The relation between neocortical serotonin 2A receptor binding and neuroticism in the risk for developing depression in healthy individuals: a BrainDrugs study

Abstract The serotonin 2A receptor (5HT2AR) and personality factors indexing stress coping mechanisms are implicated in the pathophysiology of depression. Cross-sectional studies performed in individuals with high familial risk for depression suggest that the coupling between 5-HT2AR and the inward-directed facets of neuroticism may be associated with a risk for depression. This study aimed to build a risk model for first-episode depression in healthy individuals based on serotonergic and personality biomarkers and utilizing up to 19 years of longitudinal data on depression. Such a model could have potential implications for identifying high-risk individuals for early preventative interventions. In this study, 131 healthy volunteers completed an [18F]altanserin positron emission tomography scan to measure 5-HT2AR binding and personality assessment of neuroticism, as part of research studies conducted between 2000-2008. Following study participation, information on future diagnoses of depression was obtained until 2019 from the Danish National Health Registers. Cause-specific Cox regression was used to investigate the hypothesis that neocortical 5-HT2AR binding in interaction with the inward-directed facets of neuroticism (neuroticisminward) would be associated with a risk of developing depression. The study found a significant positive interaction between neocortical 5HT2AR binding and neuroticisminward (p=0.018) such that individuals with high 5-HT2AR binding and high neuroticisminward scores had the highest risk for developing depression. In conclusion, the study provides a novel risk model for first-episode depression. Healthy individuals who have the personality phenotype of high neuroticisminward along with the serotonergic phenotype of high 5-HT2AR binding may be at the greatest risk for developing depression in the future.