Paula L Hensley, H George Nurnberg
As the indications for antidepressant medications have expanded to conditions other than depression, there has been increased recognition of the problem of sexual dysfunction due to major depressive disorder, antidepressant use, or a combination of both the disorder and the treatment. Decreased libido has long been recognized as a symptom of depression, but patients with major depressive disorder also describe other forms of sexual dysfunction. The Physician’s Desk Reference cites low rates of female sexual dysfunction due to antidepressants, since the rates listed rely on spontaneous reports from subjects in clinical trials. Rates of sexual dysfunction due to antidepressants in the psychiatric literature are much higher, some approaching 70-80%. The difficulty of determining the source of sexual dysfunction will be explored in this chapter (see Chapters 7.1—7.7 of this book). In addition, we will review the literature linking antidepressants to sexual dysfunction. Then, we will describe management strategies for this troublesome side effect. Recognition and management of sexual dysfunction is especially critical in women, since women have two to three times the rate of depressive and anxiety disorders of men and are prescribed the majority of antidepressants in the USA.
Rates of sexual dysfunction in the general population
The National Health and Social Life Survey reports that sexual dysfunction is rather common in the general population1 (see Chapters 2.1—2.4). In the 18—59-year age group, women report a higher overall rate of sexual dysfunction than men — 43% versus 31%. Women describe complaints of low sexual desire (32%), inability to achieve orgasm (26%), and absence of pleasure in sex (23%). A survey of individuals aged 18—75 years in the UK reveals similar rates (41% of women and 34% of men report a current sexual problem); of the specific forms of sexual dysfunction reported, women were most dissatisfied if they had arousal problems and dyspareunia.2 Age and general health can certainly play a role in sexual function. In a study examining the relationship between sexual dysfunction and physical, social, and psychologic complaints, Dunn et al. report that arousal difficulty increases with age in women, while dyspareunia decreases with age.3 In a random sample of community-dwelling women, however, Hawton et al. found that satisfaction with the sexual relationship was most closely related to marital adjustment, and was not related to age.4 A good understanding of the base rates of sexual dysfunction in a general population assists in the assessment of depression-related sexual dysfunction and should help avoid misattribution of pre-existing symptoms to a subsequently diagnosed illness.
Depression and sexual dysfunction
Untreated depressed patients report high rates of abnormal sexual function. Up to 70% of unipolar depressed patients complain of decreased sexual desire.5 Rates of sexual activity in depressed patients seem quite low. In a depressed population, reports of complete sexual inactivity in the preceding month were greater in women, at 49%, than in men (26%).6 Sexual dysfunction in these depressed patients was examined prospectively and followed during treatment. For the women in the study, 72% had recurrent depression and the mean duration of the current episode was 62.2 weeks (standard deviation = 64.9). Prior to treatment, Kennedy et al. report the following rates of sexual dysfunction in women: decreased sexual drive (50%), decreased sexual arousal (50%), difficulty obtaining vaginal lubrication (40%), and difficulty in achieving orgasm (15%).6 The authors suggest that depressed women are more likely to have difficulty with the early stages of sexual activity, desire and arousal, rather than with orgasm or resolution.6 Longer periods of untreated depression and recurrent depression (which may indicate poor recovery between episodes) may predispose patients to high rates of sexual dysfunction.
In the past, few studies gathered data about sexual dysfunction prospectively. But with greater recognition of antidepressant-induced sexual dysfunction, some researchers are asking more specific questions regarding sexual function prior to initiating treatment for depression, yielding some important epidemiologic data. In a three-arm clinical trial (nefazodone vs a specialized form of cognitive-behavioral therapy called “cognitive-behavioral analysis system of psychotherapy” vs combined treatment with these two modalities) of the treatment of major depressive disorder, baseline measures of sexual dysfunction found that 16% of subjects described a history of sexual dysfunction while taking prior antidepressants.7 However, few had been evaluated (1.8%) or received treatment (1.7%) for sexual dysfunction in the past.8 Of the women, 48% reported at least one symptom of sexual dysfunction at baseline; specific complaints included difficulty in achieving orgasm (30%), inability to achieve orgasm (21%), decreased intensity of orgasm (19%), inadequate swelling or vaginal lubrication during sexual arousal (18%), and decreased sensitivity in genitals upon physical contact (10%). According to the protocol, patients previously treated with antidepressants could enter the study if they were medication-free for 2 weeks, or 4 weeks if treated with fluoxetine or monoamine oxidase inhibitors. As Zajecka et al. do not note how many of their subjects stopped antidepressants prior to the baseline assessments, it is possible that the high rates of sexual dysfunction at baseline were in part secondary to residual effects of discontinued antidepressants or major depressive disorder.7,8
Ekselius and von Knorring assessed 308 depressed patients (221 women and 87 men) for pre-existing sexual dysfunction prior to initiation of medication, using the Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale for psychotropic drugs.9 The subjects were randomized to one of two selective serotonin reuptake inhibitors, sertraline or citalopram. Prior to treatment, 49% of the women in the sertraline group and 46% of the women in the citalopram group complained of decreased sexual desire. In addition, at baseline, 21% of the women in the sertraline group and 23% of the women in the citalopram group reported orgasmic dysfunction. In this study, the medication washout period was 1 week; the authors do not include data on the number of patients who discontinued another antidepressant prior to randomization.
