95082 • Antidepressant-Associated Sexual Dysfunction

Table of Contents

95082 • Antidepressant-Associated Sexual Dysfunction

How to Receive Credit

Course Overview

Audience

Accreditations & Approvals

Designations of Credit

Individual State Nursing Approvals

Individual State Behavioral Health Approvals

Special Approvals

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. INTRODUCTION

2. DEMOGRAPHICS AND ETIOLOGY OF ANTIDEPRESSANT-INDUCED SEXUAL DYSFUNCTION

3. MANAGEMENT

MALE SEXUAL DYSFUNCTION

FEMALE SEXUAL DYSFUNCTION

POST-TREATMENT ENDURING SEXUAL DYSFUNCTION

4. CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

5. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

95082 • Antidepressant-Associated Sexual Dysfunction

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2022 NetCE, All rights reserved.

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.

95082 • Antidepressant-Associated Sexual Dysfunction

Education Category. Pharmacology

Release Date. 11/01/2022

Expiration Date. 10/31/2025

How to Receive Credit

To complete this course for continuing education credit please go to http://www.netce.com/course/2478 in your browser.

For assistance with receiving continuing education credit, please contact us at help@netce.com.

Course Overview

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.

Audience

This course is designed for health and mental health professionals involved in the care of patients who have been prescribed antidepressants.

Accreditations & Approvals

In support of improving patient care, TRC Healthcare/NetCE is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. NetCE has been approved by NBCC as an Approved Continuing Education Provider, ACEP No. 6361. Programs that do not qualify for NBCC credit are clearly identified. NetCE is solely responsible for all aspects of the programs. As a Jointly Accredited Organization, NetCE is approved to offer social work continuing education by the Association of Social Work Boards (ASWB) Approved Continuing Education (ACE) program. Organizations, not individual courses, are approved under this program. Regulatory boards are the final authority on courses accepted for continuing education credit. Continuing Education (CE) credits for psychologists are provided through the co-sponsorship of the American Psychological Association (APA) Office of Continuing Education in Psychology (CEP). The APA CEP Office maintains responsibility for the content of the programs. This course, Antidepressant-Associated Sexual Dysfunction, Approval #202306-1905, provided by NetCE is approved for continuing education by the New Jersey Social Work Continuing Education Approval Collaborative, which is administered by NASW-NJ. CE Approval Collaborative Approval Period: Tuesday, September 1, 2020 through August 31, 2024. New Jersey social workers will receive 1 Clinical CE credits for participating in this course. NetCE is accredited by the International Accreditors for Continuing Education and Training (IACET). NetCE complies with the ANSI/IACET Standard, which is recognized internationally as a standard of excellence in instructional practices. As a result of this accreditation, NetCE is authorized to issue the IACET CEU. NetCE is recognized by the New York State Education Department's State Board for Social Work as an approved provider of continuing education for licensed social workers #SW-0033. This course is considered self-study, as defined by the New York State Board for Social Work. NetCE is recognized by the New York State Education Department's State Board for Mental Health Practitioners as an approved provider of continuing education for licensed mental health counselors #MHC-0021. This course is considered self-study by the New York State Board of Mental Health Counseling. NetCE is recognized by the New York State Education Department's State Board for Mental Health Practitioners as an approved provider of continuing education for licensed marriage and family therapists. #MFT-0015.This course is considered self-study by the New York State Board of Marriage and Family Therapy. Materials that are included in this course may include interventions and modalities that are beyond the authorized practice of licensed master social work and licensed clinical social work in New York. As a licensed professional, you are responsible for reviewing the scope of practice, including activities that are defined in law as beyond the boundaries of practice for an LMSW and LCSW. A licensee who practices beyond the authorized scope of practice could be charged with unprofessional conduct under the Education Law and Regents Rules.

