To the Editor: Major depressive disorder (MDD) is a mood disorder characterized by complex patterns of emotional, cognitive, and behavioral symptomology and deficits in daily functioning. Genital symptoms, including a reduction in libido and menstrual disturbances, have been considered to be a classic symptom of MDD for many decades. Previous evidence has reached a broad consensus that the incidence of genital symptoms is higher in patients with MDD than in the general population. A systematic review and meta-analysis found a bidirectional association between MDD and genital symptoms, with patients with MDD showing a 50–70% increased risk of developing genital symptoms, while individuals with genital symptoms had a 130–210% increased risk of developing MDD.[1] As previously reported, 50–70% of people with MDD experience sexual dysfunction.[2] To date, few studies have focused on the comparison of clinical features between patients with MDD with and without genital symptoms, and the longitudinal prognosis.

Data were from the Algorithm Guided Treatment Strategies for Major Depressive Disorder (AGTs-MDD) study, which was registered in ClinicalTrials.gov (https://clinicaltrials.gov/; NCT01764867). The research was approved by the Institutional Review Board of Shanghai Mental Health Center (No.2012-42), and all respondents provided written informed consent. In brief, 1746 subjects were screened from eight mental health institutes from 2012 to 2014, and among them, 964 were diagnosed with MDD according to the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition Text Revision (DSM-IV-TR) criteria. Finally, 845 subjects were enrolled and randomized into the AGT (escitalopram or mirtazapine treatment) or TAU (treatment as usual) group, as described in previous publication.[3] All patients completed the Depression and Somatic Symptoms Scale (DSSS), the 17-item Hamilton Depression Rating Scale (HAM-D), the Hamilton Anxiety Rating Scale (HAM-A), the Quality of Life (QoL) scale, and the Global Assessment Function (GAF) scale at baseline. The DSSS, HAM-D, HAM-A, and QoL scales were completed at every follow-up timepoint. In this study, individuals with a HAM-D score below 14 or a lack of major baseline data were excluded. Subjects experiencing first MDD episode were included. We examined the genital symptoms of subjects using the 14th item of the HAM-D scale. Those who scored 0 points were defined as patients with no genital symptoms (NGS), while those who scored ≥1 point were included in the genital symptoms group (GS). Finally, 325 patients (GS = 177, NGS = 148) with completed baseline information were included, of whom 243 participants completed the 2-week follow-up (GS = 136, NGS = 107), 208 completed the 4-week follow-up (GS = 115, NGS = 93), 176 completed the 6-week follow-up (GS = 99, NGS = 77), 136 completed the 8-week follow-up (GS = 73, NGS = 63), and 125 completed the 12-week follow-up (GS = 67, NGS = 58).

The total HAM-D score and its score reduction rate were used to assess the treatment responses of subjects. All continuous data are expressed as mean and standard deviation (SD) or median with interquartile range as appropriate, and all categorical data are expressed by frequency and percentage. Where data were normally distributed, a parametric Student’s t-test was used to statistically analyze the data. Otherwise, a Mann–Whitney U test was used. Chi-squared tests were applied to categorical data. A univariable binary logistic regression was used to analyze the associations between patients’ genital symptoms and other clinical characteristics. Then, a multivariable logistic regression was used with adjustment of age, sex, and body mass index (BMI). Generalized linear mixed models (GLMM) were adopted to analyze treatment outcomes during the 12-week longitudinal follow-up, and a pairwise contrast was performed using the Bonferroni method. Two-sided tests and an overall alpha level of 0.05 were employed for all primary hypotheses. IBM SPSS Statistics 25 software (IBM Corp, Armonk, NY, USA) was used to conduct statistical analyses.

In total, 325 patients with MDD were enrolled in this study, with a median age of 31.0 (14.0) years and 29.0 (26.0) years, respectively. BMI and education years showed no significant difference between the GS and NGS groups. There was no significant difference in the sex distribution (male: 37.3% [66/177] vs. 40.5% [60/148], χ2 = 0.359, P = 0.549) or medication types (χ2 = 2.278, P = 0.320) between the two groups. Compared with the NGS group, subjects in the GS group had higher scores on the HAM-D (22.0 [7.0] vs. 19.0 [5.0], Z = 4.969, P <0.001), HAM-A (17.0 [9.0] vs. 16.0 [7.0], Z = 2.755, P = 0.006), and DSSS (26.0 [18.0] vs. 22.0 [8.0], Z = 4.074, P <0.001), and lower scores on the GAF (55.0 [10.0] vs. 60.0 [13.0], Z = 2.804, P = 0.005) and QoL (14.67 ± 3.08 vs. 15.54 ± 2.90, t = 2.612, P = 0.009) scales [Supplementary Table 1, https://links.lww.com/CM9/B826].

