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Published Online: 6 May 2024

Topiramate Versus Naltrexone for Alcohol Use Disorder: A Genotype-Stratified Double-Blind Randomized Controlled Trial

Kirsten C. Morley, Ph.D. [email protected], Henry R. Kranzler, M.D., Natasha Luquin, Ph.D., Nazila Jamshidi, M.B.B.S., Ph.D., Claire Adams, B.M.Sc., Mark Montebello, M.B.B.S., F.R.A.N.Z.C.P., Chris Tremonti, B.M.B.S., F.R.A.C.P., Gezelle Dali, Ph.D., Warren Logge, Ph.D., Andrew Baillie, Ph.D., Maree Teesson, Ph.D., Ronald Trent, Ph.D., F.R.A.C.P., and Paul S. Haber, M.D., F.R.A.C.P.Authors Info & Affiliations
Publication: American Journal of Psychiatry
Volume 181, Number 5
https://doi.org/10.1176/appi.ajp.20230666
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Abstract

Objective:

There have been no well-controlled and well-powered comparative trials of topiramate with other pharmacotherapies for alcohol use disorder (AUD), such as naltrexone. Moreover, the literature is mixed on the effects of two polymorphisms—rs2832407 (in GRIK1) and rs1799971 (in OPRM1)—on response to topiramate and naltrexone, respectively. The authors sought to examine the comparative effectiveness of topiramate and naltrexone in improving outcomes in AUD and to examine the role of the rs2832407 and rs1799971 polymorphisms, respectively, on response to these medications.

Methods:

In a 12-week, double-blind, placebo-controlled, randomized, multisite, genotype-stratified (rs2832407 and rs1799971) clinical trial comparing topiramate and naltrexone in treating AUD, 147 patients with AUD were randomly assigned to treatment with topiramate (maximum dosage of 200 mg/day) or naltrexone (50 mg/day), stratified by genotype (rs2832407*CC and *AC/AA genotypes and rs1799971*AA and *AG/GG genotypes). The predefined primary outcome was number of heavy drinking days (defined as ≥ four drinks for women, ≥ five drinks for men) per week. Predefined secondary outcomes included mean standard drinks per drinking day (SDDD) per week, body mass index (BMI), craving, markers of liver injury, mood, and adverse events.

Results:

For the number of heavy drinking days per week, there was a near-significant time-by-treatment interaction. For the number of standard drinks per drinking day per week, there was a significant time-by-treatment interaction, which favored topiramate. There were significant time-by-treatment effects, with greater reductions observed with topiramate than naltrexone for BMI, craving, and gamma-glutamyltransferase level. Withdrawal due to side effects occurred in 8% and 5% of the topiramate and naltrexone groups, respectively. Neither polymorphism showed an effect on treatment response.

Conclusions:

Topiramate is at least as effective and safe as the first-line medication, naltrexone, in reducing heavy alcohol consumption, and superior in reducing some clinical outcomes. Neither rs2832407 nor rs1799971 had effects on topiramate and naltrexone treatments, respectively.

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Supplementary Material

File (appi.ajp.20230666.correction01.pdf)
File (appi.ajp.20230666.ds001.pdf)

Information & Authors

Information

Published In

Go to American Journal of Psychiatry
Go to American Journal of Psychiatry
American Journal of Psychiatry
Volume 181 • Number 5 • May 01, 2024
Pages: 403 - 411
PubMed: 38706338

History

Received: 23 August 2023
Revision received: 1 December 2023
Revision received: 8 January 2024
Accepted: 17 January 2024
Published in print: May 01, 2024
Published online: 6 May 2024

