Glutamate- and GABA-targeted drugs for Cc-occurring bipolar and alcohol use disorders: a randomized, double-blind, placebo-controlled, crossover study of N-acetylcysteine, gabapentin, and placebo.

Forty percent of people with bipolar disorder (BD) develop alcohol use disorder (AUD), with co-occurring AUD substantially worsening the course of BD. Though efficacious treatments remain elusive, frontal glutamate and GABA dysregulation represent promising targets for intervention. This study evaluated the ability of two adjunctive medications, N-acetylcysteine (NAC) and gabapentin, to modulate glutamate and GABA (primary) and to reduce heavy drinking and depressive symptoms (exploratory) in people with BD + AUD. Fifty-four individuals meeting DSM-5 criteria for BD + AUD were enrolled in a randomized, double-blind, placebo-controlled, crossover study, with 3, 1-week conditions (NAC, gabapentin, placebo). Medication effects on dorsal anterior cingulate cortex (dACC) glutamate+glutamine (Glx) and GABA levels, via proton MR spectroscopy, and percent heavy drinking days (%HDD) and depressive symptoms were evaluated with linear mixed models. Forty-nine participants (M[SD] age=41.0[12.2], 51% female, 74% white) provided 121-131 posttreatment-MRI scans, depending on analysis. Medications were well-tolerated, and adherence was excellent. DACC Glx (F = 4.76, p = 0.012) but not GABA (F = 0.96, p = 0.388) levels significantly differed across conditions, with only NAC (M[SD] = 21.50[2.55]) demonstrating significantly different(lower) glutamate levels relative to placebo (M[SD] = 22.59[2.56]; p = 0.003; SMD = 0.43). %HDD (F = 3.90, p = 0.025) also significantly differed across conditions, again with only NAC (M[SD] = 31.86[4.60]) demonstrating significantly different(lower) %HDD relative to placebo (M[SD] = 40.94[4.55]; p = 0.015; SMD = 0.33), though neither NAC (p = 0.128) nor gabapentin (p = 0.228) differed from placebo on depressive symptoms. These results support the development of mechanistic clinical trials targeting glutamatergic dysfunction in people with BD + AUD. Trial Registration: https://clinicaltrials.gov/study/NCT03220776 .