The primary aim of the present study was to investigate the association between the 5-HTTLPR and SD during treatment with antidepressants with contrasting modes of action within the context of the large pharmacogenetic GENDEP study. We hypothesised that there would be a significant association with SD during treatment with the SSRI escitalopram but not during treatment with the TCA nortriptyline.
Our most prominent finding was that the majority of subjects reported no, or only mild, SD despite explicit and frequent assessment. The highest rates of SD were reported at baseline, when subjects were still medication-free, particularly in females. Over the course of treatment, reported SD showed a slight decrease. After 12 weeks of treatment, 16% of males and 24% of females reported moderate or severe SD. The decrease over time was only statistically significant in females, and was based on a pronounced decrease in reported SD within the first study week, i.e. between baseline and week 1. Of those subjects with no SD at baseline, 15.1% in the escitalopram and 16.4% in the nortriptyline group reported SD at week 8; and 14.9% in the escitalopram group and 19.7% in the nortriptyline group reported SD at week 12.
A supplementary analysis of the two more in-depth measures (UKU and SFQ) indicated that lack of desire was the most prominent SD in both men and women. This decreased over time, and escitalopram may have had a more positive effect than nortriptyline. Desire and orgasmic dysfunction were more frequent and severe in women than in men. Sexual difficulties in the other phases of the sexual cycle showed no change, or only a slight decrease, over time. This finding is plausible, since previous reports have suggested that SSRIs and TCAs cause reduced sexual desire and orgasmic dysfunction (Clayton et al. 2006a
; Corona et al. 2009
; Rosen et al. 1999
; Serretti and Chiesa 2009
; Werneke et al. 2006
); however, it could also be due to the depressive disorder. Lack of sexual desire and orgasmic dysfunction are also more prevalent in women than in men in the general population (Laumann et al. 1999
The SD rates in the present prospective and randomised sample are substantially lower than those found in two previous studies by Clayton et al. (2006b
) which reported rates of 34 to 48.7% following eight weeks treatment with escitalopram. In comparison to the present study, the above reports had narrower inclusion criteria. Clayton et al. (2006b)
only included subjects with (self-reported) normal sexual functioning at baseline, who had agreed to report any changes in sexual functioning, and who reported that they were sexually active at least once every 2 weeks. The authors excluded subjects with pre-existing SD, anorexia nervosa, bulimia, seizure disorders, brain injury, panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder or a history of attempted suicide within the previous 6 months. The impact of these differences in study protocol on reported SD rates is unknown. It is plausible, however, that the patients’ knowledge of the explicit aim to assess SD may have enhanced their awareness of such symptoms.
The results of a multinational study that compared escitalopram with paroxetine are consistent with those of the present study (Baldwin et al. 2006
). In both treatment groups, reported SD declined over the course of treatment, and differences between treatment groups were not significant, although reported SD rates were higher than in the present study. Again, the inclusion criteria were more narrowly defined. The authors argued that the decline may have been due to the dropping-out of patients with more severe SD (Baldwin et al. 2006
). However, drop-outs in the present study did not differ substantially from subjects who completed the protocol in terms of reported SD. Moreover, a lower prevalence of ejaculatory problems has been reported for escitalopram compared with other SSRIs following 8 weeks of treatment (Hirschfeld and Vornik 2004
). A small study (N
= 47) reported a reduction in SD in the majority of subjects who switched from other SSRIs or serotonin-norepinephrine reuptake inhibitors to escitalopram (Ashton et al. 2005
). Escitalopram is associated with lower rates of treatment-withdrawal, and fewer discontinuation symptoms, than paroxetine (Baldwin et al. 2006
It is important to acknowledge that SD is widespread in the general population. Estimates of 11% for frequent or severe SD and 69% for infrequent or mild difficulties have been reported. Men predominantly report ejaculatory problems, with overall rates of between 10 and 20%, whereas lack of sexual desire is most prevalent in women, with rates of between 20 and 25%. Women also report higher rates of orgasm dysfunction than men (Laumann et al. 1999
; Montgomery et al. 2002
; Derogatis and Burnett 2008
; Laumann et al. 2009
; Christensen et al. 2010
). In the present study, the SD rates reported after 12 weeks of antidepressant treatment (16% in males and 24% in females) only slightly exceed the SD rates in the general population.
Given the rather low rates of reported SD, it is not surprising that we failed to detect a major influence of study medication or the 5-HTTLPR on reported SD or its time course in the analysis of the main outcome measure. No significant differences in reported SD were observed between patients receiving escitalopram and those receiving nortriptyline.
