Naltrexone for Antipsychotic-Induced Weight Gain (NTX)

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").

Study Overview

• Status: Completed
• Conditions: Schizophrenia; Schizoaffective Disorder; Schizophreniform Disorder; Bipolar Disorder; Severe Major Depression With Psychotic Features
• Intervention / Treatment: Drug: Placebo; Drug: Naltrexone

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 144
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06519
      • Connecticut Mental Health Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Naltrexone 50mg; Oral Naltrexone 50mg capsule taken once daily for 52 weeks	Drug: Naltrexone; 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.; Other Names: Revia
Placebo Comparator: Placebo; Oral placebo capsule taken once daily for 52 weeks	Drug: Placebo
Experimental: Naltrexone 25mg; Oral Naltrexone 25mg capsule taken once daily for 52 weeks	Drug: Naltrexone; 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.; Other Names: Revia

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Cenk Tek, MD, Yale University

Publications and helpful links

General Publications

• Tek C, Guloksuz S, Srihari VH, Reutenauer EL. Investigating the safety and efficacy of naltrexone for anti-psychotic induced weight gain in severe mental illness: study protocol of a double-blind, randomized, placebo-controlled trial. BMC Psychiatry. 2013 Jun 27;13:176. doi: 10.1186/1471-244X-13-176.

Study record dates

Study Major Dates

• Study Start: May 1, 2013
• Primary Completion (Actual): April 7, 2019
• Study Completion (Actual): April 7, 2019

Study Registration Dates

• First Submitted: March 12, 2013
• First Submitted That Met QC Criteria: May 30, 2013
• First Posted (Estimate): May 31, 2013

Study Record Updates

• Last Update Posted (Actual): October 1, 2021
• Last Update Submitted That Met QC Criteria: September 3, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: severe mental illness; weight loss; antipsychotic
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Body Weight; Schizophrenia Spectrum and Other Psychotic Disorders; Body Weight Changes; Bipolar and Related Disorders; Schizophrenia; Disease; Psychotic Disorders; Bipolar Disorder; Weight Gain; Physiological Effects of Drugs; Peripheral Nervous System Agents; Sensory System Agents; Narcotic Antagonists; Alcohol Deterrents; Naltrexone
• Other Study ID Numbers: 1207010507; 1R01DK093924-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: All de-identified data resulting from this award involving human subjects will be submitted to the NIMH Data Archive (NDA) - National Database for Clinical Trials Related to Mental Illness (NDCT) The Principal Investigator will work with NDA support staff to plan an appropriate data submission schedule and provide information on the steps for submission and sharing of data. Communication of this data sharing plan to appropriate research staff to ensure the timely submission of data. All human subject data provided will include an NDA Global Unique Identifier (GUID) and will not include personally identifiable information (PII). Analyzed data will be submitted no later than the time of publication. Even if a publication focuses on only part of an analyzed dataset, the entire analyzed dataset will be submitted when the first paper is published. All data made available for public use via NDA will be de-identified data.