Brain 5-HT1A Receptor PET Binding, Cortisol Responses to Stress, and the Familial Transmission of Suicidal Behavior

Serotonin 1A (5-HT1A) receptor has been implicated in depression and suicidal behavior. Lower resting cortisol levels are associated with higher 5-HT1A receptor binding, and both differentiate suicide attempters. However, it is not clear whether 5-HT1A receptor binding and cortisol responses to stress are related to risk and resilience for suicidal behavior. [11C]CUMI-101 PET imaging to quantify regional brain 5-HT1A receptor binding was conducted in high-risk individuals, having a first or second degree relative(s) with an early onset mood disorder and history of suicidal behavior, and subdivided into: high-risk resilient having no mood disorder or suicidal behavior (HR-R, n=29); high-risk with mood disorder (HR-MOOD n=31); and high-risk with mood disorder and suicidal behavior (HR-SA/MOOD, n=25). Groups were compared to healthy volunteers (HV, n=34). Participants underwent the Trier Social Stress Task (TSST). We observed no group differences in 5-HT1A receptor binding considering all regions simultaneously, nor did we observe heterogeneity of the effect of group across regions. These results were similar across outcome measures (BPND and BPp in a subset of the sample), and definitions of regions of interest (ROIs; standard or serotonin-specific ROIs). We also found no group differences on TSST outcomes. Within HR-SA/MOOD, lower BPp binding [=-0.084, Standard Error or SE=0.038, p=0.048] and higher cortisol reactivity to stress [=9.25, 95% CI (3.27,15.23), p=0.004] were associated with higher lethality attempts. There were no significant relationships between 5-HT1A binding and cortisol outcomes. In conclusion, 5-HT1A receptor binding in ROIs was not linked to familial risk or resilience protecting against suicidal behavior or mood disorder although it may be related to lethality of suicide attempt. Future studies are needed to better understand the biological mechanisms implicated in familial risk for suicidal behavior and how HPA axis function influences such risk.