Imaging GABAergic/Glutamatergic Drugs in Bipolar Alcoholics Alcoholics

December 8, 2023 updated by: James J. Prisciandaro, Medical University of South Carolina

Imaging Framework for Testing GABAergic/Glutamatergic Drugs in Bipolar Alcoholics

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.

Study Overview

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.

Study Type

Interventional

Enrollment (Actual)

54

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: James J Prisciandaro, Ph. D
  • Phone Number: (843) 792-1433
  • Email: priscian@musc.edu

Study Contact Backup

Study Locations

    • South Carolina
      • Charleston, South Carolina, United States, 29425
        • Medical University of South Carolina

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Gabapentin, then N-Acetylcysteine, then Placebo Oral Capsule

Three, 1-week conditions.

Week 1 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).

Gabapentin: 5 day trial of gabapentin with titration to 1,200mg

Week 2 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).

N-Acetylcysteine: 5 day trial of N-acetylcysteine with titration to 2,400mg

Week 3 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).

Placebo Oral Tablet: 5 day trial of matched placebo

5 day trial of gabapentin with titration to 1,200mg
5 day trial of N-acetylcysteine with titration to 2,400mg
5 day trial of matched placebo
Experimental: N-Acetylcysteine, then Placebo Oral Capsule, then Gabapentin

3, 1 week conditions.

Week 1 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).

N-Acetylcysteine: 5 day trial of N-acetylcysteine with titration to 2,400mg

Week 2 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).

Placebo Oral Tablet: 5 day trial of matched placebo

Week 3 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).

Gabapentin: 5 day trial of gabapentin with titration to 1,200mg

5 day trial of gabapentin with titration to 1,200mg
5 day trial of N-acetylcysteine with titration to 2,400mg
5 day trial of matched placebo
Placebo Comparator: Placebo Oral Tablet, then Gabapentin, then N-Acetylcysteine

Three, 1-week conditions. Week 1 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).

Placebo Oral Tablet: 5 day trial of matched placebo

Week 2 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).

Gabapentin: 5 day trial of gabapentin with titration to 1,200mg

Week 3 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).

N-Acetylcysteine: 5 day trial of N-acetylcysteine with titration to 2,400mg

5 day trial of gabapentin with titration to 1,200mg
5 day trial of N-acetylcysteine with titration to 2,400mg
5 day trial of matched placebo
Experimental: Placebo Oral Capsule, then N-Acetylcysteine, then Gabapentin

Three, 1-week conditions.

Week 1 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).

Placebo Oral Tablet: 5 day trial of matched placebo

Week 2 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).

N-Acetylcysteine: 5 day trial of N-acetylcysteine with titration to 2,400mg Week 3 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).

Gabapentin: 5 day trial of gabapentin with titration to 1,200mg

5 day trial of gabapentin with titration to 1,200mg
5 day trial of N-acetylcysteine with titration to 2,400mg
5 day trial of matched placebo
Experimental: Gabapentin, then Placebo Oral Capsule, then N-Acetylcysteine

Three, 1-week conditions.

Week 1 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).

Gabapentin: 5 day trial of gabapentin with titration to 1,200mg

Week 2 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).

Placebo Oral Tablet: 5 day trial of matched placebo

Week 3 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).

N-Acetylcysteine: 5 day trial of N-acetylcysteine with titration to 2,400mg

5 day trial of gabapentin with titration to 1,200mg
5 day trial of N-acetylcysteine with titration to 2,400mg
5 day trial of matched placebo
Experimental: N-Acetylcysteine, then Gabapentin, then Placebo Oral Capsule

Three, 1-week conditions.

Week 1 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).

N-Acetylcysteine: 5 day trial of N-acetylcysteine with titration to 2,400mg

Week 2 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).

Gabapentin: 5 day trial of gabapentin with titration to 1,200mg

Week 3 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).

Placebo Oral Tablet: 5 day trial of matched placebo

5 day trial of gabapentin with titration to 1,200mg
5 day trial of N-acetylcysteine with titration to 2,400mg
5 day trial of matched placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Prefrontal GABA+ Concentrations
Time Frame: Day 5 of each experimental condition
Concentrations of GABA+, referenced to unsuppressed water and corrected for within-voxel CSF proportion, in dorsal anterior cingulate cortex measured via Proton Magnetic Resonance Spectroscopy (i.e., MEGA-PRESS).
Day 5 of each experimental condition
Prefrontal Glx Concentrations
Time Frame: Day 5 of each experimental condition
Concentrations of Glx (i.e., glutamate + glutamine), referenced to unsuppressed water and corrected for within-voxel CSF proportion, in dorsal anterior cingulate cortex measured via Proton Magnetic Resonance Spectroscopy.
Day 5 of each experimental condition

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: James J Prisciandarao, Ph. D, Medical University of South Carolina

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 7, 2017

Primary Completion (Actual)

November 21, 2022

Study Completion (Actual)

November 21, 2022

Study Registration Dates

First Submitted

July 14, 2017

First Submitted That Met QC Criteria

July 14, 2017

First Posted (Actual)

July 18, 2017

Study Record Updates

Last Update Posted (Actual)

December 13, 2023

Last Update Submitted That Met QC Criteria

December 8, 2023

Last Verified

December 1, 2023

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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