1. Children and Adolescents with Bipolar Disorder
Boris Birmaher MD
Department of Child Psychiatry
Western Psychiatric Institute and Clinic
University of Pittsburgh Medical Center

2. Do children and adolescents have Bipolar Disorder (BP)?
What are the manifestations of BP disorder in children and adolescents?
What happens to these children over time?
What is the treatment for children with BP?

3. Bipolar Disorder in Youth
To validate a disorder
Reliable diagnosis
Continuous over time (follow-up studies)
Runs in Families
Biological correlates
Response to treatment
Robins and Guze, 1980

4. Clinical Manifestations

5. Bipolar Disorder – Classical Clinical Manifestations
DSM-IV Manic episode
Persistent elevated, expansive, or irritable mood for at least one week and:
Inflated self-esteem; decreased need for sleep; talkativeness; racing thoughts; distractibility; increased activity; and daring behaviors
Impairment in psychosocial functioning
Not only due to other psychiatric and medical conditions
DSM-IV Hypomanic episode: less intensity than mania, at least 4 days

6. Bipolar Disorder Clinical Manifestations
DSM-IV Major depression episode
Persistent depressed mood or irritability for at least 2 weeks and:
Motivation, sleep, appetite, concentration, and energy disturbances
Guilt, suicidal thoughts or behaviors
Impairment in psychosocial functioning
Not only due to other psychiatric and medical conditions

7. Subtypes of Bipolar Disorder
Bipolar I disorder
Manic
Depressed
Mixed
Rapid cycling
Psychotic
Bipolar II disorder (hypomania and MDD episodes)
Cyclothymic disorder (hypomania and mild depressions)
Bipolar Not Otherwise Specified (NOS)

8. Bipolar I
Bipolar II
Bipolar NOS
Not Bipolar

9. Difficulties Diagnosing Pediatric Bipolar Disorder
Variability in clinical presentation
Severity, phase of the illness (depressed, manic, mixed, rapid cycling); and subtype of BP disorder
Highly comorbid with other psychiatric disorders
Effects of development in symptom expression
Child’s problems expressing her/his symptoms
Effects of medications
Context where the BP disorder is developing

10. Developmental Manifestations of Manic Symptoms in Children
Elation/euphoria
giggling uncontrollably in class while peers are calm; laughing hysterically when talking about killing others
Dancing and laughing at home while telling parents’ they are “suspended”
Finds everything funny & they don’t know why
Decreased need for sleep
Up at 2 AM rearranging furniture, cleaning, then awake at 6 AM dressed and ready for school
Child awake at 4 AM during summer vacation
Geller et al., 2002

11. Developmental Manifestations of Manic Symptoms in Children (cont’)
Grandiosity
Telling principal to “shut up” and listen because the principal is the child’s “slave”; demanding that teacher be fired for stupidity
child stealing go-kart because he felt rules did not apply to him (acute onset of conduct d/o)
child believing he/she is a superhero & tries to fly
child spends evenings “practicing” when they become president, despite failing in school
Hypersexuality – drawing or preoccupied with pictures of naked people; inappropriate kissing, touching of others breasts/buttocks; sex lines; sexually vulgar language; sending notes propositioning peers

12. To clarify the diagnosis:
Retrospective studies of bipolar adults
Prospective studies of bipolar children
Studies of children of bipolar parents

13. Retrospective Studies of Adults with BP-I
Survey of 500 adults with Bipolar-I/II Disorders
60% had symptoms before age 20 y.o
Prodromal symptoms:
Depressed mood/hopeless (33%)
Mania/hyperactivity (32%)
Sleep problems (24%)
Mood swings (13%)
Anger/irritability (9%)
Lish et al., 1994

14. Retrospective Studies of Adults with BP- I (Cont’)
58 adults with Bipolar-I
Prodromal symptoms appeared 9-12 years before the formal diagnosis of BP-I
Depressed Mood (53%)
Increased Energy (47%)
Decreased energy/tiredenss(38%)
Anger dysregulation and /or quick temper (38%)
Irritable mood (33%)
Bold/Intrusive behavior, excessive behavior; conduct problems(28%)
Decreased need to sleep (26%
Cried (26%)
Overly sensitive(24%)
Egeland et al., 2000
Highly Episodic

15. Frequent Prodromal Features Before Onset of BP-I
Ages 0-6 (n=13)
Ages 7-10 (n=24)
11-12 (n=10)
Symptoms/Behaviors (%)
Cried -23%
Increased energy-23%
Bold/Demanding-23%
Quick temper-15%
Anxious-15%
Irritable mood-29%
Overly sensitive-25%
Cried-21%
Bold /Demanding-21%
Quick Temper-21%
Energy-17%
Depressive mood-50%
Low energy/tired-30%
Increased energy-30%
Labile/mood changes-30%
Anxious-30%
Cried-30%
Egeland et al., 2000

