• Abbott Laboratories • AstraZeneca • Bristol Myer-Squibb • Cephalon • Eli Lilly & Co. • Forest Laboratories, Inc. • GalaxoSmithKline • Janssen Research • Jazz Pharmaceuticals • Lundbeck• Mallinckrodt • Merck • Novartis • Otsuka America Pharmaceuticals Inc.• Palmlabs • Pfizer, Inc. • Sanofi Aventis • Sepacor Inc. • Shire Pharmaceuticals • Somaxon Pharmaceuticals • Sunovion Pharmaceuticals Inc. • Takeda • Teva• UCB Pharma Inc. • Vaya Pharmaceuticals• Wyeth Pharmaceuticals

HERITABILITY (GENETICS) – RELATIVE WITH BIPOLAR DISORDER AND CHILD

ODDS• One parent 25 %• Two parents 50-75%• One MZ twin 30-90%• One DZ twin 5-25 %

• American Journal of Medical Genetics Part C (Semin. Med. Genet.) 123C:48–58 (2003)

Diagnostic Problems

• Time-consuming and difficult to differentiate• Subtle Symptoms• Moody ADHD/Disruptive Disorders• Non-Bipolar Depression• Pervasive Developmental Disorders (High

Functioning autistic Spectrum• Substance Use Disorders

Cues that “Unipolar” Depression may be Bipolar Disorder:

• Early onset of depression• Highly recurrent depression (4 or more episodes)• Psychotic Depression• Postpartum onset of depression• History of mixed mood states• Family History of Bipolar Disorder• >3 failed antidepressant trials• Marked agitation with an antidepressant

• Manning JS Family Practice 300; 2 Supp S 6-9

Qualities that differ between Bipolar D/O vs. Unipolar D/O

• Total Sleep Time BP>UP• Hypersomnia BP>UP• Psychomotor Retardation BP>UP• Postpartum Depression BP>UP• Weight Loss UP>BP

20

COMORBIDITY OF PSYCHIATRIC DISORDERS IN PEDIATRIC BIPOLAR DISORDER

Pliszka SR. Pediatr Drugs. 2003;5:741-750.

ADHD = attention deficit hyperactivity disorderCD = conduct disordersODD = oppositional defiant disorder

ADHD ODD/CD

Depression/Anxiety Disorders

Learning Disorders

Tic Disorders

Bipolar Disorder

•The rule more than the exception

•Approximately 50%-90%

•Disruptive Disorders

•Anxiety Disorders

•Substance Abuse (adolescents)

Clinical Presentation of Pediatric Bipolar I Disorder

• Adolescent patients with Bipolar I Disorder are diagnosed using the same DSM-IV-TR criteria as adults

• Pediatric patients with Bipolar Disorder are more likely to present with:– Predominantly mixed episode– Rapid Cycling– Prominent irritability that may lead to violence and

explosiveness– Frequently associated with psychotic symptoms and markedly

labile mood • Often suffer from a more chronic form of the illness

characterized by longer symptomatic episodes that are often refractor to treatment

APA DSM IVAACAPPavuluri MN et al. J Am Acad Chld and Adolecnet Psychiatry 1005: 44:849-871

22

CHARACTERISTICS COMMON TO PEDIATRIC MANIA

– Severe, prolonged irritability– Affective storms– Prolonged and aggressive temper outbursts–Mixed mania or rapid cycling (> 70% of

cases)– High comorbidity with ADHD– Chronic and unremitting course

Biederman J et al. Biol Psychiatry. 2000;48:458-466.State RC et al. Am J Psychiatry. 2002;159;918-925.

DEFINITIONS• BIPOLAR DISORDER NOT OTHERWISE SPECIFIED (NOS): - recommended

to describe the large number of youths who receive a diagnosis of bipolar disorder who do not have the classic adult presentation 1

• Definitions currently used in the juvenile bipolar literature, but not provided in DSM-IV-TR, include the following:

– ULTRARAPID CYCLING: refers to brief, frequent manic episodes lasting hours to days, but less than the 4-day prerequisite for hypomania. Having 5 to 364 cycles per year 2

– ULTRADIAN CYCLING: refers to repeated brief (minutes to hours) cycles that occur daily. Having greater than 365 cycles per year 2

