Antidepressant-Induced Sexual Dysfunction and Its Management

Introduction

Sexual dysfunction is common among individuals with major depressive disorder. For instance, a study by Kennedy and colleagues[1] revealed that of 134 patients with major depression surveyed, 40% of men and 50% of women reported decreased sexual interest; 40% to 50% of the sample also reported reduced levels of arousal. Sexual dysfunction is also a common side effect of antidepressant treatment, particularly pharmacotherapy with serotonin reuptake inhibitors (SRIs). Treatment-emergent SRI-induced sexual dysfunction ranges from approximately 30% to 70% of patients treated for depression.[2-4] Bupropion (Wellbutrin) and nefazodone (Serzone) is no longer on the market), in contrast, are associated with lower rates of sexual dysfunction.^[2]

Antidepressant-induced sexual dysfunction becomes an important issue in the context of treatment effectiveness, as antidepressant medications are helpful only insofar as patients take them. Intolerable side effects may be one reason that patients are noncompliant with antidepressant treatment.^[5] Given the important clinical implications of premature discontinuation -- for example, higher rates of relapse and recurrence -- increasing attention is currently being devoted to the management of antidepressant-induced sexual dysfunction and other unwanted side effects of pharmacotherapy for depression.

The issue of sexual functioning in the context of depression was discussed by a number of clinical researchers at the 156th annual meeting of the American Psychiatric Association in San Francisco, California. Topics included a comparison of the rates of treatment-emergent sexual dysfunction across various SRI antidepressants as well as strategies for managing antidepressant-induced sexual dysfunction, such as adding as-needed sildenafil to SRI pharmacotherapy for remitted depressed patients.

Assessment and Risk Factors for Sexual Dysfunction in the Context of Major Depression

The sexual response cycle consists of 4 phases: desire, arousal, orgasm, and resolution, and, as explained by Anita Clayton, MD,^[6] Professor and Vice Chairman, Department of Psychiatric Medicine, University of Virginia, Charlottesville, the phases of the sexual response cycle are affected by reproductive hormones and neurotransmitters.

For example, according to Dr. Clayton, estrogen, testosterone, and progesterone promote sexual desire; dopamine promotes desire and arousal, and norepinephrine promotes arousal. Prolactin inhibits arousal, and oxytocin promotes orgasm. Serotonin, in contrast to most of these other molecules, appears to have a negative impact on the desire and arousal phases of the sexual response cycle, and this seems to occur through its inhibition of dopamine and norepinephrine. Serotonin also appears to exert peripheral effects on sexual functioning by decreasing sensation and by inhibiting nitric oxide. The serotonergic system, therefore, may contribute to various sexual problems across the sexual response cycle.

Dr. Clayton recommended that clinicians conduct a thorough assessment with patients when attempting to ascertain the etiology of sexual dysfunction. Factors to consider include primary sexual disorders, such as hypoactive sexual desire disorder, as well as secondary causes, such as psychiatric disorders (eg, depression) and endocrine disorders (eg, diabetes mellitus, which may cause neurologic and/or vascular complications). Physicians should also inquire about situational and psychosocial stressors (eg, relationship conflict and job changes), as well as the use of substances known to exert a negative impact upon sexual functioning, such as psychotropic medication and drugs of abuse, such as alcohol.

Antidepressant-induced sexual dysfunction is common but underreported. For instance, only 14.2% of depressed patients taking selective SRIs (SSRIs) for depression spontaneously report sexual complaints; however, if queried directly, nearly 60% of patients report sexual complaints.^[7] Using standardized instruments, such as the Arizona Sexual Experiences Scale (ASEX) and the Changes in Sexual Functioning Questionnaire (CSFQ-C), and asking phase-specific questions may facilitate the clinicians' assessment of patients' sexual dysfunction.

There are a number of patient risk factors for sexual dysfunction. These include age (being 50 years old or older), having less than a college education, not being employed full-time, tobacco use (6-20 times per day), a prior history of antidepressant-induced sexual dysfunction, a history of little or no sexual enjoyment, and considering sexual functioning as "not" or only "somewhat" important..^[2] Gender, race, and duration of treatment, in contrast, do not appear to predict sexual dysfunction.

