Pioglitazone as a Treatment for Lipid and Glucose Abnormalities In Patients With Schizophrenia

The aim of this study is to investigate the effects of pioglitazone added to weight-lifestyle
intervention vs. placebo plus lifestyle intervention on reversing or reducing impaired or
abnormal triglycerides, HDL and glucose metabolism in schizophrenics treated with first or
second-generation antipsychotics.. Another aim is to examine the effects of impaired glucose
metabolism on verbal memory and other cognitive function in schizophrenic patients treated
with these medications and the relationship to improvements in impaired glucose metabolism to
impairments in cognitive function. Clozapine and olanzapine, and some other first or
second-generation antipsychotics effective for treating schizophrenia and bipolar disorders,
have been reported to be associated with increased incidence of diabetic type metabolic
abnormalities, decreases in insulin sensitivity, and abnormal glucose tolerance tests. This
can lead to the development of type 2 diabetes and also abnormal lipid metabolic levels which
can lead to atherosclerotic changes and increased risk of cardiovascular disease and other
diabetes related complications. Drug treatments which could reduce or correct these diabetic
metabolic changes would permit many patients to continue to receive the benefits of these
antipsychotic medications with reduced drug-induced comorbidity. Previous research using
non-psychotic subjects has shown that diabetes and impaired glucose tolerance are associated
with cognitive impairments, especially in verbal memory, and provides a rationale for testing
whether corrections of impaired glucose metabolism are associated with cognitive improvements
in schizophrenic patients.

Inclusion Criteria:

1. Patients will be males or females, 18-70 yrs of age, with a diagnosis of schizophrenia
or schizoaffective disorder, and currently being treated with olanzapine or clozapine.

2. Patients will have evidence of:

1. glucose levels indicating at least impaired fasting glucose: fasting glucose 100
mg/dL or 2 hr glucose tolerance test 140 mg/dL, or current treatment with oral
antidiabetic drugs with history of hyperglycemia;

2. Triglyceride levels > 120 mg/dL and/or HDL levels < 40 mg/dL

Exclusion Criteria:

1. Diabetes mellitus, type 1

2. Recent diabetic ketoacidosis;

3. Patients not currently treated with oral antidiabetic drugs but fasting is glucose 140
mg/dL [WHO criteria] on repeat testing in last three months, or random blood glucose
>200 mg/dL plus 2 hr glucose on GTT >200 mg/dL; (these patients may need more
immediate treatment with antidiabetic drugs and it is less certain if weight-lifestyle
treatment would be effective in treating such high glucose levels);

4. Patients with active liver disease with clinical abnormalities which need current
treatment, or liver enzymes (Alt) 3 times upper limit for normal values in chart
records in last year, or patients who are recorded as positive for hepatitis C;

5. Congestive heart failure (Class III or IV cardiac status) or history of MI in medical
record (because pioglitazone can increase blood volume slightly);

6. Hematocrit greater than 10% below normal (hematocrit may be decreased 2 to 4% due to
increased plasma volume);

7. Female patients on current oral contraceptives (because pioglitazone may interfere
with effects of some oral contraceptives);

8. Patients taking ketoconazole,

9. Patients who have started on atorvastatin or gemfibrozil in the past 2 months or have
had a dose increase in atorvastatin in the last month (since these drugs can also
lower triglycerides and raise HDL, recent start of therapy with these drugs could be a
confound).

10. Patients are not concomitantly treated with aripiprazole or ziprasidone.