Evidence-Based Treatment Recommendations for Bipolar

Handout for the Neuroscience Education Institute (NEI) online activity:

Fixing the Mix-Up Over Mixed Depression

Diagnosing and Treating DSM-5 Defined Mixed Features in Mood Disorders

• Utilize evidence-based strategies to identify patients with mixed depression

• Optimize treatment strategies for patients with mixed depression

• Rationale for supplanting mixed states with mixed specifier: déjà-vu all over again! • Clinical implications of mixed features in mood disorders • Treating mixed features in mood disorders

I feel competent diagnosing patients with mixed depression.

1. 1 (strongly disagree) 2. 2 3. 3 4. 4 5. 5 (strongly agree)

I feel competent optimizing treatment for patients with mixed depression.

1. 1 (strongly disagree) 2. 2 3. 3 4. 4 5. 5 (strongly agree)

In the recently released Diagnostic and Statistical Manual of Mental Disorders (DSM-5), "mixed states" is replaced with "mixed specifier." Rationales for this revision include:

1. The real world presentation of mixed states was not captured in the DSM-IV 2. Rates of misdiagnosis of bipolar disorder were very high based on DSM-IV criteria 3. Mixed states were being inappropriately treated 4. 1 and 2 only 5. 2 and 3 only 6. All of the above

Kate is a 26-year-old patient with bipolar depression who is currently showing some manic symptoms. According to the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study, the most common subsyndromal manic symptom is:

1. Decreased need for sleep 2. Flight of ideas/racing thoughts 3. Distractibility 4. Increased activity 5. High-risk activity

BD NOS Bipolar I • Subthreshold • Increased energy/activity hypomania during • Capture subthreshold MDE in MDD • Duration, symptom count • Increased energy/ episode types • Allow mixed hypomania activity • Spectrum • Unipolar mania MDD Bipolar II

• Subthreshold features in MDD • Specifier "with mixed features" • Cyclothymia and other subthreshold presentations • Developmental issues MDE, major depressive episode; MDD, major depressive disorder; BD NOS, bipolar disorder not otherwise specified. Copyright © 2015 Neuroscience Education Institute. All rights reserved. Kraepelin Conceptualized Affective States as a Continuum

Kraepelin conceptualized not only mood cycling up and down, but also thought processes and volition

6 types of mixed states were identified Pure mania (flight of ideas, euphoria, hyperactivity)

Depressive or anxious mania (depressed mood but elevated will and thought)

1 4 6 5 7 2 1 Excited depression (depressed mood and will but elevated thought)

Manic with thought poverty (elevated mood and will but decreased thought)

Manic stupor (elevated mood but decreased will and thought)

Depression with flight of ideas (depressed mood and thought but elevated will)

1 2 3 5 6 8 1 Inhibited mania (elevated mood and thought but decreased will)

Thought Mood Volition Pure depression (thought inhibition, disturbance disturbance disturbance depressive mood, weakness of volition) Marneros A, Goodwin F. Bipolar Disorders: Mixed States, Rapid Cycling and Atypical Forms. Cambridge University Press, 2005:1-44.

Core Elevated Elevated mood + Depressed mood symptoms mood depressed mood or loss of interest or loss of interest Manic >3 >3 <3 Depressive <5 >5 >5

DSM- Manic Mixed Depressive IV-TR

Depressive with DSM-5 Manic Manic with mixed features Depressive mixed features

Core Elevated mood Elevated mood Depressed mood Depressed mood symptoms + energy + energy or loss of interest or loss of interest Manic >3 >3 >3 <3 Depressive <5 >3 >5 >5

APA. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text Rev. 2000; APA. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. 2013.

DSM-IV-TR DSM-5 Specific chapter No Yes Increased activity/energy Not core mania Yes, core mania criteria criteria Mixed episodes Mania subtype Modifier* (specifier?) categorical for either depressive or manic episodes Antidepressant switching Not bipolar Bipolar Additional "specifiers" Anxiety, suicide Other bipolar disorders NOS Other unspecified bipolar and related disorders

APA. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text Rev. 2000; APA. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. 2013.