Clinicians may employ several strategies to manage antidepressant-induced sexual dysfunction.^[4] One is waiting for tolerance to develop, although, according to Dr. Clayton, this is typically not successful, as only a small portion of patients report improvement in sexual functioning over time during SSRI pharmacotherapy.^[7,8] Another option is to reduce the current dose, but this may result in subtherapeutic doses of medication. Drug holidays may provide relief from SSRI-induced sexual dysfunction,^[9] but, cautioned Dr. Clayton, may result in SSRI discontinuation symptoms after 1 to 2 days or encourage medication noncompliance.

The use of sildenafil (Viagra), bupropion (Wellbutrin), yohimbine, or amantadine may be helpful as antidotes, but, as yet, these agents are not indicated specifically for this use.^[4,10] Switching to antidepressants with little risk of inducing sexual dysfunction -- for example, bupropion, mirtazapine, and nefazodone (no longer on market) -- may be a successful strategy for some patients,^[3,11,12]] although there is the risk that depressive symptoms may not respond as well to the second agent as they did to the first.

References

New Research Regarding the Evaluation of Serotonergic Antidepressants With Respect to Sexual Functioning During Treatment for Major Depression

Duloxetine (Cymbalta) Vs Paroxetine (Paxil)

A study comparing the incidence of treatment-emergent sexual dysfunction among depressed patients treated with duloxetine (Cymbalta), a serotonin-norepinephrine reuptake inhibitor (SNRI) currently under US Food and Drug Administration (FDA) review for the treatment of depression (ed. note: Cymbalta was approved by the FDA in 2005), vs paroxetine (Paxil), an SSRI, suggests that duloxetine is associated with lower rates of treatment-emergent sexual dysfunction than paroxetine is.^[13]

Researchers pooled data from 4 eight-week, randomized, double-blind clinical trials designed to evaluate the efficacy of duloxetine vs paroxetine for depression during the acute phase of treatment. Pooling data from the 4 studies yielded the following treatment conditions: 20-60 mg of duloxetine twice per day (n = 736), 20 mg of paroxetine once daily (n = 359), and placebo (n = 371). Two of the studies included 26-week extension phases in which acute treatment responders received duloxetine (40 or 60 mg twice per day; n = 297), paroxetine (20 mg/day; n = 140), or placebo (n = 129). Sexual functioning was assessed using ASEX, a 5-item questionnaire that taps sex drive, arousal, and ability to achieve orgasm.

The authors reported the following findings: (1) Significantly higher rates of sexual dysfunction were observed with both duloxetine and paroxetine compared with placebo, but the incidence of acute-phase treatment-emergent sexual dysfunction was significantly lower for patients treated with duloxetine than those treated with paroxetine. (2) Female patients treated with duloxetine had a significantly lower incidence of acute-phase, treatment-emergent sexual dysfunction compared with those receiving paroxetine. (3) More duloxetine-treated patients reported long-term improvement in sex drive and arousal than did paroxetine-treated patients.

Mirtazapine Fast Dissolving Tablets Vs Sertraline

Sexual functioning, as measured by the CSFQ, was compared between depressed patients receiving mirtazapine fast dissolving tablets and those treated with Sertraline.^[14] At the beginning of treatment for depression, 171 patients received mirtazapine (mean daily dose of 38.3 mg), and 168 received sertraline (mean daily dose of 92.7 mg). Findings indicated that by the second week of treatment, patients treated with mirtazapine showed a significantly greater decrease in depressive symptoms, as measured by the Hamilton Depression Scale (HAM-D), compared with those treated with sertraline.

