Clinical trial NCT00635102: Glycine and Oral D-Cycloserine in Alcoholic Patients and Healthy Subjects
Official title: Glycine and Oral D-Cycloserine in Alcoholic Patients and Healthy Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Alcohol Dependence
Keywords: Alcohol Dependence, Alcoholism, Glycine, D-Cycloserine
Lead sponsor: Yale University
Sponsor class: OTHER
First posted: 2008-03-13
Enrollment: 57
Sex: ALL
Minimum age (years): 21
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: PREVENTION

Brief summary: Question #1: Will glycine ameliorate cognitive deficits? Hypothesis #1: Based on positive findings conducted with glycine and milacemide, a glycine prodrug, in schizophrenia and dementia, we expect that glycine will ameliorate cognitive deficits.

Question #2: Will alcoholic patients show enhanced endocrinal effects to glycine? Hypothesis #2: Based on the dose-related effects of glycine in healthy subjects, we expect that glycine will increase the endocrinal response to glycine in alcoholic patients with, supposedly, dysregulated NMDA receptor function.

Question #3: Will D-cycloserine have ethanol-like effects? Hypothesis #3: If inhibition of NMDA receptor function is fundamental to the subjective effects of ethanol, then the NMDA antagonist properties of D-cycloserine should be recognized as ethanol-like (relative to placebo) in recently detoxified alcoholics and healthy subjects.

Question #4: Will D-cycloserine reverse cognitive benefits of glycine? Hypothesis 4: Based on the dose related NMDA antagonist activity of D-cycloserine, we expect that D-cycloserine will compete with the agonist activity of glycine and therefore it will reverse the cognitive benefits of glycine.

Question #5: Will D-cycloserine inhibit endocrinal effects of glycine? Hypothesis #5: If the agonist activity of glycine is necessary to determine endocrine response, then the dose-related NMDA antagonist properties of D-cycloserine should block these effects.

Detailed description: The purpose of this study is to investigate the interaction between glycine and D-cycloserine in alcoholic patients and healthy subjects. Preclinical studies have shown that compounds acting at the glycine site of the N-methyl-D-aspartate (NMDA) receptor complex, such as glycine, may reverse the effects of ethanol on the NMDA receptor function (Rabe et al., 1990). The amino acid glycine is a co-agonist of the NMDA receptor complex (Kemp et al., 1993). It binds to the strychnine-insensitive site and positively modulates the NMDA receptor (Mc Donald et al., 1990). Physiologically, the glycine site is not saturated, and administration of glycine can potentiate NMDA receptor mediated responses. In contrast, D-cycloserine (Hood et al., 1989) is a partial-agonist at the glycine site of the NMDA receptor, with dose-dependent NMDA antagonist properties. The NMDA antagonist activity of D-cycloserine should produce ethanol like-effects that can be reversed by the agonist glycine. This study is intended to evaluate possible contributions of the glycine site to the reduction of cognitive deficits of alcoholism and complements the current work at VA Connecticut Healthcare System on the NMDA antagonists in alcoholic and healthy subjects.

Eligibility criteria: Inclusion / Exclusion Criteria Alcoholic subjects:

* Male or female (post-menopausal, surgically sterile, or negative pregnancy test at screening and agreement to utilize an established birth control during the testing period) between the age of 21 and 70 yrs.
* Meet Diagnostic and Statistical Manual (DSM) IV criteria for alcohol dependence by structured clinical interview
* Meet von Knorring criteria for early onset (type II) alcoholism
* Without other DSM IV Axis I diagnoses by Structured Clinical Interview (SCID).
* Without lifetime history of other substance abuse diagnosis by SCID (excluding tobacco) and urine toxicology screen negative for drug of abuse.
* Medically and neurologically healthy on the basis of history, physical examination, sequential multiple analysis-computer (SMAC-20), complete blood count (CBC) w/diff. and EKG. In light of the proximity to alcohol dependence, liver function test (LFT) elevations of twice normal will be accepted into the study.
* Patients with stable medical problems may be included in the study if their medications have not been adjusted in the month prior to participation and if these medications lack prominent central nervous system (CNS) effects.
* Absence of alcohol within the past 15 days.
* Patients must be free of medications utilized to facilitate detoxification (lorazepam, oxazepam) for at least 3 days prior to initiating testing.
* Patients must have no history of alcoholic hallucinosis.
* Patients must not be in acute alcohol withdrawal as evidence by a score no more than 2 for each item of the Clinical Institute Withdrawal Assessment Scale
* Patients taking ethionamide or isoniazid will be not be allowed to participate in the study.

