Consistent evidence that brain serotonin 2A receptor binding is positively associated with personality-based risk markers of depression

Summary

Brain scans of 80 healthy volunteers reveal a direct link between serotonin 5-HT2A receptor activity and inward-focused neuroticism, a key personality trait in psychology. Specifically, higher receptor binding positively correlated with traits like depression and anxiety (β = 0.01). This finding, derived from functional brain imaging, suggests that targeting these serotonin receptors could offer a novel approach for clinical psychology and psychiatry in the treatment of major depression. Understanding these mechanisms advances vital mental health research topics, potentially informing personalized interventions based on an individual's personality profile.

Abstract

Background Using [ 18 F]altanserin, a serotonin 2A receptor (5-HT 2A R) antagonist Positron Emission Tomography (PET) tracer, a positive association between cortical 5-HT 2A R binding and the inward-directed facets of neuroticism has been demonstrated in healthy individuals. Psilocybin, a 5-HT 2A R agonist, shows promise for the treatment of depression, reducing neuroticism and mood symptoms potentially via hypothalamic-pituitary-adrenal (HPA) modulation. 5-HT 2A R and neuroticism are both modulated by HPA axis function. Aims In this study, we examined whether the association between 5-HT 2A R binding and the inward facets of neuroticism can be replicated in an independent healthy cohort using the new 5-HT 2A R agonist tracer [ 11 C]Cimbi-36, and if their association is moderated by cortisol awakening response (CAR), an index of HPA axis function. If so, this could advance mechanistic insights into interventions that target the 5-HT 2A R and reduce neuroticism. Method Eighty healthy volunteers underwent [ 11 C]Cimbi-36 PET scans and completed the NEO personality inventory (NEO-PI-R) for the assessment of neuroticism. Salivary samples were available for determination of CAR in 70 of the participants. Using linear latent variable models, we evaluated the association between 5-HT 2A R binding and inward facets of neuroticism, namely depression, anxiety, self-consciousness and vulnerability to stress, and whether CAR moderated this association. Results The study confirms the positive association between 5-HT 2A R binding and the inward facets of neuroticism ( β = 0.01, 95% CI = [0.0005: 0.02], P = 0.04), and this association is independent of CAR ( P = 0.33). Conclusions The findings prompt consideration of whether novel interventions such as psilocybin that actively targets 5-HT 2A R and causes changes in personality could be particularly beneficial if implemented as a targeted approach based on neuroticism profiles.

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