Pharmacogenetics may help identify drinkers likely to respond to topiramate

AVENTURA, FLA.– A single nucleotide polymorphism might help identify heavy drinkers who are most likely to respond to treatment with topiramate, but more studies are needed before testing patients is recommended, Dr. Henry R. Kranzler reported at the annual meeting of the American Academy of Addiction Psychiatry.

In a 12-week placebo-controlled, randomized study of 138 heavy drinkers, the number of days people drank heavily was significantly reduced among those treated with topiramate, compared with those on placebo. But genotyping results indicated that the effect occurred only among those with the polymorphism, according to Dr. Kranzler, the lead author of the study, who is professor of psychiatry and director of the Center for Studies of Addiction at the University of Pennsylvania, Philadelphia.

At baseline, the study participants drank about 80% of the days each week. They were randomized to treatment with 200 mg of topiramate a day, in two divided doses, or placebo, with the goal of reducing drinking to safe levels. Brief behavioral counseling was provided at each visit. Over 12 weeks, the number of days participants drank heavily dropped from about 5 days at baseline to about 1.5 days a week among those treated with topiramate, a significant reduction, and to about 3 days a week among those on placebo. In addition, the number of days participants abstained from alcohol increased among those treated with topiramate, from about 1 to almost 3 days per week. Among those on placebo, the number of abstinent days per week increased from about 1 to 1.5 days per week.

Patients were genotyped for the single nucleotide polymorphism (rs2832407) in GRIK1 (glutamate receptor, ionotropic, kainate1), a large gene on chromosome 21, which “encodes the Gluk1 subunit of the kainate (glutamate) receptor” to evaluate its impact as a moderator of topiramate’s effects on drinking and on the adverse effects of the drug. Topiramate affects multiple receptor systems, and the drug’s effects on glutamate (kainate) receptors “are most potent and selective for those containing the GluK1 and GluK2 subunits,” he said.

Genotyping was done in the 122 European Americans in the study to avoid confounding, because the frequency of the allele for the polymorphism varies widely in different populations. In this group, the significant effects over placebo was evident only among the 51 individuals who were “rs2832407 C-allele homozygotes.” They had “a substantially greater response to topiramate, compared to placebo,” and 3 and 6 months after treatment ended, evidence of a beneficial effect of topiramate in this group remained, he added.

However, unlike a small study published in 2009, conducted by different investigators, which found that individuals with this genotype were less likely to experience adverse effects of topiramate therapy, they did not see a pharmacogenetic effect on adverse events associated with topiramate.

Genotyping might help predict which patients may respond to topiramate, testing is not currently recommended, and these results need to be replicated and evaluated in other populations, Dr. Kranzler added.

These findings will also be helpful in identifying targets for more specific medications to treat alcohol abuse, he noted.

Topiramate, marketed as Topamax, also is available in generic formulations; it is not approved for treating alcohol abuse. He referred to a recently published meta-analysis indicating that topiramate had a greater effect than acamprosate or naltrexone in people with alcohol use disorders (Alcohol Clin. Exp. Res. 2014;38:1481-8).

Dr. Kranzler disclosed having received honoraria from the Alcohol Clinical Trials Initiative (ACTIVE) of the American Society of Clinical Psychopharmacology, which is supported by AbbVie, Ethypharm, Lilly, Lundbeck, and Pfizer. He also is a consultant to or advisory board member of Alkermes, Lilly, Lundbeck, Otsuka, Pfizer, and Roche. He said that industry had no role in the data he presented.

[email protected]

AVENTURA, FLA.– A single nucleotide polymorphism might help identify heavy drinkers who are most likely to respond to treatment with topiramate, but more studies are needed before testing patients is recommended, Dr. Henry R. Kranzler reported at the annual meeting of the American Academy of Addiction Psychiatry.

In a 12-week placebo-controlled, randomized study of 138 heavy drinkers, the number of days people drank heavily was significantly reduced among those treated with topiramate, compared with those on placebo. But genotyping results indicated that the effect occurred only among those with the polymorphism, according to Dr. Kranzler, the lead author of the study, who is professor of psychiatry and director of the Center for Studies of Addiction at the University of Pennsylvania, Philadelphia.

At baseline, the study participants drank about 80% of the days each week. They were randomized to treatment with 200 mg of topiramate a day, in two divided doses, or placebo, with the goal of reducing drinking to safe levels. Brief behavioral counseling was provided at each visit. Over 12 weeks, the number of days participants drank heavily dropped from about 5 days at baseline to about 1.5 days a week among those treated with topiramate, a significant reduction, and to about 3 days a week among those on placebo. In addition, the number of days participants abstained from alcohol increased among those treated with topiramate, from about 1 to almost 3 days per week. Among those on placebo, the number of abstinent days per week increased from about 1 to 1.5 days per week.

Patients were genotyped for the single nucleotide polymorphism (rs2832407) in GRIK1 (glutamate receptor, ionotropic, kainate1), a large gene on chromosome 21, which “encodes the Gluk1 subunit of the kainate (glutamate) receptor” to evaluate its impact as a moderator of topiramate’s effects on drinking and on the adverse effects of the drug. Topiramate affects multiple receptor systems, and the drug’s effects on glutamate (kainate) receptors “are most potent and selective for those containing the GluK1 and GluK2 subunits,” he said.

