Naltrexone-Bupropion Versus Placebo-Bupropion for Weight Loss in Schizophrenia and Diabetes

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 Type 2 Diabetes,
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.

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. Diabetes Mellitus (defined as prescribed an anti-diabetic medication for diabetes)

4. Body Mass Index (BMI) of 28 and over

5. On a stable dose of antipsychotic medication; i.e. at least one month with no dose
change, and three months from an antipsychotic switch

6. Deemed to be symptomatically stable by the clinical staff in the last two months

7. 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.