1. NIMH, 2001 2. Geller et al. (2000)

Clinical course of recurrent mood disorders

MEDICAL CONDITIONS THAT MAYMIMIC PEDIATRIC BIPOLAR DISORDER

• Hypothyroidism• Closed or open head injury• Temporal lobe epilepsy• Multiple Sclerosis• Systemic lupus erythematosus• Fetal alcohol spectrum disorder/ alcohol

related neurodevelopmental disorder• Wilson’ s disease

Kowatch et al. JCAAP. 2006; 15:73108

FACTORS SUGGESTIVE OF PEDIATRIC BIPOLAR DISORDER

• Depression• Family history of mood disorders• Disruptive behavior & prominent mood symptoms• Psychosis• Attention-deficit / hyperactivity disorder• Poor stimulant response• History of medication-induced manic symptoms

PEARLS TO HELP WITH DIAGNOSIS

• Family history (BP is highly heritable; Identical twin concordance – 70% vs. Fraternal – 20%) –Best Predictor

• Presence of elation/euphoria or grandiosity• Look at timeline of symptoms – not just current

mental status• Episodic worsening within chronic symptoms• MDD + Psychosis, psychomotor retardation,

childhood onset• History of medication-induced manic symptoms

PEDIATRIC BP VS. ADHD

Mania Item Bipolar ADHD

Irritable Mood 97% 72%

Grandiosity 85% 7%

Elated Mood 87% 5%

Dare devil Acts 70% 13%

Uninhibited People Seeking

68% 21%

Silliness/Laughing 65% 21%

Flight of Ideas 66% 10%

Accelerated Speech 97% 78%

Hypersexuality 45% 8%Geller et al. J Affect Disord 1998

NON-SPECIFIC SYMPTOMS

Irritability (98% vs. 72%)Accelerated Speech (97% vs. 82%)Distractability (94% vs. 96%)Unusual Energy (100% vs. 95%)

Geller et al. J Child and Adol Psychophar m.2002

CLINICAL PEARLS

• Difficult to diagnosis/Be sure diagnosed is correct• Select a evidence based medication regiment• Use the right doses of medication/Ensure the

medication trial continues for an adequate periods of time.

• Be aware of any psychiatric comorbitities• Carfully Assess for adverse reactions/Remove

agents that may be exacerbating situations• Combination interventions most often used

Predictors of Bipolar Disorder

• MDD with• Psychosis• Psychomotor retardation• Pharmacological induced mania/hypomania• Family history of bipolar disorder

… you felt so good or so hyper that other people thought you were not your normal self or you were so hyper that you got into trouble?

… you were so irritable that you shouted at people or started fights or arguments?

… you felt much more self-confident than usual?

… you got much less sleep than usual and found you didn’t really miss it?

… you were much more talkative or spoke much faster than usual?

… thoughts raced through your head or you couldn’t slowyour mind down?

Mood Disorder Questionnaire

Hirschfeld. Prim Care Companion J Clin Psychiatry. 2002;4:9-11.

Has there ever been a period of time when you were not your usual self and…

Depression Is the PredominantMood in Bipolar I Disorder

Judd LL et al. Arch Gen Psychiatry. 2002;59:530–537.

12.8-year prospective NIMH natural history study (N = 146)

• Patients with bipolar I disorder spent nearly Patients with bipolar I disorder spent nearly half of the time symptomatically illhalf of the time symptomatically ill

– Time spent depressed was Time spent depressed was 3 times more 3 times more than time spent manicthan time spent manic

– Time spent manic accounted for only 9.3% Time spent manic accounted for only 9.3% of the timeof the time

• Depression (but not mania) predicted greater Depression (but not mania) predicted greater future illness burdenfuture illness burden

Maintenance Treatment to Help Maintain Stability Against Depressive

Episodes Is Particularly Important

Maintenance Treatment to Help Maintain Stability Against Depressive

Episodes Is Particularly Important

Bowden C et al. Arch Gen Psychiatry. 2003;60:392–400.Data on file, GlaxoSmithKline.

Depression: A Dominant Next Episode Among Patients Receiving Placebo During Two 18-Month Maintenance Trials

Mania29%

Depression71%

Patients currentlyor recently depressed

Mania57%

Depression43%

Patients currentlyor recently manic/hypomanic

Mood Polarity of Events in Bipolar I

Disorder

1. Calabrese et al. J Clin Psychiatry. 2002;63(suppl 10):18-22.2. Hirschfeld et al. Am J Psychiatry. 2002;159(4 suppl):1-50.

