Prospective randomized pharmacogenetic study of topiramate for treating alcohol use disorder

Abstract

In a prior study, topiramate reduced heavy drinking among individuals who sought to reduce their drinking, with the effect moderated by a single nucleotide polymorphism (SNP; rs2832407) in GRIK1, which encodes the kainate GluK1 receptor subunit (Kranzler et al. 2014). The present study sought to replicate prospectively the effect of topiramate and rs2832407 in patients with DSM-5 alcohol use disorder (AUD) who sought to reduce or stop their drinking. We stratified the randomization on genotype (rs2832407*C-allele homozygotes vs. A-allele carriers) and assigned 170 European-American participants (71.2% male) to receive 12 weeks of treatment with topiramate (N = 85), at a maximal daily dosage of 200 mg, or matching placebo (N = 85). At each of nine treatment visits participants received brief counseling to reduce drinking and increase abstinent days. We hypothesized that topiramate-treated patients with the rs2832407*CC genotype would reduce heavy drinking days (HDDs) more than the other three groups. The rate of treatment completion was 91.8% in both groups. The mean number of HDDs per week in the placebo group was 1.67 (95% CI = (1.29, 2.16), p = 0.0001) times greater than in the topiramate group, which was confirmed by the topiramate group’s significantly greater reduction in the concentration of the liver enzyme γ-glutamyltransferase and lower alcohol-related problems score. There was no significant difference in topiramate’s effect on HDDs between genotype groups. Although consistent with other studies showing a reduction in heavy drinking with topiramate treatment, the prior finding of a moderating effect of rs2832407 genotype was not replicated in this prospective trial.

World Health Organization risk drinking levels as a treatment outcome measure in topiramate trials

“… * For the study by medication effect. Study 1, Kranzler et al, (2014); Study 2, Kranzler et al (2021a); EA = European American; SIP = Short Index of Problems; SF‐12 = Short Form Health Survey; lnGGT = natural log of the gamma‐glutamyl transferase concentration. …”

“…Full descriptions of the procedures for both studies can be found in the primary publications (Study 1, n = 138, Kranzler et al, 2014; Study 2, n = 170, Kranzler et al 2021a). In brief, 308 heavy drinking individuals were recruited to participate in 1 of 2 randomized, double‐blind, 12‐week trials in which they received up to 200 mg/day of topiramate or placebo.…”

“…In that study, European–American, C‐allele homozygotes treated with topiramate reported significantly fewer heavy drinking days than A‐allele carriers or those treated with placebo. A subsequent prospective trial (Kranzler et al 2021a) failed to replicate that finding. In a recent combined analysis of the two RCTs, although both the number of heavy drinking days and alcohol‐related problem severity were reduced in the topiramate‐treated patients, the effects were not moderated by rs2832407 (Kranzler et al, 2021b).…”

Post‐treatment effects of topiramate on alcohol‐related outcomes: A combined analysis of two placebo‐controlled trials

“…CONSORT diagrams and a full description of the procedures for both studies are provided in the primary publications. 3,7…”

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

“…Studies have found that those who quit smoking had higher rates of alcohol abstinence than those who had not quit smoking (Campbell et al, 1995;Friend & Pagano, 2005;Sobell & Sobell, 1996), which suggests that concurrent treatment of both TUD and AUD would be beneficial. One candidate medication is the anticonvulsant topiramate, a sulfamate-substituted fructopyranose derivative with both GABAergic and glutamatergic properties, which has been found to reduce drinking among those with AUD (Johnson et al, 2007;Kranzler et al, 2014Kranzler et al, , 2021. In a post hoc analysis extending their previously published report on topiramate's effects on reducing alcohol drinking (Johnson et al, 2003a), Johnson et al (2005) found that participants given topiramate were more likely to abstain from smoking than those given placebo.…”