16. Studies in BP Adults (Cont’)
Early onset BP occurs in families with high loading for affective disorders
The earlier the onset of BP the higher chance of more mixed, rapid cycling, other non-bipolar psychopathology, and poor psychosocial functioning
Age onset in adults with BP plus ADHD significantly lower than the age of onset for BP adults without ADHD
Attentional and behavior problems during childhood predict mood disorders during young adulthood
Many adults with BP disorder have persistent attentional deficits during remission
Carlson and Weintrub, 1993;Cavanaugh et al., 2002; Mendlewicz et al., 1972;Lych et al., 1994; Puls et al., 1992;Rice et al., 1987;Sachs et al., 2000)

17. WPIC Child Mood & Anxiety Disorder Outpatient Clinic
Kiddie Schedule for Affective Disorders and Schizophrenia, present episode (KSADS-P)
1,926 subjects ages 5 to y.o ( mean 14.1 ± 2.8 years) were assessed using the KSADS from April 1986 until April 1995
58% female; SES: 37  14 (Social Class III); 79% Caucasian; 18% African-American and 3% other

18. WPIC Child Mood & Anxiety Disorder Outpatient Clinic (Cont’)
120 (6.2%) had BP disorder
918 MDD
1008 non-mood psychiatric disorders
The manic and hypomanic episodes in this population were generally shorter (median= 1-2 days) than the DSM-IV duration criteria
Only 19% of BP patients had episodes of mania that lasted one week or longer

19. WPIC Child Mood & Anxiety Disorder Outpatient Clinic (Cont’)
Distinct episodes of elated mood and unusual energy differentiated BP patients from non-BP psychiatric disorders
There were no between group differences in irritability levels

20. WPIC Child Mood & Anxiety Disorder Outpatient Clinic (Cont’)
40% of the BP patients had current MDD
80% ≥ 3 criteria for MDD
Depression is a common feature of pediatric BP, and mixed state is just one end of a continuum of depressive symptoms that are associated with manic episodes

21. Hamilton Depression Scores (Cont’)

22. WPIC Child Mood & Anxiety Disorder Outpatients (Cont’)
BP > Other (p = .01)
BP > Other (p<.001)
BP > MDD (p=.003)
BP > MDD (p<.001)

23. Child & Adolescent Bipolar Services (CABS)
Referred outpatient clinic
335 patient intakes over past 4 years
Research clinicians do Mania & Depression Items from KSADS-P
KSADS-P/L for other diagnoses
Child Psychiatrist confirmatory interview
BP-NOS: clinically significant manic symptoms
At least 4 days but 1 symptom short
Full symptom criteria but brief duration (need multiple episodes)
Significant change in functioning

24. CABS Intake Diagnoses (Cont’)
21%
45% 9%
25%

25. * BP NOS, BP I > BP II (p < .01)

26. Course and Outcome of Bipolar Youth (COBY)
Multicenter study (UPMC, UCLA, Brown University)
210 children and 210 adolescents with Bipolar disorder - I, II and NOS
Evaluations of mood, behavior, life events, and school and family functioning (interviews with youth and parents)
Follow-up every 6 months for 5 years

27. BP-NOS Defined for COBY (Cont’)
Goal was to be broad at intake
Elated Mood plus 2 symptoms or Irritable Mood plus 3 symptoms
Change in functioning
At least 4 hours of symptoms in a 24-hour period to count as “one day”
Lifetime of 4 days total of symptoms (e.g. 4 one day episodes; 2 two day episodes, etc.)

28. COBY subjects at Intake (Cont’)
42%
46%
12%

29. Demographics (COBY) (Cont’)

30. COBY Subjects at Intake (Cont’)
BP I
BP II
BP NOS
KSADS-MRS (Mania Rating Scale)
18.5 ± 12.1
19.3 ± 12.1
20.9 ± 11.5
CGI-S (Depression)
2.9 ± 1.3
2.8 ± 1.4
3.1 ± 1.2
CGAS (Current)
59 ± 12
65 ± 15
60 ± 13
CGAS (Most Severe Past)
31 ± 12
39 ± 9
40 ± 11*
*BP I < BP NOS (p = .001)

31. COBY Subjects – Lifetime Presence of Psychiatric Diagnoses (Cont’)
BP I
BP II
BP NOS
ADHD
63%
39%
61%
ODD
57%
31%
42%
Conduct D/O 8%
23%
Anxiety D/O (SAD, GAD, Social Phobia)
47%
54%
51%
Psychosis
38%
25%
Major Depressive Episode
67%
100%

