The Effect of NK1R Antagonism on Alcohol Craving and PTSD Symptoms in Alcohol Dependent Patients With PTSD
Status:
Completed
Trial end date:
2014-08-01
Target enrollment:
Participant gender:
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.
Phase:
Phase 2
Details
Lead Sponsor:
National Institute on Alcohol Abuse and Alcoholism (NIAAA)