Genotyping was done in the 122 European Americans in the study to avoid confounding, because the frequency of the allele for the polymorphism varies widely in different populations. In this group, the significant effects over placebo was evident only among the 51 individuals who were “rs2832407 C-allele homozygotes.” They had “a substantially greater response to topiramate, compared to placebo,” and 3 and 6 months after treatment ended, evidence of a beneficial effect of topiramate in this group remained, he added.

However, unlike a small study published in 2009, conducted by different investigators, which found that individuals with this genotype were less likely to experience adverse effects of topiramate therapy, they did not see a pharmacogenetic effect on adverse events associated with topiramate.

Genotyping might help predict which patients may respond to topiramate, testing is not currently recommended, and these results need to be replicated and evaluated in other populations, Dr. Kranzler added.

These findings will also be helpful in identifying targets for more specific medications to treat alcohol abuse, he noted.

Topiramate, marketed as Topamax, also is available in generic formulations; it is not approved for treating alcohol abuse. He referred to a recently published meta-analysis indicating that topiramate had a greater effect than acamprosate or naltrexone in people with alcohol use disorders (Alcohol Clin. Exp. Res. 2014;38:1481-8).

Dr. Kranzler disclosed having received honoraria from the Alcohol Clinical Trials Initiative (ACTIVE) of the American Society of Clinical Psychopharmacology, which is supported by AbbVie, Ethypharm, Lilly, Lundbeck, and Pfizer. He also is a consultant to or advisory board member of Alkermes, Lilly, Lundbeck, Otsuka, Pfizer, and Roche. He said that industry had no role in the data he presented.

[email protected]

AVENTURA, FLA.– A single nucleotide polymorphism might help identify heavy drinkers who are most likely to respond to treatment with topiramate, but more studies are needed before testing patients is recommended, Dr. Henry R. Kranzler reported at the annual meeting of the American Academy of Addiction Psychiatry.

In a 12-week placebo-controlled, randomized study of 138 heavy drinkers, the number of days people drank heavily was significantly reduced among those treated with topiramate, compared with those on placebo. But genotyping results indicated that the effect occurred only among those with the polymorphism, according to Dr. Kranzler, the lead author of the study, who is professor of psychiatry and director of the Center for Studies of Addiction at the University of Pennsylvania, Philadelphia.

At baseline, the study participants drank about 80% of the days each week. They were randomized to treatment with 200 mg of topiramate a day, in two divided doses, or placebo, with the goal of reducing drinking to safe levels. Brief behavioral counseling was provided at each visit. Over 12 weeks, the number of days participants drank heavily dropped from about 5 days at baseline to about 1.5 days a week among those treated with topiramate, a significant reduction, and to about 3 days a week among those on placebo. In addition, the number of days participants abstained from alcohol increased among those treated with topiramate, from about 1 to almost 3 days per week. Among those on placebo, the number of abstinent days per week increased from about 1 to 1.5 days per week.

Patients were genotyped for the single nucleotide polymorphism (rs2832407) in GRIK1 (glutamate receptor, ionotropic, kainate1), a large gene on chromosome 21, which “encodes the Gluk1 subunit of the kainate (glutamate) receptor” to evaluate its impact as a moderator of topiramate’s effects on drinking and on the adverse effects of the drug. Topiramate affects multiple receptor systems, and the drug’s effects on glutamate (kainate) receptors “are most potent and selective for those containing the GluK1 and GluK2 subunits,” he said.

Genotyping was done in the 122 European Americans in the study to avoid confounding, because the frequency of the allele for the polymorphism varies widely in different populations. In this group, the significant effects over placebo was evident only among the 51 individuals who were “rs2832407 C-allele homozygotes.” They had “a substantially greater response to topiramate, compared to placebo,” and 3 and 6 months after treatment ended, evidence of a beneficial effect of topiramate in this group remained, he added.

However, unlike a small study published in 2009, conducted by different investigators, which found that individuals with this genotype were less likely to experience adverse effects of topiramate therapy, they did not see a pharmacogenetic effect on adverse events associated with topiramate.

Genotyping might help predict which patients may respond to topiramate, testing is not currently recommended, and these results need to be replicated and evaluated in other populations, Dr. Kranzler added.

These findings will also be helpful in identifying targets for more specific medications to treat alcohol abuse, he noted.

Topiramate, marketed as Topamax, also is available in generic formulations; it is not approved for treating alcohol abuse. He referred to a recently published meta-analysis indicating that topiramate had a greater effect than acamprosate or naltrexone in people with alcohol use disorders (Alcohol Clin. Exp. Res. 2014;38:1481-8).

Dr. Kranzler disclosed having received honoraria from the Alcohol Clinical Trials Initiative (ACTIVE) of the American Society of Clinical Psychopharmacology, which is supported by AbbVie, Ethypharm, Lilly, Lundbeck, and Pfizer. He also is a consultant to or advisory board member of Alkermes, Lilly, Lundbeck, Otsuka, Pfizer, and Roche. He said that industry had no role in the data he presented.

[email protected]