Curr Sex Health Rep (2014) 6:177–183 DOI 10.1007/s11930-014-0022-x

INTEGRATING THE PSYCHOSOCIAL (B MCCARTHY, RT SEGRAVES AND AH CLAYTON, SECTION EDITORS)

Antidepressant-Induced Sexual Dysfunction: an Updated Review Rajnish Mago & Rajeev Mahajan & Dileep Borra

Published online: 27 May 2014 # Springer Science+Business Media, LLC 2014

Abstract Antidepressant-induced sexual dysfunction (ADISD) is a common problem and is associated with a significant risk of nonadherence. Serotonergic antidepressants are associated with a substantial risk of ADISD. Bupropion, transdermal selegiline, nefazodone, and moclobemide are associated with a lower risk of ADISD, and early data suggests that this may also be true for vilazodone. Only 10 % of patients show spontaneous improvement in ADISD on waiting and watching. This strategy should be reserved for patients earlier in the course of the adverse effect. When possible, switching to an antidepressant with a lower incidence of ADISD is a recommended strategy. When continuation of the offending antidepressant is essential, addition of an antidote may be tried. While early data were not encouraging, two large randomized, controlled trials have provided strong evidence supporting the use of bupropion as an antidote for ADISD. Phosphodiesterase-5 inhibitors like sildenafil and tadalafil have been shown to be efficacious in a substantial proportion of patients. Attention to ADISD is very important given that it is an important cause of nonadherence to antidepressants. Keywords Antidepressant . Sexual dysfunction . Libido . Erectile dysfunction . Nonadherence . Orgasm . Adverse effects . SSRIs . SNRIs . Bupropion . Sildenafil . Tadalafil . Saffron . Buspirone . Vilazodone . Vortioxetine . Agomelatine . Transdermal selegiline . Reboxetine . Moclobemide

Introduction Sexual dysfunction is one of the most distressing adverse effects associated with longer-term treatment with antidepressants [1]. Antidepressants may adversely affect different aspects of sexuality: desire, arousal, or orgasm. However, problems with delayed or absent orgasm are more common than decreased desire or difficulty with arousal [2]. Antidepressant-induced sexual dysfunction (ADISD) reduces improvements in quality of life associated with antidepressant treatment [3]. In a survey of patients, ADISD was among the top 3 adverse effects that patients with depressive disorders said they wished to avoid when taking antidepressants [4]. In the STAR*D study [5], adverse effects described as being “extremely difficult to live with” included being “unable to have erection” (25 %) and “difficulty reaching orgasm” (24 %) whose prevalence was exceeded only by weight gain (31 %). Similarly, in 1,137 outpatients, the most common (for 20.3 % of patients) single reason given by the prescribing psychiatrists for choosing a particular antidepressant was to avoid sexual dysfunction [6]. ADISD is associated with an increased risk of discontinuation of the antidepressant. In a survey of outpatients [7], 38 % of patients with sexual dysfunction while taking an antidepressant reported that it was unacceptable and led to a significant risk of future nonadherence. We reviewed current literature on the epidemiology, mechanisms, and management of ADISD with emphasis on recently published literature. The review focuses on newer antidepressants and excludes tricyclic antidepressants and older monoamine oxidase inhibitors that are now infrequently used.

This article is part of the Topical Collection on Integrating the Psychosocial R. Mago (*) : R. Mahajan : D. Borra Mood Disorders Program, Department of Psychiatry and Human Behavior, Jefferson Medical College of Thomas Jefferson University, 833 Chestnut St, Suite 210E, Philadelphia, PA 19107, USA e-mail: [email protected]

Incidence of ADISD It should not be surprising that the estimated incidence and prevalence of ADISD vary depending on the definition of

