Glycine and Oral D-Cycloserine in Alcoholic Patients and Healthy Subjects

Alcohol Dependence Clinical Trial

Official title:

Glycine and Oral D-Cycloserine in Alcoholic Patients and Healthy Subjects

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00635102
• Other study ID #: 12449
• Secondary ID: VA Merit Grant
• Status: Completed
• Phase: N/A
• First received: March 6, 2008
• Last updated: December 14, 2016
• Start date: October 1997
• Est. completion date: February 2008

Study information

• Verified date: December 2016
• Source: Yale University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 57
• Est. completion date: February 2008
• Est. primary completion date: February 2008
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 21 Years to 70 Years

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Outcomes Assessor), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Alcohol Dependence
• Alcoholism

Intervention

Drug:
• D-Cycloserine PO and Glycine IV
Test days will involve administration of D-Cycloserine in the morning in pill form then 4 hours later a 30 minute infusion of Glycine.
• Placebo D-Cycloserine PO and placebo Glycine IV
Placebo
• Placebo D-Cycloserine PO and Glycine IV

• D-Cycloserine PO and placebo Glycine IV

Locations

Country	Name	City	State
United States	VA Connecticut Healthcare System	West Haven	Connecticut

Sponsors (1)

Lead Sponsor	Collaborator
Yale University

Country where clinical trial is conducted

United States, 

References & Publications (1)

