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

Abstract

Using [¹⁸F]altanserin, a serotonin 2A receptor (5-HT_2AR) antagonist Positron Emission Tomography (PET) tracer, a positive association between cortical 5-HT_2AR binding and the inward-directed facets of neuroticism has been demonstrated in healthy individuals. Psilocybin, a 5-HT_2AR agonist, shows promise for the treatment of depression, reducing neuroticism and mood symptoms potentially via hypothalamic-pituitary-adrenal (HPA) modulation. 5-HT_2AR and neuroticism are both modulated by HPA axis function. In this study, we examined whether the association between 5-HT_2AR binding and the inward facets of neuroticism can be replicated in an independent healthy cohort using the new 5-HT_2AR agonist tracer [¹¹C]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_2AR and reduce neuroticism. Eighty healthy volunteers underwent [¹¹C]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_2AR binding and inward facets of neuroticism, namely depression, anxiety, self-consciousness and vulnerability to stress, and whether CAR moderated this association. The study confirms the positive association between 5-HT_2AR binding and the inward facets of neuroticism (<i>β</i> = 0.01, 95% CI = [0.0005: 0.02], <i>P</i> = 0.04), and this association is independent of CAR (<i>P</i> = 0.33). The findings prompt consideration of whether novel interventions such as psilocybin that actively targets 5-HT_2AR and causes changes in personality could be particularly beneficial if implemented as a targeted approach based on neuroticism profiles.