Aripiprazole and Topiramate on Free-Choice Alcohol Use

Due to the modest effect of current pharmacotherapies, more effective treatments must be
developed to optimally treat alcohol dependent patients. Treatments combining
pharmacotherapies with different mechanisms of action may better address the diverse
neurobiology of alcohol and the heterogeneity of alcoholics. However, little is known about
how medication may affect behavior to reduce drinking. Aripiprazole (APZ), a partial
dopamine agonist, affects dopamine and serotonin receptors without the limiting side effects
seen with other atypical antipsychotics. Dopamine mediates reward based drinking and
craving. Topiramate (TPMT), an antiepileptic, affects glutamate and GABA-A receptors and
shows promise in reducing heavy drinking. Glutamate and GABA may mediate relief-based
drinking and protracted withdrawal. Despite strong evidence that multiple neurotransmitters
contribute to alcoholism, few studies have used two medications with such a diverse
combination of actions to examine a potential synergistic effect on reducing alcohol
consumption.

The present study will recruit 216 healthy, alcohol-dependent volunteers who are not
currently seeking treatment for their alcohol dependence to learn more about how these
medications may work.

The primary aims are to: (1) determine if APZ and TPMT are each more effective than placebo,
and the combination of APZ and TPMT is more effective than either drug alone or placebo, in
reducing alcohol use in non-treatment seeking alcohol dependent subjects in an alcohol self
administration experiment (ASAE); (2) examine a hypothesized dose-response for three doses
of APZ (0, 7.5mg/d and 15 mg/d) and three doses of TPMT (0, 100mg/d, 200mg/d); (3) examine
the putative mechanisms of action of APZ, TPMT alone and together on craving, subjective
stimulation, candidate gene influences and other behavioral effects associated with alcohol
consumption; and (4) establish the safety of giving APZ and TPMT together. We will use of a
3 X 3 drug (7.5mg, 15mg APZ vs. placebo) by drug (100mg, 200mg TPMT vs. placebo)
between-subjects factorial design. Participants are randomly assigned to one of 9 cells.
Subjects drinking and safety is monitored over a 5-week titration to their target dose,
leading to an in-laboratory alcohol self administration session, during which clinical and
behavioral effects are assessed during access to alcohol. A 1 month follow-up assesses
adverse events and drinking. The long term objectives of this research are to improve
medications available for alcoholism treatment and inform research and theory on the
mechanisms of action of such medications.

Inclusion Criteria:

- must be non-treatment seeking for alcohol dependence

- a current DSM-IV-TR diagnosis of alcohol dependence supported by the Structured
Clinical Interview for DSM-IV-TR Axis I Disorders Patient Edition (SCID-I/P a minimum
of ≥ 35drinks a week for men or ≥ 28 or more drinks a week for women

- must be suitable for outpatient treatment

- able to read English at an eighth grade level, understand their rights as provided by
the informed consent, and be willing to sign an informed consent to participate in
the study

- be between 21 and 65 years on age (inclusive)

- provide evidence of stable residence in the two months prior to enrollment and no
plans to move for the next four months

- provide a verifiable contact person prior to randomization

- be in generally good health as determined by the physical exam, medical history, ECG
and laboratory tests

- have a Body Mass Index >18kg/m2 and < 33 kg/m2

- if female, must be postmenopausal practicing an effective method of birth control,
have negative pregnancy tests at randomization and before the ASAE;

- be willing to be adherent to medication dosing.

Exclusion Criteria:

- clinically significant medical abnormalities (i.e. ECG, hematological assessment,
bilirubin > 150% of the upper limit of normal or ALT or AST elevations >300% the
upper limit of normal, biochemistry including urinalysis, electrolytes,). (Persons
with medical conditions that are adequately controlled by their primary care
physician will not be excluded.)

- have significant alcohol withdrawal symptoms (clinical institute withdrawal
assessment for alcohol revised (CIWA-Ar) >10

- a history of suicide; history of renal impairment or nephrolithiasis; creatinine
clearance of <60 dl/minute

- pregnant or lactating or not using an adequate form of birth control

- taking other medications that may have an effect on alcohol consumption or are
carbonic anhydrase inhibitors

- clinically significant diseases of the gastrointestinal system or active liver
disease; subjects compelled to receive treatment to avoid imprisonment or loss of
employment

- previously with a history of adverse reaction or hypersensitivity to either
Topiramate or aripiprazole

- have a diagnosis of with schizophrenia or bipolar disorder and/or taking
antipsychotics and other drugs that inhibit CYP3A4 or CYP2D6 isoenzymes

- history of seizures (e.g. epilepsy)

- patients currently diagnosed with a substance dependence diagnosis other than alcohol
or tobacco

- patients who have participated in any clinical trial with an investigational agent
within the past 30 days

- individuals with a reasonable expectation of being institutionalized during the
course of the trial or pending legal charges

- pregnant or nursing women.