A New Pharmacotherapy for Alcohol Dependence: Olanzapine
Condition: Alcohol Dependence
MeSH terms: Alcoholism
Study type: Interventional
Phase: Phase 3

Summary: 
      Craving for alcohol has been related to loss of control drinking and is a major target of
      biological and behavioral interventions for alcohol dependence. Our previous research has
      demonstrated that olanzapine (a dopamine antagonist) attenuates craving for alcohol, that a
      variant in the gene that expresses D4 receptors influences craving for alcohol, and that
      olanzapine is particularly effective at reducing craving among individuals with this variant.
      Pilot data from a recent 12 week trial of olanzapine indicates that olanzapine is well
      tolerated and that olanzapine reduces drinking, particularly among individuals with the
      aforementioned genetic variant. The objective of the present application is to examine the
      effectiveness of olanzapine (5 mg/day), as compared to olanzapine (2.5 mg/day) and a placebo
      control, in terms of reducing craving and alcohol use behavior among treatment seeking
      alcoholics. Furthermore, the present application will examine whether the effects of
      olanzapine on drinking outcomes are mediated by its effects on a specific putative mechanism
      (i.e., cue-elicited craving for alcohol) and determine whether the DRD4 VNTR polymorphism is
      a marker for the effectiveness of olanzapine. To that end, 202 alcohol dependent subjects
      will be randomly assigned to medication group and receive 12 weeks of medication. Subjects
      will complete follow-up assessments at 3 and 6 months after the end of the treatment. It is
      expected that olanzapine will significantly reduce cue-elicited craving and alcohol use
      behavior in a dose dependent fashion over the course of the 12 week trial and follow-up
      period, as compared to the placebo condition. Furthermore, it is expected that the effects of
      olanzapine on alcohol use behavior will be mediated by the effect of olanzapine on
      cue-elicited craving and that the effects of olanzapine on cue-elicited craving and alcohol
      use behavior will be moderated by the DRD4 VNTR, such that olanzapine will be more effective
      among individuals with the 7 repeat allele. The successful completion of the proposed
      research is expected to advance a new medication for alcohol dependence and advance genetic
      markers that predict the effectiveness of this medication.
    

Detailed description: 
      The first goal of the study is to determine whether olanzapine is effective at reducing
      cue-elicited craving (i.e., subjective craving as well as activation of the midbrain and
      prefrontal cortex after exposure to alcohol cues) for alcohol and reducing alcohol use in a
      sample of alcohol dependent subjects. The second goal is to test the putative mechanism of
      change by determining whether the effect of olanzapine on alcohol use behavior is mediated by
      the effect of olanzapine on cue-elicited craving. The final goal will be to examine whether
      genetic differences moderate the effects of olanzapine. [The polymorphism examined here
      involves the D4 dopamine receptor gene (DRD4), which has a variable number of tandem repeats
      (VNTR) in exon 3 (Van Tol et al., 1992). With respect to the DRD4 VNTR, individuals with at
      least one copy of an allele with 7 or more repeats are hereafter referred to as DRD4 L
      individuals, and individuals with alleles that have fewer than 7 repeats are hereafter
      referred to as DRD4 S individuals.]

      In addition to laboratory studies on dopamine antagonists and alcohol craving (e.g., Modell
      et al., 1993; Hutchison et al., 2001), recent clinical reports have suggested that clozapine,
      a potent D4 receptor antagonist, reduces substance abuse among individuals with comorbid
      substance abuse/dependence (Green et al., 1999; Zimmet et al., 2000; Lee et al, 1998) and
      specifically, alcohol use (Drake et al., 2000). Animal studies have also suggested that
      clozapine reduces the voluntary intake of nicotine (Kameda et al., 2000). Given some of these
      early findings, we conducted a laboratory test of the effects of olanzapine on cue-elicited
      craving and craving after alcohol consumption among heavy social drinkers (Hutchison et al.,
      2001). We decided to test olanzapine because it also targets the D4 receptor, although not as
      strongly as clozapine, and because olanzapine had the best side effect profile among FDA
      approved medications that target dopamine receptors more broadly, and the D4 more
      specifically. This initial test demonstrated that olanzapine attenuated the effects of
      alcohol cues on two separate measures of urge to drink across two separate experimental
      sessions and that olanzapine prevented increases in urge to drink after alcohol consumption.
      With respect to the effects on urge to drink, the findings of this study are generally
      consistent with the theoretical premise that this appetitive behavior is partially mediated
      by mesolimbic dopamine activation.

      To replicate and extend our previous results with olanzapine, a second study was designed to
      examine whether olanzapine (5 mg) reduced craving as compared to cyproheptadine (4 mg), which
      was used as an active control medication. It is important to note that there are no other
      published studies (to our knowledge) that have used such a stringent experimental control in
      a test of a pharmacological agent that targets alcohol craving in humans. For example,
      previous studies with naltrexone have utilized a placebo control only. The results from this
      investigation indicated that olanzapine and cyproheptadine produced equivalent levels of
      sedation. However, olanzapine significantly reduced craving before and after consuming
      alcohol, as compared to cyproheptadine (Hutchison et al., 2003). Moreover, there was a
      significant medication by DRD4 VNTR polymorphism interaction such that olanzapine reduced
      alcohol-elicited craving, particularly among DRD4 L individuals. To extend these findings, we
      conducted a 12 week, randomized, double-blind trial of olanzapine in the treatment of alcohol
      dependence (Hutchison et al., in press). Consistent with our previous studies, the results
      suggested that olanzapine reduced cue elicited craving and alcohol consumption significantly
      among DRD4 L individuals, but not DRD4 S individuals. Both of these last two studies were
      conducted at the Boulder GCRC.

      Here, a double-blind, placebo-controlled 3 (Medication: olanzapine 5 mg, olanzapine 2.5 mg,
      vs. placebo) x 7 (Time: Baseline, 2, 4, 8, 12, 24, 36 weeks) mixed factorial design, where
      medication is a between-subjects factor and time is a within-subjects factor, will be used to
      test the treatment outcome hypotheses. Subjects will be randomly assigned to receive either
      olanzapine (5 mg), olanzapine (2.5 mg), or placebo for a period of 12 weeks such that there
      are equal numbers of DRD4 L individuals in each medication group. All subjects will also
      receive 7 sessions of medication management / supportive therapy (detailed below). Follow-up
      assessments will be obtained at 4, 8, 12 weeks (the end of treatment), 24 weeks, and 36
      weeks.
    

Intervention name(s): 2.5 mg Olanzapine; 5mg Olanzapine; placebo
Intervention type(s): Drug; Drug; Drug
Intervention description(s): 2.5 mg; 5 mg; placebo
Intervention MeSH terms: Olanzapine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Olanzapine