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ADISD, population, antidepressants and instruments used, etc. Nevertheless, numerous studies have shown that the incidence and prevalence of this problem are very high. In nonrandomized, naturalistic settings, Montejo et al. [7] conducted a survey of 1,022 outpatients in Spain that used a specific questionnaire for sexual dysfunction. Sexual dysfunction, defined as dysfunction that was not preexisting but developed within 2 months of antidepressant medication initiation, was reported in 59 % of patients, varying from 4 to 73 % depending on the antidepressant. Clayton et al. [8] studied 802 patients who were on a single antidepressant using a structured questionnaire. They attempted to rule out (as much as possible) sexual dysfunction due to age, comorbid illnesses, or other medications that could affect sexual function. Sexual dysfunction was reported in 24 % of patients, varying from 7 to 30 % depending on the antidepressant. While observational studies are valuable in providing data on larger numbers of patients and in naturalistic settings, they are also heavily prone to bias. Inclusion of observational studies or of studies that did not use a specific instrument to assess sexual dysfunction is partly responsible for continued uncertainty in the literature despite publication of numerous reviews on ADISD. Therefore, in order to clarify issues of incidence of ADISD, in the rest of this section, randomized, controlled studies that used a specific questionnaire to assess sexual dysfunction have been given precedence. Differential Incidence of ADISD There is evidence that some antidepressants are associated with greater or lesser ADISD than others. Evidence for this can include comparison to an SSRI or to placebo.

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sexual dysfunction as an adverse event was 21.6 % with SSRIs and only 1.9 % with moclobemide. Reboxetine In a randomized, controlled trial (RCT) in patients with MDD, TESD with reboxetine was less than that with fluoxetine and was not different from placebo [14]. An RCT comparing reboxetine to citalopram found that though improvement in depression was numerically greater in the citalopram group, sexual functioning at end of treatment was better in patients on reboxetine [15]. On a sexual functioning questionnaire, libido improved markedly in women treated with reboxetine but remained low in the citalopram group. Among sexually active women, anorgasmia decreased from 33.3 to 5.9 % in the reboxetine group while in the citalopram group, the prevalence of anorgasmia increased from 30.8 % at baseline to 39 % at end of treatment. Among men, libido and erectile function did not differ between the two groups, while delayed ejaculation decreased in the reboxetine group but increased in the citalopram group. Nefazodone Nefazodone has been shown to have a lower incidence of sexual dysfunction than SSRIs [16]. However, due to risk of serious hepatic toxicity, nefazodone is now rarely prescribed. Others While mirtazapine and amineptine have indirect evidence for a lower incidence of ADISD than the SSRIs, neither has been evaluated in a randomized, controlled study that used a rating scale for sexual dysfunction and compared ADISD on these antidepressants to either placebo or an SSRI other than paroxetine. Newer Antidepressants

Bupropion Bupropion had a lower incidence of treatmentemergent sexual dysfunction (TESD) than fluoxetine in patients being treated for depression, those who responded to the antidepressant, and those who remitted with treatment [9]. In a pooled analysis in patients with major depressive disorder (MDD) and normal sexual functioning over 8 weeks of treatment, orgasm dysfunction occurred twice as often on escitalopram (30 %) as on bupropion (15 %) [10]. Transdermal Selegiline In 6- to 8-week randomized clinical trials, transdermal selegiline did not differ from placebo on change in Medex Sexual Dysfunction Subscale scores [11]. Moclobemide In 60 normal volunteers, treatment with moclobemide 300 mg/day (about half the usual maximum dose) did not differ from placebo on treatment-emergent sexual dysfunction [12]. Over 6 months of treatment for depression, rates of treatment-emergent sexual dysfunction were 24.3 % with moclobemide and 61.5 % with SSRIs based on physician ratings [13]. The proportion of patients reporting