A more pronounced decrease in reported SD was found in subjects whose depression improved substantially. This is consistent with previous findings for escitalopram, duloxetine, nortriptyline, and sertraline, and suggests that SD is influenced by the remission of depression and may not be a side-effect of antidepressant treatment (Lanza di Scalea et al. 2009
). The effect was similar for the three depressive symptom dimensions “observed mood and anxiety", “cognitive symptoms", and “neurovegetative symptoms". This may be due to the high correlation between the changes in depressive symptoms over time across the three dimensions. Observed mood and anxiety symptoms showed the most pronounced improvement and neurovegetative symptoms the least. The effects of study medication on the improvements in each of these three symptom dimensions have been described and discussed elsewhere (Uher et al. 2009c
We also observed an influence of age on reported SD. Younger subjects reported less SD than older subjects particularly for desire and erection difficulties. This finding is plausible, since age is an established risk factor for SD (Phanjoo 2000
; Derogatis and Burnett 2008
; Corona et al. 2010
Finally, we found no influence of 5-HTTLPR
genotype on reported SD on average, over the time course of treatment, or in interaction with the study medication. However, our data suggest a possible influence of age on the association between the 5-HTTLPR
genotype and reported SD. The influence of age on sexual function may be more pronounced in s/s subjects than in patients with the genotype s/1 or 1/1. One previous report found that the s/s genotype was associated with less SD than the 1/1 genotype during SSRI treatment, although this study did not report any influence of age (Bishop et al. 2009
). However, the age distribution of the Bishop et al. sample (2009)
differed significantly (t
= 11.70, P <
0.01) from that of the present study. In the present sample, subjects with genotype data were between 19 and 72 years of age, and the mean age was 42.11 years. The study by Bishop et al. (2009)
included relatively young patients of between 18 and 40 years of age (mean of 29.2 years) in order to minimise the confounding effect of age on the presence of SD. The lower proportion of older subjects may explain why Bishop et al. (2009)
found no influence of age on the association between the 5-HTTLPR
genotype and reported SD.
The present study met several of the methodological quality criteria for the evaluation of antidepressant related SD (Montgomery et al. 2002
; Schweitzer et al. 2009
). These included: (i) a randomised and prospective design; (ii) comparisons between different treatments; (iii) a baseline assessment; (iv) the use of defined diagnostic criteria for depression; (v) the application of reliable and validated rating scales for the assessment of SD in men and women; (vi) direct assessment of depression and sexual function before and during treatment; and (vii) consideration of the possible effects of degree of remission and gender on the outcome variables. However, the study had several limitations. Firstly, we did not control for comorbid illness or concomitant medications that might affect normal sexual function. A previous study, which involved neither random assignment nor baseline control, controlled for these factors and compared several different antidepressants. This found the highest prevalence rates for SD during treatment with the SSRI citalopram (Clayton et al. 2002
). We did, however, exclude individuals who had a contraindication to both study medications, who were currently being treated for a somatic disease using potentially depressogenic medications, or who were using other psychotropic medications, with the exception of the occasional use of hypnotics. A second very important limitation is that patients were not asked whether they had a sexual partner or questioned about their actual sexual activity during the course of the study (sexual intercourse, sexual fantasies, or other sexual activities). As already mentioned, Clayton et al. (2006b)
only included subjects who had normal orgasmic function and who were sexually active. Future comparative well-designed randomised controlled trials of SD during antide-pressants treatment for depression should include sexually active subjects, or at least involve enquiry about sexual activity, to determine the clinical significance of differences in SD (Schweitzer et al. 2009
). Thirdly, the study was not double-blind, with in most cases in fact both the treating psychiatrist and the patient knowing which medication was being prescribed. However, knowledge of the possibility of higher SD rates during SSRI treatment is likely to have resulted in increased, rather than decreased, monitoring and awareness of these symptoms by patients. A further limitation is that our assessment of SD did not include any evaluation according to the detailed DSM-IV criteria for SD (Haberfellner 2007
). Finally, our genetic analysis was limited to the 5-HTTLPR,
and it therefore remains unclear whether other polymorphisms in the serotonin transporter gene influence the development of SD.
In summary, the present study of a large multi-centre European sample found no interaction effect for 5-HTTLPR genotype and two antidepressants with contrasting primary modes of action on reported SD. In addition, no differential influence of study medication per se was found, with the exception of a possible beneficial effect on desire dysfunction for escitalopram compared to nortriptyline. The rate of reported SD was rather low, with only minor changes or improvements being reported during the course of treatment, despite the application of three different measurement tools. We identified an influence of change in depressive symptoms and age on reported SD. The unexpectedly low rate of SD reported during treatment with both medications is a noteworthy finding of the present study, which may have important implications for clinical practice.