Data regarding sexual functioning were available for a subset of the patients receiving mirtazapine (n = 140) and sertraline (n = 140) during the depression efficacy trials. By the end of 8 weeks of treatment, patients treated with mirtazapine appeared, on average, to show normal sexual functioning, whereas patients treated with sertraline, on average, were below the CSFQ cutoff for normal sexual functioning. This pattern of findings was observed for both male and female patients. Other findings included the observation that males treated with higher doses of mirtazapine (more than 30 mg/day) showed significantly greater improvements from baseline on overall sexual functioning by the fourth, sixth, and eighth week of treatment compared with males treated with higher doses of (more than 100 mg/day).

Gepironee

Gepirone, a 5-HT_1A agonist not yet approved by the FDA (ed. note: Gepirone was rejected by the FDA in June 2004) for the treatment of depression, has also been evaluated with respect to its effect on sexual functioning among patients treated for major depression. In an 8-week, randomized, double-blind, placebo-controlled trial, gepirone-ER 20-80 mg/day was administered to outpatients diagnosed with major depressive disorder.^[15] Sexual functioning was assessed using the Derogatis Interview for Sexual Functioning Self-Report (DISF-SR), a 25-item questionnaire that assesses cognition/fantasy, arousal, behavior, orgasm, and drive.

Patients receiving gepirone-ER (n = 101) demonstrated a significantly greater mean change from baseline on the HAMD-17 compared with those receiving placebo (n = 103) at weeks 3 and 8, suggesting that gepirone is an efficacious antidepressant. Sexual functioning total scores were then evaluated in a subgroup of patients who had completed the DISF-SR at baseline and at end point. Results indicated that, on average, patients treated with gepirone-ER (n = 65) showed significantly greater improvements from baseline to end point with respect to sexual functioning compared with patients who received placebo (n = 73). This pattern of results was observed when data from male and female patients were combined and when analyses were conducted separately for females. However, statistically significant improvements were not observed for males treated with gepirone-ER compared with those who received placebo. According to the authors, the lack of statistically significant differences between the male groups may have been due to the small number of men in the gepirone-ER subgroup.

References

New Research on the Treatment of SRI-Induced Sexual Dysfunction With Sildenafil

Sildenafil (Viagra) for SRI-Induced Male Sexual Dysfunction During Continuation Treatment for Major Depressive Disorder

George Nurnberg, MD,^[16] of the University of New Mexico School of Medicine, Albuquerque, presented new research on the use of for SRI-induced sexual dysfunction. Participants were male patients with remitted major depression who were receiving a stable dose of continuation SRI antidepressants and also suffered from treatment-emergent SRI-induced sexual dysfunction (n = 90). They were then randomized to placebo or sildenafil (50 mg, which could be increased to 100 mg) for 6 weeks. Sildenafil is a phosphodiesterase type-5 inhibitor that is FDA-approved for the treatment of erectile dysfunction. The main results, summarized in a study by Nurnberg and colleagues,^[17] were that sildenafil-treated patients showed significantly greater improvements in sexual functioning relative to patients receiving placebo, as measured using the International Index of Erectile Function (IIEF).

Responders from the initial trial were discontinued from sildenafil for 3 weeks. Once it was determined that sexual dysfunction occurred in the absence of sildenafil (which suggests that previously observed improvements were, as hypothesized, due to sildenafil treatment rather than the passage of time per se), these patients then received 8 weeks of additional open-label sildenafil. They continued to show improvement in sexual functioning, and there were no relapses or recurrences of major depressive disorder.

Patients from the double-blind study who had shown a partial response or no response (defined as scoring higher than 2 on the CGI; n = 43) repeated the initial 6 weeks of sildenafil treatment and then received 8 additional weeks of open-label sildenafil, just as the original responders had. This group of patients, some of whom had originally received placebo, showed improvement with continued treatment that was comparable to that achieved by responders in the sildenafil double-blind group.

