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

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

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.

Study Overview

• Status: Completed
• Conditions: Diabetes; Schizophrenia; Cognitive Impairment; Insulin Resistance
• Intervention / Treatment: Drug: Pioglitazone; Behavioral: Life style diet group; Other: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 56
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10035
      • Nathan Kline Institute for Psychiatric Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Nathan Kline Institute for Psychiatric Research
• Investigators: Principal Investigator: Robert C Smith, MD PhD, NYU School of Medicine & Nathan Kline Institute for Psychiatric Research

Publications and helpful links

General Publications

• Smith RC et al Pioglitazone as a treatment for glucose and lipid abnormalities in schizophrenic patents: A double-blind placebo controlled trial. NCDEU 51lst Annual Meeting Oral Presentation Abstract Book, 2011, p.13.
• Smith RC, Jin H, Li C, Bark N, Shekhar A, Dwivedi S, Mortiere C, Lohr J, Hu Q, Davis JM. Effects of pioglitazone on metabolic abnormalities, psychopathology, and cognitive function in schizophrenic patients treated with antipsychotic medication: a randomized double-blind study. Schizophr Res. 2013 Jan;143(1):18-24. doi: 10.1016/j.schres.2012.10.023. Epub 2012 Nov 29.

Study record dates

Study Major Dates

• Study Start: May 1, 2005
• Primary Completion (Actual): January 1, 2010
• Study Completion (Actual): January 1, 2010

Study Registration Dates

• First Submitted: October 3, 2005
• First Submitted That Met QC Criteria: October 3, 2005
• First Posted (Estimate): October 4, 2005

Study Record Updates

• Last Update Posted (Actual): December 11, 2017
• Last Update Submitted That Met QC Criteria: November 9, 2017
• Last Verified: November 1, 2017

More Information

Terms related to this study

• Keywords: schizophrenia; insulin resistance; hyperglycemia; triglycerides; HDL; cholesterol; atypical antipsychotics; verbal memory
• Additional Relevant MeSH Terms: Mental Disorders; Glucose Metabolism Disorders; Metabolic Diseases; Schizophrenia Spectrum and Other Psychotic Disorders; Hyperinsulinism; Schizophrenia; Insulin Resistance; Hypoglycemic Agents; Physiological Effects of Drugs; Pioglitazone
• Other Study ID Numbers: 04T-584 Stanley Foundation; 04T-584 (Other Grant/Funding Number: Stanley Foundation)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No