1. Introduction
Antidepressants are frequently associated with sexual dysfunction (SD), particularly SSRI serotonergic agents, dual-action drugs, and clomipramine [
1]. Other drugs with different mechanisms of action appear to cause fewer sexual adverse effects (mirtazapine, bupropion, moclobemide). Unfortunately, the real incidence of SD is underestimated, and specific questionnaires must be used. Spontaneous reporting of this adverse effect is around 15%-20%, while real figures exceed 60%-80%, [
2,
3]. The problem is significant and it is closely associated with treatment dropout, particularly in the case of long-term treatments, and has a negative impact on the quality of life of patients and their partners [
4].
Vortioxetine (VOR)] seems to have better profile in terms of SD, although most data comes from clinical trials with registration purposes that may have some methodological limitations, such as the depressive population examined and short-term data [
5]. SD rates vary between 0.9% and 45%, depending on the study methodology. Since the serotonergic mechanism of action seems to be closely linked with the etiology and pathogenesis of depression [
6], drugs increasing serotonin availability are generally associated with high rates of SD, as this neurotransmitter is very closely involved with inhibition of sexual function, impulsivity, and appetite among others.
The physio pathogenic mechanisms of these phenomena appear to be multifactorial and complex [
7]. One mechanism is the increase in circulating serotonin and the activation of serotonin 5-HT2A receptors that could affect orgasmic function and sexual interest. Erectile dysfunction appears to be caused by changes in nitric oxide functioning and activation of peripheral adrenergic receptors.
Management of SD has been attempted using various approaches [
8]: waiting for spontaneous remission, dose reduction, or switching to another drug with a lower profile of impact on sexual functioning or use of "antidotes” such as sildenafil or other similar compounds [
4,
9]. Given the high rates of sexual dysfunction nowadays usually left unaddressed by clinicians, its impact on patients’ quality of life and treatment discontinuation (estimated at over 35%), this problem must be directly investigated in all patients who receive antidepressants.
In the last 10 years, a very significant increase has been observed in the number of publications addressing this topic, and rising rates of SD have been detected with the use of specific questionnaires [
10,
11,
12], compared to the initial estimates obtained from spontaneous patient reports. Initial data on the incidence of SD obtained retrospectively ranged widely: between 5% and 75% depending on the study methodology used.
In previous studies using the validated questionnaire Psychotropic-Related Sexual Dysfunction Questionnaire [
10] the mean incidence of SD with SSRIs and dual-action agents was as high as 80% among sexually active patients [
3]. The questionnaire analyses the following variables on a scale of severity or frequency: 1) lower libido; 2) delayed orgasm/ejaculation; 3) absent orgasm/ejaculation; 4) erectile/vaginal lubrication dysfunction; and 5) patient’s tolerability of sexual dysfunction and risk of discontinuing treatment. The author and the working group have published numerous studies that use this method to evaluate frequency of SD, risk of discontinuation, impact on quality of life, studies in healthy volunteers, clinical management procedures, and global review studies, such as that of World Psychiatry 2018 [
4].
The questionnaire has been translated into multiple languages including French, English, Italian, German, Portuguese, Greek, Swedish, Finnish, Polish and Japanese, and has recently also been validated in Mandarin Chinese.
The mean incidence of SD among patients receiving SSRIs was 62.9%, although only 14%-22% [
13,
14] of these patients spontaneously reported any dysfunction. Although this is a common side effect of all SSRIs and dual-action drugs, the highest rates were reported with paroxetine for several reasons: its powerful serotonergic action, its effect on increasing prolactin and inhibiting nitric oxide, and its greater anticholinergic effect. The most common problems were reduced desire and delay in achieving orgasm. Erectile dysfunction is less common, although rates associated with paroxetine, citalopram, and venlafaxine at standard therapeutic doses were around 30%-40%. Absent orgasm or ejaculation is clearly the most poorly tolerated side effect in patients of both genders.
In contrast, the rates of SD caused by mirtazapine, bupropion, and agomelatine are lower than those of SSRIs [
1], due to their different mechanisms of action: mirtazapine blocks postsynaptic 5- HT2 receptors (the stimulation of which has been closely related with the development of ejaculation and orgasm changes); bupropion has a dopaminergic/adrenergic action; and agomelatine is a melatonin receptor agonist and HT2C antagonist.