Treatment Objectives for Bipolar Disorder

• Bipolar disorder is a lifelong illness; therefore, maintenance treatment is the core of management1

• Treatment choice should be made by collaborative effort between patient and physician2

• The goal of acute therapy is to stabilize acute episodes with the goal of remission2

• The goal of maintenance therapy is to optimize protection against recurrence of episodes2

• Concurrently, attention needs to be devoted to maximizing patient functioning and minimizing subthreshold symptoms and adverse effects of treatment2

SOMATIC TREATMENTS

• Recommendation 6. For Mania in Well-Defined DSM-IV-TR Bipolar I Disorder, Pharmacotherapy Is the Primary Treatment

THE CHOICE OF MEDICATION(S) SHOULD BE MADE BASED ON:

(1) Evidence of efficacy(2) Phase of illness(3) Presence of confounding presentations (e.g.,

rapid cycling mood swings, psychotic symptoms)(4) Agent`s side effect spectrum and safety(5) Patient`s history of medication response(6) Preferences of the patient and his or her

family. A history of treatment response in parents may predict response in offspring

Duffy et al., 2002

• Psychosocial Treatments as an adjunct to• Medications• Parent/Family Psychoeducation• Relapse Prevention• CBT or IPT for Depression• Interpersonal and Social Rhythm Therapy• Family Focused Therapy• Community Support Programs

AACAP Treatment goals for pedicatric Patients with Bipolar Disorder

• The general goals of treatment are:– Manage Symptoms and maintain response– Provide education about the illness– Promote Adherence to treatment

• AACAP Guidelines suggest using a comprehensive treatment plan, combining pharmacotherapy with behavioral/psychosocial interventions

AACAP 2007

FDA APPROVED MEDICATIONS FOR PED BPD I, MIXED OR MANIC

• Airpiprazole 10-17• Olanzapine 13-17• Quetiapine 10 - 17• Risperidone 10-17• Lithium 12-10

SCREENING

• Recommendation 1. Psychiatric Assessments for Children and Adolescents Should Include Screening Questions for Bipolar Disorder– Distinct mood changes associate sleep distrubances

and psychomotor activation– Family history of mood disorders– Symptoms of irritability, reckless behaviors or

increased energy– Perspective by family, school, peer, and other

psychosocial factors rather than simply using checklist

ASSESSMENT

ASSESSMENT (CONTINUED)

Pharmacologic Treatment Goals in Bipolar Disorder

Pharmacologic Treatment Goals in Bipolar Disorder

Hirschfeld RM et al. Am J Psychiatry. 2002;159(Suppl):1–50.

Minimize subthreshold symptoms

Delay or prevent recurrence of manic or depressive episodes

Return to normal levels of psychosocial functioning

Achieve rapid control of manic symptoms

Acutephase

Maintenancephase

Achieve remission of depressive symptoms

THE GOAL OF THERAPY

RECOMMENDATIONS:

COMPREHENSIVE TREATMENT APPROACH FOR CHILDREN AND ADOLESCENTS WITH BIPOLAR

DISORDER

Medication TherapyMedication Therapy

PsychotherapyPsychotherapyEducationalEducationalInterventionsInterventions

Kowatch R, et al. 2005.Kowatch R, et al. 2005.

Bipolar Disorder - Psychoeducation

• Symptomatology• Etiology ( e.g., genetics)• Treatment• Prognosis• Prevention (early signs of relapse/recurrence)• Psychosocial Scars• Stigma• Mood Hygiene• Importance of compliance

56

PSYCHOSOCIAL INTERVENTIONS

– Family Therapy • Psychoeducation (Diagnosis, Treatment) • Emphasize Compliance• Mood monitoring• Social skills training• Strategies aimed at increasing life style regularity

(Adhering to regular schedule, normal sleep/wake cycle)

• Parent training in behavioral interventions to deal with problematic behavior

• Therapist helps family see family dynamics that may be contributing to patient’s illness.

