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Challenging Cases in the Management of Bipolar Depression: What Would

You Do?

Manpreet Singh, MD, MSStanford University School of Medicine

Stanford, CA

Trisha Suppes, MD, PhD Stanford University School of Medicine

Stanford, CA

This activity is supported by an educational grant from Sunovion Pharmaceuticals Inc.

This activity is jointly provided byNorth American Center for Continuing Medical

Education (NACCME) and CMEology.

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Program Agenda11:15 - 11:25 AM Welcome and Introduction

11:25 - 11:40 AM Diagnosing Bipolar Disorder in a Depressed AdolescentManpreet Singh, MD, MS

11:40 - 11:55 PM Evaluating Treatment Options for Adults With Bipolar DepressionTrisha Suppes, MD, PhD

11:55 - 12:10 PM Individualizing Management of Patients With Bipolar Depression and Metabolic ComorbiditiesManpreet Singh, MD, MS

12:10 - 12:25 PM Bipolar Depression With Mixed Features: An Important Diagnosis and Clinical ConundrumTrisha Suppes, MD, PhD

12:25 - 12:45 PM Question & Answer Session/Closing Remarks

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Learning Objectives

After completing this activity, participants should be able to:

• Apply evidence-based strategies for the recognition and treatment of pediatric bipolar depression

• Discuss evidence-based approaches to the pharmacologic management of bipolar depression in adults, including adjunctive therapies

• Describe how to identify and treat bipolar depression with mixed features

• Implement strategies to monitor and manage metabolic comorbidities in patients with bipolar depression

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Disclosures

• Dr. Singh: Advisory Board of Sunovion Pharmaceuticals Inc.; Consultant for Google X and Limbix; Research Grants from Brain and Behavior Research Foundation, Janssen, NIH, and PCori; Royalties for American Psychiatric Association Publishing

• Dr. Suppes: Consultant for Allergan, Inc., Impel NeuroPharma Inc., Intracellular Therapies, and Sunovion Pharmaceuticals Inc.; Research Grants from Merck and Palo Alto Health Sciences; Royalties for American Psychiatric Association Publishing, Hogrefe Publishing, Jones & Bartlett, and Wolters Kluwer Health (UpToDate)

• CMEology planners have no relationships to disclose.

• North American Center for Continuing Medical Education (NACCME) content reviewers have no relationships to disclose.

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Off-Label Use

• The faculty have been informed of their responsibility to disclose to the audience if they will be discussing off-label or investigational use(s) of drugs, products, and/or devices (any use not approved by the US Food and Drug Administration)

• The off-label use of the following agents will be discussed: antidepressants (including SSRIs and bupropion), divalproex, lamotrigine, lithium, olanzapine, quetiapine

• This activity has been independently reviewed for balance

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Impact of COVID-19 on Child Mental Health

• Very few published data• Survey of 1784 children, grades 2-6, in Hubei province during lockdown

(mean, 34 days) in early 20201• 23% depressive symptoms • 19% anxiety symptoms

• Survey of > 1000 US parents in June 20202• 27% reported worsening mental health for themselves• 14% reported worsening behavioral health for their children• 10% reported worsening in both themselves and their children

• What history can tell us• Economic downturns are associated with an increase in childhood mental health

problems; 35%–50% increase during the last recession (2008–2009)3

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1. Xie XE, et al. JAMA Pediatr. 2020;Apr 24;e201619. 2. Loades ME, et al. J Am Acad Child Adolesc Psychiatry. 2020;Jun 3;S0890-8567(20)30337-3. 3. Golberstein E, et al. Health Econ. 2019;28(8):955-970.

Impact of COVID-19 on Adult Mental Health• US population

• Kaiser Family Foundation survey, July 20201• 53% reported stress and worry related to COVID-19 had negative impact

on their mental health; up from 45% in April and 39% in May• Women, younger adults (especially 18–29 yrs), Blacks, those experiencing

negative financial impact were more likely to report mental health impact• Health care workers (HCWs)

• Systematic review/meta-analysis of prevalence of affective symptoms in > 33,000 HCWs in China2

• Depression (22.8%), anxiety (23.2%), insomnia (38.9%)• Depression and anxiety were more prevalent among female than male

HCWs

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1. Kaiser Family Foundation Health Tracking Poll. July 27, 2020. Accessed August 20, 2020. https://www.kff.org/coronavirus-covid-19/report/kff-health-tracking-poll-july-2020 2. Pappa S, et al. Brain Behav Immun. 2020;May 8;S0889-1591(20)30845-X.