The selective serotonin reuptake inhibitors advanced the treatment of depressive and anxiety disorders by offering improved tolerability, easier titration, and safety in overdose compared to tricyclic and monoamine oxidase inhibitor antidepressants. Selective serotonin reuptake inhibitors seem to cause similar rates and types of sexual dysfunction; few statistically significant differences are found among the different medications. Studies that compare selective serotonin reuptake inhibitors for propensity to cause sexual dysfunction usually do not include prospective, systematic evaluation of sexual function.10 Moreover, antidepressant-induced sexual dysfunction appears to be a dose-related phenomenon, and determining equivalency of doses used in such studies is difficult.10,11 Selective serotonin reuptake inhibitors cause impairment in arousal (lubrication/engorgement) and orgasm (delayed or absent). Men report higher rates of antidepressant-induced sexual dysfunction, but women describe greater severity.12,13
The largest epidemiologic study of antidepressant-induced sexual dysfunction to date is a cross-sectional, observational study (n = 6297) conducted by Clayton et al.14 In this data set, immediate-release bupropion, an antidepressant without effect at serotonin receptors, was the least likely to cause sexual dysfunction, at 22%, and paroxetine, a selective serotonin reuptake inhibitor, had the highest rate of sexual dysfunction, at 43%.14 The authors identified a group of 798 people who were unlikely to develop antidepressant-related sexual dysfunction; some key features were that these subjects were younger and had no history of sexual side effects with antidepressants. In this target group, the prevalence of sexual dysfunction ranged from 7% for sustained-release bupropion to 30% for citalopram, a selective serotonin reuptake inhibitor, and extended-release venlafaxine, a serotonin and norepinephrine reuptake inhibitor. So in both the target group and the entire study population, selective serotonin reuptake inhibitors and selective serotonin and norpeinephrine reuptake inhibitors were associated with greater rates of sexual dysfunction than nonserotonergic antidepressants.
Montejo-Gonzalez et al. reported higher rates of treatment- emergent sexual dysfunction in a group of outpatients (192 women and 152 men) treated in open-label fashion with selective serotonin reuptake inhibitor antidepressants.12 Of the 344 patients, 200 complained of some form of sexual dysfunction. Although the differences were not statistically significant, the overall rates of sexual dysfunction for the various selective serotonin reuptake inhibitors were as follows: fluoxetine, 54.38%; sertraline, 56.4%; fluvoxamine, 58.94%; and paroxetine, 64.71%.12 The only statistically significant differences found among the selective serotonin reuptake inhibitors for specific types of sexual dysfunction were that paroxetine caused more delay of orgasm/ejaculation and more impotence/inadequate lubrication than fluvoxamine, fluoxetine, or sertraline (p < 0.05).12 No significant differences emerged for loss of libido or delayed orgasm/ejaculation. In this sample, men had a higher incidence of treatment-emergent sexual dysfunction, but women had greater severity of symptoms.12
A subsequent report by Montejo et al. provides additional data, with 1022 outpatients (610 women and 412 men) followed prospectively and treated in an open-label fashion with various antidepressants, not limited to selective serotonin reuptake inhibitors.13 In this sample, 604 patients (59.1%) overall reported treatment-emergent sexual dysfunction. Rates with the various antidepressants were moclobemide (a short-acting reversible inhibitor of monoamine oxidase), 3.9%; amineptine (a tricyclic antidepressant with dopamine reuptake-blocking actions), 6.9%; nefazodone (a phenylpiperazine antidepressant which blocks neuronal reuptake of serotonin and norepinephrine and blocks postsynaptic serotonin type-2 (5-HT2) receptors), 8%; mirtazapine (a tetracyclic compound which blocks alpha-2 autoreceptors, 5-HT2 receptors, and 5-HT3 receptors), 24.4%; fluoxetine, 57.7%; fluvoxamine, 62.3%; sertraline, 62.9%; venlafaxine, 67.3%; paroxetine, 70.7%; and citalopram, 72.7%.13 The medications with the two lowest rates of sexual dysfunction, moclobemide and amineptine, are not available in the USA. The third best, nefazodone, was withdrawn from the US market in June 2004. Paroxetine caused a significantly greater incidence of erectile dysfunction and decreased vaginal lubrication when compared to fluoxetine, fluvoxamine, sertraline, citalopram, venlafaxine, mirtazapine, and nefazodone (p < 0.05).13 When intensity of sexual dysfunction was analyzed, no statistically significant differences were observed between the selective serotonin reuptake inhibitors and venlafaxine for decreased libido. However, mirtazapine caused less intense delayed orgasm and anorgasmia than fluoxetine, fluvoxamine, sertraline, citalopram, venlafaxine, and paroxetine (p < 0.005).13 Use of paroxetine led to greater intensity of delayed orgasm than mirtazapine, fluoxetine, fluvoxamine, sertraline, citalopram, and venlafaxine (p < 0.005), and to greater intensity of decreased vaginal lubrication than fluoxetine, fluvoxa- mine, and sertraline (p < 0.005).13 As in the group’s earlier report, more men than women reported sexual dysfunction (62.4% of men vs 56.9% of women).13 Women reported greater intensity of decreased libido, delayed orgasm, and anorgasmia than did men (p < 0.005).13
Antidepressants may improve sexual function in some individuals, especially women. Piazza et al. compared the sexual function of depressed subjects, both men and women, before and during treatment with a selective serotonin reuptake inhibitor (sertraline or paroxetine).15 Prior to treatment, women reported statistically significantly greater impairment in sex drive, psychologic arousal, ease of orgasm, and orgasm satisfaction than men. After completing 6-week treatment with a selective serotonin reuptake inhibitor, women reported significant improvements in sex drive and psychologic arousal, although no changes were appreciated in physiologic arousal, ease of orgasm, or orgasm satisfaction. In contrast, treated depressed men reported worsening of ease of orgasm and orgasm satisfaction, and there was a trend toward worsening of sex drive. Men reported no change in psychologic or physiologic arousal. Thus, depressed women appear to experience greater rates of sexual dysfunction at baseline and show improvement of function when treated. Men had lower rates of sexual dysfunction at baseline and found their function worsened with treatment.
