This study will assess the effectiveness of pimozide in enhancing the effects of clozapine in the treatment of schizophrenia.

A significant number of schizophrenics exhibit partial or no response to typical antipsychotic medications. Clozapine has been shown to be more effective in treating schizophrenia than typical antipsychotic drugs. However, only an estimated 30% to 60% of people who are unresponsive to treatment with typical antipsychotics will respond to treatment with clozapine. Taking clozapine with pimozide, an antipsychotic drug, can increase clozapine's effects. However, sufficient research on this approach has not yet been performed. This study will assess the effectiveness of pimozide in enhancing the effects of clozapine in the treatment of schizophrenia.

Participants in this double-blind study will receive a stable dose of clozapine for eight weeks prior to enrollment. For the first 4 weeks following enrollment, baseline measurements will be taken. Once a week, participants will report to the study site, where symptom severity, cognitive ability, and functional status, including reading level, will be assessed. In addition, participants will receive a standard medical examination, which will include blood tests and an EKG. Upon completion of this initial phase, participants will be randomly assigned to one of two treatment groups: clozapine combined with pimozide; or clozapine combined with placebo. This phase will last for 12 weeks. Study visits will continue to occur weekly, and will be used to re-assess the measurements obtained during baseline. In addition, participants will have an EKG at each study visit for the first 4 weeks of treatment. All baseline measurements will be repeated in Week 12.

Inclusion Criteria:

• Diagnosis of schizophrenia according to DSM-IV criteria
• Any schizoaffective disorder or subtype
• Score greater than 60 on the Positive and Negative Syndrome Scale (PANSS)
• Currently taking clozapine
• Score of four or higher on two or more items from the positive symptom subscale of the PANSS
• Score of 4 or greater on the Clinical Global Impression (CGI) scale
• Clozapine plasma level greater than 378 µg/ml
• Stable dose of clozapine demonstrated to have been associated with a clozapine plasma level greater than 378 µg/ml for at least eight weeks
• Able to read at an 8th grade level or above

Exclusion Criteria:

• History of unstable coronary artery disease
• Congestive heart failure
• History of long Q-T syndrome
• History of cardiac arrhythmia
• History of cardiac conduction delay
• Baseline QT correction score greater than 0.425 seconds
• Liver disease
• History of stroke
• History of Neuroleptic Malignant Syndrome
• Hypokalemia
• Hypocalcemia
• Current blindness, deafness, language difficulties, or any other disability which may prevent participation or cooperation in the study
• Current suicidal or homicidal thoughts
• Currently abusing psychoactive substances
• Currently receiving antidepressants, thymoleptics, L-DOPA, buspirone, or antipsychotics other than clozapine (Valproic acid and Divalproex sodium are not criteria for exclusion)