Interactive effects of citalopram and serotonin transporter genotype on neural correlates of response inhibition and attentional orienting

Abstract

The brain's serotonergic (5-HT) system has been implicated in controlling impulsive behavior and attentional orienting and linked to impulse control and anxiety related disorders. However, interactions between genotypical variation and responses to serotonergic drugs impede both treatment efficacy and neuroscientific research. We examine behavioral and electrophysiological responses to acute intravenous administration of a selective serotonin reuptake inhibitor (SSRI) while controlling for major genetic differences regarding 5-HT transporter (5-HTT) genotypes. Out of a genotyped sample of healthy Caucasian subjects (n=878) two extreme-groups regarding 5-HTT genotypes were selected (n=32). A homozygous high-expressing group based on tri-allelic 5-HTTLPR and rs25532 (LAC/LAC=LL) was compared to homozygous S allele carriers (SS). Both groups were administered a low dose of citalopram (10mg) intravenously in a double blind crossover fashion and performed a novelty NoGo paradigm while high density EEG was recorded. Interactions between drug and genotype were seen on both behavioral and neurophysiological levels. Reaction slowing following inhibitory events was decreased by the administration of citalopram in the LL but not SS group. This was accompanied by decreases in the amplitude of the inhibitory N2 EEG component and the P3b in the LL group, which was not seen in the SS group. SS subjects showed an increase in P3a amplitudes following SSRI administration to any type of deviant stimulus possibly reflecting increased attentional capture. The acute SSRI response on inhibitory processes and attentional orienting interacts with genotypes regulating 5-HTT gene expression. SS subjects may show increased attentional side effects reflected in increases in P3a amplitudes which could contribute to treatment discontinuation. Inhibitory processes and their neural correlates are affected only in LL subjects. These findings may indicate an underlying mechanism that could relate genotypical differences to altered side effect profiles and drug responses and are compatible with a non-monotonic relationship between 5-HT levels and optimal functioning.