bipolar disorder in children and adolescents robert a. kowatch, md, phd professor of psychiatry the...

Bipolar Disorder in Children Bipolar Disorder in Children and Adolescentsand Adolescents

Bipolar Disorder in Children Bipolar Disorder in Children and Adolescentsand Adolescents

Robert A. Kowatch, MD, PhDProfessor of Psychiatry

The Ohio State University’s Wexner Medical CenterNationwide Children’s Hospital

Center for Innovation in Pediatric Practice

• Bipolar I Disorder

• “Manic Depressive Illness”

• Bipolar II Disorder

• Cyclothymia

• Bipolar Not Otherwise Specified

• BP “NOS”

DSM-IV Bipolar DisordersDSM-IV Bipolar Disorders

• Adults (NCS Replication Study, Merikangas et al. 2007)

• Bipolar I Disorder: 1.0%

• Bipolar II Disorder: 1.1%

• Bipolar Subthreshold: 2.4%

• Adolescents

• Bipolar Disorder: 1.0-1.4%

• Children

• ???

Lifetime Prevalence of Bipolar Disorder in the USA

Lifetime Prevalence of Bipolar Disorder in the USA

Goodwin and Jamison, Manic Depressive Illness, March 22, 2007 | ISBN-10: 0195135792 | ISBN-13: 978-0195135794 | Edition: 2

• Differential diagnosis of mood swings in children and adolescents

• Pharmacotherapy of pediatric bipolar disorder

TopicsTopics

Fair Use Doctrine, http://www.copyright.gov/fls/fl102.html

Differential DiagnosisDifferential Diagnosis


• ADHD

• ODD

• Anxiety Disorders

• Fetal Alcohol Spectrum Disorder

• (ARND)

Other disorders that frequently cause mood swings

Other disorders that frequently cause mood swings

Attention-Deficit/Hyperactivity Disorder (ADHD)

Attention-Deficit/Hyperactivity Disorder (ADHD)


• A persistent pattern of inattention and/or hyperactivity-impulsivity that is more frequent and severe than is typically observed in individuals at a comparable level of development

• Some impairment from the symptoms must be present in at least 2 settings (e.g., at home and at school)

• There must be clear evidence of interference with developmentally appropriate social, academic, or occupational functioning

• Present before age 7 years• 6 symptoms for at least 6 months

Attention Deficit Hyperactivity Disorder DSMIV Criteria

Attention Deficit Hyperactivity Disorder DSMIV Criteria

Geller & Williams 1998

Subjects 60 Bipolar Subjects with ADHD

Mean age of 11 + 2.7 yr. 60 ADHD Subjects with no mood

disorder Mean age of 9.6 + 2 yr.

Method CGAS < 60 WASH-U-KSADS, 16 Mania Items

Mothers Children & Adolescents

Prepubertal & Early Adolescent Bipolarity Differentiate From ADHD

by Manic Symptoms

Prepubertal & Early Adolescent Bipolarity Differentiate From ADHD

by Manic Symptoms

Oppositional Defiant Disorder(ODD)

Oppositional Defiant Disorder(ODD)


• A. A pattern of negativistic, hostile, and defiant behavior lasting at least 6 months, during which four (or more) of the following are present:

• Often loses temper

• Often argues with adults

• Often actively defies or refuses to comply with adults' requests or rules

• Often deliberately annoys people

• Often blames others for his or her mistakes or misbehavior

• Is often touchy or easily annoyed by others

• Is often angry and resentful

• Is often spiteful or vindictive

• B. The disturbance in behavior causes clinically significant impairment

• C. The behaviors do not occur exclusively during the course of a Psychotic or Mood Disorder

• D. Criteria are not met for Conduct Disorder

DSMIV Criteria for Oppositional Defiant Disorder

DSMIV Criteria for Oppositional Defiant Disorder

ODD vs. BPDODD vs. BPDSymptoms ODD BPD

Often loses temper + +

Often argues with adults + +/-Often actively defies or refuses to comply with adults' requests or rules + +/-

Often deliberately annoys people + +

ODD vs. BPDODD vs. BPDSymptoms ODD BPD

Often loses temper + +

Often argues with adults + +/-Often actively defies or refuses to comply with adults' requests or rules + +/-

Often deliberately annoys people + +

Euphoria/Irritability - +Inflated Self Esteem/grandiosity - +Decreased Need for Sleep - +More Talkative/Pressured Speech - +Flight of Ideas/Racing Thoughts - +Distractibility - +Increased Goal Activity/Agitation - +Excessive Involvement in Pleasurable Activities - +

Anxiety DisordersAnxiety Disorders


Lifetime prevalence of mental disorders in U.S. adolescentsLifetime prevalence of mental disorders in U.S. adolescents

Merikangas et al., J Am Acad Child Adolesc Psychiatry. 2010 Oct

Generalized Anxiety Disorder (GAD) Worry a lot

Headaches/Stomach Aches

Anxiety often causes mood swings

OCD Symptoms > 1 Hour/Day

Obsessions

Compulsions “Just Right” Phenomena

Frequent mood swings if things don’t go just right

Anxiety DisordersAnxiety Disorders

Fetal Alcohol DisordersFetal Alcohol Disorders


Maternal alcohol use during pregnancy

Growth deficiencies

stunted prenatal and/or postnatal growth

Permanent brain damage resulting in neurological abnormalities, delay in development, intellectual impairment and learning/behavior disabilities

Abnormal facial features including short eye opening, short nose, flat midface, thin upper lip and small chin

Fetal Alcohol Syndrome (FAS)Fetal Alcohol Syndrome (FAS)

Fetal Alcohol Syndrome FaciesFetal Alcohol Syndrome Facies


Fetal Alcohol Syndrome (FAS)Fetal Alcohol Syndrome (FAS)


• Full Dysmorphia Absent• Poor impulse control• Problems in social perception• Deficits in higher level receptive and expressive

language• Problems in memory, attention, or judgment

learning • Difficulties, deficits in school performance • Poor capacity for abstraction or metacognition• Specific deficits in mathematical skills• Mood Dysregulation

Alcohol-Related Neurodevelopmental Disorder (ARND)

Alcohol-Related Neurodevelopmental Disorder (ARND)

Slides Courtesy of

David Axelson, M.D.

