R-citalopram counteracts the antidepressant-like effect of escitalopram in a rat chronic mild stress model

The selective serotonin (5-HT) reuptake inhibitor, citalopram, is a racemic mixture of the stereoisomers, S-(+)-citalopram (escitalopram) and R-(-)-citalopram (R-citalopram). R-citalopram has been shown to counteract the 5-HT enhancing properties of escitalopram in acute studies in animals. In the present study we report, for the first time, on an interaction between R-citalopram and escitalopram after repeated dosing in a rat chronic mild stress (CMS) model of depression. The effect of escitalopram (2.0, 3.9 and 7.8 mg/kg per day), R-citalopram (7.8 mg/kg per day) and escitalopram 3.9 mg/kg per day plus R-citalopram 7.8 mg/kg per day were studied and compared to the effect of citalopram (8.0 mg/kg per day), imipramine and R-fluoxetine (8.9 mg/kg per day). Significant effects relative to a vehicle-treated group were achieved from week 1 for escitalopram (3.9 and 7.8 mg/kg per day), from week 2 for citalopram (8.0 mg/kg per day), from week 3 for R-fluoxetine (8.9 mg/kg per day) and from week 4 for escitalopram (2.0 mg/kg per day) and imipramine (8.9 mg/kg per day). R-citalopram (7.8 mg/kg per day) and escitalopram (3.9 mg/kg per day) plus R-citalopram (7.8 mg/kg per day) did not differ significantly from vehicle. There were no drug-induced effects in non-stressed control groups. In conclusion, escitalopram showed a shorter time to response in the rat CMS model of depression than citalopram, which was faster acting than R-fluoxetine and imipramine. R-citalopram counteracted the effect of escitalopram. The mechanism of action of R-citalopram is, at the moment unclear, but may be relevant to the improved clinical antidepressant activity seen with escitalopram in comparison with citalopram, and may also indicate an earlier response to escitalopram compared to other selective serotonin reuptake inhibitors (SSRIs).