• Real world presentation of mixed states not aligned with DSM-IV-TR description • Bipolar disorder: high rates of misdiagnosis • Suicidality and mixed states • Inappropriate treatment of mixed states (e.g., antidepressants)

Unemployment rate for patients with pure mania vs. mania with MFS

MFS, DSM-5 defined mixed features. McIntyre et al. International Mood Disorders Collaborative Project. 2014. Copyright © 2015 Neuroscience Education Institute. All rights reserved. Individuals With DSM-5 Defined Mixed Features: More Cardiovascular Disease

Prevalence of cardiovascular disease in patients with pure mania vs. mania with MFS

MFS=DSM-5 defined mixed features

MFS, DSM-5 defined mixed features. McIntyre et al. International Mood Disorders Collaborative Project. 2014. Copyright © 2015 Neuroscience Education Institute. All rights reserved. Evidence Base Supporting Dimensionality in Mood Disorders

Stanley Network Studies

Munich Study

NIMH Depression Collaborative Study

STEP-BD Study

BRIDGE Study

NIMH, National Institute of Mental Health; STEP-BD, Systematic Treatment Enhancement Program for Bipolar Disorder; BRIDGE, Bipolar Disorders: Improving Diagnosis, Guidance and Education.

146 Bipolar I Patients 86 Bipolar II Patients % wks Followed for 12.8 years % wks Followed for 13.4 years 50 50

40 40

30 30

20 20

10 10

Subsyndromal, Major Subsyndromal, Major minor depressive, depression/ minor depressive, depression/ hypomanic mania hypomanic mania symptoms symptoms

Judd LL et al. Arch Gen Psychiatry 2002;59:530-7; Judd LL et al. Arch Gen Psychiatry 2003;60:261-9. Copyright © 2015 Neuroscience Education Institute. All rights reserved. Progression to Bipolar Disorder From MDD With Subthreshold Hypomania

Time to Hypomania or Mania <3 Manic symptoms 1.0 Time to Hypomania 1.0 ≥3 Symptoms

Time to Mania

0.9

0.9 0.8

0.7 0.8

0.6

Proportion Without Proportion

Hypomania or Mania Hypomania Hypomania or Mania or Hypomania

0.7 0.5 0 260 520 780 1040 1300 1560 0 260 520 780 1040 1300 1560 Weeks to Follow-up Weeks to Follow-up 19.6% of patients converted to bipolar disorder during follow-up

N=550 individuals followed for >1 year (mean follow-up: 17.5 years) after a diagnosis of major depression at intake. Fiedorowicz JG et al. Am J Psychiatry 2011;168:40-8. Copyright © 2015 Neuroscience Education Institute. All rights reserved. Specific DSM-IV Manic Symptoms During an Index Episode of Bipolar Depression in STEP-BD

35 No mania Subsyndromal mania Full mixed episode (31.2%) (54.0%) (14.8%) 30

20 Percent of Patients 15

0 0 1 2 3 4 5 6 7 Number of DSM-IV Manic Symptoms Goldberg JF et al. Am J Psychiatry 2009;166:173-81. Copyright © 2015 Neuroscience Education Institute. All rights reserved. Specific DSM-IV Manic Symptoms During an Index Episode of Bipolar Depression in STEP-BD

50 Full mixed episode (n = 204) Subsyndromal mania (n = 745) 40 Percent of 30 Patients 20

Goldberg JF et al. Am J Psychiatry 2009;166:173-81. Copyright © 2015 Neuroscience Education Institute. All rights reserved. 3-Fold Higher Rate of Bipolar Disorder Among Individuals With MDD When Using Bipolar Specifier

