Author ' s personal copy Area-speci fi c modulation of neural activation comparing escitalopram and citalopram revealed by pharmaco-fMRI : A randomized cross-over study

a r t i c l e i n f o Area-specific and stimulation-dependent changes of human brain activation by selective serotonin reuptake inhibitors (SSRI) are an important issue for improved understanding of treatment mechanisms, given the frequent prescription of these drugs in depression and anxiety disorders. The aim of this neuroimaging study was to investigate differences in BOLD-signal caused by administration of the SSRIs escitalopram and citalopram using pharmacological functional magnetic resonance imaging (pharmaco-fMRI). Eighteen healthy subjects participated in a placebo-controlled, randomized, double-blind study in cross-over repeated measures design. Each volunteer performed facial emotional discrimination and a sensorimotor control paradigm during three scanning sessions. Citalopram (20 mg/d), escitalopram (10 mg/d) and placebo were administered for 10 days each with a drug-free period of at least 21 days. Significant pharmacological effects on BOLD-signal were found in the amygdala, medial frontal gyrus, parahippocampal, fusiform and middle temporal gyri. Post-hoc t-tests revealed decreased BOLD-signal in the right amygdala and left parahippocampal gyrus in both pharmacological conditions, compared to placebo. Escitalopram, compared to citalopram, induced a decrease of BOLD-signal in the medial frontal gyrus and an increase in the right fusiform and left parahippocampal gyri. Drug effects were concentrated in brain regions with dense serotonergic projections. Both escitalopram and citalopram attenuated BOLD-signal in the amygdala and parahippocampal cortex to emotionally significant stimuli compared to control stimuli. We believe that reduced reactivity in the medial frontal gyrus found for escitalopram compared to citalopram administration might explain the response differences between study drugs as demonstrated in previous clinical trials. Introduction Dysfunctions of the emotion processing circuitry are associated with depression and anxiety disorders (Akimova et al., 2009), and changes in the reactivity within this circuitry induced by selective serotonin reuptake inhibitors (SSRI) may be indicators for treatment response (Anderson et al. primarily inhibit presynaptic serotonin transporters, leading to increased extracellular serotonin (5-HT) levels. This change in 5-HT concentration engages the self-regulatory mechanism in the dorsal raphe nucleus via the somatodendritic serotonin-1A autoreceptor which exerts a modulatory influence on corticolimbic target regions, It has been suggested that the reduction of clinical symptoms under SSRI treatment may be caused by changes in the processing of emotional stimuli, i.e., enhanced positive emotion processing while simultaneously attenuated negative emotion processing (Nathan et al., 2003). Studies, however, showed inconsistent results as acute SSRI administration was reported to increase fear recognition in healthy subjects (Bhagwagar et al., 2004; Browning et al., …

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