More recently introduced antidepressants are agomelatine, vilazodone, and vortioxetine, and these will be discussed in more detail below. Agomelatine Agomelatine is an agonist at melatonin-1 and melatonin-2 receptors and an antagonist at 5-HT2C (and 5HT2B) receptors [17]. In healthy volunteers, sexual dysfunction associated with the use of agomelatine 25 or 50 mg/day (<5 %) was not greater than with placebo [18]. Vilazodone Vilazodone is an inhibitor of serotonin reuptake and a partial agonist at 5-HT1A receptors [19]. A review of data on vilazodone and sexual dysfunction [20•] looked at ADISD in the two short-term, placebo-controlled registration trials. Categorical (present or absent) sexual dysfunction at end of treatment based on predefined cutoffs on the Arizona Sexual Experiences Scale (ASEX) or the Changes in Sexual Functioning Questionnaire (CSFQ) and adjusted for baseline sexual function and change in depression severity was not

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different between vilazodone and placebo for either gender. Shift from “functional” to “dysfunctional” status in males occurred in 17.9 % of patients on vilazodone versus 16.7 % on placebo; in females, the corresponding proportions were 23.0 versus 15.4 %, though as noted above, the differences were statistically nonsignificant in both genders. In the other RCT where the CSFQ was used, in both men and women, vilazodone did not differ from placebo on total score or any of the subscales. Notably, in the short-term RCTs, at least one sexual dysfunction-related treatment-emergent adverse event (TEAE) was spontaneously reported by 8.0 % of patients on vilazodone versus 0.9 % of patients on placebo. The most common sexual function-related TEAE was decreased libido, which was reported by 3.7 % of patients on vilazodone versus 0.2 % on placebo. Vortioxetine Vortioxetine, approved for the treatment of major depressive disorder by the Food and Drug Administration in late 2013, is an inhibitor of serotonin reuptake and an agonist at 5-HT1A, partial agonist at 5-HT1B, and antagonist at 5HT3A and 5-HT7 receptors [21]. The Prescribing Information provides the proportion of men and women spontaneously reporting a sexual dysfunction-related adverse event during treatment with vortioxetine, i.e., not based on a rating scale for sexual dysfunction. In men, the percentages were 3, 4, 4, and 5 % in patients on vortioxetine 5, 10, 15, and 20 mg/day, respectively, versus 2 % in patients on placebo. In women, the overall incidence was <1, 1, <1, and 2 % in patients on vortioxetine 5, 10, 15, and 20 mg/day, respectively, versus <1 % in patients on placebo. It should be noted that the recommended dose of vortioxetine is 10–20 mg/day (Prescribing Information). In addition to reliance on spontaneously reported adverse events, the Prescribing Information also reports data from the ASEX rating scale that was used in several clinical trials of vortioxetine, based on predefined criteria for sexual dysfunction from ASEX scores. In male patients who did not have sexual dysfunction at baseline, the percentages of patients who developed sexual dysfunction during the studies were 16, 20, 19, and 29 % in patients on 5, 10, 15, and 20 mg/day, respectively, versus 14 % in patients on placebo. In female patients, the corresponding percentages were 22, 23, 33, and 34 % on vortioxetine versus 20 % on placebo. These numbers suggest that vortioxetine appears to be associated with a greater sexual dysfunction than placebo at the 15 and 20 mg/day doses (sexual dysfunction is dose-related, as it is for other antidepressants).

Management Appropriate assessment for any other factors that may be causing or at least contributing to the sexual dysfunction