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Suicide Prevention and COVID-19• Early reports are cause for concern1

• If unemployment rates rise only to levels seen during last recession, a recent study2 predicts

• 3235 excess suicides during 2020–2021• A 3.3% increase in suicides per 100,000 people compared to

2018

• Peak unemployment during last recession = 10%3

• July 2020 unemployment = 10.2%4

• Prevention measures2• Government financial assistance and policies• Psychiatric emergency services• Timely access to care for people with mental illness, substance

use disorders• Proper gun and ammunition storage• Resilience training and education

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1. The Trace/Chicago Sun Times. In Chicago, a steep rise in suicide among Black people. July 25, 2020. Accessed August 24, 2020. https://www.thetrace.org/2020/07/in-chicago-a-steep-rise-in-suicide-among-black-people/ 2. McIntyre RS, et al. World Psychiatry. 2020;19(2):250-251. 3. Bureau of Labor Statistics. The Recession of 2007–2009. February, 2012. Accessed August 24, 2020. https://www.bls.gov/spotlight/2012/recession/pdf/recession_bls_spotlight.pdf 4. Bureau of Labor Statistics. News Release. August 7, 2020. Accessed August 24, 2020. https://www.bls.gov/news.release/pdf/empsit.pdf

Data from the Cook County Medical Examiner. Graphic by Daniel Nass.1

Diagnosing Bipolar Disorder in a Depressed Adolescent

Manpreet Singh, MD, MSAssociate Professor and Akiko Yamazaki and Jerry Yang Faculty

Scholar in Pediatric Translational MedicineDepartment of Psychiatry and Behavioral Sciences

Director, Pediatric Mood Disorders ProgramDirector, Pediatric Emotion and Resilience Lab

Stanford University School of MedicineStanford, California

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Bipolar Disorder in Children and Adolescents

• The prevalence of bipolar spectrum disorders in youth is 3.9% and stable, according to a recently updated meta-analysis1

• Early-onset bipolar disorder is associated with worse long-term prognosis and increased risk for suicide compared with adult-onset bipolar disorder2

• Compared with youth with unipolar depression, youth with bipolar depression have3• More severe and frequent depressive episodes• More comorbid disorders• More hospitalizations• Lower levels of functioning

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1. Van Meter A, et al. J Clin Psychiatry. 2019;80(3):18r12180. 2. Van Meter AR, et al. J Clin Psychiatry. 2011;72(9):1250-1256. 3. Singh MK, et al. Psychiatry Rep. 2014;16(12):516.

Diagnosing Bipolar Disorder in Children and Adolescents• A family history of bipolar disorder is a key risk factor for early

development of bipolar disorder1

• Depressive episodes may be missed2• Anhedonia and fatigue can be subtle and overlooked • Irritability is mistaken for mania; it is not recognized as a symptom of depression• Depressive episodes are less common in young children

• Bipolar disorder is frequently misdiagnosed as anxiety, MDD, or ADHD2

• Other causes of irritability must be distinguished from bipolar depression1

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1. Singh MK, et al. Psychiatry Rep. 2014;16(12):516. 2. Chang K. Dialogues Clin Neurosci. 2009;11(1):73-80.

ADHD = attention-deficit/hyperactivity disorder; MDD = major depressive disorder.

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Disruptive Mood Dysregulation Disorder (DMDD) Criteria: OI VEY

• Outbursts – frequent (several times/week), impairing, in more than one place (ie, not just conflict with a parent or teacher)

• Irritable mood when not having outbursts

• Very chronic—has lasted at least 1 year

• Explained by another condition—eg, mania (at least a day), MDD, PTSD, anxiety, autism—not DMDD

• Young – starts in childhood (after age 6, before age 10, not after age 18)

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MDD = major depressive disorder; PTSD = post-traumatic stress disorder.

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. American Psychiatric Association; 2013.

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Rare

Neither DMDDnor bipolar

Change from previousbehavior or self

Child

First R/O: StressorSchool- Learning problems- Bullying

Home- Family problems- Abuse

Teen

R/O mood disorderDepressionManiaAnxiety disorderDrugsPsychosis

Chronic

Irritable betweenoutbursts

Fine untilfrustrated

DMDD+/-ASD

ADHDODD+/-

ASD

Frequent

ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; DMDD = disruptive mood dysregulation disorder; ODD = oppositional defiant disorder; R/O = rule out.

Slide Courtesy of Dr. Gabrielle Carlson.

