The Effect of NK1R Antagonism on Alcohol Craving and PTSD Symptoms in Alcohol Dependent Patients With PTSD
Condition: Alcoholism; Alcohol Dependence; Posttraumatic Stress Disorder
MeSH terms: Alcoholism; Stress Disorders, Traumatic; Stress Disorders, Post-Traumatic
Intervention: Aprepitant; Placebo
Intervention description: Aprepitant is a neurokinin 1 receptor antagonist shown to have anti-stress actions in preclinical studies, and antidepressant efficacy in human clinical trials; Non-active placebo
Intervention MeSH terms: Aprepitant
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 58.0
Sex: All
Minimum age: 21 Years
Maximum age: 50 Years
Healthy volunteers: No
Keywords: Alcohol Dependence; Alcohol Treatment; Alcoholics; Alcoholism; Posttraumatic Stress Disorder; PTSD

Summary:

      Objective:

      Alcoholism is highly co-morbid with post traumatic stress disorder (PTSD). Since stress and
      negative affective states are major relapse triggering factors for alcohol use, the negative
      symptoms associated with PTSD are thought to promote alcohol dependence. Substance P, which
      is released in the amygdala in response to stress, acts at NK1 receptors (NK1Rs) to mediate
      behavioral stress responses. Blockade of the NK1R represents a novel approach for anti-stress
      actions. In a recent double blind, placebo controlled study involving detoxified anxious
      alcoholics, we found that NK1R antagonism decreased alcohol cravings, attenuated cortisol
      response to stress, and significantly decreased insula activation in response to negative
      sensory input. The present study is intended to expand the findings and determine whether the
      NK1R is a candidate target for treating alcohol dependent patients with PTSD.

      Study Population:

      On hundred twenty participants with PTSD and co-morbid alcohol dependence will be recruited
      and stratified by PTSD etiology (60 participants each with civilian and combat PTSD, resp).
      Within each stratum, the treatment groups will be balanced for sex using urn randomization.
      Stratification is indicated since civilian and combat-related PTSD can theoretically have a
      different pathophysiology. Civilians typically experience a single trauma exposure of
      invariably high magnitude, resulting in symptoms immediately. Combat-related PTSD typically
      results from multiple traumatic exposures over a prolonged period of time, of variable
      magnitude, and frequently with delayed emergence of symptoms.

      Design:

      Participants will be admitted to the National Institute on Alcohol Abuse and Alcoholism
      (NIAAA) research inpatient unit at the NIH Clinical Research Center (CRC) under protocol
      number 05-AA-0121 for assessment and treatment of people with alcohol drinking problems,
      which provides diagnostic assessments and standard withdrawal treatment if needed.
      Participants will enter into the present protocol once such treatment, if needed is
      completed. Following inclusion, all participants will receive 1 week of single blind placebo,
      and will then be randomized to double blind treatment with aprepitant or placebo. Randomized
      treatment will be for 3 weeks. Spontaneous cravings for alcohol, and ratings of
      psychopathology will be obtained twice weekly on the inpatient unit throughout the study.
      Cravings as well as endocrine and immune responses will also be assessed in a challenge
      session that combines a social stressor and exposure to physical alcohol cues. During the
      final week, three sessions utilizing scripts will be carried out, on separate days in
      counter-balanced order, exposing the participant to personalized trauma, alcohol-associated
      or neutral stimuli. Cravings as well as endocrine and immune responses will also be assessed
      during the script presentations. A functional magnetic resonance imaging (fMRI) session will
      be carried out last to assess responses to affective stimuli. Participants will remain
      hospitalized throughout the study, and will remain on the unit for a three day
      post-medication monitoring period.

      Outcome Measures:

      The primary outcome will be craving alcohol and changes in PTSD symptoms resulting from the
      script sessions. Secondary outcomes will include cravings and changes in PTSD symptoms
      resulting from the combined social stress-alcohol cure challenge session, spontaneous craving
      and PTSD symptoms during hospitalization, and brain responses on the fMRI session. Changes in
      PTSD symptoms and cravings for alcohol are intended to be surrogate markers for the overall
      effect of the drug treatment and are not intended to represent global improvement for either
      PTSD or alcoholism.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

          -  Alcohol-dependent patients with a diagnosis of PTSD.

          -  Ages 21 - 50.

          -  Right-handed.

          -  Meet the Diagnostic and Statistical Manual (DSM)-IV diagnostic criteria for alcohol
             dependence (poly-substance abuse is common in younger alcohol-dependent patients and
             will not be exclusionary) and PTSD.

          -  Alcohol use within the last month.

          -  Females of childbearing potential must agree to use a reliable method of birth control
             during the study. Reliable methods of birth control include barrier methods such as
             diaphragms with contraceptive jelly, cervical caps with contraceptive jelly, condoms
             with contraceptive foam, or intrauterine devices; a partner with a vasectomy; or
             abstinence from intercourse. Hormonal contraceptives are not adequate in this study,
             because the study drug can render them less effective.

        EXCLUSION CRITERIA:

          -  Individuals who present with complicated medical problems requiring intensive medical
             or diagnostic management.

          -  Individuals who are infected with the Human Immunodeficiency Virus (HIV).

          -  Individuals with serious neuro-psychiatric conditions which impair judgment or
             cognitive function to an extent that precludes them from providing informed consent or
             complying with treatment, such as psychotic illness or severe dementia (incompetent
             individuals).

          -  Individuals who are evaluated and judged by a board certified psychiatrist to be
             either severely depressed or an imminent risk for suicide, violence, or impulsive
             behavior, such as self-purging.

          -  Individuals who are unlikely or unable to complete the treatment program because they
             are likely to be incarcerated while on the protocol.

          -  Individuals who are required to receive treatment by a court of law or who are
             involuntarily committed to treatment.

          -  Pregnancy or lactation (negative pregnancy test required).

          -  A history of seizures, other than documented febrile seizures.

          -  Individuals currently using psychotropic medications will not be eligible for
             participation in the protocol if they are either unwilling or unable, for medical
             reasons, to be removed from their medication during hospitalization.

          -  Individuals in whom aprepitant is contraindicated because they take medications that
             can interact with this drug. Specifically, aprepitant should not be used concurrently
             with pimozide, terfenadine, astemizole, or cisapride. Dose-dependent inhibition of
             cytochrome P450 isoenzyme 3A4 (CYP3A4) by aprepitant could result in elevated plasma
             concentrations of these drugs, potentially causing serious or life-threatening
             reactions

          -  Inability or unwillingness to participate in an fMRI scan, including presence of
             metallic objects in the body that would interfere with the scan or pronounced
             claustrophobia.