ON THE BLUE END: DIAGNOSIS AND

TREATMENT OF BIPOLAR DEPRESSION

Manpreet K. Singh, MD, MS
Associate Professor, Department of Psychiatry and Behavioral Sciences; Stanford University School
of Medicine

Andrew J. Cutler, MD
Clinical Associate Professor, Department of Psychiatry, State University of New York (SUNY)
Upstate Medical University
Chief Medical Officer, Neuroscience Education Institute

Presented at 2022 NEI Congress

 Learning Objectives

• Identify factors that contribute to the misdiagnosis of bipolar

depression

• Recognize the clinical presentation of bipolar depression in

pediatric and adult patients

• Implement appropriate tools to assess patients with depression for

signs of bipolarity

• Utilize evidence-based strategies to improve treatment of bipolar

depression in patients of all ages
 The Mood Disorder Spectrum

DSM-5-TR Major
Depressive Disorder
• Although categorical classifications may be useful for clinical practice, the
overwhelming majority of the evidence points to a dimensional (spectrum)
view of mood disorders
• e.g., treatment response (antidepressant vs. mood stabilizing agent)
and links with family history of bipolar disorder

Stahl SM. Stahl's Essential Psychopharmacology, 5th ed; 2021.

Can Unipolar Depression Convert to Bipolar
Depression?

Stahl SM. Stahl's Essential Psychopharmacology, 5th ed; 2021; Fiedorowicz JG et al. Am J
Psychiatry 2011;168(1):40-8; Van Meter A et al. J Affect Disord 2018;238:375-82.
Misdiagnoses and Underdiagnoses Are Common Among
Patients With Bipolar Disorder

Up to 60% of
depressed
patients with BPII
are initially
diagnosed with
unipolar
depression

Bipolar Depression Unipolar Depression

Stahl SM. Stahl's Essential Psychopharmacology, 5th ed; 2021; Hirschfeld RM et al. J Clin
Psychiatry 2003;64(2):161-74; Singh MK et al. Bipolar Disord 2021;23(8):834-7.
Factors That Contribute to Misdiagnosis

Reasons for misdiagnosis:

Ø Incomplete understanding of bipolar disorder by
healthcare professionals
Ø Overlooked or no history of mania
Misdiagnosis Ø Failure to differentiate symptoms that can help
identify unipolar and bipolar depression

Bipolar Consequences of misdiagnosis:

Depression Ø Inappropriate use of antidepressant agents
Ø Increased acute risk of switching from depression to
mania/hypomania with antidepressant use
Ø Delay of proper treatment

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

Why Is Making an Early and Accurate Diagnosis
of Bipolar Depression So Difficult?
• Hypomania is often pleasant for patients and may not be mentioned by them

• Mania is often atypical (especially in youth) with irritability and flight of ideas
rather than euphoria and grandiosity

• Patients with bipolar depression (BD) typically seek help during depressive,
not manic, episodes (mixed features may be present)

• Clinicians will first be confronted with differentiating between unipolar and

bipolar depression

Conus P et al. Bipolar Disord 2014;16(5):548-56; Phillips ML, Kupfer DJ. Lancet
2013;381(9878):1663-71; Bobo WV. Mayo Clin Proc 2017;92(10):1532-51.
Why Is an Early, Accurate Diagnosis Important?
Consequences of not identifying bipolar depression (BD) early:
Impaired quality of life

Inaccurate and potentially harmful treatment

Increased cycling and risk of relapse

Increased risk of suicide

Increased subsequent morbidity

High economic costs

Overall mortality rate for BP is over 2.5X higher than the general population

Conus P et al. Bipolar Disord 2014;16(5):548-56; Lomholt LH et al. Int J Bipolar

Disord 2019;7(1):6; Youngstrom EA at al. 2008;10(1 Pt 2):194-214.
 So You Think It’s Unipolar Depression?
• Correct diagnosis of bipolar disorder (BP) within the first year of symptom
onset is made in only 20% of cases