Diagnostic Decision Tree for Explosive Outbursts and Irritability

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Risk Calculator for Predicting Mood Recurrence in Young Adults with Bipolar Spectrum Disorder• Each mood recurrence worsens the prognosis of bipolar disorder• Identifying individuals at high risk for future episodes is a crucial need• Longitudinal data from 363 youths/young adults followed in the COBY study for a

median of 12.5 years were used to build a risk calculator• Accuracy: 72%–82% for predicting any recurrence; ≤ 80% accurate for depression,

89% for hypo/mania• Most influential recurrence risk factors

• Shorter recovery lengths• Younger age • Earlier onset of mood disorder• More severe prior depression

• Risk calculator available at: https://www.pediatricbipolar.pitt.edu/resources

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Birmaher B, et al. J Am Acad Child Adolesc Psychiatry. 2020;Jan 21;S0890-8567(20)30021-6.

COBY = Course and Outcome of Bipolar Youth.

• Sophie is a 13-year-old girl whose parents and primary care provider have suggested she visit a psychiatrist

• She has been irritable, has declining academic performance, and has lost interest in friends and activities

• Her parents are concerned because she is not sleeping, has lost weight, and has been impulsive (eg, staying out all night)

• A family friend confided that Sophie had said things on social media about feeling “hopeless” and “empty”

• Sophie has a family history of bipolar disorder (maternal grandmother)

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Sophie

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Negative Reactions to Antidepressants in Pediatric Bipolar Disorder

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0102030405060708090

NegativeReaction

Manic/Mixed New-Onset Suicidal Ideation

BPD NOS (n=22)BPD-II (n=7)BPD-I (n=23)

N=52

Patie

nts (

%)

All Groups (n=47)

Baumer FM, et al. Biol Psychiatry. 2006;60(9):1005-1012.

BPD = bipolar disorder; NOS = not otherwise specified.

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Lithium for Youth With Depression Associated With Bipolar I Disorder: An Open-Label Study

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*P

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Quetiapine XR in Youth With Acute Bipolar Depression

• LS mean changes in CDRS-R total score decreased with quetiapine XR (–29.6) and placebo (–27.3)

• Between-treatment group difference of –2.29 was not statistically significant (P=0.25)

• Rates of response (quetiapine 63.0% and placebo 55.0%; P=0.63) and remission (quetiapine 45.7% and placebo 34.0%; P=0.16) did not differ significantly between treatment groups

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Number needed to treat (NNT) (response) = 13; NNT (remission) = 9; number needed to harm (NNH) (≥ 7% weight gain) = 16.LS = least squares.

Findling RL, et al. J Child Adolesc Psychopharmacol. 2014;24(6):325-335.

LS M

ean

Chan

ge w

ith 2

-Sid

ed 9

5% C

I

-5

Study Day

-10

-15

-20

-25

-30

-358 15 22 29 36 43 50 57

Quetiapine XR 150-300 mg/day (n=93)Placebo (n=100)

N=193

Olanzapine-Fluoxetine Combination (OFC) for Youth With Bipolar Depression

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NNT (response) = 6; NNT (remission) = 7; NNH (≥7% weight gain) = 3.MMRM = mixed-model repeated measures.

Detke HC, et al. J Am Acad Child Adolesc Psychiatry. 2015;54(3):217-224.

0

-5

1

Weeks of Treatment

02 3 4 5 6 7 8

-10

-15

-20

-25

-30

OFC (n=170)Placebo (n=84)

*

******

*** *** *** ** **

*P

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Lurasidone: Change From Double-Blind Baseline in CDRS-R Total Score

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DelBello MP, et al. J Am Acad Child Adolesc Psychiatry. 2017;56(12):1015-1025.

Mean dose lurasidone: 32.6 mg/dayMedian dose lurasidone: 30.0 mg/day

NNT (response) = 5; NNT (remission) = 14.

Open-Label Lurasidone Treatment: Responder and Remitter Rates

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OL Baseline: open-label baseline, after 6 weeks of double-blind (DB) treatment with lurasidone vs. placebo.Responder criteria: ≥50% reduction from DB baseline in adjusted CDRS-R score (observed case analysis).Remission criteria: CDRS-R total score ≤28, YMRS total score ≤8, and CGI-BP-S depression score ≤3 (observed case analysis).

CGI-BP-S = Clinical Global Impression–Bipolar Severity; YMRS = Young Mania Rating Scale.Singh MK, et al. American Society of Clinical Psychopharmacology Meeting; May 2020; Virtual Meeting.