Designations of Credit

This activity was planned by and for the healthcare team, and learners will receive 1 Interprofessional Continuing Education (IPCE) credit(s) for learning and change. NetCE designates this enduring material for a maximum of 1 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. NetCE designates this continuing education activity for 1 ANCC contact hour(s). NetCE designates this continuing education activity for 1 pharmacotherapeutic/pharmacology contact hour(s). NetCE designates this continuing education activity for 1.2 hours for Alabama nurses. NetCE designates this continuing education activity for 0.5 NBCC clock hour(s). Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 1 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. Completion of this course constitutes permission to share the completion data with ACCME. Social workers participating in this intermediate to advanced course will receive 1 Clinical continuing education clock hours. NetCE designates this activity for 1 ACPE credit(s). ACPE Universal Activity Number: JA4008164-0000-22-022-H01-P. Successful completion of this CME activity, which includes participation in the evaluation component, enables the learner to earn credit toward the CME and/or Self-Assessment requirements of the American Board of Surgery's Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit. Through an agreement between the Accreditation Council for Continuing Medical Education and the Royal College of Physicians and Surgeons of Canada, medical practitioners participating in the Royal College MOC Program may record completion of accredited activities registered under the ACCME's "CME in Support of MOC" program in Section 3 of the Royal College's MOC Program. AACN Synergy CERP Category A. NetCE designates this continuing education activity for 1 credit(s). NetCE is authorized by IACET to offer 0.1 CEU(s) for this program.

Individual State Nursing Approvals

In addition to states that accept ANCC, NetCE is approved as a provider of continuing education in nursing by: Alabama, Provider #ABNP0353, (valid through July 29, 2025); Arkansas, Provider #50-2405; California, BRN Provider #CEP9784; California, LVN Provider #V10662; California, PT Provider #V10842; District of Columbia, Provider #50-2405; Florida, Provider #50-2405; Georgia, Provider #50-2405; Kentucky, Provider #7-0054 through 12/31/2025; South Carolina, Provider #50-2405; West Virginia RN and APRN, Provider #50-2405.

Individual State Behavioral Health Approvals

In addition to states that accept ASWB, NetCE is approved as a provider of continuing education by the following state boards: Alabama State Board of Social Work Examiners, Provider #0515; Florida Board of Clinical Social Work, Marriage and Family Therapy and Mental Health Counseling, CE Broker Provider #50-2405; Illinois Division of Professional Regulation for Social Workers, License #159.001094; Illinois Division of Professional Regulation for Licensed Professional and Clinical Counselors, License #197.000185; Illinois Division of Professional Regulation for Marriage and Family Therapists, License #168.000190;

Special Approvals

This activity is designed to comply with the requirements of California Assembly Bill 1195, Cultural and Linguistic Competency.

Course Objective

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.

Learning Objectives

Upon completion of this course, you should be able to:

1. Outline the demographics and etiology of antidepressant-associated sexual dysfunction.

2. Describe the approach to managing sexual side effects of antidepressant use in men.

3. Discuss potential sexual side effects of antidepressant use in women.

4. Evaluate the impact of post-treatment enduring sexual dysfunction in patients who were prescribed antidepressants.

Faculty

Mark Rose, BS, MA, LP, is a licensed psychologist in the State of Minnesota with a private consulting practice and a medical research analyst with a biomedical communications firm. Earlier healthcare technology assessment work led to medical device and pharmaceutical sector experience in new product development involving cancer ablative devices and pain therapeutics. Along with substantial experience in addiction research, Mr. Rose has contributed to the authorship of numerous papers on CNS, oncology, and other medical disorders. He is the lead author of papers published in peer-reviewed addiction, psychiatry, and pain medicine journals 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 law firms that represent disability claimants or criminal defendants on cases related to chronic pain, psychiatric/substance use disorders, and acute pharmacologic/toxicologic effects. Mr. Rose is on the Board of Directors of the Minneapolis-based International Institute of Anti-Aging Medicine and is a member of several professional organizations.

Faculty Disclosure

Contributing faculty, Mark Rose, BS, MA, LP, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

Margo A. Halm, RN, PhD, NEA-BC, FAAN

Alice Yick Flanagan, PhD, MSW

Randall L. Allen, PharmD

James Trent, PhD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. INTRODUCTION

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 [3]. 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.