32. COBY BPNOS Subjects (Cont’)
Median of 107 days of BP-NOS level of symptoms lifetime
Only 4 subjects had < 10 days lifetime
20th Percentile = 17 days
Duration of Continuous Symptoms are brief (most often 4 – 24 hours)

33. Prepubertal Bipolar Disorder
Geller et al., 1998
Mean age= 10.9 ± 2.6 y.o

34. Bipolar Disorder in High School Students
Suicide Attempts
Global Assessment of Function 90 50
44.4
87.5*** 88 45 86 40
83.6*** 84 35 82 30
Percentage of Subjects 80 25
22.2* 78 20 76
74.9 15 74 10 72 5
1.2*** 70 68
Bipolar
MDD
Never Mentally Ill BP
MDD
NMI
Lewinsohn et al., 1995

35. In General, BP in youth can presented as:
Typical phenotype (DSM Bipolar I and II)
Many have frequent episodes and mixed bipolar episodes
Typical phenotype but for a short time (DSM-IV BP NOS or rapid cycling)
Many have frequent episodes and mixed episodes
Broad phenotype (DSM-IV BP NOS or rapid cycling)
Nottelmann et al., 2001

36. Bipolar- Broader Phenotype (Cont’)
Many children referred to the clinics present with a broader phenotype
Mood lability, mood swings, affective storms
Irritability, anger, aggressiveness
Periodic agitation, explosiveness, severe temper tantrums
ADHD-like symptoms
Nottelmann et al., 2001

37. Clinical Manifestations - Questions?
Are the very short presentations and the broader phenotypes ?
Symptoms of other mood and non-mood disorders (e.g., recurrent unipolar agitated MDD; ADHD)?
Prodromal symptoms of bipolar disorder?
The symptoms by which bipolar disorder manifests in early childhood?
The manifestations of a tendency for mood lability?

38. In addition to different subtypes of BP disorder, severity of symptoms, and rapid changes in symptomatology it is difficult to diagnose BP in children because:
1) Coexisting disorders
2) Overlap in symptoms with other disorders

39. Bipolar Disorder - Comorbidity
The rule more than the exception
Approximately 50%-90%
Disruptive Disorders
Anxiety Disorders
Substance Abuse (adolescents)

40. Bipolar Disorder - Differential Diagnoses
Normal moodiness and behaviors
Recurrent explosive, aggressive, and irritable behaviors: Bipolar vs. unipolar recurrent agitated MDD vs. ADHD + ODD
Asperger Disorder
ADHD vs Bipolar
Abrupt onset of “ADHD”
Late onset “ADHD”
Intermittent “ADHD”
Intermittent worsening of the ADHD symptoms
( “tolerance” to the stimulants)
In adolescents: Borderline Personality Disorder

41. Diagnostic Overlap between Mania & ADHD
DSM-IV Mania
ADHD
Elevated, expansive mood No
Irritability
Commonly associated
Inflated self-esteem / grandiosity
Decreased need for sleep
Can be present
More talkative / pressured speech
DSM-IV Criteria
Flight of Ideas or racing thoughts
Hyperactivity / goal-directed activity
Pleasurable activities with high risk …for painful consequences
Distractibility

42. BP children with elation/grandiosity (n=93) vs ADHD (n=81)
Elated
Energy
Grandiose
Irritable
Sleep Need
Distractible
Judgment
Speech
Racing/Flight
Geller et al., 2002

43. Epidemiology

44. Bipolar Disorder -Epidemiology
Clinical samples: 0.6% - 15%
Community sample (adolescents): 1.0% (mostly BP-II and cyclothymia)
Subthreshold symptoms in community adolescents: 5.6%
Reported in children as young as 4 y.o
Adults studies: 20%-40% started before age 20 y.o

45. Natural Course

46. BP-I Natural Course Multicenter Pilot Study
3 Centers (WPIC, UCLA, Brown)
73 adolescents outpatients with BP-I, mean age: 17.1  1.8, 75% females, 84% Caucasian
KSADS, LIFE
At intake, 64% (47/73) were in an acute episode (11 mania, 18 MDD, and 18 mixed) and 36% (26/73) were euthymic
Follow-up every 4 months for 4 to 224 weeks (mean: 76.6  61.6 weeks)

47. BPD-I Natural Course Multicenter Pilot Study (Cont’)
68% (32 / 47) recovered (Psychiatric Status Rating -PSR:1-2 for 8 weeks)
Mania > depression > mixed
Time to recover: Mixed > Manic > Depressed
59% (19 / 32) recurrence
Patients with mixed presentations had more recurrences

48. BP I Natural Course Multicenter Pilot Study (Cont’)
96% of the follow-up time patients received medications
26% of the time patients received 3 medications (e.g., mood stabilizers, antidepressants, stimulants)
12% of the time: 5-6 medications