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FDA-Approved Agents for Bipolar Disorder in Children and Adolescents

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Acute Mania Acute Depression Longer-Term Treatment

Year Drug Year Drug Year Drug

1970/2018 Lithiuma 2013 OFCb 1974/2018 Lithiuma

2007 Risperidoneb 2018 Lurasidoneb 2008 Aripiprazoleb

2008 Aripiprazoleb

2009 Quetiapineb

2009 Olanzapinec

2015 Asenapineb

aAge ≥7 years for immediate release and ≥12 years for extended release; bAge 10–17 years; cAge 13–17 years.

FDA = Food and Drug Administration; OFC = olanzapine-fluoxetine combination.

Adapted from Ketter TA, ed. Handbook of Diagnosis and Treatment of Bipolar Disorders. American Psychiatric Publishing, Inc; 2010.

Family-Focused Therapy (FFT) Delays Depressive Episodes in Youth at High Risk for Bipolar Disorder

• 127 youth with MDD or unspecified (subthreshold) bipolar disorder, active mood symptoms, and ≥1 first- or second-degree relative with bipolar disorder

• Randomized to 4 months/12 sessions of FFT or 4 months/6 sessions of enhanced care (standard psychoeducation)

• Medication could also be used• Time to next observed depressive

episode was significantly greater in FFT group (no change for manic or hypomanic episodes)

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Miklowitz DJ, et al. JAMA Psychiatry. 2020;77(5):455-463.

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Conclusions

• Early-onset bipolar disorder is associated with poorer long-term prognosis and increased risk for suicide

• Youth with depression should be carefully screened for a family history of bipolar disorder and symptoms of mania

• A high rate of comorbidity and symptom overlap with disruptive behavioral disorders can make the diagnosis of bipolar disorder in youth challenging

• Effective pharmacologic and non-pharmacologic therapies exist for treatment of bipolar depression in youth

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Evaluating Treatment Options for Adults With Bipolar Depression

Trisha Suppes, MD, PhDProfessor

Department of Psychiatry & Behavioral SciencesStanford University School of Medicine

Director, Exploratory Therapeutics LaboratoryTreasurer Elect of the American Society of Clinical Psychopharmacology

Immediate Past President of the International Society for Bipolar DisordersFounder, VA Palo Alto Bipolar and Depression Research Program

Director, VA Palo Alto CSP NODESVA Palo Alto Health Care System

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Depression in Bipolar Disorder

• Accounts for the majority (70%) of time spent unwell in bipolar I disorder1

• Increases risk of suicide, especially with agitation and in days/weeks following hospital discharge2

• Is the main cause of psychosocial and occupational impairment in bipolar disorder2

• Contributes to medical morbidity and mortality in bipolar disorder2

• Is associated with cognitive impairment, especially among inpatients3

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1. Forte A, et al. J Affect Disord. 2015;178:71-78. 2. Baldessarini RJ, et al. Int J Bipolar Disord. 2020;8(1):1. 3. Douglas KM, et al. Bipolar Disord. 2018;20(3):260-274.

Distinguishing Bipolar Depression From Unipolar Depression

30McIntyre RS, et al. Curr Med Res Opin. 2019;35(11):1993-2005.

60%Initial misdiagnosis of bipolar depression as unipolar depression

Bipolar Depression

Reasons for misdiagnosis:• Incomplete understanding of bipolar

disorder by health care professionals• Overlooked or no history of mania• Failure to differentiate symptoms that can

help identify unipolar and bipolar depression

Consequences of misdiagnosis:• Inappropriate use of antidepressant agents• Increased acute risk of switch from

depression to mania/hypomania with antidepressant use

• Delay of proper treatment

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• 30-year-old man with history of bipolar I disorder• Computer programmer; guitar player• Hospitalized 2 years ago with a manic episode;

discharged on valproate and an atypical antipsychotic• The atypical antipsychotic was gradually tapered off

over 12 months• Valproate is his only medication currently• Now presents with inability to concentrate, sadness,

and fatigue

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Carlos

• Placeholder for Carlos animated comic

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Important unmet needs: well-tolerated treatments for acute depression and maintenance*Adjunctive and monotherapy. LAI = long-acting injectable.

UnmetNeed

UnmetNeed

Adapted from Ketter TA, ed. Handbook of Diagnosis and Treatment of Bipolar Disorders. American Psychiatric Publishing, Inc; 2010.

FDA-Approved Agents for Bipolar Disorder in Adults

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FDA-Approved Treatments for Bipolar Depression in Adults

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Drug Year Approved MonotherapyAdjunctiveWith Lithium or Valproate

Olanzapine-fluoxetine combination

2003 Yes No

Quetiapine/quetiapine XR 2006/2008 Yes No

Lurasidone 2013 Yes YesCariprazine 2019 Yes No

US Food and Drug Administration. FDA approved drug products. Accessed July 27, 2020. http://www.accessdata.fda.gov/scripts/cder/daf/

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Bipolar Depression in Adults: Olanzapine-Fluoxetine Combination

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Tohen M, et al. Arch Gen Psychiatry. 2003;60(11):1079-1088.