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 alco — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Visual Analog Scales of Similarity to Alcohol - Baseline	Visual Analog Scales of Similarity to Alcohol data using the Likert scale (0 Not at all similar to alcohol -7 Extremely similar to alcohol) evaluating the similarity of drug effects to alcohol	Baseline	No
Primary	Visual Analog Scales of Similarity to Alcohol 60 Minutes Prior to Glycine Infusion	Visual Analog Scales of Similarity to Alcohol data using the Likert scale (0 Not at all similar to alcohol -7 Extremely similar to alcohol) evaluating the similarity of drug effects to alcohol	60 minutes prior to Glycine infusion	No
Primary	Visual Analog Scales of Similarity to Alcohol 30 Minutes	Visual Analog Scales of Similarity to Alcohol data using the Likert scale (0 Not at all similar to alcohol -7 Extremely similar to alcohol) evaluating the similarity of drug effects to alcohol	30 minutes	No
Primary	Visual Analog Scales of Similarity to Alcohol 60 Minutes	Visual Analog Scales of Similarity to Alcohol data using the Likert scale (0 Not at all similar to alcohol -7 Extremely similar to alcohol) evaluating the similarity of drug effects to alcohol	60 minutes	No
Primary	Visual Analog Scales of Similarity to Alcohol 120 Minutes	Visual Analog Scales of Similarity to Alcohol data using the Likert scale (0 Not at all similar to alcohol -7 Extremely similar to alcohol) evaluating the similarity of drug effects to alcohol	120 minutes	No
Secondary	Number of Drinks Felt Consumed at 60 Minutes Prior to Glycine Infusion	The Number of Drinks Scale asks subjects to report on the number of alcoholic drinks they felt they had consumed.	60 minutes prior to Glycine infusion	No
Secondary	Number of Drinks Felt Consumed at 30 Minutes	The Number of Drinks Scale asks subjects to report on the number of alcoholic drinks they felt they had consumed.	30 minutes	No
Secondary	Number of Drinks Felt Consumed at 60 Minutes	The Number of Drinks Scale asks subjects to report on the number of alcoholic drinks they felt they had consumed.	60 minutes	No
Secondary	Number of Drinks Felt Consumed at 120 Minutes	The Number of Drinks Scale asks subjects to report on the number of alcoholic drinks they felt they had consumed.	120 minutes	No
Secondary	Biphasic Alcohol Effects Scale (BAES) Subscale Sedation - Baseline	Self-report rating scale used to measure the sedative effects (0 not at all sedated - 70 extremely sedated) of alcohol	Baseline	No
Secondary	Biphasic Alcohol Effects Scale (BAES) - Subscale Sedation 60 Minutes Prior to Glycine Infusion	Self-report rating scale used to measure the sedative effects (0 not at all sedated - 70 extremely sedated) of alcohol	60 minutes prior to Glycine infusion	No
Secondary	Biphasic Alcohol Effects Scale (BAES) Subscale Sedation - 30 Minutes	Self-report rating scale used to measure the sedative effects (0 not at all sedated - 70 extremely sedated) of alcohol	30 minutes	No
Secondary	Biphasic Alcohol Effects Scale (BAES) Subscale Sedation - 60 Minutes	Self-report rating scale used to measure the sedative effects (0 not at all sedated - 70 extremely sedated) of alcohol	60 minutes	No
Secondary	Biphasic Alcohol Effects Scale (BAES) Subscale Sedation - 120 Minutes	Self-report rating scale used to measure the sedative effects (0 not at all sedated - 70 extremely sedated) of alcohol	120 minutes	No
Secondary	Visual Analog Scales (VAS) - Baseline	Visual Analog Scales (VAS): Self-report rating scale used to measure high (0 not at all - 7 extremely)	Baseline	No
Secondary	Visual Analog Scales (VAS) - 60 Minutes Prior to Glycine Infusion	Visual Analog Scales (VAS): Self-report rating scale used to measure high (0 not at all - 7 extremely)	60 minutes prior to Glycine infusion	No
Secondary	Visual Analog Scales (VAS) - 30 Minutes	Visual Analog Scales (VAS): Self-report rating scale used to measure high (0 not at all - 7 extremely)	30 minutes	No
Secondary	Visual Analog Scales (VAS) - 60 Minutes	Visual Analog Scales (VAS): Self-report rating scale used to measure high (0 not at all - 7 extremely)	60 minutes	No
Secondary	Visual Analog Scales (VAS) - 120 Minutes	Visual Analog Scales (VAS): Self-report rating scale used to measure high (0 not at all - 7 extremely)	120 minutes	No
Secondary	Alcohol Craving Scale (ACS) Subscale: Desire to Drink- Baseline	Alcohol Craving Scale (ACS) Subscale: Desire to drink: Self-report rating scale used to measure desire to drink alcohol (0 No desire to drink alcohol - 100 Definitely desire to drink alcohol)	Baseline	No
Secondary	Alcohol Craving Scale (ACS) Subscale: Desire to Drink - 60 Minutes Prior to Glycine Infusion	Alcohol Craving Scale (ACS) Subscale: Desire to drink: Self-report rating scale used to measure desire to drink alcohol (0 No desire to drink alcohol - 100 Definitely desire to drink alcohol)	60 minutes prior to Glycine infusion	No
Secondary	Alcohol Craving Scale (ACS) Subscale: Desire to Drink: - 30 Minutes	Alcohol Craving Scale (ACS) Subscale: Desire to drink: Self-report rating scale used to measure desire to drink alcohol (0 No desire to drink alcohol - 100 Definitely desire to drink alcohol)	30 minutes	No
Secondary	Alcohol Craving Scale (ACS) Subscale: Desire to Drink - 60 Minutes	Alcohol Craving Scale (ACS) Subscale: Desire to drink: Self-report rating scale used to measure desire to drink alcohol (0 No desire to drink alcohol - 100 Definitely desire to drink alcohol)	60 minutes	No
Secondary	Alcohol Craving Scale (ACS) Subscale: Desire to Drink - 120 Minutes	Alcohol Craving Scale (ACS) Subscale: Desire to drink: Self-report rating scale used to measure desire to drink alcohol (0 No desire to drink alcohol - 100 Definitely desire to drink alcohol)	120 minutes	No