• Over 1/3 of unipolar patients are eventually re-diagnosed as bipolar

• Average time between onset of BP symptoms and first appropriate treatment

= 10 years

• Presence of even subthreshold (hypo)mania symptoms is strongly associated

with conversion to bipolar disorder
• Each (hypo)mania symptom increases risk by ~30%

Akiskal HS, Benazzi F. J Affect Disord 2003;73(1-2):113-22; Dudek D et al. J Affect Disord 2013;144(1-2):112-5;
Fiedorowicz JG et al. Am J Psychiatry 2011;168(1):40-8; Conus P et al. Bipolar Disord 2014;16(5):548-56; Kleine-Budde K
et al. Bipolar Disord 2014;16(4):337-53; Knežević V, Nedić A. Eur Rev Med Pharmacol Sci 2013;17(11):1542-5; Phillips
ML, Kupfer DJ. Lancet 2013;381(9878):1663-71; Sasdelli A et al. Psychiatry J 2013;2013:548349.
Symptoms With Potential Diagnostic Utility in Bipolar
and Unipolar Depression: A Probabilistic Approach
• Early onset of depression (<25 years)
• Multiple prior episodes (≥5)
• Positive family history of bipolar disorder
• Hypersomnia/increased daytime napping
• Hyperphagia/increased weight
Bipolar • Atypical depression signs
• Psychomotor retardation
Depression • Psychotic features/pathological guilt
• Mood lability/irritability/psychomotor agitation/racing thoughts
• Postpartum affective symptoms
• Substance abuse
• Anxiety disorders

• Late onset of first depression (>25 years)

• Long duration of current episode (>6 months)
• Negative family history of bipolar depression
• Initial insomnia/reduced sleep
Unipolar • Appetite/weight loss
Depression • Normal or increased activity levels
• Somatic complaints
• Tendency to blame others
• Anxiety

McIntyre RS, Calabrese JR. Curr Med Res Opin 2019;5:1-13; McIntyre RS et al. Lancet 2020: S0140-6736(20)31544-0.
Mood State at Presentation Across the Life Cycle
Melancholia Mixed Mania
100%
90%
80%
70%
60%
50%
%

40%
30%
20%
10%
0%
15 20 25 30 35 40 45 50 55 60 65
N=889
Age

Kraepelin E. Manic-depressive insanity and paranoia. Edinburgh: E&S Livingstone; 1921:169.

Presentation of Bipolar Depression in Youth

Bipolar Depression (BP) in Youth

• BP depression is more common than mania or hypomania in youth

• Irritability may occur without any accompanying elation or high mood
• Mixed episodes occur commonly
• Mixed presentations in youth with BP have been linked to increased suicide
• Youth with BP are more likely to relapse into depressive or mixed episodes than
manic episodes

Cosgrove et al. Pediatr Drugs 2013;15:83-91.

Screening for Bipolar
Depression
Mood Disorder Questionnaire (MDQ)
 Rapid Mood Screener (RMS)
Download for free. DOI: 10.1080/03007995.2020.1860358
Item Response
1. Have there been at least 6 different periods of time (at least 2 weeks) Yes No
when you felt deeply depressed?
2. Did you have problems with depression before the age of 18? Yes No
3. Have you ever had to stop or change your antidepressant because it Yes No
made you highly irritable or hyper?
4. Have you ever had a period of at least 1 week during which you were Yes No
more talkative than normal with thoughts racing in your head?
5. Have you ever had a period of at least 1 week during which you felt any of Yes No
the following: unusually happy; unusually outgoing; or unusually
energetic?
6. Have you ever had a period of at least 1 week during which you needed Yes No
much less sleep than usual?
Highest estimated accuracy was observed with ≥4 “yes” responses
• RMS sensitivity was 0.88 and specificity was 0.80; concordance index 0.87
• MDQ sensitivity was 0.86 and specificity was 0.78; concordance index 0.82

McIntyre RS et al. Curr Med Res Opin 2021;37(1):135-44.

