Zonisamide Treatment of Alcohol Use Disorder: an Evaluation of Efficacy and Mechanism of Action

This is a 16-week randomized, double blind, placebo-controlled trial designed to determine
the effectiveness of zonisamide treatment for reducing heavy drinking and overall drinking in
160 treatment-seeking, regularly heavy drinking, alcohol-dependent civilians who want to quit
drinking or reduce consumption to non-hazardous levels. The investigators will use
state-of-the-art methodology and outcome assessments, including medical management (MM)
therapy (a minimal behavioral intervention aimed at reinforcing treatment goals and adherence
to medication), which is simple and easily implemented in primary care settings. The use of
MM in the study will increase the generalizability of results, allowing a more accurate
assessment of zonisamide's effectiveness than if a more intensive behavioral intervention
were to be used. To demonstrate zonisamide's effectiveness in a representative civilian
sample, the investigators will include civilians with co-morbid mood and anxiety disorders.

Inclusion Criteria:

- Female/male aged 21-70 years

- Regular heavy drinkers as defined by averaging 2 heavy drinking days per week over 90
days baseline pre-treatment timeline follow-back (TLFB), and current DSM-IV-TR alcohol
dependence that recognize a need to reduce or stop drinking (Note: heavy drinking days
will be defined as follows; for men greater than or equal to 5 drinks in a day and for
women greater than or equal to 4 drinks in a day)

- Women of child-bearing potential (i.e., no hysterectomy, bilateral oophorectomy, or
tubal ligation or <2 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;

- Willingness to provide signed, informed consent to participate in the study

Exclusion Criteria:

- A current, clinically significant physical disease or abnormality (i.e., neurologic,
renal, rheumatologic, gastrointestinal, hematologic, pulmonary, endocrine,
cardiovascular, hepatic, or autoimmune disease that, in the context of the study would
represent a risk to the subject, or significant laboratory abnormalities such as
hepatic aminotransferase levels (i.e., AST and ALT) greater than 300% of the upper
limit of normal or direct bilirubin levels >150% of the upper limit of normal) on the
basis of medical history, physical examination, or routine laboratory evaluation.
Other specific exclusionary disorders include;

- History of renal calculi or renal failure; a significant indication of renal
compromise will be defined by an elevation of serum creatinine above the
investigators' laboratory's limit of normal, or a known history of renal failure or
chronic renal disease, or any current or chronic disease that could reasonably be
expected to result in renal failure

- History of hypersensitivity to ZNS or any sulfonamide, Stevens-Johnson Syndrome,
penicillin allergy, or history of any severe drug allergic reaction; History of
systemic autoimmune disease such as lupus erythematosis, fibromyalgia, or rheumatoid
arthritis;

- Current blood dyscrasia or a history of such, with the exception of a past history of
iron deficiency anemia

- History of seizure disorder

- Use of any of a number of medications that might prominently influence drinking
patterns or cause risk of harm or injury (e.g., topiramate, disulfiram, naltrexone,
acetazolamide, stimulants such as amphetamine, or tramadol; Schizophrenia, bipolar
disorder, PTSD, or substantial suicide or violence risk (i.e., can't be managed safely
in the outpatient setting) on the basis of history or psychiatric examination; j)
currently dependent on opioids or benzodiazepines or other sedatives

- Considered by the investigators to be clinically inappropriate for study participation
or have participated in another pharmacotherapy study in the past thirty days

- Subjects with prominent signs of physical dependence, and/or medical comorbidities
such that study physicians feel they should consider immediate detoxification, and
referred for medical detoxification in a normal treatment setting