A new module in the drug development process: preclinical multi-center randomized controlled trial of R-ketamine on alcohol relapse
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.
Authors
- Marcus W. Meinhardt (ORCID: https://orcid.org/0000-0002-5103-0731)
- Rainer Spanagel (ORCID: https://orcid.org/0000-0003-2151-4521)
- Sandra Bodeau (ORCID: https://orcid.org/0000-0002-7343-9212)
- Kevin Domanegg (ORCID: https://orcid.org/0000-0002-1215-4264)
- Virginie Jeanblanc
- Camille André (ORCID: https://orcid.org/0009-0004-6346-6809)
- Esi Domi (ORCID: https://orcid.org/0000-0001-5726-4814)
- Roberto Ciccocioppo (ORCID: https://orcid.org/0000-0003-3126-9240)
- Federica Benvenuti (ORCID: https://orcid.org/0000-0002-1908-8052)
- Jérôme Jeanblanc (ORCID: https://orcid.org/0000-0003-0353-2777)
- Ivan Skorodumov (ORCID: https://orcid.org/0000-0002-6749-9745)
- Mickaël Naassïla (ORCID: https://orcid.org/0000-0002-9788-0918)
- Fahd François Hilal (ORCID: https://orcid.org/0000-0002-1007-5925)
Institutions
- Università di Camerino (IT)
- Inserm (FR)
- Heidelberg University (DE)
- University Hospital Heidelberg (DE)
- Centre Hospitalier Universitaire Amiens-Picardie (FR)
- Central Institute of Mental Health (DE)
- German Center for Diabetes Research (DE)
- Université de Picardie Jules Verne (FR)
Publication Details
- Journal
- Neuropsychopharmacology
- Published
- 2025-02-28
- DOI
- https://doi.org/10.1038/s41386-025-02071-w
- Citations
- 8
- Primary Topic
- Treatment of Major Depression
- Type
- article
- Field-Weighted Citation Impact
- 11.16
Funders
- Deutsche Forschungsgemeinschaft