The objectives of this 15-day study are:

1. To compare steady-state trough plasma concentrations of clozapine and its metabolite norclozapine when given once daily and twice daily (at the same total daily dose)

2. To determine if frequency of clozapine administration has an effect on:

   1. Symptoms of schizophrenia
   2. Adverse effects of clozapine
   3. Fasting blood glucose, lipids, creatinine, and urea
   4. Weight and waist circumference

It is important that clinicians do everything possible to optimize the use of clozapine in individuals with treatment-resistant schizophrenia. To our knowledge, there are no published studies evaluating whether twice daily administration of clozapine is better than once daily administration in terms of effectiveness and tolerability. Although this may seem trivial at first, when we consider that clozapine has a relatively short half-life and dissociates quickly from the dopamine D2 receptor, it justifies further consideration. It takes on even more significance knowing that the established threshold clozapine plasma concentration for therapeutic response (i.e., 350-420 ng/ml) was determined using steady-state trough plasma samples (i.e., approximately 12 hours after the evening dose) in patients administered clozapine twice rather than once daily.

Inclusion Criteria:

• Participants must be between the ages of 19 - 65
• Participants must be fluent in English
• Participants must have a psychiatric diagnosis and are currently treated with clozapine once daily in the evening
• Participants must be on a stable dose of clozapine for at least one week to ensure steady-state has been achieved

Exclusion Criteria:

• Participants who are hypersensitive to clozapine
• Participants who are pregnant or lactating
• Participants who are of childbearing age and not using reliable contraception
• Participants who have postsurgical complications of the gastrointestinal tract that might impair absorption
• Participants who have any clinically relevant abnormalities of laboratory parameters
• Participants who have had a potent CYP1A2 metabolic inducer (e.g., carbamazepine; rifampin) or inhibitor (e.g., amiodarone; cimetidine; efavirenz; fluoroquinolone antibiotics; ticlopidine) added to and/or removed from their medication regimen in the past two weeks