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Outline

Bipolar Disorder in Children: Treatment Modalities and Options Chris Petersen, M.D. Assistant Professor in Psychiatry and Pediatrics Penn State University College of Medicine Bipolar Home Page (click here)

Objectives Briefly review diagnosis Focus on treatment and intervention Relate treatment to your specialty

Overview

Vocabulary Mood Affect Level of evidence

DEPRESSION

Major Depression Trials

More Major Depression Trials

Depression Treatment Facts No medication has FDA approval for major depression in children and adolescents, except for fluoxetine (Prozac) 10 week trial is needed to assess medication benefits Children should continue treatment for 12 months after symptoms have resolved

BIPOLAR DIAGNOSIS

“DIG FAST” Criteria Distractibility 97% Increased physical activity or goal directed activity 97% Grandiosity or extreme defiance 54% Flight of ideas 68% Activities showing poor judgment 89% Sleep - decreased need,  only 29% Talkativeness 64%

Early Childhood Mood Disorder Screen Screens young children under 9 years 32 patients Diagnosis of Mood Disorder Completed by parents Takes only 2 minutes

Early Childhood Mood Disorder Screen Complaints Violence Hyperactivity Emotional lability Uncontrollable behavior Aggression Screaming/swearing Irritability Withdrawn Depressed mood

Early Childhood Mood Disorder Screen 9 questions Cut-off score 4/9 Sensitivity 0.93 Specificity 0.75

TREATMENT ISSUES

Treatment and Interventions Medication Psychotherapy Educational intervention Parent/family work School liaison

Treatment Issues Many not improve in the first year Comorbidity is usually a factor Relapse is common

Comorbid Diagnoses Conduct disorders    35+ % Anxiety disorders     55% Reading LD              43% Depression                85% Psychosis                  15% ODD                         80-95% Substance use disorder 40%

Medication Overview Lithium, valproate, carbamazepine, gabapentin and lamictal Multiple mood stabilizers often needed Treat comorbid ADHD Treat comorbid depression,anxiety and/or psychosis Control behavior with antipsychotic as needed

Medication Issues Use medications that target more than one symptom Consider side effects, drug-drug interactions and drug-disorder interactions

Initiating Pharmacotherapy Informed consent Examinations Phase of the illness Length of treatment Medication choice

Child and Adolescent Bipolar Disorder: A Review of the Past 10 Years Prepubertal onset BD is a nonepisodic, chronic, rapid cycling, mixed manic state that may be comorbid with attention-deficit hyperactivity disorder (ADHD) and CD or have features of ADHD and/or CD as initial manifestations.

Family-Genetic Study of Prepubertal Mania First, treat mania and/or psychosis Second, treat depression Third, treat anxiety and ADHD

Pilot Family-Genetic Study of Prepubertal Mania Combined pharmacotherapy is often necessary Treatments for mania do not treat ADHD Additional treatment may be needed for ADHD

PHARMACOTHERAPY

Lithium in Children Pharmacokinetics of lithium in children Lithium has a shorter half-life in children than in adults More efficient renal system

Lithium Alkali metal, similar to sodium salt Two salt preparations Lithium carbonate Lithium citrate (liquid) Impacting on neurotransmitter systems Ion channels Serotonin Dopamine Norepinephrine

Lithium Blood Levels Recommended therapeutic serum levels for the acute phase range from 0.6 to 1.2 mEq/l Starting dosages range from 300 mg to 900 mg per day, depending on the size of the child For children, a starting dose of 900mg/sq.M. (Approximately 30 mg/kg/day) generally produced a therapeutic serum level within 5 days Some children may develop toxic levels greater than 1.4 mEq/l if started at this level

Lithium Side-effects Youth generally tolerate lithium well, and may have fewer side-effects than adults Some younger children may be more prone to side-effects than older children so consider long acting forms

Lithium Adverse Reactions Nausea Diarrhea Vomiting Tremor Weight gain Headache Polyuria Polydipsia Enuresis Fatigue Ataxia

Lithium Drug-drug Interactions Antipsychotic agents Encephalopathic syndrome Neuroleptic malignant syndrome Agents influence lithium levels Carbamazepine Nonsteroidal anti-inflammatory agents Some antibiotics (tetracycline) Thiazide diuretics

