Citalopram is a widely applied SSRI in patients suffering from affective disorder. It is a racemic mixture of the S- and R-enantiomer of citalopram, consisting of equal parts of S-citalopram and R-citalopram, respectively. It has been shown that the inhibitory potency in serotonin reuptake of S-citalopram is much higher compared to R-citalopram, and it is assumed that S-citalopram is the main carrier of the antidepressant effect.

Here we investigated the effects of the two SSRIs Citalopram (50% S-, 50% R-citalopram) and Escitalopram (100% S-citalopram) on brain networks during emotion processing using pharmacological functional magnetic resonance imaging (fMRI) and dynamic causal modelling (DCM), an advanced tool to investigate functional integration between different brain regions.

Our results are based on a placebo-controlled, randomized, double-blind, cross-over pharmacological study in 16 healthy subjects during three fMRI scanning sessions performing a facial emotional discrimination paradigm (Windischberger, Neuroimage, 2010). 32 models of pharmacological modulation within the amygdalar-parahippocampal-orbitofrontal network were analysed using Bayesian Model Averaging (BMA) as implemented in SPM8.

S-citalopram showed statistically significant modulatory effects on forward amygdala-orbitofrontal and bidirectional amygdala-parahippocampal connections. No significant modulatory effects of R-citalopram were found.

This is the first fMRI study that showed stimulus-specific differential effects of the two enantiomeres R- and S-citalopram at the neural connectivity level. Our results corroborate studies in rats where escitalopram-induced increases in extracellular serotonin levels were found attenuated when R-citalopram was coinjected. Taken together this might explain the response differences between study drugs as demonstrated in previous clinical trials.