topiramate and Alcoholism

Topiramate (TPM) has the potential to become one of the most prominent treatment options for alcohol use disorder (AUD). We investigated the efficacy of TPM for AUD treatment, considering new randomized controlled trials carried out since the publication of four prior investigations.. We searched six major databases, comparing TPM to placebo for AUD treatment. We performed a Bayesian meta-analysis. We conducted a meta-regression, analyzing the effect of age, TPM dosage, duration of treatment, gender, and attrition rate on the outcomes measured. The protocol is registered with PROSPERO: CRD42021286266.. TPM reduced heavy drinking days (. TPM has the potential to become a key pharmacological agent in the treatment of AUD.

Topics: Alcohol Drinking; Alcoholism; Bayes Theorem; Humans; Substance Withdrawal Syndrome; Topiramate

Harmful alcohol use is defined as unhealthy alcohol use that results in adverse physical, psychological, social, or societal consequences and is among the leading risk factors for disease, disability and premature mortality globally. The burden of harmful alcohol use is increasing in low- and middle-income countries (LMICs) and there remains a large unmet need for indicated prevention and treatment interventions to reduce harmful alcohol use in these settings. Evidence regarding which interventions are effective and feasible for addressing harmful and other patterns of unhealthy alcohol use in LMICs is limited, which contributes to this gap in services.. To assess the efficacy and safety of psychosocial and pharmacologic treatment and indicated prevention interventions compared with control conditions (wait list, placebo, no treatment, standard care, or active control condition) aimed at reducing harmful alcohol use in LMICs.. We searched for randomized controlled trials (RCTs) indexed in the Cochrane Drugs and Alcohol Group (CDAG) Specialized Register, the Cochrane Clinical Register of Controlled Trials (CENTRAL) in the Cochrane Library, PubMed, Embase, PsycINFO, CINAHL, and the Latin American and Caribbean Health Sciences Literature (LILACS) through 12 December 2021. We searched clinicaltrials.gov, the World Health Organization International Clinical Trials Registry Platform, Web of Science, and Opengrey database to identify unpublished or ongoing studies. We searched the reference lists of included studies and relevant review articles for eligible studies.. All RCTs comparing an indicated prevention or treatment intervention (pharmacologic or psychosocial) versus a control condition for people with harmful alcohol use in LMICs were included.. We used standard methodological procedures expected by Cochrane.. In LMICs there is low-certainty evidence supporting the efficacy of combined psychosocial and pharmacologic interventions on reducing harmful alcohol use relative to psychosocial interventions alone. There is insufficient evidence to determine the efficacy of pharmacologic or psychosocial interventions on reducing harmful alcohol use largely due to the substantial heterogeneity in outcomes, comparisons, and interventions that precluded pooling of these data in meta-analyses. The majority of studies are brief interventions, primarily among men, and using measures that have not been validated in the target population. Confidence in these results is reduced by the risk of bias and significant heterogeneity among studies as well as the heterogeneity of results on different outcome measures within studies. More evidence on the efficacy of pharmacologic interventions, specific types of psychosocial interventions are needed to increase the certainty of these results.

Topics: Acamprosate; Alcoholism; Amitriptyline; Developing Countries; Disulfiram; Humans; Male; Mirtazapine; Naltrexone; Ondansetron; Topiramate

Alcohol use disorder (AUD) is a highly prevalent but severely under-treated disorder, with only three widely-approved pharmacotherapies. Given that AUD is a very heterogeneous disorder, it is unlikely that one single medication will be effective for all individuals with an AUD. As such, there is a need to develop new, more effective, and diverse pharmacological treatment options for AUD with the hopes of increasing utilization and improving care. In this qualitative literature review, we discuss the efficacy, mechanism of action, and tolerability of approved, repurposed, and novel pharmacotherapies for the treatment of AUD with a clinical perspective. Pharmacotherapies discussed include: disulfiram, acamprosate, naltrexone, nalmefene, topiramate, gabapentin, varenicline, baclofen, sodium oxybate, aripiprazole, ondansetron, mifepristone, ibudilast, suvorexant, prazosin, doxazosin, N-acetylcysteine, GET73, ASP8062, ABT-436, PF-5190457, and cannabidiol. Overall, many repurposed and novel agents discussed in this review demonstrate clinical effectiveness and promise for the future of AUD treatment. Importantly, these medications also offer potential improvements towards the advancement of precision medicine and personalized treatment for the heterogeneous AUD population. However, there remains a great need to improve access to treatment, increase the menu of approved pharmacological treatments, and de-stigmatize and increase treatment-seeking for AUD.

Topics: Acamprosate; Alcohol Deterrents; Alcoholism; Baclofen; Disulfiram; Humans; Naltrexone; Topiramate

Topiramate has been approved by the US Food and Drug Administration for the treatment of epilepsy since the 1990s, and it has also been used off-label in the treatment of many types of addictive disorders. To date, no systematic review has embraced the entire field of addiction, both substance use and behavioral addictions, including eating disorders, to compare topiramate-based protocols and the related level of evidence in each addictive disorder. Our objective is to fill this gap.. A systematic search was conducted using the MEDLINE, PsycINFO, and Cochrane databases without a date or language limit. All trials and meta-analyses assessing the efficacy of topiramate in alcohol use disorder; cocaine use disorder; methamphetamine, nicotine, cannabis, opiate, and benzodiazepine use disorders; binge eating disorder; bulimia; and pathological gambling were analyzed. The quality of the studies was rated using the Cochrane Risk-of-Bias tool for randomized trials (ROB-2), the Risk of Bias In Nonrandomized Studies (ROBINS-I), or the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist, depending on the study design. Safety features were assessed based on a wider non-systematic review.. Sixty-two articles were reviewed. Treatment protocols were relatively homogenous across addictive disorders, with slow dose titration schemes and a maximum dose range of 200-400 mg per day. The most supportive evidence for topiramate efficacy was found in alcohol use disorder for drinking reduction parameters only. To a lesser extent, topiramate could be a promising therapeutic option for binge eating disorder and cocaine use disorder. Evidence was weak for other addictive disorders. No major tolerability issues were found, provided that basic safety rules were followed. Adverse drug reactions could lead to early treatment discontinuation.. Though off-label, addiction specialists should consider topiramate as a second-line option for drinking reduction in alcohol use disorder, as well as for binge eating disorder or cocaine use disorder.

Topics: Alcohol Drinking; Alcoholism; Anticonvulsants; Behavior, Addictive; Dose-Response Relationship, Drug; Feeding and Eating Disorders; Humans; Off-Label Use; Randomized Controlled Trials as Topic; Substance-Related Disorders; Topiramate

Topics: Alcoholism; Europe; Gabapentin; Humans; Topiramate

Effective medications for treating alcohol use disorders (AUD) are available but underutilized. Multiple barriers to their provision have been identified, and optimal strategies for addressing and overcoming barriers to use of medications for AUD treatment remain elusive. We conducted a structured review of published care delivery and implementation studies evaluating interventions that aimed to increase medication treatment for patients with AUD to identify interventions and component strategies that were most effective.. We reviewed literature through May 2018 and used networking to identify intervention studies with AUD medication receipt reported as a primary or secondary outcome. Studies were identified as care delivery studies, characterized by patient-level recruitment and willingness to be randomized to candidate treatment options, and implementation studies, characterized by inclusion of all patients treated at sites involved in the study. Each identified study was independently coded by two investigators for strategies used, guided by a published taxonomy of implementation strategies. All authors reviewed coding discrepancies and revised codes based on consensus. After reaching internal consensus, we solicited feedback from lead investigators on studies to code additional strategies. We reviewed implementation strategies used across studies to assess their relationship with medication receipt, as well as alcohol use outcomes, as available.. Nine studies were identified: four RCTs of care delivery interventions, four quasi-experimental evaluations of large-scale implementation interventions, and one quasi-experimental evaluation of a targeted single-site implementation intervention. Implementation strategies used were variable across studies; no strategy was universally used. Effects of the interventions on receipt of AUD pharmacotherapy and alcohol use outcomes also varied. Three of four care delivery interventions resulted in increased receipt of AUD medications, but only one of these three improved alcohol use outcomes. One large-scale and one single-site implementation intervention were associated with increased AUD medication receipt, and these studies did not assess alcohol use outcomes. Patterns of implementation strategies did not clearly distinguish studies that successfully increased use of pharmacotherapy versus those that did not.. Our review did not reveal strategies most effective for implementing AUD medications. Interventions designed to overcome identified barriers may have missed the mark, or differences in the intensity or targets of strategies may matter more than differences in strategies. Further research is needed to understand effective implementation methods and to better understand patient-level perspective, preferences and barriers to receipt of medications.

Topics: Acamprosate; Alcohol Deterrents; Alcohol-Related Disorders; Alcoholism; Clinical Trials as Topic; Disulfiram; Naltrexone; Practice Patterns, Physicians'; Topiramate; United States; United States Department of Veterans Affairs; Veterans

Pharmacologically controlled drinking in the treatment of alcohol dependence or alcohol use disorders (AUDs) is an emerging concept. Our objective was to explore the comparative effectiveness of drugs used in this indication.. Systematic review with direct and network meta-analysis of double-blind randomized controlled trials (RCTs) assessing the efficacy of nalmefene, naltrexone, acamprosate, baclofen or topiramate in non-abstinent adults diagnosed with alcohol dependence or AUDs. Two independent reviewers selected published and unpublished studies on Medline, the Cochrane Library, Embase, ClinicalTrials.gov, contacted pharmaceutical companies, the European Medicines Agency and the Food and Drug Administration, and extracted data.. Thirty-two RCTs.. A total of 6036 patients.. The primary outcome was total alcohol consumption (TAC). Other consumption outcomes and health outcomes were considered as secondary outcomes.. No study provided direct comparisons between drugs. A risk of incomplete outcome data was identified in 26 studies (81%) and risk of selective outcome reporting in 17 (53%). Nalmefene [standardized mean difference (SMD) = -0.19, 95% confidence interval (CI) = -0.29, -0.10; I. There is currently no high-grade evidence for pharmacological treatment to control drinking using nalmefene, naltrexone, acamprosate, baclofen or topiramate in patients with alcohol dependence or alcohol use disorder. Some treatments show low to medium efficacy in reducing drinking across a range of studies with a high risk of bias. None demonstrates any benefit on health outcomes.

Topics: Acamprosate; Alcoholism; Baclofen; Naltrexone; Narcotic Antagonists; Network Meta-Analysis; Topiramate; Treatment Outcome

The development of alcohol dependence is associated with significant morbidity and mortality. For the majority of affected people the most appropriate goal, in terms of drinking behaviour, is abstinence from alcohol. Psychosocial intervention is the mainstay of the treatment but adjuvant pharmacotherapy is also available and its use recommended.. To provide an updated analysis of current and potential pharmacotherapeutic options for the management of alcohol dependence. In addition, factors predictive of therapeutic outcome, including compliance and pharmacogenetics, and the current barriers to treatment, including doctors' unwillingness to prescribe these agents, will be explored.. Relevant papers were selected for review following extensive, language- and date-unrestricted, electronic and manual searches of the literature.. Acamprosate and naltrexone have a substantial evidence base for overall efficacy, safety and cost-effectiveness while the risks associated with the use of disulfiram are well-known and can be minimised with appropriate patient selection and supervision. Acamprosate can be used safely in patients with liver disease and in those with comorbid mental health issues and co-occurring drug-related problems. A number of other agents are being investigated for potential use for this indication including: baclofen, topiramate and metadoxine.. Pharmacotherapy for alcohol dependence has been shown to be moderately efficacious with few safety concerns, but it is substantially underutilised. Concerted efforts must be made to remove the barriers to treatment in order to optimise the management of people with this condition.

Topics: Acamprosate; Alcohol Deterrents; Alcoholism; Baclofen; Disulfiram; Drug Combinations; Fructose; Humans; Naltrexone; Polymorphism, Single Nucleotide; Pyridoxine; Pyrrolidonecarboxylic Acid; Taurine; Topiramate; Treatment Outcome

Insomnia in patients with alcohol dependence has increasingly become a target of treatment due to its prevalence, persistence, and associations with relapse and suicidal thoughts, as well as randomized controlled studies demonstrating efficacy with behavior therapies and non-addictive medications. This article focuses on assessing and treating insomnia that persists despite 4 or more weeks of sobriety in alcohol-dependent adults. Selecting among the various options for treatment follows a comprehensive assessment of insomnia and its multifactorial causes. In addition to chronic, heavy alcohol consumption and its effects on sleep regulatory systems, contributing factors include premorbid insomnia; co-occurring medical, psychiatric, and other sleep disorders; use of other substances and medications; stress; environmental factors; and inadequate sleep hygiene. The assessment makes use of history, rating scales, and sleep diaries as well as physical, mental status, and laboratory examinations to rule out these factors. Polysomnography is indicated when another sleep disorder is suspected, such as sleep apnea or periodic limb movement disorder, or when insomnia is resistant to treatment. Sobriety remains a necessary, first-line treatment for insomnia, and most patients will have some improvement. If insomnia-specific treatment is needed, then brief behavioral therapies are the treatment of choice, because they have shown long-lasting benefit without worsening of drinking outcomes. Medications work faster, but they generally work only as long as they are taken. Melatonin agonists; sedating antidepressants, anticonvulsants, and antipsychotics; and benzodiazepine receptor agonists each have their benefits and risks, which must be weighed and monitored to optimize outcomes. Some relapse prevention medications may also have sleep-promoting activity. Although it is assumed that treatment for insomnia will help prevent relapse, this has not been firmly established. Therefore, insomnia and alcohol dependence might be best thought of as co-occurring disorders, each of which requires its own treatment.

Topics: Acamprosate; Alcohol Deterrents; Alcoholism; Amines; Anti-Anxiety Agents; Anticonvulsants; Antipsychotic Agents; Cognitive Behavioral Therapy; Comorbidity; Cyclohexanecarboxylic Acids; Diagnosis, Differential; Dyssomnias; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Polysomnography; Quetiapine Fumarate; Sleep Apnea Syndromes; Sleep Initiation and Maintenance Disorders; Stress, Psychological; Taurine; Topiramate; Trazodone

Influenced by several trials and reviews highlighting positive outcomes, topiramate is increasingly prescribed as a treatment for alcohol use disorders (AUDs). The only previously published meta-analysis of topiramate for AUDs was limited by a sample of only 3 randomized, placebo-controlled trials (RCTs).. A systematic search identified 7 RCTs (including a total of 1,125 participants) that compared topiramate to placebo for the treatment for AUDs. This meta-analysis estimated the overall effects of topiramate on abstinence, heavy drinking, craving, and γ-glutamyltranspeptidase (GGT) outcomes and included several sensitivity analyses to account for the small sample of studies.. Overall, the small to moderate effects favored topiramate, although the effect on craving was not quite significantly different from 0. The largest effect was found on abstinence (g = 0.468, p < 0.01), followed by heavy drinking (g = 0.406, p < 0.01), GGT (g = 0.324, p = 0.02), and craving (g = 0.312, p = 0.07) outcomes. Sensitivity analyses did not change the magnitude or direction of the results, and tests did not indicate significant publication bias. The small sample size did not allow for examination of specific moderators of the effects of topiramate.. Topiramate can be a useful tool in the treatment of AUDs. Its efficacy, based on the current sample of studies, seems to be of somewhat greater magnitude than that of the most commonly prescribed medications for AUDs (naltrexone and acamprosate). Further research will help to identify the contexts in which topiramate is most beneficial (e.g., dose, concurrent psychotherapy, patient characteristics).

Topics: Alcohol Drinking; Alcoholism; Excitatory Amino Acid Antagonists; Fructose; Humans; Topiramate; Treatment Outcome

Alcohol use disorders (AUD) are defined as alcohol abuse and alcohol dependence, which create large problems both for society and for the drinkers themselves. To date, no therapeutic can effectively solve these problems. Understanding the underlying mechanisms leading to AUD is critically important for developing effective and safe pharmacological therapies. Benzodiazepines (BZs) are used to reduce the symptoms of alcohol withdrawal syndrome. However, frequent use of BZs causes cross-tolerance, dependence, and cross-addiction to alcohol. The FDA-approved naltrexone and acamprosate have shown mixed results in clinical trials. Naltrexone is effective to treat alcohol dependence (decreased length and frequency of drinking bouts), but its severe side effects, including withdrawal symptoms, are difficult to overcome. Acamprosate showed efficacy for treating alcohol dependence in European trials, but two large US trials have failed to confirm the efficacy. Another FDA-approved medication, disulfiram, does not diminish craving, and it causes a peripheral neuropathy. Kudzu is the only natural medication mentioned by the National Institute on Alcohol Abuse and Alcoholism, but its mechanisms of action are not yet established. It has been recently shown that dihydromyricetin, a flavonoid purified from Hovenia, has unique effects on GABAA receptors and blocks ethanol intoxication and withdrawal in alcoholic animal models. In this article, we review the role of GABAA receptors in the treatment of AUD and currently available and potentially novel pharmacological agents.

Topics: Acamprosate; Alcohol Deterrents; Alcohol Drinking; Alcoholism; Animals; Benzodiazepines; Disulfiram; Ethanol; Fructose; Humans; Naltrexone; Narcotic Antagonists; Neuroprotective Agents; Plant Preparations; Receptors, GABA-A; Taurine; Topiramate

European Medicines Agency guidelines recognize two different treatment goals for alcohol dependence: abstinence and reduction in alcohol consumption. All currently approved agents are indicated for abstinence. This systematic review aimed to identify drugs in development for alcohol dependence treatment and to establish, based upon trial design, if any are seeking market authorization for reduction in consumption.. We searched PubMed and Embase (December 2001-November 2011) to identify agents in development for alcohol dependence treatment. Additional studies were identified by searching ClinicalTrials.gov and the R&D Insight and Clinical Trials Insight databases. Studies in which the primary focus was treatment of comorbidity, or n≤20, were excluded. Studies were then classified as 'abstinence' if they: described a detoxification/alcohol withdrawal period; enrolled patients who had undergone detoxification previously; or presented relapse/abstinence rates as the primary outcome. Studies in patients actively drinking at baseline were classified as 'reduction in consumption'.. Of 602 abstracts identified, 45 full-text articles were eligible. Five monotherapies were in development for alcohol dependence treatment: topiramate, fluvoxamine, aripiprazole, flupenthixol and nalmefene. Nalmefene was the only agent whose sponsor was clearly seeking definitive approval for reduction in consumption. Development status was unclear for topiramate, fluvoxamine, aripiprazole and flupenthixol. Fifteen agents were examined in published exploratory investigator-initiated trials; the majority focused on abstinence. Ongoing (unpublished) trials tended to focus on reduction in consumption.. While published studies generally focused on abstinence, ongoing trials focused on reduction in consumption, suggesting a change in emphasis in the approach to treating alcohol dependence.