A univariable binary logistic regression analysis was used to investigate the association between baseline genital symptoms and other clinical characteristics from each item of the HAM-D, HAM-A, and QoL scales. Among all the features, guilt (odds ratio [OR] = 1.46, 95% confidence interval [CI]: 1.15–1.87, P = 0.002), anxiety-somatic (OR = 1.24, 95% CI: 1.01–1.54, P = 0.045), loss of weight (OR = 1.32, 95% CI: 1.01–1.74, P = 0.045), intelligence (OR = 1.37, 95% CI: 1.08–1.74, P = 0.010), cardiovascular symptoms (OR = 1.41, 95% CI: 1.12–1.78, P = 0.003), respiratory symptoms (OR = 1.36, 95% CI: 1.08–1.70, P = 0.009), mental condition (OR = 0.68, 95% CI: 0.47–0.99, P = 0.043), and family relationship (OR = 0.71, 95% CI: 0.56–0.90, P = 0.004) showed statistically significant associations with genital symptoms in patients with MDD. The associations were subsequently adjusted for age, sex, and BMI via a multivariable logistic regression analysis. After adjustment, guilt (OR = 1.48, 95% CI: 1.16–1.90, P = 0.002), anxiety-somatic (OR = 1.25, 95% CI: 1.00–1.55, P = 0.046), loss of weight (OR = 1.33, 95% CI: 1.01–1.77, P = 0.045), intelligence (OR = 1.38, 95% CI: 1.08–1.76, P = 0.009), cardiovascular symptoms (OR = 1.41, 95% CI: 1.12–1.78, P = 0.004), respiratory symptoms (OR = 1.38, 95% CI: 1.09–1.73, P = 0.007), mental condition (OR = 0.66, 95% CI: 0.45–0.97, P = 0.034), and family relationship (OR = 0.71, 95% CI: 0.56–0.91, P = 0.007) displayed significant correlations with patients’ genital symptoms, which was similar to the results of the non-adjusted analysis [Supplementary Table 2, https://links.lww.com/CM9/B826].

Four GLMMs were conducted with the outcome measurements (scores of HAM-D, HAMA, DSSS and HAM-D score reduction rate) as dependent variable respectively. Compared with NGS, GS is associated with higher scores of DSSS (F = 8.415, P <0.004) and HAM-D (F = 9.558, P <0.002), while no significance of the interaction effect of group and time was found. During the 2nd week of the study, the HAM-D score of the GS group was higher than that of the NGS group (15.07 ± 6.51 vs. 12.65 ± 5.83, t = 2.293, P = 0.004). Moreover, both the HAM-A (13.57 ± 7.16 vs. 11.35 ± 6.10, t = 2.538, P = 0.011) and DSSS (19.61 ± 10.41 vs. 15.35 ± 8.81, t = 3.194, P = 0.001) scores of the GS group were higher than those of the NGS group. At the 4-week follow-up, the GS group still had higher HAM-D and DSSS scores compared to the NGS group (11.30 ± 5.89 vs. 8.92 ± 4.94, t = 2.337, P = 0.002; 14.89 ± 8.96 vs. 11.68 ± 8.63, t = 2.850, P = 0.004; respectively). At the 6-week follow-up, the two groups showed no difference in the results of the clinical scales. The score reduction rate of the HAM-D displayed no difference between GS and NGS groups during the entire follow-up period [Supplementary Figure 1, https://links.lww.com/CM9/B826]. We analyzed the changes in genital symptoms in GS group over the follow-up period according to medication choices by the method of GLMM. The model showed significant difference with time as the fixed effect (F = 26.439, P <0.001), while no differences were found when it came to medication (F = 2.377, P = 0.094) and the interaction of time and medication (F = 0.982, P = 0.457). Pairwise contrast exhibited that the TAU group had a better improvement from genital symptoms than escitalopram (t = 2.111, P = 0.035) and mirtazapine (t = 2.277, P = 0.023) groups afrer 2-week treatment, as well as better recovery than the escitalopram (t = 2.502, P = 0.013) group after 4-week treatment.

The study yielded three important findings. First, in comparison to patients without genital symptoms, those with GS had higher HAM-D, HAM-A, and DSSS scores, as well as lower GAF and QoL scores. Second, guilt, loss of weight, intelligence, cardiovascular symptoms, and respiratory symptoms on the HAM-D and HAM-A scales, and the mental condition and family relation item on the QoL scale were associated with genital symptoms in MDD patients. Finally, the GS group exhibited higher HAM-D and DSSS scores after two weeks of treatment, as well as at the 4-week follow-up, indicating that those with genital symptoms would experience a slower recovery from depressive and somatic symptoms in the acute phase of treatment.

For both men and women, antidepressants may induce genital symptoms, involving all phases of sexual activity, including desire, arousal, and orgasm. Antidepressant-induced sexual dysfunction is one of the most under-reported adverse effects of antidepressants. The mechanism underlying antidepressant-induced sexual dysfunction is complex. Among major antidepressant mechanism related neurotransmitters, serotonin (5-HT) is considered to negatively affect sexual function, while dopamine and noradrenaline agonism have been reported to have positive effects on sexual function. Therefore, selective 5-HT reuptake inhibitors (SSRIs) are reported to have a high risk of inducing sexual dysfunction.[4] A previous meta-analysis concluded that escitalopram and paroxetine conferred a higher risk of sexual dysfunction than fluoxetine, mirtazapine, venlafaxine, or bupropion.[5] Therefore, for better implementation of individualized treatment, it is important to assess genital symptoms before and after treatment with antidepressants, which might provide psychiatrists with some clues for antidepressant selection. This study found that MDD patients with genital symptoms experience more severe depressive symptoms, which remind physicians of paying attention to the genital symptoms of patients with MDD and the clinical decision-making and strategies associated with medication choices.

There are several limitations in this study that should be addressed. Except item 14 of the HAM-D scale, no specific genital symptoms assessment scales were included, such as the Female Sexual Function Index (FSFI) and Arizona Sexual Experience Scale (ASEX), to divide patients with or without genital symptoms. An additional study design is needed to further explore sexual-related conditions in patients with MDD. Second, a bias may not be ruled out because HAM-D scores were used as the outcome measurement, while patients were grouped according to item 14 of the HAM-D scale. To reduce the bias, we also used DSSS and HAM-A scores as outcome variables. Finally, the sample size of this study was relatively small.

In conclusion, among MDD patients, those with genital symptoms had more severe depressive and somatic symptoms, and experienced worse QoL than those without such symptoms. In clinical practice, psychiatrists should pay attention to the genital-related symptoms of patients with MDD and ensure they complete a full course of medication.

Conflicts of interest

None.

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