Children and Adolescents with Bipolar Disorder

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 NOS
Bipolar II
Bipolar I
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
• Childs 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 dont 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 childs 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

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 (n13) Ages 7-10 (n24) 11-12 (n10)
Symptoms/Behaviors () Symptoms/Behaviors () 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, 1993Cavanaugh et al.,
2002 Mendlewicz et al., 1972Lych et al., 1994
Puls et al., 1992Rice et al., 1987Sachs 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 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

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 gt Other (p .01)
BP gt Other (plt.001)
BP gt MDD (p.003)
BP gt MDD (plt.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 gt BP II (p lt .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 lt 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 8 23
Anxiety D/O (SAD, GAD, Social Phobia) 47 54 51
Psychosis 38 23 25
Major Depressive Episode 67 100 67
32
COBY BPNOS Subjects (Cont)

• Median of 107 days of BP-NOS level of symptoms
  lifetime
• Only 4 subjects had lt 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
87.5
44.4
88
45
86
40
83.6
84
35
82
30
Percentage of Subjects
80
22.2
25
78
20
74.9
76
15
74
10
72
5
1.2
70
0
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 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
42
BP children with elation/grandiosity (n93) vs
ADHD (n81)
Elated
Energy
Irritable
Grandiose
Distractible
Sleep Need
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 CourseMulticenter Pilot Study
(Cont)

• 68 (32 / 47) recovered (Psychiatric Status
  Rating -PSR1-2 for 8 weeks)
• Mania gt depression gt mixed
• Time to recover Mixed gt Manic gt 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 (n26) BP II (n11)
  BP NOS (n23)
• 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
SubthresholdDepressive Symptoms
No Significant Mood 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 Outpatients
40
30
26.1
19.1
Percentage of Patients
20
15.7
10
3.7
0
plt.001
Suicide Attempt
Psychosis
plt.05
BP
All other diagnoses
64
Pediatric Bipolar Disorder Oregon Study
Suicide Attempts
Global Assessment of Function
90
50
87.5
44.4
88
45
86
40
83.6
84
35
82
30
Percentage of Subjects
80
22.2
25
78
20
74.9
76
15
74
10
72
5
1.2
70
0
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 (BP15 MDD15, ADHD 28 ODD10)
• 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 (Ksgt.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, CADSCHI,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, CBCLPDD

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 OffspringPreliminary
Analyses
Offspring of Bipolar Parents (n103) Offspring of Control Parents (n75) STAT p-value
Mean Age SD 11.7 3.4 11.4 3.5 t-.01 n.s.
Sex (Female) 46.6 60.0 ?23.12 .08
Race ( White) 84.5 72.0 ?24.10 .04
Siblings () 78.6 77.3 ?2 n.s.
75
BIOS- ProbandsLifetime Disorders
Disorder () Bipolar Parents (n58) Controls (n41) STAT P-value
BP-I 44.8 0 ?224.93 lt.001
BP-II 36.2 0 ?218.84 lt.001
Other BP 10.3 0 FET .04
MDD 12.1 24.4 ?22.56 n.s.
Dysthymic Disoder 5.2 9.8 FET n.s
Any Mood 98.3 36.6 ?246.09 lt.001
76
BIOS- ProbandsLifetime Disorders
Disorder () Bipolar Parents (n58) Controls (n41) STAT P-value
Any Anxiety 72.4 41.5 ?29.56 .002
Panic Disorder 29.3 7.3 ?27.2 .007
Any Disruptive 20.7 2.4 ?27.01 .008
ODD/CD 12.1 2.4 FET n.s.
ADHD 12.1 0 FET .04
Any Substance/alcohol (ETOH, marihuana, cocaine) 50 24.4 ?26.60 .01
77
BIOS- Offspring of BP parents-Lifetime Disorders-
Definite/Probable
Disorder () Offspring of BP Parents (n103) Offspring of Controls (n75) 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 ?22.67 n.s.
Any Mood (including NOS) 20.4 8.0 ?25.18 .02
78
BIOS- OffspringLifetime Disorders (Cont)
Disorder () Offspring of BP parents (n103) Offspring of Controls (n75) STAT P-value
SAD, GAD, or SP 16.5 6.7 ?23.88 .04
Any Disruptive 38.8 17.3 ?29.60 .002
ODD 23.3 6.7 ?28.81 .003
ADHD 24.3 13.3 ?23.29 .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 (n87) Offspring of Controls (n63) 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 (mean11.4 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
• gt 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)
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,
198845(3)225-231
101
Family-Focused Treatmentof 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, N31
CM, N70
Wilcoxon Test, c2 (1)3.99, P .046
Miklowitz DJ, et al. Biol Psychiatry,
200048(6)582-592
104
Positive Verbal and Nonverbal Interactional (KPI)
Behavior Among Families of Bipolar
PatientsEffects of Treatment During 1 Year (n44)
FFT, n22
CM, n22
1 year
Baseline
Analysis of covariance baseline positive
behavior F(1,41)10.08, Plt0.01 Treatment
F(1,41)5.15, Plt0.03
Frequency of positive behaviors
(patient/relative) during two 10-minute
interactions.
Simoneau TL, et al. J Abnorm Psychol,
1999108(4)58-597
105
Family-Focused Treatment of Bipolar Disorder
Effect on Depression and Mania
3
CM (N44)
Mean SADS-C Item Score
2
FFT (N23)
1
3
6
9
12
0
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,
Plt0.01 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 adolescents 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 adolescents 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 TreatmentOther 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-TreatmentOther 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 DisorderNo 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/antidepressiv
  e effects