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should precede specific management of what appears to be ADISD. Also, the need for an antidepressant as opposed to other treatment options should also be reassessed. Three broad strategies may be considered for the management of ADISD. Wait and Watch Waiting for spontaneous improvement of the ADISD is a commonly used strategy; a community study in France found that 42 % of physicians take this approach [22]. However, in two studies, over 6 months, 81 and 79 % of patients showed no improvement in the sexual dysfunction [23, 7]. In the latter study, only 11 % of patients showed full improvement. When followed for up to 38 months, in only 9.8 % of patients did the sexual dysfunction resolve on its own [24]. Switching A second strategy is to switch to an antidepressant with a lower incidence of ADISD. Data on antidepressants that appear to have a lower incidence of ADISD have been discussed above. However, we found only one randomized, controlled trial of switching to another antidepressant for ADISD [1]. In this trial, 75 patients with ADISD due to sertraline were randomized to switching to nefazodone (titrated up to 300 mg/day) or to restarting sertraline in a doubleblind manner, and were treated for 10 weeks. Patients switched to nefazodone were significantly less likely to have sexual dysfunction reemerge on nefazodone than on sertraline. However, nefazodone is now rarely used. Adding an Antidote The third type of management strategy is to add an antidote while continuing the offending antidepressant. Randomized, controlled clinical trials of these strategies that had a sample size of at least 20 and that used a specific rating scale for sexual dysfunction are summarized in Tables 1, 2, and 3. Among these, studies were excluded if patients were significantly depressed at the start of the trial and the depression improved significantly more in the treatment group than in the control group. In such situations, it cannot be ruled out that the apparent improvement in sexual dysfunction was secondary to improvement in the depression. Bupropion has been used clinically as an antidote for many years though all three randomized, placebo controlled trials available until recently [27–29] were negative (see Table 1). Two much larger RCTs [25•, 26] found addition of bupropion to be unequivocally effective. What could be reasons for this contradictory data and how should we interpret the current state of the evidence? The studies by Saferinejad have several strengths: adequate sample size (vs. the three previous RCTs), exclusion of women above 45 years and men above 50 years of age, and use of higher dose (300 vs. 150 mg/day by Masand et al.). Lack of statistical power does not explain the previous negative results because the number of patients who responded was very low. Similarly, two of the three studies used a 300 mg/day dose and the Clayton et al. study excluded

Women, 25–45 years, on SSRI for ≥6 months and on stable dose ≥4 weeks, HAM-D<10

Men, 18–50 years, on SSRI for ≥6 months, HAM-D≤10 and HRSA≤10 18–60 years, SSRIs for ≥6 weeks, ASEX≥15. No cutoff for depression but mean HAM-D=11 and mean BDI=10

Safarinejad [25•]

Safarinejad [26]

30

On SSRI for ≥6 weeks, ASEX≥19 (or any 1 item >5 or any 3 items >4), HAM-D<10

Masand et al. [29]

Bupropion SR 150 mg/day

Bupropion SR 150 mg twice daily 3

4

6

12

12

Duration (weeks)

ASEX

Bupropion>placebo on change in CGI-SF Bupropion=placebo on 50 % reduction in ASEX score (only 1 patient in each group responded) No difference on total CSFQ score

Bupropion>placebo on total FSFI score and on all domains except pain. Most improved were sexual desire and lubrication

Primary outcome measure

No difference between bupropion SR and placebo in treatment response

Improvement with bupropion>placebo on desire/frequency subscale score

Bupropion=placebo on ≥25 % improvement in ASEX (5 of 20 vs. 6 of 21 responders)

Bupropion>placebo on ASEX

CGI-SF: more than 84 % responded (≥2-point improvement) in the bupropion group versus none in placebo at 12 weeks

Other outcome measures

Population

Men, 30–64 years

21

Sildenafil

8

Sildenafil 50–100 mg 6

Sildenafil 25–100 mg 6

Sildenafil>placebo on orgasm function on secondary efficacy measures Sildenafil>placebo on all domains of IIEF and all components of EDITS

Tadalafil>placebo on 5 domains of IIEF

55.5 % on sildenafil vs. 4.4 % on placebo improved/very much improved (CGI-SF≤2). The above scores were even higher in patients who completed the study (58.5 vs. 5.7 %, respectively) Sildenafil=placebo on total Sildenafil>placebo on erectile dysfunction item of ASEX ASEX score

Tadalafil>placebo on total IIEF score Sildenafil>placebo on CGI-SF Sildenafil>placebo on Q.3 (penetration) and Q.4 (erection) of IIEF Sildenafil>placebo on CGI-SF

