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The neurokinin-1 receptor antagonist aprepitant in co-morbid alcohol dependence and posttraumatic stress disorder: a human experimental study

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Abstract

Rationale

Posttraumatic stress disorder (PTSD) and alcoholism are frequently comorbid, suggesting the possibility of overlapping neural substrates. The neurokinin 1 (NK1) receptor for substance P (SP) has been implicated in both stress- and alcohol-related behaviors. The NK1 antagonist aprepitant, clinically available as a treatment for chemotherapy-induced nausea, offers a tool to probe a potential role of the SP/NK1 system in comorbid PTSD and alcoholism.

Objectives

The aim of this study is to evaluate the efficacy of aprepitant for treatment of comorbid PTSD and alcoholism.

Methods

Fifty-three patients with PTSD and alcoholism were admitted for 4 weeks to an inpatient unit at the NIH Clinical Center and randomized to double-blind aprepitant (125 mg/day; based on PET studies reporting >90 % central receptor occupancy at this dose) or placebo. After reaching steady state, subjects were assessed for PTSD symptom severity, behavioral and neuroendocrine responses to stress and alcohol cues, and functional magnetic resonance imaging (fMRI) responses to stimuli with positive or negative emotional valence.

Results

Aprepitant treatment had no effect on PTSD symptoms or subjective or physiological responses to stress or alcohol cues. However, aprepitant robustly potentiated ventromedial prefrontal cortex (mPFC) fMRI responses to aversive visual stimuli.

Conclusions

Despite the lack of effect on PTSD symptoms and responses to stress/alcohol cues, NK1 antagonism activated the ventral mPFC, an area considered hypoactive in PTSD, during exposure to aversive stimuli. Because this brain area is critically important for extinction of fear memories and in alcohol craving and relapse, our finding suggests that NK1 antagonism might be a useful pharmacological treatment to enhance extinction-based cue-exposure therapies.

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Acknowledgments

This work was carried out under a Clinical Trial Agreement (CTA) between the US Government and Merck & Company, Incorporated. Merck had no role in study design, collection, analysis or interpretation of the data, or drafting of the manuscript. We thank the following individuals and departments: Lauren Adams, Joanna Sells, Jessica Berman, Eric Markey, Victoria Brown, Keva Garg, and Byung Joon Park; Debra Hill, Cheryl Jones, and Monte Phillips; and James Paterson, Judie Jones, Mary Ley, Jacqueline Goodson, and the 1SE nursing staff of the NIH Clinical Center.

Conflict of interest

Drs. Kwako, George, Schwandt, Spagnolo, Momenan, Hommer, Shaham, and Heilig, as well as Ms. Diamond, declare no competing financial interests. Dr. Sinha is a member of the Embera Neurotherapeutics Scientific Advisory Board. This research was supported by the Division of Intramural Clinical and Biological Research, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health.

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Authors and Affiliations

  1. Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 10 Center Drive, 1-3330, Bethesda, MD, 20892-1108, USA

    Laura E. Kwako, David T. George, Melanie L. Schwandt, Primavera A. Spagnolo, Reza Momenan, Daniel W. Hommer, Christine A. Diamond & Markus Heilig

  2. Department of Psychiatry, The Yale Stress Center, Yale University School of Medicine, New Haven, CT, 06519, USA

    Rajita Sinha

  3. Behavioral Neuroscience Branch, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, USA

    Yavin Shaham

Authors
  1. Laura E. Kwako
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  2. David T. George
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  3. Melanie L. Schwandt
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  4. Primavera A. Spagnolo
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  5. Reza Momenan
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  6. Daniel W. Hommer
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  7. Christine A. Diamond
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  8. Rajita Sinha
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  9. Yavin Shaham
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  10. Markus Heilig
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Corresponding author

Correspondence to Laura E. Kwako.

Additional information

Laura E. Kwako and David T. George contributed equally to this work.

Daniel W. Hommer—deceased.

Electronic supplementary material

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Supplementary Figure 1

Timeline of challenge procedures. Graphical representation of Trier/CR and Script procedures. The numbers represent minutes, i.e., in relation to the initiation of the procedure. S = scales, B = blood samples, V = vital signs. (GIF 26 kb)

High resolution image (TIFF 2127 kb)

Supplementary Figure 2

Cortisol response to challenge procedures. Due to missing data for cortisol levels, the sample sizes are reduced for these analyses. A) Effect of script type on cortisol levels. Covariates in the model included gender, ADS score, and total score from the ASI. B) Effect of aprepitant treatment on cortisol levels in response to the alcohol cue script. Covariates in the model included gender, ADS score, and total score from the ASI. C) Effect of aprepitant treatment on cortisol levels in response to the stress script. Covariates in the model included gender, ADS score, and total score from the ASI. D) Effect of aprepitant treatment on cortisol levels in response to the Trier/CR. Covariates in the model included gender, race, ADS score, and neuroticism. (GIF 87 kb)

High resolution image (TIFF 4736 kb)

Supplementary Figure 3

ACTH response to challenge procedures. Due to missing data for ACTH levels, the sample sizes are reduced for these analyses. A) Effect of script type on ACTH levels. Covariates in the model included gender, number of heavy drink days, total score from the CTQ, and total score from the ASI. B) Effect of aprepitant treatment on ACTH levels in response to the alcohol cue script. Covariates in the model included gender, age, overall PSSI severity score, CTQ total score, and total score from the ASI. C) Effect of aprepitant treatment on ACTH levels in response to the stress script. Covariates in the model included gender. D) Effect of aprepitant treatment on ACTH levels in response to the Trier/CR. Covariates in the model included gender and number of heavy drink days. (GIF 101 kb)

High resolution image (TIFF 4782 kb)

Supplementary Table 1

Reported side effects. This table includes side effects reported by participants, organized by group. Data are reported for all subjects for 10 side effects, and eight additional side effects are reported for a subset of participants. These side effects were added to those collected part-way through the study, which accounts for the reduced sample size. (DOCX 60 kb)

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Kwako, L.E., George, D.T., Schwandt, M.L. et al. The neurokinin-1 receptor antagonist aprepitant in co-morbid alcohol dependence and posttraumatic stress disorder: a human experimental study. Psychopharmacology 232, 295–304 (2015). https://doi.org/10.1007/s00213-014-3665-4

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