Topics: Alcohol Abstinence; Alcohol Deterrents; Alcohol Drinking; Alcoholism; Aripiprazole; Flupenthixol; Fluvoxamine; Fructose; Humans; Naltrexone; Piperazines; Psychotropic Drugs; Quinolones; Topiramate

Topics: Acamprosate; Alcoholism; Baclofen; Combined Modality Therapy; Ethanol; Fructose; Humans; Naltrexone; Psychotherapy; Secondary Prevention; Socioenvironmental Therapy; Substance Withdrawal Syndrome; Taurine; Topiramate

The prevalence of unidentified or untreated unhealthy alcohol use remains high. With the advent of pharmacotherapy and models of counseling appropriate for use in primary care settings as well as in specialty care, clinicians have new tools to manage the range of alcohol problems across the spectrum of health care settings. By extending treatment to primary care, many people who do not currently receive specialty care may have increased access to treatment. In addition, primary care providers, by virtue of their ongoing relationship with patients, may be able to provide continuing treatment over time. Extending the spectrum of care to hazardous drinkers who may not be alcohol dependent could result in earlier intervention and reduce the consequences of excessive drinking.

Topics: Acamprosate; Alcohol Drinking; Alcoholism; Animals; Disulfiram; Dopamine Agents; Fructose; Humans; Naltrexone; Selective Serotonin Reuptake Inhibitors; Taurine; Topiramate

To summarize published data on pharmacologic treatments for alcohol dependence alone and in combination with brief psychosocial therapies that may be feasible for primary care and specialty medical settings.. We conducted electronic searches of published original research articles and reviews in MEDLINE, SCOPUS, CINAHL, Embase, and PsychINFO. In addition, hand searches of reference lists of review articles, supplemental searches of internet references and contacts with experts in the field were conducted. Randomized controlled studies published between January 1960 and August 2010 that met our inclusion/exclusion criteria were included.. A total of 85 studies, representing 18,937 subjects, met our criteria for inclusion. The evidence base for oral naltrexone (6% more days abstinent than placebo in the largest study) and topiramate (prescribed off-label) (e.g., 26.2% more days abstinent than placebo in a recent study) is positive but modest. Acamprosate shows modest efficacy with recently abstinent patients, with European studies showing better results than U.S. ones. The evidence-base for disulfiram is equivocal. Depot naltrexone shows efficacy (25% greater reduction in rate of heavy drinking vs. placebo, in one of the largest studies) in a limited number of studies. Some studies suggest that patients do better with extensive psychosocial treatments added to medications while others show that brief support can be equally effective.. Although treatment effects are modest, medications for alcohol dependence, in conjunction with either brief support or more extensive psychosocial therapy, can be effective in primary and specialty care medical settings.

Topics: Acamprosate; Alcohol Deterrents; Alcoholism; Disulfiram; Fructose; Humans; Naltrexone; Narcotic Antagonists; Off-Label Use; Taurine; Topiramate; Treatment Outcome

Alcohol dependence is a major health problem worldwide. Various pharmacological agents have been used in the management of alcohol dependence. This review looks at the role of topiramate and other anticonvulsants in the management of alcohol dependence. Topiramate is the most widely used anticonvulsant in the treatment of alcohol dependence. The literature on topiramate is reviewed and critically analyzed, along with its proposed mechanism of action in alcohol dependence. A review of data available on other anticonvulsants like carbamazepine, oxcarbazepine, sodium valproate, gabapentin and levetiracetam are presented and their potential in the treatment of alcohol dependence is considered, together with future research directions.

Topics: Alcohol-Induced Disorders, Nervous System; Alcoholism; Anticonvulsants; Brain; Brain Chemistry; Fructose; Humans; Mood Disorders; Substance Withdrawal Syndrome; Topiramate

Predicated upon a neuropharmacological conceptual model, there is now solid clinical evidence to support the efficacy of topiramate for the treatment of alcohol dependence. Topiramate treatment can be initiated whilst the alcohol-dependent individual is still drinking - just when crisis intervention is most likely to be needed by a patient with or without his or her family asking the health practitioner for assistance. Because topiramate can be paired with a brief intervention, there is now the exciting possibility of treating most alcohol- dependent individuals in office-based practice or generic treatment settings. Topiramate's additional effects on other impulsedyscontrol disorders make it a particularly interesting compound for the treatment of other comorbid drug or psychiatric disorders. Additionally, future studies should explore whether topiramate can be combined with other putative therapeutic agents to increase its efficacy. One notable clinical challenge in the development of topiramate as a pharmacotherapy to treat alcohol dependence is the determination of the smallest dose that can result in efficacy, thereby achieving the optimum balance between therapeutic benefit and adverse event profile. Animal data do provide support for topiramate's general anti-drinking effects but also indicate that its mechanisms of action might rely on several complex pharmacobehavioral changes. Additional preclinical studies are needed to elucidate more clearly the basic mechanistic processes that underlie topiramate's efficacy as a treatment for alcohol dependence. Preclinical information that topiramate may have differential effects based on genetic vulnerability opens up the possibility of future methods to optimize treatment.

Topics: Alcohol Drinking; Alcoholism; Animals; Combined Modality Therapy; Dose-Response Relationship, Drug; Fructose; Humans; Neuroprotective Agents; Psychotherapy, Brief; Topiramate

Alcoholism remains a serious cause of morbidity and mortality despite progress through neurobiological research in identifying new pharmacological strategies for its treatment. Drugs that affect neural pathways that modulate the activity of the cortico-mesolimbic dopamine system have been shown to alter drinking behavior, presumably because this dopaminergic system is closely associated with rewarding behavior. Ondansetron, naltrexone, topiramate, and baclofen are examples. Subtyping alcoholism in adults into an early-onset type, with chronic symptoms and a strong biological predisposition to the disease, and a late-onset type, typically brought on by psychosocial triggers and associated with mood symptoms, may help in the selection of optimal therapy. Emerging adults with binge drinking patterns also might be aided by selective treatments. Although preliminary work on the pharmacogenetics of alcoholism and its treatment has been promising, the assignment to treatment still depends on clinical assessment. Brief behavioral interventions that encourage the patient to set goals for a reduction in heavy drinking or abstinence also are part of optimal therapy.

Topics: Adult; Aged; Alcohol Deterrents; Alcoholism; Baclofen; Chronic Disease; Depressive Disorder; Female; Fructose; Humans; Hypothalamo-Hypophyseal System; Limbic System; Male; Naltrexone; Ondansetron; Pituitary-Adrenal System; Prefrontal Cortex; Receptors, Dopamine D2; Receptors, GABA; Topiramate; Young Adult

Pharmacotherapy, in conjunction with psychosocial interventions, is emerging as a valuable tool for alcohol dependence treatment. Currently, four agents are approved by the Food and Drug Administration for this purpose: disulfiram, acamprosate, oral naltrexone, and the once-monthly injectable, extended-release naltrexone. All four agents have demonstrated some ability to reduce drinking and/or increase time spent abstinent, but results have not always been consistent. Except disulfiram, which has an aversive mechanism of action, effective pharmacotherapies for alcohol dependence are thought to work by blocking the rewards of alcohol or stabilizing systems dysregulated by chronic alcohol intake. Topiramate and baclofen have also demonstrated some efficacy in treating alcohol dependence. The efficacies of many of these regimens are modest and are limited by patient nonadherence to treatment and disease heterogeneity. Pharmacotherapeutic effectiveness could be enhanced through increased knowledge of the pathophysiology of alcohol dependence, through the identification of predictors of response to specific medications, and by modalities that improve medication adherence.

Topics: Acamprosate; Alcohol Deterrents; Alcohol Drinking; Alcoholism; Baclofen; Delayed-Action Preparations; Disulfiram; Fructose; Humans; Medication Adherence; Naltrexone; Taurine; Temperance; Topiramate

Despite the availability of currently approved medications and various psychosocial therapies, alcohol abuse and dependence are increasingly prevalent in the United States, and carry a significant socioeconomic burden. Recently, the novel anti-epileptic topiramate has shown great promise as a new treatment for this disorder. The objective of this review is to discuss the limitations of the currently available options for treating alcohol dependence, to review the results of clinical trials assessing the efficacy of topiramate in treating alcohol dependence, and to describe the pharmacological characteristics and mechanisms of action of topiramate as related to this indication. We systematically reviewed Medline, EMBASE, Cochran Reviews and PsycINFO search terms included combinations of the terms "pharmacotherapy" "topiramate", "alcoholism" and "alcohol dependence." Searches were last updated 24 October 2008. Currently approved treatments include disulfiram, naltrexone tablets and injection, and acamprosate. Of these, naltrexone has shown the most benefit, however the effect size is small and may reach its most promising potential when combined with medical management. Alternatively, through multiple mechanisms of action, topiramate in clinical trials has demonstrated safety and efficacy in decreasing both craving and withdrawal symptoms and increasing quality of life measures among alcohol-dependent individuals. The findings of this review suggest that topiramate is a promising new option for the treatment of alcohol dependence, and may offer substantial benefits over currently approved medications. While the manufacturer will not pursue approval of an indication for the treatment of alcohol dependence, the drug will soon be available generically, making it more affordable for a greater proportion of the public.

Topics: Alcohol Deterrents; Alcohol Drinking; Alcohol-Induced Disorders; Alcoholism; Anticonvulsants; Fructose; Humans; Substance Withdrawal Syndrome; Topiramate

To evaluate the evidence for the use of topiramate for alcohol dependence.. MEDLINE (1966-June 2008) and Cochrane Database (2008, Issue 1) searches were conducted using the search terms alcohol dependence and topiramate. Bibliographies of selected articles were examined for additional data sources.. English-language, randomized, controlled trials evaluating topiramate for treatment of alcohol dependence in humans were selected for review. Three randomized controlled trials and 2 reanalyses were identified. Findings pertaining to efficacy and safety were extracted.. Evidence suggests that topiramate antagonizes excitatory glutamate receptors, inhibits dopamine release, and enhances inhibitory gamma-aminobutyric acid function. These mechanisms may be significant in the treatment of alcohol dependence. Controlled trials have described the use of topiramate, titrated up to 300 mg daily, for alcohol dependence, and have reported decreases in drinking behavior and improvements in quality of life. Adverse effects associated with topiramate included abnormal skin sensation, dizziness, taste perversion, anorexia, pruritus, and difficulty with memory and concentration. In one of the reviewed trials, adverse effects did not account for an increased withdrawal rate. However, in another, when topiramate was titrated over a shortened time period, an increased withdrawal rate was seen. Recently, topiramate has been reported to increase suicide risk, primarily in patients with epilepsy. No cases of suicide were recorded in the alcohol dependence trials.. Results of published trials are promising, showing efficacy for drinking outcomes and quality of life as well as general safety. However, additional larger, longer-term trials are needed to establish the optimal patient type that would benefit most from topiramate treatment in addition to dosing, duration of treatment, and tolerability of topiramate for alcohol dependence. At this time, data are insufficient to support using topiramate in conjunction with brief weekly compliance counseling as a first-line agent for alcohol dependence.

Topics: Alcohol Drinking; Alcoholism; Excitatory Amino Acid Antagonists; Fructose; Humans; Patient Selection; Quality of Life; Randomized Controlled Trials as Topic; Time Factors; Topiramate

The past decade has seen an expansion of research and knowledge on pharmacotherapy for the treatment of alcohol dependence. The Food and Drug Administration (FDA)-approved medications naltrexone and acamprosate have shown mixed results in clinical trials. Oral naltrexone and naltrexone depot formulations have generally demonstrated efficacy at treating alcohol dependence, but their treatment effect size is small, and more research is needed to compare the effects of different doses on drinking outcome. Acamprosate has demonstrated efficacy for treating alcohol dependence in European trials, but with a small effect size. In U.S. trials, acamprosate has not proved to be efficacious. Research continues to explore which types of alcohol-dependent individual would benefit the most from treatment with naltrexone or acamprosate. The combination of the two medications demonstrated efficacy for treating alcohol dependence in one European study but not in a multi-site U.S. study. Another FDA-approved medication, disulfiram, is an aversive agent that does not diminish craving for alcohol. Disulfiram is most effective when given to those who are highly compliant or who are receiving their medication under supervision. Of the non-approved medications, topiramate is among the most promising, with a medium effect size in clinical trials. Another promising medication, baclofen, has shown efficacy in small trials. Serotonergic agents such as selective serotonin reuptake inhibitors and the serotonin-3 receptor antagonist, ondansetron, appear to be efficacious only among certain genetic subtypes of alcoholic. As neuroscientific research progresses, other promising medications, as well as medication combinations, for treating alcohol dependence continue to be explored.

Topics: Acamprosate; Alcoholism; Animals; Baclofen; Disulfiram; Fructose; Humans; Naltrexone; Ondansetron; Receptors, N-Methyl-D-Aspartate; Ritanserin; Selective Serotonin Reuptake Inhibitors; Taurine; Topiramate

Alcoholism is a major public health problem and resembles, in many ways, other chronic relapsing medical conditions. At least 2 separate dimensions of its symptomatology offer targetable pathophysiological mechanisms. Systems that mediate positive reinforcement by alcohol are likely important targets in early stages of the disease, particularly in genetically susceptible individuals. In contrast, long term neuroadaptive changes caused by chronic alcohol use primarily appear to affect systems mediating negative affective states, and gain importance following a prolonged history of dependence. Feasibility of pharmacological treatment in alcoholism has been demonstrated by a first wave of drugs which consists of 3 currently approved medications, the aldehyde dehydrogenase blocker disulfiram, the opioid antagonist naltrexone (NTX) and the functional glutamate antagonist acamprosate (ACM). The treatment toolkit is likely to be expanded in the near future. This will improve overall efficacy and allow individualized treatment, ultimately taking in account the patient's genetic makeup. In a second wave, early human efficacy data are available for the 5HT3 antagonist ondansetron, the GABA-B agonist baclofen and the anticonvulsant topiramate. The third wave is comprised of compounds predicted to be effective based on a battery of animal models. Using such models, a short list of additional targets has accumulated sufficient preclinical validation to merit clinical development. These include the cannabinoid CB1 receptor, receptors modulating glutamatergic transmission (mGluR2, 3 and 5), and receptors for stress-related neuropeptides corticotropin releasing factor (CRF), neuropeptide Y (NPY) and nociceptin. Once novel treatments are developed, the field faces a major challenge to assure their delivery to patients.

Topics: Acamprosate; Alcohol Deterrents; Alcoholism; Animals; Baclofen; Corticotropin-Releasing Hormone; Disease Models, Animal; Disulfiram; Fructose; Humans; Naltrexone; Neuropeptide Y; Nociceptin; Ondansetron; Opioid Peptides; Receptor, Cannabinoid, CB1; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Taurine; Topiramate

In the past decade, scientists have made important progress toward understanding the neurobiology underlying an alcohol disorder. This knowledge has led to the development of promising pharmacotherapies that target the neural pathways involved in the brain's reward center in such a way that the usual treatment response (via counseling) is substantially improved upon. There are now four US Food and Drug Administration (FDA)-approved pharmacotherapies for the treatment of alcohol dependence: disulfiram (Antabuse; Odyssey Pharmaceuticals, East Hanover, NJ), oral naltrexone (ReVia; Barr Pharmaceuticals, Inc., Pomona, NY), acamprosate (Campral; Forest Laboratories, Inc., New York, NY), and, as of April 2006, an extended-release (30-day) injectable suspension formulation of naltrexone (Vivitrol; Alkermes, Inc., Cambridge, MA). Other types of medications (eg, topiramate and quetiapine) are currently under investigation for the treatment of alcohol dependence. Research also has provided insights into best practices for prescribing the available medications. This report reviews the latest innovations in pharmacotherapy for the treatment of alcohol dependence, focusing on FDA-approved medications presently available to the treatment community.

Topics: Acamprosate; Alcohol Deterrents; Alcoholism; Choice Behavior; Cognitive Behavioral Therapy; Combined Modality Therapy; Fructose; Humans; Naltrexone; Narcotic Antagonists; Neuroprotective Agents; Taurine; Topiramate

Pharmacological relapse prevention in alcoholism is a rather new clinical field with few drugs being available. Acamprosate, acting predominantly via glutamatergic pathways, and the opioid receptor antagonist naltrexone, were both shown to be efficient in improving rates for continuous abstinence, and not relapsing to heavy drinking in a number of clinical trials and meta-analyses. There are conflicting data on both drugs, especially for acamprosate, according to some recent US studies. However, overall, the evidence is good. Both drugs are approved in most European countries and the US. Efficacy data for disulfiram are mixed; it is a second-line medication compared with other drugs, and is probably most effective when used in a supervised setting. Recently, anticonvulsants including carbamazepine and topiramate have been discussed as possible anti-craving drugs, but there is still limited evidence for their efficacy. Although there is a significant comorbidity for alcoholism with affective disorder, anxiety and schizophrenia, relatively few controlled clinical trials have been performed in this area. Tricyclics have been found to be more effective than serotonin reuptake inhibitors in improving depressive symptoms in these patients.

Topics: Acamprosate; Alcohol Deterrents; Alcoholism; Animals; Carbamazepine; Depression; Disease Models, Animal; Disulfiram; Fructose; Humans; Naltrexone; Secondary Prevention; Taurine; Topiramate

Alcoholism and nicotine dependence share many neurobiological underpinnings; the presence of one drug can cause a person to crave the other. Depressive illness can complicate comorbid alcohol and nicotine dependence by exacerbating the negative affect encountered during attempts to abstain from one or both drugs. Given the morbidity and mortality associated with cigarette smoking, it is imperative to identify treatments to promote smoking cessation and address comorbid psychiatric conditions contemporaneously. Pharmacotherapeutic options demonstrating varying degrees of efficacy and promise in preclinical and clinical studies include nicotine replacement therapy (NRT), selective serotonin reuptake inhibitors (SSRIs), bupropion, varenicline, tricyclic antidepressants, and bupropion plus NRT. Topiramate has shown potential for promoting smoking cessation in alcoholics, although its safety in depressed patients has not been fully explored. The efficacy of medications for treating nicotine dependence is generally enhanced by the inclusion of behavioral interventions such as cognitive behavioral therapy. When group cohesion and social support are stressed, success rates increase among depressed smokers undergoing smoking cessation treatment. Additional treatment strategies targeting dually dependent individuals with comorbid psychiatric disorders, including special populations such as women and adolescents, await further investigation.