The determination of whether a sexual disorder is primary or secondary, or whether it is due to depression or antidepressant treatment is difficult. Obtaining a complete sexual history prior to initiating treatment is important, but some people have difficulty in recalling which symptom started first. The typical pattern reported clinically is that a depressed patient suffers loss of libido as a symptom of depression, is not as sexually active as before, and then starts to take an antidepressant, regains some interest, but finds that arousal and/or orgasm is now impaired. Little rigorous study, however, has been done to define the pattern of dysfunction initiated by antidepressants. In addition, the interrelationships between the phases of sexual function potentially cause halo effects and the opposite, an undermining of one phase by difficulties in another. For example, impairment in arousal or orgasm can clearly have secondary effects on libido. This is just one of many potential confounds in evaluating sexual dysfunction.
Management of antidepressant- induced sexual dysfunction
The treatment of antidepressant-associated sexual dysfunction falls into four general treatment categories: (1) use of antidotes to reverse sexual dysfunction; (2) avoidance by use of antidepressants with fewer adverse sexual effects; (3) augmentation with or switching to an antidepressant with fewer adverse sexual effects after sexual dysfunction has emerged with another antidepressant; and (4) adaptation or tolerance by waiting, dose adjustment, or drug holiday.16, 17
Few reports of medications used as antidotes for sexual dysfunction focus on women. Most of the evidence for antidotes comes in the form of single case reports or case series. Some initially promising antidotes fail to separate from placebo in controlled trials. Open-label reports present evidence for the use of the following medications for antidepressant-induced sexual dysfunction: mianserin (7.5—15 mg/day),18—20 cyproheptadine (4—12 mg 1—2 h before sexual activity, or 4—12 mg/day),21—25 Ginkgo biloba (60—900 mg/day),26—29 amantadine (100—200 mg/day),3 32 lorata- dine (2.5—15 mg/day),33 bethanechol (10 mg 30 min before sexual activity),34,35 yohimbine (5.4 mg three times daily),36,37 and methylphenidate (10—40 mg/day).38,39
Open-label reports of the use of bupropion as an adjunct to selective serotonin reuptake inhibitors seem promising; recommended dosing varies from as-needed 1—2 h before sexual activity (75—150 mg) to a standing daily dose.4CM3 However, the first published randomized, double-blind, placebo-controlled study (31 subjects, gender breakdown not reported) of patients treated for 3 weeks with either sustained-release bupropion 150 mg/day or placebo added to a selective serotonin reuptake inhibitor did not show a difference between the groups.44 More recently, a 4-week, double-blind study of sustained-release bupropion, 150 mg twice daily, versus placebo added to a selective serotonin reuptake inhibitor in 48 women and seven men, found that bupropion increased both the desire for and frequency of sexual activity.45 However, bupropion did not do better than placebo in improving ratings of global sexual function, sexual interest, arousal, and orgasm.45
Michelson et al. enrolled 61 women with fluoxetine- induced sexual dysfunction and randomized them to buspirone (10 mg twice daily), amantadine (50 mg/day), or placebo.46 All three groups improved similarly; reported rates of improvement in sexual function were 20—50%.46 In another placebo- controlled study of 27 women and 20 men treated with a selective serotonin reuptake inhibitor, subjects were randomized to buspirone, 20—60 mg/day, or placebo and treated for 4 weeks; 58% of the buspirone-treated subjects and 30% of the placebo- treated subjects reported improvement in sexual function, a non-statistically significant difference (p = 0.07).47 Granisetron, a serotonin 5-HT3 receptor antagonist that also has affinity for the serotonin 5-HT1A receptor, showed promising initial results in an open-label trial.48 However, a placebo-controlled, crossover trial of 31 patients with sexual dysfunction secondary to selective serotonin reuptake inhibitors, randomly assigned to adjunctive granisetron (1—1.5 mg) or placebo 1—2 h before sexual activity, showed an improvement in sexual function from baseline with no differences between the groups.49 In 148 women on fluoxetine, a double-blind, placebo-controlled trial of mirtazapine (15 mg/day), yohimbine (5.4 mg/day), olanzapine (2.5 mg/day), and placebo found moderate improvement in most sexual function measures in all the groups; no medication did better statistically than placebo.50
Avoidance and switching
A survey of clinical psychiatrists indicates that 79% would augment with or switch to a novel antidepressant for selective serotonin reuptake inhibitor-induced sexual dysfunction.51 The underlying premise of switching for side-effect control is flawed because antidepressants are not interchangeable. The odds ratio of switching a true medication responder/remitted patient to another antidepressant and maintaining efficacy with a second agent is 0.64—1.2 — approximately a coin flip. The older antidepressants, such as tricyclic antidepressants and monoamine oxidase inhibitors, have sexual side effects, although their other side effects (such as weight gain, sedation, and orthostatic hypotension) usually eclipse sexual dysfunction. Three newer antidepressants, bupropion, mirtazapine, and nefazodone (recently withdrawn from the US market), may have fewer sexual side effects than serotonergic antidepres- sants.14 Of these three medications, bupropion has consistently shown the lowest incidence of sexual dysfunction, and may improve sexual desire in depressed patients.