Other outcome measures

ASEX Arizona Sexual Experiences Scale, BAI Beck Anxiety Inventory, CGI-SF Clinical Global Impression Scale for Sexual Function, EDITS Erectile Dysfunction Inventory of Treatment Satisfaction, HAM-D Hamilton Rating Scale for Depression, HRSA Hamilton Rating Scale for Anxiety, IIEF The International Index of Erectile Function, SHIM Sexual Health Inventory for Men, SRI serotonin reuptake inhibitor

Ginsberg et al. [34]

12

Duration Primary outcome measure (weeks)

Sildenafil 50–100 mg 8

Tadalafil 20 mg

Number Antidote

Evliyaoğlu Men, ≥18 years, treatment-emergent sexual 50 et al. [30•] dysfunction for ≥4 weeks Nurnberg Women, 18–50 years, on SRI ≥8 weeks and stable 98 et al. [31] dose ≥4 weeks, HAM-D≤10 and HRSA≤10 Fava et al. [32] Men, ≥18 years, on SRI ≥8 weeks and stable 142 dose ≥4 weeks, SHIM≤21, HAM-D≤10 and BAI≤10 Nurnberg Men, 18–55 years, HAM-D≤10 and HRSA≤10 83 et al. [33]

Study

Table 2 Randomized, controlled trials of phosphodiesterase-5 inhibitors as antidotes for ADISD

ASEX Arizona Sexual Experiences Scale, BDI Beck Depression Inventory, CGI-SF Clinical Global Impression Scale for Sexual Function, CSFQ Changes in Sexual Functioning Questionnaire, FSFI Female Sexual Function Index, HAM-D Hamilton Rating Scale for Depression, HRSA Hamilton Rating Scale for Anxiety, SR sustained release, SSRI selective serotonin reuptake inhibitor

42 (37 women, 5 men)

HAM-D≤7, sustained remission ≥3 months, sexual dysfunction on CSFQ

41 (24 women, 17 men)

Bupropion SR 150 mg twice daily Bupropion SR 150 mg/day

Bupropion SR 150 mg twice daily

213

227

Antidote

Number

Clayton et al. [28]

DeBattista et al. [27]

Population

Study

Table 1 Randomized, controlled trials of bupropion as an antidote for ADISD

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Women, 18–45 years, stabilized on fluoxetine 40 mg/day for ≥6 weeks with ≥50 % decrease in depression score, FSFI ≥16 at baseline Women, ≥18 years, on SSRI/SNRI

Kashani et al. [35]

57

4 weeks

2 weeks (3 sessions)

4 weeks

Buspirone (50–100 mg/day) or amantadine (20–30 mg/day)

Granisetron (1–2 mg/sexual activity), crossover design

Daily diary ratings

Saffron>placebo on total IIEF score

Exercise>no exercise in genital arousal (vaginal pulse amplitude)

Saffron>placebo on total FSFI score

Primary outcome measure

Patients on SSRIs have generally more sympathetic nervous system suppression, so they may have more genital arousal with exercise versus patients on SNRIs Saffron>placebo on erectile function and intercourse satisfaction. Saffron= placebo on orgasmic function, sexual desire, and overall satisfaction Moderate improvement in sexual function. Drugs=placebo on daily diary and computer-assisted structured interview (CASI). Olanzapine>placebo on biweekly assessment of sexual function by patient-rated questionnaire Granisetron=placebo on all components of SSES

Saffron>placebo on FSFI domains for arousal, lubrication, and pain

Other outcome measures

2 phases, Granisetron=placebo on ≤3 weeks/phase total SSES score (significant improvement in both groups) 8 weeks Drugs=placebo on daily diary Significantly higher improvement in (visual analogue scales) energy levels with amantadine versus placebo

Mirtazapine 15–30 mg/day or 6 weeks olanzapine 2.5–5 mg/day or yohimbine 5.4–10.8 mg/day

Saffron 15 mg twice daily

Exercise for 20 min (evaluation 5 min and 15 min post-exercise)