Associate Professor of Psychiatry

Western Psychiatric Institute & Clinic - UPMC

Disruptive Mood Dysregulation Disorder

(DMDD)


(DMDD)

• A. The disorder is characterized by severe recurrent temper outbursts in response to common stressors.

• B. The temper outbursts are manifest verbally and/or behaviorally, such as in the form of verbal rages, or physical aggression towards people or property.

• C. The reaction is grossly out of proportion in intensity or duration to the situation or provocation.

• The responses are inconsistent with developmental level.• Frequency

• The temper outbursts occur, on average, three or more times per week.

• Mood between temper outbursts: • Nearly every day, the mood between temper outbursts is

persistently negative (irritable, angry, and/or sad).• The negative mood is observable by others (e.g., parents,

teachers, peers).

DSM-5 Proposal: Disruptive Mood Dysregulation Disorder

DSM-5 Proposal: Disruptive Mood Dysregulation Disorder

• TDD is similar to SMD except the symptoms of hyperarousal have been removed

• SMD Hyperarousal Symptoms (need at least 3)• Insomnia

• Agitation

• Distractibility

• Racing thoughts

• Flight of ideas

• Pressured speech

• Intrusiveness

DMDD vs. Severe Mood Dysregulation (SMD)

DMDD vs. Severe Mood Dysregulation (SMD)

• Duration: Criteria A-C have been present for at least 12 months. Throughout that time, the person has never been without the symptoms of Criteria A-C for more than 3 months at a time.

• The temper outbursts and/or negative mood are present in at least two settings (at home, at school, or with peers) and must be severe in at least in one setting.

• Chronological age is at least 6 years (or equivalent developmental level).• The onset is before age 10 years.

Temper Dysregulation Disorder with Dysphoria Criteria

Temper Dysregulation Disorder with Dysphoria Criteria

• In the past year, there has never been a distinct period lasting more than one day during which abnormally elevated or expansive mood was present most of the day for most days, and the abnormally elevated or expansive mood was accompanied by the onset, or worsening, of three of the “B” criteria of mania (i.e., grandiosity or inflated self esteem, decreased need for sleep, pressured speech, flight of ideas, distractibility, increase in goal directed activity, or excessive involvement in activities with a high potential for painful consequences; see pp. XX). Abnormally elevated mood should be differentiated from developmentally appropriate mood elevation, such as occurs in the context of a highly positive event or its anticipation.

Temper Dysregulation Disorder with Dysphoria (cont.)

Temper Dysregulation Disorder with Dysphoria (cont.)

• The behaviors do not occur exclusively during the course of a Psychotic or Mood Disorder (e.g., Major Depressive Disorder, Dysthymic Disorder, Bipolar Disorder) and are not better accounted for by another mental disorder (e.g., Pervasive Developmental Disorder, post-traumatic stress disorder, separation anxiety disorder). (Note: This diagnosis can co-exist with Oppositional Defiant Disorder, ADHD, Conduct Disorder, and Substance Use Disorders.)

• The symptoms are not due to the direct physiological effects of a drug of abuse, or to a general medical or neurological condition.



• Marked upsurge in the diagnosis of bipolar disorder in youth

• Coincided with debate as to whether mania in children presented with severe, non-episodic irritability

• Presented support from post-hoc analyses of longitudinal epidemiological studies that chronic irritability does not progress to bipolar disorder in young adulthood

• Evidence from Severe Mood Dysregulation (SMD) studies in regard to differences between SMD vs. Narrow Phenotype BP youth in short-term course, family history and neural circuitry

DSM-V rationale for DMDD DSM-V rationale for DMDD

• Noted scientific support is limited but clinical need was strong for a

separate diagnosis (instead of a course specifier for ODD)

• “Based purely on scientific evidence, inclusion of a specifier might

be most easily justified. However, when both clinical need and

scientific evidence are considered together, a different conclusion

emerges.”

DMDD Rationale (con’t)DMDD Rationale (con’t)

Issues Pertinent to a Developmental Approach to Bipolar Disorder in DSM-5. accessed from www.dsm5.org. American Psychiatric Association, 2010

• “…it is clear that, from a pathophysiological perspective, TDD is

unlikely to be categorically distinct from ODD, which is itself a

heterogeneous category with disparate longitudinal outcomes.”1

• “It can certainly be argued that it is premature to suggest the addition

of the TDD diagnosis to DSM-V, since the work has been done

predominately by one research group in a select research setting”2

Problems with TDDProblems with TDD

1Issues Pertinent to a Developmental Approach to Bipolar Disorder in DSM-5. accessed from www.dsm5.org. American Psychiatric Association, 2010

2DSM-5 Childhood and Adolescent Disorders Work Group. Justification for Temper Dysregulation Disorder with Dysphoria. accessed from www.dsm5.org. American Psychiatric Association, 2010

• Abnormal mood, but no accompanying symptoms (temper outbursts are a behavioral manifestation of irritable

mood)

• Research support from studies of SMD, not TDD

• Likely to be a very heterogeneous population

• Almost all (85%) have ODD and ADHD

• Difficult to determine “not exclusively during mood disorder” & “not better accounted for by ASD, PTSD…” in

clinical settings

• May be overly broadly applied

• May stimulate drug companies to get FDA indication for TDD

Problems with DMDDProblems with DMDD

Mood Swings Quick GuideMood Swings Quick Guide

Family history of mood disorders Episodes of aggressive behavior

in the context of other manic symptoms

Early age of onset for depression Mood disorder with psychotic features Recurrent depressive episodes resistive to treatment Episodic presentation of ADHD Mood destabilization secondary to stimulant or

antidepressant

Higher Level of SuspicionHigher Level of Suspicion

When you hear hoof beats (mood

swings)…


swings)…



swings)…


swings)…

Pharmacotherapy of Children and Adolescents with

Bipolar Disorder

Pharmacotherapy of Children and Adolescents with

Bipolar Disorder


1.22.43.94.12

How many, large (n>100), placebo-controlled, double-blinded trials are there

for mania in children and adolescents?

