Background: Sexual dysfunction is a prominent feature of Major Depressive Disorder (MDD) reaching a prevalence as high as 75% and is more pronounced in women than in men with MDD [1]. Anhedonia, a core symptom in MDD, may also be reflected in reduced sexual desire and/or interest and may be related to disturbed reward processing. The serotonin 4 receptor (5-HT4R) is richly expressed in the striatum, a key hub in the reward circuitry, and appears to be associated with functional MRI measures of reward related brain activity in healthy individuals, as shown by our group [2]. Thus, disturbances in reward circuit brain function, possibly related to serotonin brain signalling, may play a role in anhedonia.

Aim: To determine if serotonergic function, in terms of striatal 5-HT4R non-displaceable binding (BPND), is associated with self-reported sexual function in the untreated depressed state and whether this depends on gender. We further evaluate if sexual health measures align with overall anhedonia psychometrics.

Methods: Data on [11C]-SB207145 PET imaging and sexual health were available from the Center for Integrated Molecular Brain Imaging (Cimbi) database [3] from 86 untreated MDD patients (male/female = 25/61) [4]. Sexual function was evaluated using the Changes in Sexual Functioning Questionnaire (CSFQ-14) for men and women respectively and was defined in a binary fashion as either being in risk of having a sexual dysfunction or not based on validated cut-off points from the CSFQ-14 total score [5]. The Snaith-Hamilton Pleasure Scale (SHAPS) was used to assess perceived level of anhedonia.

We evaluated the association between striatal 5-HT4R BPND and sexual function as a dichotomized variable using multiple linear regression models adjusting for relevant covariates (i.e. age, sex, the serotonin transporter polymorphism (5-HTTLPR) genotype (LALA or non-LALA) and injected [11C]-SB207145 mass per kg bodyweight). Further, we tested if this association was dependent on gender. Finally, we evaluated the association between the total scores of the SHAPS- and the CSFQ-14 questionnaires in a linear regression model for men and women separately since the CSFQ scale differs with sex.

Results: Eight men (14.8%) and 46 women (85.2%) met the threshold indicating a sexual dysfunction. We found no significant association between striatal 5-HT4R BPND and sexual function (0.05, CI [-0.4: 0.5], p=0.8). Likewise, such association did not differ between men and women (-0.3, CI [-0.8: 0.2], p=0.3). As expected, the total scores of the SHAPS questionnaires were negatively associated with the CSFQ-14 total scores women (-0.15, CI [-0.26: -0.05], p=0.005), whereas we were underpowered to conclude on such an association in men (-0.06, CI [-0.22: 0.09], p=0.41).

Conclusion: Overall our data suggest that sexual (dys)function in depression, for both men and women, does not map onto a marker of serotonergic wiring of the reward system, in terms of 5-HT4R BPND. Nevertheless, our data suggest that in the depressed state sexual dysfunction may serve as a proxy for anhedonia at least in women.