Imaging GABAergic/Glutamatergic Drugs in Bipolar Alcoholics Alcoholics

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.

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.