Imaging GABAergic/Glutamatergic Drugs in Bipolar Alcoholics Alcoholics

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Imaging Framework for Testing GABAergic/Glutamatergic Drugs in Bipolar Alcoholics

Conditions
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Alcohol Use Disorder, Bipolar Disorder

Intervention / Treatment
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* Drug: N-Acetylcysteine
* Drug: Gabapentin
* Drug: Placebo Oral Tablet


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gabapentin, then N-Acetylcysteine, then Placebo Oral Capsule<br>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 | Drug: N-Acetylcysteine<br>* 5 day trial of N-acetylcysteine with titration to 2,400mg<br>Drug: Gabapentin<br>* 5 day trial of gabapentin with titration to 1,200mg<br>Drug: Placebo Oral Tablet<br>* 5 day trial of matched placebo<br>|
| Experimental: N-Acetylcysteine, then Placebo Oral Capsule, then Gabapentin<br>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 | Drug: N-Acetylcysteine<br>* 5 day trial of N-acetylcysteine with titration to 2,400mg<br>Drug: Gabapentin<br>* 5 day trial of gabapentin with titration to 1,200mg<br>Drug: Placebo Oral Tablet<br>* 5 day trial of matched placebo<br>|
| Placebo Comparator: Placebo Oral Tablet, then Gabapentin, then N-Acetylcysteine<br>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 | Drug: N-Acetylcysteine<br>* 5 day trial of N-acetylcysteine with titration to 2,400mg<br>Drug: Gabapentin<br>* 5 day trial of gabapentin with titration to 1,200mg<br>Drug: Placebo Oral Tablet<br>* 5 day trial of matched placebo<br>|
| Experimental: Placebo Oral Capsule, then N-Acetylcysteine, then Gabapentin<br>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 | Drug: N-Acetylcysteine<br>* 5 day trial of N-acetylcysteine with titration to 2,400mg<br>Drug: Gabapentin<br>* 5 day trial of gabapentin with titration to 1,200mg<br>Drug: Placebo Oral Tablet<br>* 5 day trial of matched placebo<br>|
| Experimental: Gabapentin, then Placebo Oral Capsule, then N-Acetylcysteine<br>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 | Drug: N-Acetylcysteine<br>* 5 day trial of N-acetylcysteine with titration to 2,400mg<br>Drug: Gabapentin<br>* 5 day trial of gabapentin with titration to 1,200mg<br>Drug: Placebo Oral Tablet<br>* 5 day trial of matched placebo<br>|
| Experimental: N-Acetylcysteine, then Gabapentin, then Placebo Oral Capsule<br>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 | Drug: N-Acetylcysteine<br>* 5 day trial of N-acetylcysteine with titration to 2,400mg<br>Drug: Gabapentin<br>* 5 day trial of gabapentin with titration to 1,200mg<br>Drug: Placebo Oral Tablet<br>* 5 day trial of matched placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 |