How many, large (n>100), placebo-controlled, double-blinded trials are there

for mania in children and adolescents?

Trial nOxcarbazepine (Trileptal) 116

PBC: Lithium vs DVP 153

Sodium Divalproex (Depakote ER) 150

Risperidone (Risperdal) 169

Olanzapine (Zyprexa) 161

Quetiapine (Seroquel) 284

Aripiprazole (Abilify) 296

Ziprasidone (Geodon) 238

TEAM (Risp, Lith, DVP) 279

Total 1846

Large Controlled Trials in Pediatric Mania

Large Controlled Trials in Pediatric Mania

Status of Pediatric Bipolar Studies and Indications

Status of Pediatric Bipolar Studies and Indications

DivalproexLithium

OxcarbazepineTopiramate

Carbamazepine ER

RisperidoneOlanzapineAripiprazoleQuetiapineZiprasidone

Double-Blind, Placebo-Controlled

Studies

Quetiapine vs. divalproex

Lithium vs. Valproate vs

PBO

Comparator Studies

Lithium

Carbamazepine

Divalproex

TopiramateRisperidoneOlanzapineAripiprazoleQuetiapineZiprasidone

Open-Label Studies

Green=IndicatedWhite=Not Indicated

Green=IndicatedWhite=Not Indicated

Mood StabilizersMood Stabilizers

Traditional Lithium Valproate

(Sodium Divalproex)

Carbamazepine

New/Novel Gabapentin Lamotrigine Topiramate Tiagabine Oxcarbazepine Levetiracetam Zonisamide

Pediatric Lithium TrialsPediatric Lithium Trials

• 4 Older, Crossover Trials

• Average n = 18

• Response Rates 33-80%

• 1 Double-Blind Placebo Trial

• Geller et al., 1997

• 1 Discontinuation Trial• Kafantaris 2004

Lithium Salts

Pediatric Bipolar Collaborative Trial (PBC)

Pediatric Bipolar Collaborative Trial (PBC)

NIMH Funded, Multi-Site CCHMC, Case Western,

Milwaukee Children’s

Double blinded, double-dummy, placebo controlled

Randomized Monotherapy

Lithobid, Depakote, Placebo 2:2:1

6 Months of Treatment 8 Week Acute 16 Week Continuation

Stimulants for ADHD could be added

153 Subjects Randomized Ages 7-17 yr.

• FDA Indication• Indicated in the treatment of manic episodes of manic-depressive illness > age 12 years

Side effects Common

Weight gain, Exacerbation of Acne, Enuresis, Hypothyroidism

UncommonPolyuria/Polydipsia, Hair loss, NMS (Haloperidol)

Interactions NSAID Increase lithium levels Antibiotics (ampicillin, doxycyline, tertacycline…) decrease renal clearance of lithium and increase level of lithium

LithiumLithium

Target dose of 30 mg/kg/day Start outpatients 25 mg/kg/day

Serum level of 0.9 -1.1 mEq/L

Onset of action: 7-14 days Full efficacy in 6-8 Weeks

Baseline labs: CBC/diif, pregnancy, EKG, renal & thyroid function, calcium

Q 6 Months Lithium Level, TSH, BUN, serum creatinine

Lithium UseLithium Use

Management of Common Lithium Side EffectsManagement of Common Lithium Side Effects

Target dose of 20 mg/kg/day Start outpatients at 15 mg/kg/day Serum level of 80-120 mg/mL

Onset of action: 7-14 days Full efficacy in 4-6 weeks

Side effects Nausea Sedation Weight gain

Labs: pregnancy, CBC, platelets, LFTs Monitor for Polycystic Ovary Syndrome (PCOS)

Divalproex Sodium Use in Children

Divalproex Sodium Use in Children

Nausea, vomiting, diarrhea Tremor/Myoclonus Sedation, mental dulling Weight gain Hair loss, decreased platelets Liver toxicity, pancreatitis, hyperinsulinism, polycystic ovary

syndrome (PCOS) Black Box Warning

Hepatotoxicity: Hepatic failure resulting in fatalities has occurred in patients receiving valproic acid and its derivatives. Experience has indicated that children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants…

Pancreatitis:Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate.

Divalproex/Valproate Side Effects

Divalproex/Valproate Side Effects

• Clinical Indications (Adults)Clinical Indications (Adults) Acute manic and Acute manic and mixed episodesmixed episodes

• Target serum levelTarget serum level 9-11 9-11 g/mlg/ml

• Many Cytochrome P450 InteractionsMany Cytochrome P450 Interactions

• Strong association between the risk of developing SJS/TEN with Strong association between the risk of developing SJS/TEN with carbamazepine treatment and the presence of an inherited variant of carbamazepine treatment and the presence of an inherited variant of the HLA-B gene, the HLA-B gene, HLA-B*1502HLA-B*1502 Testing for HLA-B*1502 should be performed in patients with Testing for HLA-B*1502 should be performed in patients with

ancestry in patients of ancestry in patients of Chinese ancestry Chinese ancestry

• Side effectsSide effects Dizziness, somnolenceDizziness, somnolence, nausea, vomiting, ataxia, nausea, vomiting, ataxia

• Black Box WarningBlack Box Warning ““Aplastic anemia and agranulocytosis have been reported in Aplastic anemia and agranulocytosis have been reported in

association association with the use of carbamazepine.” with the use of carbamazepine.”

CarbamazepineCarbamazepine

Mood Stabilizer

Start at

Target Serum Level

Monitor Watch Out For

Lithium 25-30 mg/kg/day

0.8-1.2 Meq/L

Renal/Thyroid Function

Dehydration toxicity

Valproate 15-20 mg/kg/day

85-110 μg/mL

Liver/Pancreas/Plats.

