Diabetes Mellitus, Type 2, Obesity, Schizophrenia
Conditions
Keywords
Schizophrenia, Diabetes, Obesity
Brief summary
The purpose of this study is to determine the efficacy of combining open-label extended release bupropion (flexible dosing up to 450mg target) and naltrexone (37.5mg) versus Bupropion and placebo along with a daily 500 calorie reduction diet recommendation for weight and health risk reduction in 40 overweight/obese individuals with schizophrenia.
Detailed description
The combination of naltrexone with noradrenaline/dopamine reuptake blocker bupropion has been developed and FDA-approved for the treatment of obesity in the general population. Naltrexone does not normally produce weight loss in humans and bupropion produces modest weight loss, however the combination produces clinically significant weight loss, which appears to be more than the sum of its components would otherwise produce separately. Of interest to us, the combination has been shown to be effective for clinically significant weight loss in obese subjects with type 2 diabetes as well. Registration studies by the manufacturer of the combination pill excluded antipsychotic medication users, thus we have no information on the potential effectiveness of the combination in this population. Both naltrexone and bupropion are commonly used in psychiatry, naltrexone for co-morbid alcohol addiction, and bupropion for co-morbid depression and/or cigarette addiction. This is a 16-week pilot trial of 37.5mg naltrexone/placebo added to extended release bupropion in flexible dosing (150mg to 450mg) and a daily 500 calorie reduction diet recommendation for subjects with schizophrenia and obesity. A dose of 37.5mg is similar to the FDA-approved combination dose for naltrexone. However, based on our experience with bupropion, we have chosen to use bupropion in an un-blinded manner and reach the target dose of 450mg based on tolerance of the individual subject over the initial 3-week period. Changes to the study since registration: The study was initially registered with 3 arms (Naltrexone vs Bupropion vs Placebo)- whereas the original intent was always supposed to be a 2 armed study (Naltrexone vs Placebo- each with Bupropion included)- this was corrected when the results of the terminated study were entered. In addition, there was an initial intent to include diabetics in the study, but this was later removed as well.
Interventions
DRUGNaltrexone
37.mg oral capsule taken once daily for over the course of the study (16 weeks)
DRUGBupropion
Extended release bupropion taken once daily for the course of the study (16 weeks) flexible dosing up to 450mg target.
OTHERPlacebo
Oral placebo taken once daily for the course of the study (16 week)
Sponsors
Yale University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Naltrexone versus Placebo assignment will remain double-blinded for the duration of the study; Bupropion dosing will be open-label and not masked to either participant or investigator.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Age 18 to 75 2. Meet DSM-IV criteria for schizophrenia or schizoaffective disorder based on SCID interview (If bipolar-schizoaffective: need to be adequately stabilized on a mood stabilizer and show no mania history for the past one year, as confirmed by study psychiatrist and patient's clinician) 3. Body Mass Index (BMI) of 28 and over 4. On a stable dose of antipsychotic medication; i.e. at least one month with no dose change, and three months from an antipsychotic switch 5. Deemed to be symptomatically stable by the clinical staff in the last two months 6. Over 7% total body weight increase on antipsychotics for subjects within first year of illness
Exclusion criteria
1. Meet criteria for current opiate abuse or dependence (confirmed by positive urine drug screen for opiates or, if suspected by study doctor via patient history and or suspicion of occult opiate use.) Note: All subjects will be screened for drugs, not only those suspected of opiate use. 2. A history of seizures in the past five years (confirmed through chart review and discussion with patient's clinician) 3. Meet DSM criteria for Bipolar Disorder 4. History of mania in the past one year (confirmed through chart review and discussion with patient's clinician) 5. Uncontrolled hypertension 6. Insulin dependent diabetes mellitus 7. Current history of dementia, mental retardation 8. Not capable of giving informed consent for participation in the study 9. Women who are pregnant or breast-feeding 10. Physical conditions affecting body weight (e.g. Cushing's disease, polycystic ovary syndrome) 11. Severe liver dysfunction, (serum aminotransferases greater than three times normal), acute infectious hepatitis, liver failure. 12. History of glaucoma.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| BMI | Baseline and Week 16 | BMI will be calculated using weekly height and weight measurements (kg/m\^2) at each assessment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Weight (kg) | Baseline and Week 16 | Weight in kilograms will be measured at each assessment and change will be determined at study endpoint. |
| Health Risk Markers | Baseline to Week 16 | Serum lipid profiles, fasting glucose, and glycosylated hemoglobin (hbA1c) will be measured at baseline and week 16 and change in these markers will be determined at endpoint |
| Waist Circumference (Inches) | Baseline and Week 16 | Waist circumference will be measured in inches at each assessment. |
Countries
United States
Participant flow
Pre-assignment details
30 people were screened by telephone. 18/30 people screened were deemed ineligible. The reasons for ineligibility were: antidepressant medication use (11/18), a history of seizures (4/18) and already taking Naltrexone (3/18). 12/30 people were eligible, 6/12 were initially interested in the study and ultimately, only 5/6 were consented.
