Insulin Resistance, Schizophrenia
Conditions
Keywords
Glucose Metabolism
Brief summary
This study will evaluate the effects of combination treatment with aripiprazole and clozapine on insulin resistance, blood fat levels, and weight gain in people diagnosed with schizophrenia.
Detailed description
Schizophrenia is a severely disabling brain disorder. People with schizophrenia often experience hallucinations and delusions, as well as overall difficulty with everyday functioning. Although the medications available to treat the disorder are generally effective, many cause undesirable side effects. Clozapine, for example, is a strong tranquilizer that functions like an antipsychotic medication. It has been shown to be effective in reducing the symptoms of schizophrenia, but can bring about serious side effects, including heart failure, weight gain, and diabetes. Aripiprazole, an atypical antipsychotic medication, has been shown to have fewer side effects than older antipsychotic drugs. The addition of aripiprazole to a clozapine treatment regimen may reduce the negative side effects of clozapine. This study will evaluate the effects of combination treatment with aripiprazole and clozapine on insulin resistance, blood fat levels, and weight gain in people with schizophrenia. Individuals interested in participating in this 8-week, double-blind study will first attend a screening session at the study site. Medical and psychiatric evaluations will be completed, blood samples will be taken, and an EKG will be performed. Eligible participants will undergo baseline assessments and then be randomly assigned to receive either aripiprazole or placebo in addition to their prescribed dose of clozapine. Participants will take one 15-mg capsule of their assigned medication once a day for 8 weeks. Study visits will occur biweekly for the first 8 weeks, followed by one final follow-up visit at Week 12. At each study visit, medication will be distributed, and the following criteria will be assessed: vital signs; weight; complete blood count; medication side effects; and extrapyramidal symptoms (EPS), which are potential neurological side effects of antipsychotic medications and may include involuntary movements, tremors, and rigidity. The Week 8 visit will include an EKG, and assessments of the following criteria: vital signs; medication side effects; treatment efficacy; blood counts; weight and height; and waist and hip circumference. At baseline and Week 8, participants will also undergo a frequently sampled intravenous glucose tolerance test (FSIVGTT). This involves intravenous infusion of glucose followed by frequent blood sampling to measure insulin and glucose concentrations. During the 4 days prior to each FSIVGTT, participants will record their food intake and wear an activity monitor.
Interventions
DRUGAripiprazole
15-mg dose once a day for 8 weeks
DRUGPlacebo
1 tablet placebo dose once a day for 8 weeks
Sponsors
National Institute of Mental Health (NIMH)
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of schizophrenia (any subtype) or schizoaffective disorder (any subtype) * Treatment with clozapine for at least 1 year * Stable dose of clozapine for at least 1 month * Well established compliance with outpatient medications * Female participants of non-childbearing potential or of childbearing potential and willing to practice appropriate birth control methods (complete abstinence from sexual intercourse, female sterilization, sterilization of male partner, implants of levonorgestrel, injectable progestogen, oral contraceptives, intrauterine devices, or double barrier methods of contraception using spermicide with either a condom or diaphragm) during the study
Exclusion criteria
* Current substance abuse * Psychiatrically unstable * Significant medical illness, including severe cardiovascular, hepatic, or renal disease * History of immunosuppression * Current or recent radiation or chemotherapy treatment for cancer * Chronic use of steroids * Pregnant or breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Total Cholesterol | Measured at Baseline and Week 8 | A comparison of aripiprazole group and placebo group in change in total cholesterol measured at Baseline and Week 8. |
| Change in Weight | Measured at Baseline and Week 8 | A comparison between aripiprazole group and placebo group in change in weight measured at Baseline and Week 8. |
| Change in Body Mass Index (BMI) | Measured at Baseline and Week 8 | A comparison between aripiprazole group and placebo group of change in Body Mass Index (BMI) measured at Baseline and Week 8. |
| Change in Glucose Metabolism | Measured at Baseline and Week 8 | A comparison between the aripiprazole group and placebo group in change in glucose metabolism measured at Baseline and Week 8. |
| Change in Triglycerides | Measured at Baseline and Week 8 | — |
| Change in Insulin Resistance | Measured at Baseline and Week 8 | A comparison between aripiprazole group and placebo group of change in insulin resistance measured at Baseline and Week 8. |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited from the Freedom Trail Clinic at the Erich Lindemann Mental Health Center and were studied at the General Clinical Research Center (GCRC) at the Massachusetts General Hospital (MGH), Boston and the Freedom Trail Clinic.
