N-Methyl-D-Aspartate (NMDA) Dysregulation in Individuals With a Family Vulnerability to Alcoholism
Recruitment status was Recruiting
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Purpose
The proposed study is the first to explore the contribution of brain glutamate systems, a major target of ethanol in the brain, to the vulnerability to develop alcoholism. This study may lead to an enhanced understanding of the underlying neurobiological mechanism in high-risk individuals that may lead to the transition from moderate to excessive use of alcohol.
| Condition | Intervention |
|---|---|
|
Alcoholism |
Drug: Ketamine Drug: Thiopental Drug: Placebo |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Pharmacodynamics Study Intervention Model: Crossover Assignment Masking: Double Blind (Subject, Outcomes Assessor) Primary Purpose: Health Services Research |
| Official Title: | NMDA Dysregulation in Individuals With a Family Vulnerability to Alcoholism |
- Positive and Negative Symptom Scale (PANSS), visual analog scales of mood states (i.e., anxiety) and the Clinician-Administered Dissociative States Scale (CADSS) [ Time Frame: Test day begins at Baseline, +15 minutes, +45 minutes, +80 minutes, +110 minutes, +170 minutes, +230 minutes ] [ Designated as safety issue: Yes ]
- Visual analog scales for high, similarity to ethanol, Mini Mental Status Examination (MMSE), placement of electrodes, Biphasic Alcohol Effects Scale, Hopkins Verbal Learning, number of drinks scale [ Time Frame: Baseline, +15 minutes, +45 minutes, +80 minutes, +110 minutes, +170 minutes, +230 minutes ] [ Designated as safety issue: Yes ]
| Estimated Enrollment: | 60 |
| Study Start Date: | March 2001 |
| Estimated Study Completion Date: | September 2011 |
| Estimated Primary Completion Date: | July 2011 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Active Comparator: Ketamine
0.23 mg/kg, loading dose and infusion rate 0.58 mg/kg/minute for 60 minutes, IV Ketamine
|
Drug: Ketamine
Ketamine: 0.23 mg/kg, loading dose and infusion rate 0.58 mg/kg/minute for 60 minutes, IV
|
|
Active Comparator: Thiopental
1.5 mg/kg, loading dose and an infusion rate of 40 mcg/kg/minute for 60 minutes, IV Thiopental
|
Drug: Thiopental
Thiopental: 1.5 mg/kg, loading dose and an infusion rate of 40 mcg/kg/minute for 60 minutes
|
|
Placebo Comparator: Placebo
loading dose and an infusion for 60 minutes saline solution (Placebo)
|
Drug: Placebo
Placebo: loading dose and an infusion for 60 minutes saline solution
|
Detailed Description:
Males and females with a paternal family history of alcoholism have a high risk for developing alcoholism. These individuals have been shown to decrease dysphoric responses to alcohol self-administration that may promote the excessive use of alcohol. Ethanol has been shown to be an antagonist at the N-methyl-D-aspartate (NMDA) glutamate receptor. We have recently shown that sober alcoholics have decreased dysphoric response to the NMDA antagonist, ketamine. We propose to test the hypothesis that this characteristic exists as a vulnerability factor in those individuals susceptible to develop alcoholism. Specifically, the objective is to determine whether individuals with a family history positive (FHP) for alcoholism will experience less dysphoric, anxiogenic, and psychotogenic effects to ketamine infusion when compared to family history negative (FHN) control subjects.
Male and female subjects, FHP (biological father and one other first degree relative) between the ages of 21-30, and matched controls (FHN) will complete 3 test days in a randomized balanced order under double-blind conditions. Test days will involve the 60-minute intravenous infusion of placebo, ketamine, thiopental. Outcome measures include the Positive and Negative Symptom Scale and the Clinician-Administered Dissociative States Scale to measure perceptual responses to ketamine, and visual analog scales for mood states. Secondary measures include visual analog scales for high, similarity to ethanol, the Sensation Scale (a validated measure of ethanol-like sensations) and aspects of craving for alcohol.
Eligibility| Ages Eligible for Study: | 21 Years to 30 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | Yes |
Inclusion Criteria:
- Male and female between the ages of 21 and 30 years
- Medically and neurologically healthy on the basis of history, physical examination, EKG, screening laboratories, absence of current and/or past substance abuse
- For Family History Positive (FHP) Subjects: Biological father and another first or second-degree biological relative with history of alcoholism
Exclusion Criteria:
- DSM-IV psychiatric and substance abuse diagnosis by history on psychiatric evaluation that includes a structured diagnostic interview (The Semi-Structured Assessment for the Genetics of alcoholism: SSAGA) and the Wisconsin Scales of Psychosis Proneness
- History of counseling or psychotherapy; except family therapy centered around another family member
- Extended unwillingness to remain alcohol-free for three days prior to testing and for the duration of the testing period
- For women: positive pregnancy test at screening or intention to engage in unprotected sex during the study
- Alcohol naïve
- Previous bad experience with ketamine
- Adoptee and no contact with family members
- For Family History Negative (FHN) Subjects: NO family history of alcoholism in any first or second-degree relatives (subjects must reliably report on three first-degree relatives)
Contacts and Locations| Contact: Diana D. Limoncelli, BA | 203-932-5711 ext 5217 | arc1@yale.edu |
| United States, Connecticut | |
| VA Connecticut Healthcare System | Recruiting |
| West Haven, Connecticut, United States, 06516 | |
| Principal Investigator: | Ismene L. Petrakis, MD | Yale University |
More Information
No publications provided
| Responsible Party: | Ismene Petrakis, Yale University |
| ClinicalTrials.gov Identifier: | NCT00588952 History of Changes |
| Other Study ID Numbers: | 0103012310, 2P50-AA012870-07 NIAAA |
| Study First Received: | December 27, 2007 |
| Last Updated: | January 6, 2009 |
| Health Authority: | United States: Institutional Review Board |
Additional relevant MeSH terms:
|
Alcoholism Alcohol-Related Disorders Substance-Related Disorders Mental Disorders N-Methylaspartate Ketamine Thiopental Excitatory Amino Acid Agonists Excitatory Amino Acid Agents Neurotransmitter Agents Molecular Mechanisms of Pharmacological Action Pharmacologic Actions Physiological Effects of Drugs Anesthetics, Dissociative |
Anesthetics, Intravenous Anesthetics, General Anesthetics Central Nervous System Depressants Central Nervous System Agents Therapeutic Uses Excitatory Amino Acid Antagonists Analgesics Sensory System Agents Peripheral Nervous System Agents Hypnotics and Sedatives GABA Modulators GABA Agents Anticonvulsants |
ClinicalTrials.gov processed this record on October 17, 2012
