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Treatment of Bipolar Disorder in Youth

Janet Wozniak, M.D. Associate Professor of Psychiatry

Director, Pediatric Bipolar Disorder Research Program Harvard Medical School

Massachusetts General Hospital

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Merck/Schering-Plough research funding

SPOUSE : Associated Professional Sleep Societies, Gerson Lerman Group, Summer Street Partners, UCB, Cantor Colburn

consultation fees

Cambridge University Press royalties

My spouse/partner and I have the following relevant financial relationship with a commercial interest to disclose:

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National Trends in Visits with a Diagnosis of Bipolar Disorder as a Percentage of Total Office-Based Visits

“This increase highlights a need for clinical epidemiological reliability studies to determine the accuracy of clinical diagnoses”

Moreno et al., Arch Gen Psych, 2007

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Disruptive Mood Dysregulation Disorder DMDD Criteria

A. The disorder is characterized by severe recurrent temper outbursts that are grossly out of proportion in intensity or duration to the situation.

1. The temper outbursts are manifest verbally and/or behaviorally, such as in the form of verbal rages or physical aggression towards people or property. 2. The temper outbursts are inconsistent with developmental level.

B. Frequency: The temper outbursts occur, on average, three or more times per week. C. Mood between temper outbursts:

1. Nearly every day, most of the day, the mood between temper outbursts is persistently irritable or angry. 2. The irritable or angry mood is observable by others (e.g., parents, teachers, peers).

D. Duration: Criteria A-C have been present for 12 or more months. Throughout that time, the person has not had 3 or more consecutive months when they were without the symptoms of Criteria A-C. E. Criterion A or C is present in at least two settings (at home, at school, or with peers) and must be severe in at least in one setting. F. The diagnosis should not be made for the first time before age 6 or after age 18. G. The onset of Criteria A through E is before age 10 years.

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Published May 2013 American Psychiatric Association's Diagnostic Statistical Manual, Fifth

Edition, or DSM-5

The New Temper Tantrum Disorder Will the new diagnostic manual for psychiatrists go too far in labeling kids dysfunctional? By David Dobbs|Posted Friday, Dec. 7, 2012, at 1:12 PM ET

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Bipolar I or II Disorder affected 2.9% of >10,000 adolescents, most with severe impairment

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Merikangas, et al, National Comorbidity Survey Replication-Adolescent Supplement, 2010

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SCOPE OF THE PROBLEM Meta-analysis of Epidemiologic Studies of Pediatric Bipolar Disorder

Van Meter J Clin Psych 2011

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Pediatric-Onset Bipolar Disorder Do children ‘look’ different?

Irritability and Fluctuating Mood States/Mixed States Less euphoria (or hard to detect?) “AFFECTIVE STORMS” SEVERELY Irritable: swearing, disrespectful, threatening, wild, out of control With Explosions: frequent, for 30-60+ minutes, destructive, aggressive Lower level Irritable: whiney, complaining, difficult to please, angry, grouchy, cranky, snappy Chronicity and ?Rapid Cycling Discrete episodes may be difficult to delineate Ultradian Cycling or changes in mood presentation/’polarity’ Developmental Distinctions in Symptoms What’s grandiosity? What’s hypersexuality? Spending?

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Euphoria and Irritability in BPD Probands

Euphoric, Any = 28 Irritable, Any = 61

N=38 N=23 N=5 Irritable

Euphoric

82% (23 of 28) of Euphoric subjects met for Irritability 38% (23 of 61) of Irritable subjects met for Euphoria

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Kraepelin’s Depressed, Mixed and Manic Across the Life span

Kraepelin. Manic Depressive Insanity. 1921. Page 168 (Figure 45). Translated by RM Barclay. GM Robertson (ed). E & S Livingstone, Edinburgh.

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Developmental Course in Bipolar Children: A disorder affecting preschoolers

Children often ill for years by time of referral

Mea

n Ag

e at

Ons

et

ADHD ANX ODD MDD CD 0

1

2

3

4

5

6

7 Bipolar Onset (4.55)

2.98

4.05 4.47 4.65 4.94

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Mania Episodicity (N = 92) Youth are both episodic and chronic

0

10

20

30

40

50

60

70

80

90

100

Chronic Episodic

%

41% Single, ≥ 12 m

7% Episodic, ≥ 12 m

5% Episodic, < 12 m

7% Single, < 12 m

12% Rapid Cycling > 4 episodes/yr 27% Ultra-Rapid ≥ 20 episodes/yr 1% Ultraradian ≥ 300 episodes/yr

•Presentation varies: mixed, manic, depressed •Mood switches: irritable, euphoric, melancholy •Comorbidity evident

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The symptoms of ADHD and mania overlap and are difficult to disentangle

Talkativeness, hyperactivity (physical

agitation/energy), distractibility are symptoms of ADHD and mania

ADHD is a common disorder of childhood (5-10%) and

often includes emotional dysregulation

Pediatric-Onset Bipolar Disorder: Why is it Underdiagnosed?

