Imaging GABAergic/Glutamatergic Drugs in Bipolar Alcoholics Alcoholics
Condition: Alcohol Use Disorder; Bipolar Disorder
MeSH terms: Alcoholism; Bipolar Disorder
Study type: Interventional
Phase: Phase 2

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.
    

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.
    

Intervention name(s): N-Acetylcysteine; Gabapentin; Placebo Oral Tablet
Intervention type(s): Drug; Drug; Drug
Intervention description(s): 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 matched placebo
Intervention MeSH terms: Acetylcysteine; Gabapentin; N-monoacetylcystine
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Basic Science