Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands.
Faculty of Psychology and Neuroscience, Section Neuropsychology & Psychopharmacology, Maastricht University, Maastricht, The Netherlands.
Psychopharmacology (Berl). 2022 Jun;239(6):1853-1879. doi: 10.1007/s00213-022-06106-8. Epub 2022 Mar 29.
Recent trials with psychedelics in major depressive disorder and treatment-resistant depression showed remarkable improvements in depressive symptoms that can last for up to several months after even a single administration. The lack of an appropriate placebo control group-as patients are often able to discriminate the subjective effects of the drug-and an incomplete understanding of the role of the hallucinogenic and mystical experience, hampers the interpretation of these therapeutic effects.
To control for these factors, we developed a translational framework based on establishing pharmacokinetic/pharmacodynamic (PK/PD) relationships in rodents and humans for hallucinogenic (i.e., discriminative stimulus effects in rodents and humans; head twitch responses in rodents; questionnaires in humans) and therapeutic effects. For the latter, we selected the pattern separation and attentional set-shifting tasks as measures for cognitive flexibility because of their high translational value. We predict that these PK/PD analyses will lead to a more objective evaluation of improvements in patients compared to relying only on the currently used self-reported questionnaires. We hypothesize that-if the role of the hallucinogenic experience is not central in the antidepressant effects of psychedelics-the ED's for the therapeutic effects will be significantly lower than for the hallucinogenic and mystical effects.
Our framework will help to inform future studies that aim at the elucidation of the mechanism(s) of action of psychedelics in depression, and the role of the acute subjective and/or hallucinogenic experience in their effects.
最近在重度抑郁症和治疗抵抗性抑郁症中使用迷幻剂的试验显示，抑郁症状有显著改善，甚至在单次给药后，这种改善可持续长达几个月。缺乏适当的安慰剂对照组——因为患者通常能够辨别药物的主观效应——以及对迷幻和神秘体验作用的不完全了解，阻碍了对这些治疗效果的解释。
为了控制这些因素，我们开发了一个基于在啮齿动物和人类中建立药代动力学/药效学（PK/PD）关系的转化框架，用于研究致幻剂（即啮齿动物和人类的辨别刺激效应；啮齿动物的头部抽搐反应；人类的问卷）和治疗效果。对于后者，我们选择了模式分离和注意力定势转移任务作为认知灵活性的测量指标，因为它们具有很高的转化价值。我们预测，这些 PK/PD 分析将导致对患者改善的更客观评估，而不仅仅是依赖目前使用的自我报告问卷。我们假设——如果致幻体验在迷幻剂的抗抑郁作用中不是核心作用——那么治疗效果的 ED 值将明显低于致幻和神秘体验的 ED 值。
我们的框架将有助于为阐明迷幻剂在抑郁症中的作用机制以及急性主观和/或致幻体验在其作用中的作用的未来研究提供信息。