Tolerance, dose adjustment, and drug holiday
Some patients’ antidepressant-induced sexual dysfunction remits over time. Indirect empirical evidence of the development of tolerance comes from antidote studies that used placebo groups or studies that followed patients longitudinally; these reports suggest a range of remission of 35—70%.47,52—60 Other investigators have reported lower rates of tolerance of 6—20%.10 13,47'52—63
Because the dosage of medication required to attain depressive remission is the same as is needed to maintain remission,64 dose reduction to re-establish sexual function may result in relapse or recurrence of depression or another treated disorder. Therefore, it is not a practical strategy in most cases.
Another less practical approach is the “drug holiday”. The only published report is an uncontrolled study that described favorable results after subjects discontinued their selective serotonin reuptake inhibitor after their Thursday morning dose and restarted the medication at the usual dosage on the following Sunday at noon.65 Subjects who were taking sertraline and paroxetine noted considerable improvement in sexual function without a significant return of depressive symptoms, but those using fluoxetine did not experience improvement in sexual function, presumably due to fluoxetine’s long half-life. However, such intermittent dosing puts patients at risk of developing serotonergic discontinuation syndrome, which is more likely with the shorter half-life agents,66 and may occur within 24 h of the last dose of medication.67,68 Additional difficulties with this approach are that it hinders spontaneity and encourages noncompliance with medication.
Selective phosphodiesterase type 5 inhibitors for antidepressant- associated sexual dysfunction
Although sexual dysfunction is reversible in some individuals, patients who have recovered from depression and are experiencing increased interest in sexual activity may choose not to wait an indeterminate period of time for tolerance to occur. Use of a selective phosphodiesterase type 5 inhibitor to treat antidepressant-induced sexual dysfunction offers advantages — it is taken as needed, has a short duration of action, and has no central nervous system effects to interact with the primary antidepressant agent. Our research group postulated that a selective phosphodiesterase type 5 inhibitor could effectively assist patients to bridge the interval of waiting for full recovery of sexual function. In addition, for patients where sexual dysfunction does not remit over time, selective phosphodiesterase type 5 inhibitors can manage iatrogenic sexual dysfunction for the duration of antidepressant treatment.
Most of the evidence supporting use of selective phosphodiesterase type 5 inhibitors in antidepressant-associated sexual dysfunction comes from studies that used samples of male subjects. Price reported efficacy for sildenafil (76%) compared to placebo (11%) in male erectile dysfunction associated with major depressive disorder.69 Seidman et al. evaluated flexible-dose sildenafil treatment in men with erectile dysfunction and mild to moderate depressive symptoms (major depressive disorder was excluded) in a 12-week, randomized, double-blind, placebo- controlled trial.70 Sildenafil was strongly associated with response of erectile dysfunction and a mean Hamilton Rating Scale for Depression score decrease (—10.6) in erectile dysfunction responders compared with (—2.3) in erectile dysfunction nonresponders (p < 0.001).70 In a retrospective analysis of combined data from 10 phase II and III sildenafil double-blind, placebo-controlled, fixed and flexible dose studies, Nurnberg et al. identified a subgroup of 93 men among 3414 with erectile dysfunction taking concomitant selective serotonin reuptake inhibitor and assigned to either sildenafil 25—200 mg (n = 62) or placebo (n = 31).71 Ratings for erectile function, orgasm, and sexual satisfaction demonstrated significant improvement for all men with erectile dysfunction receiving sildenafil and concomitant selective serotonin reuptake inhibitor therapy (p <0.0001).71 A similar retrospective analysis of the use of tadalafil (10—20 mg) (vs placebo) in 111 men taking antidepressants indicates statistically significant improvement in erectile function scores, rate of successful intercourse, and percentage of patients with improved erections in those subjects taking tadalafil when compared with those taking placebo.72 Rosen and colleagues recently reported on the use of vardenafil in men with untreated mild to moderate major depressive disorder and erectile dysfunction.73 Compared to placebo, men taking vardenafil reported improved erectile function, lower Hamilton Rating Scale for Depression scores, and improved self-esteem.73
In a prospective, double-blind, placebo-controlled, flexible- dose study of sildenafil for the management of serotonergic antidepressant-associated sexual dysfunction in 90 men, Nurnberg et al. reported that sildenafil significantly improved sexual function on the primary measure, the Clinical Global Improvement Scale (p < 0.001).74 A categoric improvement of “much improved” or “very much improved” was reported by 54.5% of sildenafil-treated subjects and 4.4% of the placebo-treated sub- jects.74 In addition, the secondary sexual function inventory measures, the International Index of Erectile Function, the Arizona Sexual Experience Scale, and Massachusetts General Hospital-Sexual Functioning Questionnaire, all showed improvement from baseline to endpoint in subjects receiving sildenafil compared to those receiving placebo (p < 0.001).74 Subjects had to be free from pre-existing sexual dysfunction, to be taking a minimum of 8 weeks’ stable dose antidepressant, to maintain the dose throughout the duration of the study, and to have scores on the Hamilton Rating Scale for Depression and Hamilton Rating Scale for Anxiety both less than 10. Depression remained in remission for both groups; in addition, subjects continued the antidepressant and dose that effectively treated their depression, uninterrupted, and without relapse of major depressive disorder.74
At this time, there are insufficient comparative data to suggest that any one selective phosphodiesterase type 5 inhibitor medication is more efficacious than any other.
