Hyperglycemia, Schizoaffective Disorder, Schizophrenia, Type 2 Diabetes Mellitus
Conditions
Keywords
control, risperidone, olanzapine, quetiapine, ziprasidone
Brief summary
This project aims to a) evaluate the effects of selected antipsychotic medications on insulin action in skeletal muscle (glucose disposal), liver (glucose production) and adipose tissue (whole-body lipolysis), b) evaluate the effects of selected antipsychotic medications on abdominal adipose tissue mass, total body fat and total fat-free mass, and c) explore the longitudinal effects of treatment with selected antipsychotics on glucose tolerance, lipid profiles, abdominal adipose tissue mass, total body fat and total fat-free mass. These hypotheses will be evaluated by measuring 1) whole-body glucose and lipid kinetics with the use of gold-standard stable isotope tracer methodology, 2) body composition using dual energy x-ray absorptiometry and magnetic resonance imaging, and 3) longitudinal changes in glucose tolerance and lipid profiles. The aims will be addressed in non-diabetic schizophrenia patients chronically treated with risperidone, olanzapine, clozapine, quetiapine, ziprasidone, or haloperidol, and untreated healthy controls. Re-evaluations will also be performed in patients who are randomized to switch from their current antipsychotic (from the above groups) to risperidone, olanzapine, quetiapine, or ziprasidone for 6 months. Relevant data is critically needed to target basic research, identify long-term cardiovascular consequences, and plan therapeutic interventions.
Detailed description
Hyperglycemia and type 2 diabetes mellitus are more common in schizophrenia than in the general population. Type 2 diabetes mellitus is characterized by disturbances in insulin action on skeletal muscle, liver and adipose tissue. Diabetes causes increased morbidity and mortality due to acute (e.g., diabetic ketoacidosis) and long-term (e.g., cardiovascular disease) complications. The combination of hyperglycemia, dyslipidemia and abdominal adiposity is even more strongly associated with increased cardiovascular morbidity and mortality. The association of type 2 diabetes and hyperglycemia with schizophrenia was first noted prior to the introduction of antipsychotic medications, suggesting that these patients may be at increased risk. Since then, however, additional glucoregulatory abnormalities (e.g., new onset diabetes), dyslipidemia, and increased weight and adiposity have all been associated with antipsychotic medications. Concern about antipsychotic effects on glucose, lipids and adiposity has increased recently, focusing on the widely-used newer medications, clozapine and olanzapine. Increased abdominal adiposity can secondarily decrease insulin sensitivity and antipsychotics can increase adiposity. However, medication effects on glucose control and insulin action may also occur independent of differences in adiposity. This project aims to a) evaluate the effects of selected antipsychotic medications on insulin action in skeletal muscle (glucose disposal), liver (glucose production) and adipose tissue (whole-body lipolysis), b) evaluate the effects of selected antipsychotic medications on abdominal adipose tissue mass, total body fat and total fat-free mass, and c) explore the longitudinal effects of treatment with selected antipsychotics on glucose tolerance, lipid profiles, abdominal adipose tissue mass, total body fat and total fat-free mass. These hypotheses will be evaluated by measuring 1) whole-body glucose and lipid kinetics with the use of gold-standard stable isotope tracer methodology, 2) body composition using dual energy x-ray absorptiometry and magnetic resonance imaging, and 3) longitudinal changes in glucose tolerance and lipid profiles. The aims will be addressed in non-diabetic schizophrenia patients chronically treated with risperidone, olanzapine, clozapine, quetiapine, ziprasidone, or haloperidol, and untreated healthy controls. Re-evaluations will also be performed in patients who are randomized to switch from their current antipsychotic (from the above groups) to risperidone, olanzapine, quetiapine, or ziprasidone for 6 months. Relevant data is critically needed to target basic research, identify long-term cardiovascular consequences, and plan therapeutic interventions.
Interventions
DRUGrisperidone
randomized to 12 week trial of risperidone.
DRUGolanzapine
randomized to 12 week trial of olanzapine.