Lithium Open studies support use in aggression Better than placebo or Haldol in Conduct Disorder Helps in aggressive ADHD (?) Positive for bipolar, but 50% relapse and 36 weeks to improve Consider especially if family history of bipolar or lithium response Assure water is available for activities

Lithium Lithium level after 4 to 5 days, then frequently until stable, then 1 to 3 months Dosage 675 - 1800 mg with levels 1.0 to 1.2 did best, some do well on 0.3 to 0.4 mEq/L Monitor baseline and every 6 months TSH (or full panel), renal (Cr, BUN, U/A, calculated CRCL), Ca, P Baseline only: CBC, electrolytes, EKG

Lithium in bipolar with substance dependency Double-blind, placebo-controlled Age average 16.3 years old 25 patients 6 week study Secondary substance dependency, mostly alcohol and marijuana Intent-to-treat and completer analyses Li levels target 0.9 mEq/L

Lithium in bipolar with substance dependency Suggests lithium is effective in preventing substance use and  improving global functioning in a group of mood-disordered adolescents with co-morbid substance abuse 6 year interval between BP and SDD argues for early BP recognition

Lithium Response in Acute Adolescent Mania Lithium monotherapy effective for adolescents with acute mania especially without psychotic features Antipsychotics are indicated for psychotic features in mania

Lithium Response in Acute Adolescent Mania Placebo-controlled with 12-18 year olds 2 week trial with or without Li 108 patients 41.7% responders qualify for grouping Then divided into 2 groups: placebo or lithium

Lithium Response in Acute Adolescent Mania 52.6% on lithium had exacerbations 61.9% on placebo had exacerbations Exacerbations = increase irritability and aggression Lithium did not have a large effect due to the high rate of exacerbations

Valproate Positive results for bipolar treatment Not a major enzyme inducer Tremor, weight gain (21 kg) and alopecia Hepatotoxic usually limited to < 3 y/o Monitor liver function tests and CBC Possible high rate of polycystic ovarian disease > 80%  (controversial)

Valproate Levels of 90 to 125 in mania Initial treatment or lower levels (<90) can increase agitation Depakote ER Need about 20% more in adolescents with once daily Do not use in children under 10 years old as they need twice daily dosing due to rapid metabolism

Divalproex: Oral loading with combination drug therapy 45 hospitalized patients Mean = 9 years old Initially 15 mg/kg/day Trough levels at 4 days

Divalproex: Oral loading with combination drug therapy Initial drug levels = 37-121 ug/ml Most frequently used with atypical antipsychotic Antipsychotics resulted in no significant differences in levels or toxicity Divalproex sprinkles required higher doses for comparable levels Overweight children more likely to have higher levels (Good 2001)

Valproate Side-effects Sedation Nausea Vomiting Fatal hepatic toxicity Hematologic side-effects Polycystic ovary disease in adult women with seizure disorders

Divalproex in Children 40 children 7 – 19 years old (mean=12.1) Depakote for 2 to 8 weeks Open phase then blind phase Young Mania Rating Scale (MRS)

Divalproex in Children 22 (61%) improved by 50+% 23 children discontinued 15% ineffectiveness 15% intolerance 15% noncompliance Overall a failed trial due to 58% drop out rate and no control group

Divalproex in Children

Divalproex in Children Mania Rating Scale

Divalproex in Children Brief Psychiatric Rating Scale

Divalproex in Children Clinical Global Impressions

Combined lithium and divalproex therapy Open prospective outpatient trial 90 patients Bipolar I diagnosis Treated with lithium and divalproex Treatment for up to 20 weeks Substantial improvement Remission in about 50%

Combined divalproex and Adderall therapy Double-blind with 30 bipolar patients 21/30 responded to divalproex 22/23 still had significant ADHD Adderall caused no significant adverse events when added to divalproex Adderall appears safe and effective for co-morbid ADHD

Carbamazepine Helps for aggressive children, but can cause aggression Positive response in bipolar and 6 weeks to improve Drug-drug interactions Self-induction of metabolism

Carbamazepine Side-effects Drowsiness Dizziness Nausea Mild ataxia Leukopenia Agranulocytosis Aplastic anemia Hepatic toxicity

