A new module in the drug development process: preclinical multi-center randomized controlled trial of R-ketamine on alcohol relapse

IF 6.6 1区医学 Q1 NEUROSCIENCES

Neuropsychopharmacology Pub Date : 2025-02-28 DOI:10.1038/s41386-025-02071-w

Marcus W. Meinhardt, Ivan Skorodumov, Jérôme Jeanblanc, Federica Benvenuti, Fahd François Hilal, Esi Domi, Camille André, Sandra Bodeau, Virginie Jeanblanc, Kevin Domanegg, Roberto Ciccocioppo, Mickael Naassila, Rainer Spanagel

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引用次数: 0

Abstract

The drug development process in psychiatry faces significant challenges due to low reproducibility rates in animal testing, which often leads to translation failures. To address this issue, we introduce a new approach in psychiatric drug development: a preclinical randomized controlled trial (preRCT). To demonstrate its potential utility, we conducted a multi-center preRCT using the alcohol deprivation effect (ADE) model to assess the impact of ketamine and R-ketamine on alcohol relapse across three European research centers. Ketamine (20 mg/kg) significantly reduced relapse, while R-ketamine showed efficacy only in females. A higher dose of R-ketamine (40 mg/kg) was also effective in males. These sex-dependent effects were linked to plasma R-ketamine levels, which were two-fold higher in female compared to male rats. Notably, R-ketamine demonstrated a lasting reduction in alcohol consumption without adverse effects. In conclusion, our preRCT demonstrates R-ketamine’s effectiveness in reducing alcohol relapse and supports translation to a clinical RCT that accounts for sex-dependent effects.

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药物开发过程中的一个新模块：R-氯胺酮对酒精复发的临床前多中心随机对照试验。

精神病学药物开发过程面临着重大挑战，因为动物试验的可重复性低，这往往导致翻译失败。为了解决这一问题，我们引入了一种新的精神药物开发方法：临床前随机对照试验（preRCT）。为了证明其潜在的效用，我们在三个欧洲研究中心进行了一项使用酒精剥夺效应（ADE）模型的多中心prect，以评估氯胺酮和r -氯胺酮对酒精复发的影响。氯胺酮（20mg /kg）可显著减少复发，而r -氯胺酮仅对女性有效。较高剂量的r -氯胺酮（40 mg/kg）对男性也有效。这些性别依赖效应与血浆r -氯胺酮水平有关，雌性大鼠的r -氯胺酮水平是雄性大鼠的两倍。值得注意的是，r -氯胺酮证明了酒精消费量的持续减少而没有副作用。总之，我们的prect证明了r -氯胺酮在减少酒精复发方面的有效性，并支持将其转化为临床随机对照试验，说明了性别依赖效应。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Neuropsychopharmacology 医学-精神病学

CiteScore

15.00

自引率

2.60%

发文量

240

审稿时长

2 months

期刊介绍： Neuropsychopharmacology is a reputable international scientific journal that serves as the official publication of the American College of Neuropsychopharmacology (ACNP). The journal's primary focus is on research that enhances our knowledge of the brain and behavior, with a particular emphasis on the molecular, cellular, physiological, and psychological aspects of substances that affect the central nervous system (CNS). It also aims to identify new molecular targets for the development of future drugs. The journal prioritizes original research reports, but it also welcomes mini-reviews and perspectives, which are often solicited by the editorial office. These types of articles provide valuable insights and syntheses of current research trends and future directions in the field of neuroscience and pharmacology.