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MGH Study of Pediatric BPD

0102030405060708090

100

Major Depression Psychosis ADHD OppostionalDefiant Disorder

Conduct Disorder

Psychiatric Diagnoses

%

Bipolar 1st Cohort Bipolar 2nd Cohort

Comorbid Disorders by Bipolar Cohort, Clinic Samples Prior to 1995 and 1995-2002

P = NS

P = NS

P = NS

P = NS

P = NS

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Meta-Analysis of 5 Controlled Family Studies of Pediatric Bipolar Disorder These odds ratios indicate a risk of bipolar I disorder to relatives of bipolar I probands that is 4-14 times greater than the risk to relatives of nonbipolar probands

NO EVIDENCE OF HETEROGENEITY IN MAGNITUDE OF FAMILIAL TRANSMISSION Wozniak J Clin Psych, 2012

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Proband n = 239 162 136 Relative n = 726 511 411

Mor

bid

risk

in re

lativ

es

Familial risk of bipolar I disorder in first-degree relatives of BP-I, ADHD and Control Probands

*

Wozniak J Clin Psych, 2012

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Persistence: Most bipolar adults in STEP-BD (N=983) reported onset in childhood or

adolescence

• About 65% of adults with onset < 18 • Almost a third with onset <13

> 18 years: 35%

13 to 18 years 37%

< 13 years 28%

Perlis, Miyahara, Marangell, Wisniewski, Ostacher, DelBello, Bowden, Sachs, Nierenberg, Biol Psych 2004;55:875-881

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Pediatric Bipolar Disorder Persistence

Child Bipolar I Disorder Prospective Continuity With Adult Bipolar I Disorder; Characteristics of Second and Third Episodes; Predictors of 8-Year Outcome

Conclusions: In grown-up subjects with child BP-I, the 44.4% frequency of manic episodes was 13 to 44 times higher than population prevalences, strongly supporting continuity.

Geller, et al, Arch Gen Psychiatry, 2008;65(10):1125-1133

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Persistence of Pediatric Bipolar Disorder

Four-Year Longitudinal Course of Children and Adolescents With Bipolar Spectrum Disorders: The Course and Outcome of Bipolar Youth (COBY) Study N=214 Bipolar I and N=169 Bipolar II and NOS, followed for 4 years with the Longitudinal Interview Follow Up Evaluation Recurrences common Symptomatic on average for 60% of the follow-up period. 40% had symptoms during 75% of the followup period. 25% of BPD II and 38% of BPD NOS converted to BPI

Birmaher, et al, Am J Psychiatry. 2009 Jul;166(7):795-804

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Persistence of Pediatric Bipolar Disorder

HIGH LEVEL OF PERSISTENCE OF PEDIATRIC BIPOLAR-I DISORDER FROM CHILDHOOD ONTO ADOLESCENT YEARS: A FOUR YEAR PROSPECTIVE

78 of 105 youth with Bipolar I disorder followed up after 3.6 years •Baseline age 10.5 years, 76% male •Age of onset bipolar disorder 4.9 years •Duration of BPD at baseline 7.6 years

Wozniak et al, J Psychiatr Res, 2011

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Persistence of Bipolar Disorder in youth at 4-year Follow-up

(N=78)

Most continue with Bipolar I disorder 73.1%

Some symptoms of Mania 6.4%

Not manic, but depressed 5.1%

Better, but Treated 9.0%

Better 6.4%

Only 5 (6.4%) subjects were better without treatment

Wozniak et al, J Psychiatr Res, 2011

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Off-Label Use

• All medications, described in this presentation constitute off-label use in the USA with the exception of the following FDA approved medications: – Fluoxetine: depression and OCD age 8+ – Escitalopram: depression age 12+ – Sertraline,fluvoxamine, anfranil: pediatric OCD

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• All medications, described in this presentation constitute off-label use in the USA with the exception of the following FDA approved medications:

– Lithium: manic or mixed states, patients aged 13-17 years

– 2007 Risperidone: manic or mixed states, age 10-17 years – 2008 Aripiprazole: manic or mixed states, age 10-17 years – 2009 Olanzapine: manic or mixed states, age 13-17 years – 2009 Quetiapine: monotherapy or adjunct to lithium or

divalproex sodium, manic states, age 10-17 years – 2015 Saphris manic or mixed episodes assoc with BPD I,

age 10-17

Off-Label Use

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• All medications, described in this presentation constitute off-label use in the USA with the exception of the following FDA approved medications: – Aripiprazole: irritability associated with autistic disorder

ages 6-17 – Risperidone: irritability associated with autism ages 5-16

Off-Label Use

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Treatment algorithm

Stage I – monotherapy +/- augmentation Stage 2 – switch monotherapy agent Stage 3 – combo mood stabilizer + SGA

(Or switch monotherapy agent)

Stage 4 – Combination 1 mood stabilizer + SGA 2 mood stabilizers + SGA

Stage 5 – alternate monotherapy Stage 6 – ECT vs. Clozapine

Kowatch, JAACAP, 2005

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Can we wait?

Post, Leverich, et al. 2010.

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Bipolar adults with childhood and adolescent onset had more lifetime suicide attempts and violence

0

10

20

30

40

50

60

70

80

Suicide Attempts Violence Psychotic Features

ChildAdolescentAdult

Perlis, Miyahara, Marangell, Wisniewski, Ostacher, DelBello, Bowden, Sachs, Nierenberg, Biol Psych 2004;55:875-881

N=983

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Number of Subjects Participating in Pediatric Anti-Manic Trials

J Am Acad Child Adolesc Psychiatry, 2011;50(8):749-762.

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Mean Change in YMRS from Baseline by Medication Class

-10.99 -11.03

-16.8

-5.6

-18

-16

-14

-12

-10

-8

-6

-4

-2

0

Traditional MoodStabilizers

OtherAnticonvulsants

AtypicalAntipsychotics

NaturopathicTreatments

YM

RS S

core

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Weight Gain in 8-week Open Label Trials of Second Generation Antipsychotic Monotherapy in 116 Children

with Bipolar Disorder

00

01

02

03

04

05

06

0 1 2 3 4 5 6 7 8

Cha

nge

from

Bas

elin

e (k

g)

aripiprazole

quetiapine

risperidone

ziprasidone

olanzapine

Biederman et al (2007), AACAP; Boston

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Weight gain and metabolic risks associated with antipsychotic medications in children and adolescents

N=34 studies olanzapine 3.8 to 16.2 kg (n=353) clozapine 0.9-9.5 kg (n=97) risperidone 1.9-7.2 kg (n=571) quetiapine 2.3-6.1 kg (n=133) aripiprazole 0-4.4 kg (n=451)

Correll et al JChildAdolescPsychopharm 2011 Dec;21(6):517-35

Adverse Events

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One-year incidence rates of tardive dyskinesia in children and adolescents treated with second-generation antipsychotics: a systematic review

Correll, et al JChildAdolescPsychopharm 2007;17(5):647-56

N=783 Results across 10 studies suggest relatively low 1-year TD rates in pediatric patients

treated with SGAs. However, the available data base is limited by the small sample size of studies with SGAs other than risperidone and by the use of relatively low doses, which may have obscured a potentially greater risk for TD in children and adolescents treated with higher total SGA doses and for longer durations.

Three new cases of TD emerged during long-term treatment with SGAs of up to 3 years, resulting in crude and annualized TD rates of 0.38%. In the two cases with information, TD resolved within weeks after antipsychotic discontinuation.

Adverse Events

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Adverse Events

Pringsheim T, Lam D, Ching H, Patten S. Metabolic and neurological complications of second-generation antipsychotic use in children. Drug Saf. 34(8), 651–668 (2011).

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Lithium, Divalproex Sodium, and Carbamazepine in Bipolar Disorder

Kowatch et al. JAACAP 39, 713-720, 2000

Results • The response rates were 53% for divalproex sodium 38% for lithium 38% for carbamazepine • All 3 mood stabilizers were well tolerated with

no serious adverse effects

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Pediatric Bipolar Disorder: Progress in Treatments

• A prospective open-label trial of lamotrigine monotherapy in children and adolescents with bipolar disorder. J.CNS Neurosci Ther. 2010

• A prospective open-label trial of extended-release carbamazepine monotherapy in children with bipolar disorder. JCAP 2010

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This study was highly publicized in the major news media and suggest that 2 months of supplementation can have

positive effects after one year on psychotic symptoms

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Our own study shows that omega-3s can treat bipolar disorder in children This result is about 50% what we see with atypical antipsychotic medications, but without the

serious or annoying side effects

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Comorbid disorders

• Depression- after mania stabilized – Lithium, Lamotrigine, or bupropion – Avoid SSRI’s

• ADHD – Stimulant after mood stabilized

Joshi G, Wilens TE. Child Adolesc Psych Clin N Am 18 (2009) Comorbidity in PBD 291-319.