PCOSHyperammonemia

Carbamazepine 15-20 mg/kg/day

7-10 μg/mL

WBC/Plats. CYP450 Interactions

Mood Stabilizer ToolboxMood Stabilizer Toolbox

Newer Antiepileptic Drug (AEDs) Newer Antiepileptic Drug (AEDs)

Gabapentin Topiramate Oxcarbazepine Lamotrigine Levetiracetam Tiagabine Zonisamide


F 1,48 = 2.12, P=0.152DelBello MP, et al. J Am Acad Child Adolesc Psychiatry. 2005;44

Mean Change From Baseline

A Pilot, Controlled Trial of Topiramate for Mania in Children and Adolescents With

Bipolar Disorder

A Pilot, Controlled Trial of Topiramate for Mania in Children and Adolescents With

Bipolar Disorder

DB, Placebo-controlled 56 subjects

Mean age 13.8 ± 2.6 yrs

48% female 62% mixed episode 59% comorbid ADHD

Dose Mean 278

+121mg/day

A Double-Blind, Randomized, Placebo-Controlled Trial of Oxcarbazepine in the Treatment of Bipolar

Disorder in Children and Adolescents

A Double-Blind, Randomized, Placebo-Controlled Trial of Oxcarbazepine in the Treatment of Bipolar

Disorder in Children and Adolescents

116 OutpatientsAges 7-17 yr.Bipolar I, Mixed or

ManicDouble-Blinded, Placebo

ControlledFlexibly Dosed

900-2400 mg/dayMean dose 1515

mg/dayPrimary Efficacy Measure

YMRS

Wagner et al., Amer J Psychiatry July 2006

Blocks voltage-sensitive sodium channels Adults

2 controlled studies demonstrated efficacy for bipolar depression

Indicated for maintenance treatment of BP I in adults Concern: serious rashes/serum sickness

FDA black box warning

Not FDA-indicated < Age 16 yrs

Lamotrigine Lamotrigine

1Dooley, J, et al (1996) Neurology 46:240-2422 Messenheimer, J (2002) J Child Neurology 17:2S34-42

Higher past incidence of rash due to Higher initial dosing and faster titration1

Concomitant VPA administration 1,2

Definition of serious rash including any rash leading to discontinuation from trial 2

Regular tabs available in 25 mg, 100 mg, 150 mg, 200 mg

Chewable tabs in 2 mg, 5 mg, 25 mg Stanford Antigen Precautions by T. Ketter

Lamotrigine - Rashes & DosingLamotrigine - Rashes & Dosing

Revised Lamotrigine DosingRevised Lamotrigine Dosing

Initiating lamotrigine in adult bipolar patients:Not taking drugs known to increase the clearance of lamotrigine* or valproate

Weeks 1 & 2 Weeks 3 & 4 Week 5 Week 6

25 mg/day 50 mg/day 100 mg/day Target dose

200 mg/day

Taking valproate

Weeks 1 & 2 Weeks 3 & 4 Week 5 Week 6

25 mg/every other day

25 mg/day 50 mg/day Target dose

100 mg/day

Taking drugs known to increase the clearance of lamotrigine* and not taking valproate

Weeks 1 & 2 Weeks 3 & 4 Week 5 Week 6 Week 7

50 mg/day 100 mg/day in divided doses

200 mg/day in divided doses

300 mg/day in divided doses

Target dose up to 400 mg/day in divided doses

Chang et al. JAACAP March 2006

An Open-Label Study of Lamotrigine Adjunct or Monotherapy for the Treatment of Adolescents

with Bipolar Depression

An Open-Label Study of Lamotrigine Adjunct or Monotherapy for the Treatment of Adolescents

with Bipolar Depression

20 subjects enrolled BPI, II, NOS Mean Age 15 yr.

8-week open study Weekly assessments: CDRS-R,

YMRS, CGI-S, OAS-M, CGI-C Mean final dose = 132 ± 31

mg/day Response

CGI-C: 16/19 (84%) CDRS-R: 12/19 (63%)

CDRS-R

YMRS

Atypical Antipsychotics

Atypical Antipsychotics

1. Aripiprazole (Abilify)2. Asenapine Maleate (Saphris)3. Clozapine (Clozaril)4. Iloperidone (Fanapt)5. Lurasidone (Latuda)6. Olanzapine (Zyprexa)7. Olanzapine/Fluoxetine (Symbyax)8. Paliperidone (Invega)9. Quetiapine (Seroquel)10.Risperidone (Risperdal)

11.Ziprasidone (Geodon)


DelBello et al. JAACAP March 2006

A Double-Blind Randomized Pilot Study Comparing Quetiapine and Divalproex for

Adolescent Mania

A Double-Blind Randomized Pilot Study Comparing Quetiapine and Divalproex for

Adolescent Mania

50 Adolescent inpatients Bipolar disorder, type I,

mixed or manic Mean Age 15+1yr. Treatment duration 28 days Randomized/Double-Dummy/

DB Quetiapine 400-600 mg/day

100-200-300-400 Valproate 80-120 mg/dl

(20 mg/kg) 96% achieved level >

80mg/dl by day 7

28%

60%

010203040506070

YMRS

Remission Rates

DVP QUE

Risperidone for the Treatment of acute mania in bipolar youthRisperidone for the Treatment

of acute mania in bipolar youth

• J & J Sponsored Multisite

• BD I, mixed or manic

• N=166

• 10-17 years old

• Inpatients or Outpatients

• 3-week DBRCT

• 2 doses of RIS

• 0.5-2.5 mg/day

• 3.0-6.0 mg/day

Adverse Events: Risperidone in Pediatric Mania

Adverse Events: Risperidone in Pediatric Mania

Placebo 0.5-2.5 mg/day 3.0-6.0 mg/day

Response rate 26% 59% 63%

YMRS change, mean (SD)

9 (11) 19 (10) 17 (10)

EPS 8% 5% 25%

Prolactin change, mean (SD)

Boys 0.6 (7)Girls 2 (7)

Boys 32 (23)Girls 50 (46)

Boys 50 (23)Girls 68 (49)

Abnormal prolactin 0% 11% 25%

Weight change, mean kg (SD)

0.7 (1.9) 1.9 (1.7) 1.4 (2.4)

