Cognitive Impairment, Diabetes, Insulin Resistance, Schizophrenia
Conditions
Keywords
atypical antipsychotics, hyperglycemia, triglycerides, HDL, cholesterol, insulin resistance, schizophrenia, verbal memory
Brief summary
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
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.
Interventions
DRUGPioglitazone
pioglitazone 30-45 mg/day
BEHAVIORALLife style diet group
life style diet education group 1x/week
OTHERPlacebo
placebo comparator capsules
Sponsors
Nathan Kline Institute for Psychiatric Research
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 2 Hour Glucose From Glucose Tolerance Test US Sample | between baseline and 3 months of study drug treatment | difference between 2 hr glucose for GTT test at baseline vs after 3 months of drug treatment |
| 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 | pre-treatment and during 3 months of treatment | serum high density lipoprotein (HDL) |
| Change From Baseline in Serum Glucose at 3 Months (3 Months-baseline) US Sample | pretreatment and during 3 months of drug treatment | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in RBANS List Recognition Scores at 3 Months (3 Months-baseline) US Sample | pre-treatment and 3 months of treatment | 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. |
| Change From Baseline in Serum HDL at 3 Months (3 Months-baseline) China Site | pretreatment and during 3 months of drug 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 | between baseline and 3 months of study drug treatment | difference between 2 hr glucose for GTT test at baseline vs after 3 months of drug treatment |
Countries
United States
Participant flow
Recruitment details
Recruitment at 6 U.S. sites and one site in Shanghai, China
Participants by arm
| Arm | Count |
|---|---|
| Pioglitazone pioglitazone | 30 |
| Placebo placebo | 24 |
| Total | 54 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Pioglitazone | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 47.2 years STANDARD_DEVIATION 9.06 | 48.5 years STANDARD_DEVIATION 10.17 | 47.7 years STANDARD_DEVIATION 9.8 |
| Region of Enrollment China | 5 participants | 5 participants | 10 participants |
| Region of Enrollment United States | 25 participants | 19 participants | 44 participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 6 Participants |
| Sex: Female, Male Male | 27 Participants | 21 Participants | 48 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 31 | 2 / 25 |
| serious Total, serious adverse events | 0 / 31 | 0 / 25 |
Outcome results
Primary
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
Time frame: between baseline and 3 months of study drug treatment
Population: Data is from participants at U.S. sites N=44, Pioglitazone =25, Placebo =19, who had values of serum glucose at 2-hour point in glucose tolerance test at baseline and three months follow-up. See table 2 of published paper and its supplementary data paper cited in reference for further details.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pioglitazone | 2 Hour Glucose From Glucose Tolerance Test US Sample | -24.19 mg/dL | Standard Error 17.03 |
| Placebo | 2 Hour Glucose From Glucose Tolerance Test US Sample | 15.19 mg/dL | Standard Error 17.75 |
Primary
Change From Baseline in Serum Glucose at 3 Months (3 Months-baseline) US Sample
Time frame: pretreatment and during 3 months of drug treatment
Population: Data is from participants at U.S. sites N=44, Pioglitazone =25, Placebo =19, who had values of serum glucose at baseline and three months follow-up. See table 2 of published paper and its supplementary data paper cited in reference for further details.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pioglitazone | Change From Baseline in Serum Glucose at 3 Months (3 Months-baseline) US Sample | 0.02 mg/dL | Standard Error 8.14 |
| Placebo | Change From Baseline in Serum Glucose at 3 Months (3 Months-baseline) US Sample | 24.20 mg/dL | Standard Error 8.63 |
Primary
Change From Baseline in Serum HDL at 3 Months (3 Months-baseline) US Sample
serum high density lipoprotein (HDL)
Time frame: pre-treatment and during 3 months of treatment
Population: Data is from participants at U.S. sites N=44, Pioglitazone =25, Placebo =19, who had values of HDL at baseline and three months followup. See table 2 of published paper and its supplementary data paper cited in reference for further details.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pioglitazone | Change From Baseline in Serum HDL at 3 Months (3 Months-baseline) US Sample | 4.62 mg/dL | Standard Error 1.77 |