49. BP I Natural Course Multicenter Pilot Study (Cont’)
Increased services utilization (70% hospitalizations; 50% outpatient; 20% day hospital)
Increased family problems induced by the illness (e.g., 40% negative effect on marital relationships; 40% conflict in the family and less time with other siblings)
Increased economical burden and family problems induced by the illness (e.g. 40% increased expenses; 70% used their savings; 94% incurred in debts

50. Course and Outcome of Bipolar Youth (COBY)
Multicenter study (UPMC, UCLA, Brown University)
210 children and 210 adolescents with Bipolar disorder - I, II and NOS
Evaluations of mood, behavior, life events, and school and family functioning (interviews with youth and parents)
Follow-up every 6 months for 5 years

51. COBY subjects at Intake (Cont’)
42%
46%
12%

52. COBY follow-up (Cont’)
Occurs every 6 months – parent & subject interviewed, records reviewed
Intake Diagnoses: BP I (n=26); BP II (n=11); BP NOS (n=23)
8.8 ± 4.4 months duration (6 – 18 months)
Follow-up using the Longitudinal Interval Follow-Up Evaluation (A-LIFE)
Weekly ratings of depression and mania intensity
Ratings anchored on DSM-IV thresholds
Subthreshold manic/depression symptoms rated

53. COBY 6 Month follow up (Cont’)
Diagnosis at Intake:

54. Longitudinal Course: COBY vs BP-Adults (Judd et al., 2002
No Significant Mood Symptoms
SubthresholdDepressive Symptoms

55. COBY follow-up (Cont’)
2/11 BP II subjects converted to BP I
2/23 BP NOS subjects converted to BP I
BP I
BP II
BP NOS
CGI-S Overall
3.3 ± 1.1
2.6 ± 1.1*
3.3 ± 1.0
CGI-S Mania
2.7 ± 1.2
2.0 ± 1.2
2.5 ± 1.1
CGAS (current)
66 ± 13
64 ± 16
58 ± 15
CGAS (most severe)
39 ± 18
45 ± 13
41 ± 12

56. BP- II at Intake – Convert to BP-I
Mania
Hypomania
Euthymia
Major
Depression

57. BP-NOS at Intake – Convert to BP-I
Mania
Hypomania
Euthymia
Major Depression

58. Bipolar Disorder - Natural Course
OTHER STUDIES
Strober at al., 1995 (n = 54 adolescents, clinical sample, inpatients, BP-I)
Lewinsohn et al., 1995 (n = 18 adolescents, community sample, mostly BP-II);97 subthreshold BP
Geller et al., 2001 (Clinical sample, n = 93 children and adolescents, outpatients, subjects needed to have grandiose thoughts and/or elation

59. Natural Course General Conclusions
Approximately 40% - 70% will recover
Approximately 60% - 70% will recur
Those with mixed and rapid cycling episodes will do worse
Bipolar patients had worse course that unipolar depressed and normal controls
Bipolar patients had more functional impairment, suicidal attempts, comorbid anxiety and disruptive disorders, and mental health services utilization than the depressed and normal controls

60. Natural Course General Conclusions (Cont’)
Patients usually take multiple medications (e.g., mood stabilizers, antidepressants, stimulants) and have increased mental health services utilization
Bipolar disorder produces family conflicts (e.g., marital, siblings) and economical problems
Adolescents with subthreshold bipolar symptoms (distinct period of abnormally and persistently elevated, expansive or irritable mood) have levels of impairment and comorbidity comparable with the BP group

61. Sequela

62. 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)

63. Pediatric Bipolar Disorder - WPIC Mood & Anxiety D/O Outpatients40 30
26.1*
19.1
Percentage of Patients 20
15.7*** 10
3.7
*p<.001
Suicide Attempt
* p<.05
Psychosis BP
All other diagnoses

64. Pediatric Bipolar Disorder Oregon Study
Suicide Attempts
Global Assessment of Function 90 50
44.4
87.5*** 88 45 86 40
83.6*** 84 35 82 30
Percentage of Subjects 80 25
22.2* 78 20 76
74.9 15 74 10 72 5
1.2*** 70 68
Bipolar
MDD
Never Mentally Ill BP
MDD
NMI
Lewinsohn et al., 1995

65. Predictors of Bipolar Disorder

66. Predictors of Bipolar Disorder
MDD with
Psychosis
Psychomotor retardation
Pharmacological induced mania/hypomania
Family history of bipolar disorder

