The Effects of Topiramate on Alcohol Use and Brain Gaba Concentrations in Alcohol Dependent Subjects

Condition(s) targeted: Alcoholism

Intervention: Topiramate (Topamax) (Drug)

Phase: Phase 4

Status: Active, not recruiting

Sponsored by: Boston University

Official(s) and/or principal investigator(s):
Ofra Sarid-Segal, MD, Principal Investigator, Affiliation: Boston University

This investigation will assess the effectiveness of topiramate in reducing ethanol consumption by alcohol dependent subjects. It also will seek to establish whether topiramate can be safely used in this population including whether it might be subject to abuse by alcohol dependent individuals. An additional goal of this study is to determine whether gamma amino butyric acid (GABA) concentrations are lower in the frontal cortex (the front of the brain)of alcohol dependent individuals than in matched control subjects, whether topiramate increases GABA levels in the frontal cortex, and whether such increases are associated with decreased alcohol consumption.

Study design: Treatment, Non-Randomized, Open Label, Historical Control, Single Group Assignment, Efficacy Study

Primary outcome: The primary outcome measure will be subjects ethanol consumption over the course of the drug treatment period as assessed by the Timeline Followback method

Secondary outcome: 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.

Detailed description: 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.

Minimum age: 18 Years. Maximum age: 65 Years. Gender(s): Both.

Criteria:

Inclusion Criteria: DSM-IV Diagnosis of Alcohol Dependence; Minimal drinking level of 14 drinks per week for women and 20 drinks per week for men over a consecutive 30 day period during the last 90 days Intent to stop drinking Male or female age 18-65 Able to maintain sobriety for 3 consecutive days without the use of detoxification medications Able to provide informed consent and to comprehend study procedures. If a woman, then is willing to use an effective means of birth control during throughout the study period. These include: a. barrier (diaphragm or condom) with spermicide b. intrauterine progesterone contraceptive system c. levonorgestrel implant d. medroxyprogesterone acetate contraceptive injection e. complete abstinence Exclusion Criteria: Dependent on or extensive abuse of drugs or substances other than ethanol, nicotine, or caffeine as assessed by urine toxicology (2 out of 3 Dependent on or extensive abuse of drugs or substances other than positive consecutive urines) DSM IV Axis I diagnoses other than ethanol, caffeine, or nicotine dependence severe enough to require treatment with medication or to prevent compliance with the protocol. Currently being treated with disulfiram (Antabuse), naltrexone (ReVia), or acamprosate Currently being treated with any other psychoactive or other CNS medications or a carbonic anhydrase inhibitor (e. g. acetazolamide) In need of medical detoxification from alcohol. Prior history of kidney stones. History of liver disease. ALT or AST 3 times higher than upper range of normal values. BUN or serum creatinine outside the normal range Major neurological disorder including seizures Other major diseases including severe hypertension, renal disease, or cardiac disease. Prior participation within 60 days in another clinical study. If female, a positive serum HCG or breast feeding. If female using oral contraceptives as a means of birth control. History of allergic sensitivity to topiramate Pending imprisonment Cardiac pacemaker or metal surgical implant. History of angle closure glaucoma.

Boston University Dept of Psychiatry Clinical Studies Unit, Boston, Massachusetts 02118, United States

Starting date: September 2003
Ending date: September 2007
Last updated: December 19, 2007