Least squares (LS) mean change in MADRS (Montgomery-Åsberg Depression Rating Scale) total scores. Improvement with olanzapine and olanzapine-fluoxetine combination (OFC) was significantly greater than placebo throughout the study (P < .001). Improvement with OFC was significantly greater than with olanzapine at weeks 4 to 8 (P < .02).

Bipolar Depression in Adults: Quetiapine

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Mean Change From Baseline*

-20

-16

-12

-8

-4

01 2 43 65 7 80

QUE 600 mg/day (n=170)Placebo (n=169)

QUE 300 mg/day (n=172)

Study Week

TRIAL 11

‡

‡‡

‡ ‡

‡‡

‡

‡

‡‡

‡‡

‡‡

‡

-20

-16

-12

-8

-4

01 2 43 65 7 80

Study Week

TRIAL 22

QUE 600 mg/day (n=151)Placebo (n=161)

QUE 300 mg/day (n=155)

‡

‡‡

‡‡

‡‡

‡

‡

‡

‡

‡

‡

‡

†

‡

MADRS Total Score

*Values are LS means. †P < .01 vs placebo, ‡P < .001 vs placebo. QUE = quetiapine. 1. Calabrese JR, et al. Am J Psychiatry. 2005;162(7):1351-1360. 2. Thase ME, et al. J Clin Psychopharmacol. 2006;26(6):600-609.

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Bipolar Depression in Adults: Lurasidone Monotherapy

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*P ≤ .05, **P ≤ .01, ***P ≤ .001 vs placebo. †Effect size (Cohen’s d) was calculated from MMRM (mixed-model repeated measures) analysis. MADRS scale range, 0-60.Loebel A, et al. Am J Psychiatry. 2014;171(2):160-168.

Bipolar Depression in Adults: Cariprazine

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MMRM analysis was used to determine LS means.*P < .05 for cariprazine 1.5 mg/d vs placebo; **P < .05 for cariprazine 3.0 mg/d vs placebo (unadjusted).Earley W, et al. Am J Psychiatry. 2019;176(6):439-448.

MADRS Total Score (MMRM)

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Bipolar Depression in Adults: Cariprazine (cont’d)

39Earley WR, et al. Bipolar Disord. 2020;22(4):372-384.

MADRS response, MADRS remission, and HAMD-17 (17-item Hamilton Depression Rating Scale) at week 6 for the intent-to-treat population.P value for a between-treatment comparison at each visit based on a logistic regression model, which included treatment group and baseline MADRS and HAMD-17 total score values.

Bipolar Depression in Adults: Lurasidone Adjunctive Therapy

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*P ≤ .05, **P ≤ .01, ***P ≤ .001 vs placebo. †Effect size (Cohen’s d) was calculated from MMRM analysis. MADRS scale range, 0-60. Li = lithium; VPA = valproate.Loebel A, et al. Am J Psychiatry. 2014;171(2):169-177.

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Likelihood to be Helped or Harmed Analysis: Number Needed to Treat (NNT) vs Placebo

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Citrome L, et al. Poster presented at American Society of Clinical Psychopharmacology meeting virtual poster session, May 2020. Accessed July 27, 2020. https://www.neiglobal.com/VSP/NEIVSPDetail/tabid/562/action/VSPDetail/args/44/Default.aspx

CAR: cariprazine, 1.5 or 3.0 mg/d; LUR: lurasidone, 20-120 mg/d; OFC: olanzapine/fluoxetine combination, 6/25, 6/50, 12/50 mg/d; PBO: placebo; QUE: quetiapine XR and IR, 300-600 mg/d.Responder criteria: ≥50% reduction from double-blind baseline. Responder NNT values are shown with 95% CI.Remission criteria: endpoint MADRS total score ≤10 (LUR, CAR) or ≤12 (OFC, QUE).MADRS remission rates: OFC vs PBO (48.8% vs 24.5%; NNT=5); QUE vs PBO (52.8% vs 34.7%; NNT=6);

LUR vs PBO (34.4% vs 20.4%; NNT=8); CAR vs PBO (30.2% vs 20.9%; NNT=11).

