Topiramate and Heavy Drinking: Implications for Personalized Medicine

Figure. Number of heavy drinking days in topiramate vs placebo recipients

Note to readers: The following report is a summary of highlights from a study by Dr Kranzler and colleagues, published in The American Journal of Psychiatry, titled “Topiramate Treatment for Heavy Drinkers: Moderation by a GRIK1 Polymorphism.”

In the US, heavy drinking affects an estimated 23% of individuals aged 12 or older, who in a Substance Abuse and Mental Health Services Administration study reported that in the preceding month, 5 or more drinks were ingested “on an occasion.” Seven percent consumed that much on at least 5 days.¹

Despite the association of heavy drinking with a variety of psychosocial and medical problems, very few heavy drinkers receive treatment, and medications with demonstrated efficacy in alcohol treatment are prescribed for even fewer.² Aside from a few studies of opioid antagonists,³ research on alcohol pharmacotherapy has focused mainly on patients whose treatment goal is abstinence, rather than on those whose goal is to reduce their drinking.

Studies have shown that the anticonvulsant topiramate reduces heavy drinking and increases abstinent days in alcohol-dependent individuals whose goal is to stop drinking.^4,5 On the basis of these findings, we conducted a 12-week study to evaluate the efficacy and tolerability of topiramate in heavy drinkers whose treatment goal was to reduce their drinking to safe levels.⁶ We also tested whether a single nucleotide polymorphism (SNP), a commonly observed change in the DNA sequence, could be used to identify which patients are most likely to respond to topiramate therapy.⁶

Topiramate, among its other pharmacological effects, blocks activity at two subtypes of glutamate receptors: 2-(aminomethyl)phenylacetic acid and kainate.^7,8 The effect of topiramate on glutamate receptors are most potent and selective for those that contain the GluK1 subunit (encoded by the gene glutamate receptor, ionotropic, kainate 1 [GRIK1]).^9,10 In an earlier study to identify a potential genetic predictor of topiramate response, we examined the association of 7 SNPs in GRIK1 with the risk of alcohol dependence.¹¹ We found that a particular SNP, rs2832407, was significantly associated with alcohol dependence in European Americans.¹¹

Using findings from these studies, our recent topiramate study tested 2 hypotheses: first, that topiramate treatment would reduce the number of heavy drinking days and increase the number of abstinent days more than placebo and, second, that the SNP rs2832407 would identify the patients who respond well to topiramate.⁶ The second hypothesis was based on pharmacogenetics. If supported, these hypotheses would provide an important option for the personalized treatment of heavy drinking.

The study involved 138 heavy drinkers (86 men, 62.3%), 18 to 65 years old, who sought to reduce their drinking. The patients’ average weekly alcohol consumption was 24 or more standard drinks for men and 18 or more standard drinks for women. Patients were randomly assigned to treatment with topiramate (n = 67, 48.6%) or placebo (n = 71, 51.4%). All patients also received medical management12 and a brief psychosocial intervention delivered by a trained nurse at each of 9 treatment visits.

In the initial counseling session, a nurse discussed with the patient sensible drinking limits and provided information about pharmacotherapy, emphasizing the importance of medication adherence. At subsequent sessions, the nurse briefly assessed the patient’s drinking, monitored medication adherence, and made recommendations related to both. Men were advised to consume no more than 3 standard drinks per day and 12 standard drinks per week, and women were advised to consume no more than 2 drinks per day and 8 drinks per week, consistent with the levels at which drinking becomes problematic.¹³

Topiramate treatment was initiated at a dosage of 25 mg/d and then increased by 25 to 50 mg/d each week to a maximum of 200 mg/d, which was achieved at week 6. For patients who experienced intolerable adverse effects, the dosage was held steady or, if necessary, reduced to a tolerable level.

Main findings: effects of topiramate

Overall, 117 patients (84.8%) completed treatment (topiramate: n = 55, 82.1%; placebo: n = 62, 87.3%). The rate of medication adherence was approximately 90% in both groups. Topiramate treatment increased abstinent days and reduced heavy drinking days,γ-glutamyltranspep-tidase concentrations (consistent with reduced drinking), and scores on a measure of alcohol-related psychosocial problems.

• Abstinent days. Topiramate increased patients’ abstinent days significantly more than placebo. At the end of the study, topiramate-treated patients had an average of about 1 more abstinent day per week than placebo patients.

• Heavy drinking days. Topiramate-treated patients reduced their heavy drinking significantly more than patients who received placebo (Figure). By the last week of treatment, topiramate-treated patients reduced their heavy drinking days by more than 1 per week compared with placebo patients. Furthermore, during the final 4 treatment weeks, more than twice as many topiramate-treated patients (n = 24, 35.8%) as placebo recipients (n = 12, 16.9%) experienced no heavy drinking days, an important outcome measure in trials of this kind.

