Transcript Childhood Bipolar Disorder

Children and Adolescents
with Bipolar Disorder
Boris Birmaher MD
Department of Child Psychiatry
Western Psychiatric Institute and Clinic
University of Pittsburgh Medical Center
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?
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
Clinical Manifestations
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
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
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)
Bipolar I
Bipolar II
Bipolar NOS
Not Bipolar
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
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
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; 1-900-sex lines; sexually vulgar language;
sending notes propositioning peers
To clarify the diagnosis:
Retrospective studies of bipolar adults
Prospective studies of bipolar children
Studies of children of bipolar parents
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
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%)
Highly Episodic
Egeland et al., 2000
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 mood50%
Low energy/tired-30%
Increased energy-30%
Labile/mood changes30%
Anxious-30%
Cried-30%
Egeland et al., 2000
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)
WPIC Child Mood & Anxiety Disorder
Outpatient Clinic
• Kiddie Schedule for Affective Disorders and
Schizophrenia, present episode (KSADS-P)
• 1,926 subjects ages 5 to 17.11 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
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
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
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
Hamilton Depression Scores (Cont’)
20
Mixed
16
Number of Patients
Manic
12
8
4
0
Extracted Hamilton Depression Rating
WPIC Child Mood & Anxiety Disorder
Outpatients (Cont’)
BP-spectrum
MDD
Other non-mood D/O
25
% of Patients
20
15
10
5
0
Suicide Attempt
BP > Other (p = .01)
Psychosis
BP > Other (p<.001)
BP > MDD (p<.001)
Conduct D/O
BP > MDD (p=.003)
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
CABS Intake Diagnoses (Cont’)
BP I
(n=70)
21%
Not BP
(n=152)
45%
9%
25%
BP II
(n=28)
BP NOS
(n=85)
BP I
BP II
BP NOS
% of Patients
50
40
30
20
10
0
ADHD*
CD/ODD*
Anxiety
D/O's
* BP NOS, BP I > BP II (p < .01)
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
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 24hour period to count as “one day”
Lifetime of 4 days total of symptoms
(e.g. 4 one day episodes; 2 two day
episodes, etc.)
COBY subjects at Intake (Cont’)
BP NOS
(n=45)
42%
46%
BP II
(n=13)
BP I
12%
(n=49)
Demographics (COBY) (Cont’)
18
50
15
40
BP
NOS
30
20
10
BP I
31%
BP II
39%
42%
12
9
6
BP I
13.4
BP II
14.5
BP
NOS
12.7
3
0
% Female
0
Age (in years)
COBY Subjects at Intake (Cont’)
KSADSMRS (Mania
BP I
BP II
BP NOS
18.5 ± 12.1
19.3 ± 12.1
20.9 ± 11.5
2.9 ± 1.3
2.8 ± 1.4
3.1 ± 1.2
59 ± 12
65 ± 15
60 ± 13
31 ± 12
39 ± 9
40 ± 11*
Rating Scale)
CGI-S
(Depression)
CGAS
(Current)
CGAS (Most
Severe Past)
*BP I < BP NOS (p = .001)
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%
8%
23%
Anxiety D/O (SAD,
47%
54%
51%
Psychosis
38%
23%
25%
Major Depressive
Episode
67%
100%
67%
GAD, Social Phobia)
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)
Prepubertal Bipolar Disorder
90%
80%
70%
60%
Mixed Mania
Rapid cycling
50%
40%
Psychosis
30%
20%
10%
Suicidal (plan and
intent)
0%
Mean age= 10.9 ± 2.6 y.o
Geller et al., 1998
Bipolar Disorder in High School
Students
Suicide Attempts
Global Assessment of Function
90
Percentage of Subjects
50
45
87.5***
88
44.4
86
40
83.6***
84
35
82
30
80
22.2*
25
78
20
76
15
74.9
74
10
5
1.2***
0
Bipolar
MDD
Never
Mentally
Ill
72
70
68
BP
MDD
NMI
Lewinsohn et al., 1995
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 (DSMIV 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
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
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?
