Department of Psychiatry, University of Oxford, Oxford, UK.
Psychopharmacology (Berl). 2011 May;215(2):239-46. doi: 10.1007/s00213-010-2133-z. Epub 2010 Dec 15.
Despite early promise in phase II, the performance of the NK1 receptor antagonist aprepitant in subsequent clinical trials has been disappointing. Healthy volunteer models of emotional processing offer a potential means by which novel drugs can be screened prior to clinical trials. Here, we consider the effect of 7 days of treatment with aprepitant in such a model.
Healthy volunteers (n = 32) were randomised to receive 7-day treatment with aprepitant (125 mg) or placebo. On the seventh day, participants completed a battery of tasks measuring emotional processing previously demonstrated to be sensitive to conventional antidepressant drugs. The tasks included facial expression recognition, emotional categorisation and memory, attentional dot-probe and emotion potentiated startle task.
Aprepitant abolished the emotionally potentiated startle effect and increased recognition memory for emotionally positive versus negative stimuli. In addition, the drug decreased attention to negative relative to positive emotional stimuli on the masked version of the dot-probe task. These effects were seen in the absence of any change in subjective mood. There were no effects on emotional categorisation, recall or on facial expression recognition.
These results suggest that NK1 receptor antagonism does affect some aspects of emotional processing and, in particular, that it has anxiolytic-like effects. The profile of effects reported here is, however, more limited than that found in response to conventional antidepressant treatment, and this may explain disappointing results at clinical trial. Healthy volunteer models of emotional processing may be useful in closing the gap between preclinical and clinical trials.
尽管在 II 期临床试验中表现出早期的前景，但 NK1 受体拮抗剂阿瑞匹坦在随后的临床试验中的表现令人失望。情绪处理的健康志愿者模型提供了一种潜在的方法，可以在临床试验之前筛选新型药物。在这里，我们考虑了在这种模型中使用阿瑞匹坦治疗 7 天的效果。
健康志愿者（n=32）被随机分配接受 7 天的阿瑞匹坦（125mg）或安慰剂治疗。在第 7 天，参与者完成了一系列任务，这些任务以前被证明对传统抗抑郁药物敏感，用于测量情绪处理。这些任务包括面部表情识别、情绪分类和记忆、注意力点探测和情绪增强的惊跳反应任务。
阿瑞匹坦消除了情绪增强的惊跳反应，并增加了对情绪积极与消极刺激的识别记忆。此外，该药物降低了对情绪积极和消极刺激的注意力，在点探测任务的掩蔽版本中也是如此。这些效应是在没有任何主观情绪变化的情况下观察到的。对情绪分类、回忆或面部表情识别没有影响。
这些结果表明，NK1 受体拮抗作用确实会影响情绪处理的某些方面，特别是它具有抗焦虑样作用。这里报告的影响情况比常规抗抑郁治疗的反应更为有限，这可能解释了临床试验中的令人失望的结果。情绪处理的健康志愿者模型可能有助于缩小临床前和临床试验之间的差距。