Saffron 30 mg/day

Duration

CGI Clinical Global Impression Scale, FSFI Female Sexual Function Index, HAM-D Hamilton Rating Scale for Depression, IIEF The International Index of Erectile Function, SNRI selective serotonin and norepinephrine reuptake inhibitor, SSES Sexual Side Effect Scale, SSRI selective serotonin reuptake inhibitor

Michelson et al. [40]

20

≥18 years, SSES for recent sexual activity: total score ≥3 on the 3 items and at least 1 item ≥2, HAM-D<10 Women, ≤50 years, ≥8 weeks on a stable dose of fluoxetine, CGI≥3 and HAM-D<10

Nelson et al. [39]

Michelson et al. [38]

Men, 18–45 years, IIEF<25, stabilized 30 on fluoxetine 40 mg/day for ≥6 weeks. No cutoff for depression but mean HAM-D<10 in both groups Women, 18–50 years, ≥8 weeks on 148 fluoxetine and stabilized. No HAM-D cutoff but mean HAM-D<5

47

34

Number Antidote

Modabbernia et al. [37]

Lorenz and Meston [36]

Population

Study

Table 3 Randomized, controlled trials of other antidotes for ADISD

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women older than 45 years of age. Nevertheless, in our considered opinion, independent replication of the studies by Saferinejad is needed before more definitive conclusions can be drawn. Also, bupropion is an inhibitor of cytochrome P450 2D6; thus, if it is added to fluoxetine, paroxetine, duloxetine, venlafaxine, or vortioxetine, it may increase their levels, potentially leading to increased adverse effects. Clinicians should make sure they distinguish between a potential benefit for the remaining depressive symptoms versus a specific effect on the ADISD. Among the phosphodiesterase inhibitors, while placebocontrolled data and replication are available for sildenafil (Table 2), presumably other medications of this class will be effective for ADISD as well. For sexual dysfunction unrelated to antidepressants, tadalafil has the advantage of a longer duration of action making careful timing of dose to sexual activity less important, and this would apply to ADISD as well. While various other antidotes have been evaluated (Table 3), replication is needed before they can be recommended for use in routine clinical care.

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Approval of newer antidepressants with low or absent ADISD would be a very desirable development in the future. Compliance with Ethics Guidelines Conflict of Interest Rajnish Mago has served as a consultant for Guidepoint Global; has received grant support from the Forest Research Institute, Shire, Genomind, Bristol-Myers Squibb, and Eli Lilly and Company; and has had travel/accommodation expenses covered/ reimbursed by Forest Pharmaceuticals. Rajeev Mahajan and Dileep Borra declare that they have no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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Conclusions In summary, ADISD is a very common adverse effect of serotonergic antidepressants for which a definitive management strategy is not clear. For patients with sexual dysfunction of shorter duration that is milder or the patient is less bothered by it, wait and watch may be a reasonable strategy. However, expectant waiting is not appropriate when the sexual dysfunction is persistent and the sexual dysfunction is bothersome. Spontaneous resolution is unlikely, and the ADISD is likely to lead to nonadherence. RCTs of viable switch strategies are not available. However, even in the absence of specific data, switching to other antidepressants that have a lower incidence of ADISD, when feasible, may presumably be an efficacious and parsimonious strategy. For patients in whom such a switch is not feasible or does not work, addition of an antidote would be appropriate. In men with erectile dysfunction, addition of a phosphodiesterase-5 inhibitor is expected to have a relatively high success rate. Neither agomelatine nor moclobemide appears to be associated with sexual dysfunction, but both are not available in the USA. Initial data on vilazodone does suggest that it may be associated with a lower incidence of ADISD, but this requires verification in prospective studies with ADISD as the primary outcome measure and in switch studies. Whether vortioxetine is associated with less sexual dysfunction than other antidepressants remains to be seen. Also, data on ADISD with vortioxetine in patients who have remitted from their disorder are important to obtain.

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