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
Bipolar Disorder - Comorbidity
•The rule more than the exception
•Approximately 50%-90%
•Disruptive Disorders
•Anxiety Disorders
•Substance Abuse (adolescents)
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
Diagnostic Overlap between Mania & ADHD
DSM-IV Mania
ADHD
Elevated, expansive mood
No
Irritability
Commonly associated
Inflated self-esteem / grandiosity
No
Decreased need for sleep
Can be present
More talkative / pressured speech
DSM-IV Criteria
Flight of Ideas or racing thoughts
No
Hyperactivity / goal-directed activity
DSM-IV Criteria
Pleasurable activities with high risk
…for painful consequences
Commonly associated
Distractibility
DSM-IV Criteria
BP children with elation/grandiosity
(n=93) vs ADHD (n=81)
100
90
80
70
60
50
40
30
20
10
0
Geller et al., 2002
Epidemiology
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
Natural Course
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)
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
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
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
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
COBY subjects at Intake (Cont’)
BP NOS
(n=45)
42%
46%
BP II
(n=13)
BP I
12%
(n=49)
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
COBY 6 Month follow up (Cont’)
Diagnosis at Intake:
BP I
BP II
BP-NOS
MDD
Subsyn
70
% of weeks
60
50
40
30
20
10
0
Well
Manic/Mixed
Episode Type
Longitudinal Course: COBY vs
BP-Adults (Judd et al., 2002
Youth (COBY)
Adults (CDS)
60
50
54% 53%
40
30
20
21%
10
13%
0
No
Significant
Mood
Symptoms
9%
MDD
1.5% 2%
Manic
23%
2.3% 1%
Mixed
Subthreshold
Depressive
Symptoms
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
39 ± 18
45 ± 13
41 ± 12
(most
severe)
BP- II at Intake – Convert to BP-I
Mania
Depression
7
Mania
6
5
Hypomania
4
3
2
1
Euthymia0
-1
-2
-3
-4
-5
Major
-6
Depression
-7
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26
Weeks After Intake
BP-NOS at Intake – Convert to BP-I
Mania
Depression
7
6
Mania
5
Hypomania
4
3
2
1
0
Euthymia
-1
-2
-3
-4
-5
-6 Depression
Major
-7
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26
Weeks after Intake
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
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
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
Sequela
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)
Pediatric Bipolar Disorder - WPIC
Mood & Anxiety D/O Outpatients
Percentage of Patients
40
30
20
26.1*
19.1
15.7***
10
3.7
0
Suicide Attempt
* p<.05
Psychosis
BP
All other diagnoses
*p<.001
Pediatric Bipolar Disorder
Oregon Study
Suicide
Attempts
Percentage of Subjects
50
45
90
Global Assessment of
Function
87.5***
88
44.4
86
40
83.6***
84
35
82
30
80
22.2*
25
78
20
76
15
74.9
74
10
5
1.2***
0
Bipolar
MDD
Never
Mentally
Ill
72
70
68
BP
MDD
NMI
Lewinsohn et al., 1995
Predictors of Bipolar Disorder
Predictors of Bipolar Disorder
• MDD with
• Psychosis
• Psychomotor retardation
• Pharmacological induced
mania/hypomania
• Family history of bipolar disorder
Bipolar Disorder- Family Studies
Runs in Families
 Top- down studies
 Bottom-up studies
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
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
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)
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
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
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
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
n.s.
BIOS- Probands
Lifetime Disorders
Disorder (%)
Bipolar Parents
(n=58)
Controls
(n=41)
STAT
P-value
BP-I
44.8
0
χ2=24.93
<.001
BP-II
36.2
0
χ2=18.84
<.001
Other BP
10.3
0
FET
.04
MDD
12.1
24.4
χ2=2.56
n.s.
Dysthymic Disoder
5.2
9.8
FET
n.s
Any Mood
98.3
36.6
χ2=46.09
<.001
BIOS- Probands
Lifetime Disorders
Disorder (%)
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
2.4
FET
n.s.
ADHD
12.1
0
FET
.04
50
24.4
χ2=6.60
.01
Any
Substance/alcohol
(ETOH, marihuana,
cocaine)
BIOS- Offspring of BP parents-Lifetime DisordersDefinite/Probable
Disorder (%)
Offspring of BP
Parents (n=103)
Offspring of
Controls
(n=75)
STAT
P-value
BP-I
1.0
0
FET
n.s
BP-II
1.9
1.3
FET
n.s.