Demographic Features of the Study Sample No. (%) Country Patients, Hospitalized, Age, Mean (SD), Male Sex, Bipolar DSM-IV- Bipolar No. % y % TR Specifier Bosnia 200 46.5 46.3 (10.9) 32.5 45 (22.5) 111 (55.5) Bulgaria 300 46.0 49.8 36.5 56 (18.7) 171 (57.0) China 727 45.9 39.7 (14.4) 39.1 105 (14.4) 290 (39.9) Egypt 306 24.2 37.7 (12.8) 49.0 42 (13.7) 144 (47.1) Georgia 254 18.5 46.5 (15.0) 32.9 39 (15.4) 103 (40.6) Germany 251 59,4 48.0 (12.3) 36.8 29 (11.6) 102 (40.6) Iran 313 37.4 38.4 (12.3) 33.9 57 (18,2) 169 (54.0) Korea 212 25.5 45.0 (14.5) 27.8 15 (7.1) 55 (25.9) Macedonia 224 26,8 47.5 (13.3) 28.6 29 (12.9) 107 (47.8) Morocco 317 20.8 39.7 (11.5) 38.3 55 (17.4) 148 (46.7) Netherlands 220 12.7 46.1 (13.7) 40.0 28 (12.7) 81 (36.8) Pakistan 265 37.0 38.2 (12.0) 50.4 60 (22.6) 158 (59.6) Portugal 311 11.9 45.9 (13.0) 25.7 45 (14.5) 172 (55.3) Slovakia 297 57,6 48.4 (13.2) 38.0 50 (16.8) 166 (55.9) Spain 655 25,5 47.2 (13.9) 33.1 100 (15,3) 324 (49.5) Taiwan 420 14.8 45.3 (12.7) 27.2 64 (15.2) 149 (35.5) Ukraine 297 73.7 46.9 (13.1) 29.6 65 (21.9) 156 (52.5) Vietnam 66 37.9 40.7 (11.1) 51.5 19 (28.8) 41 (62.1) Total 5635 34.4 44.1 (13.7) 35.5 903 (16.0) 2647 (47.0)

Angst J et al. Arch Gen Psychiatry 2011;68:791-8. Copyright © 2015 Neuroscience Education Institute. All rights reserved. Mixed Features Commonly Encountered in Adults With Both Major Depressive Disorder and Bipolar Disorder: The International Mood Disorders Collaborative Project

% of individuals who met criteria for MFS during an index major depressive episode

34.0% 33.8%

26.0%

n=149 n=65 n=49 MDD BD-I BD-II

*Data from a post hoc analysis of participants who met criteria for a current mood episode as part of MDD (n=506) or BD (BD-I: n=216, BD-II: n=130)

Mixed features specifier (MFS) was operationalized as a score ≥1 on 3 or more select items on the Young Mania Rating Scale (YMRS) or ≥1 on 3 select items on the Montgomery-Åsberg Depression Rating Scale (MADRS) or the Hamilton Depression Rating Scale (HAMD-17) during an index major depressive episode (MDE) or a hypo/manic episode, respectively. McIntyre RS et al. J Affective Disord 2015;172C:259-64. Copyright © 2015 Neuroscience Education Institute. All rights reserved. MDD and Subthreshold Bipolarity

• 10-year prospective study; n=2,210 subjects (14–24 years at baseline) • Subthreshold BD = MDD + hypo/manic symptoms, but never having met criteria for (hypo)mania • Among 488 respondents with MDD, 60% had pure MDD and 40% had subthreshold BD • Subthreshold BD cases had: – Significantly increased family history of mania – Higher rates of nicotine dependence, alcohol use disorder, and panic disorder • Subthreshold BD converted more often to BD than to pure MDD

• Approximately 20–55% of MDD cases are characterized by lifetime symptoms of some degree of subthreshold hypomania • Compared to those with "pure" depression, those with lifetime subthreshold hypomanic symptoms may have more complex illness and less favorable course and outcome