Selective phosphodiesterase type 5 inhibitor use for antidepressant- associated sexual dysfunction in womenIt must be underscored that, at present, the use of selective phosphodiesterase type 5 inhibitors for antidepressant-induced sexual dysfunction in women is off-label and without Food and Drug Administration-approved indication. Women have greater prevalence of major depression and more severe treatment-emergent sexual dysfunction, and use more selective serotonin reuptake inhibitors than men. Consequently, it is to be expected that interest and questions regarding the efficacy of selective phosphodiesterase type 5 inhibitors in women would arise.
Increased understanding of the mechanisms of sexual function suggest that mechanisms analogous to men apply in female sexual dysfunction. Phosphodiesterase type 5 is present in the female genital tract, and nitric oxide synthase isoforms occur in human clitoral cavernosal tissue.75 That suggests that female erectile tissue can respond to the enhancement of the nitric oxide—cyclic guanosine monophosphate axis, specifically in cli- toral erection, labial swelling, and vaginal lubrication upon sexual stimulation.
Reports of sildenafil treatment in women describe increased vaginal vascular engorgement, enhanced clitoral responsiveness, and improved lubrication.76 Case reports for primary female sexual dysfunction treatment describe potential bene- fit.77 However, there have also been equivocal reports of efficacy in female sexual dysfunction of various etiologies.78—80 In a double-blind, placebo-controlled, crossover study of postmenopausal and posthysterectomy women, Berman et al. report that sildenafil 100 mg enhanced female sexual response physiologic parameters with visual and vibratory sexual stimulation.76 Use of sildenafil led to significant increases in vaginal pH compared with baseline and placebo (p < 0.05).76 Genital blood flow and vaginal compliance increased with sildenafil, but were not statistically greater than with placebo.76
The established safety and tolerability provided an opportunity to examine sildenafil for serotonergic antidepressant- associated sexual dysfunction in women. Open-label reports by Nurnberg et al.81 and Fava et al.82 included women who experienced sexual dysfunction improvements comparable to men. A second open-label study by Nurnberg et al. reported on 10 women with major depressive disorder in remission, without pre-existing sexual dysfunction, and serotonergic antidepressant-induced anorgasmia.83 Nine of 10 women had reversal of sexual dysfunction; dosing ranged from 50 to 100 mg taken 1—2 h before sexual activity.83 Additional open studies and case reports support these findings.84—86 It appears that sildenafil use improves arousal with increased sensitivity, clitoral tumescence, genital vascular engorgement, and lubrication in women with antidepressant-induced sexual dysfunction. Preliminary reports from the first double-blind, placebo- controlled trial of flexible-dose, sildenafil for serotonergic antidepressant-associated sexual dysfunction in 150 women indicate comparable efficacy to the male double-blind, placebo-controlled studies, with overall response rates over 80%.87 The data on treating women with antidepressant- induced sexual dysfunction are more complicated due to the importance of hormonal factors.
The last 10—15 years has seen a revolution in the treatment of depression and related disorders. Although newer medications have fewer side effects overall, it is clear that sexual dysfunction is an important, prevalent, and potentially quite distressing adverse event for patients. We are also more aware of the effects of depression on the individual’s sexual function. A variety of suggested treatment strategies exist for sexual dysfunction, but none show universal efficacy. Oral selective phosphodiesterase type 5 inhibitors appear to demonstrate a clear role for effectively managing antidepressant-associated treatment-emergent sexual dysfunction in men, but we await more data on women. Previous treatments were essentially random pharmacology. The physician in practice needs to make patients aware of the possibility of this side effect, assess for sexual dysfunction, and keep the lines of communication open so that patients do not prematurely discontinue their antidepressant, placing them at risk of relapse of their depression.
1. Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States: prevalence and predictors.
2. Dunn KM, Croft PR, Hackett GI. Satisfaction in the sex life of a general population sample. JSxMûïiialTher 2000; 26: 141-51.
3. Dunn KM, Croft PR, Hackett GI. Association of sexual problems with social, psychological, and physical problems in men and women: a cross sectional population survey.
4. Hawton K, Gath D, Day A. Sexual function in a community sample of middle-aged women with partners: effects of age, marital, socioeconomic, psychiatric, gynecological, and menopausal factors. Arch Sex Behav 1994; 23: 375-95.
5. Casper RC, Redmond DE Jr, Katz MM et al. Somatic symptoms in primary affective disorder. Presence and relationship to the classification of depression. ArchGenPychary 1985; 42: 1098-1104.