DRUGquetiapine
randomized to 12 week trial of quetiapine.
DRUGziprasidone
randomized to 12 week trial of ziprasidone.
Sponsors
National Institute of Mental Health (NIMH)
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Aged 18-60 years * Patients: otherwise healthy and meets DSM-IV criteria for schizophrenia or schizoaffective disorder, any type, treated with haloperidol, olanzapine, clozapine, quetiapine, ziprasidone, aripiprazole, or risperidone for at least 3 months * Controls: healthy * Able to give informed consent * No antipsychotic medication changes for 3 months, and no other medication changes for 2 weeks prior to Baseline Evaluations.
Exclusion criteria
* Axis I psychiatric disorder criteria met in self except for substance use disorders as below * Patients and controls: meets DSM-IV criteria for the diagnoses of substance abuse within the past 3 months * Involuntary legal status (as per Missouri law) * The presence of any serious medical disorder that may confound the assessment of relevant biologic measures or diagnosis, including: significant organ system dysfunction, metabolic diseases, type 1 diabetes mellitus, symptomatic type 2 diabetes mellitus (see below), pregnancy, endocrine disease, coagulopathy, clinically significant anemia, that would preclude blood sampling (as determined by the PI) or acute infection; * Patients taking more than one atypical antipsychotic medication; * Subjects taking certain prescription medications (as determined by PI on a case by case basis).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| DEXA Total Fat | The relevant time points include baseline, week 6 and week 12. | This study hypothesized that antipsychotic treatment would increase total body fat, as measured by whole body dual energy x-ray absorptiometry (DEXA), with larger adverse effects for olanzapine. |
| Clamp Derived Insulin Sensitivity (mg/kg/Min) | The relevant time points include baseline and week 12. | This study hypothesized that antipsychotic treatment would decrease insulin sensitivity, with larger adverse effects for olanzapine. Insulin sensitivity describes how sensitive the body is to the effects of insulin. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from wide range of sites in the St. Louis community. Some advertising with flyers was used however the majority of the recruitment was done using community outreach,doctor-to-doctor or self-referrals, and referrals from board and care and community support programs. All recruitment materials were approved by the IRB.
Pre-assignment details
Participants were enrolled in the study once they signed consent. After enrollment, participants were brought in for a screening visit consisting of a diagnostic interview, screening labs, a review of records and a discussion with their primary psychiatrist. If the patient met all inclusion criteria after screening, study visits were scheduled.
Participants by arm
| Arm | Count |
|---|---|
| Olanzapine Participants with schizophrenia were randomized to olanzapine. | 25 |
| Risperidone Patients with schizophrenia were randomized to risperidone. | 22 |
| Quetiapine Participants with schizophrenia were randomized to quetiapine. | 22 |
| Ziprasidone Participants with schizophrenia were randomized to ziprasidone. | 27 |
| Total | 96 |
Baseline characteristics
| Characteristic | Risperidone | Ziprasidone | Total | Olanzapine | Quetiapine |
|---|---|---|---|---|---|
| Age, Continuous | 39.2 years STANDARD_DEVIATION 11.1 | 38.3 years STANDARD_DEVIATION 10.2 | 37.9 years STANDARD_DEVIATION 10.2 | 37.5 years STANDARD_DEVIATION 11.2 | 36.4 years STANDARD_DEVIATION 8.6 |
| Body Mass Index | 31.04 kilograms per squared meters STANDARD_DEVIATION 6.5 | 32.27 kilograms per squared meters STANDARD_DEVIATION 5.56 | 31.87 kilograms per squared meters STANDARD_DEVIATION 6.45 | 32.27 kilograms per squared meters STANDARD_DEVIATION 7.38 | 31.76 kilograms per squared meters STANDARD_DEVIATION 6.63 |
| Body Weight | 93.88 kilograms STANDARD_DEVIATION 19.19 | 94.68 kilograms STANDARD_DEVIATION 15.9 | 95.16 kilograms STANDARD_DEVIATION 18.56 | 98.75 kilograms STANDARD_DEVIATION 21.04 | 92.95 kilograms STANDARD_DEVIATION 18.67 |