Topics: Alcoholism; Antidepressive Agents; Bupropion; Clinical Trials as Topic; Cognitive Behavioral Therapy; Combined Modality Therapy; Comorbidity; Depressive Disorder; Fructose; Humans; Nicotine; Psychotherapy, Group; Smoking Cessation; Topiramate

Neuroscientific developments have promulgated interest in developing efficacious medications for the treatment of substance dependence. Previous pharmacological strategies that involve the use of relatively specific medications to alter corticomesolimbic dopaminergic neuronal activity--the critical pathway for expression of the reinforcing effects of abused drugs--have yielded modest efficacy in the treatment of alcohol dependence, and no medication has been established as a treatment for cocaine dependence. Since corticomesolimbic dopaminergic neurons interact with other neurotransmitters that modulate the effects of dopamine in the nucleus accumbens, would it not be possible to control these dopaminergic effects more reliably with a medication that acts contemporaneously on more than one neuromodulator of dopaminergic function? Further, since the long-term use of either alcohol or cocaine results in neuronal adaptations as a result of sensitisation, would the chances of effective therapy not be bolstered by administering a medication that was also able to mitigate these chronic effects? Thus, a new conceptual approach is needed. My proposal is that a medication--in this case topiramate--that principally potentiates inhibitory GABA(A) receptor-mediated input and antagonises excitatory glutamatergic afferents to the corticomesolimbic dopaminergic system should have therapeutic potential in treating either alcohol or cocaine dependence or perhaps both. This is because the principal neurochemical effects of topiramate would not only serve to decrease the acute reinforcing effects of alcohol or cocaine, but might also facilitate cessation of their use following a period of long-term use by decreasing neuronal sensitisation. This overview highlights the scientific concepts and clinical evidence for the development of topiramate in the treatment of alcohol dependence and introduces preliminary evidence to indicate that it might also have utility in treating cocaine dependence. Finally, to place the material on topiramate in context, information has been included on the utility and development of other medications that modulate GABA- or glutamate-mediated neuronal systems for the treatment of alcohol or cocaine dependence.

Topics: Alcoholism; Animals; Cocaine-Related Disorders; Fructose; gamma-Aminobutyric Acid; Glutamic Acid; Humans; Neuroprotective Agents; Topiramate

Advances in neuroscientific knowledge have evoked interest in developing effective medications for the treatment of alcohol dependence. Pharmacological approaches that involve the use of relatively specific medications at a particular neuronal target to modulate corticomesolimbic dopamine neuronal activity, the critical pathway for expression of the reinforcing effects of abused drugs, have yielded modest efficacy in the treatment of alcohol dependence. A new approach is needed. Because corticomesolimbic dopamine neurons interact with a variety of neurotransmitters that modulate its effects in the nucleus accumbens, it might be possible to more reliably control these dopaminergic effects with a medication that acted contemporaneously on more than one neuromodulator of dopamine function. Additionally, because alcohol use results in neuronal adaptations due to sensitization, the chances of effective therapy might be bolstered by administering a medication that also has utility with mitigating its chronic effects. My proposed conceptual framework suggests that a medication that facilitates inhibitory gamma-aminobutyric acid-A input and antagonizes excitatory glutaminergic afferents to the nucleus accumbens would have pharmacotherapeutic potential in treating the alcohol dependence syndrome because these effects would act contemporaneously to suppress corticomesolimbic dopamine release. Through similar effects, topiramate might also aid chronic drinkers to wean themselves off alcohol and might ameliorate the symptoms of alcohol withdrawal. This commentary highlights the scientific concepts and clinical evidence for the development of topiramate in the treatment of alcohol dependence.

Topics: Alcoholism; Animals; Fructose; Humans; Nerve Net; Topiramate

Alcohol and nicotine dependence are commonly occurring disorders that together represent the most important preventable causes of morbidity and mortality in the United States. While there have been differences of opinion as to which disorder to treat first when they occur, there is growing evidence that a management strategy addressing both conditions contemporaneously would be optimal. Advances in the neurosciences have demonstrated not only that the reinforcing effects of both alcohol and nicotine are mediated by similar mechanisms resulting in enhanced activity of the cortico-mesolimbic dopamine system, but that their neurochemical interactions can lead to an aggregation of these effects. Despite this striking neurobiological overlap between alcohol and nicotine consumption, few studies have sought to take advantage of this commonality by devising a pharmacological approach that serves to treat both disorders. The results of our proof-of-concept study showed that topiramate is a promising medication for the treatment of both alcohol and nicotine dependence, presumably by its ability to modulate cortico-mesolimbic dopamine function profoundly; however, other mechanisms might also contribute to this effect. Further studies are ongoing to establish and extend topiramate's efficacy in the treatment of each and both disorders.

Topics: Alcoholism; Anticonvulsants; Brain; Ethanol; Fructose; Humans; Nicotine; Tobacco Use Disorder; Topiramate

Alcoholism is a devastating illness that leads to great societal losses. Despite significant health consequences, there are few medically based treatments for alcoholism. During the past decade, a better understanding of the neuroscientific underpinnings of addiction has led to the use of novel pharmacotherapeutic treatments for alcoholism. In particular, there have been new developments in the understanding of the involvement of the dopamine, opiate, serotonin, gamma-aminobutyric acid, and glutamate neurotransmitter systems in the pathophysiology of alcohol withdrawal, alcohol dependence, and in subtypes of individuals with alcoholism. In this article, new developments in the pharmacotherapy of alcohol dependence will be reviewed. In particular, the use of anticonvulsants in alcohol withdrawal and protracted abstinence syndromes will be discussed. Data on naltrexone, acamprosate, and topiramate will be highlighted. In addition, data concerning the use of serotonin reuptake inhibitors in subtypes of alcoholism and the use of combination pharmacotherapy will be reviewed.

Topics: Acamprosate; Alcohol Deterrents; Alcoholism; Anticonvulsants; Clinical Trials as Topic; Fructose; Humans; Naltrexone; Narcotic Antagonists; Neurotransmitter Agents; Taurine; Topiramate

The neurobiological basis of alcohol dependence, established pharmacotherapies for alcohol dependence, pharmacotherapies under investigation, and obstacles to treatment are discussed.. Alcohol binds to hydrophobic pockets of proteins, changing their three-dimensional structure and their function. Proteins that are particularly sensitive to alcohol include ion channels, neurotransmitter receptors, and enzymes involved in signal transduction. Established pharmacologic treatments, notably disulfiram and naltrexone, combined with behavioral therapies, may reduce the amount of drinking, the risk of relapse, the number of days of drinking, and craving in some alcohol-dependent individuals. For many patients, however, these treatments are not effective. Recent advances in molecular and behavior genetics are guiding the development of new drugs; these efforts seek to identify pharmacologic pathways relevant to alcohol dependence and to more effectively match treatments to individuals according to their genetic characteristics. Efficacy and safety concerns for acamprosate have been satisfied; the drug was recently released for marketing in the United States. Medications such as sertraline, ondansetron, topiramate, and aripiprazole represent novel lines of research and are currently being tested for use in the treatment of alcoholism. Even with more efficacious medications, however, a transformation must occur in how alcoholism treatment is viewed, not only by the public but also by clinicians.. In addition to existing drug treatments for alcohol dependence, many other medications are under investigation, particularly for specific types of alcoholism. Pharmacogenomics is expected to play an important role in this research effort.

Topics: Alcohol Deterrents; Alcoholism; Aripiprazole; Behavior Therapy; Disulfiram; Fructose; Humans; Naltrexone; Ondansetron; Pharmacogenetics; Piperazines; Quinolones; Topiramate

Topics: Acamprosate; Alcohol Deterrents; Alcoholism; Anticonvulsants; Fructose; Humans; Naltrexone; Narcotic Antagonists; Randomized Controlled Trials as Topic; Taurine; Topiramate

Previous findings have been equivocal as to whether a single-nucleotide polymorphism (rs2832407) in GRIK1, which encodes a glutamate receptor subunit, moderates the effects of topiramate treatment for drinking reduction. We leveraged intensive longitudinal data to provide greater precision and allow an examination of intermediate outcomes addressing this question. We used data from a randomized controlled trial (RCT) to test the hypotheses that topiramate treatment reduces daily heavy drinking, desire to drink and positive alcohol expectancies and that these effects are stronger in rs2832407*C-allele homozygotes.. Secondary data analysis of a randomized controlled trial.. University of Pennsylvania Treatment Research Center in the United States.. Participants were 164 individuals (70.1% male, mean age = 51.42, 36.0% rs2832407*C-allele homozygotes) who sought to reduce or stop drinking.. Participants were assigned to medication (topiramate or placebo), with stratification by genotype group (CC versus AA/AC) and treatment goal (reduce versus abstain).. During the 12-week treatment period, participants completed daily interactive voice response (IVR) surveys.. On any given day during treatment, participants who received topiramate had lower odds of IVR-reported heavy drinking [odds ratio (OR) = 0.259, b (standard error, SE) = -1.351 (0.334), P < 0.001] and lower levels of desire to drink [b (SE) = -0.323 (0.122), P = 0.009] and positive alcohol expectancies [b (SE) = -0.347 (0.138), P = 0.013] than those who received placebo. Participants who received topiramate also reported greater reductions in positive alcohol expectancies during the first 2 weeks of treatment than those who received placebo [b (SE) = -0.028 (0.008), P = 0.001], but topiramate did not impact the daily rate of change in heavy drinking or desire to drink. Genotype did not moderate the effects of topiramate on any outcomes examined (P > 0.05).. Topiramate is an effective medication for individuals seeking to reduce heavy drinking. The effects are not moderated by the single-nucleotide polymorphism rs2832407.

Topics: Alcohol Drinking; Alcoholism; Double-Blind Method; Ethanol; Female; Fructose; Genotype; Humans; Male; Topiramate; Treatment Outcome

There is preliminary evidence that the anticonvulsant topiramate increases the likelihood of both smoking and alcohol abstinence among smokers with alcohol use disorder (AUD), but its therapeutic mechanism has not been determined. We used event-related potentials (ERPs) to evaluate topiramate's effect on the salience of drug-related, emotional, and neutral pictorial cues to identify whether one of its potential therapeutic mechanisms involves reduction of the salience of motivationally relevant cues.. Participants enrolled in a multisite clinical trial treating smokers with AUD were randomly assigned to receive placebo, low-dose topiramate (up to 125 mg/day), or high-dose topiramate (up to 250 mg/day), along with brief behavioral compliance enhancement treatment. A subsample (n = 101) completed ERP assessments at baseline (1 week pre-medication) and week 5 (5 weeks on medication; 1 week pre-quit). We assessed the salience of pleasant, unpleasant, cigarette-related, alcohol-related, and neutral pictorial cues using the late positive potential (LPP) ERP component and measured self-reported substance use, reinforcement, craving, and withdrawal.. Five weeks of high-dose topiramate treatment decreased LPP amplitudes in response to both emotional (pleasant and unpleasant) and drug-related cues (alcohol and cigarette), but not to neutral cues. However, results showed that the LPPs were not significant mediators of the relationship between topiramate dose and post-quit measures of substance use, reinforcement, craving, or withdrawal.. These findings suggest that high-dose topiramate (up to 250 mg/day) decreases the motivational salience of both drug-related and emotional cues among smokers with AUD. However, the nonsignificant mediation analyses preclude any firm conclusions about whether this effect represents one of topiramate's therapeutic mechanisms of action.

Topics: Alcohol Drinking; Alcoholism; Cues; Humans; Smokers; Topiramate

Topiramate reduces drinking and alcohol-related problems and is increasingly being used to treat alcohol use disorder (AUD). In a randomized controlled trial (RCT) of topiramate, rs2832407, a single nucleotide polymorphism (SNP) in the GRIK1 gene moderated topiramate's effects (Study 1). However, a second RCT (Study 2) did not replicate the SNP's moderating effect during treatment. The current analysis combines data from these two studies to examine topiramate's effects on alcohol-related outcomes and on its pharmacogenetic moderation during a 6-month post-treatment period. This analysis includes 308 individuals with problematic alcohol use (67% male; mean age = 51.1; topiramate: 49%, placebo: 51%). It uses generalized linear mixed models to examine changes in self-reported alcohol consumption and alcohol-related problems and concentrations of the liver enzyme γ-glutamyltransferase. The report combines published 3- and 6-month follow-up data from Study 1 with similar, unpublished data from Study 2. Despite robust effects of topiramate on drinking during treatment, the overall multivariate medication effects on outcomes during 3- and 6-month follow-up were not significant (p = 0.08 and p = 0.26, respectively). The moderating effect of the SNP on primary treatment outcomes was also not significant during either follow-up period (p = 0.13 and p = 0.16, respectively). However, during the 3-month post-treatment period, drinks per day was significantly lower in the topiramate group than the placebo group in the rs2832407*CC-genotype group. The robust effects of topiramate on alcohol-related outcomes during treatment diminish substantially once the medication is discontinued. Research is needed both to determine the optimal treatment duration and to identify clinically useful pharmacogenetic moderators of topiramate for treating AUD.

Topics: Alcohol Drinking; Alcoholism; Double-Blind Method; Female; Fructose; Humans; Male; Middle Aged; Receptors, Kainic Acid; Topiramate

Topiramate, a GABA/glutamate modulator, is efficacious in reducing alcohol consumption, though the mechanisms underlying this effect are not well characterized. This study analyzed functional magnetic resonance imaging (fMRI) data from 22 heavy drinkers enrolled in a 12-week placebo-controlled, randomized clinical trial of topiramate to examine the effects of topiramate on alcohol cue-elicited brain responses, craving, and heavy drinking in individuals with DSM-5 alcohol use disorder. Patients were randomized to receive either topiramate (maximal daily dosage of 200 mg/day) or placebo and were administered an fMRI alcohol cue-reactivity task at baseline (before starting medication) and after 6 weeks of double-blind treatment. Analyses compared the topiramate (n = 12) and placebo (n = 8) groups on (1) the change in brain responses during alcohol cue exposure (vs non-alcohol cues) within five a priori regions of interest related to reward-the bilateral and medial orbitofrontal cortex (OFC) and bilateral ventral striatum (VS) and (2) change in craving and heavy drinking days (HDDs) from baseline and scan 2. Topiramate, relative to placebo, reduced alcohol cue-elicited activation of the left VS, bilateral OFC, and medial OFC, alcohol cue-elicited craving, and HDDs between baseline and 6 weeks of treatment. The reduction in alcohol cue-elicited activation in the medial OFC correlated with reductions in craving, and reduced activation in the right VS, right OFC, and medial OFC correlated with the reduction in HDD. This preliminary study provides evidence that topiramate's attenuation of alcohol cue-elicited brain activation and craving are key elements of the drug's neurobiological mechanism of action in reducing heavy drinking.

Topics: Alcohol Drinking; Alcoholism; Craving; Cues; Humans; Magnetic Resonance Imaging; Topiramate

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.

Topics: Alcohol Drinking; Alcoholism; Double-Blind Method; Female; Fructose; Humans; Male; Pharmacogenomic Testing; Prospective Studies; Topiramate; Treatment Outcome

Topiramate is an effective treatment for alcohol use disorder (AUD) and has also been used in the care of mild traumatic brain injury (mTBI). This pilot study aimed to obtain a preliminary assessment of topiramate's efficacy in reducing alcohol use and post-concussive symptoms, and its potential negative impact on cognitive function in 32 Veterans with co-occurring AUD and mTBI.. This was a prospective 12-week, randomized, double-blind, placebo-controlled pilot study of flexible-dose topiramate or placebo. Primary outcome was reduction of drinking days per week within the topiramate arm. Secondary outcomes included between group comparisons of alcohol use and craving, post-concussive symptoms, and cognitive function.. Drinking days per week significantly decreased within both the topiramate and placebo arm. There were no significant treatment-by-week interactions on alcohol use/craving, or post-concussive symptoms in intent-to-treat analyses. In per-protocol analyses, topiramate significantly reduced number of drinks per week compared with placebo. Topiramate transiently impaired verbal fluency and working memory. Processing speed, cognitive inhibition, and mental flexibility significantly improved between weeks 1 and 12, regardless of treatment arm.. Significant improvement occurred in both the topiramate and placebo groups over 12 weeks of treatment in alcohol use and post-concussive symptoms. Among treatment completers there was greater reduction of alcohol use in the topiramate arm. Topiramate was also associated with negative but transient effects on cognitive function. Results suggest both a possible benefit for topiramate treatment in reducing alcohol use and some potential for negative cognitive effects in Veterans with AUD and mTBI.

Topics: Adult; Alcohol Drinking; Alcoholism; Anticonvulsants; Brain Injuries, Traumatic; Cognition; Craving; Double-Blind Method; Female; Humans; Male; Middle Aged; Pilot Projects; Post-Concussion Syndrome; Prospective Studies; Topiramate; Treatment Outcome; Veterans

The US Food and Drug Administration recognizes total abstinence and no heavy drinking days as outcomes for pivotal pharmacotherapy trials for alcohol use disorder (AUD). Many patients have difficulty achieving these outcomes, which can discourage seeking treatment and has slowed the development of medications that affect alcohol use.. To compare 2 drinking-reduction outcomes with total abstinence and no heavy drinking outcomes.. Data were obtained from 3 multisite, randomized, placebo-controlled clinical trials of medications for treating alcohol dependence (naltrexone, varenicline, and topiramate) in adults with DSM-IV-categorized alcohol dependence.. Within each trial, the percentage of participants in active and placebo conditions who met responder definitions of abstinence, no heavy drinking days, a WHO 1-level reduction, and a WHO 2-level reduction was computed by month with corresponding effect sizes (Cohen h).. Across the 3 trials (N = 1169; mean [SD] age, 45 [10] years; 824 [70.5%] men), the percentage of participants classified as responders during the last 4 weeks of treatment was lowest for abstinence (naltrexone, 34.7% [100 of 288]; varenicline, 7.3% [7 of 96]; topiramate, 11.7% [21 of 179]) followed by no heavy drinking days (naltrexone, 51.0% [147 of 288]; varenicline, 24.0% [23 of 96]; topiramate, 20.7% [37 of 179]), WHO 2-level reduction (naltrexone, 75.0% [216 of 288]; varenicline, 55.2% [53 of 96]; topiramate, 44.7% [80 of 179]), and WHO 1-level reduction (naltrexone, 83.3% [240 of 288]; varenicline, 69.8 [67 of 96]; topiramate, 54.7% [98 of 179]) outcomes. Standardized treatment effects observed for the WHO 2-level reduction outcomes (naltrexone, Cohen h = 0.214 [95% CI, 0.053 -0.375]; varenicline, 0.273 [95% CI, -0.006 to 0.553]; topiramate, 0.230 [95% CI, 0.024-0.435]) and WHO 1-level reduction (naltrexone, Cohen h = 0.116 [95% CI, -0.046 to 0.277]; varenicline, 0.338 [95% CI, 0.058-0.617]; topiramate, 0.014 [95% CI, -0.192 to 0.219]) were comparable with those obtained using abstinence (naltrexone, Cohen h = 0.142 [95% CI, -0.020 to 0.303]; varenicline, 0.146 [95% CI, -0.133 to 0.426]; topiramate, 0.369 [95% CI, 0.163-0.574]) and no heavy drinking days (naltrexone, Cohen h = 0.140 [95% CI, -0.021 to 0.302]; varenicline, 0.232 [95% CI, -0.048 to 0.511]; topiramate, 0.207 [95% CI, 0.002-0.413]).. WHO drinking risk level reductions appear to be worthwhile indicators of treatment outcome in AUD pharmacotherapy trials. These outcomes may align with drinking reduction goals of many patients and capture clinically meaningful improvements experienced by more patients than either abstinence or no heavy drinking days.. ClinicalTrials.gov identifiers: NCT00006206; NCT01146613; NCT00210925.