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Citrome L, et al. Poster presented at American Society of Clinical Psychopharmacology meeting virtual poster session, May 2020. Accessed July 27, 2020. https://www.neiglobal.com/VSP/NEIVSPDetail/tabid/562/action/VSPDetail/args/44/Default.aspx

Likelihood to be Helped or Harmed Analysis: Number Needed to Harm (NNH) vs Placebo

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CANMAT 2018 Hierarchical Rankings of First- and Second-line Treatments Recommended for Acute Bipolar I Depression

CANMAT = Canadian Network for Mood and Anxiety Treatments.Yatham LN, et al. Bipolar Disord. 2018;20(2):97-170.

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+

CANMAT 2018 Guidelines on Antidepressants in Acute Bipolar I Depression

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• Antidepressants should not be used as monotherapy in patients with bipolar I depression, as available trials do not support their efficacy and there are concerns about their safety in terms of mood switching

• Adjunctive use of antidepressant therapy (SSRIs or bupropion) with lithium/divalproex or an atypical antipsychotic may be considered as a second-line add-on treatment

• Antidepressants should ideally be avoided, or used cautiously if necessary, in patients with a history of antidepressant-induced mania or hypomania, current or predominant mixed features, or recent rapid cycling

Yatham LN, et al. Bipolar Disord. 2018;20(2):97-170.

SSRI = selective serotonin reuptake inhibitor.

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Lithium Reduces Suicidal Behavior in Bipolar I or Bipolar II Disorder – No Prospective Trials to Date

45

8

2

4

1

0

3

5

6

7

Suici

dal A

cts p

er 1

00 P

atie

nt-Y

ears 7.11

2.3 2.29

4.86

0.355

BeforeLithium

Treatment

DuringLithium

Treatment

AfterLithium

Treatment

FirstYear OffLithium

LaterYears OffLithium

13.7-folddifferenceP < .001

6.48-folddifferenceP < .001

Baldessarini RJ, et al. J Clin Psychiatry. 1999;60(Suppl 2):77-84.

20.0-folddifferenceP < .001

N = 310 before and during lithium treatment. n = 128 (subset of 310) after lithium treatment, first year off lithium, and later years off lithium.

Conclusions

• Depressive phases of bipolar disorder have significant impact on morbidity, mortality, and disability

• Distinguishing bipolar depression from unipolar depression is the critical first step in treatment selection

• Antidepressant monotherapy should be avoided in bipolar I disorder depression

• Only FDA approved agents for bipolar depression are atypical antipsychotics or in one case a combination1

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1. Yatham LN, et al. Bipolar Disord. 2018;20(2):97-170.

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Individualizing Management of Patients With Bipolar Depression and

Metabolic Comorbidities

Manpreet Singh, MD, MSAssociate Professor and Akiko Yamazaki and Jerry Yang Faculty

Scholar in Pediatric Translational MedicineDepartment of Psychiatry and Behavioral Sciences

Director, Pediatric Mood Disorders ProgramDirector, Pediatric Emotion and Resilience Lab

Stanford University School of MedicineStanford, California

Cardiovascular and Metabolic Effects of Bipolar Disorder• More people with bipolar disorder die from comorbid cardiovascular

disease (CVD) than from suicide1

• Bipolar disorder is associated with an increased risk of death from CVD2• Standardized mortality ratio of 2.5–4 for adults ≥ 40 yrs• Standardized mortality ratio of 8 for adults < 40 yrs

• CVD starts much earlier in patients with bipolar I and bipolar II (17 and 14 yrs earlier, respectively) compared with the general population2

• Undertreatment of cardiovascular risk factors is associated with greater mortality risk2

• Medications for bipolar disorder vary in their association with metabolic cardiovascular risk factors (eg, obesity, diabetes, dyslipidemia)2

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1. Weiner M, et al. Ann Clin Psychiatry. 2011;23(1):40-47. 2. Goldstein BI, et al. Bipolar Disord. 2020 May 1. doi: 10.1111/bdi.12921.

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Figure adapted from Goldstein BI, et al. Bipolar Disord. 2020 May 1. doi: 10.1111/bdi.12921.

Vascular Disease and Bipolar Disorder

Psychiatric Disorders and Cardiovascular Risk Factors in Children and Adolescents

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Goldstein BI, et al. Can J Cardiol. 2020 Jul 3. doi: https://doi.org/10.1016/ j.cjca.2020.06.023.

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• Alyssa is a 17-year-old girl diagnosed with bipolar disorder 2 years ago

• She has a 5-year history of depression; some depressive episodes were accompanied by symptoms of hypomania

• Alyssa is visiting her psychiatrist for a routine follow-up

• Her chief concern is weight gain associated with her current second-generation antipsychotic

• Her BMI is 32.0 kg/m2 and her A1C is 5.9%

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Alyssa

A1C = glycated hemoglobin; BMI = body mass index.

