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

Juvenile Bipolar Disorder: Further Complicated by Comorbidity

Learning Objectives

• Utilize evidence-based strategies to accurately diagnose pediatric patients with bipolar disorder and mania

• Identify current best practices for the treatment of pediatric bipolar disorder and mania

Pretest Question

Tony is an 11-year-old patient with bipolar disorder I. In discussion with the patient and his parents, it is determined that an atypical antipsychotic may be the best choice of treatment. Which of the following atypical antipsychotics is currently FDA-approved for the treatment of bipolar disorder in children 10 years and older?

1. Asenapine2. Olanzapine3. Paliperidone4. All of the above5. None of the above

Case of Joey

• Joey is a 14-year-old male with a history of trauma referred because of "fights" with his mother

• Mother complains of quick temper, "rapid mood swings," agitation, inappropriate "jokes" and "touching," and times of poor sleep (and not tired)

• Marginally passing school (on educational plan)• Previous trials of stimulants for ADHD were "ineffective and

made him angry;" previous SSRI for early mood "set him in a rage"

• No medical history; no hospitalizations• MSE: Joey reports sad/mad, angry with mother; reactive;

laughs inappropriately; appears disinhibited; no psychosis; no suicidality/homicidality

• Diagnosis(es)?

Juvenile Bipolar Disorder (BPD)

• Prevalence: 2.9% of children and adolescents (Merikangas 2010)

• Estimated 10-15% of cases in child psychiatric practices (Carlson et al. 1999, Wozniak et al. 1995)

• Chronic course: under study (Geller et al. 2006, 2009; Birmaher et al. 2009, 2014; Wozniak et al. 2010; Wilens et al. 2016)

Kennedy et al. CNS Spectrums 2011;16.

Mean Age of Onset for Bipolar Disorder; Many Adult Cases Onset in Childhood

Pediatric-Onset Bipolar Disorder:Mood History

MANIA• Irritable, angry, grouchy, cranky, snappy,

swearing, disrespectful, threatening, rage attacks• Explosions: how often, how long, how

destructive, how aggressive• Giddy, goofy, silly, high, "on drugs," laughing fits,

class clownDEPRESSION• Depressed, sad, no pleasure, down on self,

suicidal, self-destructive, whiney, complaining, lower-level irritability

Mick. Biol Psychiatry 2005;58:576.

Distribution of Irritable Mood in Children With ADHD

\.

Essential Features of Pediatric BPD

• Mania is cardinal symptom:– Without mania = depressive disorder

• Several types of BPD based on duration, patterns• Manic episodes (>1 week); Hypomania (4-6 days)

– Persistently elevated/irritable mood– May alternate between irritable/expanded mood– If only irritable, then need grandiosity/inflated self esteem,

reduced sleep(not tired), pressured speech, flight of ideas, severe distractibility, increased goal directed and high risk behaviors

• DSM IV vs V: Change in mixed episodes- now mixed features ([hypo]mania+depressive symptoms)

Axelson et al. J Clin Psychiatry 201;73(10):1342-50; http://www.aacap.org/AACAP/Families_and_Youth/Facts_for_Families/FFF-Guide/Disruptive-Mood-Dysregulation-Disorder-%28DMDD%29-110.aspxl.

Disruptive Mood Dysregulation Disorder (DMDD)

• The symptoms of DMDD include:– Severe temper outbursts at least 3 times a week– Sad, irritable, or angry mood almost every day– Reaction is bigger than expected– Child must be at least 6 years old– Symptoms begin before age 10– Symptoms are present for at least a year– Child has trouble functioning in more than one place

(eg, home, school, and/or with friends)• DDX: bipolar disorder, oppositional + mood disorder,

ADHD

Predictors of Manic Switches

• Family history of mood (major depressive and bipolar) disorders (5/7 studies)– FHx of MDD, FHx of BPD– Multigenerational FHx– Family loading (>3 affected relatives per family)

• Aggression, conduct, and behavioral difficulties(2/7 studies)– Comorbid conduct disorder– Comorbid oppositional defiant disorder– Aggressive and bullying behaviors

• Emotional dysregulation (2/7 studies)• Medication-induced hypomania (3/3 studies)

Factors That Differentiate Bipolar Depression From Unipolar Depression

• Family history of psychiatric illness (3/4 studies)• Comorbid conduct or oppositional defiant

disorders/aggressive behaviors (4/4 studies)• High severity of depression (2/4 studies)• High level of impairment (2/4 studies)

Wozniak 2004, Luby 2008, Merikengas 2012, Shon 2013.