| DEXA Total Fat | 24.95 kilograms STANDARD_DEVIATION 10.07 | 31.60 kilograms STANDARD_DEVIATION 11.22 | 29.68 kilograms STANDARD_DEVIATION 11.89 | 32.24 kilograms STANDARD_DEVIATION 13.49 | 28.69 kilograms STANDARD_DEVIATION 11.63 |
| Race/Ethnicity, Customized Non-White | 15 Participants | 16 Participants | 65 Participants | 17 Participants | 17 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 7 Participants | 11 Participants | 30 Participants | 8 Participants | 4 Participants |
| Sex: Female, Male Female | 4 Participants | 11 Participants | 31 Participants | 7 Participants | 9 Participants |
| Sex: Female, Male Male | 18 Participants | 16 Participants | 65 Participants | 18 Participants | 13 Participants |
| Waist Circumference | 102.87 centimeters STANDARD_DEVIATION 16.66 | 108.50 centimeters STANDARD_DEVIATION 15.18 | 106.19 centimeters STANDARD_DEVIATION 15.95 | 108.44 centimeters STANDARD_DEVIATION 16.74 | 104.10 centimeters STANDARD_DEVIATION 15.45 |
| Whole Body Sensitivity | 5.53 mg/kg/min STANDARD_DEVIATION 3.32 | 4.33 mg/kg/min STANDARD_DEVIATION 2.01 | 4.79 mg/kg/min STANDARD_DEVIATION 2.62 | 4.39 mg/kg/min STANDARD_DEVIATION 2.16 | 5.10 mg/kg/min STANDARD_DEVIATION 2.93 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 21 | 0 / 20 | 0 / 21 |
| other Total, other adverse events | 13 / 19 | 8 / 21 | 9 / 20 | 11 / 21 |
| serious Total, serious adverse events | 0 / 19 | 0 / 21 | 0 / 20 | 0 / 21 |
Outcome results
Primary
Clamp Derived Insulin Sensitivity (mg/kg/Min)
This study hypothesized that antipsychotic treatment would decrease insulin sensitivity, with larger adverse effects for olanzapine. Insulin sensitivity describes how sensitive the body is to the effects of insulin.
Time frame: The relevant time points include baseline and week 12.
Population: Modified Intent to Treat (ITT) sample with Week 0 and Week 12 data. Two Quetiapine participants were excluded from analyses due to failure to adhere to the protocol.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Olanzapine | Clamp Derived Insulin Sensitivity (mg/kg/Min) | Baseline | 4.39 mg/kg/min | Standard Error 0.53 |
| Olanzapine | Clamp Derived Insulin Sensitivity (mg/kg/Min) | Week 12 | 3.62 mg/kg/min | Standard Error 0.49 |
| Risperidone | Clamp Derived Insulin Sensitivity (mg/kg/Min) | Baseline | 5.53 mg/kg/min | Standard Error 0.57 |
| Risperidone | Clamp Derived Insulin Sensitivity (mg/kg/Min) | Week 12 | 5.01 mg/kg/min | Standard Error 0.51 |
| Quetiapine | Clamp Derived Insulin Sensitivity (mg/kg/Min) | Baseline | 5.28 mg/kg/min | Standard Error 0.58 |
| Quetiapine | Clamp Derived Insulin Sensitivity (mg/kg/Min) | Week 12 | 5.08 mg/kg/min | Standard Error 0.53 |
| Ziprasidone | Clamp Derived Insulin Sensitivity (mg/kg/Min) | Week 12 | 4.45 mg/kg/min | Standard Error 0.47 |
| Ziprasidone | Clamp Derived Insulin Sensitivity (mg/kg/Min) | Baseline | 4.33 mg/kg/min | Standard Error 0.5 |
| Total | Clamp Derived Insulin Sensitivity (mg/kg/Min) | Baseline | 4.82 mg/kg/min | Standard Error 0.27 |
| Total | Clamp Derived Insulin Sensitivity (mg/kg/Min) | Week 12 | 4.50 mg/kg/min | Standard Error 0.25 |
Comparison: Primary analysis for change in insulin sensitivity used a likelihood-based mixed-effects model using time (0 and 12 weeks) as the independent variable, with an unstructured covariance structure specified, based on the Akaike Information Criterion-Corrected (AIC-C). The null hypothesis was that there was no difference in the outcome over time (main effect of time).p-value: 0.05Mixed Models Analysis
Comparison: Primary analysis for change in insulin sensitivity used a likelihood-based mixed-effects model using time (0 and 12 weeks) and treatment group as the independent variables, with an unstructured covariance structure specified, based on the Akaike Information Criterion-Corrected (AIC-C). The null hypothesis was that there were no differences between groups in the change over time (time by treatment condition).p-value: 0.22Mixed Models Analysis
Primary
DEXA Total Fat
This study hypothesized that antipsychotic treatment would increase total body fat, as measured by whole body dual energy x-ray absorptiometry (DEXA), with larger adverse effects for olanzapine.
