Schizophrenia
Conditions
Keywords
Schizophrenia, Glucose Metabolism, Insulin Resistance
Brief summary
We propose an eight-week, double-blind, placebo-controlled trial of rosiglitazone in schizophrenia subjects treated with clozapine using Bergman's Minimal Model (MINMOD) intravenous glucose tolerance test. Bergman's Minimal Model analysis with frequent sampled intravenous glucose tolerance test (FSIVGTT) provides a sensitive and reliable method to measure glucose effectiveness, insulin secretion and insulin sensitivity. The MINMOD determines the relationship between insulin sensitivity, insulin secretion and the degree of obesity and can be used to study drug effects upon these variables.
Detailed description
This study is an eight-week, double-blind, placebo-controlled trial of rosiglitazone in schizophrenia subjects treated with clozapine using Bergman's Minimal Model Analysis (MINMOD) frequent sampled intravenous glucose tolerance test (FSIVGTT) for examination of glucose metabolism. Rosiglitazone, used for the treatment of type 2 diabetes, improves glycemic control by improving insulin sensitivity in target tissues while increase glucose uptake and improving signaling between insulin and glucose transporters. The MINMOD determines the relationship between insulin sensitivity, insulin secretion and the degree of obesity and can be used to study drug effects upon these variables. The computer program estimates glucose effectiveness (SG), insulin sensitivity (SI), and the acute insulin response to glucose (AIRG) from glucose and insulin values measured during the FSIVGTT. The site for subject enrollment, clinical assessment and collection of blood samples at weeks 2, 4, and 6 will be at the Freedom Trail Clinic of the Erich Lindemann Mental Health Center. The FSIVGTT and blood samples at baseline and week 8 will be conducted at the Mallinckrodt General Clinical Research Center at Massachusetts General Hospital. Subjects will include 50 clozapine treated patients with the diagnosis of schizophrenia or schizoaffective disorder. Subjects will be matched according to baseline fasting glucose. Subjects will be maintained on their pre-study medication. During the baseline assessment, a member of the research team will conduct the PANSS (Positive and Negative Symptom Subscale) and HAM-D (Hamilton Rating Scale for Depression) which will be repeated at weeks 4 and 8 to determine baseline and subsequent changes in psychopathology. The neuropsychological battery will be administered at baseline and week 8 and will consist of: North America Adult Reading Test, Trail Making, Degraded Stimulus Continuous Performance Test, California Verbal Learning Test, Faces and Family Picture subtests from WMS-III, Wisconsin Card Sorting Test, Letter and Category Fluency, Letter-Number Sequencing, and Grooved Peg Board. Baseline medical evaluation will include weight, height, vital signs, AIMS score, a 12-lead EKG and a physical examination. Subjects will be instructed to eat a diet high in carbohydrates for three days before the FSIVGTT. They are instructed to fast for 12 hours preceding the test. On the morning of the test, subjects will be admitted to the General Clinical Research Center at Massachusetts General Hospital. A nutritional assessment will be performed. Baseline blood samples for fasting glucose, basic chemistry profiles, liver enzymes, complete blood count (cbc), insulin, prolactin, lipid profile, glycohemoglobin, leptin, clozapine serum levels and cortisol will be drawn. Glucose 0.3 g/kg body weight will be infused. Approximately 35 2 cc blood samples will be withdrawn for measurement of glucose and insulin concentration. At minute 20, 0.05 units/kg of insulin will be administered as an intravenous bolus injection. Following baseline FSIVGTT, subjects will be randomized, double-blind, to either rosiglitazone or placebo. Subjects randomized to receive medication will receive rosiglitazone 4mg po qd for eight weeks or until study end. Subjects will be monitored for symptoms of diabetes at weeks 2, 4, and 8. Subjects will be evaluated at weeks 2, 4, and 8 including measurements of blood pressure, pulse and weight. Adverse events will be monitored at weeks 2, 4, and 8 with the AMDP-5, a survey of side effects and somatic symptoms. The Medical Outcomes Study Short Form-12 (SF-12) will be used to measure general health status and function. The SF-12 will be performed at baseline, weeks 4, and 8 or study end. A cbc will be performed every two weeks, consistent with the requirements for treatment with clozapine. At week four, a fasting glucose, insulin level, and liver function tests will be performed. At the end of the eighth week, the FSIVGTT will be repeated and blood samples will be obtained for fasting glucose, basic chemistry profiles, liver enzymes, complete blood count (cbc), insulin, prolactin, lipid profile, glycohemoglobin, leptin, clozapine serum levels and cortisol. All other aspects of the subjects care will be treatment as usual. Potential risks associated with an intravenous line include bruising at the site, bleeding and the risk of infection. During the procedure patient may experience symptoms of low blood glucose including lightheadedness, dizziness, weakness, irritability, sweating, tremor, tachycardia, anxiety, and hunger. The amount of blood drawn with each FSIVGTT is approximately 150 cc. A low risk of anemia exists secondary to the FSIVGTT; anemia has also been a side effect of treatment with rosiglitazone. Treatment with rosiglitazone has been associated with side effects including accidental injury (cuts and abrasions), headache, back pain, anemia, edema, weight gain, decreased white blood cell count, increases in total cholesterol, LDL, and HDL and decreases in free fatty acids. Phlebotomy may produce discomfort, bruising, and rarely, infection. While the clinical assessment may be stressful, the questions contained in the SCID and PANSS do not differ from those asked in routine clinical evaluations. Potential benefits to the subject include a comprehensive diagnostic re-evaluation, screening blood tests, and estimation of risk of diabetes. The results of the tests will be shared with patients and clinicians and may contribute to medical management by helping the patient's physician in deciding if an intervention is required to reduce the risk of diabetes. An increased understanding of the process by which clozapine induces glucose intolerance and the awareness that diabetes and its complications can be prevented with concomitant treatment with an insulin sensitizer are potential benefits to this population.
