Efficacy of Pimozide Augmentation for Clozapine Partial Response

This is a 12 week outpatient study for patients with schizophrenia who are on Clozapine, but continue to experience symptoms. The purpose of this project is to find out if small doses of pimozide (an antipsychotic medication, taken by mouth) will be helpful in reducing symptoms (such as hearing voices, having trouble in organizing your thoughts, lack of interest in life events and social activities), compared to placebo (an inactive substance, "sugar pill"), when added to clozapine in patients with schizophrenia.

The participant will be asked to come in once a week to meet with the research staff and study doctor. The participant will continue to see your regular clinician during this study for all normal appointments. The participant will remain on your current medications throughout the study. During the study you will be randomly selected to be put on a small dose of Pimozide or placebo.

If you choose to participate, you will first have screening tests to find out if you are eligible. The study physician will do a number of tests including a physical examination, a routine medical history, lab tests for blood and urine, and EKG (to monitor your heart) and interviews about your physical and mental health.

At each visit you will complete an EKG (to monitor your heart), vital signs, and discuss how you are feeling with the research staff and doctor. Once a month, we will also conduct a slightly longer interview with you about your symptoms and draw one tube of blood to check your Clozapine level. At the beginning and end of the study, you will do some pencil and paper games called "Neurocognitive tests".

If you are interested in participating in this study, we will go over it in greater detail with you, including the possible benefits and risks associated with participating. We will make sure you understand the study before you begin. This study is completely voluntary, which means that you can choose to stop participating in the study at any time.

Eligibility Criteria:
Inclusion Criteria:

* Diagnosis of schizophrenia or schizoaffective disorder.
* A minimum Brief Psychiatric Rating Scale (BPRS) score of 35 and a BPRS psychotic symptom cluster score of at least 8.
* Currently taking clozapine with a blood level between 350-1000 ng/ml and on a stable dose of clozapine for the past 2 weeks.
* Able to give informed consent.

Exclusion Criteria:

* A history of significant medical/neurological disease such as thyroid, renal, hepatic abnormality, seizure disorder.
* History of Neuroleptic Malignant Syndrome.
* Current substance abuse determined by urine toxicology.
* Cardiac arrhythmia, sinus bradycardia (heart rate less than 60/min), sinus tachycardia (heart rate greater than 110/min), supraventricular tachycardia, ventricular tachycardia, Wolff-Parkinson-White Syndrome, first, second, third degree atrioventricular (AV) block, atrial fibrillation, atrial flutter and junctional complexes. in baseline electrocardiogram (EKG). Study doctors will examine the EKGs and consult with an internist/cardiologist as needed.
* on EKG: QTc \> 450 ms.
* Current use of macrolide antibiotics (e.g., erythromycin, clarithromycin), azole antifungal agents (e.g., ketoconazole, itraconazole), protease inhibitors (e.g., ritonavir, indinavir), nefazodone, and other medications that are associated with prolonged QTc.
* Current use of antipsychotics other than clozapine.
* Current use of sertraline.
* IQ level below 70.
* At high risk for suicidal/homicidal behavior.
* Pregnancy, lack of birth control for females of childbearing age (female patients must report use of effective method for birth control such as birth control pills, condoms, barrier methods, abstinence or have written statement from their doctors that they are medically sterile).
* Non-English speaking.