Topics: Adult; Alcohol Abstinence; Alcohol Deterrents; Alcohol Drinking; Alcoholism; Female; Humans; Male; Middle Aged; Naltrexone; Risk Assessment; Topiramate; Varenicline

The goal of this study was to evaluate the efficacy of topiramate up to 200 mg/day and of aripiprazole up to 15 mg/day, alone and combined, in reducing alcohol-related outcomes in a human laboratory study.. This was a 5 week, between-subject, double-blind, placebo-controlled human laboratory study with topiramate [0 mg/day (placebo), 100 mg/day, 200 mg/day] and aripiprazole [0 mg/day (placebo), 7.5 mg/day, 15 mg/day] in 90 non-treatment seeking, heavy drinking, alcohol-dependent individuals. Main outcomes were the efficacy of 200 mg/day topiramate and 15 mg/day aripiprazole, alone and combined, in reducing drinks consumed during an alcohol self-administration procedure (human laboratory phase) and while receiving the study medications prior to the laboratory session (naturalistic drinking phase). Other outcomes in the laboratory phase included alcohol craving, and alcohol biphasic effects.. In the human laboratory phase, topiramate 200 mg/day reduced alcohol craving [**P < 0.01] and amplified alcohol-induced stimulation [*P < 0.05], but did not reduce the number of drinks consumed. Topiramate 200 mg/day was also effective in reducing drinking days [*P < 0.05], and alcohol craving [*P < 0.05], in the naturalistic drinking phase. No significant findings were found for aripiprazole for any of the outcomes analyzed.. Participants receiving 200 mg/day topiramate reported reduced alcohol drinking and craving, and increased alcohol-related stimulation. These findings provide further support for the role of topiramate as a pharmacological treatment for AUD.. NCT00884884.. This study tested topiramate and aripiprazole alone and in combination. The results replicate past findings and suggest that topiramate may be an effective treatment for alcohol use disorder. The present results suggest that the combination of topiramate and aripiprazole do not warrant further evaluation.

Topics: Adult; Alcoholic Beverages; Alcoholism; Anticonvulsants; Antipsychotic Agents; Aripiprazole; Double-Blind Method; Drug Therapy, Combination; Female; Fructose; Humans; Male; Middle Aged; Topiramate; Treatment Outcome

Current treatments for alcohol use disorders have limited efficacy and there is a high degree of variability in treatment response. In a randomised, placebo-controlled clinical trial, there was a large effect size for topiramate in people homozygous for the GRIK1 rs2832407*C allele. The primary aim of the TOP study is to examine prospectively the therapeutic and cost-effectiveness of topiramate versus an active control (naltrexone) in improving treatment outcomes for alcohol dependence. Participants will be stratified on rs2832407 to compare C-allele homozygotes with A-allele carriers to examine the moderating effect of rs2832407 on drinking outcomes. An exploratory aim is to examine the moderating effects of rs1799971, a polymorphism in OPRM1, on the response to naltrexone by comparing Asn40 homozygotes with Asp40 carriers.. This double-blind trial will randomise 180 alcohol-dependent participants to a 12-week regime of either topiramate (titrating the dose up to 200 mg/day) or naltrexone (50 mg/day). Participants will be stratified on the two polymorphisms before randomisation. All participants will receive medical management. The primary drinking outcome will be the number of heavy drinking days per week and secondary drinking outcomes will include the time to relapse, the time to lapse and the percentage of abstinent days. Other secondary outcomes will include body mass index, tobacco use, anxiety symptoms and depressive symptoms.. If successful, the TOP study will improve management strategies for alcohol dependence by providing support for the use of genetic biomarkers to inform medication selection.. ClinicalTrials.gov, NCT03479086 . Registered on 27 March 2018.

Topics: Adolescent; Adult; Aged; Alcohol Abstinence; Alcohol Drinking; Alcoholism; Clinical Protocols; Double-Blind Method; Excitatory Amino Acid Antagonists; Female; Gene Frequency; Homozygote; Humans; Male; Middle Aged; Naltrexone; Narcotic Antagonists; New South Wales; Pharmacogenomic Variants; Prospective Studies; Receptors, Kainic Acid; Receptors, Opioid, mu; Recurrence; Research Design; Time Factors; Topiramate; Treatment Outcome; Young Adult

Babor's A/B typology characterizes alcohol-dependence subtypes, which differ across multiple defining variables; however, differences in cigarette smoking and cessation between these subtypes have not been previously investigated. Topiramate reduces heavy drinking and has separately been found to help non-alcohol-dependent individuals quit smoking. This study tested the hypothesis that topiramate's effects on smoking would be moderated by alcohol-dependence subtype, and explored craving as a mediator of this response.. One hundred twenty-nine abstinent alcohol-dependent outpatient male smokers participated in this 12-week, randomized controlled trial comparing topiramate (maximum dosage 200 mg/day) with placebo, both with brief counseling, for smoking cessation. Participants were followed for 24 weeks following end of treatment.. Of the 125 participants with sufficient subtyping data, k-means cluster analysis categorized 52 (42%) as Type A alcoholics and 73 (58%) as Type B. Types A and B did not differ on baseline smoking characteristics, urges to smoke, or smoking consequence scores. Longitudinal mixed-effects regression indicated that the effect of treatment on smoking was moderated by the Type × Time interaction. Specifically, during the nontreatment follow-up phase, Type B's treated with topiramate had relative suppressed levels of smoking compared with placebo-treated Type B's. This moderating effect of the Type × Time interaction was mediated by intention to smoke and craving related to relief of negative affect.. Type B alcoholics demonstrated suppressed levels of smoking in response to topiramate treatment as compared with placebo, but only during the nontreatment follow-up phase. This effect was mediated, in part, through intention to smoke and craving to smoke to relieve negative affect. Our findings extend other studies demonstrating a differential medication response by alcoholism subtype.

Topics: Adult; Alcoholism; Craving; Diagnosis, Dual (Psychiatry); Double-Blind Method; Fructose; Humans; Male; Middle Aged; Outpatients; Smoking; Smoking Cessation; Tobacco Use Disorder; Topiramate

Alcohol and nicotine dependence frequently co-occur, and quitting smoking might enhance long-term alcohol abstinence. Topiramate appears to help non-alcohol-dependent individuals quit smoking, and our pilot work suggested efficacy only in men. It also prevents relapse to alcohol in recently detoxified alcoholics. We evaluated topiramate in abstinent alcohol-dependent men to assess whether this medication (i) promotes smoking cessation and (ii) prevents alcohol and other drug relapse in the context of smoking cessation treatment.. One hundred and twenty-nine alcohol-abstinent (mean ~6 months) alcohol-dependent male smokers (80% with other substance use disorders) participated in this 12-week randomized, double blind, parallel group comparison of topiramate (up to 200 mg/d) and placebo with a 24-week nontreatment follow-up period. The study was carried out sequentially at 2 academic centers in the Midwest and Southern California between March 23, 2009 and November 20, 2014. All participants received manual-guided smoking cessation counseling combined with medication-focused compliance enhancement therapy. Randomization was block designed by the research pharmacist in a 1:1 ratio. Participants, investigators, and research personnel were masked to treatment assignment. The primary smoking end point was biochemically confirmed 4-week continuous abstinence from smoking during weeks 9 to 12, while the secondary end point was relapse to any drinking or drug use during the entire 36-week evaluation period. Logistic regression was used to determine the effects of topiramate on quitting smoking and alcohol relapse, controlling for relevant covariates. The trial is registered at ClinicalTrials.gov (number NCT00802412) and is now closed.. Only a small proportion (7.9%) of topiramate-treated participants were able to quit smoking, and this cessation rate was similar to placebo (10.6%; odds ratio = 1.60; 95% confidence interval 0.4, 6.5; p = 0.51). Roughly 30% of the sample had a documented relapse to drinking or drug use during the study, and these rates were similar in the topiramate (20/63; 31.8%) and placebo groups (18/66; 27.3%; p = 0.58). Results of a longitudinal logistic regression model examining time to any alcohol relapse revealed no medication effect.. Topiramate at a daily dosage of up to 200 mg per day, combined with smoking cessation and medication adherence counseling, had no effects on smoking cessation or the prevention of alcohol or drug relapse in male smokers who were in early or sustained full remission from alcohol and motivated to make a quit attempt. Alternative approaches for treating this high-risk, dually dependent population are needed.

Topics: Adult; Alcohol Abstinence; Alcoholism; Double-Blind Method; Fructose; Humans; Male; Middle Aged; Recurrence; Smoking; Smoking Cessation; Tobacco Use Disorder; Topiramate

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.. 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.. 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.. 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.

Topics: Adult; Alcoholism; Double-Blind Method; Female; Fructose; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Receptors, Kainic Acid; Topiramate; Treatment Outcome

Several definitions of treatment response have been proposed for alcohol clinical trials (e.g., abstinence and no heavy drinking). However, each of these outcomes allows only one definition of successful response. In contrast, the cumulative proportion of responders analysis (CPRA) includes all of the possible drinking response cutoff points, providing a more complete picture of the therapeutic effects of a treatment. CPRA has been used to examine the efficacy of analgesics but not alcohol pharmacotherapy. To demonstrate its potential utility, we conducted CPRA in two large alcohol treatment trials: the COMBINE (Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence) trial (naltrexone) and a multisite topiramate trial. CPRA was used to demonstrate the efficacy of naltrexone and topiramate on continuous measures of in-treatment drinking-heavy drinking days and drinks per day-and their reductions from pretreatment.. All possible cutoff points were portrayed for each measure. We provide graphs to illustrate the effects of the active medications compared with placebo and examined them statistically over a number of salient drinking outcomes to evaluate their efficacy.. Treatment group responder curves were not parallel across the entire range of cutoff points; rather, they separated only at lower levels of drinking. In general, effect sizes increased by 0.10-0.15 when going from the lowest drinking level cutoff (i.e., abstinence and no heavy drinking) to the cutoff associated with the maximal treatment effect.. CPRA may be useful in designing subsequent trials and helping to illustrate for treatment providers the likelihood of treatment success given various definitions of a positive response.

Topics: Alcohol Deterrents; Alcohol Drinking; Alcoholism; Double-Blind Method; Fructose; Humans; Naltrexone; Narcotic Antagonists; Topiramate; Treatment Outcome

Topiramate (TOP) and anticonvulsants in general are considered safe and effective drugs for the treatment of alcohol dependence, even though TOP-induced adverse events are quite common, especially for high initial doses or if titration to 300 mg/d is too rapid. The aim of the present study was to assess the efficacy and tolerability profile of low-dose TOP for relapse prevention.. After detoxification, 52 patients were randomized into 2 groups as follows: 26 patients received 100 mg of TOP (oral, twice daily), titrated over 2 weeks, and 26 patients received placebo (PLA). Both groups underwent rehabilitation twice a week.. After 6 weeks of treatment, compared with the PLA group, patients receiving TOP showed the following: (1) fewer drinking days (P < 0.05); (2) less daily alcohol consumption (P < 0.05); (3) more days of treatment (P < 0.05); (4) reduced levels of craving (Obsessive-Compulsive Drinking Scale) and withdrawal symptoms (Clinical Institute Withdrawal Assessment for Alcohol-Revised); and (5) improvement of anxiety, depression, and obsessive-compulsive symptom severity (Symptom Check List 90 Revised).. Despite the small sample size and the short follow-up period, the present PLA-controlled study demonstrated the potential usefulness of TOP, even when administered at a dosage of 100 mg/d, for the treatment of detoxified alcohol-dependent subjects, confirming results from previous studies testing higher doses of TOP.

Topics: Adult; Alcoholism; Anticonvulsants; Female; Follow-Up Studies; Fructose; Humans; Male; Middle Aged; Single-Blind Method; Topiramate; Treatment Outcome

Using retrospective reports obtained during treatment visits in 138 heavy drinkers, we found that topiramate's reduction of heavy drinking was moderated by a polymorphism (rs2832407) in GRIK1, which encodes the GluK1 kainate subunit (Kranzler et al., 2014a). A subsequent analysis of that 12-week topiramate treatment trial showed similar effects of medication and genotype on daily drinking reports obtained via interactive voice response technology (IVR; Kranzler et al., 2014b). Specifically, rs2832407*C-allele homozygotes treated with topiramate reported lower levels of drinking than those receiving placebo. This group also had the largest decreases in the expected positive effects of drinking (i.e., expectancies) and desire to drink. To extend that analysis, which focused on how mean levels of desire and expectancies changed over time with treatment, we used a within-person approach to examine whether daily variation in expectancies and desire to drink interact with topiramate treatment and genotype to predict nighttime drinking levels. In contrast to the previous analysis (Kranzler et al., 2014b), here we focus on whether alcohol expectancies and desire to drink moderate the effects of topiramate on drinking. Results showed a 3-way interaction of daily expectancies with genotype and medication, such that the protective effect of topiramate on nighttime drinking among rs2832407*C-allele homozygotes was decreased on days characterized by relatively high levels of anticipated positive effects of alcohol. There was no moderating effect of desire to drink or negative alcohol expectancies. Thus, there is specific moderation of the effects of topiramate by both genotype and cognitive process.

Topics: Activities of Daily Living; Adult; Alcohol Deterrents; Alcoholic Intoxication; Alcoholism; Alleles; Attitude to Health; Connecticut; Double-Blind Method; Drug Resistance; Female; Fructose; Genetic Association Studies; Humans; Male; Patient Education as Topic; Pennsylvania; Polymorphism, Single Nucleotide; Receptors, Kainic Acid; Students; Topiramate; Universities; Young Adult

Topiramate increases GABAergic activity and antagonizes the AMPA/kainate subtype of glutamate receptors. Through these mechanisms of action, topiramate may reduce alcohol and cocaine reward and may reduce alcohol and cocaine craving. Topiramate has been shown to reduce drinking in persons with alcohol dependence, and reduce relapse in stimulant-dependent patients. The current trial was intended to test the ability of topiramate to promote cocaine and alcohol abstinence among patients addicted to both drugs.. The study was a double-blind, placebo-controlled, 13-week trial involving 170 cocaine and alcohol dependent subjects. After achieving a period of cocaine and alcohol abstinence, subjects were randomized to topiramate, 300 mg daily, or identical placebo capsules. In addition, subjects received weekly individual psychotherapy. Primary outcome measures included self-reported alcohol and cocaine use, and thrice weekly urine drug screens. Secondary outcome measures included cocaine and alcohol craving, Addiction Severity Index results, cocaine withdrawal symptoms, and clinical global improvement ratings.. Topiramate was not better than placebo in reducing cocaine use on the a priori primary outcome measure, or in reducing alcohol use. Topiramate was not better than placebo in reducing cocaine craving. Topiramate-treated subjects, compared to placebo-treated subjects, were more likely to be retained in treatment and more likely to be abstinent from cocaine during the last three weeks of the trial. Subjects who entered treatment with more severe cocaine withdrawal symptoms responded better to topiramate.. Topiramate plus cognitive behavioral therapy may reduce cocaine use for some patients with comorbid cocaine and alcohol dependence.

Topics: Adolescent; Adult; Aged; Alcoholism; Anticonvulsants; Behavior, Addictive; Cocaine-Related Disorders; Cognitive Behavioral Therapy; Combined Modality Therapy; Double-Blind Method; Female; Fructose; Humans; Male; Middle Aged; Patient Compliance; Secondary Prevention; Severity of Illness Index; Substance Withdrawal Syndrome; Topiramate

Initiation of a relapse prevention medication is crucial at the end of alcohol detoxification. This study aimed to examine the efficacy and safety of topiramate for alcoholism in patients receiving a residential treatment program of alcohol detoxification and post-acute treatment.. This was a 12-week, randomized, double-blind, placebo-controlled trial of topiramate for alcoholism in patients receiving a residential treatment program. Individuals with DSM-IV alcohol dependence with minimal withdrawal were enrolled. Participants were randomly assigned to receive either 100-300 mg/day of topiramate or placebo. Primary outcomes were given as percentages of heavy drinking days and time to first day of heavy drinking. Other drinking outcomes, craving, and health-related quality of life were evaluated.. A total of 106 participants were randomized to receive topiramate (n=53) or placebo (n=53). Twenty-eight participants of the topiramate group (52.8%) and 25 participants of the placebo group (47.2%) completed the study. Averaged over the trial period, there was no significant difference between groups on the mean percentages of heavy drinking days [1.96 (-1.62 to 5.54), p=.28]. Log rank survival analysis found no difference of time to first day of heavy drinking between topiramate and placebo groups (61.8 vs. 57.5 days, respectively; χ(2)=0.61, d.f.=1, p=.81). Other secondary outcomes were not significantly different between groups.. By using a conservative model for data analysis, we could not detect the effectiveness of topiramate in this particular population. As the sensitivity analysis showed a trend of its benefit, further studies in larger sample sizes are still warranted.

