connected with friends at school, outgoing—and the above changes have occurred more in a matter of weeks than they have months/years. On interview, the pt appears dysphoric, tearful, and internally preoccupied. What else would you like to know? How would you work-up this patient? In the meantime, what would you dx and what would be your tentative tx plan?
Slide 59 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No. Belmaker RH and Agam G, NEJM 2008, 358:55-68 iproniazid (1957) imipramine (1959) The monoamine hypothesis (1965) Joseph Schildkraut Question: Do antidepressants have additional actions besides inhibition of reuptake transporters? “…the Zoloft cartoon” from: http://gifsoup.com/webroot/animatedgifs/50426_o.gif; chemical inbalance Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. J Neurosci. 2000 Dec 15;20(24):9104-10 Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Science. 2003 Aug 8;301(5634):805-9. Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Haenisch B, Bönisch H. Pharmacol Ther. 2011 Mar;129(3):352-68. Epub 2010 Dec 13. Review. Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices. Hennings EC, Kiss JP, De Oliveira K, Toth PT, Vizi ES. J Neurochem. 1999 Sep;73(3):1043-50. Block of an ether-a-go-go-like K(+) channel by imipramine rescues egl-2 excitation defects in Caenorhabditis elegans. Weinshenker D, Wei A, Salkoff L, Thomas JH. J Neurosci. 1999 Nov 15;19(22):9831-40. photo from: http://www.sciencedaily.com/releases/2006/11/061121082449.htm Subsequent hypotheses about MDD altered glutamatergic transmission ↓’d GABAergic transmission monoamine-Ach imbalance disruption of endogenous opioid signalling neurosteroid deficiencies thyroxine abnormalities cytokine-mediated x-talk betw immune system & CNS circadian abnormalities (specific brain structure/circuit dysfxns…) as summarized in Belmaker RH and Agam G, NEJM 2008, 358:55-68 MDD tx options selective serotonin reuptake inhibitors (SSRIs) fluoxetine (PROZAC), 20-80 mg/d citalopram (CELEXA), 20-40 mg/d escitalopram (LEXAPRO), 10-20 mg/d sertraline (ZOLOFT), 50-200 mg/d paroxetine (PAXIL), 20-50 mg/d serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine XR (EFFEXOR XR), 37.5-225 mg/d desvenlafaxine (PRISTIQ) duloxetine (CYMBALTA), 30-120 mg/d others bupropion SR, XL (WELLBUTRIN) 100-200 mg BID (SR) 150-450 mg/d (XL) mirtazapine (REMERON), 15-45 mg/d trazodone, 50-200mg/noc (for sleep) nefazodone tricyclic antidepressants (TCADs) amitriptyline  nortriptyline imipramine  desipramine monoamine oxidase inhibitors (MAO-Is) typically, non-selective & irreversible MAO-A (NE, EPI, 5HT, DA) MAO-B (trace amines, DA) why we “wash-out” 5HT syndrome HTNsive crisis selegiline (EMSAM) [additional] augmenting agents Li+ T3, 25 mcg/d buspirone (BuSPAR), 5-30 mg BID atypical antipsychotics Sequenced Treatment Alternatives for the Relief of Depression (STAR*D) major NIMH-funded study (PI: A. John Rush) w/ 14 regional centers & 41 clinical sites initial enrollment of 4,041 patients aim: which tx algorithms work best after an initial failure to remit non-psychotic depression w/ an antidepressant? http://www.clinicaltrials.gov/ct/show/NCT00021528?order=1 Trivedi MH et al, Am J Psychiatry. 2006 Jan;163(1):28-40 47% response rate on citalopram (by *QIDS-SR, 50% ↓ in sxs) Sequenced Treatment Alternatives for the Relief of Depression (STAR*D), n = 2,876 (qualifying pts) 33% remission rate on citalopram (by QIDS-SR, score <5) Rx choice: according to side effects (SE’s), comorbid condn’s / risks (GMC & Ψ), ?FmRxHx 6-8wk trials each (preferable) augmentation v. switch? *QIDS-SR = Quick Inventory of Depressive Symptomatology, Self-Report (range 0-27) http://www.ids-qids.org/ MDD tx options Ψtherapy cognitive bx therapy (CBT) interpersonal therapy (IPT) psychodynamic therapy interventional Ψ electroconvulsive therapy (ECT) transcranial magnetic stimulation (TMS) vagal nerve stimulation (VNS) deep brain stimulation (DBS) other lightbox therapy (mostly for MDD w/ seasonal features) Major Depressive D/O (MDD) NATURAL HISTORY (Frank E and Thase ME, 