Inclusion / Exclusion Criteria Healthy subjects:

* Male or female (post-menopausal, surgically sterile, or negative pregnancy test at screening and agreement to utilize an established birth control during the testing period) between the age of 21 and 70 yrs.
* Absence of a lifetime substance abuse diagnosis by the non-patient version of the SCID.
* Medically and neurologically healthy on the basis of history, physical examination, SMAC-20, CBC w/diff. and EKG. In light of the proximity to alcohol dependence, LFT elevations of twice normal will be accepted into the study.
* Absence of alcohol within the past 14 days
* Healthy subjects will be matched to the patient group for age, sex and educational level.

Primary outcomes:
measure: Visual Analog Scales of Similarity to Alcohol - Baseline
timeFrame: Baseline
measure: Visual Analog Scales of Similarity to Alcohol 60 Minutes Prior to Glycine Infusion
timeFrame: 60 minutes prior to Glycine infusion
measure: Visual Analog Scales of Similarity to Alcohol 30 Minutes
timeFrame: 30 minutes
measure: Visual Analog Scales of Similarity to Alcohol 60 Minutes
timeFrame: 60 minutes
measure: Visual Analog Scales of Similarity to Alcohol 120 Minutes
timeFrame: 120 minutes
Secondary outcomes:
measure: Number of Drinks Felt Consumed at 60 Minutes Prior to Glycine Infusion
timeFrame: 60 minutes prior to Glycine infusion
measure: Number of Drinks Felt Consumed at 30 Minutes
timeFrame: 30 minutes
measure: Number of Drinks Felt Consumed at 60 Minutes
timeFrame: 60 minutes
measure: Number of Drinks Felt Consumed at 120 Minutes
timeFrame: 120 minutes
measure: Biphasic Alcohol Effects Scale (BAES) Subscale Sedation - Baseline
timeFrame: Baseline
measure: Biphasic Alcohol Effects Scale (BAES) - Subscale Sedation 60 Minutes Prior to Glycine Infusion
timeFrame: 60 minutes prior to Glycine infusion
measure: Biphasic Alcohol Effects Scale (BAES) Subscale Sedation - 30 Minutes
timeFrame: 30 minutes
measure: Biphasic Alcohol Effects Scale (BAES) Subscale Sedation - 60 Minutes
timeFrame: 60 minutes
measure: Biphasic Alcohol Effects Scale (BAES) Subscale Sedation - 120 Minutes
timeFrame: 120 minutes
measure: Visual Analog Scales (VAS) - Baseline
timeFrame: Baseline
measure: Visual Analog Scales (VAS) - 60 Minutes Prior to Glycine Infusion
timeFrame: 60 minutes prior to Glycine infusion
measure: Visual Analog Scales (VAS) - 30 Minutes
timeFrame: 30 minutes
measure: Visual Analog Scales (VAS) - 60 Minutes
timeFrame: 60 minutes
measure: Visual Analog Scales (VAS) - 120 Minutes
timeFrame: 120 minutes
measure: Alcohol Craving Scale (ACS) Subscale: Desire to Drink- Baseline
timeFrame: Baseline
measure: Alcohol Craving Scale (ACS) Subscale: Desire to Drink - 60 Minutes Prior to Glycine Infusion
timeFrame: 60 minutes prior to Glycine infusion
measure: Alcohol Craving Scale (ACS) Subscale: Desire to Drink: - 30 Minutes
timeFrame: 30 minutes
measure: Alcohol Craving Scale (ACS) Subscale: Desire to Drink - 60 Minutes
timeFrame: 60 minutes