DSM-5: inter-rater reliability of diagnoses from the initial field trials (adult diagnoses) Kappa Major neurocognitive disorder 0.78 Posttraumatic stress disorder 0.67 Complex somatic symptom disorder revised 0.61 Hoarding disorder 0.59 Bipolar I disorder 0.56 Binge eating disorder 0.56 Borderline personality disorder 0.54 Schizoaffective disorder 0.50 Mild neurocognitive disorder 0.48 Schizophrenia 0.46 Attenuated psychotic symptoms syndrome 0.46 Alcohol use disorder 0.40 Bipolar II disorder 0.40 Mild traumatic brain injury 0.36 Obsessive–compulsive personality disorder 0.31 Major depressive disorder 0.28 Very good agreement Good agreement Antisocial personality disorder 0.21 Questionable agreement Generalized anxiety disorder 0.20 Unacceptable agreement Mixed anxiety-depressive disorder -0.004 Kappa: -0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 Adult diagnosis

Pooled data presented from DSM-5 field trials sites, except for the diagnosis of complex Regier et al. Am J Psychiatry 2013;170:59-70; somatic symptoms disorder revised, hoarding disorder, binge eating disorder, schizoaffective Freedman et al. Am J Psychiatry 2013;170(1):1-5; disorder, attenuated psychotic symptoms syndrome, bipolar II disorder, obsessive–compulsive APA. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. 2013. disorder, antisocial personality disorder, and generalized anxiety disorder

Full criteria for an MDE and ≥3 of these manic symptoms • Elevated, expansive mood • Inflated self-esteem or grandiosity • More talkative than usual or pressure to keep talking • Flight of ideas or racing thoughts • Increase in energy or goal-directed activity (either socially, at work or school, or sexually) • Increased or excessive involvement in activities that have a high potential for painful consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments) • Decreased need for sleep

APA. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. 2013. Copyright © 2015 Neuroscience Education Institute. All rights reserved. Anxiety Distress Specifier Also Frequently Applies to BD and MDD

• With anxious distress:

– Feeling keyed up or – Feeling unusually restless tense – Fear that something awful – Difficulty concentrating might happen because of worry

– Fear that individual

might lose control of him- or herself – Moderate-severe: 4-5 symptoms – Mild: 2 symptoms – Severe: 4-5 symptoms + – Moderate: 3 symptoms motor agitation

Diagnostic criteria Mixed features (DSM-5) Mixed episode (DSM-IV) A specifier that can be added to manic, State in which the full criteria for both hypomanic, or depressive episodes a manic and a depressive episode are met e.g., "manic episode with mixed simultaneously (depressive) features" Describing patients Mixed mania/mania with subsyndromal depression Manic/hypomanic episode with Presence of depressive symptoms during depressive symptoms a manic episode Mixed depression/depressive episode with subsyndromal mania MDE with hypomanic symptoms Presence of manic symptoms during a depressive episode MDE, major depressive episode. APA. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text Rev. 2000; APA Diagnostic and Statistical Manual of Mental Disorders. 5th ed. 2013. Copyright © 2015 Neuroscience Education Institute. All rights reserved. DSM-5: Not Included in Mixed Specifier

Symptoms that could overlap on either pole: • Distractibility • Irritability • Insomnia or hypersomnia per se • Indecisiveness • Anxiety

Bipolar I depression more likely if ≥5: Symptomatology Hypersomnia Hyperphagia Psychomotor retardation Other "atypical" symptoms Psychosis and/or pathological guilt (OR=3.3) Mood lability or manic symptoms Onset and Course Earlier onset (<25 years) (OR=1.9) Multiple (≥5) depressive episodes Family History Bipolar disorder (OR=2.6)

Confirmation of specific numbers requires further study. OR = odds ratio from Othmer E et al. J Clin Psychiatry 2007;68(1):47-51. Mitchell PB et al. Bipolar Disord 2008;10(1, pt 2):144-52. Copyright © 2015 Neuroscience Education Institute. All rights reserved. Subsyndromal Hypomanic Symptoms Increase Risk of Switching

5 2.0 * † 4 1.6

3 1.2 YMRS CGI Score Severity Mania 2 0.8

1 0.4

0 0 TEM ADR ADNR TEM ADR ADNR (n = 44) (n = 84) (n = 44) (n = 44) (n = 84) (n = 494) *F(2,169) = 4.5; P < 0.01 †F(2,169) = 3.4; P = 0.04

TEM, treatment-emergent mania; ADR, antidepressant responder; ADNR, antidepressant non-responder. Frye MA et al. Am J Psychiatry 2009;166(2):164-72. Copyright © 2015 Neuroscience Education Institute. All rights reserved. Higher Risk for Treatment-Emergent Affective Switching

• Bipolar I > bipolar II • TCA or SNRI use • History of antidepressant- • Absence of antimanic induced mania mood stabilizer • Mixed depression • Genetic factors • Low TSH with TCA use • Comorbid alcoholism • Hyperthymic • Female gender + temperament comorbid anxiety disorder

SNRI, serotonin-norepinephrine reuptake inhibitor; TCA, tricyclic antidepressant; TSH, thyroid-stimulating hormone.

Bond DJ et al. J Clin Psychiatry 2008;69:1589-1601; Frye MA et al. Am J Psychiatry 2009;166:164- 72; Salvadore G et al. J Clin Psychiatry 2010;71:1488-1501. Copyright © 2015 Neuroscience Education Institute. All rights reserved. Obesity Changes Phenotype of Mood Disorder

• Atypical features • More severe (e.g., suicide Obesity + MDD risk) • Poor cognitive performance

• Predominance of depressive symptoms • More severe (e.g., suicide Obesity + BD risk) • Anxiety symptoms • Poor cognitive performance

ISBD Task Force Recommendations 1. Adjunctive antidepressants for acute bipolar depression a. Permissible if history of positive antidepressant response b. Avoid in the presence of ≥2 core manic symptoms, psychomotor agitation, or rapid cycling 2. Antidepressant monotherapy for acute bipolar depression a. Avoid in bipolar I disorder b. Avoid in bipolar II disorder in the presence of ≥2 core manic symptoms 3. Adjunctive antidepressants for bipolar maintenance a. Permissible if patient relapses into depressive episode after stopping antidepressant therapy

See ISBD Task Force description at http://www.isbd.org/task-forces/past-task-forces. Pacchiarotti I et al. Am J Psychiatry 2013;170(11):1249-62; Vieta E. Antidepressant Use in Bipolar Disorder: The ISBD Task Force Consensus Report. Presented at International Conference on Bipolar Disorders. 2013. Copyright © 2015 Neuroscience Education Institute. All rights reserved. Antidepressant Use in Bipolar Disorder (cont)

ISBD Task Force Recommendations 4. Antidepressant-Induced Switching to Mania/Hypomania or Mixed Features and Rapid Cycling a. Monitor patient and discontinue antidepressants in response to emergent mania, hypomania, or psychomotor agitation b. Discourage antidepressants if there is a history of antidepressant-emergent mania/hypomania or mixed episodes c. Avoid if there is high mood instability or a history of rapid cycling 5. Antidepressant Use in Mixed States a. Avoid during manic or depressive episodes with mixed features b. Avoid in patients with predominantly mixed states c. Discontinue if a mixed state emerges 6. Antidepressant Classes and Increased Risk of Mood Switching (SNRIs and TCAs) a. Permissible only after trials of other antidepressants tried and if patient is closely monitored for switch or mood destabilization See ISBD Task Force description at http://www.isbd.org/task-forces/past-task-forces. Pacchiarotti I et al. Am J Psychiatry 2013;170(11):1249-62; Vieta E. Antidepressant Use in Bipolar Disorder: The ISBD Task Force Consensus Report. Presented at International Conference on Bipolar Disorders. 2013. Copyright © 2015 Neuroscience Education Institute. All rights reserved. Mixed Features Specifier Common in Bipolar Depression

• 56.1% met the severity criterion (YMRS score ≥4) for mixed features • (43.1%) met an alternative item-based criterion (YMRS score ≥2 on 2 or more items) • Mixed features were more likely • Female • White • Earlier age at onset of bipolar illness • History of rapid cycling • Higher baseline levels of anxiety YMRS, Young Mania Rating Scale. McIntyre RS et al. J Clin Psychiatry 2015;76(4):398-405. Copyright © 2015 Neuroscience Education Institute. All rights reserved. Lurasidone Effective in Bipolar Depression With Hypomanic Symptoms (DSM-5 Specifier)

