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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
7
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
12
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)
13
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.
14
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
18
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
21
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
22
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
23
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)
26
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
29
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
31
Carlos
• Placeholder for Carlos animated comic
32
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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
33
FDA-Approved Treatments for Bipolar Depression in Adults
34
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
35
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
36
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
37
*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
38
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
40
*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
41
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).
42
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.
43
+
CANMAT 2018 Guidelines on Antidepressants in Acute Bipolar I
Depression
44
• 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
46
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
48
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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25
49
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
50
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%
51
Alyssa
A1C = glycated hemoglobin; BMI = body mass index.
52
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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
53
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
54
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28
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
-
29
Lurasidone: Results of 2-Year Open-Label Study; Weight and
BMI
57
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
58
Figure adapted from Goldstein BI, et al. Bipolar Disord. 2020
May 1. doi: 10.1111/bdi.12921.
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30
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).
60
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
-
31
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:
61
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
62
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]
-
32
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
63
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
64
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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
65
John
PCP = primary care provider; SSRI = selective serotonin reuptake
inhibitor.
-
34
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
67
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%
68
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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35
Bipolar Depression With Subsyndromal Hypomania: Lurasidone
McIntyre RS, et al. J Clin Psychiatry. 2015;76(4):398-405.
69
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
70
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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
71
1. Yatham LN, et al. Bipolar Disord. 2018;20(2):97-170.