Objectives
Sexual dysfunction is a prominent feature of Major Depressive Disorder (MDD), which affects depressed women more frequently and more pronounced compared to men. Reduced sexual desire might reflect overall anhedonia, a core symptom of MDD, which is putatively related to disturbed reward processing. Here, we aim to illuminate plausible underlying neurobiology of sexual dysfunction and in particular sexual desire in women with depression. We map associations between serotonin 4 receptor (5-HT4R) brain binding in the striatum, a key hub of the reward circuitry, and self-reported sexual function, where we focused on sexual desire, in the unmedicated depressed state. In addition, within women, we evaluate if pre-treatment sexual desire score predicted treatment outcome after eight weeks of treatment.

Methods
From the NeuroPharm study, we had access to brain scans of 5-HT4R binding and self-reports on sexual functioning (CSFQ-14 F&M) from 85 untreated MDD patients (71% women) who underwent eight weeks of antidepressant drug treatment. Whether pre-treatment sexual desire score predicted treatment outcome was evaluated using the area under the ROC curve (AUC). Treatment outcome was dichotomized as 50% or more reduction in Hamilton Depression Rating Scale 6-item (HDRS6) or not at 8 weeks clinical follow-up.

Results
We found a positive association between sexual desire and 5-HT4R binding in women (b=0.07, 95%CI [0.02:0.13], p.adj=0.024), but not in men (b=0.05, 95%CI [-0.05:0.15], p.adj=0.62). We did not find an association between overall sexual functioning and serotonin 4 receptor binding neither in women nor in men. Sexual desire at baseline did not predict treatment outcome i.e. ≥50% reduction in HDRS6 from baseline to week 8 (AUC=51.7% [36%:67%]).

Conclusions
Taken together, we find evidence for an association between low sexual desire and low striatal 5-HT4R agonist capacity in depressed women. Interestingly, this raises the question if direct 5-HT4R agonism can target reduced sexual desire in MDD.

Conflicts of Interest
Annamaria Giraldi declares that she has served as a lecturer for Eli Lilly, Pfizer, Astellas, Viatris in addition to serving as a consultant for Eli Lilly as well as being on the advisory board of Futura Medical, OvacoBio and FREYA Pharmaceuticals. Further, she states that she holds stocks in Novo Nordic. Vibe G Frokjaer declares that she has served as a consultant for H. Lundbeck and Sage Therapeutics.