Sexual dysfunction is a common symptom of major depressive disorder (MDD), and a side effect of treatment with serotonergic antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs).
Antidepressant treatment may improve sexual dysfunction, as sexual functioning may improve as depressive symptoms improve. However, treatment-emergent sexual dysfunction (TED) is a common side effect of serotonergic antidepressant therapy, with an estimated prevalence between 4% to 73%.
SSRIs and SNRIs alter the three phases of the sexual response cycle (desire, arousal and orgasm), potentially reducing self-esteem and quality of life and affecting relationships. MDD is a chronic, relapsing disease that requires long-term treatment. Adequately treated patients with depression who experience DSET may not mention their sexual side effects to their doctor, which may lead to noncompliance or complete discontinuation of treatment.
Management strategies to alleviate DSET include dosage or antidepressant changes, medication holidays, and complementary therapies to improve symptoms. Switching to a different antidepressant is common in patients who do not respond to treatment; but there is a lack of studies that evaluate the change in patients whose symptoms are adequately treated.
Vortioxetine is a multimodal antidepressant for the treatment of MDD. It combines two modes of action: direct modulation of 5-HT receptor activity and inhibition of serotonin reuptake.
During its development program, randomized controlled trials (RCTs) were conducted in adults with MDD that prospectively evaluated DSET using the Arizona Scale of Sexual Experiences (ASEX). Lower doses of vortioxetine had similar incidences of DSET to placebo, and while DSET increased with increasing dose, no dose of vortioxetine had a significantly higher risk of developing DSET vs. placebo.
To evaluate the effects of direct switching to vortioxetine in patients with MDD and DSET attributed to current treatment with SSRIs (citalopram, sertraline or paroxetine), but with well-treated depressive symptoms, a comparative trial of vortioxetine vs. escitalopram (an SSRI).
Primary analyzes showed that vortioxetine was superior to escitalopram in improving SSRI-induced sexual dysfunction as assessed by the Changes in Sexual Functioning Questionnaire-14 (CSFQ-14), while maintaining antidepressant efficacy in adults with MDD. Vortioxetine was significantly superior in all three phases of the sexual functioning cycle assessed by the CSFQ-14.
The objective of this study was to provide descriptive characteristics and analyzes of DSET, antidepressant efficacy, and tolerability as a result of direct switching in adults with well-treated MDD, but SSRI-induced sexual dysfunction, from SSRI monotherapy to vortioxetine monotherapy or escitalopram.
Pre-specified analyzes included analysis of individual CSFQ-14 items for the escitalopram or vortioxetine groups, and post hoc analyzes measuring CSFQ-14 total scores for both groups based on pre-switch SSRI and sex.
Additional analyzes were performed to determine the influence of factors such as age, duration of prior SSRI therapy, prior treatment for MDD, number of prior major depressive episodes (MDEs), and any childhood traumatic events on the CSFQ-14 total score after of treatment with vortioxetine or escitalopram.
The efficacy of both drugs was compared with the pre-switch efficacy of SSRIs against depressive symptoms. Finally, treatment-emergent adverse events (TEAEs) were analyzed.
| Methods |
An 8-week, multicenter, randomized, double-blind, parallel-group, flexible-dose head-to-head comparison of vortioxetine and escitalopram was conducted in male and female patients with well-treated MDD who were experiencing SSRI-induced DSET.
Patients who previously received citalopram, sertraline, or paroxetine for at least 8 weeks were eligible for switch to vortioxetine or escitalopram. The objective of the study was to evaluate the improvement in SSRI-induced sexual dysfunction in participants who switched to vortioxetine vs. escitalopram as assessed by the CSFQ-14.
Men and women aged 18 to 55 years who were receiving a stable regimen of citalopram, paroxetine, or sertraline monotherapy for ≥8 weeks to treat MDE were included.
Eligible participants had stable depressive symptoms, were sexually active prior to initiation of current MDE and/or SSRI use; and were experiencing DSET attributed to their current SSRI treatment according to the investigator’s judgment.
In the clinical study, participants were randomly assigned to receive 10 mg daily of escitalopram or vortioxetine during the first week, with the dose titrated to 20 mg during the second week. After the second week, flexible dosing (10/20 mg) was allowed.
Sexual functioning was assessed at each clinic visit using the CSFQ-14. Total possible scores ranged from 14 to 70, with lower scores indicating worsening/poverty of sexual functioning.
Additional outcomes included antidepressant efficacy based on the Montgomery-Åsberg Depression Rating Scale (MADRS), and the Clinical Global Impression-Severity [CGI-S] and Improvement (CGI-I) scales. 15 TEAEs were assessed for all participants at baseline and at the end of weeks 1, 2, 4, 6, and 8.
