Naltrexone for Antipsychotic-Induced Weight Gain

Study Overview
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Brief Summary
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This study is designed to look at the effects of naltrexone on weight loss in individuals treated with antipsychotic medications. Naltrexone is an FDA approved medication for the management of alcohol dependence and drug dependence, but has not been fully evaluated for its effect on weight loss in individuals with severe mental illness (i.e. schizophrenia, schizoaffective disorder, bipolar disorder etc.) The purpose of this study is to find out how effective two different doses of oral naltrexone is on reducing body weight when compared to placebo (an inactive substance or sugar pill).

Detailed Description
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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.

Official Title
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Naltrexone for Antipsychotic-Induced Weight Gain

Conditions
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Schizophrenia, Schizoaffective Disorder, Schizophreniform Disorder, Bipolar Disorder, Severe Major Depression With Psychotic Features

Intervention / Treatment
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* Drug: Naltrexone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Naltrexone 50mg<br>Oral Naltrexone 50mg capsule taken once daily for 52 weeks | Drug: Naltrexone<br>* 25 or 50mg (randomized) oral capsule taken once daily for 52 weeks to establish optimal dose for weight loss over the course of the study.<br>* Other names: Revia;|
| Placebo Comparator: Placebo<br>Oral placebo capsule taken once daily for 52 weeks | Drug: Placebo<br> <br> |
| Experimental: Naltrexone 25mg<br>Oral Naltrexone 25mg capsule taken once daily for 52 weeks | Drug: Naltrexone<br>* 25 or 50mg (randomized) oral capsule taken once daily for 52 weeks to establish optimal dose for weight loss over the course of the study.<br>* Other names: Revia;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Weight From Baseline | Weight (kilograms; kg) will be measured at each assessment and change in weight will be determined at study endpoint. | Baseline and 52 weeks | 
| Percent of Subjects Who Lost More Than 5% of Body Weight From Baseline | Body Mass Index will be calculated at each assessment and change over time will be assessed at endpoint. | 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Fasting Glucose From Baseline | Fasting glucose will be collected over the course of participation and changes will be evaluated at study endpoint. | Baseline and 52 weeks | 
| Changes in Glycosylated Hemoglobin (HbA1c) From Baseline | Glycosylated hemoglobin (HbA1c) will be collected over the course of participation and changes will be evaluated at study endpoint. | Baseline and 52 weeks | 
| Changes in Insulin From Baseline | Insulin will be collected over the course of participation and changes will be evaluated at study endpoint. | Baseline and 52 weeks | 
| Changes in Total Cholesterol From Baseline | Total Cholesterol will be collected over the course of participation and changes will be evaluated at study endpoint. | Baseline and 52 weeks | 
| Changes in HDL From Baseline | High-density lipoprotein (HDL) will be collected over the course of participation and changes will be evaluated at study endpoint. | Baseline and 52 weeks | 
| Changes in LDL From Baseline | Low-density lipoprotein (HDL) will be collected over the course of participation and changes will be evaluated at study endpoint. | Baseline and 52 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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antipsychotic, severe mental illness, weight loss