•
•
•
•
•
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
COMORBIDITY OF PSYCHIATRIC
DISORDERS IN PEDIATRIC BIPOLAR DISORDER
Bipolar Disorder
ADHD
ODD/CD
Tic
Disorders
Depression
/Anxiety
Disorders
ADHD = attention deficit hyperactivity disorder
CD = conduct disorders
ODD = oppositional defiant disorder
Pliszka SR. Pediatr Drugs. 2003;5:741-750.
20
Learning
Disorders
•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 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
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.
2.
NIMH, 2001
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
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
Irritable Mood
Grandiosity
Elated Mood
Dare devil Acts
Uninhibited People Seeking
Silliness/Laughing
Flight of Ideas
Accelerated Speech
Hypersexuality
Bipolar
97%
85%
ADHD
72%
7%
87%
5%
70%
68%
65%
66%
13%
21%
21%
10%
97%
45%
78%
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
Mood Disorder Questionnaire
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.
Depression Is the Predominant
Mood in Bipolar I Disorder
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
Two 18-Month Maintenance Trials
Mania
57%
Mania
29%
Depression
71%
Placebo During
Mood Polarity of
Events in Bipolar I
Disorder
Patients currently
or recently depressed
Bowden C et al. Arch Gen Psychiatry. 2003;60:392–400.
Data on file, GlaxoSmithKline.
Depression
43%
Patients currently
or recently manic/hypomanic
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
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.
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
Achieve
rapid control of
manic symptoms
Acute
phase
Achieve remission
of depressive symptoms
Maintenance
phase
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.
THE GOAL OF THERAPY
RECOMMENDATIONS:
COMPREHENSIVE TREATMENT APPROACH FOR
CHILDREN AND ADOLESCENTS WITH BIPOLAR
DISORDER
Medication Therapy
Educational
Interventions
Psychotherapy
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
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.
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
RISK 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.
2.
3.
4.
5.
Nurnberg and Foroud, 2000
Faraone et al., 2003
Carlson, 1990; Fergus et al., 2003; Geller et al., 2002a; McClellan et al., 2003; Werry et al., 1991; Wozniak et al., 1995)
Findling et al. 2001; Geller et al., 2002a; Wozniak et al., 1995).
Geller et al., 1994, 2001; Kovacs, 1996; Rao et al., 1995; Strober and Carlson, 1982).
Depression is the Predominant Mood
in Bipolar I Disorder
Time spent symptomatically ill (%)
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
80
60
67%
40
Depressed
20
0
13%
Cycling/
mixed
20%
Manic
• In another naturalistic study, patients treated for bipolar disorder
experienced 121 days of depression, versus 40 of mania, in a single
*76% of patient cohort were
2* patients with bipolar I disorder.
year
1. Judd LL et al. Arch Gen Psychiatry. 2002;59:530–537.
2. Post RM et al. Clin Neurosci Res. 2002;2:142–157.
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
700
624.8
600
495.9
500
360.8
400
322.8
300
200
100
138.3
11.7
0
Single
manic
episode
Responsive
NonNonFluctuating Fluctuating
stable
responsive responsive responsive
nonchronic
responsive
Begley et al. Pharmacoeconomics. 2001;19(5 pt 1):483-495.
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 headachesresults 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.
RESOURCES
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
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