Olanzapine in the Treatment of Acute Manic or Mixed Episodes in Adolescents


3 Week, Double-blind, placebo 2:1 Randomization

161 Subjects BP I, Mixed or Manic Mean Age 15+1.1 yr.

Age Range 13-17 Psychotic 18% Baseline YMRS 32

Modal Dose 9.7+4.5 mg/day

Olanz Placebo

Tohen et al. AJP 2007

Efficacy



3 Week, Double-blind, placebo 2:1 Randomization

161 Subjects BP I, Mixed or Manic Mean Age 15+1.1 yr.

Age Range 13-17 Psychotic 18% Baseline YMRS 32

Modal Dose 9.7+4.5 mg/day

Olanz.N/N (%)

Placebon/N (%)

**p Value

Weight ≥ 7% of baseline***

44/105 (41.9)

1/54 (1.9) <.001

Olanz Placebo

Weight Gain

Tohen et al. AJP 2007

Efficacy

Olanzapine 26 Week Open-Label Extension TreatmentOlanzapine 26 Week Open-Label Extension Treatment

• 146 adolescents with bipolar I, manic or mixed who completed a 3 week double-blind placebo controlled study

• Open label olanzapine (2.5 mg–20 mg/day) for up to 26 weeks

• Results:• Response rate 62.9%

• ≥50% decrease YMRS and CGI-BP severity ≤3


Summary of Atypical Controlled Trials in Pediatric Bipolar Disorder

Summary of Atypical Controlled Trials in Pediatric Bipolar Disorder

Study/Sponsor

Ref N Sites AgeRange

Yr.

DXDesign

Duration(Days)

Dose(mg/day)

Response Rate

(YMRS)

Mean Weight Gain(kg)

Olanz./Lilly

TohenAm J

Psych.

161 26 10-17 BPD IManic,Mixed

DBPCRT2:1

21 10.4+4.5

49% 3.66+2.18

Risper./Janssan

AACAP2007

169 M 10-17 BPD IManic,Mixed

DBPCRT1:1:1

21 0.5-2.53-6

59%63%

1.91.4

Aripip/BMS

ACNP2007


DBPCRT1:1:1

28 1030

45%64%

0.90.54

Que/Astra-

Zeneca

ACNP2007

284 M 10-17 BPD IManic

DBPCRT1:1:1

21 400600

64%58%

1.7

Zipras/Pfizer

APA2008


DBPCRT2:1

28 80-160 -13.83 (Zipras)

-8.61(PBO)

-

YMRS Change ScoresAtypical Antipsychotics vs. Mood Stabilizers

YMRS Change ScoresAtypical Antipsychotics vs. Mood Stabilizers

Atypical Antipsychotic

Start at(mg/day)

Target Dose

(mg/day)Monitor Watch Out

For

Aripiprazole 2.5-5 5-20 Weight/Height/BMI EPS

Olanzapine 5 5-20 Weight/Height/BMI Weight (Choles/FAs)

Quetiapine 50-100 300-600 Weight/Height/BMI Weight

Risperidone 0.35-0.50 1-3 Weight/Height/BMI EPS/TD/Weight

Ziprasidone 20-40 80-160 Weight/Height/BMIECG

Take with foodAssess cardiac risk factors

Atypical ToolboxAtypical Toolbox

Geller, B. et al. Arch Gen Psychiatry 2012;0:Archgenpsychiatry.2011.1508v1-14

Comparisons of end-point Clinical Global Impressions for Bipolar Illness Improvement-

Mania (CGI-BP-IM) response rates by medication

• 279 antimanic medication–naive subjects age, 10.1 years; 50.2% female)

• 100% elated mood and/or grandiosity, 77.1% psychosis, 97.5% mixed mania, 99.3% daily rapid cycling,

• mean (SD) mania duration of 4.9 (2.5) years.

• Dosing• Mean (SD) titrated

lithium level was 1.09 (0.34) mEq/L,

• Mean (SD) divalproex sodium level was 113.6 (23.0) μg/mL.

• Mean (SD) titrated risperidone dose was 2.57 (1.21) mg.

A Randomized Controlled Trial of Risperidone, Lithium, or Divalproex A Randomized Controlled Trial of Risperidone, Lithium, or Divalproex Sodium for Initial Treatment of Bipolar I Disorder, Manic or Mixed Sodium for Initial Treatment of Bipolar I Disorder, Manic or Mixed

Phase, in Children and AdolescentsPhase, in Children and Adolescents

Treatment Algorithm for Mania/ Hypomania in Children and Adolescents

Treatment Algorithm for Mania/ Hypomania in Children and Adolescents

Stage 1 Monotherapy

Stage 2 Augmentation

Stage 3 2 drug combinations

Evaluate

Continue

1A: Mixed/ManicQuetiapine/ Aripiprazole/Risperidone

1B: Lithium/Valproate/Olanzapine/Ziprasidone

2: Add mood stabilizer to atypical or vice versa

3: 2 mood stabilizers + 1 atypical or 2 atypicals + mood stabilizer

Continue

Partial response or nonresponse

Positive response

Partial response

Evaluate

Negativeresponse

Positive response

Kowatch RA et al. Clinical Manual for the Management of Bipolar Disorder in Children and Adolescents. Arlington, VA: American Psychiatric Publishing, Inc; 2008.

Pediatric BPD Comorbid Disorders

Pediatric BPD Comorbid Disorders

Disorder Prepubertal Adolescent

ADHD 70-90% 30-60%

Anxiety Disorders

20-30% 30-40%

Conduct Disorders

30-40% 30-60%

Oppositional Defiant Disorder

60-90% 20-30%

Substance Abuse

10% 40-50%

Learning Disabilities

30-40% 30-40%

Young Children Mania TrialYoung Children Mania Trial• Sponsored by the Stanley Research

Foundation• 6 week, double-blinded, placebo, controlled• Randomized to:

• Liquid valproate, risperidone or placebo• 46 Subjects

• Ages 3-7 yr.; mean age 5.5 yr• ~70% Caucasian• ~60% Male

• DSM-IV Criteria for Bipolar Disorder I, Mixed or Manic Episode, Current

Family History in Mother or Father

Family History in Mother or Father

Young Mania Rating ScaleYoung Mania Rating Scale

B 1 2 3 4 5 6

Week

p=0.008

• The Consensus of Opinion Was That Medication Tapering or Discontinuation Be Considered If the Patient Has Achieved Remission for a Minimum of 12-24 Consecutive Months

• For Less Severely Ill Patients, or in Patients for Whom a Diagnosis Is Less Clear, a Briefer Treatment Period May Be Indicated

Guidelines: How Long to Treat?