67. Bipolar Disorder- Family Studies
Runs in Families
Top- down studies
Bottom-up studies

68. Children of Parents with BP
Children of BP parents have 4 times greater risk to develop BP when compared with controls
Children of parents with BP are also at risk to develop MDD, anxiety, ADHD, and disruptive behavior disorders
Methodological problems (small sample sizes, instruments, no- controls, no blindness to parental diagnosis, no direct evaluation of children).
Very few follow –up studies ( a total of 20 children for a period of 1-3 years).
Chang et al., 2001; DelBello and Geller, 2000; LaPalme et al 1994

69. Children of Parents with BP
60 children (mean age 11 years old) of 37 families with at least one parent with BP-I or II.
No controls, no blind to parental diagnosis
55% Axis I (BP=15%; MDD=15%, ADHD 28%; ODD=10%)
Children with BP had more severity of mood symptoms and problems with mood regulation
Parents of children with BP had earlier onset mood disorder and history of ADHD
Chang et al., 2000

70. NIMH-Bipolar Offspring Study (BIOS)
Children (ages 6-18 y.o) of bipolar parents
Children of community control parents:
Other non-bipolar psychiatric disorders
Healthy controls
Evaluations at intake and yearly for 5 years blind to parental diagnosis
Interviews are performed by research assistants trained to good reliability (Ks>.8)
All assessments are staffed by a child psychiatrist (DA, DB and BB)

71. Bipolar Offspring Study (BIOS) Instruments
Psychopathology (dimensional and categorical)
Parents: SCID I and II; Aggression questionnaire; BDI, Young adult self report history of abuse and suicide
Children and parents about their children:
Categorical: KSADS,
Dimensional: CBCL,MFQ, SCARED, DBD, CADS;CHI,YSR
Pubertal stage and medical history
Teacher Report Form

72. Bipolar Offspring Study (BIOS) Instruments
Psychosocial Functioning: GAS,CBCL,TRF
Family: psychiatric history first and second degree relatives, CBQ, FACES-II
Life Events: SLES
Children 2-5 years old: KSADS (parents about the child), EAS, ECI, TRF, CBCL;PDD

73. BIOS - SAMPLE
This presentation includes cases recruited until March 1, 2003
Bipolar parents = 58
Controls parents = 41
Parents with non-BP psychopathology = 26
Parents without any psychopathology = 15
Offspring of bipolar parents = 103
Offspring of control parents = 75
Offspring of parents with non-BP psychopathology = 46
Offspring of healthy controls = 29

74. BIOS - Demographics – Offspring Preliminary Analyses
Offspring of Bipolar Parents
(n=103)
Offspring of Control Parents
(n=75)
STAT
p-value
Mean Age [SD]
11.7 [3.4]
11.4 [3.5]
t=-.01
n.s.
Sex (%Female)
46.6
60.0
χ2=3.12
.08
Race (% White)
84.5
72.0
χ2=4.10
.04
Siblings (%)
78.6
77.3 χ2

75. BIOS- Probands Lifetime Disorders
Bipolar Parents (n=58)
Controls (n=41)
STAT
P-value
BP-I
44.8
χ2=24.93
<.001
BP-II
36.2
χ2=18.84
Other BP
10.3
FET
.04
MDD
12.1
24.4
χ2=2.56
n.s.
Dysthymic Disoder
5.2
9.8
n.s
Any Mood
98.3
36.6
χ2=46.09

76. BIOS- Probands Lifetime Disorders
Bipolar Parents (n=58)
Controls (n=41)
STAT
P-value
Any Anxiety
72.4
41.5
χ2=9.56
.002
Panic Disorder
29.3
7.3
χ2=7.2
.007
Any Disruptive
20.7
2.4
χ2=7.01
.008
ODD/CD
12.1
FET
n.s.
ADHD
.04
Any Substance/alcohol
(ETOH, marihuana, cocaine) 50
24.4
χ2=6.60
.01

77. BIOS- Offspring of BP parents-Lifetime Disorders- Definite/Probable
Offspring of BP Parents (n=103)
Offspring of Controls (n=75)
STAT
P-value
BP-I
1.0
FET
n.s
BP-II
1.9
1.3
n.s.
Other BP
2.9
All BP disorders
5.8
MDD/Dysthymia
10.7
4.0
χ2=2.67
Any Mood (including NOS)
20.4
8.0
χ2=5.18
.02

78. BIOS- Offspring Lifetime Disorders (Cont’)
Offspring of BP parents (n=103)
Offspring of Controls (n=75)
STAT
P-value
SAD, GAD, or SP
16.5
6.7
χ2=3.88
.04
Any Disruptive
38.8
17.3
χ2=9.60
.002
ODD
23.3
χ2=8.81
.003
ADHD
24.3
13.3
χ2=3.29
.07
Any Substance/alcohol
1.9
2.7
FET
n.s.