Secondary	Alcohol Craving Scale (ACS) Subscale: Mood Improvement - Baseline	Alcohol Craving Scale (ACS) Subscale: Mood improvement : Self-report rating scale used to measure expected alcohol-related mood improvement (0 Not at all - 100 Definitely)	Baseline	No
Secondary	Alcohol Craving Scale (ACS) Subscale: Mood Improvement - 60 Minutes Prior to Glycine Infusion	Alcohol Craving Scale (ACS) Subscale: Mood improvement : Self-report rating scale used to measure expected alcohol-related mood improvement (0 Not at all - 100 Definitely)	60 minutes prior to Glycine infusion	No
Secondary	Alcohol Craving Scale (ACS) Subscale: Mood Improvement - 30 Minutes	Alcohol Craving Scale (ACS) Subscale: Mood improvement : Self-report rating scale used to measure expected alcohol-related mood improvement (0 Not at all - 100 Definitely)	30 minutes	No
Secondary	Alcohol Craving Scale (ACS) Subscale: Mood Improvement - 60 Minutes	Alcohol Craving Scale (ACS) Subscale: Mood improvement : Self-report rating scale used to measure expected alcohol-related mood improvement (0 Not at all - 100 Definitely)	60 minutes	No
Secondary	Alcohol Craving Scale (ACS) Subscale: Mood Improvement - 120 Minutes	Alcohol Craving Scale (ACS) Subscale: Mood improvement : Self-report rating scale used to measure expected alcohol-related mood improvement (0 Not at all - 100 Definitely)	120 minutes	No
Secondary	Alcohol Craving Scale (ACS) Subscale: Discomfort - Baseline	Alcohol Craving Scale (ACS) Subscale: Discomfort: Self-report rating scale - subscale reflecting expected alcohol-related relief from discomfort (0 Not at all - 100 Definitely)	Baseline	No
Secondary	Alcohol Craving Scale (ACS) Subscale: Discomfort - 60 Minutes Prior to Glycine Infusion	Alcohol Craving Scale (ACS) Subscale: Discomfort: Self-report rating scale - subscale reflecting expected alcohol-related relief from discomfort (0 Not at all - 100 Definitely)	60 minutes prior to Glycine infusion	No
Secondary	Alcohol Craving Scale (ACS) Subscale: Discomfort - 30 Minutes	Alcohol Craving Scale (ACS) Subscale: Discomfort: Self-report rating scale - subscale reflecting expected alcohol-related relief from discomfort (0 Not at all - 100 Definitely)	30 minutes	No
Secondary	Alcohol Craving Scale (ACS) Subscale: Discomfort - 60 Minutes	Alcohol Craving Scale (ACS) Subscale: Discomfort: Self-report rating scale - subscale reflecting expected alcohol-related relief from discomfort (0 Not at all - 100 Definitely)	60 minutes	No
Secondary	Alcohol Craving Scale (ACS) Subscale: Discomfort - 120 Minutes	Alcohol Craving Scale (ACS) Subscale: Discomfort: Self-report rating scale - subscale reflecting expected alcohol-related relief from discomfort (0 Not at all - 100 Definitely)	120 minutes	No
Secondary	Alcohol Craving Scale (ACS) Subscale: Reduced Control of Alcohol Use - Baseline	Alcohol Craving Scale (ACS) Subscale: Self-report rating scale used to measure reduced control of alcohol (0 Not at all - 100 Definitely)	Baseline	No
Secondary	Alcohol Craving Scale (ACS) Subscale: Reduced Control of Alcohol Use - 60 Minutes Prior to Glycine Infusion	Alcohol Craving Scale (ACS) Subscale: Self-report rating scale used to measure reduced control of alcohol (0 Not at all - 100 Definitely)	60 minutes prior to Glycine infusion	No
Secondary	Alcohol Craving Scale (ACS) Subscale: Reduced Control of Alcohol Use - 30 Minutes	Alcohol Craving Scale (ACS) Subscale: Self-report rating scale used to measure reduced control of alcohol (0 Not at all - 100 Definitely)	30 minutes	No
Secondary	Alcohol Craving Scale (ACS) Subscale: Reduced Control of Alcohol Use - 60 Minutes	Alcohol Craving Scale (ACS) Subscale: Self-report rating scale used to measure reduced control of alcohol (0 Not at all - 100 Definitely)	60 minutes	No
Secondary	Alcohol Craving Scale (ACS) Subscale: Reduced Control of Alcohol Use - 120 Minutes	Alcohol Craving Scale (ACS) Subscale: Self-report rating scale used to measure reduced control of alcohol (0 Not at all - 100 Definitely)	120 minutes	No
Secondary	Continuous Performance Task (CPT) - Distractibility A-Prime - 30 Minutes	gordon diagnostic system is a continuous performance task (CPT) to measure distractibility - (A-Prime score range 0 minimum - 1 maximum - the higher number the better the performance)	30 minutes	No
Secondary	Continuous Performance Task (CPT) - Vigilance - A-Prime Score 30 Minutes	gordon diagnostic system is a continuous performance task (CPT) to measure Vigilance - (A-Prime score range 0 minimum - 1 maximum - The higher number the better the performance)	30 minutes	No
Secondary	Hopkins Verbal Learning Task - Immediate Recall - 60 Minutes - Trial 1	Hopkins Verbal Learning Task (HVLT) - measures verbal memory and hippocampus function. (Three immediate recall trials) (0 No words recalled - 12 all words recalled)	60 minutes - Trial 1	No
Secondary	Hopkins Verbal Learning Task - Immediate Recall - 60 Minutes - Trial 2	Hopkins Verbal Learning Task (HVLT) - measures verbal memory and hippocampus function. (Three immediate recall trials) (0 No words recalled - 12 all words recalled)	60 minutes - Trial 2	No
Secondary	Hopkins Verbal Learning Task - Immediate Recall - 60 Minutes - Trial 3	Hopkins Verbal Learning Task (HVLT) - measures verbal memory and hippocampus function. (Three immediate recall trials) (0 No words recalled - 12 all words recalled)	60 minutes - Trial 3	No
Secondary	Hopkins Verbal Learning Task - Delay Recall - 90 Minutes	Hopkins Verbal Learning Task (HVLT) - measures verbal memory and hippocampus function. (delay recall - 30 minutes after Trials 1-3 were given) (0 No words recalled - 12 all words recalled)	90 minutes	No