0
Get Alert
Please Wait... Processing your request... Please Wait.
You must sign in to sign-up for alerts.

Please confirm that your email address is correct, so you can successfully receive this alert.

Articles   |    
Topiramate Treatment for Heavy Drinkers: Moderation by a GRIK1 Polymorphism
Henry R. Kranzler, M.D.; Jonathan Covault, M.D., Ph.D.; Richard Feinn, Ph.D.; Stephen Armeli, Ph.D.; Howard Tennen, Ph.D.; Albert J. Arias, M.D.; Joel Gelernter, M.D.; Timothy Pond, M.P.H.; Cheryl Oncken, M.D., M.P.H.; Kyle M. Kampman, M.D.
Am J Psychiatry 2014;171:445-452. doi:10.1176/appi.ajp.2013.13081014
View Author and Article Information

Dr. Kranzler has served as a consultant to or advisory board member for 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 Abbott, Lilly, Lundbeck, and Pfizer. Dr. Oncken has received study supplies from Pfizer for a smoking cessation study. All other authors report no financial relationships with commercial interests.

Supported by National Institutes of Health grants P60 AA03510 and K24 AA13736, from the National Institute on Alcohol Abuse and Alcoholism, and the VISN 4 Mental Illness Research, Education, and Clinical Center of the U.S. Department of Veterans Affairs.

ClinicalTrials.gov registry number, NCT00626925 (www.clinicaltrials.gov).

From the Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia; VISN 4 Mental Illness, Research, Education, and Clinical Center, Philadelphia Veterans Administration Medical Center, Philadelphia; the Alcohol Research Center, Department of Psychiatry, University of Connecticut School of Medicine, Farmington, Conn.; the Frank Netter School of Medicine, Quinnipiac University, Hamden, Conn.; the Department of Psychology, Fairleigh Dickinson University, Teaneck, N.J.; the Department of Community Medicine and Healthcare, University of Connecticut School of Medicine, Farmington, Conn.; the Department of Psychiatry, Yale University School of Medicine, New Haven, Conn.; VA Connecticut Healthcare System, West Haven, Conn.; and the Department of Medicine, University of Connecticut School of Medicine, Farmington, Conn.

Address correspondence to Dr. Kranzler (kranzler@mail.med.upenn.edu).

Copyright © 2014 by the American Psychiatric Association

Received August 02, 2013; Revised October 08, 2013; Accepted November 25, 2013.

An erratum to this article has been published | view the erratum
Abstract

Objective  Topiramate has been shown to reduce drinking and heavy drinking in individuals with alcohol dependence whose goal was to stop drinking. The authors evaluated the efficacy and tolerability of topiramate in heavy drinkers whose treatment goal was to reduce drinking to safe levels.

Method  A total of 138 individuals (62.3% men) were randomly assigned to receive 12 weeks of treatment with topiramate (N=67), at a maximal daily dose of 200 mg, or matching placebo (N=71). Both groups received brief counseling to reduce drinking and increase abstinent days. It was hypothesized that topiramate-treated patients would be better able to achieve these goals, and it was predicted that based on prior research, the effects would be moderated by a single nucleotide polymorphism (rs2832407) in GRIK1, encoding the kainate GluK1 receptor subunit.

Results  The rate of treatment completion was 84.9% and equal by treatment group. Topiramate treatment significantly reduced heavy drinking days and increased abstinent days relative to placebo. Patients receiving topiramate also had lower concentrations of the liver enzyme γ-glutamyl transpeptidase and lower scores on a measure of alcohol-related problems than the placebo group. In a European American subsample (N=122), topiramate’s effect on heavy drinking days was significantly greater than that for placebo only in rs2832407 C-allele homozygotes.

Conclusions  These findings support the use of topiramate at a daily dose of 200 mg to reduce heavy drinking in problem drinkers. The moderator effect of rs2832407, if validated, would facilitate the identification of heavy drinkers who are likely to respond well to topiramate treatment and provide an important personalized treatment option. The pharmacogenetic findings also implicate the kainate receptor in the mechanism of topiramate’s effects on heavy drinking.

Abstract Teaser
Figures in this Article

Your Session has timed out. Please sign back in to continue.
Sign In Your Session has timed out. Please sign back in to continue.
Sign In to Access Full Content
 
Username
Password
Sign in via Athens (What is this?)
Athens is a service for single sign-on which enables access to all of an institution's subscriptions on- or off-site.
Not a subscriber?