1999 & DSM-5) recovery usually begins: w/in 3mos for two in five indivs w/in 1y for four in five indivs risk of subsequent episodes (w/in 3y) increases w/ n: ≥50% if n=1 ≥70% if n=2 ≥90% if n=3 dz course does not typically change as one ages 5-10% will eventually be dx’d w/ bipolar disorder (BD) more likely w/: onset of ‘MDD’ in adolescence a family history of BD ‘mixed features’ 6% lifetime SUI risk (Davies S et al, 2001); up to 15% w/ severe MDD Persistent depressive disorder (dysthymia) 2y of depressed mood (1y in children/adolescents) most of the day, more days than not, plus 2 of the following: appetite disturbance (↓ or ↑) veg sleep disturbance (↓ or ↑) veg ↓energy E ↓esteem E poor [ ] C hopeless H never sx-free for more than 2mos at a time overlapping dx of MDD is now allowed there has never been mania, hypomania, or cyclothymia MDD specifiers can also be used for dysthymia additionally: early onset (before age 21) late onset (at age 21 or older) w/ pure dysthymic syndrome from DSM-5 w/ persistent MDE w/ intermittent MDE’s, w/ current episode w/ intermittent MDE’s, w/o current episode --these last 3 are essentially a co-dx of MDD, but captured within the specifier… Persistent depressive disorder (dysthymia) may be more treatment-resistant (TxR) than straightforward MDD EPIDEMIOLOGY lifetime prevalence = 6% 12-mo prevalence = 0.5%, compared w/ 1.5% for MDD high comorbidity w/ personality d/o’s (particularly clusters B, C) From Sadock & Sadock & DSM-5 Case 1. 36yo F presenting w/ 3mos of ↓mood. She reports getting only ~4h of sleep/noc b/c of regular early AM awakenings. She feels drained everyday, all day long. She’s gained about 10 lbs in the last 2mos. What else would you like to ask? How would you work-up this patient? In the meantime, what would you dx and what would be your tentative tx plan? She returns 1mo later and reports that her mood continues to spiral downward. Now, she adds that she’s starting to think more morbid thoughts and that maybe it wouldn’t be such a bad thing if she weren’t around anymore. What would you ask now? How would you revise your tx plan? The pt’s sxs are finally stabilized and she returns at a later date w/ her sxs in remission x 1mo. “Doctor, I’m feeling so much better now. Do you think I can stop my psych Rxs?” How would you answer? Premenstrual dysphoric d/o Criterion A. In most menstrual cycles, ≥5 sxs in the final week before onset of menses, w/ improvement w/in a few days after onset of menses, and near-absent in the week post-menses Criterion B. ≥1 (or more) sx of marked: 1. lability (e.g., mood swings, suddenly sad, increased rejection sensitivity) 2. irritability /anger / increase in interpersonal conflicts 3. anxiety / tension / keyed-up feeling/edginess Criterion C. ≥1 (or more) sx to reach a total of 5 in combation w/ previous list: 1. anhedonia 2. [ ] impairment 3. anergia 4. significant appetite change (including specific food cravings) 5. sleep disturbance (↑ or ↓) 6. feeling overwhelmed or out of control 7. px sxs (e.g., breast tenderness/swelling, arthralgias/myalgias, bloating, wt gain) Special notes. Can’t just be menstrual exacerbation of MDD or other Axis I or II dx; must have confirmation by prospective daily rating scales during at least 2 sx-ic cycles (provisional dx allowed beforehand) Premenstrual dysphoric d/o (M)ood (labile &/or irritable &/or anxious) Sleep Interest Body Energy Concentration Appetite Out of control Treatment: SSRI daily luteal phase only (i.e., day 14 of cycle  menses) some data suggest successful in tx’ing mixed episodes, BD indivs w/ comorbid substance issues Areas of concern: Li+ ↔ renal; interaction w/ NSAIDs VPA ↔ liver; VPA in young ♀  polycystic ovarian syndrome (PCOS) Teratogenicity Li+  Ebstein’s anomaly (1st trimester) hazard ratio 10-20, but AR still 1:1000 VPA  neural tube defects AR 10% OTHER NOTES: CBZ: auto-induction, agranulocytosis Lamictal: Stevens-Johnson syndrome (SJS), interaxn w/ oral contraceptives (OCPs), interaxn w/ VPA Bipolar Disorder (BD) – treatment (cont’d) How many agents to use? combination