MADRS responder rates (6-week LOCF-endpoint): Change from baseline in YMRS score groups with groups with and without subsyndromal hypomania and without subsyndromal hypomania 70 0.5 0.3

Lurasidone Placebo 0.1

60 ** 0.0 ** ** 53.2 51.2 51.1

50 -0.5

40 -1.0

32.2 31.1

30 27.8 -1.5 Responder rate (%) rate Responder 20 -2.0

-2.3 10 -2.5 -2.4 -2.4 LS mean YMRS mean scoreYMRS LS change (Week 6) Lurasidone Placebo 0 -3.0 -2.8 Subsyndromal Subsyndromal No subsyndromal Subsyndromal Subsyndromal No subsyndromal hypomania hypomania (score of hypomania hypomania hypomania (score of hypomania (baseline YMRS ≥4) ≥2 for 2 or more (baseline YMRS ≥4) ≥2 for 2 or more YMRS items) YMRS items) Lurasidone (20–120 mg/day) Lurasidone (20–120 mg/day) **p<0.01

36 McIntyre RS et al. J Clin Psychiatry 2015;76(4):398-405. Copyright © 2015 Neuroscience Education Institute. All rights reserved. Lurasidone for the Treatment of Major Depressive Disorder With Mixed Features: A Randomized, Double-Blind, Placebo- Controlled Study

Double-Blind Phase Study dosing Days 1–7: 20 mg/day Days 8–43: flexible, 20–60 mg/day

Lurasidone 20–60 mg/day

Extension Screening Study 306

(US Sites) Baseline 3–14 Placebo

Days

Day 1

Planned N=200 (100/arm) 6 Weeks 12 Weeks FPI: Sep 2011 LPO: Oct 2014

FPI, first patient in; LPO, last patient out; US, United States. Suppes T et al. Am J Psychiatry 2015; Epub ahead of Print. Copyright © 2015 Neuroscience Education Institute. All rights reserved. Key Inclusion Criteria

• All patients (aged 18–75 years) were required to meet criteria for major depressive disorder plus 2 or 3 of the following manic symptoms (occurring on most days over the last 2 weeks or longer):

• Elevated, expansive mood • Inflated self-esteem or grandiosity • More talkative than usual or pressure to keep talking • Flight of ideas or subjective experience that thoughts are racing • Increase in energy or goal-directed activity (socially, at work or school, or sexually) • Increased or excessive involvement in activities that have a high potential for painful consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments) • Decreased need for sleep (feeling rested despite sleeping less than usual; in contrast to insomnia)

Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

0.0

-5.0 Effect size = 0.8 *

-10.0 ** -13.0

-15.0 *** *** -20.0 *** -20.5 ***

LS MeanLS Change From Baseline -25.0 Placebo (N=100) Lurasidone (N=108) BL mean = 33.3 BL mean = 33.2

*P<0.05; **P<0.01; ***P<0.001. ITT population. MADRS scale range, 0-60. Mean daily dose of lurasidone was 36.2 mg/day. Suppes T et al. Am J Psychiatry 2015; Epub ahead of Print. Copyright © 2015 Neuroscience Education Institute. All rights reserved. Lurasidone Reduces Hypomanic Severity in Adults With MDD and Mixed Features

Placebo (N=100) Lurasidone (N=108)

0.0

-5.0 -4.7

-7.0** BL mean = 10.3 BL mean = 11.1

-10.0 Mean Mean Change From Baseline

**P<0.01.

YMRS, Young Mania Rating Scale. Suppes T et al. Am J Psychiatry 2015; Epub ahead of Print. Copyright © 2015 Neuroscience Education Institute. All rights reserved. Lurasidone Reduces Anxiety Severity in Adults With MDD and Mixed Features

Placebo (n=99) Lurasidone (n=106)

0.0

-5.0 -5.6

BL mean = 16.7 -10.0 -9.9***

***P<0.001 BL mean = 17.0 -15.0

Mean Mean Change From Baseline HAM-A, Hamilton Anxiety Rating Scale.