Post-hoc analysis of change in CSFQ-14 was performed based on age, duration of prior SSRI treatment, prior SSRI, number of prior MDEs, MDD treatment history, history of traumatic events infants and remission status on the MADRS (total score ≤10).
The age limit of the women was related to the perimenopausal hormonal level that could affect sexuality, so this cohort was divided into those under or over 45 years of age. Previous SSRI use was divided into two subgroups: those taking SSRIs for ≤1 year or >1 year. The number of previous MDEs can influence recurrence and response to treatment, so subgroups were separated according to the number of occurrences.
| Results |
Of 711 participants, 447 were randomized and 348 (77.9%) completed the study. Fifty-six (24.9%) patients in the vortioxetine group and 43 (19.4%) in the escitalopram group discontinued the study prematurely due to TEAEs. At the start of the study, most patients were in remission.
The mean CSFQ-14 scores at baseline for vortioxetine and escitalopram were 36.5 and 36.3, respectively, indicating significant sexual dysfunction. After 2 weeks of treatment, the majority of participants were on a therapeutic dose of 20 mg (escitalopram, 71.9%; vortioxetine, 65.6%). There were no significant differences in demographic data or clinical characteristics between both groups.
Of the 447 participants, approximately half were pretreated with citalopram (n = 235), followed by sertraline (n = 146) and paroxetine (n = 66). Baseline CSFQ-14 total scores and mean age were similar across prior SSRI treatments. More than 65% indicated having one to three previous EDMs, and the rest between zero and more than three previous EDMs.
Participants who switched from citalopram had the lowest number of MDEs ([mean ± standard deviation (SD)] 1.9 ± 1.65 vs. 2.1 ± 1.37 for paroxetine and 2.0 ± 1.74 for sertraline ), the lowest mean MADRS score (7.6 ± 5.94 vs. 8.9 ± 6.62 and 8.5 ± 6.97 for paroxetine and sertraline, respectively), and the lowest mean score on the CGI- S (2.0 ± 0.81 vs. 2.2 ± 0.84 and 2.1 ± 0.83 for paroxetine and sertraline, respectively). In contrast, the subgroup with prior paroxetine had the highest number of prior MDEs, and the highest mean MADRS and CGI-S scores.
Subgroup distributions were similar for duration of current MDE, with half of patients reporting a duration between 3 months and 1 year and the other half more than 1 year; the median MDE for all subgroups was 53 weeks. 40% of participants indicated having had traumatic events in childhood, with a higher incidence in the citalopram group.
Participants who switched to vortioxetine had significantly greater improvements in CSFQ-14 total and individual item scores across 8 weeks of treatment than those who switched to escitalopram.
In post hoc analyses, improvements in sexual function were observed with both vortioxetine and escitalopram regardless of the prior SSRI. The citalopram/vortioxetine and sertraline/vortioxetine subgroups experienced greater improvement in overall sexual function than participants treated with citalopram/escitalopram or sertraline/escitalopram, respectively, while the greatest improvement with escitalopram was demonstrated in the paroxetine/escitalopram subgroup. .
Improvements in sexual function were observed beginning in the 2nd week and continued to increase in those treated with vortioxetine, but those treated with escitalopram appeared to experience a plateau.
After 8 weeks of treatment, overall, the greatest improvements in sexual functioning were seen in the citalopram/vortioxetine group for men, while the greatest improvements for women were seen in the sertraline/vortioxetine group.
Post-hoc analysis in the female subgroup revealed that the improvement in sexual function was greater in the vortioxetine group, regardless of age. In women ≤45 years of age, the improvement in the vortioxetine group vs. escitalopram was also statistically significant.
In the subgroup of participants with ≤1 year of prior SSRI treatment, improvement in sexual function was similar for both vortioxetine and escitalopram. In the subgroup with >1 year of prior treatment, the improvement in those treated with vortioxetine was significantly greater. In those without a history of prior EDM (first episode), the improvement in sexuality was similar for vortioxetine and escitalopram, and was greater than for the other two groups (1–3, >3 EDM).
In the subgroup of ≥3 MDEs, the improvement in the escitalopram group was greater but not significant, and in participants with a history of 1 to 3 MDEs, the improvements in the vortioxetine group were significantly greater.
Participants with prior SSRI treatment for EDM had significantly greater improvements with vortioxetine than with escitalopram. Those receiving “other therapies (including SNRIs)” had greater improvements with vortioxetine, but the number for this subgroup was low. Although there was greater improvement in the group with childhood traumatic events treated with vortioxetine vs. escitalopram, the differences were not significant.
Participants who entered the study were well treated for their depressive symptoms and generally had low MADRS and CGI-S scores at entry. Those who switched to vortioxetine and escitalopram maintained the antidepressant efficacy achieved with their previous SSRI as measured by these scales.