2. DEMOGRAPHICS AND ETIOLOGY OF ANTIDEPRESSANT-INDUCED SEXUAL DYSFUNCTION

In 2015–2018, 13.2% of adults 18 years of age and older used antidepressant medications in the past 30 days [4]. Antidepressants are among the most widely prescribed drugs in the United States, 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 [8]. In a study involving 2,163 adults who had undergone at least eight weeks of treatment with antidepressants, 79% showed some degree of sexual dysfunction [51].

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 synthase 1, and prolactin elevation [11,12].

Evidence Based Practice Recommendation

The American Psychiatric Association recommends that men and women who are taking antidepressants be asked whether sexual side effects are occurring with these medications.

http://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf

Last Accessed: October 27, 2022

Strength of Recommendation: I (Recommended with substantial clinical confidence)

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 discussed, 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) [15].

Table 1: LIKELIHOOD OF SEXUAL SIDE EFFECTS WITH SPECIFIC ANTIDEPRESSANTSa

Agent

Percent of Male Patients Affected

Percent of Female Patients Affected

Desire Dysfunction

Citalopram

84.11%

70.78%

Fluoxetine

86.18%

74.39%

Paroxetine

73.65%

72.89%

Sertraline

84.15%

71.92%

Venlafaxine

80.62%

72.00%

Arousal Dysfunction

Paroxetine

64.51%

83.96%

Sertraline

67.05%

82.00%

Venlafaxine

75.00%

77.71%

Orgasm Dysfunction

Citalopram

74.05%

39.47%

Fluoxetine

77.23%

40.36%

Paroxetine

80.23%

44.84%

Sertraline

71.64%

44.22%

Venlafaxine

82.14%

44.85%

aThese figures are based on data that did not record the duration of, or distress from, sexual side effects.

Source: [15]

3. MANAGEMENT

As noted, switching medications to an antidepressant with fewer sexual side effects has been considered highly undesirable and should be avoided, if possible, in patients showing an otherwise positive therapeutic response. However, it may be an option of select patients. A 2019 study analyzed the effects of switching agents on participants with well-treated depressive symptoms but SSRI-associated sexual dysfunction. The patients were directly switched from an SSRI (citalopram, paroxetine, or sertraline) to vortioxetine or escitalopram [50]. Both groups maintained antidepressant efficacy after eight weeks, but patients switched to vortioxetine experienced greater improvements in treatment-emergent sexual dysfunction. The authors concluded that vortioxetine was a safe and effective option for adults with SSRI-induced sexual dysfunction [50].

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 [19]. 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 [18].

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].

MALE SEXUAL DYSFUNCTION

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) [46].

Trazodone

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].

S-Adenosyl-L-methionine

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 [29].

FEMALE SEXUAL DYSFUNCTION

Up to 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% [32].

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 [33].

Exercise

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 [34].

Bupropion

Adding bupropion 300 mg/day to a current SSRI regimen seems to improve sexual function in women experiencing sexual side effects [35]. 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 [36].

Testosterone

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 [37]. 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 [37].

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 [38].

Sublingual Testosterone Plus Buspirone or Sildenafil

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 [39].

Bremelanotide and Flibanserin

Beginning in 2015, two medications have been approved for the treatment of hypoactive sexual desire disorder in premenopausal women—bremelanotide and flibanserin. Flibanserin is a mixed 5-HT1A agonist/5-HT2A antagonist, while bremelanotide is a synthetic heptapeptide with strong binding affinity and agonist action with melanocortin receptor 4. There is some evidence that flibanserin may be safely added to a stable SSRI or SNRI treatment regimen in premenopausal women with remitted or mild depression [49]. However, the efficacy of addressing SSRI/SNRI-associated sexual dysfunction was not analyzed. It is important to note that these medications are specifically approved to treat low female sexual desire not the result of the effects of a medication, so their use in the management of antidepressant-associated sexual dysfunction is off-label.

Saffron

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 [40].

