Identifying and adhering to an effective antidepressant regimen can be difficult, and the presence of sexual side effects makes the task even more difficult. These side effects are relatively common, particularly with SSRIs/SNRIs, but they may be under-reported and undertreated as a result of the stigma surrounding mental health care and patients' and healthcare providers' reluctance to discuss sexual topics. This course will briefly outline the demographics of antidepressant-associated sexual dysfunction and gender-specific manifestations. Enriching one's knowledge of sexual side effects and approaches to management will improve patients' adherence to antidepressant therapy and overall quality of life.
The course is designed for health and mental health professionals involved in the care of patients who have been prescribed antidepressants.
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The purpose of this course is to provide needed information about the relationship between antidepressants and sexual dysfunction and the resultant impact on treatment efficacy and adherence so healthcare professionals may select the best possible treatment plan.
Upon completion of this course, you should be able to:
- Outline the demographics and etiology of antidepressant-associated sexual dysfunction.
- Describe the approach to managing sexual side effects of antidepressant use in men.
- Discuss potential sexual side effects of antidepressant use in women.
- Evaluate the impact of post-treatment enduring sexual dysfunction in patients who were prescribed antidepressants.
Mark Rose, BS, MA, is a licensed psychologist and researcher in the field of alcoholism and drug addiction based in Minnesota. He has written or contributed to the authorship of numerous papers on addiction and other medical disorders and has written books on prescription opioids and alcoholism published by the Hazelden Foundation. He also serves as an Expert Advisor and Expert Witness to various law firms on matters related to substance abuse, is on the Board of Directors of the Minneapolis-based International Institute of Anti-Aging Medicine, and is a member of several professional organizations.
Contributing faculty, Mark Rose, BS, MA, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.
John M. Leonard, MD
Jane C. Norman, RN, MSN, CNE, PhD
Alice Yick Flanagan, PhD, MSW
The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.
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#95080: Antidepressant-Associated Sexual Dysfunction
Before the 1980s, reports of antidepressant-associated sexual dysfunction were rare, mainly due to under-reporting, lack of patient assessment and discussion, and the widespread assumption that persons with mental health problems were asexual and/or lacked sexual desire [1,2]. Since then, research has established that sexual side effects are associated with all commercially available antidepressants, including tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), and dual serotonergic/noradrenergic reuptake inhibitors (SNRIs). Among antidepressants, SSRIs/SNRIs show the highest rates of sexual dysfunction, including impaired sexual motivation, desire, arousal, and orgasm affecting men and women. Prescribers dramatically underestimate the prevalence and patient burden of sexual side effects and other adverse effects from antidepressants and other medications . Comparison of spontaneous patient reporting with systematic inquiry has led to estimated sexual side effect rates that differ by ≥60% [1,2]. SSRIs account for most antidepressant prescriptions, and primary care providers should have a good understanding of the risk and patient impact of sexual side effects and management of this iatrogenic condition.
In 2010, antidepressant prescriptions were purchased by 9.9% (23.3 million) of the pre-adolescent and older U.S. population, for a total of 212.5 million prescriptions . With 6% to 10% of the U.S. and European population treated with antidepressants, they are among the most widely prescribed drugs, and SSRIs/SNRIs account for roughly 85% of these prescriptions [5,6]. An estimated 1 in 6 American women have been prescribed antidepressants, the result of women seeking care for depression at higher rates than men and being twice as likely to be prescribed antidepressants for the same complaint [6,7]. Side effects largely contribute to the 31% to 60% non-adherence rate with antidepressants. Sexual side effects are the most frequent antidepressant side effect reported by primary care patients .
