Abstract
Topiramate, a GABA/glutamate modulator, is efficacious in reducing alcohol consumption, though the mechanisms underlying this effect are not well characterized. This study analyzed functional magnetic resonance imaging (fMRI) data from 22 heavy drinkers enrolled in a 12-week placebo-controlled, randomized clinical trial of topiramate to examine the effects of topiramate on alcohol cue-elicited brain responses, craving, and heavy drinking in individuals with DSM-5 alcohol use disorder. Patients were randomized to receive either topiramate (maximal daily dosage of 200 mg/day) or placebo and were administered an fMRI alcohol cue-reactivity task at baseline (before starting medication) and after 6 weeks of double-blind treatment. Analyses compared the topiramate (n = 12) and placebo (n = 8) groups on (1) the change in brain responses during alcohol cue exposure (vs non-alcohol cues) within five a priori regions of interest related to reward—the bilateral and medial orbitofrontal cortex (OFC) and bilateral ventral striatum (VS) and (2) change in craving and heavy drinking days (HDDs) from baseline and scan 2. Topiramate, relative to placebo, reduced alcohol cue-elicited activation of the left VS, bilateral OFC, and medial OFC, alcohol cue-elicited craving, and HDDs between baseline and 6 weeks of treatment. The reduction in alcohol cue-elicited activation in the medial OFC correlated with reductions in craving, and reduced activation in the right VS, right OFC, and medial OFC correlated with the reduction in HDD. This preliminary study provides evidence that topiramate’s attenuation of alcohol cue-elicited brain activation and craving are key elements of the drug’s neurobiological mechanism of action in reducing heavy drinking.
Highlights
Alcohol misuse and alcohol use disorder (AUD) are leading risk factors for premature death and disability [1]
The change in neural responses to alcohol cues correlated with the change in alcohol cue-elicited craving in the medial orbitofrontal cortex (OFC) (ρ = 0.60, 95% confidence interval (CI) [0.14, 0.88], p = 0.005) and the change in heavy drinking days (HDDs) in the right ventral striatum (VS) (ρ = 0.56, 95% CI [0.30, 0.77], p = 0.01), right OFC (ρ = 0.60, 95% CI [0.21, 0.83], p = 0.006), and medial OFC (ρ = 0.52, 95% CI [0.12, 0.81], p = 0.02) (Fig. 3)
Among topiramate-treated patients, the change in neural responses to alcohol cues correlated with the change in alcohol cue-elicited craving in the the medial OFC (ρ = 0.53, 95% CI [0.05, 0.81], p = 0.04) and the change in HDD in the right VS (ρ = 0.50, 95% CI [0.11, 0.84], p < 0.05)
Summary
Alcohol misuse and alcohol use disorder (AUD) are leading risk factors for premature death and disability [1]. In the United States, an estimated 16.5 million adults engage in heavy alcohol use (consuming 5 or more drinks for males or 4 or more drinks for females on 5 or more days during the preceding month), and 14.4 million meet criteria for an AUD [2]. There are effective treatments for heavy drinking and AUD, the majority of affected individuals receive no treatment, and among those that do, up to 70% return to drinking within the first year following treatment [3]. An extensive neuroimaging literature has examined brain responses to alcohol cues in individuals at risk for or diagnosed with AUD [5, 7,8,9,10]. According to a quantitative meta-analysis and systematic review, AUD is associated with robust alcohol cue-induced activation in rewardrelated mesolimbic and prefrontal brain regions, including the ventral striatum (VS) and orbitofrontal cortex (OFC), and cueelicited activation of the VS is most frequently correlated with behavioral measures and reduced with treatment [6]
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