Subscribe Now/Learn More

PsychiatryOnline subscription options offer access to the DSM-5 library, books, journals, CME, and patient resources. This all-in-one virtual library provides psychiatrists and mental health professionals with key resources for diagnosis, treatment, research, and professional development.

Need more help? PsychiatryOnline Customer Service may be reached by emailing PsychiatryOnline@psych.org or by calling 800-368-5777 (in the U.S.) or 703-907-7322 (outside the U.S.).

FIGURE 1. Mean Heavy Drinking Days Per Week by Medication Groupa

a There was a significant main effect of medication group (F=23.37, df=1, 1399, p<0.001) and interaction of medication group-by-treatment week (F=19.91, df=1, 1399, p<0.0001). The standard error of the mean is represented.

FIGURE 2. Mean Abstinent Days Per Week by Medication Groupa

a There was a significant main effect of medication group (F=4.63, df=1, 1398, p=0.03) and interaction of medication group-by-treatment week (F=6.26, df=1, 1398, p=0.01). The standard error of the mean is represented.

FIGURE 3. Mean Heavy Drinking Days Per Week by Medication Group and rs2832407 Genotypea

a There was a significant medication group-by-genotype interaction (F=5.50, df=2, 1227, p=0.004). The standard error of the mean is represented.

FIGURE 4. Mean Abstinent Days Per Week by Medication Group and rs2832407 Genotypea

a The interaction of medication group-by-genotype group was not statistically significant. The standard error of the mean is represented.

Anchor for Jump
TABLE 1.Demographic and Pretreatment Clinical Measures
Table Footer Note

a For continuous measures, t tests were used; chi-square tests were used for categorical measures.

Table Footer Note

b Income data were missing for one topiramate patient.

Table Footer Note

c Data represent the proportion of the 90 days preceding the screening visit.

Anchor for Jump
TABLE 2.Baseline Demographic and Clinical Characteristics by Genotype (rs2832407) and Treatment Assignment of European American Patients (N=122)
Table Footer Note

a The genotype frequencies in European Americans were consistent with Hardy-Weinberg equilibrium expectations (χ2=0.61, df=2, p=0.74).

Table Footer Note

b There was statistical significance for a main effect between groups (p=0.04) (topiramate patients: mean age=50.7 years [SD=7.3]; placebo patients: mean age=53.1 years [SD=7.3]).

Table Footer Note

c The data represent information preceding the screening visit.

+

References

SAMHSA: National Survey on Drug Use and Health. Washington, DC, US Department of Health and Human Services, 2013. http://www.oas.samhsa.gov/nsduhLatest.htm
 
Kranzler  HR;  Babor  TF;  Lauerman  RJ:  Problems associated with average alcohol consumption and frequency of intoxication in a medical population.  Alcohol Clin Exp Res 1990; 14:119–126
[CrossRef] | [PubMed]
 
Cohen  E;  Feinn  R;  Arias  A;  Kranzler  HR:  Alcohol treatment utilization: findings from the National Epidemiologic Survey on Alcohol and Related Conditions.  Drug Alcohol Depend 2007; 86:214–221
[CrossRef] | [PubMed]
 
Kranzler  HR;  Armeli  S;  Tennen  H;  Blomqvist  O;  Oncken  C;  Petry  N;  Feinn  R:  Targeted naltrexone for early problem drinkers.  J Clin Psychopharmacol 2003; 23:294–304
[PubMed]
 
Kranzler  HR;  Tennen  H;  Armeli  S;  Chan  G;  Covault  J;  Arias  AJ;  Oncken  C:  Targeted naltrexone for problem drinkers.  J Clin Psychopharmacol 2009; 29:350–357
[CrossRef] | [PubMed]
 
Mann  K;  Bladström  A;  Torup  L;  Gual  A;  van den Brink  W:  Extending the treatment options in alcohol dependence: a randomized controlled study of as-needed nalmefene.  Biol Psychiatry 2013; 73:706–713
[CrossRef] | [PubMed]
 
van den Brink  W;  Sorensen  P;  Torup  L;  Mann  K;  Gaul  A:  Long-term efficacy, tolerability, and safety of nalmefene as-needed in alcohol dependence: a randomized, double-blind, placebo-controlled study.  Alcohol Clin Exp Res 2012; 36:247A
 
Gual  A;  He  Y;  Torup  L;  van den Brink  W;  Mann  K; ESENSE 2 Study Group:  A randomised, double-blind, placebo-controlled, efficacy study of nalmefene, as-needed use, in patients with alcohol dependence.  Eur Neuropsychopharmacol 2013; 23:1432–1442
[CrossRef] | [PubMed]
 