Interventions
DRUGrosiglitazone
Rosiglitazone 4mg, one capsule per day for eight weeks
DRUGplacebo
matched placebo for rosiglitazone 4mg/day
Sponsors
National Alliance for Research on Schizophrenia and Depression
Stanley Medical Research Institute
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Male or female * Age 18-65 years * Diagnosis of schizophrenia, any subtype, schizoaffective disorder, any subtype or schizophreniform disorder * Well established compliance with out-patient medications * Current treatment with clozapine for a minimum of one year * Evidence of insulin resistance: impaired fasting glucose (glucose ≥100 mg/dl) or hyperinsulinemia (fasting insulin ≥ 15 ng/dl) or a HOMA-IR (homeostasis model assessment for insulin resistance) (fasting glucose X fasting insulin/22.5) ≥2 or a SI (insulin sensitivity index)
Exclusion criteria
* Inability to provide informed consent * Current substance abuse * Significant medical illness, including congestive heart failure, severe cardiovascular disease, renal disease (serum creatinine \> 1.5), anemia (Hemoglobin \< 11.0 gm/dL) or psychiatrically unstable * Severe hepatic impairment, active liver disease or increased serum transaminase levels (ALT\>2.0X upper limit of normal) If at any time, ALT increases to 2X ULN, the subject's participation in the study will be terminated. * Women of child bearing potential who are pregnant, breastfeeding, or who are unwilling or unable to use an effective form of birth control during the entire study * Treatment with agents that induce weight loss * History of diabetes mellitus or thyroid disease * Current treatment with an oral hypoglycemic agent or insulin * Known hypersensitivity to rosiglitazone or any of its components * Fasting Glucose \>126 mg/dL11. Treatment with other atypical antipsychotic agents thought to impair glucose metabolism (olanzapine) or low potency conventional agents (thioridazine, chlorpromazine)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Insulin Sensitivity | baseline, week 8 | Insulin Sensitivity (IS) was assessed using a Frequently Sampled Intravenous Glucose Tolerance Test (FSIVGTT), performed at Baseline and at week 8 (study endpoint). Subjects in the Rosiglitazone treatment arm were compared to subjects in the placebo treatment arm on their change in IS between Baseline and week 8. SI was calculated from plasma glucose and serum insulin values using the MINMOD Millennium computer program. SI represents the increase in net fractional glucose clearance rate per unit change in serum insulin concentration after the intravenous glucose load (microUnits/mL). |
| Change From Baseline on Glucose Utilization (SG) | baseline, week 8 | Glucose utilization (SG) was assessed using a Frequently Sampled Intravenous Glucose Tolerance Test (FSIVGTT), performed at Baseline and at week 8 (study endpoint). Subjects in the Rosiglitazone treatment arm were compared to subjects in the placebo treatment arm on their change in SG between Baseline and week 8. SG was calculated from plasma glucose and serum insulin values using the MINMOD Millennium computer program. SG represents the net fractional glucose clearance rate because of the increase in glucose independent of any increase in circulating insulin concentrations above baseline. |
| Change From Baseline in Acute Insulin Response to Glucose (AIRG) | baseline, week 8 | Acute insulin response to glucose (AIRG) was assessed using a Frequently Sampled Intravenous Glucose Tolerance Test (FSIVGTT), performed at Baseline and at week 8 (study endpoint). Subjects in the Rosiglitazone treatment arm were compared to subjects in the placebo treatment arm on their change in SG between Baseline and week 8. AIRG was calculated from plasma glucose and serum insulin values using the MINMOD Millennium computer program. AIRG measures the acute(0-10 min) beta\\ cell response to a glucose load calculated by the areas under the curve higher than basal insulin values. The AIRG was assessed as the incremental area under the curve (calculated by the trapezoid rule) from 0 to 10 min of the FSIVGTT. |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited from the Freedom Trial Clinic at the Erich Lindemann Mental Health Center and were studied at the Mallinckrodt General Clinical Research Center (GCRC) at Massachusetts General Hospital (MGH), Boston.
