Using [18F]altanserin, a serotonin 2A receptor (5-HT2AR) antagonist Positron Emission Tomography (PET) tracer, a positive association between cortical 5-HT2AR binding and the inward-directed facets of neuroticism has been demonstrated in healthy individuals. Psilocybin, a 5-HT2AR agonist, shows promise for the treatment of depression, reducing neuroticism and mood symptoms potentially via hypothalamic-pituitary-adrenal (HPA) modulation. 5-HT2AR and neuroticism are both modulated by HPA axis function.

In this study, we examined whether the association between 5-HT2AR binding and the inward facets of neuroticism can be replicated in an independent healthy cohort using the new 5-HT2AR 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-HT2AR 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-HT2AR 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-HT2AR 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).

The findings prompt consideration of whether novel interventions such as psilocybin that actively targets 5-HT2AR and causes changes in personality could be particularly beneficial if implemented as a targeted approach based on neuroticism profiles.

The COVID-19 pandemic has disproportionately affected women's mental health. However, most evidence has focused on mental illbeing outcomes, and there is little evidence on the mechanisms underlying this unequal impact.

To investigate gender differences in the long-term trajectories of life satisfaction, how these were affected during the pandemic and the role of time-use differences in explaining gender inequalities.

We used data from 6766 (56.2% women) members of the 1970 British Cohort Study (BCS70). Life satisfaction was prospectively assessed between the ages of 26 (1996) and 51 (2021) years, using a single question with responses ranging from 0 (lowest) to 10 (highest). We analysed life satisfaction trajectories with piecewise latent growth curve models, and investigated whether gender differences in the change in the life satisfaction trajectories with the pandemic were explained by self-reported time spent doing different paid and unpaid activities.

Women had consistently higher life satisfaction than men before the pandemic (Δintercept,unadjusted = 0.213, 95% CI 0.087–0.340; P = 0.001) and experienced a more accelerated decline with the pandemic onset (Δquad2,unadjusted = −0.018, 95% CI −0.026 to −0.011; P < 0.001). Time-use differences did not account for the more accelerated decrease in women's life satisfaction levels with the pandemic (Δquad2,adjusted = −0.016, 95% CI −0.031 to −0.001; P = 0.035).

Our study shows pronounced gender inequalities in the impact of the pandemic on the long-term life satisfaction trajectories of adults in their 50s, with women losing their pre-pandemic advantage over men. Self-reported time-use differences did not account for these inequalities. More research is needed to tackle gender inequalities in population mental health.