6. Kennedy SH, Dickens SE, Eisfeld BS et al. Sexual dysfunction before antidepressant therapy in major depression. J Affect Disord 1999; 56(2-3): 201-8.
7. Zajecka J, Dunner DL, Gelenberg AJ et al. Sexual function and satisfaction in the treatment of chronic major depression with nefazodone, psychotherapy, and their combination. J Clin Psychiatry 2002; 63: 709-16.
8. Zajecka J, Dunner DL, Hirschfeld RM et al. Sexual function and satisfaction in the treatment of chronic major depression with nefazodone, CBAS-psychotherapy (CBASP) and their combination. Paper presented at American College of Neuropsychopharmacology, 2000, San Juan, Puerto Rico.
9. Ekselius L, von Knorring L. Effect on sexual function of long-term treatment with selective serotonin reuptake inhibitors in depressed patients treated in primary care. J Psychopharmacol 2001; 21: 154-60.
10. Rosen RC, Lane RM, Menza M. Effects of SSRIs on sexual function: a critical review. JmC^nP^^hspha^macol 1999; 19: 67-85.
11. Altman CA. Effects of selective serotonin reuptake inhibitors on sexual function. Jm£Jjnpy£h£pharmO££l 2001; 21: 241-2.
12. 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: 176-94.
13. Montejo AL, Llorca G, Izquierdo JA et al. Incidence of sexual dysfunction associated with antidepressant agents: a prospective multicenter study of 1022 outpatients. Spanish Working Group for the Study of Psychotropic-Related Sexual Dysfunction. J Clin Psychiatry 2001; 62(Suppl 3): 10-21.
14. Clayton AH, Pradko JF, Croft HA et al. Prevalence of sexual dysfunction among newer antidepressants. J Clin Psychiatry 2002; 63: 357-66.
15. Piazza LA, Markowitz JC, Kocsis JH et al. Sexual functioning in chronically depressed patients treated with SSRI antidepressants: a pilot study. Am J Psychiatry 1997; 154: 1757-9.
16. Nurnberg HG, Hensley PL, Lauriello J. Sildenafil in the treatment of sexual dysfunction induced by selective serotonin reuptake inhibitors - an overview. CNS Drugs 2000; 13: 321-35.
17. Nurnberg HG. Managing treatment-emergent sexual dysfunction associated with serotonergic antidepressants: before and after sildenafil. Jpychiatpact 2001; 7: 92-108.
18. Aizenberg D, Gur S, Zemishlany Z et al. Mianserin, a 5-HT2a/2c and alpha 2 antagonist, in the treatment of sexual dysfunction induced by serotonin reuptake inhibitors. Clin Neuropharmacol 1997; 20: 210-14.
19. Aizenberg D, Naor S, Zemishlany Z et al. The serotonin antagonist mianserin for treatment of serotonin reuptake inhibitor- induced sexual dysfunction in women: an open-label add-on study. Clin Neuropharmacol 1999; 22: 347-50.
20. Dolberg OT, Klag E, Gross Y et al. Relief of serotonin selective reuptake inhibitor induced sexual dysfunction with low-dose mianserin in patients with traumatic brain injury. Psychopharmacology 2002; 161: 404-7.
21. Aizenberg D, Zemishlany Z, Weizman A. Cyproheptadine treatment of sexual dysfunction induced by serotonin reuptake inhibitors. Clin Neuropharmacol 1995; 18: 320-4.
22. Lauerma H. Successful treatment of citalopram-induced anorgas- mia by cyproheptadine. Aç$aPyhGïSand 1996; 93: 69-70.
23. McCormick S, Olin J, Brotman AW. Reversal of fluoxetine- induced anorgasmia by cyproheptadine in two patients. J Clin Psychiatry 1990; 51: 383-4.
24. Steele TE, Howell EF. Cyproheptadine for imipramine-induced anorgasmia. J Clin Psychopharmacol 1986; 6: 326-7.
25. Arnott S, Nutt D. Successful treatment of fluvoxamine-induced anorgasmia by cyproheptadine. Br J Psychiatry 1994; 164: 838-9.
26. Ashton AK, Ahrens K, Gupta Setal. Antidepressant-induced sexual dysfunction and Ginkgo biloba. Am J Psychiatry 2000; 157: 836-7.
27. Ellison JM, DeLuca P. Fluoxetine-induced genital anesthesia relieved by Ginkgo biloba extract. J Clin Psychiatry 1998; 59: 199-200.
28. Cohen AJ, Bartlik B. Ginkgo biloba for antidepressant-induced sexual dysfunction. J Sex Marital Ther 1998; 24: 139-43.
29. Balon R. Ginkgo biloba for antidepressant-induced sexual dysfunction? J Sex Marital Ther 1999; 25: 1-2.
30. Balogh S, Hendricks SE, Kang J. Treatment of fluoxetine-induced anorgasmia with amantadine. J Clin Psychiatry 1992; 53: 212-13.
31. Balon R. Intermittent amantadine for fluoxetine-induced anorgas- mia. J Sex Marital Ther 1996; 22: 290-2.
32. Shrivastava RK, Shrivastava S, Overweg N et al. Amantadine in the treatment of sexual dysfunction associated with selective serotonin reuptake inhibitors. J Clin Psychopharmacol 1995; 15: 83-4.
