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
Study type: Interventional
Phase: Phase 2

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.
    

Detailed description: 
      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 NlAAA 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 approximately 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. An fMRI session will be carried out
      during week 4 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 change in craving for 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 cue challenge session,
      spontaneous craving and PTSD symptoms during hospitalization, and brain responses on the fMRI
      session. Changes in PTSD symptoms and change in craving 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.
    

Intervention name(s): Aprepitant; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 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
Other intervention name(s): Emend
Intervention MeSH terms: Aprepitant
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: Alcohol Dependence; Alcohol Treatment; Alcoholics; Alcoholism; Posttraumatic Stress Disorder; PTSD