tx often helpful in acute stabilization antipsychotics REQ’D when there are psychotic features to mood episode Adjuncts benzos --Don’t forget about ECT… Manic switch w/… reuptake blockers Lamictal, too! (van der Loos ML et al, 2009) Bipolar Disorder (BD) – natural history 60% of manic episodes immediately precede an MDE MDE’s usually significantly outnumber hypomanic and manic episodes ~10% of BD II’s  BD I episodes tend to increase in frequency/duration w/ age re: suicide… 35% lifetime prevalence of at least one SUI attempt in bipolar 15% suicide completion rate (may be an overestimate) 15x the risk of the general population (for completions) perhaps ¼ of all suicides in the population >lethality of SUI attempts in BD II (than BD I) adapated, in part,from DSM-5 Cyclothymic D/O 2y of fluctuating mood (1y in children, adolescents) hypomanic symptoms (but NOT episodes) dysthymic symptoms (but no MDEs) ≥ half the time & (no more than 2mos sx-free) EXCLUSIONS no manic/hypomanic episodes no depressive episodes Differential diagnosis Phenocopies and gray areas… Anxiety D/O’s (esp. GAD, PTSD) Schizoaffective D/O Delirium Dementia Personality D/O’s Substance/Medication-induced Depressive D/O Depressive D/O d/t Another Medical Condition Other Specified Depressive D/O Unspecified Depressive D/O Substance/Medication-induced Bipolar and Related D/O Bipolar and Related D/O d/t Another Medical Condition Other Specified Bipolar and Related D/O Unspecified Bipolar and Related D/O Depressive, Bipolar & Related D/O d/t a Another Medical Condition Endocrine (e.g., thyroid, hypothalamic-pituitary-adrenal/HPA) Neurologic (e.g., multiple sclerosis, CVA, brain tumor, Parkinson’s, Alzheimer’s/other dementia, Huntington’s, seizure d/o) Neoplastic (e.g., pancreas) TBI Autoimmune (e.g., neuropsychiatric systemic lupus erythematosus / NPSLE) Hematologic (e.g., acute intermittent porphyria / AIP) typically: anx/depr >> s/t Ψosis, mania (rare) acute abdominal pain, muscle weakness port wine-colored urine (porphobilinogen) transient damage to nerve cells Nutritional (e.g., B12) Infectious (e.g., HIV, Syphilis) Substance/Medication-induced Depressive, Bipolar & Related D/O ILLICITS can be from intoxication or withdrawal phases EtOH – typically depressive stimulants – typically manic/hypomanic --good to ask about sxs during windows of sobriety (ideally, ≥6mos) high substance comorbidity rates w/ endogenous Axis I Ψ d/o’s, though (esp. BD I) Prescription Rxs steroids IFN-α2b, RBV (HCV tx) β-blockers antidepressants α-TB drugs Other Specified / Unspecified v. Adjustment D/O (e.g., w/ depressed mood, w/ mixed anxiety & depressed mood) What is Adjustment D/O? develops in response to a stressor (w/in 3mos) terminates w/in 6mos of the end of the original precipitating stressor clinically significant b/c: there is marked distress out of proportion to the severity of the stressor or there is significant impairment Intended, in DSM-5, to be < of a residual dx and to be thought of as more in the same spectrum as Acute Stress D/O (ASD) and PTSD, but: not necessarily w/ as severe a stressor as in ASD or PTSD not necessarily w/ as severe a sx response as in ASD or PTSD Mood D/O’s lab w/u CBC Chem panel TSH B12 U-tox U-preg (dep on demographics) RPR HIV-1,2 ELISA (lower threshold for BD patients…) Summary – cont’d Diagnostic building blocks (not counting mixed feature possibilities…) Summary – cont’d Mood D/O’s are Ψ conditions where emotional dysregulation is the primary issue. Mood d/o’s can be endogenous, due to substances/medication, or due to another medical condition. There are additional phenocopies which should always be in your Ddx, including Anxiety D/O’s, Schizoaffective D/O, Personality D/O’s, Delirium, and Mild/Major Neurocognitive D/O’s. The monoamine hypothesis of depression is only a preliminary framework for conceptualizing Mood d/o’s and their tx, and requires significant theoretical revision. Mood D/O’s, like other Ψ conditions in the DSM, are best conceived as syndromes rather than as unitary or homogeneous medical conditions. A little less than ½ of tx-naïve pts will respond to their first antidepressant; only 1/3 will remit without further intervention. Non-pharmacologic approaches to treating Mood D/O’s include psychotherapy and interventional procedures (e.g., ECT). Additional case presentations Case 2. 