Sildenafil for SRI-Induced Erectile Dysfunction in Men With Remitted Depression

Maurizio Fava, MD,^[18] Director of the Depression Clinical and Research Program, Massachusetts General Hospital, and Professor of Psychiatry, Harvard Medical School, Boston, Massachusetts, presented results from a prospective, multicenter, randomized, double-blind, placebo-controlled study of sildenafil for SRI-induced erectile dysfunction. Participants were males with remitted depression (HAMD !--=1 0) and the absence of clinically significant anxiety symptoms (Beck Anxiety Inventory 10). Patients (mean age of 51 years) had been taking a serotonergic antidepressant for at east 8 weeks or more at a stable dose for at least 4 or more weeks, and they had no previous history of erectile dysfunction. Seventy-one patients were randomized to sildenafil (50 mg on an as-eeded basis, flexible to 25 mg or 100 mg), and 71 were randomized to placebo.

Ninety-four percent of patients in the sildenafil group and 90% of those in the placebo group completed treatment. No patient discontinued in the study due to the study drug. At the end of treatment, sildenafil-treated patients reported significantly higher rates of frequency of penetration and maintenance of erection after penetration, as measured using the International Index of Erectile Function (IIEF), compared with patients receiving placebo. Patients in the sildenafil group also reported significantly higher levels of quality of life with respect to sexual functioning compared with those receiving placebo. The most frequently reported adverse events during treatment were headache (9% sildenafil vs 9% placebo), dyspepsia (9% vs 1%), and facial flushing (9% vs 0%).

Sildenafil for SRI-Induced Female Sexual Dysfunction

Nurnberg and colleagues presented results from an open-label extension phase of a double-blind, placebo-controlled trial of sildenafil treatment for SRI-induced female sexual dysfunction.^[19] Women with remitted major depression and SRI-induced sexual dysfunction were randomly assigned to receive sildenafil (50 mg, which could be increased to 100 mg) or placebo for 8 weeks (n = 150). Sexual dysfunction was characterized by arousal dysfunction or orgasmic dysfunction that interfered with sexual functioning for 4 or more weeks. The double-blind phase of the study was followed by 8 weeks of single-blind sildenafil. Results were presented for the first 42 patients who completed the extension phase of the study.

At baseline, the women in this subgroup of patients were taking fluoxetine (42%), sertraline (28%), paroxetine (10%), citalopram (10%), venlafaxine (5%), nefazodone (5%), and clomipramine (1%), and the most commonly reported aspects of sexual dysfunction were decreased libido (95%), orgasm delay (70%), decreased satisfaction (68%), and difficulties achieving lubrication (55%). At the end of the double-blind phase of the study, 39% of the 42 women were considered responders, defined as

Conclusions

Sexual dysfunction commonly occurs in the context of major depressive disorder. Although sexual dysfunction is not a symptom of major depressive disorder per se, decreased sexual desire and arousal may be characteristics associated with depression-related anhedonia. Sexual dysfunction is also a common side effect of treatment with serotonergic antidepressants and may be a reason that patients on SSRIs and other serotonergic medications discontinue treatment prematurely.

Given the importance of continuation and maintenance treatment for major depression, researchers are devoting increasing attention to understanding which treatments may be helpful or, alternatively, unhelpful with respect to sexual functioning so that compliance may be maintained and treatment optimized. Clinically, this suggests that as additional data regarding the differential impact of certain medications on sexual functioning in the context of depression become available, clinicians may be able to make more empirically informed decisions regarding which antidepressants might be effective for a given patient at the beginning of treatment. They may also have an empirically informed selection of "next-step" strategies to employ in the event that treatment-emergent sexual dysfunction develops over the course of pharmacotherapy.

