• 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

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

• 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

• 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
• Hypersomnia
BP>UP
BP>UP
• Psychomotor Retardation BP>UP
• Postpartum Depression BP>UP
• Weight Loss UP>BP

COMORBIDITY OF PSYCHIATRIC
DISORDERS IN PEDIATRIC BIPOLAR DISORDER
Bipolar Disorder
ADHD ODD/CD
Tic
Disorders
ADHD = attention deficit hyperactivity disorder
CD = conduct disorders
ODD = oppositional defiant disorder
Depression
/Anxiety
Disorders
Learning
Disorders
•The rule more than the exception
•Approximately 50%-90%
•Disruptive Disorders
•Anxiety Disorders
•Substance Abuse (adolescents)

• 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 IV
AACAP
Pavuluri MN et al. J Am Acad Chld and Adolecnet Psychiatry 1005: 44:849-871

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.
22

• 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 MAY
MIMIC 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

• 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

• 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

Mania Item
Irritable Mood
Grandiosity
Elated Mood
Dare devil Acts
Uninhibited People Seeking
Silliness/Laughing
Flight of Ideas
Accelerated Speech
Hypersexuality
Bipolar
97%
85%
87%
ADHD
72%
7%
5%
70%
68%
65%
66%
13%
21%
21%
10%
97% 78%
45% 8%
Geller et al. J Affect Disord 1998

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

• 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

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

Has there ever been a period of time when you were not your usual self and…
… 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 slow your mind down?
Hirschfeld. Prim Care Companion J Clin Psychiatry. 2002;4:9-11.

12.8-year prospective NIMH natural history study (N = 146)
• Patients with bipolar I disorder spent nearly half of the time symptomatically ill
– Time spent depressed was  3 times more than time spent manic
– Time spent manic accounted for only 9.3% of the time
• Depression (but not mania) predicted greater future illness burden
Judd LL et al. Arch Gen Psychiatry.
2002;59:530 – 537.

Maintenance Treatment to Help
Maintain Stability Against Depressive
Episodes Is Particularly Important
Depression: A Dominant Next Episode Among Patients Receiving Placebo During
Two 18-Month Maintenance Trials
Mania
29%
Mania
57%
Depression
71%
Mood Polarity of
Events in Bipolar I
Disorder Depression
43%
Patients currently or recently depressed
Patients currently or recently manic/hypomanic
Bowden C et al. Arch Gen Psychiatry. 2003;60:392–400.
Data on file, GlaxoSmithKline.

• Bipolar disorder is a lifelong illness; therefore, maintenance treatment is the core of management 1
• Treatment choice should be made by collaborative effort between patient and physician 2
• The goal of acute therapy is to stabilize acute episodes with the goal of remission 2
• The goal of maintenance therapy is to optimize protection against recurrence of episodes 2
• Concurrently, attention needs to be devoted to maximizing patient functioning and minimizing subthreshold symptoms and adverse effects of treatment 2
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.

•

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

• 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

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

• 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

Pharmacologic Treatment Goals in Bipolar Disorder
Maintenance phase
Acute phase
Achieve rapid control of manic symptoms
Achieve remission of depressive symptoms
Return to normal levels of psychosocial functioning
Delay or prevent recurrence of manic or depressive episodes
Minimize subthreshold symptoms
Hirschfeld RM et al. Am J Psychiatry. 2002;159(Suppl):1–50.

COMPREHENSIVE TREATMENT APPROACH FOR
CHILDREN AND ADOLESCENTS WITH BIPOLAR
DISORDER
Medication Therapy
Educational
Interventions
Psychotherapy

Kowatch R, et al. 2005.

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

– 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.
56

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

Strong 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, 2000
2.
Faraone et al., 2003
3.
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).

Depression is the Predominant Mood in Bipolar I Disorder
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 symptoms 1
80
60
40
67%
Depressed
20 13%
Cycling/ mixed
20%
Manic
0
• In another naturalistic study, patients treated for bipolar disorder experienced 121 days of depression, versus 40 of mania, in a single year 2 *
1. Judd LL et al. Arch Gen Psychiatry. 2002;59:530–537.
2. Post RM et al. Clin Neurosci Res. 2002;2:142–157.

• 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

• 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.

700
600
500
400
300
200
100
0
360.8
624.8
322.8
495.9
138.3
11.7
Single manic episode
Responsive stable
Nonresponsive
Nonresponsive chronic
Fluctuating responsive
Fluctuating nonresponsive
Begley et al. Pharmacoeconomics. 2001;19(5 pt 1):483-495.

• 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 headachesresults counterintuitive

• 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.

• Difficult to diagnosis
• Comorbidity
• Comprehensive treatments
• Goals and re-evaluation
• Prognosis?

• 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.

WEBSITES:
– 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