HAM-A, Hamilton Anxiety Rating Scale.

Suppes T et al. Am J Psychiatry 2015; Epub ahead of Print. Copyright © 2015 Neuroscience Education Institute. All rights reserved. Lurasidone Reduces Global Illness Severity in Adults With MDD and Mixed Features

Placebo (n=80) Lurasidone (n=80)

0.0

-5.0

-6.4

-10.0 -10.7*** BL mean = 20.5

-15.0 BL mean = 19.9 Mean Mean Change From Baseline ***P<0.001.

SDS, Sheehan Disability Scale. Suppes T et al. Am J Psychiatry 2015; Epub ahead of Print. Copyright © 2015 Neuroscience Education Institute. All rights reserved. Olanzapine Monotherapy Is Efficacious in the Treatment of Bipolar Depression With Mixed Features

Remission rate by mixed features category. Abbreviation: NNT=number needed to treat. Mixed feature was defined by the number of baseline Young Mania Rating Scale items with scores ≥1. Remission was defined as the patient whose Montgomery–Åsberg Depression Rating Scale total .s exact test. Interaction p-values are from the Breslow–Day test׳score was ≤12 at 6 weeks. Treatment comparison p-values are from Fisher Tohen M et al. J Affective Disord 2014;164:57-62. Copyright © 2015 Neuroscience Education Institute. All rights reserved. Bipolar I and II Depression: Quetiapine XR

Week 0 1 2 3 4 5 6 7 8

Quetiapine XR 300 mg/day (n=133) aseline aseline

B -5 Placebo (n=137)

rom rom

otal Score Score otal F

T -10

*** -15 *** MADRS MADRS *** *** *** -20 *** ***

LSM Change Change LSM *** Improvement -25

***P<0.001 vs. placebo XR, extended release. Suppes T. J Affective Disord 2010;121:106. Copyright © 2015 Neuroscience Education Institute. All rights reserved. 6-Week, Randomized, Double-Blind, Placebo-Controlled Trial of Ziprasidone for the Acute Depressive Mixed State

Ziprasidone vs. placebo: 6-week change in MADRS from baseline. Error bars indicate standard deviation. Treatment response by categorical group was 52.9% for ziprasidone vs. 28.9% for placebo (χ2 = 4.29, df = 1, p = 0.04). Treatment remission by categorical group was 50.0% for ziprasidone vs. 18.4% for placebo (χ2 = 8.05, df = 1, p = 0.0045). Patkar A et al. PLOS ONE 2012;7(4):e34757. Copyright © 2015 Neuroscience Education Institute. All rights reserved. Asenapine in Mania With Depressive Symptoms (DSM-5 Specifier)

Improvement of depressive symptoms at Week 3

Mild depressive symptoms Moderate depressive symptoms Severe depressive symptoms 70 70 70

* ** *

60 60 60

50 50 50

40 40 40

30 30 30

20 20 20

Remission rate (%) rate Remission (%) rate Remission (%) rate Remission 10 10 10

0 0 0 Placebo (n=69) Placebo (n=40) Placebo (n=12) Asenapine (n=113) Asenapine (n=56) Asenapine (n=12) Olanzapine (n=132) Olanzapine (n=66) Olanzapine (n=16) *p≤0.05, **p≤0.01 vs. placebo

Cut-offs used to define depressive symptom severity in patients with ≥3 depressive features: mild (score ≥1 for MADRS items and ≥2 for PANSS item), moderate (score ≥2 MADRS, ≥3 PANSS) and severe (score ≥3 MADRS, ≥4 PANSS) symptoms; remission defined as MADRS 12; post hoc analysis. McIntyre et al. J Affective Disord 2013;150(2):378-83. Copyright © 2015 Neuroscience Education Institute. All rights reserved. Adverse Effect Profiles for Atypical Antipsychotics

