Aripiprazole and Topiramate on Free-Choice Alcohol Use
Condition: Alcohol Dependence
MeSH terms: Alcoholism
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      The current study investigates the effects of two potential alcohol treatment medications on
      drinking in a laboratory setting. Aripiprazole (APZ), effects dopamine and serotonin
      receptors with fewer limiting side effects seen with other atypical antipsychotics.
      Topiramate (TPMT), an antiepileptic, affects glutamate and GABA-A receptors and shows promise
      in reducing heavy drinking. Few studies have used two medications with such a diverse
      combination of actions to examine a potential synergistic effect on reducing alcohol
      consumption.

      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 a laboratory based alcohol
           self-administration experiment (ASAE)

        2. examine a hypothesized dose-response for three doses of APZ (0, 7.5 mg/d and 15 mg/d)
           along with three doses of TPMT (0, 100mg/d and 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

        4. establish the safety of giving APZ and TPMT together. Non-treatment seeking, alcohol
           dependent Participants (N=216) will be recruited from the community and randomly
           assigned to one of the 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.
    

Detailed description: 
      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.
    

Intervention name(s): Double Placebo; Aripiprazole 15, placebo; Aripiprazole 7.5, Placebo; Topiramate 100, Placebo; Topiramate 200, Placebo; Topiramate 100, Aripiprazole 15; Topiramate 100, Aripiprazole 7.5; Topiramate 100, Aripiprazole 15mg; Topiramate 200, Aripiprazole 7.5mg; Topiramate 200, Aripiprazole 15
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): 1 capsule daily; 15 mg Aripiprazole daily plus placebo daily; Aripiprazole 7.5 mg daily plus Placebo daily; Topiramate 100 mg daily plus Placebo daily; Topiramate 200 mg daily plus Placebo daily; Topiramate 100 mg daily plus Aripiprazole 15mg daily; Topiramate 100 mg daily plus Aripiprazole 7.5mg daily; Topiramate 100 mg daily plus Aripiprazole 15mg daily; Topiramate 200 mg daily plus Aripiprazole 7.5mg daily; Topiramate 200mg daily plus Aripiprazole 15mg daily
Other intervention name(s): Abilify, Topamax; Abilify, Topamax; Abilify; Topamax; Abilify; Topamax; Abilify; Topamax
Intervention MeSH terms: Topiramate; Aripiprazole
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Alcohol dependence; alcohol abuse; topiramate; aripiprazole