Screening for Signs of
Bipolarity in Depression:
Mania/ Hypomania
 Family History

• Although the majority of patients with BD do not have a family

history of BP, family history of BP is arguably the most robust and
reliable risk factor for BD

• Individuals with a first-degree relative with BP are at an 8x greater

risk of developing BP compared to the general population

• The importance of questioning depressed patients about family

history of affective disorders can not be overemphasized

Duffy A et al. Br J Psychiatry 2014;204(2):122-8; Malhi GS et al. Bipolar Disord 2014;16(5):455-70;

Perlis RH et al. Am J Psychiatry 2006; 163(2):225-31; Wilde A et al. J Affect Disord 2014;158:37-47;
Birmaher B et al. Am J Psychiatry 2009;166(7):795-804.
Screening for Mixed Features

Stahl SM. Stahl's Essential Psychopharmacology, 5th ed; 2021.

Detection of Subthreshold Hypomanic Symptoms
• Mood Disorder Questionnaire (MDQ)
• Rapid Mood Screener (RMS)
• Bipolar Depression Rating Scale (BDRS)
• Hypomania Interview Guide (HIG)
• Mini International Neuropsychiatric Interview (M.I.N.I.)
• Clinically Useful Depression Outcome Scale with DSM-5 Mixed
(CUDOS-M)
• Hypomania Checklist (HCL-32)
• Altman Mania Rating Scale
• General Behavior Inventory (GBI)
Hirschfeld RM et al. Am J Psychiatry 2000;157(11):1873-5; Montano CM et al. NEI VPL 2020; Galvão F et al. Comp
Psychiatry 2013;54(6):605-10; Williams JB et al. Depress Anxiety 1999;9(2):92-100; Benazzi F. Prog
Neuropsychopharmacol Biol Psychiatry 2003;27(1):129-34; Hergueta T, Weiller E. Int J Bipolar Disord 2013;1:21;
Zimmerman M et al. J Affect Disord 2014;168:357-62; Prieto ML et al. J Affect Disord 2015;172:355-60; Altinbas K et al. J
Affect Disord 2014;152-154:478-82; Altman EG et al. Biol Psychiatry 1997;42(10):948-55; Stahl SM et al. CNS Spectr
2017;22(2):203-19; Youngstrom EA et al. J Clin Child Adolesc Psychol 2021;50(5):579-95.
The “Four A’s” Increase Suspicion of
Mixed Features

Clinicians should be aware of “the four

A’s”:
§ Anxiety
§ Agitation
§ Anger/irritability
§ Attentional disturbance-distractibility

These symptoms are highly suggestive of

mixed features in individuals with mood
disorders

McIntyre RS et al. Lancet 2020;396(10256):1841-56.

One of the Most Important Questions to Ask Any
Patient With Depression

Any
manic/hypomanic
symptoms
and/or
family history of
bipolar disorder?

Every patient. Every time.

 Barbara Geller’s Work in Pediatric Bipolar
Disorder
• Geller B, et al. J Child Adolesc Psychopharmacol. 2002 Spring;12(1):3-9. This article talks
about grandiosity, hypersexuality, etc in helping diagnose BPD vs ADHD.

• Geller B, Fox LW, Clark KA (1994), Rate and predictors of prepubertal bipolarity during follow-
up of 6- to 12-year-old depressed children. J Am Acad Child Adolesc Psychiatry 33(4):461-468

• Geller B, Luby J (1997), Child and adolescent bipolar disorder: a review of the past 10 years.
[Erratum appears J Am Acad Child Adolesc Psychiatry 1997; 36(11):1642.] J Am Acad Child
Adolesc Psychiatry 36(9):1168-1176

• Geller, B., & DelBello, M. P. (Eds.). (2003). Bipolar disorder in childhood and early
adolescence. The Guilford Press. This is a landmark book.
Treatments for Bipolar
Depression
 Serotonin/Dopamine Antagonists/Partial
Agonists Across the Depression Spectrum

• There is a major paradigm shift away from monoamine reuptake

inhibitors for depression with mixed features
• Serotonin/ dopamine antagonists/ partial agonists are
effective at treating: bipolar depression and treatment-resistant
depression (TRD)

• Several of the agents that are approved for bipolar depression are also
effective for depression with mixed features

• There are currently no agents approved to treat mixed depression

Stahl SM. Stahl's Essential Psychopharmacology, 5th ed; 2021.