COBY BP Spectrum Conversion to BP-I/II

*

Axelson et al. J Am Acad Child Adolesc Psychiatry 2011;50:1001-16.

Psychiatric Comorbidity Is Common in Adolescent BPD

020406080

100

ConductDisorder

OppositionalDefiantDisorder

ADHD MultipleAnxietyDisorder

%Psychiatric Comorbidity

BPDnon-BPD

p

0 10 20 30 40 50 60

Percent Comorbid

GAD

PTSD

Panic

Social Phobia

Simple Phobia

Agoraphobia

OCD

Avoidant DisorderBPD+PsychosisBPD-Psychosis

**

**

*

**

*

ψ

Psychiatric Comorbidity in Youth With BPD Stratified by Presence of Psychosis

OCD: obsessive compulsive disorder PTSD: posttraumatic stress disorder GAD: generalized anxiety disorder BPD: bipolar disorder

*p

30

35

40

45

50

Lowe

st Pa

st G

AF S

core

BPD-Psychosis BPD+Psychosis

40.3 ± 5.8

35.8 ± 5.6

t = 5.93, p < 0.01

Global Assessment of Functioning (GAF) Associated With Psychosis in Pediatric BPD

Hua et al. J Clin Psychiatry 2011;72(3):397-405.

05

101520253035404550

Controls BP-I

Per

cent

17

45

Doyle et al. Biol Psychiatry 2013.

High Rates of Neuropsychologically Defined Executive Function Deficits in Bipolar Disorder

Treatment of Bipolar Disorder

• Thorough diagnostics (use of DSM-5)• Education assessment (remember

neuropsychological issues, comorbidity)• Family evaluation• Level of care if acute crisis• Pharmacotherapy• Psychotherapy

Psychotherapy for Juvenile BPD

• Psychoeducation family groups• Family-focused therapy • Cognitive behavioral therapy• Group therapy

Pavuluri et al. J Am Acad Child Adolesc Psychiatry 2004;43:528-37; Fristad et al. Arch Gen Psychiatry 2009;66:1013-21; West et al. Minerva Psichiatrica 2011;52(1):21-35.

Effect Size for Change in Manic Youth With Mood Stabilizers

Medication Effect Size 95% CIDivalproex-IR/ER 0.28 0.01-0.54Lithium 0.31 -0.12-0.73Oxcarbazepine 0.11 -0.26-0.49Topiramate 0.51 0.03-1.04Weighted 0.24 0.06-0.41

Courtesy M. DelbelloYMRS = Young Mania Rating Scale

Correll et al. Bipolar Disord 2010.

Effect Size for Bipolar Change in Manic Youth With Second-Generation Antipsychotics (SGAs)

Medication Effect Size 95% CIAripiprazole 0.69 0.44-0.94Olanzapine 0.75 0.41-1.08Quetiapine 0.60 0.35-0.86Risperidone 0.81 0.48-1.14Ziprasidone 0.48 0.21-0.76Weighted SGAs 0.65 0.53-0.78

YMRS = Young Mania Rating Scale

Correll et al. Bipolar Disord 2010.

Courtesy M. Delbello

FDA-Approved Uses of Mood Stabilizers and SGAs in Children With Bipolar Disorder

• Lithium 12+ years*• Aripiprazole (Abilify) 10+ years• Asenapine (Saphris) 10+ years• Olanzapine (Zyprexa) 13+ years• Quetiapine (Seroquel) 10+ years• Risperidone (Risperdal) 10+ years• Ziprasidone (Geodon) 10+ years

*Under consideration for label change

Adverse Effects of Medications for Juvenile BPD

• SGAs- Weight gain, sedation, metabolic abnormalities, dyskinesias,

prolactin elevation, EPS/TD- Risk depends on agent

• Mood stabilizers- Weight gain, sedation (general), thyroid

abnormalities/renal/dermatological (Li), polycystic ovary syndrome (valproic acid), blood dyscrasia, rash (carbamazepine)

• Monitoring required- Height, weight, BMI, glucose/lipid panel, levels, other depending on

agent

De Hert et al. Eur Psychiatry 2011;26:144-58: Martin et al, eds. Pediatric Psychopharmacology. Oxford University Press, 2010.