References

References

1. Kennedy SH, Dickens SE, Eisfeld BS, Bagby RM. Sexual dysfunction before antidepressant therapy in major depression. J Affect Disord. 1999;56:201-208.
2. Clayton AH, Pradko JF, Croft HA, et al. Prevalence of sexual dysfunction among newer antidepressants. J Clin Psychiatry. 2002;63:357-366.
3. Ferguson JM. The effects of antidepressants on sexual functioning in depressed patients: a review. J Clin Psychiatry. 2001;62(suppl 3):22-34.
4. Rosen RC, Lane RM, Menza M. Effects of SSRIs on sexual function: a critical review. J Clin Psychopharmacol. 1999;19:67-85.
5. Lin EH, Von Korff M, Katon W, et al. The role of the primary care physician in patients' adherence to antidepressant therapy. Med Care. 1995;33:67-74.
6. Clayton ALH. Sexual dysfunction in depression. Tricks of the trade in the long-term treatment of depression. Program and abstracts of the American Psychiatric Association 156th Annual Meeting; May 17-22, 2003; San Francisco, California. Abstract IS 17B.
7. Montejo-Gonzalez AL, Llorca G, Izquierdo JA, et al. SSRI-induced sexual dysfunction: fluoxetine, paroxetine, sertraline, and fluvoxamine in a prospective, multicenter, and descriptive clinical study of 344 patients. J Sex Marital Ther. 1997;23:176-194.
8. Ashton AK, Rosen RC. Accommodation to serotonin reuptake inhibitor-induced sexual dysfunction. J Sex Marital Ther. 1998;24:191-192.
9. Rothschild AJ. Selective serotonin reuptake inhibitor-induced sexual dysfunction: efficacy of a drug holiday. Am J Psychiatry. 1995;152:1514-1516.
10. Ashton AK, Rosen RC. Bupropion as an antidote for serotonin reuptake inhibitor-induced sexual dysfunction. J Clin Psychiatry. 1998;59:112-115.
11. Kavoussi RJ, Segraves RT, Hughes AR, Ascher JA, Johnston JA. Double-blind comparison of bupropion sustained release and sertraline in depressed outpatients. J Clin Psychiatry. 1997;58:532-537.
12. Gelenberg AJ, McGahuey C, Laukes C, et al. Mirtazapine substitution in SSRI-induced sexual dysfunction. J Clin Psychiatry. 2000;61:356-360.
13. Brannon SK, Detke MJ, Wang F, Mallinckrodt CH, Tran PV, Delgado PL. Comparison of sexual functioning in patients receiving duloxetine or paroxetine: acute and long-term data. Program and abstracts of the American Psychiatric Association 156th Annual Meeting; May 17-22, 2003; San Francisco, California. Abstract NR477.
14. Vester-Blokland ED, Van der Flier S, Rapid Study Group. Sexual functioning of patients with major depression treated with mirtazapine orally disintegrating tablet or sertraline. Program and abstracts of the American Psychiatric Association 156th Annual Meeting; May 17-22, 2003; San Francisco, California. Abstract NR494.
15. Davidson JRT, Gibertini M. Effect of gepirone extended release on sexual function in patients with major depression. Program and abstracts of the American Psychiatric Association 156th Annual Meeting; May 17-22, 2003; San Francisco, California. Abstract NR473.
16. Nurnberg HG. Maintaining compliance and remission in MDD with sildenafil prescription for SSRI-SD. Issues in the treatment of depression and sexual dysfunctions. Program and abstracts of the American Psychiatric Association 156th Annual Meeting; May 17-22, 2003; San Francisco, California. Abstract S&CR110.
17. Nurnberg HG, Hensley PL, Gelenberg AJ, Fava M, Lauriello J, Paine S. Treatment of antidepressant-associated sexual dysfunction with sildenafil: a randomized controlled trial. JAMA. 2003;289:56-64.
18. Fava M, Nurnberg HG, Seidman SN, et al. Efficacy and safety of sildenafil citrate in men with serotonergic-antidepressant-associated erectile dysfunction: results of a prospective, multicenter, randomized, double-blind, placebo-controlled trial. Issues in the treatment of depression and sexual dysfunctions. Program and abstracts of the American Psychiatric Association 156th Annual Meeting; May 17-22, 2003; San Francisco, California.
19. Nurnberg HG, Hensley PL, Croft HA, Fava M, Warnock JK, Paine S. Sildenafil citrate treatment for SRI-associated female sexual dysfunction. Program and abstracts of the American Psychiatric Association 156th Annual Meeting; May 17-22, 2003; San Francisco, California.