Time frame: The relevant time points include baseline, week 6 and week 12.
Population: Modified Intent to Treat (ITT) sample with week 0, week 6 and week 12 data. Two Quetiapine participants were excluded from analyses due to failure to adhere to the protocol.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Olanzapine | DEXA Total Fat | 6 Weeks | 34.38 kilograms of body fat | Standard Error 2.48 |
| Olanzapine | DEXA Total Fat | Baseline | 32.24 kilograms of body fat | Standard Error 2.48 |
| Olanzapine | DEXA Total Fat | 12 Weeks | 35.45 kilograms of body fat | Standard Error 2.49 |
| Risperidone | DEXA Total Fat | 6 Weeks | 28.29 kilograms of body fat | Standard Error 2.64 |
| Risperidone | DEXA Total Fat | 12 Weeks | 29.23 kilograms of body fat | Standard Error 2.64 |
| Risperidone | DEXA Total Fat | Baseline | 27.66 kilograms of body fat | Standard Error 2.64 |
| Quetiapine | DEXA Total Fat | 6 Weeks | 29.60 kilograms of body fat | Standard Error 2.77 |
| Quetiapine | DEXA Total Fat | 12 Weeks | 30.10 kilograms of body fat | Standard Error 2.77 |
| Quetiapine | DEXA Total Fat | Baseline | 28.83 kilograms of body fat | Standard Error 2.77 |
| Ziprasidone | DEXA Total Fat | 12 Weeks | 30.66 kilograms of body fat | Standard Error 2.4 |
| Ziprasidone | DEXA Total Fat | 6 Weeks | 31.18 kilograms of body fat | Standard Error 2.39 |
| Ziprasidone | DEXA Total Fat | Baseline | 31.60 kilograms of body fat | Standard Error 2.38 |
| Total | DEXA Total Fat | Baseline | 30.25 kilograms of body fat | Standard Error 1.27 |
| Total | DEXA Total Fat | 6 Weeks | 31.05 kilograms of body fat | Standard Error 1.27 |
| Total | DEXA Total Fat | 12 Weeks | 31.52 kilograms of body fat | Standard Error 1.28 |
Comparison: Primary analysis for change in DEXA total fat used a likelihood-based mixed-effects model using time (0, 6, and 12 weeks) as the independent variable, with Toeplitz covariance structure specified, based on Akaike Information Criterion-Corrected (AIC-C). The null hypothesis was that there was no difference in the outcome over time (main effect of time).p-value: 0.002Mixed Models Analysis
Comparison: Primary analysis for change in DEXA total fat used a likelihood-based mixed-effects model using time (0, 6, and 12 weeks) and treatment group as independent variables, with Toeplitz covariance structure specified, based on Akaike Information Criterion-Corrected (AIC-C). The null hypothesis was that there were no differences between groups in the change over time (time by treatment condition).p-value: 0.002Mixed Models Analysis