 Atypical Antipsychotics

DMX: depressive mixed state;

MMX: mania with mixed features Stahl SM. Stahl's Essential Psychopharmacology, 5th ed; 2021.
Olanzapine-Fluoxetine Combination (OFC) in
Bipolar Depression fluo
apine xet
olanz ine

olanzapine-fluoxetine

Data from two 8-week randomized clinical trials for bipolar depression. Primary measure was change in MADRS;
OFC was significantly superior to both OLZ and PBO.
OFC: n=86, mean daily dose 7.4 mg/39.3 mg. OLZ: n=370, mean daily dose 9.7 mg. PBO: n=377.
Citrome L. Expert Opinion Pharmacother 2011;12(17):2751-8.
 Quetiapine in Bipolar Depression
quetiapine
Study MADRS WMD (95% CI)
Calabrese et al. 2005 -6.47 (-8.67; -4.27)
Thase et al. 2006 -4.07 (-6.03; -2.11)
Young et al. 2010 -4.29 (-6.28; -2.3)
McElroy et al. 2010 -3.71 (-6.22; -1.2)
Quetiapine 600 pooled -4.64 (-5.82; -3.46)
Heterogeneity: Q=3.64; p=0.303
Overall: Z=-7.71; p=0; n=1396

Calabrese et al. 2005 -6.13 (-8.33; -3.93)

Thase et al. 2006 -5.01 (-6.95; -3.07)
Young et al. 2010 -3.55 (-5.55; -1.55)
McElroy et al. 2010 -3.59 (-6.1; -1.08)
Suppes et al. 2010 -5.51 (-7.88; -3.14)
Quetiapine 200 pooled -4.76 (-5.75; -3.76)
Heterogeneity: Q=4.19; p=0.381
Overall: Z=-9.37; p=0; n=1661
Favors: QUET PBO

Chiesa A et al. Int Clin Psychopharmacol 2012;27(2):76-90.

Lurasidone Monotherapy in the Treatment of
Bipolar I Depression
lurasidone

A randomized,
double-blind,
placebo-controlled
study

A. Mean scores at baseline were 30.3 (SD=5.0), 30.6 (SD=4.9), and 30.5 (SD=5.0) for the lurasidone 20–60 mg, lurasidone 80–120 mg,
and placebo groups, respectively.
B. Mean scores at baseline were 4.52 (SD=0.62), 4.55 (SD=0.64), and 4.48 (SD=0.61) for the lurasidone 20–60 mg, lurasidone 80–120 mg, and
placebo groups, respectively.
* p,0.05; ** p,0.01; *** p,0.001

Loebel A et al. Am J Psychiatry 2014;171:160

 Lurasidone as Adjunctive Therapy for the
Treatment of Bipolar I Depression
lurasidone
lithium lurasidone valproate

A randomized,
double-blind,
placebo-controlled
study

A. Mean scores at baseline were 30.6 (SD=5.3) and 30.8 (SD=4.8) for the lurasidone and placebo groups, respectively.
B. Mean scores at baseline were 4.47 (SD=0.65) and 4.60 (SD=0.63) for the lurasidone and placebo groups, respectively.
* p,0.05; ** p,0.01; *** p,0.001

Loebel A et al. Am J Psychiatry 2014;171:169-77.

Bipolar Depression With Mixed Features: Lurasidone

Change From Baseline in MADRS Score (MMRM):

Patients With and Without Mixed Features at Baseline (mITT Population)
Baseline Wk 1 Wk 2 Wk 3 Wk 4 Wk 5 Wk 6
0 Lurasidone effective in
improving depressive
LS Mean Change in MADRS Score

-2 *P ˂.05. †P ˂.01. ‡P ˂.001.

-4 symptoms both with
-6
* and without mixed
-8 features
* *
-10 LS, least squares; MADRS,

-12 * Montgomery-Asberg Depression

* Rating Scale; mITT, modified intention-
to-treat; MMRM, mixed model for
-14 * repeated measures.
‡ †
-16 ‡
†
-18 With mixed features lurasidone (n = 182) With mixed features placebo (n = 90)
Without mixed features lurasidone (n = 141) Without mixed features placebo (n = 72)

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

Cariprazine for Bipolar Depression
cariprazine

Earley W et al. Am J Psychiatry 2019;176(6):439-48.