TREATING COMORBIDITY WITH BPD

Conduct Disorder

N=116BPD

N=110

Diagnostic Overlap Between Conduct Disorder and BPD

Biederman et al. J Am Acad Child Adolesc Psychiatry 1999;38:468-76; Biol Psychiatry 2003;53:952-60; Joshi G, Wilens TE. In: Strakowski S et al, eds. Bipolar Disorder in

Youth: Presentation, Treatment and Neurobiology. Oxford University Press: 2015:56-93.

N=76

ADHD in BPD Youth

Geller et al. J Child Adolesc Psychopharmacol 10(3):56-93.

ManiaN=43 N=42

ADHDN=206

Juvenile BPD MGH Sample

• 17% of outpatient psychopharmacology referrals under age 12 met criteria for BPD

• 91% comorbid with ADHD

Wozniak, Biederman. J Am Acad Child Adolesc Psychiatry 1995;34:867-76.

Prepubertal and Early Adolescent ADHD and Bipolar Disorder

• 87% (81/93) of BPD sample with ADHD

• Subjects with comorbid ADHD were significantly younger (10 years vs. 14 years, p

Wozniak et al. J Am Acad Child Adolesc Psychiatry 2005; Faraone et al. 1997; Wiens et al. Drug Alcohol Dependence 2008; Nierenberg et al. Biol Psychiatry 2005.

ADHD Rates in Children, Adolescents, and Adults With BPD

0

20

40

60

80

100

%

Rates of ADHD

Manic Children

Manic Adolescents(Childhood

Onset)

Manic Adolescents(Adolescent

Onset)

ManicAdults

N=68 N=25

p

Volumetric Differences Between ADHD Patients and Controls

Blue: volumetric decreaseRed: volumetric increaseLight blue: trend towards volumetric decreases

CGa: anterior cingulate gyrus F1: superior frontal gyrusF3o: inferior frontal gyrus, pars opercularisF3t: inferior frontal gyrus, pars triangularis

Biederman et al. 2006.

Volumetric Differences Between BPD Patients and Controls

Blue: volumetric decreases in the BPD groupRed: volumetric increases in the BPD group FOC: frontal orbital cortex

Biederman et al. 2006.

0

10

20

30

40

50

60

70

80

90

Impatient Quick toAnger, Get

Upset

EasilyFrustrated

OverreactEmotionally

Easily Excited

ADHDCommunity

Barkley RA et al. ADHD in Adults: What the Science Says. New York, NY: Guilford Press; 2008:176-9.

Emotional Impulsivity in Adults With ADHD vs. Community Controls

Adults With ADHD and BPD

0 20 40 60 80 100 120

Loses Things

Difficulty Concentrating

Difficulty Organizing Tasks/Activities

Careless/Sloppy

Difficulty Following Instructions

Forgetful

Doesn't Listen

Easily Distracted

Difficulty Sustaining Attention

ADHD+BPD

ADHD-BPD

Percent with SymptomWilens et al. Biol Psychiatry 2003.

DSM-IV ADHD: Inattention Symptoms

Adults With ADHD and BPD

1.6

5.7

0

2

4

6

8ADHD-BPD ADHD+BPD

Bipolar Symptoms

**p

Wilens et al. In: Hendren, ed. Disruptive Behavioral Disorders in Youth. 1998; Gagan, Wilens. Comorbidity in Bipolar Disorder. 2015.

ADHD vs Bipolar DisorderThe picture can't be displayed.

