Sex hormones and serotonin 4 receptor brain binding in men with and without major depressive disorder

Sex hormones may contribute to the pathophysiology of Major Depressive Disorder (MDD) through effects on the serotonergic brain system. Estradiol is associated with serotonergic neurobiology in rodent models and humans across sexes. In healthy men, we have previously observed a negative association between testosterone and serotonin 4 receptor (5-HT4R) levels, a receptor implicated in depression and a promising novel antidepressant target. Here, we investigate the associations between sex hormone levels and 5-HT4R binding in unmedicated men with MDD compared to healthy men. We used a latent variable model to evaluate the association between estradiol and testosterone, and cerebral 5-HT4R binding based on [¹¹C]SB207145 Positron Emission Tomography (PET) data from 25 males with MDD from the Neuropharm trial and 52 healthy males (aged 18-49), which included 38 healthy males from our previous study. As previously shown in the complete group of men and women with MDD from the Neuropharm trial, we here confirm that a lower cerebral 5-HT4R level is also observed in the male MDD population alone compared to healthy men (β = -0.07, p = 0.012). In addition to the previously shown negative association between global 5-HT4R levels and testosterone (β = -0.007, p = 0.006) in healthy men, we also observe a positive association with estradiol (β = 1.74, p = 0.001). However, we do not observe this in men with MDD (testosterone: β = 0.0001, p = 0.97; estradiol: β = 0.64, p=0.36). There was a trend towards a group difference in the association between testosterone and global 5-HT4R (β = 0.008, p = 0.082). In summary, we found evidence for a coupling between 5-HT4R and sex hormone levels in healthy men. This neuroendocrine connection appeared unclear in unmedicated men with depression, possibly due to a different and weaker coupling.