Maca Root

Maca root (Lepidium meyenii) has been suggested as an option for the management of antidepressant-related sexual side effects in postmenopausal women. In one small study, women given maca root were approximately twice as likely as the placebo group to experience remission of sexual side effects [52].

POST-TREATMENT ENDURING SEXUAL DYSFUNCTION

Post-SSRI sexual dysfunction is little known in the broader medical community and, when reported, has been partially attributed to psychologic factors [12]. 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 [41].

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 [42]. 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 [42].

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 [43].

In a data report from 2017 including 300 cases of enduring sexual dysfunction, the highest rates of PTESD occurred with isotretinoin (18%), escitalopram (14%), citalopram (13.7%), and paroxetine (13.3%) [48]. The duration of the treatment ranged from a single dose to more than 16 years. The report also found that many cases of sexual dysfunction appeared or became worse when treatment came to an end. Subjects consistently reported difficulty maintaining romantic relationships and 30% reported that their work had been affected [48].

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 [43,44,48]. Pleasureless orgasm has also been reported [45,48].

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 [43]. Additional research into the underlying etiology of persistent sexual dysfunction following antidepressant cessation will hopefully give insight into an effective treatment.

4. CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

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.

5. CONCLUSION

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.

Works Cited

1. Balon R. SSRI-associated sexual dysfunction.Am J Psychiatry. 2006;163(9):1504-1509.

2. Higgins A, Nash M, Lynch AM. Antidepressant-associated sexual dysfunction: impact, effects, and treatment. Drug Healthc Patient Saf. 2010;2:141-150.

3. Hu XH, Bull SA, Hunkeler EM, et al. Incidence and duration of side effects and those rated as bothersome with selective serotonin reuptake inhibitor treatment for depression: patient report versus physician estimate. J Clin Psychiatry. 2004;65(7):959-965.

4. Brody DJ, Gu Q. Antidepressant use among adults: United States, 2015–2018. NCHS Data Brief. 2020;377:1-7.

5. Wouters H, Van Dijk L, Van Geffen EC, Gardarsdottir H, Stiggelbout AM, Bouvy ML. Primary-care patients' trade-off preferences with regard to antidepressants. Psychol Med. 2014;44(11):2301-2308.

6. Paulose-Ram R, Safran M, Jonas B, Gu Q, Orwig D. Trends in psychotropic medication use among U.S. adults. Pharmacoepidemiol Drug Saf. 2007;16(5):560-570.

7. Thiels C, Linden M, Grieger F, Leonard J. Gender differences in routine treatment of depressed outpatients with the selective serotonin reuptake inhibitor sertraline. Int Clin Psychopharmacol. 2005;20(1):1-7.

8. Demyttenaere K, Enzlin P, Dewé W, et al. Compliance with antidepressants in a primary care setting, 1: beyond lack of efficacy and adverse events. J Clin Psychiatry. 2001;62(Suppl 22):30-33.

9. Bijlsma EY, Chan JSW, Olivier B, et al. Sexual side effects of serotonergic antidepressants: mediated by inhibition of serotonin on central dopamine release? Pharmacol Biochem Behav. 2014;121:88-101.

10. Clayton AH, El Haddad S, Iluonakhamhe JP, Ponce Martinez C, Schuck AE. Sexual dysfunction associated with major depressive disorder and antidepressant treatment. Expert Opin Drug Saf. 2014;13(10):1361-1374.

11. Kennedy SH, Rizvi S. Sexual dysfunction, depression, and the impact of antidepressants. J Clin Psychopharmacol. 2009;29(2):157-164.

12. Sienaert P. Managing the Adverse Effects of Antidepressants. Available at https://www.psychiatrictimes.com/view/managing-adverse-effects-antidepressants. Last accessed October 21, 2022.

13. Clayton AH, Hamilton DV. Female sexual dysfunction. Obstet Gynecol Clin. 2009;36(4):861-876.

14. Rizvi SJ, Kennedy SH. Management strategies for SSRI-induced sexual dysfunction. J Psychiatry Neurosci. 2013;38(5):E27-E28.