Keywords

  1. Topiramate
  2. Naltrexone
  3. Alcohol Use Disorder
  4. Pharmacogenetics
  5. GRIK1
  6. OPRM1

Authors

Affiliations

Kirsten C. Morley, Ph.D. [email protected]
Specialty of Addiction Medicine, Sydney Medical School (Morley, Adams, Montebello, Tremonti, Dali, Logge, Haber), School of Health Sciences (Baillie), and Matilda Centre for Mental Health and Substance Use (Teesson), Faculty of Medicine and Health, University of Sydney, Sydney, Australia; Edith Collins Centre for Translational Research in Alcohol, Drugs, and Toxicology (Morley, Jamshidi, Logge, Haber) and Department of Medical Genomics (Luquin, Trent), Royal Prince Alfred Hospital, Camperdown, Australia; Center for Studies of Addiction, Perelman School of Medicine, University of Pennsylvania, and Mental Illness Research, Education, and Clinical Center, Crescenz VA Medical Center, Philadelphia (Kranzler); Northern Sydney Local Health District Drug and Alcohol Services, St Leonards, Australia (Montebello); St Vincent’s Hospital Sydney, Sydney, Australia (Tremonti).
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Henry R. Kranzler, M.D.
Specialty of Addiction Medicine, Sydney Medical School (Morley, Adams, Montebello, Tremonti, Dali, Logge, Haber), School of Health Sciences (Baillie), and Matilda Centre for Mental Health and Substance Use (Teesson), Faculty of Medicine and Health, University of Sydney, Sydney, Australia; Edith Collins Centre for Translational Research in Alcohol, Drugs, and Toxicology (Morley, Jamshidi, Logge, Haber) and Department of Medical Genomics (Luquin, Trent), Royal Prince Alfred Hospital, Camperdown, Australia; Center for Studies of Addiction, Perelman School of Medicine, University of Pennsylvania, and Mental Illness Research, Education, and Clinical Center, Crescenz VA Medical Center, Philadelphia (Kranzler); Northern Sydney Local Health District Drug and Alcohol Services, St Leonards, Australia (Montebello); St Vincent’s Hospital Sydney, Sydney, Australia (Tremonti).
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Natasha Luquin, Ph.D.
Specialty of Addiction Medicine, Sydney Medical School (Morley, Adams, Montebello, Tremonti, Dali, Logge, Haber), School of Health Sciences (Baillie), and Matilda Centre for Mental Health and Substance Use (Teesson), Faculty of Medicine and Health, University of Sydney, Sydney, Australia; Edith Collins Centre for Translational Research in Alcohol, Drugs, and Toxicology (Morley, Jamshidi, Logge, Haber) and Department of Medical Genomics (Luquin, Trent), Royal Prince Alfred Hospital, Camperdown, Australia; Center for Studies of Addiction, Perelman School of Medicine, University of Pennsylvania, and Mental Illness Research, Education, and Clinical Center, Crescenz VA Medical Center, Philadelphia (Kranzler); Northern Sydney Local Health District Drug and Alcohol Services, St Leonards, Australia (Montebello); St Vincent’s Hospital Sydney, Sydney, Australia (Tremonti).
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Nazila Jamshidi, M.B.B.S., Ph.D.
Specialty of Addiction Medicine, Sydney Medical School (Morley, Adams, Montebello, Tremonti, Dali, Logge, Haber), School of Health Sciences (Baillie), and Matilda Centre for Mental Health and Substance Use (Teesson), Faculty of Medicine and Health, University of Sydney, Sydney, Australia; Edith Collins Centre for Translational Research in Alcohol, Drugs, and Toxicology (Morley, Jamshidi, Logge, Haber) and Department of Medical Genomics (Luquin, Trent), Royal Prince Alfred Hospital, Camperdown, Australia; Center for Studies of Addiction, Perelman School of Medicine, University of Pennsylvania, and Mental Illness Research, Education, and Clinical Center, Crescenz VA Medical Center, Philadelphia (Kranzler); Northern Sydney Local Health District Drug and Alcohol Services, St Leonards, Australia (Montebello); St Vincent’s Hospital Sydney, Sydney, Australia (Tremonti).
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Claire Adams, B.M.Sc.
Specialty of Addiction Medicine, Sydney Medical School (Morley, Adams, Montebello, Tremonti, Dali, Logge, Haber), School of Health Sciences (Baillie), and Matilda Centre for Mental Health and Substance Use (Teesson), Faculty of Medicine and Health, University of Sydney, Sydney, Australia; Edith Collins Centre for Translational Research in Alcohol, Drugs, and Toxicology (Morley, Jamshidi, Logge, Haber) and Department of Medical Genomics (Luquin, Trent), Royal Prince Alfred Hospital, Camperdown, Australia; Center for Studies of Addiction, Perelman School of Medicine, University of Pennsylvania, and Mental Illness Research, Education, and Clinical Center, Crescenz VA Medical Center, Philadelphia (Kranzler); Northern Sydney Local Health District Drug and Alcohol Services, St Leonards, Australia (Montebello); St Vincent’s Hospital Sydney, Sydney, Australia (Tremonti).