33. Brubaker RV. Fluoxetine-induced sexual dysfunction reversed by loratadine. 34. Gross MD. Reversal by bethanechol of sexual dysfunction caused by anticholinergic antidepressants. Am J Psychiatry
35. Segraves RT. Reversal by bethanechol of imipramine-induced ejaculatory dysfunction. Am J Psychiatry 1987; 144: 1243-4.
36. Segraves RT. Reversing anorgasmia associated with serotonin uptake inhibitors. JAMA 1991; 266: 2279.
37. Jacobsen FM. Fluoxetine-induced sexual dysfunction and an open trial of yohimbine. J Clin Psychiatry 1992; 53: 119-22.
38. Bartlik BD, Kaplan P, Kaplan HS. Psychostimulants apparently reverse sexual dysfunction secondary to selective serotonin reuptake inhibitors. J Sex Marital Ther 1995; 21: 264-71.
39. Stoll AL, Pillay SS, Diamond Letal. Methylphenidate augmentation of serotonin selective reuptake inhibitors: a case series. J Clin Psychiatry 1996; 57: 72-6.
40. Labbate LA, Grimes JB, Hines Aetal. Bupropion treatment of serotonin reuptake antidepressant-associated sexual dysfunction. Ann Clin Psychiatry 1997; 9: 241-5.
41. Bodkin JA, Lasser RA, Wines JD Jr et al. Combining serotonin reuptake inhibitors and bupropion in partial responders to antidepressant monotherapy.42. Clayton AH, McGarvey EL, Abouesh AI et al. Substitution of an SSRI with bupropion sustained release following SSRI-induced sexual dysfunction. J Clin Psychiatry 2001; 62: 185-90.
43. Ashton AK, Rosen RC. Bupropion as an antidote for serotonin reuptake inhibitor-induced sexual dysfunction. J Clin Psychiatry 1998; 59: 112-15.
44. Masand PS, Ashton AK, Gupta Setal. Sustained-release bupropion for selective serotonin reuptake inhibitor-induced sexual dysfunction: a randomized, double-blind, placebo-controlled, parallel-group study. Am J Psychiatry 2001; 158: 805-7.
45. Clayton AH, Warnock JK, Kornstein SG et al. A placebo- controlled trial of bupropion SR as an antidote for selective serotonin reuptake inhibitor-induced sexual dysfunction. J Clin Psychiatry 2004; 65: 62-7.
46. Michelson D, Bancroft J, Targum Setal. Female sexual dysfunction associated with antidepressant administration: a randomized, placebo-controlled study of pharmacologic intervention. Am J Psychiatry 2000; 157: 239-43.
47. Landen M, Eriksson E, Agren H et al. Effect of buspirone on sexual dysfunction in depressed patients treated with selective serotonin reuptake inhibitors. J Clin Psychopharmacol 1999; 19: 268-71.
48. Nelson EB, Keck PE Jr, McElroy SL. Resolution of fluoxetine- induced sexual dysfunction with the 5-HT3 antagonist granisetron. 1997; 58: 496-7.
49. Nelson EB, Shah VN, Welge JA et al. A placebo-controlled, crossover trial of granisetron in SRI-induced sexual dysfunction. J Clin Psychiatry 2001; 62: 469-73.
50. Michelson D, Kociban K, Tamura R et al. Mirtazapine, yohimbine or olanzapine augmentation therapy for serotonin reuptake-associated female sexual dysfunction:
51. Dording CM, Mischoulon D, Petersen TJ et al. The pharmacologic management of SSRI-induced side effects: a survey of psychiatrists. Ann Clin Psychiatry 2002; 14: 143-7.
52. Nurnberg HG, Levine PE. Spontaneous remission of MAOI- induced anorgasmia. Am J Psychiatry 1987; 144: 805-7.
53. Harrison WM, Rabkin JG, Ehrhardt AA et al. Effects of antidepressant medication on sexual function: a controlled study. J Clin Psychopharmacol 1986; 6: 144-9.
54. Kavoussi RJ, Segraves RT, Hughes AR et al. Double-blind comparison of bupropion sustained rel
55. Clayton AH, Owens JE, McGarvey EL. Assessment of paroxetine- induced sexual dysfunction using the Changes in Sexual Functioning Questionnaire. Psychopharmacol Bull 1995; 31: 397-413.
56. Feiger A, Kiev A, Shrivastava RK et al. Nefazodone versus sertraline in outpatients with major depression: focus on efficacy, tolerability, and effects on sexual function and satisfaction. J Clin Psychiatry 1996; 57(Suppl 2): 53-62.
57. Zajecka J, Mitchell S, Fawcett J. Treatment-emergent changes in sexual function with selective serotonin reuptake inhibitors as measured with the Rush Sexual Inventory. Psychopharmacol Bull 1997; 33: 755-60.
58. Labbate LA, Grimes J, Hines Aetal. Sexual dysfunction induced by serotonin reuptake antidepressants. J Sex Marital Ther 1998; 24: 3-12.
59. Labbate LA, Grimes JB, Arana GW. Serotonin reuptake antidepressant effects on sexual function in patients with anxiety disorders. BiolPychiatry 1998; 43: 904-7.
60. Reimherr FW, Chouinard G, Cohn CK et al. Antidepressant efficacy of sertraline: a double-blind, placebo- and amitriptyline- controlled, multicenter comparison study in outpatients with major depression. J Clin Psychiatry 1990; 51(Suppl B): 18-27.