Participants by arm
| Arm | Count |
|---|---|
| Rosiglitazone rosiglitazone 4mg/day | 9 |
| Placebo matched placebo for rosiglitazone 4mg/day | 11 |
| Total | 20 |
Baseline characteristics
| Characteristic | Placebo | Rosiglitazone | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 9 Participants | 20 Participants |
| Age, Continuous | 39.36 years STANDARD_DEVIATION 7.06 | 41.11 years STANDARD_DEVIATION 10.29 | 40.15 years STANDARD_DEVIATION 8.46 |
| Region of Enrollment United States | 11 participants | 9 participants | 20 participants |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 5 Participants |
| Sex: Female, Male Male | 8 Participants | 7 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 9 | 0 / 11 |
| serious Total, serious adverse events | 0 / 9 | 0 / 11 |
Outcome results
Primary
Change From Baseline in Acute Insulin Response to Glucose (AIRG)
Acute insulin response to glucose (AIRG) was assessed using a Frequently Sampled Intravenous Glucose Tolerance Test (FSIVGTT), performed at Baseline and at week 8 (study endpoint). Subjects in the Rosiglitazone treatment arm were compared to subjects in the placebo treatment arm on their change in SG between Baseline and week 8. AIRG was calculated from plasma glucose and serum insulin values using the MINMOD Millennium computer program. AIRG measures the acute(0-10 min) beta\\ cell response to a glucose load calculated by the areas under the curve higher than basal insulin values. The AIRG was assessed as the incremental area under the curve (calculated by the trapezoid rule) from 0 to 10 min of the FSIVGTT.
Time frame: baseline, week 8
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rosiglitazone | Change From Baseline in Acute Insulin Response to Glucose (AIRG) | -151 Units/mL per 10 minutes | Standard Deviation 457 |
| Placebo | Change From Baseline in Acute Insulin Response to Glucose (AIRG) | 19 Units/mL per 10 minutes | Standard Deviation 22 |
p-value: 0.21ANCOVA
Primary
Change From Baseline in Insulin Sensitivity
Insulin Sensitivity (IS) was assessed using a Frequently Sampled Intravenous Glucose Tolerance Test (FSIVGTT), performed at Baseline and at week 8 (study endpoint). Subjects in the Rosiglitazone treatment arm were compared to subjects in the placebo treatment arm on their change in IS between Baseline and week 8. SI was calculated from plasma glucose and serum insulin values using the MINMOD Millennium computer program. SI represents the increase in net fractional glucose clearance rate per unit change in serum insulin concentration after the intravenous glucose load (microUnits/mL).
Time frame: baseline, week 8
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rosiglitazone | Change From Baseline in Insulin Sensitivity | 3.2 microUnits/mL | Standard Deviation 3.9 |
| Placebo | Change From Baseline in Insulin Sensitivity | 0.4 microUnits/mL | Standard Deviation 0.1 |
p-value: 0.08ANCOVA
Primary
Change From Baseline on Glucose Utilization (SG)
Glucose utilization (SG) was assessed using a Frequently Sampled Intravenous Glucose Tolerance Test (FSIVGTT), performed at Baseline and at week 8 (study endpoint). Subjects in the Rosiglitazone treatment arm were compared to subjects in the placebo treatment arm on their change in SG between Baseline and week 8. SG was calculated from plasma glucose and serum insulin values using the MINMOD Millennium computer program. SG represents the net fractional glucose clearance rate because of the increase in glucose independent of any increase in circulating insulin concentrations above baseline.
Time frame: baseline, week 8
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rosiglitazone | Change From Baseline on Glucose Utilization (SG) | .002 min^-1 | Standard Deviation 0.002 |
| Placebo | Change From Baseline on Glucose Utilization (SG) | -0.01 min^-1 | Standard Deviation 0.01 |
p-value: 0.05ANCOVA