This study will determine the effectiveness of clozapine versus olanzapine in treating people with schizophrenia that has not improved with treatment.

This is a two-year open-label, randomized trial of the comparative effectiveness of clozapine versus olanzapine in patients with treatment refractory schizophrenia. The objective is to determine whether in a naturalistic setting olanzapine is a logical treatment choice (before using the more toxic clozapine) for some treatment refractory patients.

Inclusion Criteria:

• Age 20-60 years;
• Diagnosis of treatment refractory schizophrenia or schizoaffective disorder;
• BPRS score > 21 (0-6) scale;
• Either two 6-8 week trials of typical neuroleptics given at a dosage of 600 mg/day of CPZ or its equivalent or one 6-8 week trial of an atypical antipsychotic at a reasonable dose (i.e. risperidone 4-6 mg/day);
• The patient (or the patient's authorized legal representative) must understand the nature of the study and sign the informed consent;
• Clinically appropriate for clozapine or olanzapine

Exclusion Criteria:

• Current substance abuse;
• Suicide or homicide risk;
• Pregnancy or lactation;
• History of seizures or blood dyscrasias