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

A positive association between serotonin 2A receptor binding in the brain and inward-directed facets of neuroticism—depression, anxiety, self-consciousness, and vulnerability to stress—was confirmed in a new cohort of 80 healthy volunteers using the tracer [11C]Cimbi-36. This association was independent of the cortisol awakening response, an index of hypothalamic-pituitary-adrenal axis function. The findings suggest that interventions targeting the serotonin 2A receptor, such as psilocybin, might be especially effective when tailored to individuals' neuroticism profiles.

Study at a glance

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.