Bipolar: To Be or Not To Be… Pediatric Bipolar Update

Stephen Grcevich, MD

President and Founder, Family Center by the Falls Chagrin Falls, OH

Department of Psychiatry Northeastern Ohio Universities College of Medicine

Presented at: Children’s Hospital Medical Center of Akron August 20, 2010

E-mail: drgrcevich@fcbtf.com Phone: (440) 543-3400 Twitter: @drgrcevich

Educational objectives:

Familiarize health care professionals with current information regarding the diagnosis of Bipolar Disorder in Children

Review recent evidence-based literature regarding Bipolar Spectrum Disorders

Identify treatment options, including medication management, of mood disorders in children

Pharmaceutical Industry Consulting:

Shire US (100% of compensation donated to

charity since 1/1/08)

Grant/Research Support

Child and Adolescent Psychiatry Trials (CAPTN)

Network-ASK, PARCA, NOTA studies funded through NIMH

Speakers’ Bureaus None since 2006

Other Financial/Material Support

Web MD/MedscapeLeerink-Swann

Major Shareholder None

Stephen Grcevich, MD: disclosures:

The greatest controversy in our field?

40X increase in outpatient visits for pediatric bipolar disorder between 1994-95 and 2002-03 (6X increase in prevalence of bipolar diagnosis)

The majority of kids receiving the diagnosis don’t meet traditional DSM-IV criteria for the disorder

Average number of psychotropic medications: 3.4

Average number of medication trials: 6.3 (+/- 3.7)

Medications approved for pediatric bipolar disorder associated with rapid, large increases in weight, lipid, cholesterol elevation, Type 2 diabetes

Moreno C, Laje G, Blanco C, et al. Arch. Gen. Psychiatry 64, 1032–1039 (2007).

Weight gain in antipsychotic naïve pediatric patients:

Correll, CU et al., JAMA. 2009;302:1765–1773.

Metabolic effects of second-generation antipsychotics in

pediatric patients:Agent: Metabolic Effects:Olanzapine fasting glucose

insulininsulin resistance

Quetiapine total cholesteroltriglyceridesHDL cholesteroltriglyceride:HDL ratio

Risperidone triglyceridesAripiprazole No significant metabolic effects

Correll, CU et al., JAMA. 2009;302:1765–1773.

Diagnostic criteria for Bipolar Disorder:

A distinct period of elevated, expansive or irritable mood lasting at least one week in which three or more of the following are present (four if mood is only irritable):

Inflated self-esteem, grandiosity

Decreased need for sleep

Pressured speech

Flight of ideas, racing thoughts

Increased distractibility

Increased goal-directed activity (psychomotor agitation)

Involvement in pleasurable behaviors with potential for painful consequences

Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition - Text Revision (DSM IV-TR)

Diagnostic criteria for Bipolar Disorder:

Mixed episodes: symptoms of mania and depression last at least seven days

Bipolar II: major depression and hypomania last at least four days

Rapid Cycling: four or more full episodes in a calendar year

Bipolar NOS: cases that don’t meet criteria for other bipolar conditions…the majority of pediatric cases

*Ultrarapid Cycling: brief, frequent episodes lasting from a few hours to less than four days

*Ultradian Cycling: cycles last minutes to hours, >365 cycles/year

*Condition not listed in DSM-IV

Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition - Text Revision (DSM IV-TR)

Comorbidity and pediatric bipolar disorder:

ADHD: 90% in children with bipolar disorder, 60% in teens with bipolar disorder, 13% in adults with bipolar disorder

Prevalence of anxiety disorders: 56-76%

Increased substance abuse risk-greater risk in adolescent-onset vs. childhood onset BPD

4X greater risk of post-traumatic stress disorder

Joshi G, Wilens T. Child Adolesc Psychiatric Clin N Am 18 (2009) 291–319

Differentiating between ADHD and BPD in early adolescence:

SymptomSymptom

BPDBPD(n=60)(n=60)

%%

ADHDADHD(n=60)(n=60)

%% P ValueP Value

Elated moodElated mood 86.786.7 55 0.0010.001

GrandiosityGrandiosity 8585 6.76.7 0.0010.001

HypersexualityHypersexuality 4545 8.38.3 0.0010.001

Decreased need for Decreased need for sleepsleep 43.343.3 55 0.0010.001

Racing thoughtsRacing thoughts 48.348.3 00 0.0010.001

HyperenergeticHyperenergetic 96.796.7 91.791.7 0.440.44

DistractibilityDistractibility 91.791.7 9595 0.720.72

Geller et al. J Affect Disord. 1998;51:81.Geller B, Luby J. J Am Acad Child Adolesc Psychiatry (1998): 37(10) 1005

Differential diagnosis of pediatric bipolar disorder :

Medical/neurologic concerns (iatrogenic)

ADHD/Conduct Disorder

Anxiety disorders

Psychotic disorders

Substance use disorders

Borderline Personality Disorder (and other Cluster B conditions)

Environmental, psychosocial, parenting factors

The center of the controversy:

There’s a large group of kids who demonstrate:

Irritability as their predominant mood state

Problems with emotional self-regulation often resulting in aggression

Problems with attention, concentration, academic performance

“At-risk” behaviors…self-injury, substance use, suicidal threats

Temper Dysregulation Disorder (TDD) with Dysphoria (proposed in

DSM-V): Characterized by severe recurrent temper outbursts in response to

common stressors

Temper outbursts are manifest verbally and/or behaviorally, such as in the form of verbal rages, or physical aggression towards people or property

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

Responses inconsistent with developmental level

Temper outbursts occur, on average, three or more times per week.

