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

NCT ID: NCT00896038

Last Updated: 2015-11-03

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 58 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-05-31
• Study Completion Date: 2014-08-31

Brief 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.

Conditions

Alcoholism; Alcohol Dependence; Posttraumatic Stress Disorder

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Aprepitant

Following a 1-week placebo lead-in period subjects were given 125 mg of Aprepitant orally daily for 21 days

Group Type: EXPERIMENTAL

Aprepitant

Intervention Type: DRUG

Aprepitant is a neurokinin 1 receptor antagonist shown to have anti-stress actions in preclinical studies, and antidepressant efficacy in human clinical trials

Placebo

Subjects received oral placebo during the 1-week placebo lead-in and then daily for 21 days

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Non-active placebo

Interventions

Aprepitant

Aprepitant is a neurokinin 1 receptor antagonist shown to have anti-stress actions in preclinical studies, and antidepressant efficacy in human clinical trials

Intervention Type: DRUG

Placebo

Non-active placebo

Intervention Type: DRUG

Other Intervention Names

Emend

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.

• Minimum Eligible Age: 21 Years
• Maximum Eligible Age: 50 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

David T George, M.D.

Role: PRINCIPAL_INVESTIGATOR

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Locations

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, United States

Countries

United States

References

Andrews B, Brewin CR, Philpott R, Stewart L. Delayed-onset posttraumatic stress disorder: a systematic review of the evidence. Am J Psychiatry. 2007 Sep;164(9):1319-26. doi: 10.1176/appi.ajp.2007.06091491.

Reference Type: BACKGROUND

PMID: 17728415 (View on PubMed)

Asberg M, Schalling D. Construction of a new psychiatric rating instrument, the Comprehensive Psychopathological Rating Scale (CPRS). Prog Neuropsychopharmacol. 1979;3(4):405-12. doi: 10.1016/0364-7722(79)90055-9.

Reference Type: BACKGROUND

PMID: 400996 (View on PubMed)

Bergstrom M, Hargreaves RJ, Burns HD, Goldberg MR, Sciberras D, Reines SA, Petty KJ, Ogren M, Antoni G, Langstrom B, Eskola O, Scheinin M, Solin O, Majumdar AK, Constanzer ML, Battisti WP, Bradstreet TE, Gargano C, Hietala J. Human positron emission tomography studies of brain neurokinin 1 receptor occupancy by aprepitant. Biol Psychiatry. 2004 May 15;55(10):1007-12. doi: 10.1016/j.biopsych.2004.02.007.

Reference Type: BACKGROUND

PMID: 15121485 (View on PubMed)

Kwako LE, Spagnolo PA, Schwandt ML, Thorsell A, George DT, Momenan R, Rio DE, Huestis M, Anizan S, Concheiro M, Sinha R, Heilig M. The corticotropin releasing hormone-1 (CRH1) receptor antagonist pexacerfont in alcohol dependence: a randomized controlled experimental medicine study. Neuropsychopharmacology. 2015 Mar 13;40(5):1053-63. doi: 10.1038/npp.2014.306.

Reference Type: DERIVED

PMID: 25409596 (View on PubMed)

Other Identifiers

09-AA-0136

Identifier Type: OTHER

Identifier Source: secondary_id

090136

Identifier Type: -

Identifier Source: org_study_id