R ‐citalopram functionally antagonises escitalopram in vivo and in vitro : evidence for kinetic interaction at the serotonin transporter

Clinical observations with the selective serotonin reuptake inhibitor (SSRI), S ‐citalopram, indicate that S ‐citalopram is more efficacious and produces earlier symptom relief than RS ‐citalopram. Since R ‐citalopram is at least 20‐fold weaker than S ‐citalopram as inhibitor of the 5‐HT transporter (SERT) in preclinical studies, the clinical data suggest an unexpected antagonistic interaction between the two enantiomers. We therefore characterised the interaction of R ‐ and S ‐citalopram with the SERT in in vivo and in vitro assays. In both behavioural (potentiation of 5‐hydroxytryptophan (5‐HTP)‐induced behaviour) and electrophysiological studies (inhibition of 5‐HT‐elicited ion currents in Xenopus oocytes expressing the human SERT (hSERT) R ‐citalopram inhibited the effects of S ‐citalopram in a dose‐dependent manner. With S ‐citalopram : R ‐citalopram ratios of 1 : 2 and 1 : 4, 5‐HTP potentiation was significantly smaller than with S ‐citalopram alone. emsp; R ‐citalopram did not antagonise the effects of another SSRI (fluoxetine) in either behavioural or electrophysiological studies. In oocytes, inhibition of hSERT‐mediated currents by R ‐citalopram was almost completely reversible and characterised by fast on‐ and off‐sets of action. In contrast, the off‐set for S ‐citalopram was 35‐fold slower than for R ‐citalopram. Kinetic analysis of the oocyte experiments suggests that S ‐citalopram binding to SERT induces a long‐lasting, inhibited state of the transporter and that coapplication of R ‐citalopram partially relieves SERT of this persistent inhibition. We propose that the kinetic interaction of R ‐ and S ‐citalopram with SERT is a critical factor contributing to the antagonistic effects of R ‐citalopram on S ‐citalopram in vitro and in vivo .British Journal of Pharmacology (2004) 142 , 172–180. doi: 10.1038/sj.bjp.0705738