Topiramate Treatment of Problem Drinkers

It is estimated that 30% of the general population are problem drinkers (NIAAA 2007). Despite
its high prevalence, problem drinkers are understudied, particularly with respect to
medications that may help them to reduce their drinking to safe levels. The study will extend
to this patient population findings from a trial of topiramate, which showed the drug to be
well tolerated and efficacious in moderately-severe alcohol-dependent patients (Johnson et
al. 2003).

This is a 13-week, double-blind, placebo-controlled study of topiramate (12 weeks during
which the dosage of study medication is gradually increased up to 200 mg orally and then
maintained, and 1 week of medication taper) and medical management counseling to reduce
drinking among problem drinkers (i.e., heavy drinkers without evidence of physical dependence
on alcohol) who want to reduce their drinking.

Participants attend weekly study visits for the first 5 weeks and then bi-weekly visits for
the last 8 weeks of the study, and are randomly assigned to receive topiramate or placebo on
a daily basis. In addition to study visits, participants report daily moods, drinking, and
medication usage through an Interactive Voice Response (IVR) system they call each night.
In-person follow-up evaluations are conducted at 3 and 6 months post-treatment to provide a
measure of the durability of treatment effects. This study also aims to examine the relation
between genotype and the response to topiramate treatment.

An additional aim is to conduct a substudy to examine neural cells generated from skin
fibroblast cells obtained from study participants via a skin biopsy (participation in the
substudy is completely optional). Initially, we will examine variables key to reliably
generating neurons from the cells and characterize these neurons using a variety of
laboratory measures. A longer term goal is to compare gene expression in individuals who show
a robust reduction in drinking following treatment with topiramate with those who show no
beneficial treatment effects.

A second additional aim is to explore whether the therapeutic and adverse effects of
topiramate are similar in patients on a stable regimen of an antidepressant to those not
receiving such therapy. Although exploratory, given the absence of data that directly address
this issue, we will stratify subjects by the presence or absence of current antidepressant
therapy.

Careful evaluation of the study's hypotheses will provide important information on the
efficacy and mechanism of effects of topiramate as a treatment for problem drinkers.

Inclusion Criteria:

- age 18 to 65 years, inclusive;

- have an average weekly ethanol consumption of >=24 standard drinks for men, or >=18
standard drinks for women;

- be able to read English at the 8th grade or higher level and show no evidence of
significant cognitive impairment;

- be willing to nominate an individual who will know the patient's whereabouts in order
to facilitate follow up during the study;

- if a woman of child-bearing potential (i.e., who has not had a hysterectomy, bilateral
oophorectomy, tubal ligation or who are less than two years postmenopausal), must be
non-lactating, practicing a reliable method of birth control, and have a negative
serum pregnancy test prior to initiation of treatment;

- if applicable, individuals being treated with a single antidepressant that has been
stable in dosage for a minimum of four weeks; and

- be willing to provide signed, informed consent to participate in the study (including
a willingness to reduce drinking to non-hazardous levels).

Exclusion Criteria:

- a current, clinically significant physical disease or abnormality on the basis of
medical history, physical examination, or routine laboratory evaluation, including
direct bilirubin elevations of >110% or transaminase elevations >300% normal (We will
not exclude patients with hypertension, diabetes mellitus, asthma or other common
medical conditions, as long as these are adequately controlled and the patient has an
ongoing relationship with a primary-care practitioner);

- a history of nephrolithiasis;

- a history of glaucoma;

- a serious psychiatric illness (i.e., schizophrenia, bipolar disorder, severe or
psychotic major depression, panic disorder, borderline or antisocial personality
disorder, organic mood or mental disorders, eating disorder, or substantial suicide or
violence risk) on the basis of history or psychiatric examination;

- a current Diagnostic & Statistical Manual of Mental Disorders 4th ed (DSM-IV)
diagnosis of drug dependence (other than nicotine dependence);

- a current Diagnostic and Statistical Manual of Mental Disorders 4th ed (DSM-IV)
diagnosis of alcohol dependence that is clinically moderate or severe;

- a history of hypersensitivity to topiramate;

- currently taking any tricyclic antidepressant (e.g., Adapin (doxepin), Anafranil
(clomipramine), Elavil (amitryptyline), Pamelor (nortryptyline), Tofranil
(imipramine), Sinequan (doxepin); or

- are considered by the investigators to be an unsuitable candidate for receipt of an
investigational drug.