Imaging GABAergic/Glutamatergic Drugs in Bipolar Alcoholics Alcoholics

Bipolar Disorder Clinical Trial

Official title:

Imaging Framework for Testing GABAergic/Glutamatergic Drugs in Bipolar Alcoholics

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03220776
• Other study ID #: 64964
• Secondary ID: R01AA025365
• Status: Completed
• Phase: Phase 2
• Start date: August 7, 2017
• Est. completion date: November 21, 2022

Study information

• Verified date: December 2023
• Source: Medical University of South Carolina
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 54
• Est. completion date: November 21, 2022
• Est. primary completion date: November 21, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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.

Related Conditions & MeSH terms

• Alcohol Use Disorder
• Alcoholism
• Bipolar Disorder

Intervention

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

Locations

Country	Name	City	State
United States	Medical University of South Carolina	Charleston	South Carolina

Sponsors (3)

Lead Sponsor	Collaborator
Medical University of South Carolina	National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH)

Country where clinical trial is conducted

United States, 

References & Publications (161)

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Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Prefrontal GABA+ Concentrations	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
Primary	Prefrontal Glx Concentrations	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