Guidelines: How Long to Treat?

CABF Guidelines 2006

• 115 Children• Enrolled 1995-1998• First Episode Bipolar I• Ages 7-16 yr.• Elation and/or

Grandiosity• Retention Rate 94%• Assessed

• 6, 12, 18 months• 2, 3, 4, 5, 6, 8 yr.

• Treated in community

• 115 Children• Enrolled 1995-1998• First Episode Bipolar I• Ages 7-16 yr.• Elation and/or

Grandiosity• Retention Rate 94%• Assessed

• 6, 12, 18 months• 2, 3, 4, 5, 6, 8 yr.

• Treated in community

• After Reaching Age 18 yr.• 54 Subjects• Mean Age 20.6+1.8 yr

• Outcome• 44% BPD I• 30% Depressive

Disorder• 35% SUD

Pediatric Bipolar SummaryPediatric Bipolar SummaryDifficult to recognize and

manageMore Research Is Needed

Single AgentsCombination

PharmacotherapyPharmacotherapy + DBT

Recurrent Disorder That Requires Psychosocial Therapy & Pharmacotherapy

We are making progress Fair Use Doctrine, http://www.copyright.gov/fls/fl102.html

Course of Illness & Course of Illness & Psychosocial Treatment of Psychosocial Treatment of

Bipolar Disorder in Children Bipolar Disorder in Children

Course of Illness & Course of Illness & Psychosocial Treatment of Psychosocial Treatment of

Bipolar Disorder in Children Bipolar Disorder in Children

Mary A. Fristad, PhD, ABPPProfessor, Psychiatry, Psychology & NutritionDirector, Research & Psychological Services

Division of Child & Adolescent PsychiatryThe Ohio State University’s Wexner Medical Center

Just Because I’m Bipolar14 Year Old 8th Grader

Former MF-PEP Study Participant

Just Because I’m Bipolar14 Year Old 8th Grader

Former MF-PEP Study Participant

Just because I’m bipolarI’m not a freakI’m not weirdI just want to be noticed

Just because I’m bipolarI still have feelingsI still have emotionsI just have trouble expressing them

Just because I’m bipolarI can still be trustedI can still be reliable

Just because I’m bipolar—I’m still a normal kid

Conflict of Interest/FundingConflict of Interest/Funding

Dr. Fristad receives royalties from CFPSI: MF-PEP and IF-PEP Workbooks Guilford Press:

Raising a Moody Child: How to Cope with Depression and Bipolar Disorder

Psychotherapy for Children with Bipolar and Depressive Disorders

APPI: Clinical Manual for Management of Bipolar

Disorder in Children and Adolescents Children’s Interview for Psychiatric

Syndromes (ChIPS)

When Will My Child Get Better...? The MDD Picture

Birmaher et al, 96

When Will My Child Get Better...? The MDD Picture

Birmaher et al, 96

Single episode length: 7-9 months 90% get well by 1.5-2 years 6-10% stay impaired

Recurrence 40%, 2 yrs 70% 5 yrs

When Will My Child Get Better?The DD PictureKovacs et al, 94

When Will My Child Get Better?The DD PictureKovacs et al, 94

Single untreated episode: 4 years MDD episode usually comes 2-3 years after DD onset

Can lead to: Bipolar disorder: 13% Substance abuse: 15%

Early Age of Onset Linked to Longest Delay to Treatment

Leverich et al (2007) J Ped 150: 485-490

Early Age of Onset Linked to Longest Delay to Treatment

Leverich et al (2007) J Ped 150: 485-490

0

2

4

6

8

10

12

14

16

18

< 12 13-18 19-29 30+

Yrs Delay to FirstTreatment

480 outpts w/ BPD retrospectively rated for onset and prospectively followed for one year

Adults—BPD Rea et al, JCCP, 2003Adults—BPD Rea et al, JCCP, 2003

UCLA study, N=53: delays rehospitalization

0.0

0.2

0.4

0.6

0.8

1.0

0 26 52 78 104 130 156 182

Weeks

Individually-focused treatment

Family-focused treatment

1

1.21.4

1.6

1.8

22.2

2.4

2.6

0 3 6 9 12 18 24

Mo

od

Sy

mp

tom

Sc

ore

s

Does Expressed Emotion Predict Mood Symptom Scores Over 2 Years Among Adolescent Bipolar

Patients (N=20)?

(Miklowitz et al., 2006; Dev and Psychopathology)

F(1, 17) = 6.33, p = .02; Cohen’s d = 0.98

High-EE

Low-EE

Time (Months)

Psychosocial Impact on Course of Illness Geller et al, 2000; 2002; 2004

Psychosocial Impact on Course of Illness Geller et al, 2000; 2002; 2004

At baseline, families of youth with BPD, compared to healthy and ADHD control groups: Less warmth Greater tension and hostility

At 2 and 4 year follow-up, Lower maternal warmth predicted faster relapse after recovery from mania Intact families associated with faster rate of recovery Medication status was not predictive of illness course

Empirically Supported Psychosocial Adjunctive Treatments for Childhood

Bipolar Disorder

Empirically Supported Psychosocial Adjunctive Treatments for Childhood

Bipolar Disorder

Fristad, Goldberg-Arnold & Gavazzi, 1999Bipolar Disorders-None

Current Psychotherapies for Youth with Bipolar Disorder

Current Psychotherapies for Youth with Bipolar Disorder

CBT/Family Systems Based Pavuluri/West—RAINBOW program Miklowitz-FFT-A PEP (MF-PEP, IF-PEP)

DBT—T. Goldstein IP-SRT--Hlastala

How to Conceptualize Family-Based Intervention

How to Conceptualize Family-Based Intervention

Historically, families Have been blamed Have not gotten useful information/support/skill building

This can result in families being “skittish” or “defensive” about family-based intervention

Goals of PsychoeducationGoals of Psychoeducation

Teach parents and children about The child’s illness & its treatment

Provide support Peers (“I’m not the only one”) Professionals - understand the disorder

Build skills problem-solving communication symptom management

Our MottoOur Motto

It’s not your fault, but it’s your challenge!

