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

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.

SUBMITTER: Kwako LE

PROVIDER: S-EPMC4512162 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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

Kwako Laura E LE George David T DT Schwandt Melanie L ML Spagnolo Primavera A PA Momenan Reza R Hommer Daniel W DW Diamond Christine A CA Sinha Rajita R Shaham Yavin Y Heilig Markus M

Psychopharmacology 20140718 1

<h4>Rationale</h4>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.<h4>Objectives</h4>The aim of t ...[more]

PMID: 25030801

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Project description:Alcohol dependence comorbid with major depressive disorder poses a major challenge in the clinical setting. The results in the treatment with selective serotonin re-uptake inhibitors have been conflicting. Thus, we compared in alcohol-dependent patients with co-morbid major depressive disorder the selective serotonin re-uptake inhibitor escitalopram to a compound that acts on different transporter system and may reduce craving, the glutamate receptor antagonist memantine.Eighty alcohol-dependent patients comorbid with major depressive disorder in municipal alcohol clinics were randomized 1:1 to receive memantine 20 mg or escitalopram 20 mg in a double-blind manner. During the 26-week study period patients continued their routine treatment at the clinics. Abstinence was not required but encouraged. The patients attended visits weekly during the first month, and then at 3 and at 6 months. Outcome measures were Alcohol Use Disorders Identification Test (AUDIT), Obsessive Compulsive Drinking Scale (OCDS) and Drinking Diary.The completion rate was high in both groups, especially among the patients who had been abstinent at the beginning of the study. However, among those patients who were not abstinent at baseline, 47% in both groups discontinued the study. Numbers of abstinent days were high in both groups throughout the study. Alcohol consumption measured by the AUDIT QF (quantity-frequency) score was significantly reduced in both groups, as was the craving for alcohol measured by the OCDS. Early age at first alcohol intoxication predicted poor treatment outcomes in patients treated with escitalopram, and the same was seen with the early onset of the first depressive episode. The same predictive effects were not found in patients treated with memantine.Our results indicate that both memantine and escitalopram are useful adjunct medications for the treatment of alcohol dependence co-morbid with major depression. Memantine was at least as effective with regard to drinking as escitalopram. We believe that a direct comparison of memantine, with the commonly used escitalopram, can provide useful information for clinicians on the treatment of alcohol dependency co-morbid with MDD.

Dataset Information

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

Publications

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

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