BIPOLAR DISORDER NO RESPONSE TO TREATMENT

• Misdiagnosis• Compliance• Adequate treatment (type, doses, duration)• Comorbidity ( e.g., substance abuse)• Exposure to Stressful Life Events (e.g., abuse)• Psychosocial Factors

RISK FACTORSStrong genetic component in Adults –four- to six fold increase risk of disorder in

first degree relatives of affected individuals 1

Degree of familiality appears even higher in early onset, highly comorbid cases 2

Premorbid psychiatric problems are common in early-onset bipolar disorder,

especially difficulties with disruptive behavior disorders, irritability, and behavioral dyscontrol 3

Most childhood cases are associated with Attention Deficit Hyperactivity Disorder 4

In those whose first mood episode is a depressive disorder. Approximately 20% of

youths with major depression go on to experience manic episodes by adulthood 5

1. Nurnberg and Foroud, 20002. Faraone et al., 20033. Carlson, 1990; Fergus et al., 2003; Geller et al., 2002a; McClellan et al., 2003; Werry et al., 1991; Wozniak et al., 1995)4. Findling et al. 2001; Geller et al., 2002a; Wozniak et al., 1995).5. Geller et al., 1994, 2001; Kovacs, 1996; Rao et al., 1995; Strober and Carlson, 1982).

*76% of patient cohort were patients with bipolar I disorder.1. Judd LL et al. Arch Gen Psychiatry. 2002;59:530–537.2. Post RM et al. Clin Neurosci Res. 2002;2:142–157.

Based on the 12.8-year NIMH natural history study (n = 146), of the 47% of time spent symptomatically ill, patients experienced depressive symptoms 3

times more than manic symptoms1

• In another naturalistic study, patients treated for bipolar disorder experienced 121 days of depression, versus 40 of mania, in a single year2*

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67%

20%13%

Depressed

Cycling/mixed Manic

Depression is the Predominant MoodDepression is the Predominant Moodin Bipolar I Disorderin Bipolar I DisorderDepression is the Predominant MoodDepression is the Predominant Moodin Bipolar I Disorderin Bipolar I Disorder

PROGNOSITIC INDICATORS:• Good• Short Duration of manic episodes• Advanced age of onset• Few suicidal thoughts• Few coexisting psychiatric disorder• Few medical problems• • Poor• Poor premorbid occupational status• Alcohol Dependence• Psychotic features• Depressive features• Interepisode depressive features• Male gender• coexisting psychiatric disorder

BIPOLAR DISORDER - SEQUELA

• Poor academic functioning• Interpersonal and family difficulties• Increased risk for suicide• Increased use of tobacco, alcohol, and other

substances• Behavior problems• Legal difficulties• Increased health services utilization (e.g.,

hospitalizations)

Emslie GJ, Mayes TL. Biol Psychiatry. 2001;49:1082-1090.

Estimated Total Lifetime Cost per Case by Prognosis Group

Begley et al. Pharmacoeconomics. 2001;19(5 pt 1):483-495.

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HEADACHE IN TEENS WITH BIPOLAR DISORDER

• Unpublished, presented at AACAP• Canadian teens, bipolar d/o• 55 outpts., 13 y/o-19 y/o BP I, II, NOS• 60% F, 60% with HA – Sig. > severity on depressive,

manic and CGI• Teens with BP with HA Sig. rates of identity confusion,

anger/depression, and disinhibition /persistence • Results BP teen w/ HA more prone to > severity than

BP teens w/o• Psy. Hosp. and psychosis > BP teen without headaches-

results counterintuitive

HEADACHE IN TEENS WITH BIPOLAR DISORDER (Cont.)

• Rational: – 1) BP teens with HA a different subtype? –unique

course, characterisics and perhaps treatment?– 2) under dx or tx in adult BP and headaches is well

doc. Potential treating in youth is important.

Summary

• Difficult to diagnosis

• Comorbidity

• Comprehensive treatments

• Goals and re-evaluation

• Prognosis?

Unmet Needs in Pediatric Bipolar Disorder

• Diagnostic Criteria

• Faster improvement

• Fewer side effects and better tolerability

• Greater efficacy

• Long term efficacy

Source: Datamonitor, Stakeholder Insight: MDD, Q1.2; Adult population figures from www.census.gov and MDD prevalence rates applied.

RESOURCESWEBSITES:– The Child and Adolescent Bipolar

Foundation• www.bpkids.org

– Depression and Bipolar Support Alliance• www.dbsalliance.org

– The Bipolar Child• www.bipolarchild.com

– Parents of Bipolar Children• www.bpparent.org

– The Gray Center for Social Learning and Understanding• www.thegraycenter.org/Social_Stories.htm

– National Institute of Mental Health (NIMH)• www.nimh.org