18yo M high school student who was BIB his parents to the ER after ingesting a bottle of 50 Tylenol pills. Recently, he has been isolating himself to his room more, sitting- out dinners with the family, and has been overheard at home talking about what a horrible “sinner” he is. He has shown increasing despondence and mood lability. He is well-connected with friends at school, outgoing—and the above changes have occurred more in a matter of weeks than they have months/years. On interview, the pt appears dysphoric, tearful, and internally preoccupied. What else would you like to know? How would you work-up this patient? In the meantime, what would you dx and what would be your tentative tx plan? Case 3. 50yo F, under-employed and barely hanging-on with temp agency work, comes in for her first office visit to see you about “mood swings” that haven’t responded well to venlafaxine XR. She is dysphoric on presentation—but also quite irritable with your Q’s. This has been a lifelong issue for her, but she has managed to stay out of IP hospitalization through it all. What would you like to ask her? W/u and provisional dx & tx plan? A U-tox comes back (+)for methamphetamine. A week later, you get an angry call from the pt’s E. Coast-based sister—who complains that you have the pt on the ‘wrong Rxs.’ She shares additional hx (in her voicemail) that the pt has had past episodes of elevated mood, sexual and financial indiscretions, and demands to know how you are going to modify the tx plan. What would you tell the pt’s sister? How does this change your working dx and tx plan?
Slide 60 - Stanley Shyn, MD, PhD UW Psychiatry and Behavioral Sciences Harborview Medical Center Mood Disorders No disclosures / conflicts of interest Objectives Mood, affect, mood disorders (mood D/O’s) Nosology, epidemiology, treatment (tx) of: Major depressive disorder (MDD) Persistent depressive disorder Premenstrual dysphoric disorder Disruptive mood dysregulation disorder Bipolar disorder (BD) Cyclothymic disorder Differential diagnosis (Ddx), including: Depressive v. bipolar & related disorder due to another medical condition Substance/medication-induced depressive v. bipolar & related disorder Other specified depressive v. bipolar & related disorder Unspecified depressive v. bipolar & related disorder Mood v. Affect “mood” a sustained emotional attitude typically garnered through pt self-report “affect” the way a pt’s emotional state is conveyed relates more to others’ perception of the pt’s emotional state, responsiveness Mood disorders Ψ conditions where mood is primary, the predominant problem. Major Depressive Disorder Major Depressive D/O (MDD) Diagnosis req’s ≥1 major depressive episode (MDE) MDE = ≥2wks of signif wt Δ (↓ or ↑) insomnia or hypersomnia Ψmotor agitation/retardation (PMA/PMR) fatigue or anergia guilt/worthlessness (G/W) ↓’d [ ] recurrent thoughts of death or SI ↓’d mood anhedonia Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide 5 symptoms (with ≥1 sx in blue) Epidemiology (Kendler et al, 1993; Schlesser & Altshuler, 1983) leading cause of disability among adults under 45y of age lifetime prevalence of 12% in ♂, 20% in ♀ relative risk (RR) of 2-3 in 1o relatives of probands; 41%:13% (monozygotic: dizygotic) concordance incidence peaks in 20s (but onset in late life not uncommon) Question: When does a major depressive episode (MDE) ≠ Major Depressive Disorder? Major Depressive D/O (MDD) EXCLUSIONS: not attributable to a substance/medication or another medical condition no prior [endogenous] episodes of mania or hypomania Regarding bereavement: no longer a formal exclusion in DSM-5 because: the ‘2 month’ rule did not reflect reality the depressive feelings associated with bereavement-related depression respond to the same psychosocial and Rx txs evidence does not support a different natural course once criteria are met for an MDE… use your clinical judgment, consider norms for the individual, his/her hx, culture consider: pangs of grief, preserved self-esteem (v. self-loathing), guilt of failing the deceased (v. more general self-criticism), etc. Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥2 of the following: keyed-up/tense unusually restless can’t concentrate b/c of worry fear something awful may happen might lose control Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥3 of the following nearly everyday during an MDE: [drawn from list of sxs for a manic/hypomanic episode, minus distractibility; this list includes elevated/expansive mood…] Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern ≥1 of the following during the most severe portion of the current episode: absolute anhedonia or absolute mood non-reactivity plus ≥3 of the following: a distinct quality of depressed mood (e.g., worse than prior MDEs) worse in the AM early AM awakening (by at least 2h) marked PMA or PMR significant appetite or wt loss excessive guilt Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern mood reactivity plus ≥2 of the following: significant appetite or wt increase hypersomnia leaden paralysis long-standing interpersonal rejection sensitivity leading to social/work problems Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern delusions &/or hallucinations examples of congruent delusions: personal inadequacy, guilt, death, nihilism, deserved punishment Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during most of the episode, ≥3 of the following: stupor catalepsy (passive induction of a posture held against gravity) waxy flexibility mutism negativism posturing (spontaneous, maintenance against gravity) mannerism (odd cariacture of a normal action) stereotypy agitation (indep of external stimulus) grimacing echolalia or echopraxia Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern during pregnancy or in the 4wks after delivery Major depressive disorder w/ anxious distress w/ mixed features w/ atypical features w/ melancholic features w/ mood-[congruent, incongruent] psychotic features w/ catatonia w/ peripartum onset w/ seasonal pattern relapses and remissions occur at characteristic times of the year at least 2 seasonal MDE’s in the last 2y (and no non-seasonal MDEs during this period) seasonal episodes outnumber non-seasonal episodes (lifetime) If a patient always gets depressed with season unemployment (or the beginning of the school year), would we call this ‘w/ seasonal pattern?’ No. Belmaker RH and Agam G, NEJM 2008, 358:55-68 iproniazid (1957) imipramine (1959) The monoamine hypothesis (1965) Joseph Schildkraut Question: Do antidepressants have additional actions besides inhibition of reuptake transporters? “…the Zoloft cartoon” from: http://gifsoup.com/webroot/animatedgifs/50426_o.gif; chemical inbalance Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. J Neurosci. 2000 Dec 15;20(24):9104-10 Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Science. 2003 Aug 8;301(5634):805-9. Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Haenisch B, Bönisch H. Pharmacol Ther. 2011 Mar;129(3):352-68. Epub 2010 Dec 13. Review. Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices. Hennings EC, Kiss JP, De Oliveira K, Toth PT, Vizi ES. J Neurochem. 1999 Sep;73(3):1043-50. Block of an ether-a-go-go-like K(+) channel by imipramine rescues egl-2 excitation defects in Caenorhabditis elegans. Weinshenker D, Wei A, Salkoff L, Thomas JH. J Neurosci. 