Effects of topiramate on neural responses to alcohol cues in treatment-seeking individuals with alcohol use disorder: preliminary findings from a randomized, placebo-controlled trial

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.

Topiramate decreases the salience of motivationally relevant visual cues among smokers with alcohol use disorder

“…While we found that increasing drug dose resulted in lower CPD, expired CO, and WSWS craving scores, we did not find an effect of topiramate dose on self‐reported measures of cigarette‐related reinforcement or withdrawal or on corresponding alcohol‐related measures, unlike several previous studies. Our craving findings are inconsistent with those of previous work that found that topiramate reduced self‐reported craving to alcohol (Batki et al, 2014; Johnson et al, 2003a; Miranda et al, 2016; Wetherill et al, 2021). With regards to smoking, our lack of a drug effect on withdrawal symptoms is inconsistent with a study that found that topiramate produced lower smoking withdrawal scores over time than placebo (Anthenelli et al, 2017).…”

“…Notably, topiramate, which is a known AMPA and kainate receptor antagonist (Gibbs et al, 2000; Skradski & White, 2000), has been found to reduce nicotine‐induced dopamine (DA) release in the mesocorticolimbic DA pathways (Schiffer et al, 2001), the activation of which plays a key role in reward and drug addiction (Hyman et al, 2006; Volkow et al, 2002). Recent imaging work has found that topiramate, compared to placebo, reduces DA‐mediated activity in mesocorticolimbic reward–related regions of the brain (Wetherill et al, 2021). Conversely, disruption of DA‐mediated activity should reduce the incentive salience of drug cues, making them less attractive and less likely to induce appetitive motivation to use the drug (Berridge & Robinson, 1998).…”

“…The evidence for topiramate's ability to block drug craving in humans has been mixed. On one hand, studies have found that topiramate decreases alcohol-related tonic craving (Johnson et al, 2003a) and alcohol cue-elicited craving (Wetherill et al, 2021), but another trial failed to find an effect of topiramate on cue-induced alcohol craving (Miranda et al, 2008). With smoking cessation, one small, open-label study reported that most smokers who reduced or quit smoking while taking topiramate reported decreased craving to smoke (Khazaal et al, 2006), but another small, double-blind study found that, compared with placebo, low-dose topiramate had no effect on cue-induced craving to smoke (Reid et al, 2007).…”

A Bayesian meta-analysis of topiramate’s effectiveness for individuals with alcohol use disorder

“…Although both studies supplied data on heavy drinking, they were not analyzed for such a purpose, and their sample size was not computed to avoid result bias and sample overlap. Six prospective studies were ruled out: two were secondary analyses (Hartwell et al, 2021; Wetherill et al, 2021), another one due to the difficulty of differentiating TPM’s effect from other medications (Krupitsky et al, 2007), and one was conducted in the laboratory (Miranda et al, 2008). Two trials were randomized but not blinded (Flórez et al, 2008, 2011).…”

How laboratory studies of cigarette craving can inform the experimental alcohol craving literature

“…Finally, many laboratory studies using human participants over the past two decades have evaluated alcohol treatment approaches aimed at reducing self-reported cravings. For instance, a number of pharmacological approaches to reduce cue-elicited craving for alcohol have been investigated (e.g., Haass-Koffler et al, 2014;Ray et al, 2019), with promising results for naltrexone (Hendershot et al, 2017), oxytocin (Bach et al, 2019), prazosin (Fox et al, 2012;Milivojevic et al, 2020), memantine (Krupitsky et al, 2007), quetiapine (Ray et al, 2011), topiramate (Wetherill et al, 2021), and citalopram (Zorick et al, 2019). Furthermore, researchers have offered suggestions to improve cue exposure therapy for alcohol dependence (e.g., Buckfield et al, 2021;Conklin & Tiffany, 2002) after unsuccessful studies were noted to suffer from several methodological concerns (Mellentin et al, 2017).…”