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Racial Disparities and Bipolar Disorder

• Compared with White individuals with bipolar disorder, Black and Hispanic individuals with bipolar disorder:• Are more likely to be misdiagnosed with schizophrenia1

• Are less likely to receive minimally adequate mood-stabilizing treatment2,3

• Racial disparities in diagnosis and treatment may be due, in part, to misattribution of symptoms and racial bias1

• People of color are underrepresented in psychiatric research studies, which may also contribute to racial disparities1

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1. Akinhanmi MO, et al. Bipolar Disord. 2018;20(6):506-514. 2. Johnson KR, et al. Psychiatr Serv. 2014;65(2):255-258. 3. Salcedo S, et al. J Racial Ethn Health Disparities. 2017;4(3):354-363.

BMI = body mass index.American Diabetes Association. Diabetes Care. 2004;27(2):596-601.

Baseline 4 wk 8 wk 12 wk Quarterly Annually Every 5 y

Personal/family history X X

Weight (BMI) X X X X X

Waist circumference X X

Blood pressure X X X

Fasting plasma glucose X X X

Fasting lipid profile X X X

Short-Term Long-Term

More frequent assessments may be warranted based on clinical status.

American Diabetes Association Consensus on Antipsychotic Monitoring

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Olanzapine-Fluoxetine Combination for Bipolar Depression in Youth: Weight, Glucose, and Lipids

55

52.4

4.8

39.4

12.3 13.4

0.03.6

1.5

19.4

4.5 6.50.0

0.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

Weight Fasting Glucose FastingTriglycerides

Fasting TotalCholesterol

Fasting LDL Fasting HDL

Patie

nts (

%)

OFC (n=170) Placebo (n=84)P

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Lurasidone: Results of 2-Year Open-Label Study; Weight and BMI

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Expected weight values are based on CDC growth charts; expected BMI values are based on WHO reference growth charts.CDC = Centers for Disease Control and Prevention; DB = double blind; OL = open label; WHO = World Health Organization.

DelBello MP, et al. Psych Congress; October 3-6, 2019; San Diego, CA. Abstract 303.

Conclusions• CVD is a major cause of morbidity and

mortality in bipolar disorder

• Cardiovascular risk factors in children and adolescents may contribute to the early onset of CVD in adults

• Some treatments for bipolar disorder can contribute to the increased risk of metabolic complications and CVD

• Routine monitoring of metabolic parameters is recommended for patients taking antipsychotic medications

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Figure adapted from Goldstein BI, et al. Bipolar Disord. 2020 May 1. doi: 10.1111/bdi.12921.

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Bipolar Depression With Mixed Features: An Important Diagnosis

and Clinical ConundrumTrisha Suppes, MD, PhD

Professor Department of Psychiatry & Behavioral Sciences

Stanford University School of MedicineDirector, Exploratory Therapeutics Laboratory

Treasurer Elect of the American Society of Clinical PsychopharmacologyImmediate Past President of the International Society for Bipolar Disorders

Founder, VA Palo Alto Bipolar and Depression Research ProgramDirector, VA Palo Alto CSP NODESVA Palo Alto Health Care System

DSM-5 Bipolar Mixed Features

DSM-IV-TR = Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision; DSM-5 = DSM, Fifth Edition.

Hu J, et al. Prim Care Companion CNS Disord. 2014;16(2).

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Depressive with mixed features

Manic Mixed DepressiveDSM-IV-TR

Manic DepressiveManic with mixed featuresDSM-5

From Categorical to Dimensional:Conceptualization of Bipolar Mixed Features

Manic symptomsDepressive symptoms

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DSM-5 Criteria for Mixed FeaturesFull criteria for a major depressive episode and at least 3 of the following symptoms present nearly every day during the episode:

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Elevated, expansive mood

Inflated self-esteem or grandiosity

More talkative or pressured speech

Flight of ideas or racing thoughts

Increase in energy or goal-directed behavior

Increased activities that have a high potential for painful consequences

Decreased need for sleep

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. American Psychiatric Association; 2013.

Mixed Symptoms Are Common in Adults With Depressive or [Hypo]manic Episodes

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Systematic review of reports prior to 2017 of patients with major depressive disorder (n = 12,331), bipolar depression (n = 5071), or bipolar [hypo]mania (n = 1796). Mixed symptoms were defined by DSM-5 (≥3 features opposite to the dominant mood polarity but not overlapping those of the primary disorder) or as having ≥3 features of opposite polarity.