Participants by arm
| Arm | Count |
|---|---|
| Naltrexone With Bupropion Oral Naltrexone taken once a day and Oral Bupropion taken once a day for 16 weeks.
Naltrexone: 37.mg oral capsule taken once daily for over the course of the study (16 weeks)
Bupropion: Extended release bupropion taken once daily for the course of the study (16 weeks) flexible dosing up to 450mg target. | 3 |
| Placebo With Bupropion Oral placebo capsule and Oral Bupropion taken once a day for 16 weeks.
Bupropion: Extended release bupropion taken once daily for the course of the study (16 weeks) flexible dosing up to 450mg target.
Placebo: Oral placebo taken once daily for the course of the study (16 week) | 2 |
| Total | 5 |
Baseline characteristics
| Characteristic | Naltrexone With Bupropion | Total | Placebo With Bupropion |
|---|---|---|---|
| Age, Continuous | 46.33 years STANDARD_DEVIATION 8.14 | 51.00 years STANDARD_DEVIATION 8.63 | 58.00 years STANDARD_DEVIATION 1.41 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 2 Participants | 1 Participants |
| Region of Enrollment United States | 3 participants | 5 participants | 2 participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 3 Participants | 4 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 2 |
| other Total, other adverse events | 2 / 3 | 0 / 2 |
| serious Total, serious adverse events | 0 / 3 | 0 / 2 |
Outcome results
Primary
BMI
BMI will be calculated using weekly height and weight measurements (kg/m\^2) at each assessment.
Time frame: Baseline and Week 16
Population: Presented are the baseline and 16 weeks summary data on the 5 patients enrolled.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Naltrexone With Bupropion | BMI | Baseline | 39.06 kg/m^2 | Standard Deviation 6.03 |
| Naltrexone With Bupropion | BMI | 16 Weeks | 37.33 kg/m^2 | Standard Deviation 5.81 |
| Placebo With Bupropion | BMI | Baseline | 29.55 kg/m^2 | Standard Deviation 0.07 |
| Placebo With Bupropion | BMI | 16 Weeks | 30.65 kg/m^2 | Standard Deviation 3.88 |
Secondary
Health Risk Markers
Serum lipid profiles, fasting glucose, and glycosylated hemoglobin (hbA1c) will be measured at baseline and week 16 and change in these markers will be determined at endpoint
Time frame: Baseline to Week 16
Population: These labratory data were not collected and summarized due to the removal of diabetes from the study criteria and the early termination of the study.
Secondary
Waist Circumference (Inches)
Waist circumference will be measured in inches at each assessment.
Time frame: Baseline and Week 16
Population: Presented are the baseline and 16 weeks summary data on the 5 patients enrolled.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Naltrexone With Bupropion | Waist Circumference (Inches) | Baseline | 50.08 inches | Standard Deviation 5.26 |
| Naltrexone With Bupropion | Waist Circumference (Inches) | 16 Weeks | 48.50 inches | Standard Deviation 5.76 |
| Placebo With Bupropion | Waist Circumference (Inches) | Baseline | 41.87 inches | Standard Deviation 1.23 |
| Placebo With Bupropion | Waist Circumference (Inches) | 16 Weeks | 43.37 inches | Standard Deviation 2.29 |
Secondary
Weight (kg)
Weight in kilograms will be measured at each assessment and change will be determined at study endpoint.
Time frame: Baseline and Week 16
Population: Presented are the baseline and 16 weeks summary data on the 5 patients enrolled.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Naltrexone With Bupropion | Weight (kg) | Baseline | 118.78 kg | Standard Deviation 11.17 |
| Naltrexone With Bupropion | Weight (kg) | 16 Weeks | 113.60 kg | Standard Deviation 11.24 |
| Placebo With Bupropion | Weight (kg) | Baseline | 87.25 kg | Standard Deviation 15.48 |
| Placebo With Bupropion | Weight (kg) | 16 Weeks | 91.25 kg | Standard Deviation 27.64 |