1999 Nov 15;19(22):9831-40. photo from: http://www.sciencedaily.com/releases/2006/11/061121082449.htm Subsequent hypotheses about MDD altered glutamatergic transmission ↓’d GABAergic transmission monoamine-Ach imbalance disruption of endogenous opioid signalling neurosteroid deficiencies thyroxine abnormalities cytokine-mediated x-talk betw immune system & CNS circadian abnormalities (specific brain structure/circuit dysfxns…) as summarized in Belmaker RH and Agam G, NEJM 2008, 358:55-68 MDD tx options selective serotonin reuptake inhibitors (SSRIs) fluoxetine (PROZAC), 20-80 mg/d citalopram (CELEXA), 20-40 mg/d escitalopram (LEXAPRO), 10-20 mg/d sertraline (ZOLOFT), 50-200 mg/d paroxetine (PAXIL), 20-50 mg/d serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine XR (EFFEXOR XR), 37.5-225 mg/d desvenlafaxine (PRISTIQ) duloxetine (CYMBALTA), 30-120 mg/d others bupropion SR, XL (WELLBUTRIN) 100-200 mg BID (SR) 150-450 mg/d (XL) mirtazapine (REMERON), 15-45 mg/d trazodone, 50-200mg/noc (for sleep) nefazodone tricyclic antidepressants (TCADs) amitriptyline  nortriptyline imipramine  desipramine monoamine oxidase inhibitors (MAO-Is) typically, non-selective & irreversible MAO-A (NE, EPI, 5HT, DA) MAO-B (trace amines, DA) why we “wash-out” 5HT syndrome HTNsive crisis selegiline (EMSAM) [additional] augmenting agents Li+ T3, 25 mcg/d buspirone (BuSPAR), 5-30 mg BID atypical antipsychotics Sequenced Treatment Alternatives for the Relief of Depression (STAR*D) major NIMH-funded study (PI: A. John Rush) w/ 14 regional centers & 41 clinical sites initial enrollment of 4,041 patients aim: which tx algorithms work best after an initial failure to remit non-psychotic depression w/ an antidepressant? http://www.clinicaltrials.gov/ct/show/NCT00021528?order=1 Trivedi MH et al, Am J Psychiatry. 2006 Jan;163(1):28-40 47% response rate on citalopram (by *QIDS-SR, 50% ↓ in sxs) Sequenced Treatment Alternatives for the Relief of Depression (STAR*D), n = 2,876 (qualifying pts) 33% remission rate on citalopram (by QIDS-SR, score <5) Rx choice: according to side effects (SE’s), comorbid condn’s / risks (GMC & Ψ), ?FmRxHx 6-8wk trials each (preferable) augmentation v. switch? *QIDS-SR = Quick Inventory of Depressive Symptomatology, Self-Report (range 0-27) http://www.ids-qids.org/ MDD tx options Ψtherapy cognitive bx therapy (CBT) interpersonal therapy (IPT) psychodynamic therapy interventional Ψ electroconvulsive therapy (ECT) transcranial magnetic stimulation (TMS) vagal nerve stimulation (VNS) deep brain stimulation (DBS) other lightbox therapy (mostly for MDD w/ seasonal features) Major Depressive D/O (MDD) NATURAL HISTORY (Frank E and Thase ME, 1999 & DSM-5) recovery usually begins: w/in 3mos for two in five indivs w/in 1y for four in five indivs risk of subsequent episodes (w/in 3y) increases w/ n: ≥50% if n=1 ≥70% if n=2 ≥90% if n=3 dz course does not typically change as one ages 5-10% will eventually be dx’d w/ bipolar disorder (BD) more likely w/: onset of ‘MDD’ in adolescence a family history of BD ‘mixed features’ 6% lifetime SUI risk (Davies S et al, 2001); up to 15% w/ severe MDD Persistent depressive disorder (dysthymia) 2y of depressed mood (1y in children/adolescents) most of the day, more days than not, plus 2 of the following: appetite disturbance (↓ or ↑) veg sleep disturbance (↓ or ↑) veg ↓energy E ↓esteem E poor [ ] C hopeless H never sx-free for more than 2mos at a time overlapping dx of MDD is now allowed there has never been mania, hypomania, or cyclothymia MDD specifiers can also be used for dysthymia additionally: early onset (before age 21) late onset (at age 21 or older) w/ pure dysthymic syndrome from DSM-5 w/ persistent MDE w/ intermittent MDE’s, w/ current episode w/ intermittent MDE’s, w/o current episode --these last 3 are essentially a co-dx of MDD, but captured within the specifier… Persistent depressive disorder (dysthymia) may be more treatment-resistant (TxR) than straightforward MDD EPIDEMIOLOGY lifetime prevalence = 6% 12-mo prevalence = 0.5%, compared w/ 1.5% for MDD high comorbidity w/ personality d/o’s (particularly clusters B, C) From Sadock & Sadock & DSM-5 Case 1. 