Prevalence of patients with ≥ 3 features of opposite polarity during an index major depressive or [hypo]manic episode

Vazquez GH, et al. J Affect Disord. 2018;225:756-760.

Prevalence of Patients (%) [95% CI]

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Outcomes and Comorbid Disorders Associated With Mixed Features

• Longer duration and severity of illness1

• More lifetime episodes1

• Alcohol/substance use1

• Poor response to pharmacotherapy1

• Suicide1

• Anxiety disorders1

• Higher mental health–related costs2

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1. Swann AC, et al. Am J Psychiatry. 2013;170(1):31-42. 2. Ng-Mak DS, et al. Presented at: American Psychiatric Association Annual Meeting; May 14-18, 2016; Atlanta,GA. Abstract P8-096.

Mean time to recoveryPure depressive state = 5.1 monthsSubthreshold mixed state = 7.0 monthsDepressive mixed state = 7.7 months

Overall group comparison: P = .0018

Depressive mixed state vs puredepressed: P = .022

Subthreshold mixed state vs puredepressed: P = .035

BP = bipolar disorder.Shim IH, et al. J Affect Disord. 2014;152-154:340-346.

131 Korean BP I or II inpatients

Longer Time to Recovery in Mixed vs Pure Bipolar Depression

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33

• John is a 59-year-old executive at a large advertising firm• He was admitted to the hospital after an “accidental”

overdose of benzodiazepines• He has a history of bipolar I disorder• Following a divorce, his PCP prescribed an SSRI for

depression; medical workup was negative• His daughter reports he had not been sleeping and had

problems at work that led to his dismissal• Before admission, he was detained for punching a wall

after an argument in a restaurant

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John

PCP = primary care provider; SSRI = selective serotonin reuptake inhibitor.

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Goldberg JF, et al. Am J Psychiatry. 2007;164(9):1348-1355.

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

355 STEP-BD entrants with major depression with >1 manic symptom

Interaction effect: Antidepressant use x # of mania symptoms at baseline = higher YMRS score after 3 months (P = .003).

Stanley Bipolar Network: Antidepressants exacerbate mania when low-grade baseline mania symptoms are present

Frye MA, et al. Am J Psychiatry. 2009;166(2):164-172.

F = 4.5, df = 2, 169, P < .01 for between-group comparison

Poorer Outcomes With Antidepressants in Bipolar Depression With Subthreshold Mixed Features

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STEP-BD = Systematic Treatment Enhancement Program for Bipolar Disorder; YMRS = Young Mania Rating Scale.

Bipolar Depression With Manic Symptoms: Olanzapine

LS = least squares; MADRS = Montgomery-Åsberg Depression Rating Scale. Tohen M, et al. J Affect Disord. 2014;164:57-62.

-4

-3

-2

-1

0

-3.76P = .002

Change in MADRS Score vs Placebo (P for olanzapine vs placebo)

-3.20P < .001 -3.44

P = .002

Response Rate in Patients With ≥3 Mixed Features

0

5

10

15

20

25

30

35

40

45 42.1%

33.8%

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LS m

ean

diffe

renc

e

Mixed feature category

0 1-2 ≥3

Perc

enta

ge o

f Pat

ient

s (%

)

Olanzapinen=166

Placebon=204

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Bipolar Depression With Subsyndromal Hypomania: Lurasidone

McIntyre RS, et al. J Clin Psychiatry. 2015;76(4):398-405.

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Definitions: 1. YMRS score ≥4. 2. Presence of 2 or more YMRS symptoms having a severity score ≥2.

Cariprazine for Bipolar Depression With Manic Symptoms: Post hoc Analysis

*P < .05, **P < .01, ***P ≤ .001 vs placebo.Change in MADRS score, mixed-effects model for repeated measures.Patients from 3 randomized studies with bipolar I and current major depressive episode plus concurrent manic symptoms (baseline YMRS total score ≥4).McIntyre RS, et al. CNS Spectr. 2020;25(4):502-510.

Patients With Manic Symptoms Patients Without Manic Symptoms

n = 808 n = 575

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36

Conclusions

• In adults, the presence of DSM-5–defined mixed features is common during a major depressive episode in patients with bipolar depression

• The presence of mixed features contributes to greater illness complexity and worse outcomes, and likely increases self-harm behaviors

• Antidepressant monotherapy should be avoided in patients with bipolar depression and mixed features; evidence supports preferential use of an atypical antipsychotic1

• Atypical antipsychotics have been shown in post hoc analyses to be effective in bipolar depression with mixed features

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1. Yatham LN, et al. Bipolar Disord. 2018;20(2):97-170.