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Mark Montebello, M.B.B.S., F.R.A.N.Z.C.P.
Specialty of Addiction Medicine, Sydney Medical School (Morley, Adams, Montebello, Tremonti, Dali, Logge, Haber), School of Health Sciences (Baillie), and Matilda Centre for Mental Health and Substance Use (Teesson), Faculty of Medicine and Health, University of Sydney, Sydney, Australia; Edith Collins Centre for Translational Research in Alcohol, Drugs, and Toxicology (Morley, Jamshidi, Logge, Haber) and Department of Medical Genomics (Luquin, Trent), Royal Prince Alfred Hospital, Camperdown, Australia; Center for Studies of Addiction, Perelman School of Medicine, University of Pennsylvania, and Mental Illness Research, Education, and Clinical Center, Crescenz VA Medical Center, Philadelphia (Kranzler); Northern Sydney Local Health District Drug and Alcohol Services, St Leonards, Australia (Montebello); St Vincent’s Hospital Sydney, Sydney, Australia (Tremonti).
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Chris Tremonti, B.M.B.S., F.R.A.C.P.
Specialty of Addiction Medicine, Sydney Medical School (Morley, Adams, Montebello, Tremonti, Dali, Logge, Haber), School of Health Sciences (Baillie), and Matilda Centre for Mental Health and Substance Use (Teesson), Faculty of Medicine and Health, University of Sydney, Sydney, Australia; Edith Collins Centre for Translational Research in Alcohol, Drugs, and Toxicology (Morley, Jamshidi, Logge, Haber) and Department of Medical Genomics (Luquin, Trent), Royal Prince Alfred Hospital, Camperdown, Australia; Center for Studies of Addiction, Perelman School of Medicine, University of Pennsylvania, and Mental Illness Research, Education, and Clinical Center, Crescenz VA Medical Center, Philadelphia (Kranzler); Northern Sydney Local Health District Drug and Alcohol Services, St Leonards, Australia (Montebello); St Vincent’s Hospital Sydney, Sydney, Australia (Tremonti).
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Gezelle Dali, Ph.D.
Specialty of Addiction Medicine, Sydney Medical School (Morley, Adams, Montebello, Tremonti, Dali, Logge, Haber), School of Health Sciences (Baillie), and Matilda Centre for Mental Health and Substance Use (Teesson), Faculty of Medicine and Health, University of Sydney, Sydney, Australia; Edith Collins Centre for Translational Research in Alcohol, Drugs, and Toxicology (Morley, Jamshidi, Logge, Haber) and Department of Medical Genomics (Luquin, Trent), Royal Prince Alfred Hospital, Camperdown, Australia; Center for Studies of Addiction, Perelman School of Medicine, University of Pennsylvania, and Mental Illness Research, Education, and Clinical Center, Crescenz VA Medical Center, Philadelphia (Kranzler); Northern Sydney Local Health District Drug and Alcohol Services, St Leonards, Australia (Montebello); St Vincent’s Hospital Sydney, Sydney, Australia (Tremonti).
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Warren Logge, Ph.D.
Specialty of Addiction Medicine, Sydney Medical School (Morley, Adams, Montebello, Tremonti, Dali, Logge, Haber), School of Health Sciences (Baillie), and Matilda Centre for Mental Health and Substance Use (Teesson), Faculty of Medicine and Health, University of Sydney, Sydney, Australia; Edith Collins Centre for Translational Research in Alcohol, Drugs, and Toxicology (Morley, Jamshidi, Logge, Haber) and Department of Medical Genomics (Luquin, Trent), Royal Prince Alfred Hospital, Camperdown, Australia; Center for Studies of Addiction, Perelman School of Medicine, University of Pennsylvania, and Mental Illness Research, Education, and Clinical Center, Crescenz VA Medical Center, Philadelphia (Kranzler); Northern Sydney Local Health District Drug and Alcohol Services, St Leonards, Australia (Montebello); St Vincent’s Hospital Sydney, Sydney, Australia (Tremonti).
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Andrew Baillie, Ph.D.