 Cariprazine in Bipolar Depression
With or Without Manic Symptoms
Pooled Analysis of 3 Randomized Trials
Patients With Manic Symptoms Patients Without Manic Symptoms
Baseline Wk 2 Wk 4 Wk 6 Baseline Wk 2 Wk 4 Wk 6
0 0

LS Mean Change From Baseline

LS Mean Change From Baseline

-2 -2
-4 -4
-6 -6
*
-8 -8 †
*
-10 -10 ‡
‡ †
-12 * -12

-14 † -14 ‡
‡
-16 Placebo ‡ -16 Placebo ‡
Cariprazine 1.5 mg/day Cariprazine 1.5 mg/day
*P <.05
Cariprazine 3 mg/day †P <.01 Cariprazine 3 mg/day
‡P ≤.001

McIntyre et al. CNS Spectr 2020;25:502-10.

Cariprazine Mechanism of Action

Stahl SM. Stahl's Essential Psychopharmacology, 5th ed; 2021.

 Lumateperone in Bipolar Depression
lumateperone

Received FDA approval for bipolar depression on Dec 20, 2021

Lumateperone 42mg vs. placebo once daily for 6 weeks
• Greater improvement from
baseline on MADRS
• Greater improvement from
baseline in CGI-Bipolar
• 51% responders (MADRS
improvement ≥50%) vs. 37%
for placebo
• 40% remission rate (MADRS
total score ≤12) vs. 34% for
placebo

Blair HA. Drugs 2020;80:417-23.

Lumateperone for MDE in BPI and BPII

Calabrese JR et al. Am J Psychiatry 2021;178(12):1098.

 Safety Profile of Lumateperone in Bipolar
Disorder

* The only extrapyramidal symptom-related treatment-emergent adverse event was one case (0.5%) of mild
dyskinesia in the lumateperone group. This patient had a history of tardive dyskinesia.

Calabrese JR et al. Am J Psychiatry 2021;178(12):1098.

Lumateperone As Adjunctive Therapy to Lithium
or Valproate
• Study 402 (6-week, Phase 3 Trial that included 529 patients with moderate to severe depressive
episodes associated with bipolar I and bipolar II disorder)

• Randomized to 42mg of lumateperone, 28mg of lumateperone, or placebo in addition to lithium or

valproate

• At week 6, once-daily 42mg of lumateperone met the primary endpoint for improvement in
depressive symptoms (measured as change from baseline on the Montgomery-Asberg
Depression Rating Scale)

• Statistically significant improvement on the Clinical Global Impression Scale for Bipolar for
Severity of Illness-Depression subscale score was also observed with 42mg lumateperone

• Results suggest that lumateperone is effective for bipolar depression as monotherapy or

adjunctive therapy
Intracellular Press Release: [Link]
therapies-announces-positive-topline-results
 Mood Stabilizers
Evidence of FDA-approved FDA-approved FDA-approved FDA-approved
efficacy in DMX for BP for BP for BP for MDD
depression mania maintenance
Carbamazepine
R
Lamotrigine
R
Lithium
R R
Valproate
R
• No mood stabilizer is approved for use in depression of any kind (unipolar,
mixed, bipolar)
• There are some data for the efficacy of lamotrigine or valproate for bipolar
depression
• Lithium is well known for its anti-suicide effects; however, neither lithium nor
carbamazepine monotherapy is recommended for the treatment of bipolar
depression
Stahl SM. Prescriber’s guide. 6th ed. Cambridge University Press; 2018; Goodwin GM et al. J
Psychopharmacol 2009;23(4):346-88; Connolly KR, Thase MD. Primary Care Companion CNS Disord
2011;13(4):PCC.10r01097; Musetti L et al. CNS Spectrums 2013;18(4):177-87.
 Lithium
lithium

