The Effect of NK1R Antagonism on Alcohol Craving and PTSD Symptoms in Alcohol Dependent Patients With PTSD



Status:Completed
Conditions:Psychiatric
Therapuetic Areas:Psychiatry / Psychology
Healthy:No
Age Range:21 - 50
Updated:4/21/2016
Start Date:May 2009
End Date:August 2014

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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.

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.

- 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.
We found this trial at
1
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Bethesda, Maryland 20892
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from
Bethesda, MD
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