measure: Alcohol Craving Scale (ACS) Subscale: Desire to Drink - 120 Minutes
timeFrame: 120 minutes
measure: Alcohol Craving Scale (ACS) Subscale: Mood Improvement - Baseline
timeFrame: Baseline
measure: Alcohol Craving Scale (ACS) Subscale: Mood Improvement - 60 Minutes Prior to Glycine Infusion
timeFrame: 60 minutes prior to Glycine infusion
measure: Alcohol Craving Scale (ACS) Subscale: Mood Improvement - 30 Minutes
timeFrame: 30 minutes
measure: Alcohol Craving Scale (ACS) Subscale: Mood Improvement - 60 Minutes
timeFrame: 60 minutes
measure: Alcohol Craving Scale (ACS) Subscale: Mood Improvement - 120 Minutes
timeFrame: 120 minutes
measure: Alcohol Craving Scale (ACS) Subscale: Discomfort - Baseline
timeFrame: Baseline
measure: Alcohol Craving Scale (ACS) Subscale: Discomfort - 60 Minutes Prior to Glycine Infusion
timeFrame: 60 minutes prior to Glycine infusion
measure: Alcohol Craving Scale (ACS) Subscale: Discomfort - 30 Minutes
timeFrame: 30 minutes
measure: Alcohol Craving Scale (ACS) Subscale: Discomfort - 60 Minutes
timeFrame: 60 minutes
measure: Alcohol Craving Scale (ACS) Subscale: Discomfort - 120 Minutes
timeFrame: 120 minutes
measure: Alcohol Craving Scale (ACS) Subscale: Reduced Control of Alcohol Use - Baseline
timeFrame: Baseline
measure: Alcohol Craving Scale (ACS) Subscale: Reduced Control of Alcohol Use - 60 Minutes Prior to Glycine Infusion
timeFrame: 60 minutes prior to Glycine infusion
measure: Alcohol Craving Scale (ACS) Subscale: Reduced Control of Alcohol Use - 30 Minutes
timeFrame: 30 minutes
measure: Alcohol Craving Scale (ACS) Subscale: Reduced Control of Alcohol Use - 60 Minutes
timeFrame: 60 minutes
measure: Alcohol Craving Scale (ACS) Subscale: Reduced Control of Alcohol Use - 120 Minutes
timeFrame: 120 minutes
measure: Continuous Performance Task (CPT) - Distractibility A-Prime - 30 Minutes
timeFrame: 30 minutes
measure: Continuous Performance Task (CPT) - Vigilance - A-Prime Score 30 Minutes
timeFrame: 30 minutes
measure: Hopkins Verbal Learning Task - Immediate Recall - 60 Minutes - Trial 1
timeFrame: 60 minutes - Trial 1
measure: Hopkins Verbal Learning Task - Immediate Recall - 60 Minutes - Trial 2
timeFrame: 60 minutes - Trial 2
measure: Hopkins Verbal Learning Task - Immediate Recall - 60 Minutes - Trial 3
timeFrame: 60 minutes - Trial 3
measure: Hopkins Verbal Learning Task - Delay Recall - 90 Minutes
timeFrame: 90 minutes
Other outcomes:
Locations:
city: West Haven
country: United States
facility: VA Connecticut Healthcare System
state: Connecticut
Study officials:
affiliation: Yale University
name: John H Krystal, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Krystal JH, Petrakis IL, Limoncelli D, Nappi SK, Trevisan L, Pittman B, D'Souza DC, Suckow RF. Characterization of the interactive effects of glycine and D-cycloserine in men: further evidence for enhanced NMDA receptor function associated with human alcohol dependence. Neuropsychopharmacology. 2011 Feb;36(3):701-10. doi: 10.1038/npp.2010.203. Epub 2010 Dec 1.