Neocortical serotonin 2A receptor binding, neuroticism and risk of developing depression in healthy individuals

The serotonin 2A receptor (5-HT_2AR) and personality trait neuroticism are implicated in the pathophysiology of depression and represent potential targets for prevention and treatment. Here we evaluate whether 5-HT_2AR and neuroticism in healthy individuals are related to the risk of developing a future depressive episode by utilizing a large 5-HT_2AR molecular-imaging cohort comprising 131 healthy individuals who underwent molecular brain imaging and neuroticism assessments and up to 19 years of data on future depression diagnosis from the Danish Registers. Using cause-specific Cox regression analysis, we found that neocortical 5-HT_2AR binding coupled with the inward-directed facets of neuroticism elevated the risk of depression. The risk was greatest in individuals with both high 5-HT_2AR binding and high neuroticism. Our data provide novel insights into the risk of depression and support the evaluation of clinical strategies that target 5-HT_2AR, such as psychedelics, in conjunction with psychotherapy that addresses personality-based risk factors.