Topiramate (TOP) has been reported to be efficacious in reducing drinking rates in men and women with alcohol dependence (Johnson et al., 2003; Rubio et al., 2004). Recent preclinical studies are also encouraging. The fact that TOP reduced drinking and increased periods of abstinence in non-abstinent alcoholics suggests that it is effective for initiating abstinence (Johnson et al., 2003). However, while significant differences on self-reported drinking measures started at the 200 mg/day dose in week 6 of Johnson et al. (2003), doses continued to increase up to week 8 so the effects of time and dose were confounded. Because TOP requires a slow titration and because the probability of experiencing side effects increases at doses higher than 200 mg/day, it is of considerable clinical importance to determine at what dose TOP has the most favorable benefit-to-side effect ratio. In addition, mechanisms that mediate TOP's effects on drinking are not understood. Evidence suggests that attenuation of craving may mediate TOP'S effects, however, no laboratory studies have assessed urge to drink while on TOP and studies of other putative behavioral mechanisms of effects have not been done. Further, studies have yet to identify which individuals are most likely to benefit from TOP. Improvements in pharmacological treatments may occur through identification of individual difference variables associated with differential treatment response. ? We propose to randomize alcohol dependent individuals not seeking treatment to one of three ? conditions in a three-group, placebo-controlled design: (1) TOP (200 mg/day); (2) TOP (300 mg/day); (3) placebo. As in our current segment, both Ecological Momentary Assessment (EMA) and cue reactivity (CR) will be measured. EMA will be conducted by having all participants use palm top computers daily for three weeks to record drinking behavior, urges to drink, and environmental circumstances in which urges occur. CR will be assessed in laboratory. Effects of potential genetic moderators of TOP response will be examined, as will certain mediators. This project will provide an efficient and comprehensive analysis of the effects of TOP on drinking and craving and will add important new information about putative biobehavioral mechanisms. Results will afford a better understanding of whether large-scale randomized clinical trials with long-term follow ups are warranted. ? ?
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