15. Serretti A, Chiesa A. Treatment-emergent sexual dysfunction related to antidepressants: a meta-analysis. J Clin Psychopharmacol. 2009;29(3):259-266.

16. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013.

17. Balon R, Segraves RT. Survey of treatment practices for sexual dysfunction(s) associated with anti-depressants. J Sex Marital Ther. 2008;34(4):353-365.

18. Baldwin DS, Palazzo MC, Masdrakis VG. Reduced treatment-emergent sexual dysfunction as a possible target in the development of new antidepressants. Depress Res Treat. 2013;2013:256841.

19. Clayton AH, Croft HA, Handiwala L. Antidepressants and sexual dysfunction: mechanisms and clinical implications. Postgrad Med. 2014;126(2):91-99.

20. Atmaca M, Korkmaz S, Topuz M, Mermi O. Mirtazapine augmentation for selective serotonin reuptake inhibitor-induced sexual dysfunction: a retropective investigation. Psychiatry Investig. 2011;8(1):55-57.

21. Ravindran LN, Eisfeld BS, Kennedy SH. Combining mirtazapine and duloxetine in treatment-resistant depression improves outcomes and sexual function. J Clin Psychopharmacol. 2008;28(1):107-108.

22. Aizenberg D, Zemishlany Z, Weizman A. Cyproheptadine treatment of sexual dysfunction induced serotonin reuptake inhibitors. Clin Neuropharmacol. 1995;18(4):320-324.

23. Lauerma H. Successful treatment of citalopram-induced anorgasmia by cyproheptadine. Acta Psychiatr Scand. 1996;93(1):69-70.

24. Landén M, Eriksson E, Agren H, Fahlén T. Effect of buspirone on sexual dysfunction in depressed patients treated with selective serotonin reuptake inhibitors. J Clin Psychopharmacol. 1999;19(3):268-271.

25. Segraves RT, Balon R. Antidepressant-induced sexual dysfunction in men. Pharmacol Biochem Behav. 2014;121:132-137.

26. Althof SE, McMahon CG, Waldinger MD, et al. An update of the International Society of Sexual Medicine's guidelines for the diagnosis and treatment of premature ejaculation (PE). J Sex Med. 2014;11(6):1392-1422.

27. Andersson KE. Mechanisms of penile erection and basis for pharmacological treatment of erectile dysfunction. Pharmacol Rev. 2011;63(4):811-859.

28. Stryjer R, Spivak B, Strous RD, et al. Trazodone for the treatment of sexual dysfunction induced by serotonin reuptake inhibitors: a preliminary open-label study. Clin Neuropharmacol. 2009;32(2):82-84.

29. Dording CM, Mischoulon D, Shyu I, Alpert JE, Papakostas GI. SAMe and sexual functioning. Eur Psychiatry. 2012;27(6):451-454.

30. Clayon A, Keller A, McGarvey EL. Burden of phase-specific sexual dysfunction with SSRIs. J Affect Disord. 2006;91(1):27-32.

31. Rosen R, Lane R, Menza M. Effects of SSRIs on sexual function: a critical review. J Clin Psychopharmacol. 1999;19(1):67-85.

32. La Torre A, Giupponi G, Duffy D, et al. Sexual dysfunction related to psychotropic drugs: a critical review—part I: antidepressants. Pharmacopsychiatry. 2013;46(5):191-199.

33. Uphouse L. Pharmacology of serotonin and female sexual behavior. Pharmacol Biochem Behav. 2014;121:31-42.

34. Lorenz TA, Meston CM. Acute exercise improves physical sexual arousal in women taking antidepressants. Ann Behav Med. 2012;43(3):352-361.

35. Taylor MJ, Rudkin L, Bullemor-Day P, Lubin J, Chukwujekwu C, Hawton K. Strategies for managing sexual dysfunction induced by antidepressant medication. Cochrane Database Syst Rev. 2013;5:CD003382.