• Most effective drug for the treatment of recurrent depression and bipolar disorders
• Most stabilizing agent available
• Little risk to worsen depression (like antipsychotics)
• Little risk to worsen mania (like antidepressants)
• Anti-suicidal
• Depression with mixed features is associated with high risk of suicidality
• Lithium has been shown to prevent suicide, regardless of diagnosis
• May have side effects less dangerous than those associated with antipsychotics or other
anticonvulsants
• Can be used in populations where mixed states are more prevalent
• Pediatric (age 12+)
• Postpartum
• Protective effect against neurodegenerative changes
• Randomized, controlled studies are lacking but observational studies support the use of
lithium in mixed depression
• More clinical studies are needed
Kelly T. Bipolar Disord 2019;21(4):302-8; Manchia M et al. Bipolar Disord
2019;21(5):458-9; Sani G, Fiorillo A. CNS Spectr 2020;25(4):449-51.
 Meta-Analysis of Lamotrigine
in Acute Treatment of Bipolar Depression
Study Risk Ratio Weight, %
(95% CI)
SCAB2001 1.71 (1.08–2.69) 8.3
Lamotrigine: >50%
SCAA2010 1.11 (0.83–1.48) 20.6 reduction on the
SCA40910 1.09 (0.81–1.48) 21.7 Montgomery-Asberg
Depression Rating
SCA30924 1.24 (0.91–1.70) 19.9
Scale (MADRS)
SCA10022 1.26 (0.95–1.67) 20.7
LAMLIT 1.63 (1.05–2.53) 8.8

Overall (95% CI) 1.26 (1.10–1.44)

0.371223 Risk Factors 2.6938 Lamotrigine shows some efficacy

Favors PBO Favors drug
in bipolar depression.
PBO, placebo.

Geddes JR, Calabrese JR, Goodwin GM. Br J Psychiatry 2009;194(1):4-9.

Van der Loos MLM. J Clin Psychiatry 2009;70(2):223-31.
 Lamotrigine* as Add-On Treatment
to Lithium in Bipolar Depression
*Not approved by the FDA.

Mean ↓MADRS Score

(Baseline to Wk 8)

P = .024

CGI-BP, Clinical Global Impressions

scale, bipolar version; MADRS,
Montgomery-Asberg Depression Rating
Scale.

Endpoint, % Lamotrigine Placebo P

≥50% ↓ MADRS 51.6 31.7 .03
CGI-BP change of depression ≤2 64.1 49.2 .105
Switch to mania/hypomania 7.8 3.3 .441
Response and no switch to mania/hypomania 60.9 46.7 .149

Van der Loos MLM. J Clin Psychiatry 2009;70(2):223-31.

 FDA-Approved Treatments for Pediatric Bipolar Disorder
Acute Mania Acute Bipolar Depression Longer-Term

Year/ Drug Year/ Drug Year/ Drug

1970 Lithium (Age ≥ 12–17) 2014 Olanzapine+fluoxetine 1 Lithium (Age ≥ 12–17)
2007 Risperidone (Age 10–17) combination (Age 10–17) 2008 Aripiprazole (Age 10–17, ->e)
2008 Aripiprazole (Age 10–17),(*->e)
2018 Lurasidone(Age 10–17)
2009 Quetiapine (Age 10–17)
2009 Olanzapine (Age 13–17) Unmet
2015 Asenapine (Age 10–17) Unmet
Need
*Adjunctive (as well as monotherapy); Need
(->e)Extrapolated
indication

Important unmet needs—well-tolerated treatments for acute depression

and maintenance
Adapted from Ketter TA (ed). Advances in the treatment of bipolar disorder, Am Psych Pub, Inc., Washington,
DC; 2015; Roley-Roberts ME, Fristad MA. J Clin Child Adolesc Psychol 2021;50(4):464-77.
Olanzapine/Fluoxetine Combination (OFC) in Children
and Adolescents With Bipolar I Depression:

Rates of and times to response and

remission were statistically significantly
greater for OFC- than for placebo-
treated patients.

