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.
RCT Entities:
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.
Authors: D P Bernstein; L Fink; L Handelsman; J Foote; M Lovejoy; K Wenzel; E Sapareto; J Ruggiero Journal: Am J Psychiatry Date: 1994-08 Impact factor: 18.112
Authors: Lisa M Shin; Scott P Orr; Margaret A Carson; Scott L Rauch; Michael L Macklin; Natasha B Lasko; Patricia Marzol Peters; Linda J Metzger; Darin D Dougherty; Paul A Cannistraro; Nathaniel M Alpert; Alan J Fischman; Roger K Pitman Journal: Arch Gen Psychiatry Date: 2004-02
Authors: Mats Bergström; Richard J Hargreaves; H Donald Burns; Michael R Goldberg; David Sciberras; Scott A Reines; Kevin J Petty; Mattias Ogren; Gunnar Antoni; Bengt Långström; Olli Eskola; Mika Scheinin; Olof Solin; Anup K Majumdar; Marvin L Constanzer; Wendy P Battisti; Thomas E Bradstreet; Cynthia Gargano; Jarmo Hietala Journal: Biol Psychiatry Date: 2004-05-15 Impact factor: 13.382
Authors: Charles L Pickens; Sam A Golden; Tristan Adams-Deutsch; Sunila G Nair; Yavin Shaham Journal: Biol Psychiatry Date: 2009-01-23 Impact factor: 13.382
Authors: Britta S Nelson; Hannah D Fulenwider; Sadie E Nennig; Britessia M Smith; Michelle K Sequeira; Scott H Chimberoff; Christopher T Richie; Kejun Cheng; Kenner C Rice; Brandon K Harvey; Markus Heilig; Jesse R Schank Journal: Neuroscience Date: 2019-06-23 Impact factor: 3.590
Authors: Primavera A Spagnolo; Vijay A Ramchandani; Melanie L Schwandt; Laura E Kwako; David T George; Leah M Mayo; Cecilia J Hillard; Markus Heilig Journal: Alcohol Clin Exp Res Date: 2016-09-26 Impact factor: 3.455
Authors: A Frick; F Åhs; Å M Palmquist; A Pissiota; U Wallenquist; M Fernandez; M Jonasson; L Appel; Ö Frans; M Lubberink; T Furmark; L von Knorring; M Fredrikson Journal: Mol Psychiatry Date: 2015-12-01 Impact factor: 15.992