36yo F presenting w/ 3mos of ↓mood. She reports getting only ~4h of sleep/noc b/c of regular early AM awakenings. She feels drained everyday, all day long. She’s gained about 10 lbs in the last 2mos. What else would you like to ask? How would you work-up this patient? In the meantime, what would you dx and what would be your tentative tx plan? She returns 1mo later and reports that her mood continues to spiral downward. Now, she adds that she’s starting to think more morbid thoughts and that maybe it wouldn’t be such a bad thing if she weren’t around anymore. What would you ask now? How would you revise your tx plan? The pt’s sxs are finally stabilized and she returns at a later date w/ her sxs in remission x 1mo. “Doctor, I’m feeling so much better now. Do you think I can stop my psych Rxs?” How would you answer? Premenstrual dysphoric d/o Criterion A. In most menstrual cycles, ≥5 sxs in the final week before onset of menses, w/ improvement w/in a few days after onset of menses, and near-absent in the week post-menses Criterion B. ≥1 (or more) sx of marked: 1. lability (e.g., mood swings, suddenly sad, increased rejection sensitivity) 2. irritability /anger / increase in interpersonal conflicts 3. anxiety / tension / keyed-up feeling/edginess Criterion C. ≥1 (or more) sx to reach a total of 5 in combation w/ previous list: 1. anhedonia 2. [ ] impairment 3. anergia 4. significant appetite change (including specific food cravings) 5. sleep disturbance (↑ or ↓) 6. feeling overwhelmed or out of control 7. px sxs (e.g., breast tenderness/swelling, arthralgias/myalgias, bloating, wt gain) Special notes. Can’t just be menstrual exacerbation of MDD or other Axis I or II dx; must have confirmation by prospective daily rating scales during at least 2 sx-ic cycles (provisional dx allowed beforehand) Premenstrual dysphoric d/o (M)ood (labile &/or irritable &/or anxious) Sleep Interest Body Energy Concentration Appetite Out of control Treatment: SSRI daily luteal phase only (i.e., day 14 of cycle  menses) some data suggest successful in tx’ing mixed episodes, BD indivs w/ comorbid substance issues Areas of concern: Li+ ↔ renal; interaction w/ NSAIDs VPA ↔ liver; VPA in young ♀  polycystic ovarian syndrome (PCOS) Teratogenicity Li+  Ebstein’s anomaly (1st trimester) hazard ratio 10-20, but AR still 1:1000 VPA  neural tube defects AR 10% OTHER NOTES: CBZ: auto-induction, agranulocytosis Lamictal: Stevens-Johnson syndrome (SJS), interaxn w/ oral contraceptives (OCPs), interaxn w/ VPA Bipolar Disorder (BD) – treatment (cont’d) How many agents to use? combination tx often helpful in acute stabilization antipsychotics REQ’D when there are psychotic features to mood episode Adjuncts benzos --Don’t forget about ECT… Manic switch w/… reuptake blockers Lamictal, too! (van der Loos ML et al, 2009) Bipolar Disorder (BD) – natural history 60% of manic episodes immediately precede an MDE MDE’s usually significantly outnumber hypomanic and manic episodes ~10% of BD II’s  BD I episodes tend to increase in frequency/duration w/ age re: suicide… 35% lifetime prevalence of at least one SUI attempt in bipolar 15% suicide completion rate (may be an overestimate) 15x the risk of the general population (for completions) perhaps ¼ of all suicides in the population >lethality of SUI attempts in BD II (than BD I) adapated, in part,from DSM-5 Cyclothymic D/O 2y of fluctuating mood (1y in children, adolescents) hypomanic symptoms (but NOT episodes) dysthymic symptoms (but no MDEs) ≥ half the time & (no more than 2mos sx-free) EXCLUSIONS no manic/hypomanic episodes no depressive episodes Differential diagnosis Phenocopies and gray areas… Anxiety D/O’s (esp. GAD, PTSD) Schizoaffective D/O Delirium Dementia Personality D/O’s Substance/Medication-induced Depressive D/O Depressive D/O d/t Another Medical Condition Other Specified Depressive D/O Unspecified Depressive D/O Substance/Medication-induced Bipolar and Related D/O Bipolar and Related D/O d/t Another Medical Condition Other Specified Bipolar and Related D/O Unspecified Bipolar and Related D/O Depressive, Bipolar & Related D/O d/t a Another Medical Condition Endocrine (e.g., thyroid, hypothalamic-pituitary-adrenal/HPA) Neurologic (e.g., multiple sclerosis, CVA, brain tumor, Parkinson’s, Alzheimer’s/other dementia, Huntington’s, seizure d/o) Neoplastic (e.g., pancreas) TBI Autoimmune (e.g., neuropsychiatric systemic lupus erythematosus / NPSLE) Hematologic (e.g., acute