• The primary outcome measure will be subjects ethanol consumption over the course of the drug treatment period as assessed by the Timeline Followback method [ Time Frame: 85 days ] [ Designated as safety issue: No ]
  

• Secondary outcome measures will include frontal brain GABA concentrations, responses on subjective measures of mood and craving assessment scales, withdrawal rating scales, and on neuropsychological tests of cognitive functioning. [ Time Frame: 85 days ] [ Designated as safety issue: No ]
  

Drug: Topiramate (Topamax)
Medication Dosing Schedule: Days 1-3 50 mg q PM Days 4-7 50 mg BID Days 8-11 50 mg q AM & 100 mg q PM Days 12-15 100mg BID Days 16-19 100 mg q AM & 150 mg q PM Days 20-23 150 mg BID Days 24-27 150 mg qAM & 200 mg q PM Days 28-70 200 mg BID Days 71-77 150 mg BID Days 78-84 100mg BID Days 85-87 50 mg BID Days 88-91 50 mg qPM

Alcoholism is a disorder that produces extensive morbidity and mortality. Substantial progress has been made in the development of medications that can help to promote abstinence in alcohol dependent individuals. However, investigations of the most promising drugs, particularly naltrexone and acamprosate, suggest that these agents have at best moderate efficacy and there is a great need for additional medications for the treatment of alcoholism.

The results of a recent study suggest that the administration of the anticonvulsant agent ,topiramate helps alcoholic individuals to maintain abstinence (Johnson et al., 2003). Topiramate administration in Magnetic Resonance Spectroscopy (MRS) studies appears to increase GABA concentrations several fold in the brains of both healthy individuals (Kuzniecky et al., 1998) and in patients receiving anticonvulsant medications (Petroff et al., 1999). Although the mechanism through which topiramate produces this effect is unknown, the possibility exists that this agent, may, by enhancing the activity of brain GABAergic systems, act to reduce ethanol reinforcing actions. The objectives of this study are to determine whether topiramate will reduce the consumption of alcohol in subjects dependent on this substance, as has been previously reported, and to establish whether changes in alcohol consumption correlate with alteration in prefrontal GABA levels. Other study objectives are to assess the abuse liability properties of topiramate in alcohol dependent subjects and to examine the effects of chronic topiramate administration on cognitive functioning.

This will be a thirteen week long open label clinical trial of the effects of topiramate administration on ethanol consumption by alcohol dependent subjects. In addition GABA levels in the frontal cortices of alcohol dependent subjects after three days of abstinence will be compared to levels obtained for these individuals during the tenth week of topiramate administration. Baseline GABA cortical concentrations for alcohol dependent subjects also will be compared with those determined for a matched group of healthy control subjects who will be enrolled in a separate concurrent study.

Subjects will be asked to provide informed consent and then will be screened on the same day to determine if they meet study eligibility criteria. Subjects will be asked to return to provide two urines over the following week.

Subjects will be asked to remain abstinent for three days. On the third day of abstinence subjects will then undergo MRS imaging for GABA levels in the frontal cortex. Baseline measures of mood, craving, withdrawal, cognitive functioning and physical health will be obtained. In the afternoon they will receive their first dose of medication. Their responses to this medication challenge will be assessed over a 3-hour period.

During the drug treatment phase subjects will be asked to come to the clinic weekly for assessment and manual guided therapy during weeks 1-4 and biweekly during weeks 6-8. On days 68, 69, or 70 of the treatment phase subjects will undergo a second MRS study. On day 85 subjects will be seen at the clinic for a termination visit.