Naltrexone for Antipsychotic-Induced Weight Gain

Persons with severe mental illness (SMI) die, on average, 25 years earlier than the general
population1. Most of this early mortality can be attributed to cardiovascular disease (CVD)
and diabetes mellitus (DM), which are directly related to obesity. Obesity is a leading cause
of preventable death in the United States, second only to smoking. The physical health of
patients has become a major focus of schizophrenia care, as recent decades have seen immense
gains in symptom control and community integration. There is an urgent need for the
development of interventions that address the obesity crisis in schizophrenia.

Patients treated with antipsychotic medications have been shown to have a preference for
diets high in fat and sugar. Patients with schizophrenia typically seek behaviors that
increase dopamine mediated reward in the brain such as smoking and substance use, both of
which occur more often in this group than the general population. The system might require
intact dopamine and opioid function.

Naltrexone is an oral agent that competitively antagonizes all known opioid receptors in the
brain. Human studies with naltrexone were completed in individuals with different illnesses,
including schizophrenia, and have been shown to be a safe and easy agent to use. It is shown
to decrease craving in alcoholics and is approved by the FDA for the treatment of alcohol
dependence. Naltrexone is reported to decrease craving for other substances of abuse, like
nicotine. Furthermore, it has been shown to prevent secondary weight gain due to cessation of
cigarette smoking at low (25mg and 50 mg), but not higher doses. Naltrexone has been tested
in human feeding studies, and has been shown to reduce both the quantity of food eaten and
the choice of palatable foods.

Subjects will be randomized to either 25, 50 or 0mg of Naltrexone and will take the study
medication daily for 52 weeks. Subjects will be seen weekly for the first 4 weeks of the
study, thereafter they will be seen on a bi-weekly (every other week) basis to be assessed
(i.e. weight, side effect check, paper questionnaires) throughout the remaining 48 weeks of
treatment.

The purpose of this study is to determine the efficacy of two doses of naltrexone (25mg &
50mg) versus placebo for weight and health risk reduction in 144 obese individuals with
severe mental illness treated with an antipsychotic medication.

Inclusion Criteria:

- Age 18 to 75

- Meet Diagnostic & Statistical Manual - 4 (DSM-IV) criteria for schizophrenia,
schizoaffective disorder, bipolar disorder, major depression, or another psychotic
disorder based on Structured Clinical Interview for the DSM-IV (SCID) interview

- Body Mass Index (BMI) of 28 and over

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

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

- Over 7% total body weight increase on antipsychotics for subjects within first year of
illness

Exclusion Criteria:

- 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, a naloxone challenge will be performed.)

- Current history of dementia, mental retardation

- Not capable of giving informed consent for participation in the study

- Women who are pregnant or breast-feeding

- Physical conditions affecting body weight (e.g. Cushing's disease, polycystic ovary
syndrome) Diabetes Mellitus (defined as prescribed an anti-diabetic medication for
diabetes or a hemoglobin A1c level > 7 confirmed by primary care physician at
screening)

- Severe liver dysfunction, (serum aminotransferases greater than three times normal),
acute infectious hepatitis, liver failure.