Topics: Adult; Alcoholism; Diagnostic and Statistical Manual of Mental Disorders; Double-Blind Method; Female; Follow-Up Studies; Fructose; Humans; Male; Middle Aged; Motivational Interviewing; Neuroprotective Agents; Outpatients; Patient Compliance; Residential Treatment; Secondary Prevention; Topiramate; Treatment Outcome

Various statistical methods have been used for data analysis in alcohol treatment studies. Trajectory analyses can better capture differences in treatment effects and may provide insight on the optimal duration of future clinical trials and grace periods. This improves on the limitation of commonly used parametric (e.g., linear) methods that cannot capture nonlinear temporal trends in the data.. We propose an exploratory approach, using more flexible smoothing mixed effects models, more accurately to characterize the temporal patterns of the drinking data. We estimated the trajectories of the treatment arms for data sets from 2 sources: a multisite topiramate study, and the Combined Pharmacotherapies (acamprosate and naltrexone) and Behavioral Interventions study.. Our methods illustrate that drinking outcomes of both the topiramate and placebo arms declined over the entire course of the trial but with a greater rate of decline for the topiramate arm. By the point-wise confidence intervals, the heavy drinking probabilities for the topiramate arm might differ from those of the placebo arm as early as week 2. Furthermore, the heavy drinking probabilities of both arms seemed to stabilize at the end of the study. Overall, naltrexone was better than placebo in reducing drinking over time yet was not different from placebo for subjects receiving the combination of a brief medical management and an intensive combined behavioral intervention.. The estimated trajectory plots clearly showed nonlinear temporal trends of the treatment with different medications on drinking outcomes and offered more detailed interpretation of the results. This trajectory analysis approach is proposed as a valid exploratory method for evaluating efficacy in pharmacotherapy trials in alcoholism.

Topics: Acamprosate; Adult; Aged; Aged, 80 and over; Alcohol Deterrents; Alcoholism; Algorithms; Behavior Therapy; Combined Modality Therapy; Data Interpretation, Statistical; Double-Blind Method; Female; Fructose; Humans; Linear Models; Male; Middle Aged; Models, Statistical; Naltrexone; Narcotic Antagonists; Neuroprotective Agents; Nonlinear Dynamics; Regression Analysis; Research; Research Design; Taurine; Topiramate; Treatment Outcome; Young Adult

A 6-month naturalistic, randomized and open-label, trial of topiramate versus naltrexone was conducted, with assessments at enrollment and after 3 and 6 months of treatment. 182 alcohol-dependent patients who had been drinking heavily during the past month were included.. Outcome was measured using tools that assessed alcohol intake, cravings, disability, and quality of life; changes in biomarkers of alcohol intake were also used.. At the 6-month evaluation, patients taking topiramate had significantly lower scores on the OCDS (all subscales), the EuropASI (medical, alcohol, family/social, and psychiatric) and the WHO/DAS (employment/social). More patients taking topiramate remained in the abstinence group and the moderate drinking without problems group.. Topiramate at a mean dose of 200 mg/day was better than naltrexone at a mean dose of 50 mg/day at reducing alcohol intake and cravings throughout the study.

Topics: Alcohol Drinking; Alcoholism; Excitatory Amino Acid Agents; Female; Fructose; Humans; Male; Medication Adherence; Middle Aged; Naltrexone; Quality of Life; Time Factors; Topiramate; Treatment Outcome

GABAergic anticonvulsants have been recommended for the treatment of alcohol dependence and the prevention of relapse. Several studies have demonstrated topiramate's efficacy in improving drinking behaviour and maintaining abstinence. The objective of the present open-label controlled study was to assess efficacy and tolerability of low-dose topiramate as adjunctive treatment in alcohol dependence during the immediate post-detoxification period and during a 16-week follow-up period after alcohol withdrawal.. Following a 7-10 day inpatient alcohol detoxification protocol, 90 patients were assigned to receive either topiramate (up to 75 mg per day) in addition to psychotherapeutic treatment (n = 30) or psychotherapy alone (n = 60). Symptoms of depression and anxiety, as well as craving, were monitored for 4-6 weeks immediately following detoxification on an inpatient basis. Thereafter, both groups were followed as outpatients at a weekly basis for another 4 months in order to monitor their course and abstinence from alcohol.. A marked improvement in depressive (p < 0.01), anxiety (p < 0.01), and obsessive-compulsive drinking symptoms (p < 0.01) was observed over the consecutive assessments in both study groups. However, individuals on topiramate fared better than controls (p < 0.01) during inpatient treatment. Moreover, during the 4-month follow up period, relapse rate was lower among patients who received topiramate (66.7%) compared to those who received no adjunctive treatment (85.5%), (p = 0.043). Time to relapse in the topiramate augmentation group was significantly longer compared to the control group (log rank test, p = 0.008). Thus, median duration of abstinence was 4 weeks for the non-medicated group whereas it reached 10 weeks for the topiramate group. No serious side effects of topiramate were recorded throughout the study.. Low-dose topiramate as an adjunct to psychotherapeutic treatment is well tolerated and effective in reducing alcohol craving, as well as symptoms of depression and anxiety, present during the early phase of alcohol withdrawal. Furthermore, topiramate considerably helps to abstain from drinking during the first 16-week post-detoxification period.

Topics: Adult; Alcoholism; Anticonvulsants; Anxiety; Combined Modality Therapy; Depression; Dose-Response Relationship, Drug; Female; Fructose; Humans; Male; Middle Aged; Psychotherapy; Topiramate; Treatment Outcome

The severity of dependence on alcohol and the efficacy of diverse types of treatments for alcoholism have been the subject of various researches. This study focused on the types of beverages preferentially consumed by alcohol-dependent outpatients and their effects on the severity of dependence and therapeutic outcomes. Our sample comprised 153 patients, 18-60 years of age, with an International Classification of Diseases (ICD-10) diagnosis of alcohol dependence, who were randomly divided into three different groups to receive topiramate (up to 300mg/day), naltrexone (50mg/day), or placebo during 12 weeks of follow-up. Spirits and beer were the main beverages consumed. At the start of this research, the group of spirits drinkers showed higher severity of alcohol dependence, higher craving for alcohol, more frequent history of treatments for alcoholism, and lower income than the group of beer preference drinkers. During the study, beer preference drinkers demonstrated higher adherence to the treatment, independently of the types of medications prescribed (P=.02, odds ratio, 2.46, 95% confidence interval, 1.17-5.19). This study suggests that the severity of dependence and the adherence to the treatment can be factors that set apart beer drinkers from spirits drinkers. As the compliance with the treatment for alcoholism was lower among spirits preference drinkers, a more intensive model of treatment would be necessary.

Topics: Adolescent; Adult; Alcoholic Beverages; Alcoholism; Beer; Fructose; Humans; Male; Middle Aged; Motivation; Naltrexone; Narcotic Antagonists; Patient Compliance; Topiramate; Treatment Outcome

Topiramate, an anticonvulsant medication, is an efficacious treatment for alcohol dependence. To date, little is known about genetic moderators of side effects from topiramate. The objective of this study was to examine 3 single nucleotide polymorphisms (SNPs) of the glutamate receptor GluR5 gene (GRIK1) as predictors of topiramate-induced side effects in the context of a laboratory study of topiramate. Heavy drinkers (n=51, 19 women and 32 men), 75% of whom met criteria for an alcohol use disorder, completed a 5-week dose escalation schedule to a target dose of either 200 or 300 mg or matched placebo. The combined medication groups were compared with placebo-treated individuals for side effects at target dose. Analyses revealed that an SNP in intron 9 of the GRIK1 gene (rs2832407) was associated with the severity of topiramate-induced side effects and with serum levels of topiramate. Genes underlying glutamatergic neurotransmission, such as the GRIK1 gene, may help predict heterogeneity in topiramate-induced side effects. Future studies in larger samples are needed to more fully establish these preliminary findings.

Topics: Adult; Alcoholism; Anticonvulsants; Dose-Response Relationship, Drug; Female; Fructose; Humans; Male; Middle Aged; Pharmacogenetics; Polymorphism, Single Nucleotide; Receptors, Kainic Acid; Severity of Illness Index; Topiramate

There are no reports examining the safety of taking both topiramate and aripiprazole together with alcohol. The ultimate aim for this research is to determine whether this combination is safe and is superior to either drug taken alone in reducing alcohol use in alcohol dependent patients.. This was an open-label trial. Thirteen heavy drinking participants not seeking treatment for alcoholism were randomized. Participants were titrated up to 300 mg of topiramate and 30 mg of aripiprazole a day over 35 days. Participants reported adverse events (AEs) daily alcohol use and participated in an alcohol challenge session (ACS).. The eight participants who completed the study achieved the maximum doses of drugs. The AEs of the drugs would suggest that the AEs profile is broader but not additive. Alcohol use from the 28 days before screening to the seven days before the ACS was reduced (p = 0.08).. There was no evidence that AEs of aripiprazole and topiramate are additive and can, therefore, be administered safely together with a modest amount of alcohol. There was also a trend for a reduction of alcohol use by participants. This finding has implications for further investigation of this combination of drugs for alcohol dependence.

Topics: Adult; Alcohol Drinking; Alcoholism; Antipsychotic Agents; Aripiprazole; Dose-Response Relationship, Drug; Drug Interactions; Female; Fructose; Humans; Male; Middle Aged; Neuroprotective Agents; Piperazines; Quinolones; Topiramate; Young Adult

A high smoking prevalence has been registered among alcoholics. It has been pointed out that alcoholic smokers may have a more severe course and greater severity of alcoholism. This study aims at comparing smoking and non-smoking alcoholics in terms of treatment outcomes and verifying the efficacy of topiramate and naltrexone to decrease the use of cigarettes among alcoholic smokers.. The investigation was a double-blind, placebo-controlled, 12-week study carried out at the University of São Paulo, Brazil. The sample comprised 155 male alcohol-dependent outpatients (52 non-smokers and 103 smokers), 18-60 years of age, with an International Classification of Diseases (ICD-10) diagnosis of alcohol dependence. After a 1-week detoxification period, the patients randomly received placebo, naltrexone (50mg/day) or topiramate (up to 300 mg/day). Only the alcoholic smokers who adhered to the treatment were evaluated with reference to the smoking reduction.. Cox regression analysis revealed that the smoking status among alcoholics increased the odds of relapse into drinking by 65%, independently of the medications prescribed, using the intention-to-treat method. Topiramate showed effectiveness to reduce the number of cigarettes smoked when compared to placebo among adherent patients (mean difference=7.91, p<0.01). There were no significant differences between the naltrexone group and the placebo group.. The results of this study confirm that the treatment is more challenging for smoking alcoholics than for non-smoking ones and support the efficacy of topiramate in the smoking reduction among male alcoholic smokers who adhered to the treatment.

Topics: Adolescent; Adult; Alcoholism; Analysis of Variance; Anticonvulsants; Dose-Response Relationship, Drug; Double-Blind Method; Fructose; Humans; Male; Middle Aged; Naltrexone; Narcotic Antagonists; Outpatients; Patient Compliance; Secondary Prevention; Smoking; Smoking Cessation; Socioeconomic Factors; Topiramate; Treatment Outcome; Young Adult

Topiramate (TP), an anticonvulsant drug, has been widely used in the treatment of disorders characterized by impulsivity symptoms, so it goes to reason that it might be useful in addictive disorders. Recently, TP has been used to treat alcohol dependence, but it is still not known whether the effects of TP on alcohol consumption are related with its action on impulsivity. The aim of this preliminary study was to investigate which dimension of behavioral impulsivity is associated with the effects of TP. A 12-week, double-blind, placebo-controlled pilot study of TP for the treatment of alcohol dependence was conducted. Subjects were men recruited from alcoholism treatment units (TP = 31; placebo = 32). Diagnoses were made using the Structured Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). Behavioral inhibition was assessed using the continuous performance test (CPT) and the stop-signal task. Differential reinforcement for low-rate responding (DRLR) was used to evaluate the delay-discounting dimension. Alcohol craving and alcohol consumption during the study were evaluated. Patients treated with TP presented lower rates of alcohol consumption in the number of drinks per drinking day (P < 0.05) and the number of heavy drinking days (P < 0.001). Scores on alcohol craving scales decreased significantly, and there was more improvement on the continuous performance test (total omissions and total commissions) and on the stop-signal task in the TP group than in the control group. Improved alcohol consumption behavior was associated with performance on the behavioral inhibition paradigm. The results of this study indicate that TP reduces drinking and that the mechanisms underlying this effect may involve, at least in part, modulation of the behavioral inhibition paradigm.

Topics: Adolescent; Adult; Alcohol Deterrents; Alcoholism; Double-Blind Method; Fructose; Humans; Impulsive Behavior; Male; Middle Aged; Pilot Projects; Topiramate; Young Adult

Topiramate can improve drinking outcomes via a hypothesized mechanism of facilitating gamma-aminobutyric acid function and inhibiting glutaminergic pathways in the corticomesolimbic system. We sought to determine whether topiramate's antidrinking effects are bolstered by improvements in physical and psychosocial well-being.. In a 17-site, 14-week, double-blind, randomized controlled trial, we compared the effects of topiramate (up to 300 mg/d) vs placebo on physical health, obsessional thoughts and compulsions about using alcohol, and psychosocial well-being among 371 alcohol-dependent subjects who received weekly adherence enhancement therapy.. Topiramate was more efficacious than placebo in reducing body mass index (calculated as weight in kilograms divided by height in meters squared) (mean difference, 1.08; 95% confidence interval [CI], 0.81-1.34; P < .001), all liver enzyme levels (P < .01 for all comparisons), plasma cholesterol level (mean difference, 13.30 mg/dL; 95% CI, 5.09-21.44 mg/dL; P = .002), and systolic (mean difference, 9.70 mm Hg; 95% CI, 6.81-12.60 mm Hg; P < .001) and diastolic (mean difference, 6.74 mm Hg; 95% CI, 4.57-8.90 mm Hg; P < .001) blood pressure to about prehypertension levels-effects that might lower the risk of fatty liver degeneration and cirrhosis as well as cardiovascular disease. Topiramate compared with placebo significantly (P < .05 for all comparisons) decreased obsessional thoughts and compulsions about using alcohol, increased subjects' psychosocial well-being, and improved some aspects of quality of life, thereby diminishing the risk of relapse and longer-term negative outcomes. Paresthesia, taste perversion, anorexia, and difficulty with concentration were reported more frequently for topiramate than for placebo.. Topiramate appears to be generally effective at improving the drinking outcomes and physical and psychosocial well-being of alcoholic subjects.

Topics: Alcoholism; Double-Blind Method; Female; Fructose; Health Status Indicators; Humans; Male; Middle Aged; Quality of Life; Topiramate; Treatment Outcome; United States

To compare the efficacy of topiramate with naltrexone in the treatment of alcohol dependence.. The investigation was a double-blind, placebo-controlled, 12-week study carried out at the University of São Paulo, Brazil.. A total of 155 patients, 18-60 years of age, with an International Classification of Diseases (ICD-10) diagnosis of alcohol dependence.. After a 1-week detoxification period, patients were assigned randomly to receive topiramate (induction to 300 mg/day), naltrexone (50 mg/day) or placebo.. Time to first relapse (consumption of >60 g ethyl alcohol), cumulative abstinence duration and weeks of heavy drinking.. In intention-to-treat analyses, topiramate was statistically superior to placebo on a number of measures including time to first relapse (7.8 versus 5.0 weeks), cumulative abstinence duration (8.2 versus 5.6 weeks), weeks of heavy drinking (3.4 versus 5.9) and percentage of subjects abstinent at 4 weeks (67.3 versus 42.6) and 8 weeks (61.5 versus 31.5), but not 12 weeks (46.2 versus 27.8).. remained significant after controlling for Alcoholics Anonymous attendance, which was higher in topiramate than in other groups. There were no significant differences between naltrexone versus placebo or naltrexone versus topiramate groups, but naltrexone showed trends toward inferior outcomes when compared to topiramate.. The results of this study support the efficacy of topiramate in the relapse prevention of alcoholism. Suggestive evidence was also obtained for superiority of topiramate versus naltrexone, but this needs to be verified in future research with larger sample sizes.

Topics: Adolescent; Adult; Alcohol Deterrents; Alcoholism; Double-Blind Method; Fructose; Humans; Male; Middle Aged; Naltrexone; Patient Compliance; Socioeconomic Factors; Topiramate; Treatment Outcome; Young Adult

This study compared the efficacy of disulfiram (DSF) and topiramate (TPM) for preventing alcoholic relapse in an open study of routine clinical practice in India. One hundred alcohol-dependent men with family members who agreed to encourage medical compliance and to accompany them for follow-up were randomly allocated to 9 months of treatment with DSF or TPM. Weekly psychotherapy was also provided. There was no blinding of conditions for the psychiatrist, patient, or family members. Supervision and support of the family member were used in the maintenance of compliance among the patients. Alcohol consumption, craving, and adverse events were recorded weekly for 3 months and then biweekly. Serum gamma glutamyl transferase was measured at the start and at the end of the study. At the end of the trial, 92 patients were still in contact. Relapse occurred at a mean of 133 days for DSF as compared with 79 days for TPM. At 9 months, 90% of DSF patients, as compared with 56% of TPM patients, remained abstinent. TPM-treated patients did show less craving than DSF patients did. Further comparisons between these drugs in different treatment settings and patient populations are warranted.

Topics: Adult; Alcohol Deterrents; Alcoholism; Demography; Disulfiram; Female; Fructose; Humans; Male; Neuroprotective Agents; Topiramate; Treatment Outcome

To compare topiramate versus naltrexone in the treatment of alcohol dependence.. A 6-month naturalistic, randomized and open-label, trial of topiramate versus naltrexone, with assessments at enrollment and after 3 and 6 months of treatment. The setting was an outpatient alcohol clinic. One hundred and two alcohol-dependent patients who had been drinking heavily during the past month were included. Two randomized groups were created. In one, naltrexone was used as the therapeutic agent and, in the other, topiramate was chosen as the therapeutic agent. Both groups received psychological relapse prevention therapy. Outcome was measured using tools that assessed alcohol intake, cravings, disability, and quality of life; changes in biomarkers of alcohol intake were also used. With all the data, a secondary composite measure was created in order to assess each patient's global alcohol intake and its consequences.. Both groups showed substantial reduction in their drinking. Naltrexone patients had higher nicotine consumption throughout the study. Topiramate was better at reducing alcohol-related cravings throughout the study. Both treatments had a similar mean cost throughout the study.. Both topiramate and naltrexone were efficacious in the treatment of alcohol dependence, and the treatment costs were similar. There is a trend for topiramate to be superior to naltrexone on critical measures of drinking; however, the study did not have adequate statistical power to establish this fact.

Topics: Adult; Alcoholism; Female; Fructose; Humans; Male; Middle Aged; Naltrexone; Narcotic Antagonists; Neuroprotective Agents; Psychological Tests; Severity of Illness Index; Topiramate

Benzodiazepines are the standard pharmacotherapies for ethanol detoxification, but concerns about their abuse potential and negative effects upon the transition to alcohol abstinence drive the search for new treatments. Glutamatergic activation and glutamate receptor up-regulation contribute to ethanol dependence and withdrawal. This study compared 3 antiglutamatergic strategies for ethanol detoxification with placebo and to the benzodiazepine, diazepam: the glutamate release inhibitor, lamotrigine; the N-methyl-D-aspartate glutamate receptor antagonist, memantine; and the AMPA/kainite receptor inhibitor, topiramate.. This placebo-controlled randomized single-blinded psychopharmacology trial studied male alcohol-dependent inpatients (n=127) with clinically significant alcohol withdrawal symptoms. Subjects were assigned to 1 of 5 treatments for 7 days: placebo, diazepam 10 mg TID, lamotrigine 25 mg QID, memantine 10 mg TID, or topiramate 25 mg QID. Additional diazepam was administered when the assigned medication failed to suppress withdrawal symptoms adequately.. All active medications significantly reduced observer-rated and self-rated withdrawal severity, dysphoric mood, and supplementary diazepam administration compared with placebo. The active medications did not differ from diazepam.. This study provides the first systematic clinical evidence supporting the efficacy of a number of antiglutamatergic approaches for treating alcohol withdrawal symptoms. These data support the hypothesis that glutamatergic activation contributes to human alcohol withdrawal. Definitive studies of each of these medications are now needed to further evaluate their effectiveness in treating alcohol withdrawal.

Topics: Adult; Alcoholism; Arousal; Autonomic Nervous System; Depression; Diazepam; Excitatory Amino Acid Antagonists; Fructose; GABA Modulators; Humans; Inpatients; Lamotrigine; Male; Memantine; Middle Aged; Mood Disorders; Substance Withdrawal Syndrome; Topiramate; Triazines

Hypothetically, topiramate can improve drinking outcomes among alcohol-dependent individuals by reducing alcohol's reinforcing effects through facilitation of gamma-aminobutyric acid function and inhibition of glutaminergic pathways in the corticomesolimbic system.. To determine if topiramate is a safe and efficacious treatment for alcohol dependence.. Double-blind, randomized, placebo-controlled, 14-week trial of 371 men and women aged 18 to 65 years diagnosed with alcohol dependence, conducted between January 27, 2004, and August 4, 2006, at 17 US sites.. Up to 300 mg/d of topiramate (n = 183) or placebo (n = 188), along with a weekly compliance enhancement intervention.. Primary efficacy variable was self-reported percentage of heavy drinking days. Secondary outcomes included other self-reported drinking measures (percentage of days abstinent and drinks per drinking day) along with the laboratory measure of alcohol consumption (plasma gamma-glutamyltransferase).. Treating all dropouts as relapse to baseline, topiramate was more efficacious than placebo at reducing the percentage of heavy drinking days from baseline to week 14 (mean difference, 8.44%; 95% confidence interval, 3.07%-13.80%; P = .002). Prespecified mixed-model analysis also showed that topiramate compared with placebo decreased the percentage of heavy drinking days (mean difference, 16.19%; 95% confidence interval, 10.79%-21.60%; P < .001) and all other drinking outcomes (P < .001 for all comparisons). Adverse events that were more common with topiramate vs placebo, respectively, included paresthesia (50.8% vs 10.6%), taste perversion (23.0% vs 4.8%), anorexia (19.7% vs 6.9%), and difficulty with concentration (14.8% vs 3.2%).. Topiramate is a promising treatment for alcohol dependence.. clinicaltrials.gov Identifier: NCT00210925.

Topics: Adult; Alcoholism; Behavior Therapy; Double-Blind Method; Excitatory Amino Acid Antagonists; Female; Fructose; GABA Modulators; Humans; Male; Middle Aged; Patient Compliance; Topiramate

Having demonstrated previously the efficacy of topiramate--a sulfamate-substituted fructopyranose derivative-as pharmacotherapy for treating alcohol dependence, promoting abstinence and reducing the harmful psychosocial consequences of drinking, we investigated whether topiramate also promoted 'safe' levels of drinking: < or = 1 and < or = 2 standard drinks/day for women and men, respectively, among alcohol-dependent individuals.. In a double-blind, randomized, controlled, 12-week clinical trial conducted in San Antonio, Texas, 75 alcohol-dependent adults received topiramate and 75 received placebo as an adjunct to weekly standardized medication compliance management.. For this secondary analysis of data from that trial, we calculated, based on self-reports, specific intervals of up to 30 days of continuous 'safe' drinking for each subject.. The average longest 'safe' drinking period was 16.7 days for topiramate recipients versus 8.9 days for placebo recipients. By day 50 of treatment, 44% versus 26.4% had achieved > or = 7 and 30.8% versus 10% had achieved > or = 14 continuous 'safe' drinking days. Similarly, topiramate increased the relative likelihood of continuous 'safe' drinking from 77% for > or = 7 days [relative risk (RR) for achieving continuous 'safe' drinking = 1.77] to threefold for > or = 14 days (RR = 3.37) and fourfold for > or = 28 days (RR = 4.07). Thus, participants who received topiramate were more likely to achieve longer periods of 'safe' drinking compared with those who received placebo.. For alcohol-dependent individuals who drank within an abstinence-oriented treatment program, topiramate promoted 'safe' drinking. Topiramate's potential to decrease the public health consequences of hazardous drinking needs to be established in future long-term studies.

Topics: Adult; Alcoholism; Community Health Services; Double-Blind Method; Drug Administration Schedule; Female; Fructose; Harm Reduction; Humans; Male; Middle Aged; Neuroprotective Agents; Primary Health Care; Texas; Time Factors; Topiramate

Previously, our group has shown that topiramate, a sulfamate-substituted fructopyranose derivative, is an effective treatment for alcohol dependence. Herein, we extend that proof-of-concept study by determining whether cigarette-smoking, alcohol-dependent individuals from the earlier study also experienced improved smoking outcomes.. As a subgroup analysis of a larger double-blind, randomized, controlled, 12-week study comparing topiramate vs placebo as treatment for alcohol dependence, a 12-week clinical trial compared topiramate vs placebo in 94 cigarette-smoking, alcohol-dependent individuals. Of these, 45 were assigned to receive topiramate (escalating dose from 25 to 300 mg/d) and the remaining 49 had placebo as an adjunct to weekly standardized medication compliance management. The primary outcome was smoking cessation ascertained by self-report and confirmed by the level of serum cotinine (nicotine's major metabolite).. Topiramate recipients were significantly more likely than placebo recipients to abstain from smoking (odds ratio, 4.46; 95% confidence interval, 1.08-18.39; P = .04). Using a serum cotinine level of 28 ng/mL or lower to segregate nonsmokers from smokers, we found that the topiramate group had 4.97 times the odds of being nonsmokers (95% confidence interval, 1.1-23.4;P = .04). Smoking cessation rates for topiramate recipients were 19.4% and 16.7% at weeks 9 and 12, respectively, compared with 6.9% at both time points for placebo recipients.. In this trial, topiramate (up to 300 mg/d) showed potential as a safe and promising medication for the treatment of cigarette smoking in alcohol-dependent individuals.

Topics: Administration, Oral; Adult; Aged; Alcoholism; Anticonvulsants; Cotinine; Double-Blind Method; Drug Administration Schedule; Female; Fructose; Humans; Male; Middle Aged; Smoking; Smoking Cessation; Topiramate; Treatment Outcome

Topiramate, a fructopyranose derivative, was superior to placebo at improving the drinking outcomes of alcohol-dependent individuals.. To determine whether topiramate, compared with placebo, improves psychosocial functioning in alcohol-dependent individuals and to discover how this improvement is related to heavy drinking behavior.. Double-blind, randomized, controlled, 12-week clinical trial comparing topiramate vs placebo for treating alcohol dependence (1998-2001).. One hundred fifty alcohol-dependent individuals, diagnosed using the DSM-IV.. Seventy-five participants received topiramate (escalating dose of 25 mg/d to 300 mg/d), and 75 had placebo and weekly standardized medication compliance management.. Three elements of psychosocial functioning were measured: clinical ratings of overall well-being and alcohol-dependence severity, quality of life, and harmful drinking consequences. Overall well-being and dependence severity and quality of life were analyzed as binary responses with a generalized estimating equation approach; harmful drinking consequences were analyzed as a continuous response using a mixed-effects, repeated-measures model.. Averaged over the course of double-blind treatment, topiramate, compared with placebo, improved the odds of overall well-being (odds ratio [OR] = 2.17; 95% confidence interval [CI], 1.16-2.60; P =.01); reported abstinence and not seeking alcohol (OR = 2.63; 95% CI, 1.52-4.53; P =.001); overall life satisfaction (OR = 2.28; 95% CI, 1.21-4.29; P =.01); and reduced harmful drinking consequences (OR = -0.07; 95% CI, -0.12 to -0.02, P =.01). There was a significant shift from higher to lower drinking quartiles on percentage of heavy drinking days, which was associated with improvements on all measures of psychosocial functioning.. As an adjunct to medication compliance enhancement treatment, topiramate (up to 300 mg/d) was superior to placebo at not only improving drinking outcomes but increasing overall well-being and quality of life and lessening dependence severity and its harmful consequences.

Topics: Administration, Oral; Adult; Aged; Alcohol Drinking; Alcoholism; Anticonvulsants; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Fructose; Humans; Male; Middle Aged; Patient Compliance; Placebos; Quality of Life; Severity of Illness Index; Topiramate; Treatment Outcome

Topiramate, a sulphamate fructopyranose derivative, might antagonise alcohol's rewarding effects associated with abuse liability by inhibiting mesocorticolimbic dopamine release via the contemporaneous facilitation of gamma-amino-butyric acid activity and inhibition of glutamate function. We aimed to see whether topiramate was more effective than placebo as a treatment for alcohol dependence.. We did a double-blind randomised controlled 12-week clinical trial comparing oral topiramate and placebo for treatment of 150 individuals with alcohol dependence. Of these 150 individuals, 75 were assigned to receive topiramate (escalating dose of 25-300 mg per day) and 75 had placebo as an adjunct to weekly standardised medication compliance management. Primary efficacy variables were: self-reported drinking (drinks per day, drinks per drinking day, percentage of heavy drinking days, percentage of days abstinent) and plasma gamma-glutamyl transferase, an objective index of alcohol consumption. The secondary efficacy variable was self-reported craving.. At study end, participants on topiramate, compared with those on placebo, had 2.88 (95% CI -4.50 to -1.27) fewer drinks per day (p=0.0006), 3.10 (-4.88 to -1.31) fewer drinks per drinking day (p=0.0009), 27.6% fewer heavy drinking days (p=0.0003), 26.2% more days abstinent (p=0.0003), and a log plasma gamma-glutamyl transferase ratio of 0.07 (-0.11 to -0.02) less (p=0.0046). Topiramate-induced differences in craving were also significantly greater than those of placebo, of similar magnitude to the self-reported drinking changes, and highly correlated with them.. Topiramate (up to 300 mg per day) is more efficacious than placebo as an adjunct to standardised medication compliance management in treatment of alcohol dependence.

Topics: Administration, Oral; Adult; Aged; Alcohol Drinking; Alcoholism; Dopamine Antagonists; Double-Blind Method; Drug Administration Schedule; Female; Fructose; gamma-Glutamyltransferase; Humans; Male; Middle Aged; Substance Abuse Detection; Topiramate

Topiramate, which is increasingly being used to treat alcohol use disorder (AUD), is commonly associated with reduced serum bicarbonate concentrations. However, estimates of the prevalence and magnitude of this effect are from small samples and do not address whether topiramate's effects on acid-base balance differ in the presence of an AUD or by topiramate dosage.. Veterans Health Administration electronic health record (EHR) data were used to identify patients with a minimum of 180 days of topiramate prescription for any indication and a propensity score-matched control group. We differentiated patients into two subgroups based on the presence of a diagnosis of AUD in the EHR. Baseline alcohol consumption was determined using Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) scores in the EHR. Analysis also included a three-level measure representing mean daily dosage. The topiramate-associated changes in serum bicarbonate concentration were estimated in difference-in-differences linear regression models. A serum bicarbonate concentration <17 mEq/L was considered to represent possible clinically significant metabolic acidosis.. The cohort comprised 4287 topiramate-treated patients and 5992 propensity score-matched controls with a mean follow-up period of 417 days. The mean topiramate-associated reductions in serum bicarbonate concentration were <2 mEq/L in the low (≤88.75), medium (>88.75 and ≤141.70), and high (>141.70) mg/day dosage tertiles, irrespective of AUD history. Concentrations <17 mEq/L occurred in 1.1% of topiramate-treated patients and 0.3% of controls and were not associated with alcohol consumption or an AUD diagnosis.. The excess prevalence of metabolic acidosis associated with topiramate treatment does not differ with dosage, alcohol consumption, or the presence of an AUD. Baseline and periodic serum bicarbonate concentration measurements are recommended during topiramate therapy. Patients prescribed topiramate should be educated about the symptoms of metabolic acidosis and urged to report their occurrence promptly to a healthcare provider.

Topics: Acidosis; Alcoholism; Bicarbonates; Humans; Topiramate; Veterans

Alcohol-associated liver disease (ALD) is one of the most devastating complications of alcohol use disorder (AUD), an increasingly prevalent condition. Medical addiction therapy for AUD may play a role in protecting against the development and progression of ALD.. To ascertain whether medical addiction therapy was associated with an altered risk of developing ALD in patients with AUD.. This retrospective cohort study used the Mass General Brigham Biobank, an ongoing research initiative that had recruited 127 480 patients between its start in 2010 and August 17, 2021, when data for the present study were retrieved. The mean follow-up duration from AUD diagnosis was 9.2 years. International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnosis codes were used to identify ALD and AUD diagnoses.. Medical addiction therapy was defined as the documented use of disulfiram, acamprosate, naltrexone, gabapentin, topiramate, or baclofen. Patients were considered to be treated if they initiated medical addiction therapy before the relevant outcome.. Adjusted odds ratios (aORs) for the development of ALD and hepatic decompensation were calculated and adjusted for multiple risk factors.. The cohort comprised 9635 patients with AUD, of whom 5821 were male individuals (60.4%), and the mean (SD) age was 54.8 (16.5) years. A total of 1135 patients (11.8%) had ALD and 3906 patients (40.5%) were treated with medical addiction therapy. In multivariable analyses, medical addiction therapy for AUD was associated with decreased incidence of ALD (aOR, 0.37; 95% CI, 0.31-0.43; P < .001). This association was evident for naltrexone (aOR, 0.67; 95% CI, 0.46-0.95; P = .03), gabapentin (aOR, 0.36; 95% CI, 0.30-0.43; P < .001), topiramate (aOR, 0.47; 95% CI, 0.32-0.66; P < .001), and baclofen (aOR, 0.57; 95% CI, 0.36-0.88; P = .01). In addition, pharmacotherapy for AUD was associated with lower incidence of hepatic decompensation in patients with cirrhosis (aOR, 0.35; 95% CI, 0.23-0.53, P < .001), including naltrexone (aOR, 0.27; 95% CI, 0.10-0.64; P = .005) and gabapentin (aOR, 0.36; 95% CI, 0.23-0.56; P < .001). This association persisted even when medical addiction therapy was initiated only after the diagnosis of cirrhosis (aOR, 0.41; 95% CI, 0.23-0.71; P = .002).. Results of this study showed that receipt of medical addiction therapy for AUD was associated with reduced incidence and progression of ALD. The associations of individual pharmacotherapy with the outcomes of ALD and hepatic decompensation varied widely.

Topics: Alcoholism; Baclofen; Female; Gabapentin; Humans; Incidence; Liver Cirrhosis; Male; Middle Aged; Naltrexone; Retrospective Studies; Topiramate

Topiramate is a medication that is widely prescribed to treat a variety of conditions, including alcohol use disorder (AUD). We used electronic health record (EHR) data to measure topiramate's effects on drinking in individuals differentiated by a history of AUD.. Parallel-groups comparison of patients prescribed topiramate and a propensity score-matched comparison group.. A large US integrated health-care system.. Patients with Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) scores prior to and after a minimum of 180 days of topiramate prescription for any indication and a propensity score-matched group. The sample included 5918 patients with an electronic health record diagnosis of alcohol use disorder at any time (AUD-hx-pos) (1738 topiramate-exposed and 4180 controls) and 23 614 patients with no EHR diagnosis of AUD (AUD-hx-neg) (6324 topiramate-exposed and 17 290 controls).. Regression analyses compared difference-in-difference (DiD) estimates, separately by AUD history. DiD estimates represent exposure-group (i.e. topiramate versus control) differences on the pre-post difference in AUDIT-C score. Effects of baseline AUDIT-C score and daily topiramate dosage were also tested.. AUD-hx-neg patients who received topiramate had a greater reduction in AUDIT-C score (-0.11) than matched controls (-0.04). This yielded a DiD score of -0.07 [95% confidence interval (CI) = -0.11,-0.03; P = 0.002], with the greatest effect among AUD-hx-neg patients with a baseline AUDIT-C score of 4+ (DiD = -0.35, 95% CI = -0.49, -0.21; P < 0.0001) and those prescribed > 150 mg/day of the medication (DiD = -0.15, 95%CI = -0.23, -0.07; P < 0.001).. Among individuals with no history of alcohol use disorder, topiramate appears to be associated with reduced drinking. This small effect is most evident among patients with higher baseline drinking levels and at a higher average daily topiramate dosage.

Topics: Alcohol Drinking; Alcoholism; Electronic Health Records; Humans; Topiramate

In an initial study, we reported that topiramate reduced heavy drinking among individuals who sought to reduce their drinking and that the effect was moderated by a single nucleotide polymorphism (SNP; rs2832407) in GRIK1, which encodes the kainate GluK1 receptor subunit (Kranzler et al., 2014). In a subsequent study that prospectively randomized patients to medication group based on their rs2832407 genotype, we replicated the main effect of topiramate but not the moderating effect of the SNP (Kranzler et al., 2021). Given the similar design of the two studies, here we combined the findings to provide greater statistical power to test the pharmacogenetic effect.. This secondary analysis of two 12-week, randomized controlled trials of topiramate included a total of 292 European-ancestry individuals (67.1 % male; topiramate: 48.3 %, placebo: 51.7 %) with problematic alcohol use. Using MANOVA, we examined changes in self-reported alcohol consumption, problems resulting from alcohol use, and quality of life, and the biomarker γ-glutamyltransferase. To test the pharmacogenetic hypothesis, all patients were genotyped for rs2832407.. Although topiramate is an efficacious medication for reducing drinking and alcohol-related problems among patients with problematic alcohol use, rs2832407 does not appear to moderate its therapeutic effects. www.clinicaltrials.gov registrations: NCT00626925 and NCT02371889.

Topics: Alcohol Drinking; Alcoholism; Female; Fructose; Humans; Male; Polymorphism, Single Nucleotide; Quality of Life; Topiramate

Although abstinence has traditionally been considered the only suitable outcome for alcohol treatment, reduced drinking is also associated with improved functioning and medical and psychiatric outcomes. The World Health Organization (WHO) risk drinking levels (RDLs) have been shown to be valid outcome measures in treatment trials for alcohol use disorder (AUD).. We conducted a secondary analysis of two 12-week, randomized controlled trials (RCTs), in which a total of 308 individuals with problematic alcohol use received topiramate or placebo treatment. We compared the utility of the WHO RDLs with other treatment outcomes, including self-reported measures of alcohol consumption, alcohol-related problems, and quality of life, and the biomarker gamma-glutamyltransferase.. Topiramate treatment was associated with small effect sizes for both a 1-level (d = 0.26) and a 2-level (d = 0.19) reduction in WHO RDL, effects that were not significant after correction for multiple comparisons. No heavy drinking days, one of the outcome measures recommended by the US Food and Drug Administration for alcohol medication registration trials, also exhibited a small effect (0.21), while an effect size for abstinence could not be calculated. There were medium effects of topiramate on continuous measures of percent heavy drinking days (d = 0.49) and alcohol-related problems (d = 0.41).. Topiramate is an efficacious pharmacotherapy for AUD. Although continuous measures of drinking and alcohol-related problems yielded larger effect sizes than the WHO RDLs, the latter nonetheless provide a categorical alternative for use in both clinical care and pharmacotherapy trials.

Topics: Adult; Alcohol Drinking; Alcoholism; Anticonvulsants; Female; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Topiramate; World Health Organization

Topics: Alcohol Deterrents; Alcoholism; Appetite Depressants; Humans; Naltrexone; Social Support; Topiramate

A 45 year-old man with bilateral acute angle-closure and myopia after starting treatment with topiramate, secondary to alcohol and heroin dependence. Using Visante® OCT (Optical Coherence Tomography) and B-scan Ultrasound he was diagnosed with bilateral ciliochoroidal effusion as the pathophysiological mechanism. Topiramate was stopped and ocular hypotensive therapy with a topical cycloplegic and corticosteroids were started, resolving ciliochoroidal effusion syndrome. Visante® OCT and B-scan Ultrasound are useful tools for the diagnosis and follow-up of patients with acute angle-closure and myopia due to topiramate. As a result of broad spectrum of indications for topiramate, physicians and ophthalmologists should be aware of the possible ophthalmological manifestations attributable to this drug.

Topics: Adrenal Cortex Hormones; Alcoholism; Anticonvulsants; Choroidal Effusions; Follow-Up Studies; Glaucoma, Angle-Closure; Heroin Dependence; Humans; Male; Microscopy, Acoustic; Middle Aged; Mydriatics; Myopia; Tomography, Optical Coherence; Topiramate

Topics: Acamprosate; Alcohol Drinking; Alcoholism; Baclofen; Humans; Naltrexone; Narcotic Antagonists; Network Meta-Analysis; Topiramate

Adults with alcohol dependence (AD) have exceptionally high smoking rates and poor smoking cessation outcomes. Discovery of factors that predict reduced smoking among AD smokers may help improve treatment. This study examined baseline predictors of smoking quantity among AD smokers in a pharmacotherapy trial for smoking cessation.. The sample includes male, AD smokers (N = 129) with 1-32 months of alcohol abstinence who participated in a 12-week trial of medication (topiramate vs. placebo) and adjunct counseling with 6 months of follow-up. Baseline measures of nicotine dependence, AD severity, psychopathology, motivation to quit smoking, and smoking-related cognitions were used to predict smoking quantity (cigarettes per day) at post-treatment and follow-up.. Overall, the sample had statistically significant reductions in smoking quantity. Greater nicotine dependence (Incidence rate ratios (IRRs) = 0.82-0.90), motivation to quit (IRRs = 0.65-0.85), and intrinsic reasons for quitting (IRRs = 0.96-0.98) predicted fewer cigarettes/day. Conversely, greater lifetime AD severity (IRR = 1.02), depression severity (IRRs = 1.05-1.07), impulsivity (IRRs = 1.01-1.03), weight-control expectancies (IRRs = 1.10-1.15), and childhood sexual abuse (IRRs = 1.03-1.07) predicted more cigarettes/day.. Smokers with AD can achieve large reductions in smoking quantity during treatment, and factors that predict smoking outcomes in the general population also predict greater smoking reductions in AD smokers. Treatment providers can use severity of nicotine dependence and AD, motivation to quit, smoking-related cognitions, and severity of depression to guide treatment and improve outcomes among AD smokers.

Topics: Adult; Adult Survivors of Child Abuse; Alcohol Abstinence; Alcoholism; Cognition; Depression; Humans; Impulsive Behavior; Male; Middle Aged; Motivation; Prognosis; Randomized Controlled Trials as Topic; Smoking; Smoking Cessation; Smoking Reduction; Tobacco Use Disorder; Topiramate

Two-part random effects models (Olsen and Schafer,(1) Tooze et al.(2)) have been applied to repeated measures of semi-continuous data, characterized by a mixture of a substantial proportion of zero values and a skewed distribution of positive values. In the original formulation of this model, the natural logarithm of the positive values is assumed to follow a normal distribution with a constant variance parameter. In this article, we review and consider three extensions of this model, allowing the positive values to follow (a) a generalized gamma distribution, (b) a log-skew-normal distribution, and (c) a normal distribution after the Box-Cox transformation. We allow for the possibility of heteroscedasticity. Maximum likelihood estimation is shown to be conveniently implemented in SAS Proc NLMIXED. The performance of the methods is compared through applications to daily drinking records in a secondary data analysis from a randomized controlled trial of topiramate for alcohol dependence treatment. We find that all three models provide a significantly better fit than the log-normal model, and there exists strong evidence for heteroscedasticity. We also compare the three models by the likelihood ratio tests for non-nested hypotheses (Vuong(3)). The results suggest that the generalized gamma distribution provides the best fit, though no statistically significant differences are found in pairwise model comparisons.

Topics: Alcohol Deterrents; Alcoholism; Biostatistics; Data Interpretation, Statistical; Fructose; Humans; Likelihood Functions; Linear Models; Models, Statistical; Proportional Hazards Models; Randomized Controlled Trials as Topic; Topiramate

Topics: Alcoholism; Female; Fructose; Humans; Male; Polymorphism, Single Nucleotide; Receptors, Kainic Acid; Topiramate

The effect of topiramate (topamax) on the electrical activity of frontal cortical neurons of neoencephalon was studied by microelectrode techniques in rats. Topiramate upon acute intraperitoneal administration and microionophoretic application dose-dependently reduced the frequency of spike activity within 17 - 30 min after injection at a dose of 40 and 80 mg/kg. At the same time, the agent did not change the membrane rest potential, and the magnitude and form of action potentials. Microionophoretically applied topiramate decreased the excitatory response to electroosmotically applied ethanol at "small doses" (ejected current < 50 nA) and enhanced the neuronal depression induced by ethanol at "large doses" (ejected current > 50 nA). It is suggested that the attenuation of alcohol seeking behavior observed after topiramate administration is due to suppression of ethanol activating effects in neoencephalon neurons, while the alleviation of alcohol withdrawal is associated with the central depressant activity.

Topics: Action Potentials; Alcoholism; Animals; Ethanol; Frontal Lobe; Fructose; Injections, Intraperitoneal; Male; Microelectrodes; Neocortex; Neuroprotective Agents; Rabbits; Rats; Rats, Wistar; Stereotaxic Techniques; Substance Withdrawal Syndrome; Topiramate

The present study investigated the effectiveness of topiramate (TPM) treatment for decreasing alcohol consumption in alcoholics.. Alcoholics of outpatients, relapsed repeatedly, were included in this study. The study was conducted over 24 weeks. Subject characteristics (e.g., gender) and medical variables (e.g., age of onset) were recorded. Autistic features were determined using the Autism - Spectrum Quotient (>or=27 points). The average daily alcohol consumption was assessed at the start of the study and at 4, 12, and 24 weeks after its start. The five-step alcohol consumption scale of the Obsessive-Compulsive Drinking Scale (OCDS) was used. The extent of the change between the first assessment and subsequent assessment was considered the primary evaluation point. Responders were defined as subjects showing an improvement of at least two steps in the score. Patients not treated with TPM were retrospectively selected according to the same criteria on the basis of their medical records and were used as controls. The TPM group was further subdivided into responders and nonresponders.. Of the 31 subjects who consented to TPM therapy, 11 stopped or discontinued TPM, and they were considered nonresponders. The average TPM maintenance dosage (standard deviation) was 62.9 (38.1) mg. Alcohol consumption scores significantly decreased at each assessment point in the study. The percentage of responders in the TPM group (n = 31) was significantly higher than that in the control group (n = 41) at the 24-week assessment point (45.2% vs. 19.5%, p=0.0193). A significant difference was observed between responders (n = 14) and nonresponders (n = 17) only in well-educated and autistic subjects (50% vs. 5.9%, p = 0.0109).. TPM decreased the amount of alcohol consumption in alcoholics. In addition, a correlation between autistic features and TPM treatment response was suggested.

Topics: Adult; Aged; Aged, 80 and over; Alcohol Drinking; Alcoholics; Alcoholism; Female; Fructose; Humans; Male; Middle Aged; Topiramate; Treatment Outcome

In this article, we implement a practical computational method for various semiparametric mixed effects models, estimating nonlinear functions by penalized splines. We approximate the integration of the penalized likelihood with respect to random effects with the use of adaptive Gaussian quadrature, which we can conveniently implement in SAS procedure NLMIXED. We carry out the selection of smoothing parameters through approximated generalized cross-validation scores. Our method has two advantages: (1) the estimation is more accurate than the current available quasi-likelihood method for sparse data, for example, binary data; and (2) it can be used in fitting more sophisticated models. We show the performance of our approach in simulation studies with longitudinal outcomes from three settings: binary, normal data after Box-Cox transformation, and count data with log-Gamma random effects. We also develop an estimation method for a longitudinal two-part nonparametric random effects model and apply it to analyze repeated measures of semicontinuous daily drinking records in a randomized controlled trial of topiramate.

Topics: Alcohol Drinking; Alcoholism; Fructose; Humans; Likelihood Functions; Linear Models; Neuroprotective Agents; Poisson Distribution; Randomized Controlled Trials as Topic; Topiramate

Pharmacological treatment currently used for alcohol dependence is not sufficient for the all patients, and there is a crucial need to find more effective treatments. Recent studies indicate that topiramate is likely the most promising new medication for alcohol dependence. The rationale for topiramate as treatment for alcohol addiction is based on its multifaceted neurochemical activity that targets multiple neural pathways.. This study aims to assess the effect of repeated treatment with topiramate on voluntary alcohol intake and beta-endorphin plasma level in rats selectively bred for high alcohol preference.. Initially, Warsaw high preferring rats (N = 50) were given a 24-h/day free choice between a 10 % (v/v) alcohol solution and water for three consecutive weeks. Subsequently, rats were administered with topiramate (40 or 80 mg/kg b.w.) or vehicle for 14 days and ethanol intake was measured daily. Subsequently, we examined the effects of topiramate on plasma beta-endorphin levels, while alcohol was available and when it was not available for an extended period time.. We observed significantly increase in the levels of beta-endorphin in rats with free access to alcohol both in a topiramate- or vehicle-treated group. However, in topiramate-treated group, a voluntary consumption of alcohol diminished in comparison with the vehicle-treated rats.. The results from this study indicated that topiramate reduces voluntary alcohol intake and support our previous findings that the increase of beta-endorphin level is responsible at least partly for the effectiveness of drugs in treating the alcohol addiction.

Topics: Alcohol Drinking; Alcoholism; Animals; Anticonvulsants; beta-Endorphin; Dose-Response Relationship, Drug; Ethanol; Female; Fructose; Rats; Time Factors; Topiramate

The aim of this study was to determine the 12-week cognitive changes in topiramate-treated patients recently detoxified from alcohol.. Participants were inpatients with DSM-IV alcohol dependence. All of them were discharged within 14 days after the initiation of topiramate treatment. The topiramate dose range was 50-300 mg/day. The Montreal Cognitive Assessment (MoCA) was used on day 0, day 29, day 57, and day 85. Differences of the MoCA total and seven subtest scores among four time-points were compared.. Thirty-eight participants (36 men and two women) had a mean ± SD age of 43.1 ± 8.6 years old. At enrollment, they were abstinent for a mean ± SD of 11.5 ± 5.3 days. Five, one, and three patients dropped out of the study on day 29, day 57, and day 85, respectively. On day 85, the mean ± SD dose of topiramate was 253.1 ± 60.8 mg/day. Alcohol consumption decreased drastically during follow up. At each time-point, 75%-80% of the participants were continuous abstainers. The mean ± SD MoCA total, language subtest, and delayed recall subtest scores increased significantly from day 0 to day 85, from 22.0 ± 4.7 to 24.7 ± 3.4 (P < 0.01), from 1.1 ± 1.0 to 1.3 ± 1.0 (P = 0.03), and from 2.7 ± 1.7 to 4.1 ± 1.0 (P < 0.01), respectively.. Topiramate-treated patients recently detoxified from alcohol usually have an improvement of their cognitive function, especially in the language and delayed recall domains. This phenomenon may be caused by the greater influence of cognitive recovery associated with decreased drinking as compared with topiramate-induced cognitive impairment.

Topics: Adolescent; Adult; Alcoholic Intoxication; Alcoholism; Cognition; Cognition Disorders; Diagnostic and Statistical Manual of Mental Disorders; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Fructose; Humans; Male; Middle Aged; Neuroprotective Agents; Neuropsychological Tests; Patient Dropouts; Prospective Studies; Psychomotor Performance; Recovery of Function; Socioeconomic Factors; Topiramate; Treatment Outcome; Young Adult

Alcohol dependence is the third leading cause of preventable death in the USA. While single-agent pharmacotherapies have variable efficacy, medication combinations may produce additive effects by modulating multiple neural pathways.. Here, we examined in animal models of ethanol consumption and relapse the combined effects of ondansetron (a serotonin-3 antagonist) and topiramate (a GABA/glutamate modulator), two medications with demonstrated efficacy for treating alcohol dependence, hypothesizing that their combination would produce a more efficacious response.. The effects of acutely administered ondansetron (0-0.01 mg/kg) and topiramate (0-10 mg/kg) alone and in combination on ethanol consumption were examined in alcohol preferring (P) rats (N = 20) and in rats from their background strain (Wistars, N = 20) using a 24-h access free-choice paradigm. Next, we examined their ability to prevent an increase in ethanol consumption following a deprivation period (i.e., an animal model of relapse).. Whether administered alone or combined with ondansetron, topiramate produced a similar modest but persistent reduction in ethanol consumption. However, an analysis of efficacy by drinking level revealed that the combination was superior to topiramate alone in heavy-drinking P rats, but was without effect in lighter-drinking P rats and Wistar rats. Both topiramate alone and the combination blocked the alcohol deprivation effect in both Wistar and P rats with the combination tending to produce a greater decrease than topiramate alone.. The combination of ondansetron and topiramate may be a promising treatment for preventing relapse and for treating alcohol dependence in heavy-, but not lighter-drinkers.

Topics: Alcohol Drinking; Alcoholism; Animals; Behavior, Animal; Disease Models, Animal; Drug Therapy, Combination; Ethanol; Fructose; GABA Modulators; Male; Ondansetron; Rats; Rats, Wistar; Secondary Prevention; Serotonin 5-HT3 Receptor Antagonists; Severity of Illness Index; Time Factors; Topiramate; Treatment Outcome

6-month naturalistic, open-label trial to compare amisulpride versus topiramate and naltrexone as a treatment for patients with alcohol dependence, with assessments at enrolment and after 3 and 6 months of treatment.. 274 alcohol-dependent patients who had been drinking heavily during the past month were included. Once detoxified, patients were assigned to one of three treatment groups (naltrexone 50 mgr per day, topiramate 200 mgr per day or amisulpride 100 mgr per day). Patients were assessed at baseline and after 3 and 6 months of follow-up. Outcome was measured using tools that assessed alcohol intake (EuropASI and Alcohol Timeline Followback), craving (OCDS), disability (WHO/DAS), and quality of life (EQ-5D); changes in biomarkers of alcohol intake were also noted.. at the 6-month follow-up patients taking amisulpride had poorer results than those taking topiramate in direct measures of alcohol intake (OCDS, alcohol intake, number of drinks per day and heavy drinking days), but no significant differences were found in these measures on comparing the amisulpride patients with those taking naltrexone.. in this study, amisulpride, at a dose of 100 mgr per day, was less effective than topiramate, at a dose of 200 mg per day, but as effective as naltrexone, at a dose of 50 mg per day, for reducing alcohol intake and craving over the period of the study.

Topics: Alcoholism; Amisulpride; Anticonvulsants; Antipsychotic Agents; Female; Fructose; Humans; Male; Naltrexone; Narcotic Antagonists; Sulpiride; Topiramate

Topics: Alcoholism; Anticonvulsants; Benzodiazepines; Central Nervous System Agents; Female; Fructose; Humans; Lamotrigine; Middle Aged; Secondary Prevention; Substance-Related Disorders; Time Factors; Topiramate; Treatment Outcome; Triazines

Percent subjects with no heavy drinking days (PSNHDDs), an efficacy end point recommended by the Food and Drug Administration, considers abstinent individuals or those engaging in low-risk drinking behavior as successful responders to treatment. As PSNHDD has been used infrequently in previous alcohol clinical trials, we evaluated the utility and validity of the PSNHDD outcome measure in 2 large alcohol clinical trials.. Data sets from 2 alcohol trials, COMBINE and a multisite topiramate trial, were used to analyze PSNHDDs and other traditional end points for the topiramate, naltrexone, acamprosate, and placebo groups. Effect sizes of PSNHDDs were determined for each month of active treatment and by varying grace periods-early periods in the trial where outcome is not considered in the analysis-and were compared with that of other traditional outcome measures. Long-term outcomes were compared for groups that had no heavy drinking days versus those that had heavy drinking days during active treatment.. PSNHDD effect sizes were significant for both topiramate (0.34 and 0.25 at months 2 and 3, respectively) and naltrexone (0.24 and 0.26 at months 3 and 4, respectively). Given a 2-month grace period for naltrexone, the effect size of PSNHDDs was comparable to the effect sizes using traditional outcome measures. With a 1-month grace period for topiramate, it was greater than the majority of traditional outcome measures. Little is gained by allowing up to 1, 2, or 3 heavy drinking days as an end point. Subjects with no HDDs during treatment fared better than those with some HDDs on drinking outcomes and alcohol-related consequences during a 1-year follow-up.. PSNHDD appears to be a clinically informative end point measure, especially when used with a grace period, and is as sensitive as most traditional outcome measures in detecting differences between the medication and placebo groups. Nonetheless, these findings should be replicated in other clinical data sets, particularly with medications that work via different mechanisms.