Visitwise mean change in Children’s Depression Rating Scale–Revised (CDRS-R) total score (mixed-model
repeated measures). LS= least-squares; OFC=olanzapine/fluoxetine combination.

Detke HC et al. JAACAP 2015;54(3):217-24.

Lurasidone in Pediatrics With Mixed Features
Youth with Bipolar I Depression have similar
efficacy/safety profiles with/without subsyndromal
hypomania

Singh et al. Journal of Child and Adolescent Psychiatry 2020;30(10):590-8.

Positive Studies for “Mood Stabilizers” in Pediatric BD

• LITHIUM: FDA-approved down to age 12 y/o; lithium superior to placebo in children with BD,
little weight gain

• LAMOTRIGINE: Open studies find efficacy in pediatric acute mania, mixed mania, depression;
maintenance RCT study showed benefit as an adjunct

• DIVALPROEX: Extended-release form was negative for acute mania; unpublished data
suggests immediate-release more effective than placebo; inferior to quetiapine and risperidone

• CARBAMAZEPINE: ER form with open label data showing mild to moderate improvement in
pediatric mania
PIPELINE
CARIPRAZINE: effective and well tolerated in youth down to age 6 in retrospective chart review;
RCT results pending

Liu et HY al. J Am Acad Child Adolesc Psychiatry 2011;50(8):749-62; Findling RL et al. J Am Acad Child Adolesc Psychiatry
2015;54(12):1020-31; Findling RL et al. Pediatrics 2015;136(5):885-94; Findling RL et al. J Am Acad Child Adolesc Psychiatry
2019;58(2):287-96; Wagner KD et al. J Am Acad Child Adolesc Psychiatry 2009;48(5):519-32; Joshi G et al. J Child Adolesc
Psychopharmacol 2010;20(1):7-14; Poweleit EA et al. J Child Adolesc Psychopharmacol 2020;30(4):267-72.
Network Meta-Analysis: Bipolar Depression in
Youth

DelBello MP et al. JAACAP 2022;61(2):243-54.

Prevention: Family-Focused Therapy (FFT) Delays New Mood
Episodes by 20 More Weeks Than Enhanced Care (EC)

Finding: Family
prosocial skills-training
for youths at high risk for
bipolar disorder is
associated with longer
intervals between
depressive episodes.

Future Direction: Clarify

the relation between
changes in family
function and changes in
the course of high-risk
syndromes.

Miklowitz DJ et al. JAMA Psychiatry 2020;77(5):455-63.

 Possible Treatment Algorithm for
Pediatric Bipolar Depression
BIPOLAR DEPRESSION

First-Line: Psychotherapy
Next: Lurasidone, Olanzapine-Fluoxetine (with metformin?)
Consider
Lithium, Lamotrigine, Aripiprazole
Next: Quetiapine, Bupropion,
careful SSRI titration

Schneck CD et al. JCAP 2017;27(9):796-805; DelBello MP et al. JAACAP 2017;56(12):1015-25;

Findling RL et al. J Am Acad Child Adolesc Psychiatry 2015;54(12):1020-31.
 Summary

• Up to 60% of patients with bipolar depression are misdiagnosed

with unipolar depression
• There are many factors and challenges that contribute to
misdiagnosis
• Being able to distinguish bipolar from unipolar depression with
accurate screening for hypomania/mania will improve diagnoses
• There are several agents on-label and off-label that are effective
in the treatment of bipolar depression across the lifespan
 Posttest Question 1

According to research, which features are more common in

bipolar depression than in unipolar depression?

1. Longer depressive episodes

2. Somatic complaints
3. Hypersomnia/increased daytime napping
4. Later age of onset (>25)
5. Weight loss
 Posttest Question 2

In bipolar disorder, which mood state is most likely to present in

the earlier part of the life cycle versus the later part?

1. Melancholia
2. Mixed
3. Mania
4. 1 and 2
5. 2 and 3
 Posttest Question 3
Which of the following medications approved for bipolar
depression in adults is also approved for bipolar depression in
pediatrics?

1. Olanzapine-fluoxetine
2. Lumateperone
3. Lurasidone
4. Quetiapine
5. 1 and 3
6. 2 and 4