intermittent porphyria / AIP) typically: anx/depr >> s/t Ψosis, mania (rare) acute abdominal pain, muscle weakness port wine-colored urine (porphobilinogen) transient damage to nerve cells Nutritional (e.g., B12) Infectious (e.g., HIV, Syphilis) Substance/Medication-induced Depressive, Bipolar & Related D/O ILLICITS can be from intoxication or withdrawal phases EtOH – typically depressive stimulants – typically manic/hypomanic --good to ask about sxs during windows of sobriety (ideally, ≥6mos) high substance comorbidity rates w/ endogenous Axis I Ψ d/o’s, though (esp. BD I) Prescription Rxs steroids IFN-α2b, RBV (HCV tx) β-blockers antidepressants α-TB drugs Other Specified / Unspecified v. Adjustment D/O (e.g., w/ depressed mood, w/ mixed anxiety & depressed mood) What is Adjustment D/O? develops in response to a stressor (w/in 3mos) terminates w/in 6mos of the end of the original precipitating stressor clinically significant b/c: there is marked distress out of proportion to the severity of the stressor or there is significant impairment Intended, in DSM-5, to be < of a residual dx and to be thought of as more in the same spectrum as Acute Stress D/O (ASD) and PTSD, but: not necessarily w/ as severe a stressor as in ASD or PTSD not necessarily w/ as severe a sx response as in ASD or PTSD Mood D/O’s lab w/u CBC Chem panel TSH B12 U-tox U-preg (dep on demographics) RPR HIV-1,2 ELISA (lower threshold for BD patients…) Summary – cont’d Diagnostic building blocks (not counting mixed feature possibilities…) Summary – cont’d Mood D/O’s are Ψ conditions where emotional dysregulation is the primary issue. Mood d/o’s can be endogenous, due to substances/medication, or due to another medical condition. There are additional phenocopies which should always be in your Ddx, including Anxiety D/O’s, Schizoaffective D/O, Personality D/O’s, Delirium, and Mild/Major Neurocognitive D/O’s. The monoamine hypothesis of depression is only a preliminary framework for conceptualizing Mood d/o’s and their tx, and requires significant theoretical revision. Mood D/O’s, like other Ψ conditions in the DSM, are best conceived as syndromes rather than as unitary or homogeneous medical conditions. A little less than ½ of tx-naïve pts will respond to their first antidepressant; only 1/3 will remit without further intervention. Non-pharmacologic approaches to treating Mood D/O’s include psychotherapy and interventional procedures (e.g., ECT). Additional case presentations Case 2. 18yo M high school student who was BIB his parents to the ER after ingesting a bottle of 50 Tylenol pills. Recently, he has been isolating himself to his room more, sitting- out dinners with the family, and has been overheard at home talking about what a horrible “sinner” he is. He has shown increasing despondence and mood lability. He is well-connected with friends at school, outgoing—and the above changes have occurred more in a matter of weeks than they have months/years. On interview, the pt appears dysphoric, tearful, and internally preoccupied. What else would you like to know? How would you work-up this patient? In the meantime, what would you dx and what would be your tentative tx plan? Case 3. 50yo F, under-employed and barely hanging-on with temp agency work, comes in for her first office visit to see you about “mood swings” that haven’t responded well to venlafaxine XR. She is dysphoric on presentation—but also quite irritable with your Q’s. This has been a lifelong issue for her, but she has managed to stay out of IP hospitalization through it all. What would you like to ask her? W/u and provisional dx & tx plan? A U-tox comes back (+)for methamphetamine. A week later, you get an angry call from the pt’s E. Coast-based sister—who complains that you have the pt on the ‘wrong Rxs.’ She shares additional hx (in her voicemail) that the pt has had past episodes of elevated mood, sexual and financial indiscretions, and demands to know how you are going to modify the tx plan. What would you tell the pt’s sister? How does this change your working dx and tx plan?