In both men and women, antidepressant-induced sexual side effects largely result from increased serotonin (5-HT) neurotransmission via reuptake blockade of serotonin transporters. Antidepressants that primarily increase dopamine and norepinephrine neurotransmission produce markedly fewer sexual side effects. SSRI/SNRI-induced sexual side effects are likely mediated by inhibitory actions on dopamine signaling in sex brain circuits and can be decreased by simultaneously increasing norepinephrine and dopamine neurotransmission but not by increasing norepinephrine alone. This provides the rationale for treatment using bupropion and other agents that simultaneously increase norepinephrine and dopamine signaling. It also suggests the theoretic basis for developing novel antidepressants that increase 5-HT and dopamine signaling. These findings are clinically relevant for patients who develop sexual side effects but also attain substantial clinical improvement or remission of depression with serotonergic agents. All reasonable options to mitigate the antidepressant-induced sexual side effect should be explored before lowering the dose or switching effective antidepressant therapies [9,10]. Serotonergic antidepressants produce the highest rates of sexual side effects, but a multifactorial etiology is more likely than a specific monotransmitter action. Other possible mechanisms for SSRI/SNRI-induced sexual side effects include decreased dopaminergic transmission, cholinergic and alpha-adrenergic blockade, inhibition of nitric oxide 1 synthase, and prolactin elevation [11,12].
The association between major depressive disorder and sexual dysfunction is bidirectional. Estimated prevalence rates of antidepressant-induced sexual side effects are very high for several antidepressants, but estimation of true prevalence is complicated by the high prevalence of sexual dysfunction in all patients with mood disorders and by the under-reporting of sexual side effects. Baseline sexual functioning should be assessed with validated rating scales at the same time depression is evaluated [10,13].
As noted, the prevalence of sexual side effects in antidepressant use is highest for SSRIs and venlafaxine. TCAs and MAOIs have moderate rates of sexual side effects, and low rates are noted with bupropion, trazodone, nefazodone, mirtazapine, agomelatine, and vilazodone. Perhaps the lowest rate is associated with moclobemide, a reversible MAOI [1,14]. Women often require considerably more time to climax than men, which can make SSRI-induced delayed orgasm unwanted in women but a desired effect in men. A meta-analysis of sexual side effect rates with SSRIs and venlafaxine reported that orgasm and desire dysfunction are more common in men, while arousal dysfunction is more common in women (Table 1) .
LIKELIHOOD OF SEXUAL SIDE EFFECTS WITH SPECIFIC SSRIsa
|SSRI Agent||Percent of Male Patients Affected||Percent of Female Patients Affected|
|aThese figures are based on data that did not record the duration of, or distress from, sexual side effects.|
As noted, switching medications to an antidepressant with fewer sexual side effects is highly undesirable and should be avoided, if possible, in patients showing an otherwise positive therapeutic response. If low sexual response or libido is a known problem prior to the initiation of antidepressant therapy, selection of an effective agent with the lowest rate of sexual side effects is recommended. Another strategy is antidepressant dose reduction, on the basis of a dose-response relationship in sexual side effects. Although common as a first-line approach and suggested by the American Psychiatric Association, this may precipitate symptomatic relapse and should be avoided in most patients with serious depression [16,17,18]. Taking a drug holiday by stopping the antidepressant for a few days has also been suggested . This may be feasible with fluoxetine, owing to its long half-life, but it is not advised with other antidepressants, as patients can experience discontinuation symptoms, disruption of therapeutic effect, and worsening of depression symptoms .
Adding medications with mechanisms that offset the SSRI/SNRI side effects is a valid approach. 5-HT receptor antagonists or agonists or dopamine agonists are most commonly used for this purpose. Several trials have found favorable response with the 5-HT2 and 5-HT3 receptor antagonist mirtazapine, which broadly improves sexual side effects but can cause weight gain; the 5-HT2A antagonist cyproheptadine, which alleviates SSRI-induced orgasm disruption but can cause sedation; the 5-HT1A agonist buspirone; and the norepinephrine and dopamine agonist bupropion, which has the greatest evidence support and most extensive use for this indication [20,21,22,23,24].
The incidence of male sexual dysfunction is much higher with SSRIs/SNRIs and much lower with antidepressants with primary adrenergic or dopaminergic mechanism. Ejaculatory delay is highly prevalent with serotonergic antidepressants. However, as noted, this can be a desired instead of adverse effect in men with premature ejaculation. In fact, the SSRI dapoxetine has become first-line therapy in the treatment of premature ejaculation [25,26]. Certain antidepressants, particularly trazodone, may rarely cause priapism (prolonged and painful erection) .