The largest mean reductions in MADRS total scores were observed in participants who switched from sertraline, and the smallest in the prior paroxetine subgroups. Changes in CGI-S scores from baseline to week 8 were small and consistent with changes in the MADRS.
CGI-I scores at week 8 were similar between the treatment cohorts analyzed. At baseline, most participants were in remission. The paroxetine subgroup had a lower percentage of participants in remission at week 8.
Remission rates in all subgroups were similar during the 8-week treatment period. By week 8, there were no significant differences in the percentage of MDD remitters between vortioxetine and escitalopram, regardless of prior antidepressant. These data suggest that escitalopram or vortioxetine at the doses administered in this study were adequate to maintain remission for at least an 8-week period in participants switching from SSRI treatment.
Both escitalopram and vortioxetine were well tolerated, with low discontinuation rates due to TEAEs (6.3% and 9.4%, respectively). The most common TEAEs in the vortioxetine treatment group were nausea, headache, dizziness, and generalized pruritus. Prior treatment with SSRIs did not appear to influence the overall incidence or severity of TEAEs, except for nausea, with a higher incidence in the vortioxetine group.
| Discussion |
Individuals with MDD whose symptoms of depression are adequately treated with SSRIs may experience DSET. This study provides relevant information on the tolerability and efficacy of switching from SSRIs citalopram, sertraline or paroxetine to vortioxetine or escitalopram. Considering that DSET rates vary depending on antidepressant treatment, we investigated whether the SSRI had an effect on post-switch DSET and efficacy with vortioxetine or escitalopram.
Regardless of prior SSRI, both treatment groups showed maintenance or improvement in sexual function after the direct switch. Those who switched from sertraline to vortioxetine showed greater improvements in CSFQ-14 total scores than those who switched to escitalopram. There were no significant differences for those switching from paroxetine or citalopram.
We investigated whether the immediate pre-switch SSRI would affect the post-switch DSET response differently between sexes. Although there was some difference observed between men and women in change from baseline in CSFQ-14 function, the small number of participants in each subgroup limited interpretation of the findings. We also evaluated whether participant characteristics predicted improvement in DSET after switching to vortioxetine vs. escitalopram.
Participants’ age and sex (≤45 years, female), at least 1 year of prior SSRI treatment, one to three prior MDEs, and prior treatment with sertraline, other SSRIs, or non-SSRI therapies were all factors that appeared to correlate with Vortioxetine-mediated improvements in sexual functioning. Although the difference in the treatment effect on the CSFQ score was statistically significant for each of the subgroups, the sample sizes varied making comparisons difficult.
Participants who switched directly from citalopram, sertraline, or paroxetine to escitalopram or vortioxetine maintained antidepressant efficacy. In participants switching from citalopram, greater improvements in MADRS total scores were seen with vortioxetine vs. escitalopram. In the subpopulation switching from paroxetine or sertraline, only modest differences were observed between treatment groups.
The findings of the present study demonstrated that in adults with well-treated MDD and SSRI-associated sexual dysfunction, abrupt switching to once-daily vortioxetine was a safe and feasible approach to improve sexual function while maintaining antidepressant efficacy. Although direct switching to vortioxetine was well tolerated in most individuals, it was a reason for discontinuation in some. Higher rates of nausea were observed with vortioxetine than with escitalopram, and this effect persisted throughout the treatment period.
Although the incidence of TEAEs was comparable between treatment groups, nausea, dizziness, and pruritus were more common in the vortioxetine group. However, in practice, the risk and severity of these symptoms with vortioxetine can be considered reasonable, especially when switching to agents that may improve DSET.
Additional strategies may be considered to mitigate the risk of nausea-related treatment discontinuation, such as initiating vortioxetine at a lower dose (avoiding abrupt discontinuation of the previous SSRI) and/or increasing the dose from baseline over a longer period of time. long, instead of in just 1 week.
In this study, the increase to 20 mg of vortioxetine was done over a short period of time to ensure evaluation of antidepressant efficacy and sexual dysfunction at the highest approved dose.
Although there is a relationship between DSET and high doses of vortioxetine, the majority of subjects remained on 20 mg. Therefore, there are many options to address treatment-associated nausea and sexual dysfunction.
Interpretation of these findings is limited by the nature of the study design, limiting the ability to detect statistically significant differences. The study was not powered to perform subgroup analyzes of the primary or efficacy endpoints.
| Conclusion |
These analyzes support the findings that switching antidepressant therapy from SSRIs to vortioxetine in well-treated adults with MDD experiencing DSET can improve sexual dysfunction independently of prior SSRIs, while maintaining antidepressant efficacy and tolerability.
Overall, switching to vortioxetine appears to be a safe and effective alternative for patients who experience sexual dysfunction during antidepressant therapy with an SSRI.