ADHD

+++Environmental role+/–++Effect of structure

SevereModerateImpairment

Chronic (cycling)ConstantCourse

BipolarCharacteristicDistinguishing Factors

-18.44-20

-10

0Baseline: 34.7

p

Treating Juvenile BPD+ADHD

-5

-4

-3

-2

-1

0

Placebo Amph Salts

• Study of BPD spectrum youth

• Ages 6-17 (9 ± 2.4 years)

• Design– 8-week open (N=40)

with DPK– 4-week double-blind

(N=30) DPK + Adderall (5 mg BID) or PBO YMRS scores (endpoint)

• PBO 5.9• Amph 7.1 (pNS)

p

37.6

7

32.1

9

30.1

9

26.3

3

19.8

1

20.8

1

10

20

30

40

Bas

elin

e

Plac

ebo

5 m

g

10 m

g

15 m

g

Bes

t Dos

eW

eek

Findling R et al. J Am Acad Child Adolesc Psychiatry 2007;46:11:1445-53.

*ARS-IV: parent-completed ADHD Rating Scale-IV

ADHD RS

Dose condition (BID)

N=16; ages 4-17 (mean 11 years)

Euthymic-stable on thymoleptic

1 week Tx

No effect on mania

p

Association Between Adolescent BPD and Smoking and Substance Use Disorders (SUD)

• Emerging data suggests a bidirectional over-representation of BPD and SUD across the life cycle

• About half of referred and community samples of adults with BPD have a lifetime history of SUD

Himmelhoch, 1979; Reich, 1974; Strakowski, 1998; Winokur, 1995.

Impact of SUD in Juvenile BD

MSIT: Multisource Interference TaskHC: healthy controls

Gruber et al. J Am Acad Child Adolesc Psychiatry 2015.

Life

time

Prev

alen

ce

p=0.001

Wilens et al. J Clin Psychiatry 2016;77(10):1420-1427.

Control

Bipolar

Development of Nicotine Dependence in BPD Youth

Life

time

Prev

alen

ce p=0.004Bipolar

Control

Development of Substance Use Disorders (SUD) in BD Youth

Wilens et al. J Clin Psychiatry 2016;77(10):1420-1427.

Persistence of Adolescent BPD:BPD Status From Ages 14 to 19 (N=68)

0

10

20

30

40

50

60

No BPD Subthreshold BPD Full BPD

%

DX based on KSAD/SCID66% have BPD

Wilens et al. J Clin Psychiatry 2016;77(10):1420-1427.

Chart1

No BPD

Subthreshold BPD

Full BPD

Series 1

34

13

53

Sheet1

Series 1Series 2Series 3

No BPD342.42

Subthreshold BPD134.42

Full BPD531.83

Category 44.52.85

To resize chart data range, drag lower right corner of range.

Life

time

Prev

alen

ce

Persistent BPD vs. Control: p=0.001Persistent BPD vs. Non-Persistent BPD: p=0.2 Non-Persistent BPD vs. Controls: p=0.2

Persistent BPD

Nonpersistent BPD

Control

Development of SUD in BPD Youth

Wilens et al. J Clin Psychiatry 2016;77(10):1420-1427.

BPD Adolescent Substance Use and Self-Medication

1 1.5 2 2.5 3 3.5 4

Start to Aid Sleep,p=0.5

Start to Get High,p=0.7

Cont to ChangeMood, p=0.1

Start to ChangeMood, p=0.02

Motivation from 1=“very true” to 4=“not true at all”

Lorberg et al. Am J Addict 2010;19:474-80.

BPDControl

Deficits in Emotional Regulation Are Related to SUD in Bipolar Youth

Association remained significant when controlling for both BP and ADHD (HR: 5.16; 95% CI: 2.06, 12.90; p

Deficits in Emotional Regulation Are Associated With Polysubstance Abuse

*p

Temporal Association of BPD and SUD

0

10

20

30

40

50

60

70

BPD prior to SUD

BPD within 1 year of SUD BPD after SUD

%

Wilens et al. Drug Alcohol Dependence 2008.

