title: The neurokinin-1 receptor antagonist aprepitant in co-morbid alcohol dependence and posttraumatic stress disorder: a human experimental study.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
authors.affiliation: 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.kwako@nih.gov.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Kwako
authors.forename: David T
authors.initials: DT
authors.lastname: George
authors.forename: Melanie L
authors.initials: ML
authors.lastname: Schwandt
authors.forename: Primavera A
authors.initials: PA
authors.lastname: Spagnolo
authors.forename: Reza
authors.initials: R
authors.lastname: Momenan
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Hommer
authors.forename: Christine A
authors.initials: CA
authors.lastname: Diamond
authors.forename: Rajita
authors.initials: R
authors.lastname: Sinha
authors.forename: Yavin
authors.initials: Y
authors.lastname: Shaham
authors.forename: Markus
authors.initials: M
authors.lastname: Heilig
mesh_terms: D000328:Adult; D000437:Alcoholism / Q000188:drug therapy* / Q000453:epidemiology* / Q000523:psychology; D000077608:Aprepitant; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D015897:Comorbidity; D004311:Double-Blind Method; D004644:Emotions / Q000187:drug effects / Q000502:physiology; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000494:pharmacology / Q000627:therapeutic use*; D064729:Neurokinin-1 Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D010775:Photic Stimulation / Q000379:methods; D013313:Stress Disorders, Post-Traumatic / Q000175:diagnosis / Q000188:drug therapy* / Q000453:epidemiology*
chemical_list: D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D000077608:Aprepitant