Characterizing post-SSRI sexual dysfunction and its impact on quality of life through an international online survey

1. Introduction

Post-SSRI sexual dysfunction (PSSD) is a condition in which patients experience persistent symptoms of sexual dysfunction after the discontinuation of selective serotonin reuptake inhibitors (SSRIs). PSSD may also develop after discontinuation of serotonin-norepinephrine reuptake inhibitors (SNRIs) and other atypical antidepressants which inhibit serotonin reuptake. Individuals with PSSD describe symptoms including difficulty becoming aroused, pleasureless or muted orgasms, an inability to orgasm, decreased libido, delayed ejaculation, and/or genital numbness [1]. While PSSD is often characterized as a disorder of sexual function, it is not limited to sexual symptoms. Emotional numbing, changes in cognition, and a significant decrease in quality of life have also been reported [1,2].

Since the introduction of SSRIs in the late 1980s, knowledge of the relationship between depression, SSRI use, and sexual dysfunction has continued to grow. When the SSRI fluoxetine first became available, sexual dysfunction was not considered a common side effect of treatment. Early clinical trials relying on self-reporting of side effects found only 1.9% of subjects experiencing sexual dysfunction attributed to medication use [3]. Later trials, which asked specific questions regarding sexual dysfunction, found that as many as 80% of individuals experienced new sexual dysfunction during treatment with an SSRI [4].

The first case of PSSD was reported in 1991, nearly a decade after the introduction of SSRIs [1]. Later in 2006, a series of three case reports were published detailing patients with persistent sexual side effects after discontinuing an SSRI [5]. In 2011, the manufacturer of Prozac (fluoxetine) amended their product information sheet to include that persistent sexual side effects had been reported [6]. The Diagnostic and Statistical Manual of Mental Disorders (DSM-5), published in 2013, now includes a sentence acknowledging potential persistent sexual dysfunction after the discontinuation of SSRIs [7]. Increasing awareness of this condition led to the European Medicine Agency (EMA) formally recognizing PSSD as a medical condition in 2019. The EMA Pharmacovigilance Risk Assessment Committee has also added warnings regarding persistent sexual dysfunction on product information sheets for SSRIs [8].

While PSSD has gained some recognition, little is known regarding its pathophysiology, disease course, or potential treatments. Current theories regarding the development of PSSD include SSRI-induced epigenetic changes in gene expression, down-regulation of serotonin 5HT_1A receptors, and hormonal changes. While most medications cited as potential contributors to PSSD are serotonin reuptake inhibitors, some atypical antidepressants with different mechanisms of action have been reported. Mirtazapine is an atypical antidepressant and potent antagonist of serotonin 5HT_2A receptors. Bupropion, another atypical antidepressant, may indirectly affect transport of serotonin via vesicular monoamine transporter-2 (VMAT2) [9]. For the purposes of this study, we use the term “serotonin reuptake inhibitors” with the understanding that the condition of PSSD may be influenced by additional medications which impact the regulation of serotonin.

Two other conditions of note in the discussion of PSSD are Post Finasteride Syndrome (PFS) and Post Accutane Syndrome (PAS) [10]. Finasteride is a 5α-reductase inhibitor used to treat androgenic alopecia and benign prostatic hyperplasia. Accutane is a retinoid used in the treatment of severe acne [11–13]. Similar symptoms of sexual dysfunction have been reported by individuals who have taken these medications [11,14]. The different mechanisms of action of these medications adds to the uncertainty regarding the pathophysiology of persistent sexual dysfunction in discontinuation syndromes. It remains unclear if these conditions have a similar underlying etiology or arise via different mechanisms.

Currently, there are no formal diagnostic criteria to assist in the evaluation of patients who may have PSSD [15]. An assessment of personal accounts from patients with PSSD suggests there may be a large degree of variability in disease course, symptom characteristics, and potential alleviating therapies for this condition. These factors compound the challenges of evaluating patients who may have PSSD. This study aims to better characterize the variable presentations of PSSD and determine the impact this condition can have on quality of life.

2. Methods

This study was approved by the Institutional Review Board (IRB #202005598). A survey was created to better characterize the symptoms of PSSD, disease course, potential treatments, and overall impact of this condition on quality of life. This survey was distributed using the REDCap web application. Permission to distribute the survey on PSSDforum.org was obtained. Subjects were invited to complete the survey between 09/10/2020 and 11/28/2020. Electronic informed consent was obtained from all subjects.

Respondents were asked if they had ever taken an antidepressant which modulates serotonin activity such as an SSRI or SNRI. Those who reported they had taken one of these medications proceeded with the survey and completed a section on demographic information including their age, gender, and nationality. The first section of the survey focused on medication history and symptoms of PSSD. Respondents selected which SSRIs/SNRIs they had taken from a list of SSRIs/SNRIs which are most prescribed in the United States. A space was left for respondents to report other medications which may have contributed to PSSD which were not included on the list. A multiple choice question was provided for respondents to select the amount of time they had taken these medications.

Respondents were then asked if they recalled receiving counseling regarding the potential sexual side effects reportedly associated with SSRIs/SNRIs treatment. Those who responded that they did not receive counseling were asked if additional counseling would have influenced their decision to take the medication. Respondents were also asked if sexual side effects constituted the primary reason for discontinuing treatment with an SSRI/SNRI.

