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

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.

Fig. 1. Timeline and results of the preRCT in the whole population (males and females).

A Numbers indicate weeks of every experimental phase. After habituation first alcohol consumption phase was initiated followed by an alcohol-free period (alcohol deprivation) and re-access (relapse/alcohol deprivation effect) to alcohol. Drug application is highlighted in red. B Effects of acute R-ketamine and ketamine on relapse-like drinking. Intake of total ethanol (calculated in g of pure alcohol per kg of body weight per day) before and after a deprivation period of two weeks. The last 3 days measurements of ethanol intake is given as baseline drinking—‘BL’. Arrows indicate the administration of either vehicle, or 20 mg/kg of R-ketamine/Ketamine. In addition effect size for different treatments are displayed in (C). D Changes in locomotion in percent to baseline are presented indicative for sedative effects of ketamine. All data are presented as means ± SEM. significant differences from the vehicle control group: *P < 0.05, **P < 0.01, ***P < 0.001.

Fig. 2. Sex differences of R-ketamine and ketamine on relapse-like drinking within the preRCT.

ADE measurement by intake of total ethanol (calculated in g of pure alcohol per kg of body weight per day) for female (A, B) and male (C, D) rats respectively. The last 3 days measurements of ethanol intake is given as baseline drinking - ‘BL’. Arrows indicate the administration of either vehicle, or 20 mg/kg of R-ketamine/ketamine. show the efficacy to reduce relapse (in percent to baseline). Data are presented as means ± SEM. significant differences from the vehicle control group: *P < 0.05, **P < 0.01, ***P < 0.001.#.

Fig. 3. Pharmacokinetic analysis of different ketamine enantiomers in males and females.

Plasma concentrations of ketamine, R-ketamine and S-ketamine (A) and their main metabolite norketamine (B) in male and female rats measured 15 min after intra-peritoneal administration of the respective enantiomers. Data are presented as means ± SEM, ***P < 0.001.

Fig. 4. Effects of acute R-ketamine (40 mg/kg) on relapse-like drinking in male rats.

Intake of total ethanol (calculated in g of pure alcohol per kg of body weight per day) (A) before and after a deprivation period of two weeks. The last 3 days measurements of ethanol intake is given as baseline drinking - ‘BL’. Arrows indicate the administration of either vehicle or 40 mg/kg of R-ketamine. B Shows the efficacy to reduce relapse (in percent to baseline). Data are presented as means ± SEM. significant differences are display in relation to the vehicle control group, *P < 0.05, **P < 0.01, ***P < 0.001.

Fig. 5. Summary of efficacy data and potential long-lasting effect of drug treatment.

A Drug treatment of all treatment modalities displayed for their first day of alcohol relapse represented in effect size to responding of the respective vehicle-treated group. B Long-term effects of treatment with different ketamine enantiomers on baseline alcohol intake represented in percentage change to drinking behavior of the respective vehicle-treated group. Color coding represents: Green = Saline, purple = S-ketamine [20 mg/kg], blue = R-ketamine [20 mg/kg], black = ketamine [20 mg/kg], orange = R-ketamine [40 mg/kg]. Data are presented as means, significant differences from the vehicle control group: *P < 0.05.