• γ-Glutamyltranspeptidase concentrations. Topiramate-treated patients had a significantly greater decrease in γ-glutamyltranspeptidase concentrations than placebo patients, which provides objective support for the self-reported drinking data.

• Short Index of Problems score. At study end point, scores on this measure of alcohol-related problems decreased nearly twice as much in topiramate-treated patients as in the placebo group.

Medication-genotype interaction

When rs2832407 genotype was used to subdivide the sample, the effect of topiramate was clearly significant only for heavy drinking days, although the finding for abstinent days was in a similar direction.

• Heavy drinking days. Topiramate reduced heavy drinking days significantly more than placebo among individuals in the CC genotype group, but not in A-allele carriers (Figure).

• Abstinent days. Although not statistically significant, the effect of topiramate also appeared to be limited to the CC genotype group.

Adverse effects

Topiramate-treated patients reported significantly more adverse effects than patients who received placebo. Although two-thirds of these events were rated as mild, the topiramate group also reported more moderate or severe adverse effects than placebo recipients. The adverse effects associated with topiramate treatment included numbness/tingling, change in taste, loss of appetite, weight loss, difficulty in concentrating, and difficulty with memory. Despite these adverse effects, the rate of dropout from treatment did not differ between the topiramate and placebo groups.

Implications for medication development and personalized treatment

In summary, we found that topiramate 200 mg/d reduced heavy drinking days and increased abstinent days significantly more than placebo.⁶ These findings compare favorably with those from 2 clinical trials that compared topiramate 300 mg/d with placebo in patients whose ultimate goal was abstinence from alcohol.^4,5

We also found that rs2832407, an SNP in GRIK1, which encodes a kainate receptor subunit, helped identify who benefited from topiramate’s effects on heavy drinking. The similar, though nonsignificant, effect on the number of abstinent days may reflect the need for a larger sample to provide adequate statistical power to test this outcome.

Although the mechanism by which the rs2832407 SNP affects the response to topiramate is not yet known, efforts are under way to understand how topiramate reduces drinking. An understanding of this mechanism should make it possible to design medications that are more specific than topiramate (which has multiple pharmacological effects) in reducing drinking, thereby causing fewer adverse effects.

The topiramate-induced reduction in heavy drinking days, particularly in patients with the CC genotype, is clinically important because the frequency of heavy drinking is correlated with a variety of negative consequences.^14,15 Although these findings require replication, they support the use of topiramate to treat heavy drinking in problem drinkers at a dosage as low as 200 mg/d. Topiramate caused more adverse effects than placebo, but the high rate of treatment completion in the study showed that it was generally well tolerated. Key to ensuring the tolerability of topiramate is to start it at a low dosage and increase the dosage gradually over 6 to 8 weeks.^4-6

Replication of the pharmacogenetic effect with topiramate is required before it can be used to personalize treatment with the medication. However, because the prevalence of the responsive (CC) genotype for rs2832407 is 42% in European Americans, the pharmacogenetic findings could be applicable to a large proportion of the general US population. This, in combination with pharmacogenetic advances made using other medications to treat alcohol use disorder, could usher in the personalized treatment of alcohol use disorder.¹⁶

Key take-aways

➡ Topiramate is a useful medication to treat alcohol use disorder, even in patients who are actively drinking.

➡ Because topiramate can cause a variety of adverse effects, treatment with this medication should be initiated at a low dosage and increased gradually over 6 to 8 weeks, to a maximum dosage of 300 mg/d, as tolerated.

➡ Pharmacogenetic studies promise to provide insight into how topiramate works and to identify patients who may be most responsive to the medication. Further work is needed to substantiate the initial pharmacogenetic findings.

This article was originally posted on 4/28/2014 and has since been updated.

Disclosures:

Dr Kranzler is Professor of Psychiatry and Director of the Center for Studies of Addiction, Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, and Co-Associate Director of Research of the VISN 4 Mental Illness, Research, Education, and Clinical Center, Philadelphia Veterans Administration Medical Center, Philadelphia. Ms Zindel is a medical writer and study coordinator with the Center for Studies of Addiction, Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia.

Dr Kranzler has been a consultant or advisory board member for the following pharmaceutical companies: Alkermes, Lilly, Lundbeck, Pfizer, and Roche. He is also a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative, which is supported by AbbVie, Ethypharm, Lilly, Lundbeck, and Pfizer.

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