Pre-assignment details
After providing written informed consent, subjects underwent a diagnostic evaluation by a research psychiatrist using the Structured Clinical Interview for DSM-IV (SCID). All subjects were screened and enrolled based on eligibility criteria. Baseline study assessments were completed prior to intervention.
Participants by arm
| Arm | Count |
|---|---|
| Aripiprazole Participants will take aripiprazole for 8 weeks. | 20 |
| Placebo Participants will take placebo for 8 weeks. | 18 |
| Total | 38 |
Baseline characteristics
| Characteristic | Placebo | Aripiprazole | 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 | 18 Participants | 20 Participants | 38 Participants |
| Age, Continuous | 44.2 years STANDARD_DEVIATION 8.9 | 44.3 years STANDARD_DEVIATION 8.2 | 44.25 years STANDARD_DEVIATION 8.6 |
| Region of Enrollment United States | 18 participants | 20 participants | 38 participants |
| Sex: Female, Male Female | 8 Participants | 4 Participants | 12 Participants |
| Sex: Female, Male Male | 10 Participants | 16 Participants | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / 16 | 3 / 14 |
| serious Total, serious adverse events | 0 / 16 | 0 / 14 |
Outcome results
Primary
Change in Body Mass Index (BMI)
A comparison between aripiprazole group and placebo group of change in Body Mass Index (BMI) measured at Baseline and Week 8.
Time frame: Measured at Baseline and Week 8
Population: The number of participants for analysis (intent to treat) were those that completed the study (N=30).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aripiprazole | Change in Body Mass Index (BMI) | -0.52 kg/m^2 | Standard Deviation 0.79 |
| Placebo | Change in Body Mass Index (BMI) | 0.03 kg/m^2 | Standard Deviation 0.85 |
p-value: 0.229ANCOVA
Primary
Change in Glucose Metabolism
A comparison between the aripiprazole group and placebo group in change in glucose metabolism measured at Baseline and Week 8.
Time frame: Measured at Baseline and Week 8
Population: The number of participants for analysis (intent to treat) were those that completed the study (N=30).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aripiprazole | Change in Glucose Metabolism | 0.003 min^-1 | Standard Deviation 0.006 |
| Placebo | Change in Glucose Metabolism | -0.005 min^-1 | Standard Deviation 0.007 |
p-value: 0.01ANCOVA
Primary
Change in Insulin Resistance
A comparison between aripiprazole group and placebo group of change in insulin resistance measured at Baseline and Week 8.
Time frame: Measured at Baseline and Week 8
Population: The number of participants for analysis (intent to treat) were those that completed the study (N=30)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aripiprazole | Change in Insulin Resistance | 0.6 HOMA score | Standard Deviation 3.8 |
| Placebo | Change in Insulin Resistance | 0.65 HOMA score | Standard Deviation 1.9 |
p-value: 0.082ANCOVA
Primary
Change in Total Cholesterol
A comparison of aripiprazole group and placebo group in change in total cholesterol measured at Baseline and Week 8.
Time frame: Measured at Baseline and Week 8
Population: The number of participants for analysis (intent to treat) were those that completed the study (N = 30).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aripiprazole | Change in Total Cholesterol | -15.3 mg/dL | Standard Deviation 33.3 |
| Placebo | Change in Total Cholesterol | 5.6 mg/dL | Standard Deviation 34 |
p-value: 0.125ANCOVA
Primary
Change in Triglycerides
Time frame: Measured at Baseline and Week 8
Population: The number of participants for analysis (intent to treat) were those that completed the study (N=30)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aripiprazole | Change in Triglycerides | -5.9 mg/dL | Standard Deviation 75.1 |
| Placebo | Change in Triglycerides | -7.3 mg/dL | Standard Deviation 100.3 |
p-value: 0.982ANCOVA
Primary
Change in Weight
A comparison between aripiprazole group and placebo group in change in weight measured at Baseline and Week 8.
Time frame: Measured at Baseline and Week 8
Population: The number of participants for analysis (intent to treat) were those that completed the study (N=30).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aripiprazole | Change in Weight | -1.5 kg | Standard Deviation 2.3 |
| Placebo | Change in Weight | 0.3 kg | Standard Deviation 2.3 |
p-value: 0.109ANCOVA