ABSTRACT
RATIONALE: Citalopram is a racemate consisting of a 1:1 mixture of the R(-)- and S(+)-enantiomers. Non-clinical studies show that the serotonin reuptake inhibitory activity of citalopram is attributable to the S-enantiomer, escitalopram. A series of recent non-clinical and clinical studies comparing escitalopram and citalopram to placebo found that equivalent doses of these two drugs, i.e. containing the same amount of the S-enantiomer, showed better effect for escitalopram. These results suggested that the R-citalopram in citalopram inhibits the effect of the S-enantiomer. OBJECTIVE: To review the pharmacological and non-clinical literature that describes the inhibition of escitalopram by R-citalopram, as well as the implications of this inhibition for the clinical efficacy of escitalopram compared to citalopram. METHODS: The information in this review was gathered from published articles and abstracts. RESULTS: In appropriate neurochemical, functional, and behavioural non-clinical experiments, escitalopram shows greater efficacy and faster onset of action than comparable doses of citalopram. The lower efficacy of citalopram in these studies is apparently due to the inhibition of the effect of the S-enantiomer by the R-enantiomer, possibly via an allosteric interaction with the serotonin transporter. Data from randomised clinical trials consistently show better efficacy with escitalopram than with citalopram, including higher rates of response and remission, and faster time to symptom relief. CONCLUSION: The R-enantiomer present in citalopram counteracts the activity of the S-enantiomer, thereby providing a possible basis for the pharmacological and clinical differences observed between citalopram and escitalopram.
Subject(s)
Brain/drug effects , Citalopram/therapeutic use , Depressive Disorder, Major/drug therapy , Panic Disorder/drug therapy , Selective Serotonin Reuptake Inhibitors/therapeutic use , Animals , Behavior, Animal/drug effects , Brain/metabolism , Citalopram/chemistry , Drug Interactions , Humans , Mice , Randomized Controlled Trials as Topic , Rats , Selective Serotonin Reuptake Inhibitors/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The 5-HT (5-hydroxytryptamine, serotonin) transporter (SERT) mediates the reuptake of 5-HT from the synaptic cleft into the neuron, and inhibition of this uptake is the target of selective serotonin reuptake inhibitors (SSRIs). Escitalopram (S-citalopram) is the most selective SSRI available, whereas the other enantiomer, R-citalopram, is approximately 30-40 times less potent than the S-enantiomer. Both biochemical experiments (measurement of extracellular 5-HT in the frontal cortex of rats) and behavioural studies (using the chronic mild stress and conditioned fear stress models) demonstrate that R-citalopram appears to counteract the effect of escitalopram, and that it is a dose-dependent action. When escitalopram is administered at a specific dose, it produces a greater effect than when the same dose of the S-enantiomer is administered in combination with the R-enantiomer, i.e. when citalopram is administered. While mainly the S-enantiomer is bound to the primary binding site on the SERT, both enantiomers bind to the allosteric binding site. However, the R-enantiomer stabilises the binding of the S-enantiomer at the primary site less than the S-enantiomer. Furthermore, R-citalopram has an inhibitory effect on the association of escitalopram with the transporter, thereby possibly reducing escitalopram's effect. In summary, escitalopram appears to possess a unique mechanism of action at the 5-HT transporter protein. Furthermore, escitalopram (S-citalopram) is different from citalopram because R-citalopram counteracts the activity of the S-enantiomer.