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Children and Adolescents with Bipolar Disorder

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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 Outpatients
40 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 Mania
3 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

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