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Objective: Topiramate has been shown to reduce drinking and heavy drinking in alcohol-dependent individuals whose goal was to stop drinking. The present study evaluated the efficacy and tolerability of topiramate in heavy drinkers whose treatment goal was to reduce drinking to safe levels. Method: We randomly assigned 138 individuals (62.3% male) to receive 12 weeks of treatment with topiramate (N=67), at a maximal daily dosage of 200 mg, or matching placebo (N=71), both groups receiving brief counseling to reduce drinking and increase abstinent days. We hypothesized that topiramate-treated patients would be better able to achieve these goals and predicted that, based on prior research, the effects would be moderated by a single nucleotide polymorphism (rs2832407) in GRIK1, encoding the kainate GluK1 receptor subunit. Results: The rate of treatment completion was 84.9% and equal by treatment group. Topiramate treatment significantly reduced heavy drinking days (p<0.001) and increased abstinent days (p=0.032) relative to placebo. The topiramate group also had lower concentrations of the liver enzyme γ-glutamyltranspeptidase 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 (p=0.004) was significantly greater than for placebo only in rs2832407 C-allele homozygotes. Conclusions: These findings support the use of topiramate 200 mg/day 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. www.clinicaltrials.gov registration: NCT00626925

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We examined the prevalence and course of psychiatric and substance dependence (SD) disorders in subjects with SD and attention deficit hyperactivity disorder (ADHD).Method-We interviewed 1,761 adults with a lifetime diagnosis of cocaine and/or opioid dependence using the Semi-Structured Assessment for Drug Dependence and Alcoholism. Generalized linear regression with generalized estimating equation analysis was used to examine the associations between a lifetime diagnosis of ADHD and indicators of clinical course, and to identify unique correlates of ADHD.Results-Lifetime ADHD prevalence in the SD sample was 5.22% (vs. 0.85% in a group of individuals without SD). ADHD was associated with an earlier age of first substance use, more SD and psychiatric diagnoses, a greater likelihood of attempted suicide, and more hospitalizations. After controlling for conduct disorder and bipolar type I disorder, there were unique effects of ADHD on age of first substance use and number of SD diagnoses.Conclusion-In subjects with cocaine or opioid dependence, ADHD is associated with greater SD and psychiatric comorbidity and a more severe course of illness.

Aims Adverse childhood events (ACEs) are associated with negative health outcomes. We examined ACEs as risk factors for substance dependence (SD) and the mediating effects of mood and anxiety disorders on the relations between ACEs and SD risk. Design We compared early life experiences in 2,061 individuals with a lifetime diagnosis of alcohol, cocaine, or opioid dependence and 449 controls. Measurements Diagnostic and ACE data were obtained using the Semi-Structured Assessment for Drug Dependence and Alcoholism. Findings Childhood abuse or exposure to violent crime was positively related to the number of lifetime mood and anxiety disorders and to SD risk. Mood and anxiety disorders had their first onset a mean of nearly 3 years before the first SD diagnosis and mediated the effect of ACEs on SD risk. Conclusion ACEs appear to contribute additively to the risk of SD, with mood and anxiety disorders in the causal path for a portion of this risk. The identification and effective treatment of mood and anxiety disorders associated with ACEs could reduce the risk of developing SD.