Sexual health and serotonin 4 receptor brain binding in unmedicated patients with depression-a NeuroPharm study

Sexual dysfunction is prominent in Major Depressive Disorder (MDD) and affects women with depression more than men. Patients with MDD relative to healthy controls have lower brain levels of the serotonin 4 receptor (5-HT₄R), which is expressed with high density in the striatum, i.e. a key hub of the reward system. Reduced sexual desire is putatively related to disturbed reward processing and may index anhedonia in MDD. Here, we aim to illuminate plausible underlying neurobiology of sexual dysfunction in unmedicated patients with MDD. We map associations between 5-HT₄R binding, as imaged with [¹¹C]SB207145 PET, in the striatum, and self-reported sexual function. We also evaluate if pre-treatment sexual desire score predicts 8-week treatment outcome in women. From the NeuroPharm study, we include 85 untreated MDD patients (71% women) who underwent eight weeks of antidepressant drug treatment. In the mixed sex group, we find no difference in 5-HT₄R binding between patients with sexual dysfunction vs normal sexual function. However, in women we find lower 5-HT₄R binding in the sexual dysfunctional group compared to women with normal sexual function (β = -0.36, 95%CI[-0.62:-0.09], p = 0.009) as well as a positive association between sexual desire and 5-HT₄R binding (β = 0.07, 95%CI [0.02:0.13], p = 0.012). Sexual desire at baseline do not predict treatment outcome (ROC curve AUC = 52%[36%:67%]) in women. Taken together, we find evidence for a positive association between sexual desire and striatal 5-HT₄R availability in women with depression. Interestingly, this raises the question if direct 5-HT₄R agonism can target reduced sexual desire or anhedonia in MDD.