ODMH Study Fristad, Goldberg-Arnold & Gavazzi, JMFT, 2003

ODMH Study Fristad, Goldberg-Arnold & Gavazzi, JMFT, 2003

35 children and their parents 54% depressive; 46% bipolar disorders M=3.6 comorbid diagnoses/child

(range, 1-7) C-GAS=51 at baseline 29/35 (83%) on meds 8-11 years old (average, 10.1 yrs) 77% boys

6 month wait-list design 6 sessions, 75 minutes/session, manual-driven

treatment

ODMH Findings Fristad, Goldberg-Arnold & Gavazzi, JMFT, 2003

ODMH Findings Fristad, Goldberg-Arnold & Gavazzi, JMFT, 2003

Parents Increased knowledge of mood disorders Increased positive family interactions Increased efficacy in seeking treatment Improved coping skills Increased social support Improved attitude toward child/treatment

Children Increased social support from parents Increased social support from peers (trend)

Multi-Family Psychoeducational Psychotherapy (MF-PEP)

Fristad, Verducci, Walters & Young (2009) Arch Gen Psych, 66(9): 1013-1021

Multi-Family Psychoeducational Psychotherapy (MF-PEP)

Fristad, Verducci, Walters & Young (2009) Arch Gen Psych, 66(9): 1013-1021

Children aged 8-11 (any mood disorder) 8 sessions, 90 minutes each

Begin/end with parents/children together Middle (largest) portion-separate groups

Children receive in vivo social skills training (in gym) after formal “lesson” is completed

Therapists: 1-parents; 2-children Families receive projects to do between

sessions

8 Session Outline - Parents8 Session Outline - Parents

1. Welcome, symptoms & disorders2. Medications3. “Systems”: school/treatment team4. Negative family cycle, WRAP-UP 1st ½ 5. Problem solving6. Communication7. Symptom management8. WRAP-UP 2nd ½ of program & graduate

8 Session Outline - Children8 Session Outline - Children

1. Welcome, symptoms & disorders2. Medications3. “Tool kit” to manage emotions4. Connection between thoughts, feelings

and actions (responsibility/choices)5. Problem solving 6. Nonverbal communication 7. Verbal communication 8. Review & GRADUATE!

Demographics—Various SamplesDemographics—Various Samples

VariableVariable BPD-ITTBPD-ITT

n=115n=115

Treated BPD Treated BPD n=89n=89

AgeAge 9.89.8 9.79.7

% Male% Male 7272 6969

% White% White 9191 9494

% Fam Hx-Mania% Fam Hx-Mania 5353 5555

% Fam Hx-% Fam Hx-DepressionDepression

7373 7272

% Fam Hx-Either% Fam Hx-Either 8484 8383

NIMH Study Design, N=165NIMH Study Design, N=165Groupa Time 1

Month 0

Time 2

Month 6

Time 3

Month 12

Time 4

Month 18

MF-PEP + TAUb

Baseline:

Pre-treatment

Follow-up Follow-up Follow-up

WLC +

TAUc

Baseline Follow-up Pre-treatment

Follow-up

aFamilies were enrolled in 11 sets of 15 (7-MFPG/8-WLC) = 165 familiesbMulti-Family Psychoeducational Psychotherapy + Treatment As UsualcWait-List Control + Treatment As Usual

Outcome MeasureOutcome Measure

MSI=Mood Severity Index CDRS-R + MRS (equal contributions) <10: minimal symptoms 11-20: mild symptoms 21-35: moderate symptoms >35: severe symptoms

Dr. Fristad--R01 MH61512

Mood Severity Index (Parent, Current)MF-PEP BPD Sample

Mood Severity Index (Parent, Current)MF-PEP BPD Sample

N=115, all BPD

n=55 Immediate n=60 Wait List

Linear Mixed Effects Modeling

Χ2=6.19, p<.02 Slope difference=

-7.76/12 mos Pre-post Imm=WLC

15

20

25

30

35

Immediate Wait List

Dr. Fristad--R01 MH61512

Mood Severity Index (Parent, Current)MF-PEP Treated BPD Sample

Mood Severity Index (Parent, Current)MF-PEP Treated BPD Sample

N=89

n=54 Immediate n=35 Wait List

Linear Mixed Effects Modeling

Χ2=5.91, p<.02 Slope

difference=-7.96/12 mos

Pre-Post Imm=WLC

15

20

25

30

35

Immediate Wait List

Impact of MFPG on Service Utilization & Mood Severity

Mendenhall, Fristad & Early, 2009, J Cons Clin Psychol

Impact of MFPG on Service Utilization & Mood Severity

Mendenhall, Fristad & Early, 2009, J Cons Clin Psychol

Parental attitudes toward treatment changes with MF-PEP; impacts quality of services sought

Improved quality of services leads to better mental health outcomes

MF-PEP appears to improve quality of services utilized & child’s mood severity over time as designed to do. It helps parents become better consumers.

Anecdotal Evaluations-ParentsAnecdotal Evaluations-Parents

No matter how bad the situation is…there is hope and treatment. Don’t give up. This program was an eye opener for me. I also was encouraged and relieved to find out that I was not alone.

Listen to what they are saying. They can really help you. Learn what is going on with your child. Stay focused on what is going with your child and do not give up on your child.

Anecdotal Evaluations-Children

Anecdotal Evaluations-Children

You get to meet new people you never knew before. They help you with your symptoms.