Adverse Event ARI ASE CLZ ILE LUR OLZ QUE RIS ZIP

METABOLIC Weight gain +/0 +/0 ++++ ++ +/0 +++ ++ ++ +/0 Dyslipidemia 0 0 ++ 0 0 +++ + + 0 Glucose dysregulation 0 0 ++ 0 0 ++ + + 0

NEUROLOGICAL Somnolence/sedation + 0/+ ++++ + 0 +++ +++ ++ + EPS + 0 0 0 0/+ + 0 ++ +

CARDIOVASCULAR Myocarditis/cardiomyopathy 0 0 +/0 0 0 0 0 0 0 QTc prolongation 0 0 +/0 + 0 +/0 + +/0 +

HORMONAL Prolactin 0 0 0 0 0 +/0 0 ++ 0 Number of + symbols signifies extent of adverse event; 0 neutral EPS: extrapyramidal symptoms; CLZ: clozapine; ILE: iloperidone; OLZ: olanzapine; RIS: risperidone; QUE: quetiapine; ZIP: ziprasidone; ARI: aripiprazole; ASE: asenapine; LUR: lurasidone.

Cha D, McIntyre RS. Expert Opin Pharmacother 2012;13(11):1587-98. Copyright © 2015 Neuroscience Education Institute. All rights reserved. No Faster Recovery From Mixed Depression in Bipolar Disorder When Antidepressants Are Added to Mood Stabilizers (STEP-BD)

355 STEP-BD entrants with major depression + 1 or more manic symptoms

N=145 w/AD N=190 w/o AD

Goldberg et al. Am J Psychiatry 2007;164(9):1348-55. Copyright © 2014 Neuroscience Education Institute. All rights reserved. Treatment-Resistant Bipolar Depression: Randomized Controlled Trial of Electroconvulsive Therapy vs. Algorithm-Based Pharmacological Treatment

FIGURE 2. Change in Depression Severity in Patients With Treatment-Resistant Bipolar Depression Randomly Assigned to ECT or Algorithm-Based Pharmacological Therapy

A linear mixed-effects analysis showed that the mean score at 6 weeks was 6.6 points lower in the ECT group (SE=2.05, 95% CI=2.5–10.6, p=0.002).

LEVEL 1A: Established efficacy* Quetiapine monotherapy (bipolar disorder I & II) Lurasidone monotherapy (bipolar disorder I) Lurasidone or quetiapine adjunctive to lithium or divalproex (bipolar disorder I)

LEVEL 1B: Established efficacy, but with safety concerns* Olanzapine + fluoxetine (bipolar disorder I)

*Tolerability limitations include sedation and weight gain

LEVEL 2: Established tolerability, but limited efficacy* Consult specialist Lithium (bipolar disorder I) Lamotrigine adjunctive to lithium (bipolar disorder I) Lamotrigine (bipolar disorder I) 2-drug combination of above medications

*Efficacy limitations include negative randomized controlled trials but positive meta-analyses Florida Medicaid Drug Therapy Management Program for Behavioral Health. 2014. Copyright © 2015 Neuroscience Education Institute. All rights reserved. Treatment of Acute Bipolar Depression

LEVEL 3: If levels 1 and 2 are ineffective or treatment not tolerated* Electroconvulsive therapy (ECT)

*Consideration merited due to clinical need, despite even greater efficacy/tolerability limitations than level 1 and 2 treatments LEVEL 4: If levels 1-3 are ineffective or if treatment is not tolerated Transcranial magnetic stimulation (TMS) Antimanic therapy + (FDA-approved medication for major depression)* Pramipexole Adjunctive: modafinil, thyroid, or stimulants 3-drug combination

*There is inadequate information, including negative trials, to recommend adjunctive antidepressants, aripiprazole, ziprasidone, levetiracetam, armodafinil, or omega-3 fatty acids for bipolar depression

• Mood disorders are multidimensional • Zone of delimitation (i.e., division point) between bipolar disorder and MDD does not exist organically • MDD has prominent hypomanic features

• Antidepressants are hazardous when treating MDE with hypomanic features

• Antipsychotics are preferred in treating MDE with hypomanic features