79. Offspring of BP vs. Controls-CBCL Scores
CBCL-T scores
Offspring of BP (n=87)
Offspring of Controls (n=63)
STAT
P-value
Total Problem
51.2 [13.7]
47.1 [12.2]
T=-1.88
.06
Externalizing
50.7 [12.4]
48.3 [12.1] T
n.s.
Internalizing
51.5 [12.2]
47.6 [11.7]
T=-1.99
.05
Somatic Complaints
57.0 [9.4]
54.4 [7.5]
T=-1.83
.07
Anxious/
depressed
55.3 [7.5]
53.4 [5.6]
T=-1.76
.08

80. Treatment

81. TREATMENT Acute Maintenance (prevention of relapses and recurrences)
Treatment of Mania, Depression, Rapid Cycling, Mixed episodes, and sometimes Psychosis
Tools:
Medications
Psychotherapy

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

83. Pharmacological Treatment
Mood Stabilizers
Lithium
Anticonvulsants
Valproate (Depakote); carbamazepine (Tegretol); oxcarbamazepine (Tryleptal); lamotrigine (Lamictal) etc.
New antipsychotics
Riperidol (Risperdal), olanzapine (Zyprexa); quetiapine (Seroquel), ziprasedone (Geodon), aripripazol (Abilify) etc.
Antidepressants
Selective Serotonin Reuptake Inhibitors
Venlafaxine (Effexor), bupropion (Wellbutrim) etc.
Others: benzodiazepines etc.

84. Bipolar Disorder – Pharmacological Treatment (Cont’)
Very few studies in youth - mostly open
Response to acute treatment with mood stabilizers (lithium, VPA, CBZ) approx. 40%-80%
Small study showed that valproate + quetiapine was better than valproate + placebo for children with mania
Open studies suggest that the atypicals alone or in combination may be efficacious
Need treatment with multiple medications

85. Bipolar Disorder – Pharmacological Treatment (Cont’)
Presence of psychosis predicts poor response to treatment
Conflicting reports on the effects of comorbid ADHD and substance abuse
Poor compliance
Approximately 70% relapse in those who discontinue treatment with lithium
Ongoing studies

86. Lithium vs. Valproate vs. CBZ
42 outpatients (mean:11.4 y.o.) with BP-I and BP-II disorder
Randomly assigned to 6 weeks open treatment with lithium, valproate, or carbamazepine
Primary outcome measures:
Young Mania Rating Scale ( 50%)
Clinical Global Impression Scale - Improvement subscale (1 or 2)
Kowatch et al., 2000

87. Lithium vs. Valproate vs. CBZ Intent-to-treat Analysis (Y-MRS) (Cont’)
Lithium: ( 0.8 mEq/L); Response: 38%
Valproate: ( 80 g/L); Response: 53%
Carbamazepine: ( 7.0 g/L); Response: 38%
Poor Compliance: 30%
> 50% needed other medications (atypical neuroleptics and/or stimulants)
Kowacht et al., 2000

88. Lithium Vs. Valproate Vs. CBZ (Cont’)

89. Lithium vs. Valproate vs. CBZ (Cont’)
Adverse Effect
% (No.)
LITH
N=14
CBZ
N=13
DVP
N=15
Nausea
21% (3)
46% (6)
20% (3)
Sedation 0%
15% (2)
Rash
8% (1)
Dizziness
Increased Appetite
14% (2)
Polyuria
7% (1)
Diarrhea

90. Divalproex Treatment for Bipolar Disorder
Multicenter (5 sites)
40 children and adolescents (7-17 y.o.)
69% (16) had comorbid diagnosis
First open-label study (2-8 weeks)
Responders randomized to continue divalproex or placebo
Wagner et al., 2000

91. Divalproex Treatment for Bipolar Disorder (Cont’)
Open phase:
61% improved ( 50% on the YMRS)
58% (23) discontinued the study (no response, side effects)
Wagner et al., 2000

92. Lithium for Adolescents with Acute Mania
85 adolescents (12-18 y.o.) with mania or mixed mania
Most were inpatients who completed the study as outpatients
At least 4 weeks open lithium treatment
Psychotic subjects initially received 4 weeks of antipsychotics
Kanfataris et al., 2000

93. Lithium for Adolescents with Acute Mania (Cont’)
Response rate 59.2% (45/85)
With psychosis 28.6% (8/28)
Without psychosis 64.9% (37/57)
No effect on response:
Depressive symptoms
Comorbid ADHD
Substance Abuse
Kanfataris et al., 2000

