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

Study Overview
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Brief Summary
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This is a study with an approved drug for treating type 2 diabetes, for its effects on treating glucose and lipid abnormalities in patients being treated with first or second-generation antipsychotics, and comparison of effects of this drug with another treatment lifestyle modification. Patients who meet inclusion criteria will be treated with pioglitazone for 12 weeks. They will be evaluated for fasting glucose and lipids, glucose-tolerance tests, and neurocognitive battery and tests of verbal memory at baseline and during treatment with pioglitazone.

Detailed Description
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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.

Official Title
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Pioglitazone as a Treatment for Lipid and Glucose Abnormalities In Patients With Schizophrenia Treated With Antipsychotic Medication And Potential Effects on Cognitive Function

Conditions
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Diabetes, Schizophrenia, Insulin Resistance, Cognitive Impairment

Intervention / Treatment
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* Drug: Pioglitazone
* Behavioral: Life style diet group
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Patients will have evidence of: 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; Triglyceride levels > 120 mg/dL and/or HDL levels < 40 mg/dL Exclusion Criteria: Diabetes mellitus, type 1 Recent diabetic ketoacidosis; 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); 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; Congestive heart failure (Class III or IV cardiac status) or history of MI in medical record (because pioglitazone can increase blood volume slightly); Hematocrit greater than 10% below normal (hematocrit may be decreased 2 to 4% due to increased plasma volume); Female patients on current oral contraceptives (because pioglitazone may interfere with effects of some oral contraceptives); Patients taking ketoconazole, 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). Patients are not concomitantly treated with aripiprazole or ziprasidone.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Pioglitazone and life-style group<br>Pioglitazone (30-45 mg/daily) plus life-style diet group | Drug: Pioglitazone<br>* pioglitazone 30-45 mg/day<br>* Other names: Actos;Behavioral: Life style diet group<br>* life style diet education group 1x/week<br>|
| Placebo Comparator: Placebo and life style group<br>Placebo capsules daily plus life-style diet group | Behavioral: Life style diet group<br>* life style diet education group 1x/week<br>Other: Placebo<br>* placebo comparator capsules<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Serum Triglycerides at 3 Months ( 3 Months-baseline) US Sample |  | pre-treatment and during 3 months of treatment | 
| Change From Baseline in Serum HDL at 3 Months (3 Months-baseline) US Sample | serum high density lipoprotein (HDL) | pre-treatment and during 3 months of treatment | 
| Change From Baseline in Serum Glucose at 3 Months (3 Months-baseline) US Sample |  | pretreatment and during 3 months of drug treatment | 
| 2 Hour Glucose From Glucose Tolerance Test US Sample | difference between 2 hr glucose for GTT test at baseline vs after 3 months of drug treatment | between baseline and 3 months of study drug treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in RBANS List Recognition Scores at 3 Months (3 Months-baseline) US Sample | The scale is Repeatable Battery for the Assessment to Neuropsychological Status (RBANS). This scale measure cognitive function in patients with schizophrenia. Range for list learning sub-score is 0 to 20 . Higher values indicate better performance. For change score (3 months -baseline) positive values indicate improved performance for this cognitive function and negative values indicate poorer performance on this cognitive function. | pre-treatment and 3 months of treatment | 
| Change From Baseline in Serum Glucose at 3 Months ( 3 Months -Baseline) China Sample |  | pretreatment and during 3 months of drug treatment | 
| Change From Baseline in Serum Triglycerides at 3 Months (3 Months-baseline) China Sample |  | pretreatment and during 3 months of drug treatment | 
| 2 Hour Glucose From Glucose Tolerance Test China Sample | difference between 2 hr glucose for GTT test at baseline vs after 3 months of drug treatment | between baseline and 3 months of study drug treatment | 
| Change From Baseline in Serum HDL at 3 Months (3 Months-baseline) China Site |  | pretreatment and during 3 months of drug treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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atypical antipsychotics, hyperglycemia, triglycerides, HDL, cholesterol, insulin resistance, schizophrenia, verbal memory