Carbamazepine Side Effects Nausea, dizziness, sedation, diplopia, slurred speech, ataxia Hematopoetic with relative neutropenia Agranulocytosis only 1 in 20,000 CBC weekly x 3, then monthly x 3, then every 1 to 3 months If WBC < 3,000, ANC < 1200-1500, discontinue drug Hepatic toxicity, LFT monitoring

Gabapentin Currently questionable or doubtful benefits Not used as a single agent Positive response in bipolar at 330 to 3600 mg/day, average of 539 mg in one adult study with other medications Few side effects but oversedation, overactivation, disinhibition or greater rapid cycling are possible No major drug-drug interactions No blood levels needed

Lamotrigine Helps in refractory adult bipolar High rate (10%) of serious or fatal rashes in children make it a last resort New findings may allow broader use such as fewer rashes when medication started very slowly

How to Add or Change Mood Stabilizers Overlap medications during transitions Don’t expect ADHD symptoms to change Target irritability and aggression Monitor for safety as 20-40% serious suicide attempts

Recent Bipolar Trials

Antipsychotics Risperidone, start 0.5 mg at bedtime Olanzapine, start 2.5 mg at bedtime Quetiapine, start 25 - 50 mg at bedtime Ziprasidone, start 10 mg daily Clozapine, last due to serious side effects Haloperidal to stabilize in acute mania but more side effects Rare instances 3 to 4 other medications at once for adequate control

Risperdal Treatment of Juvenile Mania Open study; N=28 Age (mean) =10 years 82% of patients had anti-manic effect Rapid patient stabilization No EPS No increased agitation No anti-ADHD effect

Risperidone tolerability in children Administered 0.04 mg/kg/day Age 7 to 10 years Total 10 hospitalized patients Ratings at baseline, within 24 hours of starting, at target dose and at discharge

Risperidone tolerability in children: Side effects Changed appetite Weight gain or loss Diarrhea Rigidity Drooling Slurred speech Sedation

Risperidone tolerability in children: Conclusions High rate of side effects Short duration Mild severity Monitor weight change Assess for EPS

Open Trial of olanzapine in juvenile mania 8 week prospective open trial 23 patients Age = 5-14 years old YMRS, CGI-S and others

Open Trial of Olanzapine in Juvenile Mania 22 of 23 completed the trial YMRS fell 19 points (significant) Response rate 61% with >30% reduction in YMRS and CGI-S<3

Open Trial of Olanzapine in Juvenile Mania Olanzapine was effective in improving patients’ levels of mania, depression and psychosis. Treatment was well tolerated. No significant changes in extrapyramidal symptoms. Weight increased 2.3 kg

Olanzapine for bipolar disorder 4 week open prospective trial 9 manic or mixed bipolar patients Age = 12-18 years old Olanzapine 5-20 mg/day YMRS, CDRS and PANSS-P to assess

Olanzapine for bipolar disorder 67% with >50% reduction in YMRS All scales with significant reductions Side effects of sedation, increased appetite and dizziness Safe, well tolerated and effective for manic, depressive and psychotic symptoms

Olanzapine in psychosis 16 patients from 12-17 years old Schizophrenia spectrum disorder 8 weeks Mean dose = 12.4 mg/day (3.8-20) Improved Low EPS (2 needed tx) Weight gain

Open Trail of Zyprexa in Juvenile Mania Zyprexa was highly effective in improving patients’ levels of mania, depression and psychosis. Treatment was well tolerated. No significant changes in extrapyramidal symptoms. Only one discontinuation due to an adverse event (depression).

Quetiapine in the Treatment of Adolescent Mania Open study; N=30 Age (mean) = 14 (12 - 18 years) Valproate alone or valproate + quetiapine Mean dose = 432 mg/day 87% response with combined treatment 53% drop out rate

Benzodiazepines Used in conjunction with antimanic agents In place of neuroleptics In adults, clonazepam and lorazapam Long-term use in children should be discouraged, given both the lack of research supporting this practice, and the potential problems with dependency

Psychostimulants Reports of exacerbating or inducing psychosis/mania Case reports of stimulants having antimanic effects Reports of using lithium or valproate and methylphenidate together in treating preadolescent children Avoided during acute manic phases