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Quetiapine not effective in Adolescent Bipolar Depression

Mean (SD) change in CDRS-R scores from baseline to endpoint

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Open Label Lamotrigine and Lithium Effective in Adolescent Bipolar Depression

Chang et al JAmAcadChildAdolPsyc 2006

N=20

Adjunctive or monotherapy lamotrigine

63% responders (at least 50% decrease in CDRS)

84% much or very much improved CGI-I

Patel et al JAmAcadChildAdolPsyc 2006

N=27

Monotherapy Lithium

48% responders (at least 50% decrease in CDRS)

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Treatment of ADHD comorbid with Pediatric BPD

Some SGA studies of bipolar disorder in youth also demonstrate improvement of ADHD (eg, paliperidone, joshi et al 2013; Aripiprazole, Tramontina 2007, 2009; Risperidone, Biederman 2008) One study correlated the improvement of ADHD with the improvement in mania In a chart review of risperidone, mania improved, but not ADHD (Frazier 1999) In studies of Equetro (Joshi 2010) and lamotrigine (Biederman, 2010), mania, depression and ADHD all improved

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Treatment of ADHD comorbid with Pediatric BPD

Improvement in ADHD shown in two ‘add-on’ studies: Adderall v placebo, 4 week study, Scheffer 200 Methylphenidate v placebo, 4 week study, Findling 2007 However, methylphenidate v placebo in youth stabilized with Abilify showed no differences in improvement in ADHD. Zeni, 2009. Chart review of Strattera demonstrated improvement in ADHD symptoms in stabilized bipolar subjects, Chang 2005 8 wk open trial adjunct treatment in euthymic youth demonstrated improvement, Chang 2009

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N=22,797 cases diagnosed with pediatric ADHD odds of developing BD were significantly and positively associated with: -- longer treatment with methylphenidate, mixed amphetamine salts, or atomoxetine being -- treatment with certain antidepressant medications, most notably fluoxetine, sertraline, bupropion, trazodone or venlafaxine

Jerrell JM, J Clin Psychiatry.

Treatment of ADHD comorbid with Pediatric BPD

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Euthymic youths with bipolar disorder and ADHD may benefit from short-term concomitant treatment with methylphenidate

Findling et al., J. Am. Acad. Child Adolesc. Psychiatry, 2007;46(11):1445-1453.

A 4-week double-blind, placebo-controlled trial in youths ages 5 to 17 years with bipolar disorder and ADHD, were currently receiving a stable dose of at least one thymoleptic, and while euthymic continued to have clinically significant symptoms of ADHD. Patients received 1 week each of placebo, methylphenidate 5 mg twice daily, methylphenidate 10 mg twice daily, and methylphenidate 15 mg twice daily using a crossover design. Subjects were randomly assigned to receive one of six possible dosing orders. The primary outcome measure was the total score on the parent-completed ADHD RESULTS Lower scores during best dose treatment compared to the week of placebo treatment were found on the ADHD Rating Scale-IV (p < .05), suggesting a therapeutic benefit. A large effect size (Cohen's d = 0.90) was found for methylphenidate. Treatment was generally well tolerated. Rating Scale-IV.

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Treatment of substance abuse comorbid with Pediatric BPD

Lithium improved substance abuse, not bipolar, in comorbid pediatric subjects

Geller, JAACAP, 1998

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Treatment of autism comorbid with Pediatric BPD

SGA secondary analysis of SGA trials demonstrated improvement of bipolar disorder in the autism subjects (Joshi, et al ) SGAs demonstrated improvement in ASD subjects (Hamrin, 2008; Atlas, 1995)

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Pediatric Bipolar Disorder Treatment Summary

• Atypical antipsychotic agents outperform traditional mood stabilizers and other anticonvulsants

• Emerging evidence to support combination pharmacotherapy or natural treatments

• Highly comorbid, so combined therapies routine • Depression difficult to treat

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Future Research Questions

• Studies of young children < 12 years old and preschoolers

• Combination pharmacotherapy trials • Pharmacotherapy of comorbid disorders

– ADHD – Depression – OCD

• Psychosocial treatment

Psychopharmacology Friday, September 28 – Sunday, September 30, 2012

The Westin Copley Place

39th Annual Psychopharmacology Conference Thursday – Sunday, October 22– 25, 2015

The Westin Copley Place MGHCME.ORG

Massachusetts General Hospital Department of Psychiatry

Presents

39th Annual Psychopharmacology

Conference

THURSDAY-SUNDAY, OCTOBER 22-25, 2015 THE WESTIN COPLEY PLACE

BOSTON, MA