Johnson  BA;  Ait-Daoud  N;  Bowden  CL;  DiClemente  CC;  Roache  JD;  Lawson  K;  Javors  MA;  Ma  JZ:  Oral topiramate for treatment of alcohol dependence: a randomised controlled trial.  Lancet 2003; 361:1677–1685
[CrossRef] | [PubMed]
 
Johnson  BA;  Rosenthal  N;  Capece  JA;  Wiegand  F;  Mao  L;  Beyers  K;  McKay  A;  Ait-Daoud  N;  Anton  RF;  Ciraulo  DA;  Kranzler  HR;  Mann  K;  O’Malley  SS;  Swift  RM; Topiramate for Alcoholism Advisory Board; Topiramate for Alcoholism Study Group:  Topiramate for treating alcohol dependence: a randomized controlled trial.  JAMA 2007; 298:1641–1651
[CrossRef] | [PubMed]
 
Miranda  R  Jr;  MacKillop  J;  Monti  PM;  Rohsenow  DJ;  Tidey  J;  Gwaltney  C;  Swift  R;  Ray  L;  McGeary  J:  Effects of topiramate on urge to drink and the subjective effects of alcohol: a preliminary laboratory study.  Alcohol Clin Exp Res 2008; 32:489–497
[CrossRef] | [PubMed]
 
White  HS;  Brown  SD;  Woodhead  JH;  Skeen  GA;  Wolf  HH:  Topiramate modulates GABA-evoked currents in murine cortical neurons by a nonbenzodiazepine mechanism.  Epilepsia 2000; 41(suppl 1):S17–S20
[CrossRef] | [PubMed]
 
Skradski  S;  White  HS:  Topiramate blocks kainate-evoked cobalt influx into cultured neurons.  Epilepsia 2000; 41(suppl 1):S45–S47
[CrossRef] | [PubMed]
 
Gibbs  JW  3rd;  Sombati  S;  DeLorenzo  RJ;  Coulter  DA:  Cellular actions of topiramate: blockade of kainate-evoked inward currents in cultured hippocampal neurons.  Epilepsia 2000; 41(suppl 1):S10–S16
[CrossRef] | [PubMed]
 
Gryder  DS;  Rogawski  MA:  Selective antagonism of GluR5 kainate-receptor-mediated synaptic currents by topiramate in rat basolateral amygdala neurons.  J Neurosci 2003; 23:7069–7074
[PubMed]
 
Kaminski  RM;  Banerjee  M;  Rogawski  MA:  Topiramate selectively protects against seizures induced by ATPA, a GluR5 kainate receptor agonist.  Neuropharmacology 2004; 46:1097–1104
[CrossRef] | [PubMed]
 
McDonald  R;  Rogawski  M:  Cellular effects of antiepileptic drugs, in  Epilepsy: A Comprehensive Textbook , 2nd ed. Edited by Engel  J  Jr;  Pedley  TA.  Philadelphia,  Lippincott, Williams, and Wilkins, 2006, pp 1433–1446
 
Kranzler  HR;  Gelernter  J;  Anton  RF;  Arias  AJ;  Herman  A;  Zhao  H;  Burian  L;  Covault  J:  Association of markers in the 3′ region of the GluR5 kainate receptor subunit gene to alcohol dependence.  Alcohol Clin Exp Res 2009; 33:925–930
[CrossRef] | [PubMed]
 
Ray  LA;  Miranda  R  Jr;  MacKillop  J;  McGeary  J;  Tidey  JW;  Rohsenow  DJ;  Gwaltney  C;  Swift  RW;  Monti  PM:  A preliminary pharmacogenetic investigation of adverse events from topiramate in heavy drinkers.  Exp Clin Psychopharmacol 2009; 17:122–129
[CrossRef] | [PubMed]
 
Pettinati H, Weiss R, Miller W, Donovan D, Ernst D, Rounsaville B: COMBINE Monograph Series, vol 2: Medical Management Treatment Manual: A Clinical Research Guide for Medically Trained Clinicians Providing Pharmacotherapy as Part of the Treatment for Alcohol Dependence (Publication number, NIH 04-5289). Bethesda, Md, National Institute on Alcohol Abuse and Alcoholism, 2004
 
WHO Brief Intervention Study Group:  A cross-national trial of brief interventions with heavy drinkers.  Am J Public Health 1996; 86:948–955
[CrossRef] | [PubMed]
 
Sanchez-Craig  M;  Wilkinson  DA;  Davila  R:  Empirically based guidelines for moderate drinking: 1-year results from three studies with problem drinkers.  Am J Public Health 1995; 85:823–828
[CrossRef] | [PubMed]
 
