Effect of LY686017 on Alcohol Craving
Condition: Alcohol Dependence; Alcoholism
MeSH terms: Alcoholism
Study type: Interventional
Phase: Phase 2

Summary: 
      This study will determine whether the experimental drug LY686017 can reduce a person's desire
      for alcohol. A brain chemical called Substance P acts at places in the brain called NK1
      receptors. Substance P is released in response to stress and gives rise to behaviors that are
      thought to represent anxiety. LY686017 blocks Substance P from acting at the NK1 receptors.

      People between 21 and 65 years of age who have been drinking on a regular basis for at least
      one month before entering the study, who meet the criteria for alcohol dependence and who
      have an elevated score on a general test of anxiety may be eligible for this study.

      Participants are admitted to the NIH Clinical Center for 35 days. They participate in an
      alcohol treatment program in addition to the research study. After having been withdrawn from
      alcohol for at least 2 days, participants receive either 50 mg of LY686017 or placebo (an
      inactive substance that looks like the study drug) every morning for 28 days. In addition to
      drug treatment, they undergo the following procedures:

        -  Functional magnetic resonance imaging (fMRI): In the last week of the study, subjects
           undergo MRI to study the amount of blood going to brain structures thought to be
           involved in anxiety and craving. During the procedure, they look at pictures of faces
           exhibiting various emotions and pictures related to alcohol.

        -  Cue reactivity: At the beginning and towards the end of the study, subjects are asked to
           rate their alcohol craving and their anxiety level while they sniff and handle their
           favorite alcoholic beverage or water.

        -  Metyrapone test: During weeks 1 and 4 of the study, subjects are given metyrapone - a
           drug that interferes with the body's ability to make the stress hormone cortisol - to
           determine how LY686017 affects the body's hormonal response. The drop in cortisol from
           metyrapone administration causes the brain to release ACTH, a hormone that causes the
           adrenal gland to make cortisol.

        -  Trier test: In the last week of the study, subjects give a 5-minute speech to three
           people and are then asked to subtract numbers in their head. Then they are asked to rate
           their feelings and desire for alcohol on two rating scales. Blood is drawn from a saline
           lock at the beginning and end of the test to measure hormone levels.

        -  Rating scales: Subjects complete an Obsessive Drinking Scale weekly and an Alcohol Urge
           Questionnaire and Comprehensive Psychiatric Rating Scale twice a week.

        -  Blood tests: Blood samples are collected periodically to check blood chemistries,
           clotting time, and the amount of LY686017 in the blood.
    

Detailed description: 
      Background:

      Alcoholism is a chronic relapsing disorder characterized by cycles of intoxication
      interspersed with phases of withdrawal and abstinence. Co-morbidity with depression and
      anxiety disorders is high. Even in absence of independent psychiatric co-morbidity, anxiety
      symptoms are almost invariably present during early as well as protracted abstinence,
      sensitized over repeated cycles of intoxication and withdrawal, and are correlated with
      craving for alcohol upon exposure to alcohol associated cues. This psychopathology is likely
      to maintain the dependent state since it has been shown that stress and negative affective
      states are major relapse triggering factors. Substance P, released in the amygdala in
      response to stress, acts at NK1 receptors as an important mediator of behavioral stress
      effects in experimental animals. Blockade of this receptor subtype represents a novel
      principle for anxiolytic like actions, which is well documented in animal models and has some
      supportive data in humans. Furthermore, decreased opiate reward following NK1 receptor
      inaction is indicated by the reports that deletion of the NK1 receptor decreases both
      conditioned place preference and self-administration of opiates, while a similar reduction of
      alcohol reward is suggested by preliminary data showing decreased voluntary intake of alcohol
      in NK1 null-mutants.

      Aims:

      The present study is aimed at providing an initial, exploratory evaluation of whether the NK1
      receptor is a candidate target for treatment of alcohol dependence that would merit further
      clinical development in conventional, full-scale clinical trial designs. To evaluate this,
      the aim of the present study is to determine whether NK1 antagonism can beneficially affect,
      in anxious alcohol dependent subjects during early abstinence, surrogate variables correlated
      with clinical outcomes, i.e.

        -  reduce craving for alcohol, measured as baseline self-reported urges, or in response to
           presentation of alcohol associated cues

        -  reduce negative affect

        -  influence corresponding objective measures (brain fMRI responses to alcohol-associated
           cues and to fear stimuli, respectively; and endocrine stress responses).

      This study will address this aim using a novel, orally bioavailable and brain penetrant NK1
      antagonist. Positive data in this exploratory study would be the first of their kind, and
      provide a rationale for evaluating the NK1 antagonist for anti-craving / anti-dipsotropic and
      anti-anxiety actions in alcohol dependent subjects in a longer term, suggesting that it might
      aid relapse prevention.

      Methods:

      The study will be carried out in 50 subjects aged 21-65 years, with alcohol dependence as
      their primary complaint, and without other serious medical or psychiatric conditions. An
      additional inclusion criterion will be the presence or history of significant anxiety
      symptoms on self report. Subjects will be admitted to the NIAAA research inpatient unit at
      the NIH Clinical Center through a platform training and natural history protocol which
      provides basic assessments and standard withdrawal treatment if needed. Patients will enter
      into the present protocol once such treatment, if needed, is completed. The present protocol
      will be started with a 1 week single blind placebo lead-in. During this phase, a baseline
      alcohol cue-reactivity session will be carried out according to established procedures, and
      urges to drink will be assessed. Cue-responsive subjects only, appr. 70% of alcohol dependent
      inpatients, will be randomized to active treatment or placebo, and enter the active treatment
      phase. The active treatment arm will receive 50 mg once daily of LY686017by oral intake,
      while the placebo group will continue to receive placebo in a double-blind fashion. The
      duration of active treatment will be 3 weeks.

      Patients will remain hospitalized throughout this protocol. During this period, no
      psychotropic medication will be allowed, and abstinence from alcohol and other drugs will be
      monitored. Measures of craving will be obtained using: 1) ratings completed twice a week on
      the established Alcohol Urge Questionnaire (AUQ); 2) assessments of urge to drink (at
      baseline and under medication) during an established cue reactivity paradigm during which
      each patient undergoes an invivo exposure to his or her preferred alcoholic beverage. The
      medicated cue reactivity session will follow immediately after the Trier Test, a social
      stress task that independently induces urges for alcohol (stress induced craving); and
      augments subsequent cue-induced urges (stress-potentiated cue induced craving); 3) weekly
      assessment of alcohol related cognitions using the Obsessive Drinking Scale (ODS), a
      pharmacologically validated subscale of the established Obsessive Compulsive Drinking Scale
      (OCDS). In addition, measures of anxiety and depression symptoms will be obtained
      twice-weekly using the Comprehensive Psychiatric Rating Scale (CPRS). During the last
      treatment week, subjects will undergo an fMRI scan using established paradigms to evoke
      emotional responses, and to evoke alcohol-cue associated responses, respectively.
      Psychophysiological measures will be obtained in conjunction with the scan. Blood draws will
      be carried out on the day of the scan to allow for analysis of plasma concentrations of the
      experimental drug. The neuroendocrine stress response will be probed, using the standard
      metyrapone challenge test, in unmedicated state following the baseline CR session, and then
      again under active treatment or placebo following the fMRI scan.
    

Intervention name(s): LY686017; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 50 mg administered orally on a daily basis; Administered on a daily basis
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Anxiety; Alcohol Dependence; Alcoholism