Bupropion in ADHD + Bipolar Treatment with bupropion Open Prospective 6 weeks 16 adults completed trial

Bupropion in ADHD + Bipolar 53% improvement ADHD Clinical Global Impression Severity of ADHD Little evidence of activation Only 12% taking mood stabilizer Reduced ratings of mania and depression

Bupropion in ADHD + Bipolar

Bupropion in ADHD + Bipolar

Pediatric mania treatment recommendations Taper stimulant or antidepressant medications If still bipolar, then Euphoric  à  lithium Mixed à valproate (male), female ? Partial response à lithium + valproate Stable, but ADHD à stimulant

Mania with psychosis treatment recommendations First Mixed      à valproate + atypical Euphoric  à lithium + atypical Nonreponders Add second mood stabilizer Lithium + valproate Carbamazepine + lithium Not carbamazepine + valproate (unstable)

Electroconvulsive Therapy In adults, electroconvulsive therapy (ECT) is as effective as lithium for the treatment of mania Extremely safe as long as modern methods are used in adults Case reports of benefit in childhood mania, rapid cycling, and depressed phases No controlled studies in children

ECT: When with adults? Pregnancy Catatonia Neuroleptic Malignant Syndrome Other medical condition where more standard medication regimens are contraindicated

PSYCHOTHERAPY

Psychotherapy and Other Interventions   Cognitive therapy - to increase compliance with medication   Psychotherapy - if patient interested, can increase compliance   Family therapy to support the family structure   Group therapy

Group Therapy for Adolescents 8 adolescents Age: 15 to 17 years 10 - week group Prospective Pre and post ratings

Group Therapy for Adolescents Pre-group CBCL=76.3 (high level) CAFAS Prior=110.0 Post=48.2  (p=0.02) Supportive element of the group was the most important to the patients

Individual Psychotherapy Forming rapport Modeling assertiveness Firm boundaries Clarification of the agenda Integrating polarities Dissolving rigid boundaries Cognitive therapy: "Two Hand Integration Method.” ”Good voice" and "bad voice"

SUMMARY AND RESOURCES

Summary Discussed the issues in treatment of childhood onset bipolar disorder Seek consultations and collaboration in treatment of bipolar kids Please include your suggestions for additions or modifications of this presentation on the evaluation form

Where to Get More Information on the Internet The Child Advocate http://www.childadvocate.net Child & Adolescent Bipolar Foundation http://www.bpkids.org American Academy of Child and Adolescent Psychiatry http://www.aacap.org Bipolar Home Page (click here)

Where to Get More Information PRACTICE PARAMETERS FOR THE ASSESSMENT AND TREATMENT OF CHILDREN AND ADOLESCENTS WITH BIPOLAR DISORDER by Jon McClellan, M.D. and John Werry, M.D. by AACAP, 1996 Mood stabilizer combinations: a review of safety and efficacy. [Review] [121  refs] American Journal of Psychiatry.  155(1):12-21, Jan 1998.

Where to Get More Information Child and Adolescent Bipolar Disorder: A Review of the Past 10 Years. Journal of the AACAP 1997;36:1168-1176. BARBARA GELLER, M.D., JOAN LUBY, M.D. Mood stabilizer combinations: a review of safety and efficacy. [Review] [121  refs] American Journal of Psychiatry.  155(1):12-21, Jan 1998.

More Information Wozniak J. Biederman J. Richards JA. Diagnostic and therapeutic dilemmas in the management of pediatric-onset bipolar disorder. [Review] [39 refs] Journal of Clinical Psychiatry. 62 Suppl 14:10-5, 2001 Expert consensus guidelines can be found in Journal of Clinical Psychiatry 1996;57 (suppl 12A) as a reference for the family

Referral and Consultation For an outpatient child/adolescent psychiatric evaluation at Penn State Hershey Medical Center:   (717) 531-8338 To refer a child age 15 or under for inpatient treatment:  (717) 531-7146 To refer an adolescent age 16 or over for inpatient treatment:    (717) 531-8822

Bipolar Disorder in Children: Treatment Modalities and Options Chris Petersen, M.D. Assistant Professor in Psychiatry and Pediatrics Penn State University College of Medicine Bipolar Home Page (click here)