Facilitation of NMDA Receptor Function in Patients With Schizophrenia and Co-morbid Alcoholism

• ClinicalTrials.gov Identifier: NCT00338598
• Recruitment Status: Completed
• First Posted: June 20, 2006
• Results First Posted: April 12, 2017
• Last Update Posted: January 17, 2018
• Sponsor: Yale University
• Collaborator: Stanley Medical Research Institute
• Information provided by (Responsible Party): Yale University

Study Description

Brief Summary:

This placebo-controlled study is designed to evaluate the efficacy of glycine, an agonist of the glycine-B co-agonist site of the NMDA receptor, on alcohol consumption and craving as well as negative symptoms in schizophrenia.

Glycine will decrease the rewarding action of ethanol and reduce ethanol consumption. Also, glycine will improve negative symptoms and cognitive deficits in schizophrenia.

Condition or disease	Intervention/treatment	Phase
Alcoholism; Schizophrenia	Drug: Glycine; Drug: placebo	Phase 2

Detailed Description:

OBJECTIVE: Schizophrenia affects about 1% of the general population and is a highly disabling disease. Additionally, the rate of alcohol dependency for patients with schizophrenia is very high. There are no established treatments for alcohol dependency and negative symptoms in schizophrenia. This study will examine whether the addition of glycine to neuroleptic medications will help patients with schizophrenia and alcoholism decrease their drinking as well as improve negative symptoms.

RESEARCH PLAN: An abnormality of the glutamate neurotransmitter system has been hypothesized for both alcoholism and schizophrenia. Studies suggest that the amino acid glycine may improve alcohol dependency and symptoms of schizophrenia by acting on the N methyl D aspartate (NMDA) glutamate receptor. Glycine causes reversal of the effects of ethanol in animal studies and improves mood, social withdrawal and other so called "negative symptoms" of schizophrenia. Consequently, the use of glycine by patients with schizophrenia and alcohol dependency may potentially decrease alcohol craving and alcohol consumption and also improve certain symptoms of schizophrenia. The potential of glycine to improve both alcohol dependency and negative symptoms could represent an important step in the improvement of the quality of life for patients with schizophrenia.

METHODOLOGY/FINDINGS/RESULTS: In order to test this hypothesis, we will use a double blind, placebo controlled study and measure the number of drinks, the degree of craving for alcohol and symptoms of schizophrenia among other parameters. Our principal approach to analyses of medication effectiveness will be the application of the linear mixed effect model. The linear mixed effect model permits a flexible approach for studying change in individuals through time as a random effect, and does not require all patients to have data at all measured points. Our principal model of analysis includes treatment (placebo or glycine), as between subject factor, and time, as within subject factor. Compliance will be also included as a time varying independent variable. This project continues to recruit subjects.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Facilitation of NMDA Receptor Function in Patients With Schizophrenia and Co-morbid Alcoholism
• Study Start Date: June 2003
• Actual Primary Completion Date: December 2015
• Actual Study Completion Date: December 2015

Arms and Interventions

Arm	Intervention/treatment
Experimental: Glycine; Glycine, 0.8 gr per kg given in two daily doses	Drug: Glycine; Glycine, 0.8 gr per kg given in two daily doses
Placebo Comparator: placebo; placebo will be administered.	Drug: placebo

Outcome Measures

Primary Outcome Measures :

1. Self Reported Weekly Alcohol Consumption [ Time Frame: 12 weeks ]
   Percentage of drinking days and heavy drinking days using timeline follow back
2. Self Reported Weekly Alcohol Craving [ Time Frame: 12 weeks ]
   The Obsessive Compulsive Drinking Scale (OCDS) is consisted by 14 items rated 0 - 4. The minimum and maximum values possibly obtained in this scale are respectively 0 and 56, this last one, meaning the most craving possible experienced. It is a short and easy to administer scale (average of 5 minutes per self-rating), built to measure severity and improvement during alcoholism treatment trials.
3. Weekly Ratings of Negative/Positive Psychotic Symptoms [ Time Frame: 12 weeks ]
   The PANSS or the Positive and Negative Syndrome Scale is a medical scale used for measuring symptom severity of patients with schizophrenia. The patient is rated from 1 to 7 on 30 different symptoms based on the interview as well as reports of family members or primary care hospital workers. Of the 30 items included in the PANSS, 7 constitute a Positive Scale, 7 a Negative Scale, and the remaining 16 a General Psychopathology Scale.The scores for these scales are arrived at by summation of ratings across component items. Therefore, the potential ranges are 7 to 49 for the Positive and Negative Scales, and 16 to 112 for the General Psychopathology Scale. A higher score indicates more severe symptoms for each scale.
4. Baseline and End of Treatment Cognitive Functioning Measures (Hopkins) [ Time Frame: 12 weeks ]
   Hopkins Verbal Learning Test Assesses short term verbal learning and memory. Subscales include immediate recall (0-36), delayed recall (0-12) , and recognition (0-12). A higher score indicates better memory performance.

Secondary Outcome Measures :

1. Weekly Drug Use [ Time Frame: 12 weeks ]
2. Baseline and End of Treatment Quality of Life [ Time Frame: 12 weeks ]
3. Baseline and End of Treatment Neurophysiological Measures [ Time Frame: 12 weeks ]

Eligibility Criteria

• Ages Eligible for Study: 21 Years to 60 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• DSM-IV diagnosis of schizophrenia or schizoaffective disorder
• DSM-IV diagnosis of alcohol dependence
• Stable treatment with typical or atypical antipsychotics

Exclusion Criteria:

• Axis I diagnosis other than alcohol dependence, schizophrenia, schizoaffective disorder, OCD, and PTSD.
• current drug dependence
• evidence of significant hepatocellular injury evidence by abnormal SGOT or SGPT levels
• history of seizures
• diabetes and medical conditions that would alter glycine metabolism
• positive pregnancy test
• treatment with clozapine, naltrexone or disulfiram

Contacts and Locations

Locations

United States, Connecticut

VA Connecticut Healthcare System

West Haven, Connecticut, United States, 06516

Sponsors and Collaborators

Yale University

Stanley Medical Research Institute

Investigators

• Principal Investigator: Ismene Petrakis, M.D.; Yale University

More Information

• Responsible Party: Yale University
• ClinicalTrials.gov Identifier: NCT00338598
• Other Study ID Numbers: 20915
• First Posted: June 20, 2006
• Results First Posted: April 12, 2017
• Last Update Posted: January 17, 2018
• Last Verified: January 2018

Keywords provided by Yale University:

glycine; treatment; alcohol dependence; schizophrenia

Additional relevant MeSH terms:

Alcoholism; Schizophrenia; Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders; Alcohol-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Glycine; Glycine Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs