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Industrial Psychiatry Journal 2018Alcohol use disorders (AUDs) is an important public health concern as estimates of the prevalence of AUD range at 4%-6% in the Indian population. Currently, there is... (Review)
Review
Alcohol use disorders (AUDs) is an important public health concern as estimates of the prevalence of AUD range at 4%-6% in the Indian population. Currently, there is limited literature on the pharmacotherapeutic interventions for AUD in the Indian setting. It is imperative to identify the possible variations in their effects from Western studies, and hence the current review was attempted to perform a comprehensive evaluation and critical appraisal of the methodology of the evidence on pharmacological strategies of relapse prevention of AUD in the Indian setting. A total of 18 studies were included in the review. Disulfiram was the most common pharmacological agent to be studied. The initial literature before 2000 focused primarily on disulfiram, whereas the studies in the next decade compared it to acamprosate and naltrexone and emerging interest in anticraving agents such as baclofen and topiramate had been noted over the past few years. No studies were available on newer agents such as ondansetron, selective serotonin reuptake inhibitors or formulations such as depot and implants. Deterrent agents were found to be better when compared to anticraving agents in terms of abstinence and relapse, whereas the latter were more effective for control of craving. Among the pharmacological agents studied, the greatest evidence exists for disulfiram for relapse prevention which could be due to affordability of disulfiram and social support in the Indian context. The chief methodological limitations include the lack of randomized trials and objective measures for assessing abstinence.
PubMed: 31359967
DOI: 10.4103/ipj.ipj_79_17 -
The Cochrane Database of Systematic... Nov 2018Alcohol use disorder (AUD) and alcohol-related impairments belong to the most widespread psychiatric disorders leading to specific psychophysical, affective and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Alcohol use disorder (AUD) and alcohol-related impairments belong to the most widespread psychiatric disorders leading to specific psychophysical, affective and cognitive symptoms and consequences for psychosocial well-being and health. Alcohol consumption is increasingly becoming a problem in many developing regions and AUD prevalence is estimated at 4.1% worldwide, with highest prevalence in European countries (7.5%), and the North America (6.0%). Therapeutic approaches, including pharmacotherapy, play an important role in treating patients with AUD.
OBJECTIVES
To assess the efficacy and safety of baclofen for treating people with AUD, who are currently drinking, with the aim of achieving and maintaining abstinence or reducing alcohol consumption.
SEARCH METHODS
We searched the Cochrane Drugs and Alcohol Specialised Register, CENTRAL, MEDLINE, Embase, two further databases and two clinical trials registries, conference proceedings, and the reference lists of retrieved articles. The date of the most recent search was 30 January 2018.
SELECTION CRITERIA
Randomised controlled trials (RCTs) of at least four weeks' treatment duration and 12 weeks' overall study duration comparing baclofen for relapse prevention of AUD with placebo, no treatment or other treatments.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane.
MAIN RESULTS
We included 12 RCTs (1128 participants). All studies but three recruited fewer than 100 participants. Participants had a diagnosis of alcohol dependence according the Diagnostic and Statistical Manual of Mental Disorders (DSM) IV or the International Classification of Diseases (ICD)-10 criteria who were currently drinking. The mean age of participants was 48 years, and there were more men (69%), than women. All studies compared baclofen to placebo, except for one study that evaluated baclofen versus acamprosate. The included studies considered baclofen at different doses (range 10 mg a day to 150 mg a day). In all but one of the studies, participants in both the baclofen and placebo groups received psychosocial treatment or counselling of various intensity.We judged most of the studies at low risk of selection, performance, detection (subjective outcome), attrition and reporting bias.We did not find any difference between baclofen and placebo for the primary outcomes: relapse-return to any drinking (RR 0.88, 95% CI 0.74 to 1.04; 5 studies, 781 participants, moderate certainty evidence); frequency of use by percentage of days abstinent (MD 0.39, 95% CI -11.51 to 12.29; 6 studies, 465 participants, low certainty evidence) and frequency of use by percentage of heavy drinking days at the end of treatment (MD 0.25, 95% CI -1.25 to 1.76; 3 studies, 186 participants, moderate certainty evidence); number of participants with at least one adverse event (RR 1.04, 95% CI 0.99 to 1.10; 4 studies, 430 participants, high certainty evidence); the dropout rate at the end of treatment (RR 0.98, 95% CI 0.77 to 1.26, 8 studies, 977 participants, high certainty evidence) and dropout due to adverse events (RR 1.11, 95% CI 0.59 to 2.07; 7 studies, 913 participants, high certainty evidence).We found evidence that baclofen increases amount of use (drink per drinking days), (MD 1.55, 95% CI 1.32 to 1.77; 2 studies, 72 participants, low certainty evidence).Among secondary outcomes, there was no difference on craving (MD 1.38, 95% CI -1.28 to 4.03, 5 studies, 469 participants), and anxiety (SMD 0.07, 95% CI -0.14 to 0.28; 5 trials, 509 participants). We found that baclofen increased depression (SMD 0.27, 95% CI 0.05 to 0.48; 3 studies, 387 participants).Concerning the specific adverse events we found that baclofen increased: vertigo (RR 2.16, 95% CI 1.24 to 3.74; 7 studies, 858 participants), somnolence/sedation (RR 1.48, 95%CI 1.11 to 1.96; 8 studies, 946 participants), paraesthesia (RR 4.28, 95% CI 2.11 to 8.67; 4 studies, 593 participants), and muscle spasms/rigidity (RR 1.94, 95%CI 1.08 to 3.48; 3 studies, 551 participants). For all the other adverse events we did not find significant differences between baclofen and placebo.For the comparison baclofen versus acamprosate, we were only able to extract data for one outcome, craving. For this outcome, we found that baclofen increased craving compared with acamprosate (MD 14.62, 95% CI 12.72 to 16.52; 1 study, 49 participants).
AUTHORS' CONCLUSIONS
None of the primary or secondary outcomes of the review showed evidence of a difference between baclofen and placebo. The high heterogeneity among primary studies results limits the interpretation of the summary estimate, the identification of moderators and mediators of baclofen's effects on alcohol use remains a challenge for further research. Even though some results from RCTs are promising, current evidence remains uncertain regarding the use of baclofen as a first-line treatment for people with AUDs.
Topics: Acamprosate; Alcohol Deterrents; Alcohol Drinking; Alcoholism; Baclofen; Craving; Depression; Female; GABA-B Receptor Agonists; Humans; Male; Middle Aged; Patient Dropouts; Randomized Controlled Trials as Topic; Recurrence
PubMed: 30484285
DOI: 10.1002/14651858.CD012557.pub2 -
CNS Drugs Jan 2018Previous reviews have examined the use of theoretically supported combinations of drugs for the treatment of alcohol use disorder. This review seeks to examine the...
BACKGROUND
Previous reviews have examined the use of theoretically supported combinations of drugs for the treatment of alcohol use disorder. This review seeks to examine the strengths and limitations of current clinical evidence for the use of combined pharmacological interventions intended to treat alcohol use disorder.
OBJECTIVES
The objective of this review was to identify combinations of pharmacological treatments for alcohol use disorder, and assess the strength of clinical evidence for these treatments.
METHODS
We conducted searches using PubMed, EMBASE through Ovid (1974 to present), MEDLINE through Ovid (1946 to present), and Psychinfo through Ovid (1806 to present). Our primary search included the terms "alcoholism" and "drug therapy, combination". Search results were restricted to human subjects and English language. Search criteria were not restricted based on study design or patient age. Studies were evaluated for randomization, blinding, group similarity, power determination, outcome reporting, and number of patients analyzed.
RESULTS
Nine hundred and eighty-four publications were initially screened for inclusion after duplicates were removed. The search identified 16 publications evaluating drug combinations for the treatment of alcohol use disorder. The majority of published trials included naltrexone combined with one of the following: gabapentin, ondansetron, acamprosate, gamma-hydroxybutyrate, sertraline, quetiapine, or escitalopram plus gamma-hydroxybutyrate. Other combinations included 5-hydroxytryptophan with carbidopa/levodopa, gamma-hydroxybutyrate with disulfiram, acamprosate with disulfiram, and mirtazapine with quetiapine. Interpretation of results across studies was limited by low statistical power, and heterogeneity of drug combinations and outcome measures. Drug combination effect sizes were comparable to those observed in single-agent trials.
CONCLUSIONS
No significant benefit for the use of combinations over single agents was observed. However, benefit may be observed when combined pharmacological interventions address specific symptoms of alcohol use disorder known to be influenced by combination components, or when combinations are used in specific subpopulations in which combination components demonstrate benefit.
Topics: Alcohol Deterrents; Alcoholism; Drug Therapy, Combination; Humans; Naltrexone; Outcome Assessment, Health Care
PubMed: 29273901
DOI: 10.1007/s40263-017-0484-2 -
Therapeutic Advances in... Sep 2017Psychotic illnesses, such as schizophrenia, are typically enduring and disabling conditions, impacting individual, family, and societal outcomes. Individuals with these... (Review)
Review
BACKGROUND
Psychotic illnesses, such as schizophrenia, are typically enduring and disabling conditions, impacting individual, family, and societal outcomes. Individuals with these face greater vulnerabilities in developing alcohol-use disorder (AUD). Furthermore, the nature of psychoses, often manifesting with paranoia, cognitive impairment, a lack of insight, sub-optimal treatment adherence, and stigma from others, means that they can pose unique treatment challenges when these two conditions comorbidly occur. These challenges mean that the standard literature on the effectiveness of the opioid antagonist naltrexone in AUD does not necessarily translate to this vulnerable population.
METHODS
Following PRISMA guidelines, we herein systematically reviewed the evidence for naltrexone in individuals with both psychosis and AUD. Overall, there is a paucity of research in this important area, with only nine reports meeting search criteria, only four of which were randomized control trials. Studies compared naltrexone with: placebo, another pharmaceutical agent, or upon changes to baseline drinking behaviour. One study evaluated the long-acting injectable formulation of this drug.
RESULTS
Most studies, including the methodologically more robust ones, supported naltrexone's effectiveness over placebo in terms of reduction in drinking days and numbers of drinks consumed on such days in this cohort. Work comparing naltrexone to other pharmaceutical interventions showed approximate equivalence with disulfiram, and modest superiority over acamprosate.
CONCLUSIONS
On this limited evidence base, this review endorses the use of naltrexone as both safe and effective in those with both psychotic illnesses and AUD. Several key issues remain to be elucidated. Critically, study designs meant that they were limited to individuals with good engagement with services, and levels of adherence were attained that are unlikely to be replicated in this cohort in real-world settings. Finally, effects of specific psychosis symptomatology, not least paranoia and insight, upon naltrexone use, and the reverse directional potential of 'double dysphoria' from an opioid antagonist remain largely unexplored.
PubMed: 28959434
DOI: 10.1177/2045125317709975 -
Addiction (Abingdon, England) Feb 2018Pharmacologically controlled drinking in the treatment of alcohol dependence or alcohol use disorders (AUDs) is an emerging concept. Our objective was to explore the... (Meta-Analysis)
Meta-Analysis
Pharmacologically controlled drinking in the treatment of alcohol dependence or alcohol use disorders: a systematic review with direct and network meta-analyses on nalmefene, naltrexone, acamprosate, baclofen and topiramate.
BACKGROUND AND AIMS
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.
DESIGN
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.
SETTING
Thirty-two RCTs.
PARTICIPANTS
A total of 6036 patients.
MEASUREMENTS
The primary outcome was total alcohol consumption (TAC). Other consumption outcomes and health outcomes were considered as secondary outcomes.
FINDINGS
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 = 0%], baclofen (SMD = -1.00, 95% CI = -1.80, -0.19; one study) and topiramate (SMD = -0.77, 95% CI = -1.12, -0.42; I = 0%) showed superiority over placebo on TAC. No efficacy was observed for naltrexone or acamprosate. Similar results were observed for other consumption outcomes, except for baclofen (the favourable outcome on TAC was not reproduced). The number of withdrawals for safety reasons increased under nalmefene and naltrexone. No treatment demonstrated any harm reduction (no study was powered to explore health outcomes). Indirect comparisons suggested that topiramate was superior to nalmefene, naltrexone and acamprosate on consumption outcomes, but its safety profile is known to be poor.
CONCLUSIONS
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
PubMed: 28940866
DOI: 10.1111/add.13974 -
The World Journal of Biological... Mar 2017These practice guidelines for the biological treatment of alcohol use disorders are an update of the first edition, published in 2008, which was developed by an... (Review)
Review
These practice guidelines for the biological treatment of alcohol use disorders are an update of the first edition, published in 2008, which was developed by an international Task Force of the World Federation of Societies of Biological Psychiatry (WFSBP). For this 2016 revision, we performed a systematic review (MEDLINE/PUBMED database, Cochrane Library) of all available publications pertaining to the biological treatment of alcoholism and extracted data from national guidelines. The Task Force evaluated the identified literature with respect to the strength of evidence for the efficacy of each medication and subsequently categorised it into six levels of evidence (A-F) and five levels of recommendation (1-5). Thus, the current guidelines provide a clinically and scientifically relevant, evidence-based update of our earlier recommendations. These guidelines are intended for use by clinicians and practitioners who evaluate and treat people with alcohol use disorders and are primarily concerned with the biological treatment of adults with such disorders.
Topics: Advisory Committees; Alcoholism; Antipsychotic Agents; Biological Psychiatry; Drug Therapy, Combination; Electroconvulsive Therapy; Evidence-Based Medicine; Humans; International Cooperation; Practice Guidelines as Topic; Psychotherapy; Randomized Controlled Trials as Topic
PubMed: 28006997
DOI: 10.1080/15622975.2016.1246752 -
Journal of Autism and Developmental... Mar 2016Autism spectrum disorders are an emerging health problem worldwide, but little is known about their pathogenesis. It has been hypothesized that autism may result from an... (Review)
Review
Autism spectrum disorders are an emerging health problem worldwide, but little is known about their pathogenesis. It has been hypothesized that autism may result from an imbalance between excitatory glutamatergic and inhibitory GABAergic pathways. Commonly used medications such as valproate, acamprosate, and arbaclofen may act on the GABAergic system and be a potential treatment for people with ASD. The present systematic review aimed at evaluating the state-of-the-art of clinical trials of GABA modulators in autism. To date there is insufficient evidence to suggest the use of these drugs in autistic subjects, even if data are promising. Of note, short-term use of all the reviewed medications appears to be safe. Future well designed trials are needed to elucidate these preliminary findings.
Topics: Autism Spectrum Disorder; GABA Modulators; Humans; gamma-Aminobutyric Acid
PubMed: 26443675
DOI: 10.1007/s10803-015-2619-y -
Addiction (Abingdon, England) Jun 2015To determine the efficacy of acamprosate and naltrexone in the treatment of those who are alcohol-dependent in reducing lapse/relapse to alcohol consumption and... (Meta-Analysis)
Meta-Analysis Review
AIMS
To determine the efficacy of acamprosate and naltrexone in the treatment of those who are alcohol-dependent in reducing lapse/relapse to alcohol consumption and treatment discontinuation, and to examine whether a proportion of the variance in study outcome can be explained by the country in which the trials have taken place.
METHOD
A systematic review and meta-analysis of randomized controlled trials published before September 2013 was conducted. The primary outcome measures were the efficacy of acamprosate or naltrexone in reducing lapse/relapse compared to placebo in the treatment of alcohol dependence and treatment discontinuation. Twenty-two randomized controlled trials (RCTs) of the efficacy of acamprosate met inclusion criteria for the meta-analysis, with a total of 2649 participants in the acamprosate group and 2587 in the placebo group. Twenty-seven RCTs of the efficacy of naltrexone met inclusion criteria for the meta-analysis, with a total of 2253 participants in the naltrexone group and 1946 in the placebo group. A random-effects model using a Mantel-Haenszel method was applied to conduct the meta-analysis. Variance in study outcomes was explored using subgroup analysis of Europe versus the rest of the world (ROW).
RESULTS
The risk of returning to any drinking at 6 months was significantly lower for acamprosate [risk ratio (RR) = 0.83, 95% confidence interval (CI) = 0.78-0.89]. There was little difference in the risk of participants discontinuing treatment for any reason (RR = 0.91, 95% CI = 0.83-1.00) or due to adverse events (RR = 1.30, 95% CI = 0.96-1.75) for the acamprosate compared to placebo groups. The risk of individuals returning to any drinking at approximately 3 months was reduced significantly for the naltrexone group (RR = 0.92, 95% CI = 0.86-1.00), as was the risk of individuals relapsing to heavy drinking at 3 months (RR = 0.85, 95% CI = 0.78-0.93). There was no significant difference between naltrexone and placebo for the risk of individuals discontinuing treatment for any reason (RR = 0.94, 95% CI = 0.84-1.05). There was a significantly greater risk of participants in the naltrexone group discontinuing treatment due to adverse events compared to placebo (RR = 1.72, 95% CI = 1.10-2.70). Subgroup analysis by country (Europe versus ROW) revealed no difference in risk between acamprosate and placebo for the outcomes returning to any drinking at 6 months and discontinuing treatment due to adverse events. For the outcome discontinuation of treatment for any reason, there was a significant difference in RR between Europe and the ROW (χ(2) = 11.65, P <0.001) for acamprosate. Acamprosate was associated with a reduction in risk of discontinuing treatment for Europe (RR = 0.86, 95% CI = 0.79-0.95), but an increase in risk of discontinuing treatment for ROW (RR = 1.23, 95% CI = 1.03-1.48).
CONCLUSIONS
Both acamprosate and naltrexone appear to reduce the risk of individuals returning to drinking alcohol in those who are alcohol-dependent. The country in which a randomized control trial (RCT) for the efficacy of acamprosate and naltrexone is completed does not appear to explain the variance in trial outcomes for returning to drinking alcohol or discontinuing drinking due to adverse effects. However, the country in which the RCT of acamprosate are completed may be important for explaining the variance between studies for the outcome 'discontinuing treatment for any reason'.
Topics: Acamprosate; Adult; Alcohol Deterrents; Alcoholism; Europe; Female; Global Health; Humans; Male; Middle Aged; Naltrexone; Randomized Controlled Trials as Topic; Recurrence; Taurine; Treatment Outcome
PubMed: 25664494
DOI: 10.1111/add.12875 -
BMJ Clinical Evidence Oct 2014Up to 18% of people in industrialised societies are mildly affected by chronic tinnitus, and 0.5% report tinnitus having a severe effect on their daily life. Tinnitus... (Review)
Review
INTRODUCTION
Up to 18% of people in industrialised societies are mildly affected by chronic tinnitus, and 0.5% report tinnitus having a severe effect on their daily life. Tinnitus can be associated with hearing loss, acoustic neuromas, drug toxicity, ear diseases, and depression. Tinnitus can last for many years, and can interfere with sleep and concentration.
METHODS AND OUTCOMES
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for chronic tinnitus? We searched: Medline, Embase, The Cochrane Library, and other important databases up to November 2013 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
RESULTS
We found 33 studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
CONCLUSIONS
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: acamprosate, acupuncture, antidepressant drugs, benzodiazepines, carbamazepine, electromagnetic stimulation, ginkgo biloba, hearing aids, hypnosis, psychotherapy, tinnitus-masking devices, and cognitive behavioural therapy plus tinnitus-masking device (tinnitus retraining therapy).
Topics: Humans; Tinnitus
PubMed: 25328113
DOI: No ID Found -
JAMA May 2014Alcohol use disorders cause substantial morbidity and early mortality yet remain greatly undertreated. Medications are considerably underused. (Meta-Analysis)
Meta-Analysis Review
IMPORTANCE
Alcohol use disorders cause substantial morbidity and early mortality yet remain greatly undertreated. Medications are considerably underused.
OBJECTIVE
To conduct a systematic review and meta-analysis of the benefits and harms of medications (US FDA-approved and others) for adults with alcohol use disorders.
DATA SOURCES
PubMed, Cochrane Library, PsycINFO, CINAHL, EMBASE, FDA website, and clinical trials registries (January 1, 1970, to March 1, 2014).
STUDY SELECTION
Two reviewers selected randomized clinical trials (RCTs) with at least 12 weeks' duration that reported eligible outcomes and head-to-head prospective cohort studies reporting health outcomes or harms.
DATA EXTRACTION AND SYNTHESIS
We conducted meta-analyses using random-effects models and calculated numbers needed to treat for benefit (NNTs) or harm (NNHs).
MAIN OUTCOMES AND MEASURES
Alcohol consumption, motor vehicle crashes, injuries, quality of life, function, mortality, and harms.
RESULTS
We included 122 RCTs and 1 cohort study (total 22,803 participants). Most assessed acamprosate (27 studies, n = 7519), naltrexone (53 studies, n = 9140), or both. The NNT to prevent return to any drinking for acamprosate was 12 (95% CI, 8 to 26; risk difference [RD], -0.09; 95% CI, -0.14 to -0.04) and was 20 (95% CI, 11 to 500; RD, -0.05; 95% CI, -0.10 to -0.002) for oral naltrexone (50 mg/d). The NNT to prevent return to heavy drinking was 12 (95% CI, 8 to 26; RD -0.09; 95% CI, -0.13 to -0.04) for oral naltrexone (50 mg/d). Meta-analyses of trials comparing acamprosate to naltrexone found no statistically significant difference between them for return to any drinking (RD, 0.02; 95% CI, -0.03 to 0.08) or heavy drinking (RD, 0.01; 95% CI, -0.05 to 0.06). For injectable naltrexone, meta-analyses found no association with return to any drinking (RD, -0.04; 95% CI, -0.10 to 0.03) or heavy drinking (RD, -0.01; 95% CI, -0.14 to 0.13) but found an association with reduction in heavy drinking days (weighted mean difference [WMD], -4.6%; 95% CI, -8.5% to -0.56%). Among medications used off-label, moderate evidence supports an association with improvement in some consumption outcomes for nalmefene (heavy drinking days per month: WMD, -2.0; 95% CI, -3.0 to -1.0; drinks per drinking day: WMD, -1.02; 95% CI, -1.77 to -0.28) and topiramate (% heavy drinking days: WMD, -9.0%; 95% CI, -15.3% to -2.7%; drinks per drinking day: WMD, -1.0; 95% CI, -1.6 to -0.48). For naltrexone and nalmefene, NNHs for withdrawal from trials due to adverse events were 48 (95% CI, 30 to 112) and 12 (95% CI, 7 to 50), respectively; risk was not significantly increased for acamprosate or topiramate.
CONCLUSIONS AND RELEVANCE
Both acamprosate and oral naltrexone were associated with reduction in return to drinking. When directly compared with one another, no significant differences were found between acamprosate and naltrexone for controlling alcohol consumption. Factors such as dosing frequency, potential adverse events, and availability of treatments may guide medication choice.
Topics: Acamprosate; Alcohol-Related Disorders; Fructose; Harm Reduction; Humans; Naltrexone; Outpatients; Randomized Controlled Trials as Topic; Taurine; Topiramate
PubMed: 24825644
DOI: 10.1001/jama.2014.3628