The antidepressant trazodone inhibits central nervous system 5-HT uptake and increases central dopamine transmission without peripheral norepinephrine reuptake inhibition. While efficacy in erectile dysfunction has been inconsistent in controlled trials, trazodone may be effective in treating SSRI-induced sexual dysfunction [27,28].
Men with SSRI/SNRI-induced sexual dysfunction were randomized to daily S-adenosyl-l-methionine (SAMe) or placebo for six weeks, while maintaining their SSRI/SNRI. Controlling for baseline sexual dysfunction severity and depression improvement from baseline, significantly greater reduction in arousal and erectile dysfunction was found with SAMe versus placebo. SAMe is used for mild-to-moderate depression, and the authors state improvements in male sexual dysfunction were likely independent of an antidepressant effect .
Approximately 96% of women taking antidepressants report at least one sexual side effect, with 20% to 50% qualifying as a distinct clinical problem [30,31]. Antidepressants can prominently affect female sexual functioning and cause decreased libido, problems with arousal, and anorgasmia at prevalence rates as high as 80% .
Drugs that increase 5-HT negatively impact female sexual behavior, while decreases in 5-HT apparently facilitate sexual behavior facilitation. In particular, 5-HT1A receptor agonists inhibit sexual behavior, while 5-HT2 or 5-HT3 receptors may exert a positive influence. There is substantial evidence to support a role for 5-HT in the modulation of female consummatory sexual experience, but studies on the role of 5-HT in other elements of female sexuality, such as desire, motivation, and sexual appetite, are much fewer .
Exercise may improve antidepressant-related genital arousal problems. Because exercise increases genital arousal in healthy women most likely by increasing sympathetic nervous system (SNS) activity, a clinical trial measured the impact of exercise on genital arousal in 47 women taking antidepressants (68% SSRIs) and reporting antidepressant-related sexual arousal problems. Measures of genital and SNS arousal while watching an erotic film were compared when preceded by no exercise or 20 minutes of exercise 5 or 15 minutes before the film. Exercise prior to sexual stimuli was associated with increased genital arousal in both groups. Women reporting more severe sexual dysfunction had greater increases in genital arousal post-exercise. For women taking SSRIs, genital arousal was linked to SNS activity .
Adding bupropion 300 mg/day to a current SSRI regimen seems to improve sexual function in women experiencing sexual side effects . Treatment of SSRI-induced female sexual dysfunction with adjunctive bupropion 300 mg/day for 12 weeks was studied in 218 women (25 to 45 years of age). Compared to placebo, the bupropion group showed greater improvement in mean total Female Sexual Function Index (FSFI) score (17.2 vs. 25.9) and in all FSFI domain scales. The bupropion group showed greatest increase from baseline in FSFI scores for desire (86.4%) and lubrication (69.2%) domains .
A randomized controlled trial evaluated transdermal testosterone therapy 300 mcg/day in 44 women (35 to 55 years of age) with SSRI/SNRI-emergent libido loss . After 12 weeks, the increase in frequency of satisfactory sexual events and reduction in sexual distress were significantly greater with transdermal testosterone than placebo. No women withdrew because of androgenic adverse events. No improvement was found on the primary measure of sexual function, possibly from poor sensitivity in the study's measuring instrument. The researchers concluded that transdermal testosterone therapy benefits some women with SSRI/SNRI-associated libido loss .
Interesting results were found in a comparison of premenopausal women with major depressive disorder and a premenopausal non-depressed control group. Before successful antidepressant treatment, mean total testosterone and bioavailable testosterone were significantly lower in the treatment group relative to controls. Following antidepressant treatment, these parameters significantly increased from baseline levels and were comparable to controls. The authors state the significant increase in testosterone to normal levels following antidepressant therapy suggests that testosterone may be involved in the etiology of depression for some women .
Androgen receptor gene polymorphism, encoded by the nucleotides cysteine, adenine, and guanine, may influence the effect of testosterone on female sexual functioning and treatment. In one study, 21 pre- and postmenopausal women with SSRI-induced sexual dysfunction received daily sublingual testosterone 0.5 mg, plus buspirone 10 mg or sildenafil 50 mg. Women using low-dose SSRIs showed marked improvement in sexual function from both treatments relative to placebo. Sublingual testosterone combined with sildenafil or buspirone may be beneficial in subgroups of women with SSRI-induced sexual dysfunction .