94. Side Effects/Laboratory Tests Prior and During Psychopharmacological Treatment
Lithium
GI, weight gain, tiredness, polydipsia, polyuria, cognition, tremor, and dermatological problems
Signs of toxicity: “drunkenness”
Renal and Thyroid Function Tests, electrolytes, CBC + differential, U/A, glucose?, EKG?
Valproate
GI, weight gain, tiredness, sedation, tremor, hair loss, hepatitis, pancreatitis, cognition?, polycystic ovary?
Liver Function Tests, CBC + differential
Carbamazepine
Ataxia, dizziness, tiredness, sedation, nystagmus, liver, hematological, and dermatological side effects
CBC +differential; electrolytes, LFTs
Oxacarbamazepine, topiramate, lamotrigine, gabapentin etc.
Check for presence of “side effects” prior to starting treatment

95. Side Effects/Laboratory Tests Prior and During Psychopharmacological Treatment
Typical Antipsychotics
Drowsiness, EPS, tardive dyskinesia, hyperprolactinemia; Low potency: weight gain, cardiovascular
CBC + diff; low potency: EKG (QTc)
Atypical Antipsychotics
Neurological disturbances, hypotension, dizziness, weight gain, ,drowsiness, liver problems, diabetes, hyperlipidemia, and hyperprolactinemia
Liver Function Tests; Glucose; lipid profile; CBC + diff; ziprasedone: EKG (QTc); clozapine: EEG + EKG.
Clozapine: agranulocytosis, eosinophilia, seizures, myocarditis, orthostatic hypotension, and salivation
Check for presence of “side effects” prior to starting treatment

96. Bipolar Depression- Treatment
BP II/NOS
Hypomania
(? SSRI)
Pure
Unipolar
Pure
Bipolar
“too little”
Hypomania
(Use SSRI)
BP-I depressed or BP-II with “Too Much” Hypomania
(Use Mood Stabilizer, if no response add an antidepressant)

97. Bipolar Depression - Treatment
Mood stabilizers
Consider adding antidepressants (SSRIs, bupropion, venlafaxine, MAOIs )
For BP-II, if hypomania is not severe and not frequent: An antidepressant alone ?
Psychosocial interventions (CBT, IPT) alone or in conjunction with medications

98. Psychosocial Treatments
Family Focus Therapy (FFT)
Cognitive Behavior Therapy (CBT)
Interpersonal Psychotherapy (IPT)
Interpersonal and Social Rhythms Therapy (IPSRT)

99. Why Treat Adolescent Bipolar Patients with Adjunctive Family Psychoeducation?
Family psychoeducation is a powerful adjunct to pharmacotherapy for adult bipolar I patients
Family factors are correlated with the course of recurrent mood disorders in adults and children
Early-onset mood and behavioral disturbances are associated with a high familial loading for major affective disorder
Mood stabilizers can be difficult to dispense safely to adolescents living in chaotic family environments

100. Family Expressed Emotion Status as a Predictor of 9-Month Clinical Outcome
c2(1) = 3.82, p=.05
Miklowitz DJ , et al. Arch Gen Psychiatry, 1988;45(3):

101. Family-Focused Treatment of Bipolar Disorder
21 outpatient sessions over 9 months
Assessment of family
Psychoeducation about bipolar disorder
Communication skills training
Problem solving skills training
Miklowitz DJ and Goldstein MJ. Bipolar Disorder: A Family-Focused Treatment Approach. NY: Guilford Press, 1997

102. Bipolar Disorder- Family Focused Treatment (FFT)
Education about bipolar disorder
Strategies for preventing relapses and re-hospitalizations
Enhance adherence to treatment
Effective communication strategies
Training in problem solving for illness related family conflicts
David J. Miklowitz, Ph.D.

103. 1-Year Survival Rates Among Bipolar Patients in Family-Focused Treatment versus Case Management
FFT, N=31
CM, N=70
Pretreatment
Follow-up
Treatment
Wilcoxon Test, c2 (1)=3.99, P =.046
Miklowitz DJ, et al. Biol Psychiatry, 2000;48(6):

104. Positive Verbal and Nonverbal Interactional (KPI) Behavior Among Families of Bipolar Patients Effects of Treatment During 1 Year (n=44)
FFT, n=22
CM, n=22
Baseline
1 year
Analysis of covariance: baseline positive behavior F(1,41)=10.08, P<0.01; Treatment F(1,41)=5.15, P<0.03
*Frequency of positive behaviors (patient/relative) during two 10-minute interactions.
Simoneau TL, et al. J Abnorm Psychol, 1999;108(4):58-597

105. Family-Focused Treatment of Bipolar Disorder: Effect on Depression and Mania3
Mean SADS-C Item Score
CM (N=44) 2
FFT (N=23) 1 3 6 9 12 18 24
Months of follow-up
Repeated measures ANOVA (linear time effects): Treatment F(1,65)=0.66, ns; Time F(1,65)=13.49, P<0.01; Treatment / Time F(1,65)=4.91, P =0.03.