61. Monteiro WO, Noshirvani HF, Marks IM et al. Anorgasmia from clomipramine in obsessive-compulsive disorder. A controlled trial. Br J Psychiatry 1987; 151: 107-12.
62. Ashton AK, Rosen RC. Accommodation to serotonin reuptake inhibitor-induced sexual dysfunction. J Sex Marital Ther 1998; 24: 191-2.
63. Shen WW, Hsu JH. Female sexual side effects associated with selective serotonin reuptake inhibitors: a descriptive clinical study of 33 patients. Int J Psychiatry Med 1995; 25: 239-48.
64. Hirschfeld RM, Schatzberg AF. Long-term management of depression. Am J Med 1994; 97(6A): 33S-8.
65. Rothschild AJ. Selective serotonin reuptake inhibitor-induced sexual dysfunction: efficacy of a drug holiday. Am J Psychiatry 1995; 152: 1514-16.
66. Rosenbaum JF, Fava M, Hoog SL et al. Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial. BiolPychay 1998; 44: 77-87.
67. Coupland NJ, Bell CJ, Potokar JP. Serotonin reuptake inhibitor withdrawal. J Clin Psychopharmacol 1996; 16: 356-62.
68. Lane RM. Withdrawal symptoms after discontinuation of selec tive serotonin reuptake inhibitors (SSRIs). J Serotonin Res 1996; 3: 75-83.
69. Price D. Sildenafil citrate (Viagra) efficacy in the treatment of erectile dysfunction in patients with common concomitant conditions. Sildenafil Study Group. Int J Clin Pract Suppl 1999; 102: 21-3.
70. Seidman SN, Roose SP, Menza MA et al. Treatment of erectile dysfunction in men with depressive symptoms: results of a placebo-controlled trial with sildenafil citrate. Am J Psychiatry 2001; 58: 1623-30.
71. Nurnberg HG, Gelenberg A, Hargreave TB et al. Efficacy of sildenafil citrate for the treatment of erectile dysfunction in men taking serotonin reuptake inhibitors. 72. Segraves RT, Stevenson R, Lee Jetal. Tadalafil for treatment of erectile dysfunction in men on antidepressants. New Research Poster presented at American Psychiatric Association, 3 May 2004, New York.
73. Rosen R, Montorsi F, Assalian P et al. Efficacy and tolerability of vardenafil in men with mild depressive disorder and erectile dysfunction: the Depression Related Improvement with Vardenafil for Erectile Response (DRIVER) study. Paper presented at 19th Congress of the European Association of Urology, 26 March 2004, Vienna, Austria.
74. Nurnberg HG, Hensley PL, Gelenberg AJ et al. Treatment of antidepressant-associated sexual dysfunction with sildenafil: a randomized controlled trial. JAMA 2003; 289: 56-64.
75. Park K, Moreland RB, Goldstein I et al. Sildenafil inhibits phosphodiesterase type 5 in human clitoral corpus cavernosum smooth muscle.76. Berman J, Goldstein I, Werbin Tetal. Double blind placebo controlled study with crossover to assess effect of sildenafil on physiological parameters of the female sexual response. J Urol 1999; 161(Suppl 210): 210.
77. Bartlik B, Kaplan P, Kaminetsky Jetal. Medications with the potential to enhance sexual responsivity in women. Psychiatr Ann 1999; 29: 46-52.
78. Kaplan SA, Reis RB, Kohn IJ et al. Safety and efficacy of sildenafil in postmenopausal women with sexual dysfunction. Urology 1999; 53: 481-6.
79. Basson R, McInnes R, Smith MD et al. Efficacy and safety of sildenafil in estrogenized women with sexual dysfunction associated with female sexual arousal disorder. Obstet Gynecol 2000; 95(4 Suppl 1): S54.
80. Sipski ML, Rosen RC, Alexander CJ et al. Sildenafil effects on sexual and cardiovascular responses in women with spinal cord injury. Urology 2000; 55: 812-15.
81. Nurnberg HG, Lauriello J, Hensley PL et al. Sildenafil for iatrogenic serotonergic antidepressant medication-induced sexual dysfunction in 4 patients. J Clin Psychiatry 1999; 60: 33-5.
82. Fava M, Rankin MA, Alpert JE et al. An open trial of oral sildenafil in antidepressant-induced sexual dysfunction. Psychother Psychosom 1998; 67: 328-31.
83. Nurnberg HG, Hensley PL, Lauriello Jetal. Sildenafil for women patients with antidepressant-induced sexual dysfunction. Psychiatr Serv 1999; 50: 1076-8.
84. Ashton AK. Sildenafil treatment of paroxetine-induced anorgas- mia in a woman. Am J Psychiatry 1999; 156: 800.
85. Rosenberg KP. Sildenafil citrate for SSRI-induced sexual side effects. Am J Psychiatry 1999; 156: 157.
86. Shen WW, Urosevich Z, Clayton DO. Sildenafil in the treatment of female sexual dysfunction induced by selective serotonin reuptake inhibitors. J Reprod Med 1999; 44: 535-42.
87. Nurnberg HG, Hensley PL, Croft H et al. Sildenafil citrate treatment for SRI-associated female sexual dysfunction. Poster presented at American Psychiatric Association, 21 May 2003, San Francisco.