An American group led by Anita Clayton (University of Virginia) also used a specific questionnaire, the Changes in Sexual Function Questionnaire (CSFQ) [
12]. After screening a population sample with inclusion and exclusion criteria, their results were similar to the Spanish series, and contributed data on the low prevalence of bupropion associated SD, lower than 10% [
15].
There appear to be differences between genders. Males over 40 years of age generally tolerate SD worse than females [
3], but this is not observed in younger individuals, and at least one third of patients considered discontinuing treatment for this reason. In contrast, other patients, such as those with premature ejaculation, accepted their SD well: the delay in achieving ejaculation experienced after starting antidepressant treatment “normalized” their ejaculatory time. Surveys conducted in large patient series report discontinuation figures between 41.7% and 50.8% [
14].
Although reports from medical records of antidepressant use refer to a very low incidence of SD (2%-16%) [
16], the real incidence almost always goes unnoticed unless targeted interviews are conducted to explore this adverse effect. In studies in which patients were directly asked about their sexual functioning after starting treatment, only 14%-20% reported SD spontaneously, and the rest concealed it from their doctor, even if they suspected that this could be due to the medication [
13,
14].
In clinical practice, doctors are often unaware and unable to manage the appearance of these side effects. This approach would avoid the possibility of patients discontinuing treatment, particularly among those who require it at long-term.
With regards to clinical management, the treatment of SD caused by antidepressants has not been examined using controlled and extensive studies. Scant data are available to guide clinicians on the most appropriate choice in each case, and no controlled clinical trials have been performed in this area.
In the ELIXIR study [
17] clinicians were asked about their treatment choice in cases of SD due to antidepressants. The results indicated that most psychiatrists opted for no intervention, and preferred to wait for spontaneous remission, and a small percentage chose to switch treatment or to add an antidote. In Spain, [
3] a clinical study with more than 2,000 patients found a rate of SD of over 80% in patients who were receiving SSRIs or dual-action agents. Spanish doctors opted to wait for spontaneous remission in 25% of cases or else switched to bupropion or agomelatine in 30% of cases. Results were better for agomelatine (80% reduction in SALSEX scores [
18,
19]. The use of PDE5 inhibitors, such as sildenafil or weekend drug holidays, was very rare.
The experience in our country shows that while patients with at least 3 months following can benefit from switching to other non-serotonergic antidepressants in order to Improve SD, they can be at risk of clinical deterioration or depressive relapses in one in three cases. Therefore, new therapeutic alternatives must be found. In the absence of meta-analyses and specifically designed clinical trials, the recommendations obtained from analyzed data from published studies [
18] suggest different levels of evidence including switching to another antidepressant (agomelatine, bupropion or mirtazapine), weekend drug holidays (useful in the absence of orgasm), and PD
5 Inhibitors among others.
Due to the lack of an effective treatment with favorable, persistent results in antidepressant treatment- emergent SD, newer products with different mechanisms of action that could have less effect on sexual functioning must be explored. One of them is vortioxetine, which has a multimodal mechanism of action on different receptors, with full agonist effect on 5-HT1A, partial antagonism on 5-HT1B, and antagonist effects on 5HT1D, 5-HT3 and 5-HT7, in addition to displaying a dopaminergic, adrenergic, histaminergic, and cholinergic effects. Given the lack of current evidence regarding this topic, specific studies in routine clinical practice and in carefully selected populations are required to confirm these preliminary data.
2. Study Rationale:
Vortioxetine is a recently developed antidepressant with a novel mechanism of action. Data from clinical trials for registration purposes suggest a neutral, or even beneficial, effect on sexual functioning in depressive patients receiving vortioxetine [
20,
21], which has since been proved again in a recent phase IV randomized study [
22]. A switching study showed that vortioxetine is a safe and effective switch therapy for treating SSRI-induced sexual dysfunction in adults with well-treated MDD [
23]. Also, improvement in sexual dysfunction with vortioxetine or escitalopram may be influenced by prior SSRI usage, sex, age (≤45 years, women) and history of one to three major depressive episodes [
24]. For example, a recent study in postmenopausal transition women observed less antidepressant induced SD with vortioxetine when compared to paroxetine [
25], although the exact dose was not specified. However, overall limited data have been published to date regarding the effects of this antidepressant on sexual functioning.
