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.
