Discussion
depression
CORTEX
In this study, we aimed to investigate how 5-HTT availability during an acute citalopram challenge is differentially associated with FC of 5-HTT- and 5-HT1AR-enriched networks at rest and during an emotional face-matching task. We found thalamic [The (expected) negative relationship we observed between thalamic 5-HTT availability and 5-HTT-enriched FC showcases a direct link between citalopram-induced changes in neurotransmission and functional changes within a network defined by the canonical distribution of the drug’s main target in the healthy human brain. Therefore, our results align well with predictions from the simplest pharmacodynamic models that posit regional variability in 5-HTT density at the core of pharmacological effects on the brain. Interestingly, we observed that 5-HTT-enriched FC was less strong for individuals with lower 5-HTT availability in clusters encompassing the occipito-temporal and opercular cortex, which have previously been shown to exhibit alterations in connectivity and/or activity in patients with depression compared to healthy controls (In contrast to our hypothesis, we found no relationship between thalamic 5-HTT availability and 5-HT1AR-enriched FC at rest, suggesting that the 5-HT1AR-enriched functional response to citalopram is at least not linearly dependent on 5-HTT occupancy by citalopram. Interestingly, we found preliminary evidence of group differences in the PCC and anterior cingulate cortex (ACC), which are compatible with a nonlinear dose–response pattern where FC in the low-dose group appeared lower in comparison with the placebo group, but no differences between the high-dose and placebo groups could be identified. However, we note that these findings should be interpreted with caution since they arise from exploratory pairwise tests in the absence of a significant overarching main effect of group. Moreover, interpreting this dose–response pattern on the 5-HT1AR-enriched functional network with our current understanding of the pharmacology of citalopram is admittedly challenging. One possible explanation could be that low and high doses of citalopram (indirectly) differently engage auto- and postsynaptic receptors. Here, a low dose could increase 5-HT to a smaller extent and might predominantly affect auto- or postsynaptic 5-HT1AR, while the larger 5-HT increases induced by the high dose might engage both types of receptors, leading to compensatory effects summing to a null effect. Nevertheless, this hypothesis remains speculatory. It is worth noting that the regions where this effect occurred appear in line with previous literature and are highly relevant within the context of previous studies in depression. For instance, the PCC, as part of the DMN, has frequently been implicated in the functional response to SSRIs (In line with our hypothesis, results from the emotional face-matching task showed a negative relationship between 5-HTT availability and task-dependent 5-HT1AR-enriched FC. 5-HT1AR-enriched FC varied linearly with variations in 5-HTT availability in large clusters of cortical and subcortical areas, which show considerable overlap with the corticolimbic system. Interestingly, while previous studies have shown that limbic system activity during emotional processing is dependent on the 5-HT1AR (We also investigated main effects of the task and treatment effect on BOLD responses, since data have not been published previously. The main task effect we observed is in line with previous studies using a similar paradigm, showing increased BOLD signal mostly in key limbic areas (Citalopram is considered a conventional antidepressant medication, but several other compounds binding to 5-HT receptors have gained a renewed interest for the treatment of depression, including 3,4-methylenedioxymethamphetamine (MDMA) (This study has some limitations. First, the sample included only a relatively small sample of healthy young women, which limits statistical power and impedes detection of smaller effects and the possibility to extrapolate findings beyond women. Therefore, future larger and well-powered studies attempting to replicate our findings would be welcome. Second, [