Other BP
2.9
0
FET
n.s.
All BP disorders
5.8
1.3
FET
n.s.
MDD/Dysthymia
10.7
4.0
χ2=2.67
n.s.
Any Mood (including
NOS)
20.4
8.0
χ2=5.18
.02
BIOS- Offspring
Lifetime Disorders (Cont’)
Disorder (%)
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
6.7
χ2=8.81
.003
ADHD
24.3
13.3
χ2=3.29
.07
Any
Substance/alcohol
1.9
2.7
FET
n.s.
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
Treatment
TREATMENT
Acute
Maintenance (prevention of relapses
and recurrences)
Treatment of Mania, Depression, Rapid
Cycling, Mixed episodes, and
sometimes Psychosis
Tools:
 Medications
 Psychotherapy
Bipolar Disorder - Psychoeducation
•
•
•
•
•
•
•
•
•
Symptomatology
Etiology ( e.g., genetics)
Treatment
Prognosis
Prevention (early signs of relapse/recurrence)
Psychosocial Scars
Stigma
Mood Hygiene
Importance of compliance
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.
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
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
Lithium vs. Valproate vs. CBZ
• 42 outpatients (mean:11.4 y.o.) with BP-I and BPII 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
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
Lithium Vs. Valproate Vs. CBZ (Cont’)
Lithium vs. Valproate vs. CBZ (Cont’)
Adverse Effect
LITH
CBZ
DVP
% (No.)
N=14
N=13
N=15
Nausea
21% (3)
46% (6)
20% (3)
Sedation
0%
15% (2)
20% (3)
Rash
0%
8% (1)
0%
Dizziness
0%
8% (1)
0%
Increased Appetite
14% (2)
0%
0%
Polyuria
7% (1)
0%
0%
Diarrhea
7% (1)
0%
0%
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
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
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
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
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
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
Bipolar Depression- Treatment
BP II/NOS
Hypomania
(? SSRI)
Pure
Pure
Unipolar
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)
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
Psychosocial Treatments
Family Focus Therapy (FFT)
Cognitive Behavior Therapy (CBT)
Interpersonal Psychotherapy (IPT)
Interpersonal and Social Rhythms
Therapy (IPSRT)
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
Family Expressed Emotion Status as a Predictor
of 9-Month Clinical Outcome
Number of Patients
14
12
10
8
6
4
2
0
Low EE (7/13)
No Relapse
High EE (9/10)
Relapse
c2(1) = 3.82, p=.05
Miklowitz DJ , et al. Arch Gen Psychiatry, 1988;45(3):225-231
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
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
.
1-Year Survival Rates Among Bipolar Patients in
Family-Focused Treatment versus Case Management
Cumulative Survival Rate
1
FFT, N=31
0.8
0.6
0.4
CM, N=70
0.2
0
0
5
10
Pretreatment
15
20
25
30
35
Treatment
40
45
50
55
Follow-up
Wilcoxon Test, c2 (1)=3.99, P =.046
Miklowitz DJ, et al. Biol Psychiatry, 2000;48(6):582-592
Positive Verbal and Nonverbal Interactional (KPI)
Behavior Among Families of Bipolar Patients
Effects of Treatment During 1 Year (n=44)
300
FFT, n=22
250
Mean KPI
positive score*
200
CM, n=22
150
100
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
Mean SADS-C Item Score
Family-Focused Treatment of Bipolar Disorder:
Effect on Depression and Mania
3
CM (N=44)
2
FFT (N=23)
0 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.
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 ageappropriate moodiness from bipolar disorder
 Use developmentally appropriate terminology
 Empathize with the adolescent’s discomfort with
diagnosis
 Use visually stimulating handouts and homework
sheets
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.
Adolescents’
functioning at
baseline
FFT vs. TAU
Parental distress
and mood instability
Adolescent outcomes
at one year
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
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
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
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
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
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
Conclusions
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
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
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
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
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
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