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Imaging GABAergic/Glutamatergic Drugs in Bipolar Alcoholics Alcoholics

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ClinicalTrials.gov Identifier: NCT03220776
Recruitment Status : Recruiting
First Posted : July 18, 2017
Last Update Posted : March 29, 2021
Sponsor:
Collaborators:
National Institutes of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Information provided by (Responsible Party):
James J. Prisciandaro, Medical University of South Carolina

Brief Summary:
The proposed 3-week, double-blind, crossover, proof of concept study aims to manipulate neurochemical dysfunctions characteristic of individuals with co-occurring BD and AUD (i.e., abnormally low prefrontal GABA and glutamate), using medications that have been shown to normalize cortical GABA (i.e., gabapentin) and glutamate (i.e., NAC) levels in past research, and to evaluate medication-related changes in response inhibition and alcohol cue-reactivity fMRI tasks as well as drinking and mood in individuals with AUD+BD.

Condition or disease Intervention/treatment Phase
Alcohol Use Disorder Bipolar Disorder Drug: N-Acetylcysteine Drug: Gabapentin Drug: Placebo Oral Tablet Phase 2

Detailed Description:
Bipolar disorder (BD) is the Axis I psychiatric condition most strongly associated with substance use disorder (SUD); diagnostic co-occurrence is particularly high between BD and alcohol use disorder (AUD). Individuals with co-occurring SUD and BD (SUD+BD) have substantially worse clinical outcomes than those with either BD or SUD alone. Nonetheless, little is known about optimal treatment for individuals with SUD+BD; response to lithium appears to be poor, and only one double-blind, randomized, placebo-controlled trial of valproate has demonstrated improved drinking outcomes in this population. Traditionally, treatment trials for SUD+BD have investigated medications that have been FDA approved to treat either BD or SUD in hopes that such medications would prove efficacious in individuals with SUD+BD. A different approach to selecting, and ideally developing, medications for SUD+BD treatment trials would be to target neurochemical dysfunctions characteristic of individuals with both BD and SUD. Recent research by the current investigator has demonstrated unique disturbances in prefrontal gamma-Aminobutyric acid (GABA) and glutamate concentrations in this population using proton magnetic resonance spectroscopy (1H-MRS), with individuals with co-occurring alcohol dependence (AD) and BD having significantly lower levels of GABA and glutamate relative to individuals with BD alone, AD alone, or healthy controls. Lower levels of prefrontal GABA and glutamate were in turn associated with elevated impulsivity and alcohol craving. The proposed 3-week, double-blind, crossover, proof of concept study will evaluate: a) whether medications that have been demonstrated to normalize cortical GABA (i.e., gabapentin) and glutamate (i.e., N-Acetylcysteine [NAC]) concentrations in individuals with epilepsy and cocaine dependence, respectively, may similarly act to normalize prefrontal GABA and glutamate levels in individuals with AUD+BD, and b) whether normalization of prefrontal GABA and glutamate levels will be associated with improvements in functional brain activity to tasks that assess core neurobehavioral deficits of AUD and BD (i.e., response inhibition, alcohol cue-reactivity), as well as drinking and mood symptoms. Positive results may support investigation of gabapentin and/or NAC as adjunctive treatments for AUD+BD in large-scale, randomized clinical trials. Most importantly, the proposed study may provide successful demonstration of a neuro-behavioral, multimodal neuroimaging platform for evaluating the potential promise of GABAergic and glutamatergic drugs for AUD and/or BD, as well as other conditions marked by GABAergic/glutamatergic dysfunction.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 81 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Double-Blind
Primary Purpose: Basic Science
Official Title: Imaging Framework for Testing GABAergic/Glutamatergic Drugs in Bipolar Alcoholics
Actual Study Start Date : August 7, 2017
Estimated Primary Completion Date : February 1, 2022
Estimated Study Completion Date : April 30, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: N-Acetylcysteine
Each 1-week condition will consist of an in-person study visit for assessment and dispensing of medication (Day 1), titration to maximum dose (i.e., 2,400mg N-acetylcysteine) (Days 1-5), MRI (Day 5), and medication washout (Days 5-7).
Drug: N-Acetylcysteine
5 day trial of N-acetylcysteine with titration to 2,400mg

Experimental: Gabapentin
Each 1-week condition will consist of an in-person study visit for assessment and dispensing of medication (Day 1), titration to maximum dose (i.e., 1,200mg gabapentin) (Days 1-5), MRI (Day 5), and medication washout (Days 5-7).
Drug: Gabapentin
5 day trial of gabapentin with titration to 1,200mg

Placebo Comparator: Placebo Oral Tablet
Each 1-week condition will consist of an in-person study visit for assessment and dispensing of medication (Day 1), titration to maximum dose (Days 1-5), MRI (Day 5), and medication washout (Days 5-7).
Drug: Placebo Oral Tablet
5 day trial of matched placebo




Primary Outcome Measures :
  1. Prefrontal GABA and glutamate concentrations [ Time Frame: Day 5 of each experimental condition ]
    Concentrations of GABA and glutamate in dorsal anterior cingulate measured via Proton Magnetic Resonance Spectroscopy.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion:

  • Meets DSM-V diagnostic criteria for Bipolar Disorder
  • Using at least one mood stabilizing medication
  • Meets diagnostic criteria Alcohol Use Disorder, with active drinking in the past month.

Exclusion:

  • Serious medical or non-inclusionary psychiatric disease
  • Concomitant use of benzodiazepine medications or any medications hazardous if taken with gabapentin/N-acetylcysteine
  • History of clinically significant brain injury
  • Presence of non-MRI safe material, or clinically significant claustrophobia.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03220776


Contacts
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Contact: James J Prisciandaro, Ph. D (843) 792-1433 priscian@musc.edu
Contact: Sara Hix 8437920572 hixs@musc.edu

Locations
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United States, South Carolina
Medical University of South Carolina Recruiting
Charleston, South Carolina, United States, 29425
Contact: James J Prisciandaro, PhD    843-792-1433    priscian@musc.edu   
Principal Investigator: James Prisciandaro, PhD         
Sub-Investigator: Kevin Gray, MD         
Sub-Investigator: Truman Brown, PhD         
Sub-Investigator: Will Mellnick, PhD         
Sub-Investigator: Bryan Tolliver, PhD         
Sub-Investigator: Raymond Anton, MD         
Sponsors and Collaborators
Medical University of South Carolina
National Institutes of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Investigators
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Principal Investigator: James J Prisciandarao, Ph. D Medical University of South Carolina
Publications:

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Responsible Party: James J. Prisciandaro, Principal Investigator, Medical University of South Carolina
ClinicalTrials.gov Identifier: NCT03220776    
Other Study ID Numbers: 64964
R01AA025365 ( U.S. NIH Grant/Contract )
First Posted: July 18, 2017    Key Record Dates
Last Update Posted: March 29, 2021
Last Verified: March 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Disease
Alcoholism
Bipolar Disorder
Pathologic Processes
Bipolar and Related Disorders
Mental Disorders
Alcohol-Related Disorders
Substance-Related Disorders
Chemically-Induced Disorders
Acetylcysteine
Gabapentin
N-monoacetylcystine
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anticonvulsants
Anti-Anxiety Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Antimanic Agents
Antiviral Agents
Anti-Infective Agents
Expectorants
Respiratory System Agents