Vortioxetine with this novel mechanism of action could have some implications in less sexual dysfunction. In a recent randomized, double-blind trial with vortioxetine (15–20 mg/day), treatment-emergent sexual dysfunction symptoms were not significantly different versus placebo using the ASEX Scale [
20]. In addition, in another short (8 weeks) randomized, double blind clinical trial with vortioxetine 10–15 mg/day in depressed patients ASEX total scores were similar across groups [
26]. In an open-label, flexible-dose (2.5–10 mg/day), 52-week extension study that evaluated the long-term safety and tolerability of vortioxetine, the rate of adverse events related to sexual dysfunction was low [
27]. Moreover, a recent prospective epidemiological study shows that females (but not males) treated with vortioxetine presented better sexual function than those treated with SSRIs or Duals and a lower risk of sexual dysfunction. [
28]
In a recent review [
29], authors stated that vortioxetine is well tolerated, but is associated with significantly increased sexual dysfunction at a dosage of 20 mg; however, vortioxetine was shown to improve previous-treatment-emergent sexual dysfunction in patients with well- treated MDD to a greater degree than escitalopram. These studies show some limitations when studying this topic, such as lack of a control group with sexually active patients in a naturalistic setting, so further specific studies are needed.
Therefore, the aim of this study is to determine the frequency and intensity of sexual dysfunction (SD) after a switching to vortioxetine from another antidepressant due to TESD.
6. Project Development Stages
The study was conducted in the Department of Psychiatry of the Hospital Universitario de Salamanca, with the participation of 10 investigators from 5 Mental Health outpatient Units located in Salamanca, which provides care for a population close to 300,000 inhabitants.
The study was performed in 3 phases between July 2019 and September 2022. The recruitment was delayed due to COVID 19.
All administrative permissions, including submission of the protocol for qualification by the Spanish Agency of Medicines, agreement from the Research Ethics Committee of the Salamanca Health Area, and agreement from the Government of Castile and Leon were obtained in 2019. Investigators’ meeting was carried out in January 2020 for an explanation of the protocol, standardization of procedures, training, and practical administration of the SALSEX questionnaire to reduce inter-investigator variability. The collection of baseline socio-demographic data was obtained and included in the CRF, as well as all selection criteria, presence, and severity of the psychiatric disease (measured using the CGI-S scale), presence and severity of SD (measured with the SALSEX questionnaire and the CGI-S-SD), and randomized therapeutic strategy of antidepressant switch for the management of SD associated with antidepressant treatment.
Clinical follow-up of patients with SD detected at baseline visit included the measurement, within 3 months after baseline, of the effectiveness of the intervention using the SALSEX scale (lower scores indicate improvement), and a Clinical Global Impression-Improvement for depression (CGI-IDep) and for sexual functioning (CGI-ISex) after intervention. A determination of the number of patients withdrawing from the study due to lack of efficacy, adverse effects or loss to follow-up was performed.
9. Conclusions
According to our primary objective, the global Sexual Dysfunction measured with the SALSEX Scale, decreased significantly from baseline visit to follow-up visit (3 months). Switching to vortioxetine is an effective and reliable strategy to treat patients with poorly tolerated previous antidepressant -related sexual dysfunction and at risk of treatment discontinuation in real-life clinical settings. After switching to Vortioxetine, 83.81% of patients improved their sexual function.
All components of sexual dysfunction (decreased libido, orgasmic functioning, and arousal difficulties) improved significantly after switching to vortioxetine, especially decreased libido. Individual tolerance and risk of treatment discontinuation improved using the PSRSexDQ-SALSEX questionnaire from baseline to endpoint visit.
Both sexes improved significantly with vortioxetine, although females had a higher rate of SD than males both at baseline and at follow-up.
No significant differences in SD were found between different dosages of vortioxetine although there was an increase in the SALSEX score as the dose increased mainly with 20 mg/day.
Most patients (83.3%) who switched to vortioxetine continued treatment after the 3 months follow-up visit. Additionally, 58.1% of patients showed an improvement in depressive symptoms from baseline visit.