Topics: Acamprosate; Alcohol Deterrents; Alcohol Drinking; Alcoholism; Female; Fructose; Humans; Male; Naltrexone; Randomized Controlled Trials as Topic; Taurine; Temperance; Time Factors; Topiramate; Treatment Outcome

Posttraumatic stress disorder (PTSD) is a disabling psychiatric disorder that is common among combat veterans and may lead to very poor sleep and disturbing nightmares.. To examine the safety and effectiveness of topiramate as add-on therapy for the management of combat-related PTSD and to examine the effects of topiramate on sleep and alcohol consumption.. We conducted an 8-week open-label pilot study of topiramate for male combat veterans (N = 43) with PTSD, with analysis of veterans who completed the protocol. Psychometric, sleep, and alcohol consumption assessments were conducted at baseline and at week 8.. Twenty-nine subjects completed the 8-week study. Significant reductions in Clinician Administered PTSD Scale scores were observed at the 8-week endpoint (from 86.3 +/- 21.1 to 67.1 +/- 25.1; p < 0.01). Decreases were seen in both Stanford Sleepiness Scale scores (from 10.5 +/- 0.72 to 9.0 +/- 0.58; p = 0.08) and Mississippi PTSD scores (from 120.4 +/- 6.5 to 111.5 +/- 20.9; p = 0.08), but the extent of the changes did not attain statistical significance for either scale. There was a significant reduction in the proportion of patients with nightmares (from 100% to 62%; p < 0.001) and patients who experienced anxiety that interfered with falling asleep (from 90% to 62%; p < 0.05). The proportion of patients with high-risk drinking patterns also decreased (from 31% to 14%). Two serious adverse events were reported during the study: an increase in low back pain and an episode of acute confusion.. When used in addition to other empiric therapy, topiramate may be effective at reducing general symptoms of combat-related PTSD and reducing high-risk alcohol intake and nightmares. Further randomized controlled trials of topiramate for the treatment of combat-related PTSD are warranted.

Topics: Adult; Aged; Aged, 80 and over; Alcoholism; Combat Disorders; Fructose; Humans; Male; Middle Aged; Pilot Projects; Stress Disorders, Post-Traumatic; Surveys and Questionnaires; Topiramate; Veterans

It is important to manage alcohol withdrawal properly. Mismanagement could lead to permanent brain damage or even death. The principles are simple and easily learnt. New pharmacological agents have come into use which helps in maintaining abstinence. Clinicians should update themselves on their use.

Topics: Acamprosate; Alcohol Deterrents; Alcoholism; Disulfiram; Fructose; Humans; Naltrexone; Narcotic Antagonists; Neuroprotective Agents; Taurine; Topiramate; Vitamins

Topics: Acamprosate; Alcohol Deterrents; Alcohol Drinking; Alcohol-Related Disorders; Alcoholics; Alcoholism; Anticonvulsants; Baclofen; Clinical Trials as Topic; Combined Modality Therapy; Disulfiram; France; Fructose; Health Status; Humans; Naltrexone; Psychotherapy; Randomized Controlled Trials as Topic; Secondary Prevention; Self-Help Groups; Social Support; Taurine; Temperance; Topiramate; Treatment Outcome

Topics: Alcoholics Anonymous; Alcoholism; Fructose; Humans; Neuroprotective Agents; Topiramate

Frontotemporal dementia (FTD) is an insidious presenile neurodegenerative disorder presenting with personality changes, compulsive behaviors, psychosis, apathetic, aberrant, and elated mood and behavior. No psychopharmacologic strategy has proven to be efficacious in the treatment of FTD yet. This is a case report of FTD in a 53-year-old male engineer whose alcohol abuse, but not other compulsive behaviors, responded to topiramate. Alcohol exerts reinforcing effects on cortico-mesolimbic dopamine pathways through the disinhibition of the inhibitory effects of gamma-amino-butyric acid-A neurons in the ventral tegmental area. Topiramate is a sulfamate-substituted fructopyranose derivative that may antagonize the reinforcing effects associated with the abuse liability of alcohol by modulation of cortico-mesolimbic dopamine function. On the basis of the mechanism of action of topiramate, we discuss the possible specificity of action of topiramate to control abusive drinking, but not to treat other clinical symptoms of FTD.

Topics: Alcoholism; Anticonvulsants; Cerebral Cortex; Compulsive Behavior; Dementia; Diagnostic Imaging; Dopamine; Dose-Response Relationship, Drug; Follow-Up Studies; Fructose; Humans; Limbic System; Male; Mental Status Schedule; Middle Aged; Neural Pathways; Topiramate

Topics: Alcoholism; Fructose; Humans; Nootropic Agents; Randomized Controlled Trials as Topic; Topiramate

Two-part random effects models (J. Am. Statist. Assoc. 2001; 96:730-745; Statist. Methods Med. Res. 2002; 11:341-355) have been applied to longitudinal studies for semi-continuous outcomes, characterized by a large portion of zero values and continuous non-zero (positive) values. Examples include repeated measures of daily drinking records, monthly medical costs, and annual claims of car insurance. However, the question of how to apply such models to multi-level data settings remains. In this paper, we propose a novel multi-level two-part random effects model. Distinct random effects are used to characterize heterogeneity at different levels. Maximum likelihood estimation and inference are carried out through Gaussian quadrature technique, which can be implemented conveniently in freely available software-aML. The model is applied to the analysis of repeated measures of the daily drinking record in a randomized controlled trial of topiramate for alcohol-dependence treatment.

Topics: Alcoholism; Algorithms; Female; Fructose; Humans; Longitudinal Studies; Male; Models, Statistical; Neuroprotective Agents; Placebos; Randomized Controlled Trials as Topic; Topiramate

Topics: Alcoholism; Excitatory Amino Acid Antagonists; Fructose; GABA Modulators; Humans; Psychotherapy; Topiramate

Topics: Alcoholism; Excitatory Amino Acid Antagonists; Fructose; GABA Modulators; Humans; Mood Disorders; Topiramate

Topics: Alcoholism; Excitatory Amino Acid Antagonists; Fructose; GABA Modulators; Glaucoma, Angle-Closure; Humans; Topiramate

Previous reports indicate that topiramate (TPM) might be an effective treatment for alcohol dependence, perhaps due to a decrease alcohol's rewarding effects resulting from inhibition mesocorticolimbic dopamine (DA) release. Additional reports indicate that TPM antagonizes chronic changes induced by alcohol at the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainate receptors. In the present study, a C57BL/6 (B6) murine model (n = 40) was used to evaluate the effect of TPM on the consumption of 12% alcohol over a 21-h period.. TPM (0, 10, 30, 90 mg/kg) injected subcutaneously into B6 mice 60 min prior to access to a 12% ethanol solution (v/v) over 8 days produced dose-responsive reduction in consumption during the first 2-h period after injection.. Across the 8 days of treatment ethanol intake (g/kg) for SAL, T10, T30, and T90, respectively, was 1.34, 1.03, 0.72, and 0.67. This reduction appears to require systemically available TPM since it was not statistically supported when assessed over the entire 21-h period of ethanol availability. None of the TPM doses affected food consumption or body weight, and T90 dose did not reduce motor activity either by itself or in combination with ethanol.. Unlike previous experiments using the same B6 mouse model to assess naltrexone or tiagabine, there was no evidence that mice developed tolerance to the TPM-induced reductions in ethanol consumption. Thus, in the B6 mouse, TPM reduced ethanol intake at doses with no readily apparent adverse side effects, an effect consistent with recent clinical reports. Additional study will be directed toward characterizing TPM as a treatment for alcohol dependence.

Topics: Administration, Oral; Alcoholism; Animals; Anticonvulsants; Body Weight; Brain; Central Nervous System Depressants; Disease Models, Animal; Dose-Response Relationship, Drug; Down-Regulation; Drug Tolerance; Eating; Ethanol; Fructose; Injections, Subcutaneous; Mice; Mice, Inbred C57BL; Receptors, AMPA; Synaptic Transmission; Topiramate; Treatment Outcome

Recent research indicates that topiramate has a role in the treatment of alcohol dependence. Topiramate has multiple mechanisms of action including enhancement of GABA-ergic inhibitory transmission and blocking excitatory glutamate neurotransmission, and modulating voltage-gated sodium and calcium ion channels and inhibiting carbonic anhydrase. In this study, we examined the effect of topiramate on endogenous opioid systems, which have an important role in the development of alcohol dependence. We investigated the beta-endorphin plasma level of animals with high- and low-risks of alcohol dependency after repeated treatment with topiramate. We used the Warsaw High Preferring (WHP) and Warsaw Low Preferring (WLP) rats, and treated them with topiramate at a dose of 80 mg/kg p.o. for 14 days. In WHP rats treatment with topiramate led to an increase in beta-endorphin plasma levels, which persisted at the same level even after a single injection of alcohol. The level of this peptide with topiramate was lower than in alcohol-injected WHP rats who did not receive topiramate. Beta-endorphin levels in WHP rats after topiramate or topiramate and ethanol treatment were similar to the basal level of this peptide in WLP rats. In WLP rats, topiramate did not prevent the ethanol-induced increase in beta-endorphin plasma level. We propose that administration of topiramate may have different effects on the opioid system involved in dependence according to genetic susceptibilities to alcoholism.

Topics: Alcoholism; Animals; beta-Endorphin; Drug Administration Schedule; Female; Fructose; Neuroprotective Agents; Radioimmunoassay; Rats; Topiramate

In recent human studies, the anticonvulsant drug topiramate (TPM) has shown efficacy in treating alcohol craving and mood disorders. However, preclinical evidence supporting such effects is surprisingly sparse. Three experiments were conducted here to assess possible anticraving and antidepressant effects of TPM using animal models.. In Experiment 1, rats were given 23 weeks ad libitum access to food, water, and either beer (4.44% ethanol v/v) or "near-beer" (a calorie-matched nonalcoholic beer, 0.44% ethanol) in their home cages. They were then restricted to daily 1 hour operant sessions in which they licked for water and either beer or near-beer under a progressive ratio schedule of reinforcement in a lickometer apparatus. The acute effects of TPM on the motivation to consume beer or near-beer were then assessed. The effects of naloxone were also assessed (as a positive control) after TPM testing. In Experiment 2, rats were given 11 weeks of ad libitum home-cage access to food, water, and beer. They then received repeated daily injections of TPM and effects on beer consumption under ad libitum home cage access conditions were monitored. In Experiment 3, the effects of TPM were assessed in the modified Porsolt forced swim test, emergence test, and elevated plus-maze (EPM) using alcohol naïve rats.. Topiramate (10, 20, and 40 mg/kg) significantly reduced the motivation to lick for beer, although the maximal effect was moderate in comparison with naloxone (10 mg/kg). However, naloxone, unlike TPM, also reduced responding for near-beer suggesting an alcohol-specific effect of TPM. In Experiment 2, TPM (40 and 80 mg/kg) tended to transiently reduce alcohol consumption in the home cage under ad libitum access but this effect disappeared with repeated administration of the drug. TPM (10 to 80 mg/kg, given twice over 4 hours before test) produced a robust dose-dependent decrease in immobility and increase in active coping strategies in the forced swim test similar to that seen with desipramine (2 x 20 mg/kg). There were modest anxiolytic effects of TPM on the EPM and emergence tests.. With acute administration, TPM is moderately effective and relatively selective in reducing the drive to consume alcohol in Wistar rats. This anti-alcohol effect is modest in comparison with naloxone and appears to dissipate under conditions of chronic treatment and ad libitum alcohol access. A marked antidepressant-like effect in the forced swim test and partial anxiolytic effects in other animal models suggests that TPM may be a beneficial treatment for affective disorders. These preliminary results suggest further research is warranted to resolve the mechanisms involved in TPM modulation of both mood and alcohol consumption.

Topics: Alcohol Drinking; Alcoholism; Animals; Antidepressive Agents; Anxiety; Behavior, Animal; Depression; Fructose; Male; Maze Learning; Motivation; Naloxone; Narcotic Antagonists; Rats; Rats, Wistar; Swimming; Topiramate

Topics: Alcoholism; Behavior Therapy; Continuity of Patient Care; Excitatory Amino Acid Antagonists; Fructose; GABA Modulators; Humans; Topiramate

Topics: Acamprosate; Alcohol Deterrents; Alcoholism; Behavior Therapy; Disulfiram; Family Practice; Fructose; Humans; Naltrexone; Taurine; Topiramate

Topiramate, an anticonvulsant, has been reported to increase the number of abstinent days and decrease craving in alcohol-dependent individuals. However, the neurobiological basis for topiramate's effect is unknown. To assess topiramate's effect on ethanol's rewarding and conditioning rewarding effects, the present experiments examined the effects of topiramate on the acquisition and expression of ethanol-induced conditioned place preference (CPP) in DBA/2J and C57BL/6J mice.. A biased apparatus and subject assignment were used. Mice received ethanol (2 g/kg) or saline paired with an initially nonpreferred floor (CS+) and saline paired with an initially preferred floor (CS-) for 5-minute conditioning trials. During the acquisition experiments, mice received a pretreatment of topiramate (0, 5, 10, 20, 50, or 100 mg/kg) 1 hour before the CS+ trials. On intervening CS- trials, mice received a pretreatment of saline. For the preference test, all mice received saline injections and were placed on a split floor for a 30-minute test. During the expression experiments, mice received no drug pretreatment on conditioning trials, but were pretreated with topiramate (0, 10, 50, or 100 mg/kg) 1 hour before the test session.. Ethanol-induced CPP was observed in both strains, but topiramate did not affect the acquisition or expression of ethanol-induced CPP in either strain. Despite its failure to alter CPP, topiramate produced dose-dependent locomotor activating effects in both strains. These effects were observed both in the presence and in the absence of ethanol.. These findings indicate that topiramate has no effect on ethanol's rewarding or conditioned rewarding effects as indexed by the place conditioning procedure. Thus, these studies raise the possibility that topiramate's efficacy in the treatment of alcoholism results from its impact on brain areas other than those that mediate ethanol's rewarding or conditioned rewarding effects. One alternative possibility is that topiramate decreases withdrawal-induced negative affective states that normally contribute to relapse.

Topics: Alcoholism; Animals; Anticonvulsants; Conditioning, Psychological; Ethanol; Fructose; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Motor Activity; Topiramate

Two cases of patients with a severe comorbidity of alcohol abuse treated with topiramate are reported. The first case is a 52-year-old patient who has been suffering from schizophrenia for many years. Topiramate prescription was associated with a discontinuation of his chronic, refractory alcohol consumption. The second case is a 41-year-old patient with bipolar disorder that mainly manifests itself through manic episodes. Topiramate treatment allowed him to decrease his alcohol intake to an acceptable level. Consequently, his bipolar symptoms also improved, without the appearance of any side effects. Thus, topiramate may improve alcohol intake among patients with schizophrenia or bipolar disorder. Certain studies have shown the efficacy of topiramate in alcoholic patients without such associated disorders, but further research is needed for this special population.

Topics: Adult; Alcohol Drinking; Alcoholism; Bipolar Disorder; Fructose; Humans; Male; Middle Aged; Schizophrenia; Topiramate

Topics: Adult; Alcoholism; Drug Administration Schedule; Fructose; Humans; Male; Selective Serotonin Reuptake Inhibitors; Topiramate

Topics: Acamprosate; Alcohol Deterrents; Alcoholism; Antidepressive Agents; Disulfiram; Fructose; Humans; Naltrexone; Substance Withdrawal Syndrome; Taurine; Topiramate

Anticonvulsant drugs have been used in the treatment of alcohol addiction with relatively good results. The purpose of the present study was to evaluate tolerance and safety of topiramate in patients presenting alcohol dependence.. We studied 24 patients that fulfilled alcohol-dependence criteria (DSM-IV) and presented other psychiatric disorders for which the use of topiramate was indicated. During the 12 weeks of the study, the patients received topiramate (262 mg/day) plus the psychoactive drugs they were taking for the other disorders. Carbohydrate-deficient transferrin (CDT) values and measures of craving and alcohol use were taken every 2 weeks.. Baseline rating of amount and frequency of craving and alcohol use decreased significantly by week 2, and CDT values decreased from week 6. Topiramate was well tolerated, and there were only three dropouts due to adverse events.. Topiramate is safe and well tolerated, and may be beneficial in the treatment of alcohol dependence. A placebo-controlled study would be of interest.

Topics: Adult; Alcoholism; Anticonvulsants; Biomarkers; Comorbidity; Drug Therapy, Combination; Female; Fructose; Humans; Male; Mental Disorders; Middle Aged; Topiramate; Transferrin; Treatment Outcome

This article represents the proceedings of a symposium, "Development of Novel Pharmacotherapies for the Treatment of Alcohol Dependence: Focus on Antiepileptics," presented at the 2003 annual meeting of the Research Society on Alcoholism in Fort Lauderdale, FL. The organizers and cochairs were Bankole A. Johnson and Robert M. Swift. The presentations were (1) Development of topiramate in the treatment of alcoholism, by Bankole A. Johnson; (2) Craving as a predictor of treatment outcome in pharmacotherapy trials for the treatment of alcoholism, by Nassima Ait-Daoud; (3) Use of biomarkers as a predictor of treatment response in treating alcoholism, by Martin A. Javors; (4) Psychotherapy to enhance compliance with pharmacotherapy in treatment trials for alcohol dependence, by Carlo C. DiClemente; (5) Synopsis of promising medications to treat alcoholism, by Robert M. Swift; and (6) New knowledge on the development of antiepileptic medications for the treatment of alcoholism, by Robert J. Malcolm, Jr.

Topics: Alcoholism; Animals; Anticonvulsants; Biomarkers; Fructose; Humans; Psychotherapy; Societies, Medical; Topiramate; United States

Topics: Alcoholism; Anticonvulsants; Behavior, Addictive; Bipolar Disorder; Comorbidity; Female; Fructose; Humans; Male; Middle Aged; Topiramate; Treatment Outcome

Topics: Alcohol Drinking; Alcoholism; Anticonvulsants; Fructose; Humans; Randomized Controlled Trials as Topic; Topiramate

Topics: Alcoholism; Fructose; GABA Agonists; Humans; Topiramate

Topics: Agoraphobia; Alcoholism; Cyclohexanols; Depressive Disorder; Female; Fructose; Hallucinations; Humans; Infarction, Posterior Cerebral Artery; Middle Aged; Neuroprotective Agents; Obesity; Psychiatric Status Rating Scales; Selective Serotonin Reuptake Inhibitors; Topiramate; Venlafaxine Hydrochloride