106. Family-Focused Treatment for Adolescent Bipolar Patients
Focus on day-to-day mood fluctuations and changes in functioning rather than discrete episodes
Help adolescent and parents distinguish age-appropriate moodiness from bipolar disorder
Use developmentally appropriate terminology
Empathize with the adolescent’s discomfort with diagnosis
Use visually stimulating handouts and homework sheets

107. Family-Focused Treatment for Adolescent Bipolar Patients (Cont’)
Support parents’ behavioral management efforts
Address the adolescent’s medication-taking habits
Emphasize sleep/wake regularity, avoiding overstimulation
Address mood disturbances in other family members
From: Miklowitz, D. & George, E. (2000). Clinicians’ Manual for Family-Focused Treatment of Bipolar Adolescents.

108. Adolescents’
functioning at
baseline
Parental distress
and mood instability
FFT vs. TAU
Adolescent outcomes
at one year

109. Interpersonal and Social Rhythms Therapy (IPSRT)
Principles of Interpersonal Psychotherapy (IPT)
Circadian Rhythms (Sleep)
Intensive Clinical Management
Education about bipolar disorder
Education about medications used to treat bipolar disorder
Education about basic sleep hygiene
Careful review of side effects
Medical and behavior management of side effects
Nonspecific support
Education regarding early warning signs of impending episodes and use of rescue medications
24-hout on call-service

110. Bipolar Disorder – Treatment Other Considerations
Treat comorbid disorders
Manage psychosocial factors (e.g., family conflicts, peer problems)
Recommend mood hygiene (circadian rhythms)
Remediation of academic problems

111. Bipolar Disorder-Treatment Other Considerations
Need for Inclusion of Parents
Children depend on parents
Usually family has psychiatric disorder or conflicts
Family conflicts increase the risk of onset, relapses, and depressive recurrences

112. 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

113. Bipolar Disorder – Prevention of Further Episodes
Who
Those with 2 ( 3 ?) or more episodes of mania/depression
Those with 1 (2 ?) episode :
difficult to treat
severe (suicide, poor functioning)
psychosis
family loading for bipolar disorder or MDD with psychosis

114. Bipolar Disorder – Prevention of Further Episodes
How Long?
Depends on severity, frequency, type, motivation, compliance, treatment response and side effects
One year (?) to lifelong treatment

115. Conclusions

116. Conclusions Bipolar disorder in children and adolescents exist
Reliable diagnoses
Prevalent (in adolescents 1%)
Runs in families
Continuous overtime
Pending- biological studies
Response to Treatment

117. BP – Conclusions (Cont’)
BP disorder in youth is a chronic and difficult to treat illness that conveys high morbidity (e.g., behavior problems, substance abuse), poor psychosocial functioning, psychosis, and risk for suicide
Youth with BP usually have mixed and rapid cycling which are the types of bipolar disorder that have worst prognosis and are more difficult to treat
BP is highly comorbid with other psychiatric disorders. These disorders require identification and treatment
The differential diagnosis of BP may be difficult and requires longitudinal follow-up

118. Bipolar Disorder – Conclusions (Cont’)
Despite that a substantial number may recover (30%-70%), most patients experience recurrences (up to 70%)
BP has severe adverse impact on family relationships and economics
Most patients do not seek treatment
Patients require multiple medications and psychosocial interventions
The mood stabilizers and the atypicals seem useful but there is an urgent need for acute treatment and preventative studies

119. Bipolar Disorder - Conclusions (Cont’)
Patients and their families require education and intensive support and follow-up systems
In adults, psychotherapy, particularly FFT, CBT and IPSRT increase adherence to treatment, diminish the relapses and recurrences, and FFT improves family communication
Psychotherapies seems more efficacious to manage periods of depression than mania

120. Bipolar Disorder - Conclusions (Cont’)
Offspring of parents with bipolar disorder seem to be at high risk to develop bipolar, depression and other psychiatric disorders
Youth with MDD and psychosis, psychomotor retardation, pharmacological-induced mania, and/or family history of BPD are at risk to develop BPD
Youth with subthreshold bipolar symptoms have as much problems as those with the full syndrome

121. Bipolar Disorder- Conclusions (Cont’)
Bipolar Disorder is associated with high risk for suicide
Need prompt identification and treatment of BPD because at least in adults, the highest rate of suicide happens during the first years of illness
Continuous reappraisal of suicidal risk
Persons with early onset, previous attempts, severe depression, mixed episodes, rapid cycling, psychosis, comorbid disorders (substance, disruptive, anxiety?), family history of suicidal attempts; availability of methods, and exposure to stressful events are at higher risk
In adults, lithium seems beneficial to prevent suicide independent of its antimanic/antidepressive effects