Saffron (Crocus sativus L.) has shown beneficial aphrodisiac effects, but little is known of its efficacy in the management of medication-induced sexual dysfunction. A random controlled trial evaluated saffron 30 mg/day in 38 women with SSRI-induced sexual dysfunction, stabilized on fluoxetine for major depression. After four weeks of treatment, the saffron group had significantly greater improvement in total FSFI score and arousal, lubrication, and pain domains, but not desire, satisfaction, or orgasm domains. Side effects were similar between the two groups. Saffron may safely and effectively improve some fluoxetine-induced sexual problems, including arousal, lubrication, and pain .
Post-SSRI sexual dysfunction is little known in the broader medical community and, when reported, has been partially attributed to psychologic factors . However, the adverse impact from antidepressant-induced sexual side effects and post-SSRI sexual dysfunction may be worse than the condition for which treatment has been sought .
In the first review of post-SSRI sexual dysfunction in 2008, Bahrick and Harris challenged conventional wisdom that sexual side effects resolve with SSRI cessation, stating that research literature had failed to include systematic follow-up to support this assumption . This emerging problem is supported by a convergence of case reports, consumer reports, and robust evidence from efficacy studies of healthy men documenting SSRI-induced delayed ejaculation persisting long after SSRI cessation. Internet drug consumer sites may provide a database of this qualitative information not captured within research paradigms or existing post-market pharmacovigilance mechanisms .
In 2014, the broader category of post-treatment enduring sexual dysfunction (PTESD) was investigated and 120 cases (mean age: 30.9 years) were identified. Highest rates occurred with SSRI agents (11.2% to 15.5%), venlafaxine (7.8%), isotretinoin (6.0%), and finasteride (5.2%). Women comprised 20% of SSRI cases, and all of the isotretinoin and finasteride cases occurred in men. PTESD occurred following medication exposure of 3 to 5,840 days, and a common feature was sexual side effect onset after medication was discontinued. The consequences of PTESD were severe, including several well-documented cases of suicide. The longest case was 18 years, from a brief exposure to fluoxetine at 18 years of age .
PTESD symptoms can include the entire spectrum of male and female sexual dysfunction, but the triad of penile or clitoral anesthesia, loss of libido, and loss of function is the core characteristic of PTESD, across all identified drug classes and agents [43,44]. Pleasureless orgasm has also been reported .
Efforts to manage PTESD have involved serotonin and dopamine system modulation with the 5HT-1 agonist buspirone, the 5HT-2 and 5HT-3 antagonists trazodone and mirtazapine, and dopamine agonists (e.g., pramipexole, cabergoline, bupropion, dexamphetamine). Phosphodiesterase type 5 inhibitors, testosterone, ketamine, donepezil, and metformin have all been tried for PTESD. However, none of these have helped. This treatment-refractory characteristic may reflect epigenetic changes in PTESD . Additional research into the underlying etiology of persistent sexual dysfunction following antidepressant cessation will hopefully give insight into an effective treatment.
In this multicultural landscape, interpreters are a valuable resource to help bridge the communication and cultural gap between clients/patients and practitioners. Discussions of depression and sexuality can be sensitive, and removing possible language barriers using professional interpreters is recommended for patients for whom English is not their first language. Interpreters are more than passive agents who translate and transmit information back and forth from party to party. When they are enlisted and treated as part of the interdisciplinary clinical team, they serve as cultural brokers who ultimately enhance the clinical encounter. In any case in which information regarding diagnostic procedures, treatment options and medication/treatment measures are being provided, the use of an interpreter should be considered.
Identifying and adhering to an effective antidepressant regimen can be challenging, and the presence of sexual side effects makes the task even more difficult. These side effects are relatively common, particularly with SSRIs/SNRIs, but they may be under-reported and undertreated as a result of the stigma surrounding mental health care and patients' and healthcare providers' reluctance to discuss sexual topics. This course has briefly outlined the demographics of antidepressant-associated sexual dysfunction and gender-specific manifestations. Enriching one's knowledge of sexual side effects and approaches to management will improve patients' adherence to antidepressant therapy and overall quality of life.
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