Clozapine vs. Placebo in Treatment-Refractory Bipolar Disorder in Children and Adolescents

INCLUSION CRITERIA (All 5 must be met): Children with BPD Ages 8-17 Currently meets criteria for bipolar disorder, manic or mixed, as determined by the K-SADS diagnostic interview. Treatment-resistant, defined as a history of unsuccessful trials of lithium (documented level of greater than 0.8 mEq/L), valproic acid (documented level of greater than 50 ug/ml), carbamazepine (documented level greater than or equal to 6 ug/ml), a neuroleptic as well as a combination of two of these agents. Each trial must have been at least 6 weeks long. A trial will be considered unsuccessful if the medication was discontinued because of intolerable side-effects. The child should be in treatment with a community psychiatrist to whom they will return upon completion of the study. Current CGAS score less than 50 EXCLUSION CRITERIA: Children with BPD Full scale IQ less than 80 Meets criteria for substance use disorder in the three months prior to randomization Currently pregnant, lactating, or sexually active without using a barrier method of contraception Previous treatment with clozapine History of seizures History of leukopenia or agranulocytosis Presence of an unstable medical illness INCLUSION CRITERIA: CONTROLS Control subjects will be age- and sex- matched to the BPD subjects. They will have normal physical and neurological examinations, and an identified primary care physician. Both control subjects and their first-degree relatives must be free of current or past psychopathology. EXCLUSION CRITERIA: CONTROLS I.Q less than 80; ongoing medical illness; neurologic disorder (including seizures); pregnancy; meeting past or present criteria for any diagnosis on the K-SADS-PL; meeting criterion A of post-traumatic stress disorder (exposure to a traumatic event).