First  M;  Spitzer  R;  Gibbon  M;  Williams  J:  Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition with Psychotic Screen (SCID-I/P W/PSY Screen) .  New York,  New York State Psychiatric Institute, Biometrics Research, 2001
 
American Psychiatric Association:  Diagnostic and Statistical Manual of Mental Disorders , 4th ed.  Washington, DC,  American Psychiatric Publishing, 1994
 
Sobell  L;  Sobell  M:  Timeline follow-back: a technique for assessing self-reported alcohol consumption, in  Measuring Alcohol Consumption . Edited by Allen  J.  New York,  Humana Press, 1992, pp 41–65
 
Miller  W;  Tonigan  J:  The Drinker Inventory of Consequences (DrInC), NIAAA Project MATCH Monograph Series , vol 4.  Bethesda, Md,  National Institutes of Health, 1995, pp 95–3911
 
Feinn  R;  Tennen  H;  Kranzler  HR:  Psychometric properties of the Short Index of Problems as a measure of recent alcohol-related problems.  Alcohol Clin Exp Res 2003; 27:1436–1441
[CrossRef] | [PubMed]
 
Beck  AT;  Ward  CH;  Mendelson  M;  Mock  J;  Erbaugh  J:  An inventory for measuring depression.  Arch Gen Psychiatry 1961; 4:561–571
[CrossRef] | [PubMed]
 
Falk  D;  Wang  XQ;  Liu  L;  Fertig  J;  Mattson  M;  Ryan  M;  Johnson  B;  Stout  R;  Litten  RZ:  Percentage of subjects with no heavy drinking days: evaluation as an efficacy endpoint for alcohol clinical trials.  Alcohol Clin Exp Res 2010; 34:2022–2034
[CrossRef] | [PubMed]
 
1,000 Genomes Project Consortium;  Abecasis  GR;  Auton  A;  Brooks  LD;  DePristo  MA;  Durbin  RM;  Handsaker  RE;  Kang  HM;  Marth  GT;  McVean  GA:   An integrated map of genetic variation from 1,092 human genomes.  Nature 2012; 491:56–65
[CrossRef] | [PubMed]
 
Raney  BJ;  Cline  MS;  Rosenbloom  KR;  Dreszer  TR;  Learned  K;  Barber  GP;  Meyer  LR;  Sloan  CA;  Malladi  VS;  Roskin  KM;  Suh  BB;  Hinrichs  AS;  Clawson  H;  Zweig  AS;  Kirkup  V;  Fujita  PA;  Rhead  B;  Smith  KE;  Pohl  A;  Kuhn  RM;  Karolchik  D;  Haussler  D;  Kent  WJ:  ENCODE whole-genome data in the UCSC genome browser (2011 update).  Nucleic Acids Res 2011; 39:D871–D875
[CrossRef] | [PubMed]
 
Breslow  RA;  Graubard  BI:  Prospective study of alcohol consumption in the United States: quantity, frequency, and cause-specific mortality.  Alcohol Clin Exp Res 2008; 32:513–521
[CrossRef] | [PubMed]
 
Dawson  DA;  Li  TK;  Grant  BF:  A prospective study of risk drinking: at risk for what? Drug Alcohol Depend 2008; 95:62–72
[CrossRef] | [PubMed]
 
Jackson  KM:  Heavy episodic drinking: determining the predictive utility of five or more drinks.  Psychol Addict Behav 2008; 22:68–77
[CrossRef] | [PubMed]
 
References Container
+
+

CME Activity

There is currently no quiz available for this resource. Please click here to go to the CME page to find another.
Submit a Comments
Please read the other comments before you post yours. Contributors must reveal any conflict of interest.
Comments are moderated and will appear on the site at the discertion of APA editorial staff.

* = Required Field
(if multiple authors, separate names by comma)
Example: John Doe



Web of Science® Times Cited: 6

Related Content
See Also...
Books
The American Psychiatric Publishing Textbook of Substance Abuse Treatment, 4th Edition > Chapter 38.  >
The American Psychiatric Publishing Textbook of Substance Abuse Treatment, 4th Edition > Chapter 38.  >
The American Psychiatric Publishing Textbook of Substance Abuse Treatment, 4th Edition > Chapter 38.  >
The American Psychiatric Publishing Textbook of Substance Abuse Treatment, 4th Edition > Chapter 12.  >
The American Psychiatric Publishing Textbook of Substance Abuse Treatment, 4th Edition > Chapter 12.  >
Topic Collections
Psychiatric News
PubMed Articles