Lithium Versus Divalproex for Treating Pediatric Bipolar Disorder

Primary Aim:

To compare the efficacy of lithium (LI), divalproex (DVP), and placebo (PBO) in the acute phase treatment of symptomatic bipolar I disorder, mixed or manic episode, in children and adolescents. Our hypothesis is that differential efficacy will be observed with the following predicted order of response: divalproex (DVP) = lithium (LI) > placebo (PBO).

Secondary Aims:

• To collect systematic safety data on the incidence of weight gain and the development of insulin resistance and hyperandrogenism in bipolar adolescent females treated with LI, DVP, or LI + DVP.
• To collect data on possible predictors of acute treatment response to the two active treatments.
• To provide descriptive information on the stability of acute phase response to monotherapy with either LI or DVP over 6 months of continuation phase treatment.
• To develop safety and efficacy data about the use of stimulant medications in these subject while treated with a mood stabilizer.

Inclusion criteria

• 7.0 - 17 years of age
• Bipolar I Disorder, mixed or manic episode, psychotic or non-psychotic, according to DSM IV criteria
• Score of > 14 on the Y-MRS
• Normal intelligence
• Ability and willingness to provide assent and informed, written consent from at least one parent or legal guardian
• No current general medical illnesses requiring medication

Exclusion criteria

• 1. A current or lifetime DSM-IV diagnosis of schizophrenia, autistic disorder, schizoaffective disorder, pervasive developmental disorder, or obsessive compulsive disorder 2. IQ < 70 3. Patients with serious suicide risk 4. Concurrent cognitive-behavior therapy that is specifically focused on the child or adolescent's bipolar symptoms within 6 weeks of enrolling in this trial.

• Any use of psychotropic agents within the preceding 2 weeks, including neuroleptics, monoamine oxidase inhibitors, stimulants, antidepressants, or depot neuroleptics or fluoxetine in the past month 6. Current or history in past 3 months of a DSM-IV diagnosis of Substance Abuse/Dependence or use of illicit drugs or alcohol in the past 3 weeks. Patients who have a positive drug screen at intake, who would otherwise be eligible for the study, will be given the opportunity to repeat the drug screen 3 weeks later. They will be excluded if the second drug screen is positive.

• Pregnancy or sexually active females not using a reliable form of contraception 8. Previous adequate trial of either LI or DVP defined as; 3 weeks of DVP at serum levels between 75-125 OR dosage of at least 20 mg/kg; Lithium for at least 4 weeks at serum levels of .8 - 1.2 or dosage of at least 30 mg/kg.

• Allergies to LI, DVP or chlorpromazine. 10. Bipolar subjects who are currently stable on mood stabilizers or atypical neuroleptics.

• Bipolar subjects with Bipolar I disorder and ADHD who are stable on stimulants with or without concurrent mood stabilizers.

• Inpatient hospitalization within 6 months prior to screening. Partial hospitalization is acceptable.