A new module in the drug development process: preclinical multi-center randomized controlled trial of R-ketamine on
Marcus W Meinhardt1,2, Ivan Skorodumov1, Jérôme Jeanblanc3
1Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
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.
Insights
This study introduces a preclinical randomized controlled trial (preRCT) for psychiatric drug development. A preRCT found ketamine and R-ketamine effectively reduce alcohol relapse in rats, with sex-dependent effects.
Area of Science:
- Neuroscience
- Psychopharmacology
- Translational Medicine
Background:
- Psychiatric drug development faces challenges with low reproducibility in animal models.
- Translation failures from preclinical to clinical studies are common.
- A novel preclinical randomized controlled trial (preRCT) approach is proposed.
Purpose of the Study:
- To evaluate the efficacy of ketamine and R-ketamine in reducing alcohol relapse using a preRCT.
- To investigate sex-dependent effects of ketamine and R-ketamine in an animal model of alcohol relapse.
- To assess the translational potential of a preRCT in psychiatric drug development.
Main Methods:
- Conducted a multi-center preRCT across three European research centers.
- Utilized the alcohol deprivation effect (ADE) model in rats.
- Administered ketamine (20 mg/kg) and R-ketamine (20 and 40 mg/kg) to assess alcohol relapse.
Main Results:
- Ketamine (20 mg/kg) significantly reduced alcohol relapse.
- R-ketamine showed efficacy in females at 20 mg/kg and in males at 40 mg/kg.
- Sex-dependent effects correlated with higher plasma R-ketamine levels in female rats; R-ketamine reduced alcohol consumption without adverse effects.
Conclusions:
- The preRCT successfully demonstrated the efficacy of ketamine and R-ketamine in reducing alcohol relapse.
- R-ketamine shows promise for treating alcohol use disorder, with notable sex-dependent effects.
- This study supports the utility of preRCTs for advancing psychiatric drug development towards clinical trials.