36. Safarinejad MR. Reversal of SSRI-induced female sexual dysfunction by adjunctive bupropion in menstruating women: a double-blind, placebo-controlled and randomized study. J Psychopharmacol. 2011;25(3):370-378.

37. Fooladi E, Bell RJ, Jane F, Robinson PJ, Kulkarni J. Davis SR. Testosterone improves antidepressant-emergent loss of libido in women: findings from a randomized, double-blind, placebo-controlled trial. J Sex Med. 2014;11(3):831-839.

38. Kumsar ş, Kumsar NA, Sağlam HS, Köse O, Budak S, Adsan Ö. Testosterone levels and sexual function disorders in depressive female patients: effects of antidepressant treatment. J Sex Med. 2014;11(2):529-535.

39. van Rooij K, Poels S, Worst P, et al. Efficacy of testosterone combined with a PDE5 inhibitor and testosterone combined with a serotonin 1A receptor agonist in women with SSRI-induced sexual dysfunction: a preliminary study. Eur J Pharmacol. 2015;753:246-251.

40. Kashani L, Raisi F, Saroukhani S, et al. Saffron for treatment of fluoxetine-induced sexual dysfunction in women: randomized double-blind placebo-controlled study. Hum Psychopharmacol. 2013;28(1):54-60.

41. Bahrick AS, Harris MM. Sexual side effects of antidepressant medications: an informed consent accountability gap. J Contemp Psychother. 2008;39(2):135-143.

42. Bahrick AS. Persistence of sexual dysfunction side effects after discontinuation of antidepressant medications: emerging evidence. Open Psychol J. 2008;1:42-50.

43. Hogan C, Le Noury J, Healy D, Mangin D. One hundred and twenty cases of enduring sexual dysfunction following treatment.Int J Risk Saf Med. 2014;26(2):109-116.

44. Csoka AB, Bahrick A, Mehtonen OP. Persistent sexual dysfunction after discontinuation of selective serotonin reuptake inhibitors. J Sex Med. 2008;5(1):227-233.

45. Antonuccio D, Healy D. Relabeling the medications we call antidepressants. Scientica. 2012;2012:965908.

46. Khazaie H, Rezaie L, Payam NR, Najafi F. Antidepressant-induced sexual dysfunction during treatment with fluoxetine, sertraline, and trazodone: a randomized controlled trial. Gen Hosp Psychiatry. 2015;37(1):40-45.

47. Pratt LA, Brody DJ, Gu Q. Antidepressant use among persons aged 12 and over: United States, 2011–2014. NCHS Data Brief. 2017;(283):1-8.

48. Healy D, Le Noury J, Mangin D. Enduring sexual dysfunction after treatment with antidepressants, 5 α-reductase inhibitors and isotretinoin: 300 cases. Int J Risk Saf Med. 2018;29(3-4):125-134.

49. Clayton AH, Croft HA, Yuan J, Brown L, Kissling R. Safety of flibanserin in women treated with antidepressants: a randomized, placebo-controlled study. J Sex Med. 2018;15(1):43-51.

50. Jacobsen P, Nomikos G, Zhong W, Cutler A, Affinito J, Clayton A. Clinical implications of directly switching antidepressants in well-treated depressed patients with treatment-emergent sexual dysfunction: a comparison between vortioxetine and escitalopram. CNS Spectr. 2019:1-14.

51. Montejo AL, Calama J, Rico-Villademoros F, Montejo L, González-García N, Pérez J; SALSEX Working Study Group. A real-world study on antidepressant-associated sexual dysfunction in 2144 outpatients: The SALSEX I Study. Arch Sex Behav. 2019;48(3):923-933.

52. Dording CM, Schettler PJ, Dalton ED, et al. A double-blind placebo-controlled trial of maca root as treatment for antidepressant-induced sexual dysfunction in women. Evid Based Complement Alternat Med. 2015;2015:949036.

Evidence-Based Practice Recommendations Citations

1. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd ed. Arlington, VA: American Psychiatric Association; 2010. Available at http://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf. Last accessed October 27, 2022.