Specialty of Addiction Medicine, Sydney Medical School (Morley, Adams, Montebello, Tremonti, Dali, Logge, Haber), School of Health Sciences (Baillie), and Matilda Centre for Mental Health and Substance Use (Teesson), Faculty of Medicine and Health, University of Sydney, Sydney, Australia; Edith Collins Centre for Translational Research in Alcohol, Drugs, and Toxicology (Morley, Jamshidi, Logge, Haber) and Department of Medical Genomics (Luquin, Trent), Royal Prince Alfred Hospital, Camperdown, Australia; Center for Studies of Addiction, Perelman School of Medicine, University of Pennsylvania, and Mental Illness Research, Education, and Clinical Center, Crescenz VA Medical Center, Philadelphia (Kranzler); Northern Sydney Local Health District Drug and Alcohol Services, St Leonards, Australia (Montebello); St Vincent’s Hospital Sydney, Sydney, Australia (Tremonti).
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Maree Teesson, Ph.D.
Specialty of Addiction Medicine, Sydney Medical School (Morley, Adams, Montebello, Tremonti, Dali, Logge, Haber), School of Health Sciences (Baillie), and Matilda Centre for Mental Health and Substance Use (Teesson), Faculty of Medicine and Health, University of Sydney, Sydney, Australia; Edith Collins Centre for Translational Research in Alcohol, Drugs, and Toxicology (Morley, Jamshidi, Logge, Haber) and Department of Medical Genomics (Luquin, Trent), Royal Prince Alfred Hospital, Camperdown, Australia; Center for Studies of Addiction, Perelman School of Medicine, University of Pennsylvania, and Mental Illness Research, Education, and Clinical Center, Crescenz VA Medical Center, Philadelphia (Kranzler); Northern Sydney Local Health District Drug and Alcohol Services, St Leonards, Australia (Montebello); St Vincent’s Hospital Sydney, Sydney, Australia (Tremonti).
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Ronald Trent, Ph.D., F.R.A.C.P.
Specialty of Addiction Medicine, Sydney Medical School (Morley, Adams, Montebello, Tremonti, Dali, Logge, Haber), School of Health Sciences (Baillie), and Matilda Centre for Mental Health and Substance Use (Teesson), Faculty of Medicine and Health, University of Sydney, Sydney, Australia; Edith Collins Centre for Translational Research in Alcohol, Drugs, and Toxicology (Morley, Jamshidi, Logge, Haber) and Department of Medical Genomics (Luquin, Trent), Royal Prince Alfred Hospital, Camperdown, Australia; Center for Studies of Addiction, Perelman School of Medicine, University of Pennsylvania, and Mental Illness Research, Education, and Clinical Center, Crescenz VA Medical Center, Philadelphia (Kranzler); Northern Sydney Local Health District Drug and Alcohol Services, St Leonards, Australia (Montebello); St Vincent’s Hospital Sydney, Sydney, Australia (Tremonti).
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Paul S. Haber, M.D., F.R.A.C.P.
Specialty of Addiction Medicine, Sydney Medical School (Morley, Adams, Montebello, Tremonti, Dali, Logge, Haber), School of Health Sciences (Baillie), and Matilda Centre for Mental Health and Substance Use (Teesson), Faculty of Medicine and Health, University of Sydney, Sydney, Australia; Edith Collins Centre for Translational Research in Alcohol, Drugs, and Toxicology (Morley, Jamshidi, Logge, Haber) and Department of Medical Genomics (Luquin, Trent), Royal Prince Alfred Hospital, Camperdown, Australia; Center for Studies of Addiction, Perelman School of Medicine, University of Pennsylvania, and Mental Illness Research, Education, and Clinical Center, Crescenz VA Medical Center, Philadelphia (Kranzler); Northern Sydney Local Health District Drug and Alcohol Services, St Leonards, Australia (Montebello); St Vincent’s Hospital Sydney, Sydney, Australia (Tremonti).
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Notes

Send correspondence to Dr. Morley ([email protected]).

Competing Interests

Dr. Kranzler has served on advisory boards for Dicerna Pharmaceuticals, Sophrosyne Pharmaceuticals, Entheon Pharmaceuticals, and Clearmind Medicine and as a consultant for Sobrera Pharmaceuticals; he has received research funding and medication supplies for an investigator-initiated study from Alkermes; he is a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative, which was supported in the past 3 years by Alkermes, Dicerna, Ethypharm, Lundbeck, Mitsubishi, Otsuka, and Pear Therapeutics; and he is a holder of a patent for genotype-guided dosing of opioid agonists (U.S. 10,900,082). Dr. Tremonti has served as a speaker for Invidior. Dr. Haber has received research funding from Invidior. The other authors report no financial relationships with commercial interests.

Funding Information

Supported by a grant (Drs. Haber, Morley, Kranzler, Luquin, Trent, Baillie, and Teesson) and fellowships (Drs. Haber and Morley) from the National Health and Medical Research Council of Australia.

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