Cortico-limbic functional connectivity mediates the effect of early life stress on suicidality in bipolar depressed 5-HTTLPR*s carriers

Background: In bipolar disorder (BD) the risk of suicide in adult life can be influenced by the interaction of adverse childhood experiences with the serotonin transporter polymorphism (5-HTTLPR). The cortico-limbic connectivity is a candidate endophenotype for the disorder, also related to suicidality and affected by the 5-HT system. Methods: In 64 (*s carriers = 41; l/l = 23) depressed BD patients, we explored the effect of 5-HTTLPR on corticolimbic functional connectivity (FC) during emotional processing, and the role of FC in moderating/mediating the effect of early stressful events on suicidality among 5-HTTLPR groups, by implementing Generalized Structural Equation Model. Results: 5-HTTLPR affects FC between amygdala (Amy) and anterior cingulate cortex (ACC), temporal pole, putamen/thalamus, and precuneus. The short allele was associated to a more inefficient corticolimbic connectivity. In 5-HTTLPR*s carriers, but not in l/l, the Amy-ACC functional coupling mediated the relationship between stress load and current suicidality. Limitations: Patients were not drug-naive, and the recruitment took place in a single center, thus raising the possibility of population stratifications. The sample size is relatively small, but our findings can provide the background for replication study in independent and larger datasets. Conclusions: Our results confirm the link between the 5-HTT promoter polymorphism and susceptibility to stress in BD, and suggest that cortico-limbic functional connectivity mediates these effects. This pattern could identify a vulnerability factor for the exacerbation of mood episodes after stressful life events particularly relevant in *s carriers.