Mood between temper outbursts is persistently negative (irritable, angry, and/or sad).

Negative mood is observable by others (e.g., parents, teachers, peers).

DSM-V Task Force, American Psychiatric Association, 2010

AACAP concerns about “TDD”

Diagnosis Is imprecise

Syndrome based on work in patients described as “SMD”

Invites criticism for “pathologizing” temper tantrums

Proposed criteria are almost certainly premature

Research hasn’t clarified boundaries between “TDD”, ADHD, Oppositional Defiant Disorder and developmentally acceptable behavior

More information needed on how the phenotype changes over the lifespan

American Academy of Child and Adolescent Psychiatry, March 30, 2010

What will kids with SMD/TDD look like in your clinic?

They have ADHD

They have difficulty with transitions

They tend to “ruminate”…indecisive, think too much about things, perseverate

They may experience some improvement in some settings from ADHD medication, but become more irritable, have more meltdowns at home

They have a higher than expected prevalence of anxiety disorders, but are probably subsyndromal for OCD

They’re prone to behavioral activation on SSRIs, often mistaken for mania, hypomania

AACAP Practice Parameters for Assessment and Treatment of Bipolar Disorder (2007)

Pharmacotherapy is the primary treatment in well-defined DSM-IV Bipolar I disorder

A comprehensive treatment plan, combining medications with psychotherapeutic interventions is needed to address the symptomatology and confounding psychosocial factors found in children and adolescents with bipolar disorder

J . Am. Acad. Child Adolesc. Psychiatry, 46:1, January 2007

FDA-approved medications for youth with Bipolar Disorder

Risperidone: Bipolar mania (10-17)

Aripiprazole: Bipolar mania (10-17)

Quetiapine: Bipolar mania (10-17)

Olanzapine: (labeling-consider other drugs first) Bipolar mania (13-17)

Lithium Carbonate: Bipolar mania (12-17)

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/PediatricAdvisoryCommittee/UCM193200.pdf

Second generation antipsychotics in pediatric bipolar disorder:

As of July, 2010: 26 studies published, including 5 RCTs (but several others completed)-all RCTs published in 2007 or later

Response rates in acute RCTs 45-89%, remission achieved in 25-72%

Treatment-refractory nature of patients enrolled at academic medical centers attenuated magnitude of AEs

Little data examining long-term course on SGAs, efficacy in preventing relapse

Hamrin V, Ienacco J. Expert Rev Neurother. 2010;10(7):1053-1088.

Lithium in pediatric bipolar disorder:

One acute RCT: Li>PBO (46% response rate vs. 8%)

Didn’t appear to prevent relapse

Negative RCT in SMD

Narrow therapeutic window, toxicity in overdose concerns in adolescents

Hamrin V, Ienacco J. Expert Rev Neurother. 2010;10(7):1053-1088

Anticonvulsants in pediatric bipolar disorder:

Divalproex sodium: open-label studies have demonstrated response rates of 56-92%, but two RCTs have failed to demonstrate efficacy

Lamotrigine: Three open-label studies suggest 50-60% remission rates, helpful with bipolar depression results confounded by adjunct meds

Topiramate, oxcarbazepine: Negative RCTs

Hamrin V, Ienacco J. Expert Rev Neurother. 2010;10(7):1053-1088

Strategies for treating ADHD with comorbid Bipolar

Disorder: Effective mood stabilization may be necessary

before patients will respond to stimulants

Stimulants will be used in combination with mood stabilizers/antipsychotics

Many patients have histories of failed stimulant trials, or use of high doses of stimulant before bipolar disorder identified

RCT: Mixed amphetamine salts highly effective for ADHD in patients who had achieved mood stabilization on divalproex

Scheffer R et al. Am J Psychiatry (2005) 162:58-64

Psychotherapy/psychosocial treatment:

Multi-family psychoeducational groups: 1 RCT (N=35), families did better, no effect on severity of child’s mood symptoms

IFP (Individual/family psychoeducation) 1 RCT (N=20) improved children’s mood symptoms

FFT (Family focused therapy) psychoeducation, communication enhancement training, and problem solving skills training-two year RCT indicated improvement in depressive sx. With bipolar disorder

DBT: One open label trial (N=10)

CFF-CBT: Open-label trial (N=34) with three year follow-up showed benefits of treatment were maintained

West A, Pavuluri M. Child Adolesc Psychiatric Clin N Am 18 (2009) 471–482

Take-home points:

Use of the term “Bipolar Disorder” in pediatric population should be reserved for mood episodes lasting four days or longer

A large subset of patients exists with chronic irritability, explosive outbursts, chronic negativism, long-term risk of ADHD, depression, differences in neural circuitry and cognitive flexibility. Little research is available to inform our treatment of them.

Careful evaluation and a comprehensive treatment plan developed by a fully trained child and adolescent psychiatrist, combining medications with psychotherapeutic interventions, are essential

Resources for pediatricians:

AACAP Bipolar Disorder Resource Center http://www.aacap.org/cs/BipolarDisorder.ResourceCenter

Child and Adolescent Bipolar Foundation http://www.bpkids.org/

Psychopharmacology of Pediatric Bipolar Disorder Expert Review of Neurotherapeutics http://www.medscape.com/viewarticle/724852 (Medscape membership required-membership, article free. Click on print version for summary tables of all studies)

Questions?