They’re nice and they’re helpful. And you guys support us and give us snacks. You’ve been nice to us and treated us with respect.

It really helps out if you let it.

Efficacy-to-Effectiveness TrialMacPherson, Fristad, et al, ABCT, ‘08,’09, ‘10, KS

Conference ‘10


Conference ‘10

Parent Findings: ↑ knowledge of mood disorders ↑ satisfaction with treatment

Child Findings: ↑ satisfaction with treatment

Referring Therapist Findings: ↑ satisfaction with MF-PEP ↑ agreement with MF-PEP goals/concepts ↑ parental knowledge and coping smooth transition to usual care discussion of MF-PEP content by family in

therapy sessions intention to refer future families to MF-PEP


Conference ‘10


Conference ‘10

Treating Therapist Findings: positive experience and general satisfaction

with training in and implementation of MF-PEP

interested in running future MF-PEP Preliminary results support the

transportability and acceptability of the intervention

Individual-Family Psychoeducation (IF-PEP) OH Dept Mental Health, 2002-2004

Individual-Family Psychoeducation (IF-PEP) OH Dept Mental Health, 2002-2004

N=20 16 sessions

Alternate child and parent with parent Same content + Healthy Habits

diet, exercise, sleep Comparable design to MFPG

IF-PEP Primary Outcome:MSI-Parent-Cur—Power Analyses

IF-PEP Primary Outcome:MSI-Parent-Cur—Power Analyses

15

20

25

30

35

40

Baseline (T1) 6 Mos (T2) 12 Mos (T3)

MS

I-P

-Cu

r

Imm n=6 WLC n=7

VariableVariable N per ConditionN per Condition Effect SizeEffect Size

MSI-Parent-CUR MSI-Parent-CUR T1-T2T1-T2

6464 .45.45

MSI-Parent-CUR MSI-Parent-CUR T1-T3T1-T3

3636 .60.60

IF-PEP: Parent EvaluationsIF-PEP: Parent Evaluations

Anonymous evaluations completed after treatment

Parents report (1-5 rating, overall 1.6) ↑ knowledge re: symptoms, medication,

accessing treatment ↑ skills re: working with schools and

treatment team, managing symptoms at home

Feeling supported/not blamed

IF-PEP: Children’s EvaluationsIF-PEP: Children’s Evaluations

1-5 Rating Scale Overall rating, 1.7 Item Range: 1.3 (therapist) to 2.2 (learned about

medications) ↑ knowledge re: mood symptoms, medication ↑ ability to get along with family, friends and at school ↑ skill re: symptom management ↑ support/ ↓ isolated, “not the only one” parents’ behavior toward them better

IF-PEP 24: Two Case StudiesLeffler, Fristad & Klaus, 2010, J Fam Psychotherapy

IF-PEP 24: Two Case StudiesLeffler, Fristad & Klaus, 2010, J Fam Psychotherapy

Expanded from 16 to 24 sessions 1 sibling session 1 additional systems-of-care (school, mental health) session 1 school professionals session (face-to-face or conference call

attendance) 2 Healthy Habits sessions 3 additional “in-the-bank” sessions

IF-PEP 24: Case StudiesLeffler, Fristad & Klaus, 2010, J Fam Psychotherapy

IF-PEP 24: Case StudiesLeffler, Fristad & Klaus, 2010, J Fam Psychotherapy

11 yr old girl “Jane” Long treatment history

sertraline, 3 mos: akathesia, elevated mood, dangerous behaviors divalproex sodium, clonidine, quetiapine, ages 9-11: no significant

improvement fluvoxamine and clonazapam: for compulsive behavior and agitation School and private therapeutic support

IF-PEP 24: Case StudiesLeffler, Fristad & Klaus, 2010

IF-PEP 24: Case StudiesLeffler, Fristad & Klaus, 2010

10 yr old boy “John” Extensive treatment history

2 yrs, divalproex sodium (trial of methylphenidate)

4 yrs, risperidone 6 yrs, atomoxetine 8 yrs, trials of methylphenidate,

amphetamine/dextroamphetamine, clonidine, lithium, and aripiprazole

9 yrs, trials of quetiapine and escitalopram 10 yrs, oxcarbazepine very significant weight gain Extensive psychotherapy history

Jane’s DiagnosesLeffler, Fristad & Klaus, 2010Jane’s DiagnosesLeffler, Fristad & Klaus, 2010

BP-1: Most Recent Episode Mixed: current moderate to severe symptoms: dysphoric mood, irritability, psychomotor agitation, increased appetite, strong craving for sweets, weight gain, rejection sensitivity, irritability, motor hyperactivity, derailment, mood lability

ADHD-Combined ODD GAD OCD

John’s DiagnosesLeffler, Fristad & Klaus, 2010John’s DiagnosesLeffler, Fristad & Klaus, 2010

BP-1 Most Recent Episode Hypomanic: current mild symptoms: irritability, negative self-image, elevated

mood, uninhibited people seeking, hypersexuality ADHD-combined ODD Specific Phobia-dark & heights SAD

Jane’s Treatment Response

Jane’s Treatment Response

MeasureMeasure PrePre PostPost ChangeChange

C-GAS: CurrentC-GAS: Current 3636 4848 ImprovedImproved

C-GAS: WorstC-GAS: Worst 3131 4141 ImprovedImproved

KMRSKMRS 4545 2828 ImprovedImproved

KDRSKDRS 6767 5555 ImprovedImproved

TBQ-PTBQ-P 3.93.9 4.24.2 ImprovedImproved

John’s Treatment Response

John’s Treatment Response

MeasureMeasure PrePre PostPost ChangeChange

C-GAS: CurrentC-GAS: Current 3535 4040 ImprovedImproved

C-GAS: WorstC-GAS: Worst 1515 3838 ImprovedImproved

KMRSKMRS 4848 2828 ImprovedImproved

KDRSKDRS 4343 5555 WorsenedWorsened

TBQ-PTBQ-P 3.33.3 4.24.2 ImprovedImproved

bipolar disorder in children and adolescents robert a. kowatch, md, phd professor of psychiatry the...

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