| Placebo | Change From Baseline in Serum HDL at 3 Months (3 Months-baseline) US Sample | -2.59 mg/dL | Standard Error 2.11 |
Primary
Change From Baseline in Serum Triglycerides at 3 Months ( 3 Months-baseline) US Sample
Time frame: pre-treatment and during 3 months of treatment
Population: Data is from participants at U.S. sites N=44, Pioglitazone =25, Placebo =19, who had values of triglycerides at baseline and three months followup. See table 2 of published paper given in reference for further details.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pioglitazone | Change From Baseline in Serum Triglycerides at 3 Months ( 3 Months-baseline) US Sample | -49.65 mg/dL | Standard Error 24.01 |
| Placebo | Change From Baseline in Serum Triglycerides at 3 Months ( 3 Months-baseline) US Sample | 30.99 mg/dL | Standard Error 26.82 |
Secondary
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
Time frame: between baseline and 3 months of study drug treatment
Population: Data is from participants at china site N=10, Pioglitazone =5, Placebo =5, who had values of serum glucose at 2-hour point in glucose tolerance test at baseline and three months follow-up. See published paper and its supplementary data paper cited in reference for further details.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pioglitazone | 2 Hour Glucose From Glucose Tolerance Test China Sample | -6.82 mg/dL | Standard Error 21.28 |
| Placebo | 2 Hour Glucose From Glucose Tolerance Test China Sample | -40.72 mg/dL | Standard Error 21.28 |
Secondary
Change From Baseline in Serum Glucose at 3 Months ( 3 Months -Baseline) China Sample
Time frame: pretreatment and during 3 months of drug treatment
Population: Data is from participants at China site N=10, Pioglitazone =5, Placebo =5, who had values of fasting glucose at baseline and three months follow-up. See published paper and its supplementary data paper cited in reference for further details.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pioglitazone | Change From Baseline in Serum Glucose at 3 Months ( 3 Months -Baseline) China Sample | -13.33 mg/dL | Standard Error 11.08 |
| Placebo | Change From Baseline in Serum Glucose at 3 Months ( 3 Months -Baseline) China Sample | -11.5 mg/dL | Standard Error 3.44 |
Secondary
Change From Baseline in Serum HDL at 3 Months (3 Months-baseline) China Site
Time frame: pretreatment and during 3 months of drug treatment
Population: Data is from participants at china. site N=10, Pioglitazone =5, Placebo =5, who had values of HDL at baseline and three months followup. See of published paper and its supplementary data paper cited in reference for further details
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pioglitazone | Change From Baseline in Serum HDL at 3 Months (3 Months-baseline) China Site | 6.52 mg/dL | Standard Error 1.14 |
| Placebo | Change From Baseline in Serum HDL at 3 Months (3 Months-baseline) China Site | 7.72 mg/dL | Standard Error 3.37 |
Secondary
Change From Baseline in Serum Triglycerides at 3 Months (3 Months-baseline) China Sample
Time frame: pretreatment and during 3 months of drug treatment
Population: Data is from participants at China site N=10, Pioglitazone =5, Placebo =5, who had values of triglycerides at baseline and three months followup. See published paper and its supplementary data paper cited in reference for further details.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pioglitazone | Change From Baseline in Serum Triglycerides at 3 Months (3 Months-baseline) China Sample | 32.56 mg/dL | Standard Error 24.76 |
| Placebo | Change From Baseline in Serum Triglycerides at 3 Months (3 Months-baseline) China Sample | -79.12 mg/dL | Standard Error 40.72 |
Secondary
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.
Time frame: pre-treatment and 3 months of treatment
Population: Data is from participants at U.S. sites N=43, Pioglitazone =25, Placebo =18, who had scores of RBANS List learning at 2-hour point at baseline and three months follow-up. See table 2 of published paper and its supplementary data paper cited in reference for further details.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pioglitazone | Change in RBANS List Recognition Scores at 3 Months (3 Months-baseline) US Sample | 0.27 Units on RBANS scale | Standard Error 0.41 |
| Placebo | Change in RBANS List Recognition Scores at 3 Months (3 Months-baseline) US Sample | -1.11 Units on RBANS scale | Standard Error 0.44 |