BPD and SUD: Clinical Implications

• Assess youth with severe or bingesubstance use disorders for BPD

• Assess all adolescents with BPD for cigarette smoking and substance use disorders

Controlled Study of Lithium for Bipolar Adolescents With SUD

0

10

20

30

40

50

60

3 4 5 6

Substance Use

Weeks

Perc

ent P

ositi

ve U

rines

Placebo (N=12)

Lithium (N=13)

Functioning

35

40

45

50

55

60

65

BSL 1 2 3 4 5 6

Mea

n C

GA

S Sc

ores

Weeks

Lithium (N=13)

Placebo (N=12)

p

Quetiapine Plus Topiramate Reduces Cannabis Use in Adolescents With BPD

0

2

4

6

8

10

12

14

Baseline End of Study

Quetiapine+placeboQuetiapine+Topiramate

BPD YMRS scores improved with both treatments-14 quetiapine + topiramate-16 quetiapine + placebo

Delbello et al. AACAP presentation, 2011.

p

Juvenile BPD and Comorbidity

• BPD often onsets in childhood• BPD may manifest differently than adult BPD• BPD assessment requires consideration of the

mood, educational, environmental, and family needs

• Multimodal treatment is necessary• Pharmacologically, second-generation

antipsychotics are often first-line agents (and FDA-approved)

Juvenile BPD and Comorbidity

• Juvenile BPD is commonly comorbid with other major psychiatric disorders

• Evidence suggests that these disorders are not just a manifestation of BPD

• ADHD, conduct disorder, and substance use disorders are among the most common and disconcerting disorders

• Treatment of both the underlying BPD and comorbidity is often necessary

Juvenile Bipolar Disorder: �Further Complicated by ComorbidityLearning ObjectivesPretest QuestionCase of JoeyJuvenile Bipolar Disorder (BPD)Mean Age of Onset for Bipolar Disorder; Many Adult Cases Onset in ChildhoodPediatric-Onset Bipolar Disorder:�Mood HistoryDistribution of Irritable Mood in Children With ADHDEssential Features of Pediatric BPDDisruptive Mood Dysregulation Disorder (DMDD)Predictors of Manic SwitchesFactors That Differentiate Bipolar Depression From Unipolar DepressionCOBY BP Spectrum Conversion to BP-I/IIPsychiatric Comorbidity Is Common in Adolescent BPDPsychiatric Comorbidity in Youth With BPD Stratified by Presence of Psychosis Global Assessment of Functioning (GAF) Associated With Psychosis in Pediatric BPDHigh Rates of Neuropsychologically Defined Executive Function Deficits in Bipolar DisorderTreatment of Bipolar DisorderPsychotherapy for Juvenile BPDEffect Size for Change in �Manic Youth With Mood StabilizersEffect Size for Bipolar Change in Manic Youth With Second-Generation Antipsychotics (SGAs)FDA-Approved Uses of Mood Stabilizers and SGAs in Children With Bipolar DisorderAdverse Effects of Medications for Juvenile BPDSlide Number 24Diagnostic Overlap Between Conduct Disorder and BPDADHD in BPD YouthJuvenile BPD MGH SamplePrepubertal and Early Adolescent �ADHD and Bipolar DisorderADHD Rates in Children, Adolescents, and Adults With BPDVolumetric Differences Between ADHD Patients and ControlsVolumetric Differences Between BPD Patients and Controls Emotional Impulsivity in Adults With ADHD vs. Community ControlsAdults With ADHD and BPDAdults With ADHD and BPDADHD vs Bipolar DisorderMGH Open Study: Bupropion for ADHD in Adults With Bipolar DisorderTreating Juvenile BPD+ADHDEffect of Methylphenidate on ADHD in Stabilized Youth With BPDAssociation Between Adolescent BPD and Smoking and Substance Use Disorders (SUD)Impact of SUD in Juvenile BDDevelopment of Nicotine Dependence �in BPD YouthDevelopment of Substance Use Disorders (SUD) in BD YouthPersistence of Adolescent BPD:�BPD Status From Ages 14 to 19 (N=68)Development of SUD in BPD YouthBPD Adolescent Substance Use �and Self-MedicationDeficits in Emotional Regulation Are Related to SUD in Bipolar Youth Deficits in Emotional Regulation Are Associated With Polysubstance AbuseTemporal Association of BPD and SUDBPD and SUD: Clinical ImplicationsControlled Study of Lithium for Bipolar Adolescents With SUDQuetiapine Plus Topiramate Reduces Cannabis Use in Adolescents With BPDJuvenile BPD and ComorbidityJuvenile BPD and Comorbidity