Respondents were provided with a list of symptoms of sexual dysfunction commonly reported by those with PSSD. This list included: decreased sex drive, difficulty becoming aroused, muted or pleasureless orgasms, delayed ejaculation, inability to orgasm, decreased genital sensation, erectile dysfunction, soft glans, inability to become aroused by visual stimuli, absence of sexual attraction, vaginal dryness, and painful intercourse. A space was provided for respondents to report additional symptoms not included in this list. Respondents reported which of these symptoms they experienced while taking an SSRI/SNRI and which symptoms persisted after discontinuing treatment. A Likert scale was used to assess the magnitude of symptoms shortly after the discontinuation of an SSRI/SNRI and overall trajectory of symptoms since their onset.

The second section of the survey focused on different treatments for PSSD, treatment efficacy, and the types of providers respondents had approached for treatment. Respondents reported the different specialists and non-physician healthcare providers they had seen when seeking treatment for PSSD. Respondents then selected the different treatments they had tried from a list of medications commonly prescribed to treat PSSD, different therapies, vitamins, supplements, and complimentary medical practices. A space was provided for respondents to report treatments which were not included on this list. A Likert scale was used to assess the impact of each treatment modality as reported by the respondent.

In the final section of the survey, a Likert scale was used to rate the overall impact of PSSD on quality of life. After completing the multiple-choice portion of the survey, an open response section was included for respondents to add any additional information which they thought may be useful for investigators.

To meet inclusion criteria, a subject had to be between 18 and 99 years of age and must have completed the demographics section of the survey. Eligible subjects also had to report use of an SSRI, SNRI, or atypical antidepressants which either inhibit serotonin reuptake or modulate serotonin regulation. Survey results were assessed for eligibility based on inclusion criteria for this study. Questions with short written response sections were assessed and integrated into the dataset. Short answers which did not answer the question were excluded. The frequency of responses was assessed to evaluate trends within a subset of individuals with PSSD.

3. Results

Of 266 surveys initiated during study enrollment, 239 satisfied inclusion criteria. Excluded surveys were either incomplete or did not report use of a medication which inhibited serotonin reuptake. Respondents represented 39 countries and six continents. Surveys were conducted in English and 88% of respondents were from North American or European countries (Table 1). Two respondents declined to report nationality. Regions with known PSSD support groups and a greater online presence were well represented in this study and included the United States (36%), Germany (12%), United Kingdom (10%), Canada (6%), and Italy (6%).

Three quarters of respondents were male. The median age of male and female respondents were 29 and 30, respectively. The median age a respondent began treatment with a serotonin reuptake inhibitor was 22 years with the youngest and oldest starting treatment at 7 and 57 years of age, respectively (Table 1). Two thirds of respondents reported diagnoses of depression, 64% reported anxiety, 9% reported post-traumatic stress disorder, 6% reported obsessive compulsive disorder, and 20% reported other neuropsychiatric conditions. Other conditions reported by respondents included chronic pain, insomnia, specific phobias, panic disorders, and attention deficit hyperactivity disorder.

Respondents reported taking a variety of serotonin reuptake inhibitors and modulators of serotonergic activity. SSRIs were taken by 92% of respondents while the remaining 8% of respondents took only SNRIs or atypical antidepressants (Table 2). Atypical antidepressants suspected of contributing to PSSD symptoms included mirtazapine (n = 8), bupropion (n = 5), vilazodone (n = 4), vortioxetine (n = 4), and trazodone (n = 2) (Table 3). Not all respondents reported the initial reason for beginning treatment, though two reported they started an SNRI for chronic pain and did not have a diagnosis of depression at the time. Respondents who reported anxiolytics or antipsychotics as contributors to their symptoms were also on an SSRI. Only psychiatric medications were reported as contributing to PSSD. While 53% of respondents were prescribed only one serotonin reuptake inhibitor, 40% were prescribed two to four and one respondent had tried at least nine. The majority (72%) of respondents took at least one of these medications for more than six months. Only 13 (5%) took a serotonin reuptake inhibitor for less than one week (Table 2).

Respondents were asked about different sexual side effects they experienced while taking a serotonin reuptake inhibitor. Greater than 50% of respondents reported experiencing decreased sex drive, difficulty becoming aroused, decreased genital sensation, muted or pleasureless orgasms, no arousal by visual stimuli, or absence of sexual attraction while taking a serotonin reuptake inhibitor. Erectile dysfunction and delayed ejaculation were reported by 65% and 51% of male respondents, respectively (Table 4). Vaginal dryness was reported by 47% of female respondents. Genital shrinkage was noted by 5 male respondents in the open-ended portion of the survey.

Respondents were then asked to report which sexual side effects either persisted or developed after discontinuation of treatment with a serotonin reuptake inhibitor. The most common sexual side effects experienced while taking a serotonin reuptake inhibitor were also the most common to be experienced after discontinuation of these medications. Common symptoms experienced by more than 50% of respondents while on an SSRI were reported to persist or newly develop in up to 18% of respondents after the discontinuation of treatment. Soft glans, which was experienced by only 26% of male respondents during treatment was reported to persist or develop in 13% of respondents after discontinuation of treatment. Vaginal dryness was the only sexual side effect with complete resolution after the discontinuation of treatment with a serotonin reuptake inhibitor.

Only 12% of respondents reported receiving counseling regarding potential sexual side effects while taking a serotonin reuptake inhibitor. Of those not informed, 90% reported that knowledge of these potential sexual side effects would have prompted them to decline treatment and request different medications or counseling options. Sexual side effects while taking serotonin reuptake inhibitors constituted the primary reason for discontinuing the medication in 69% of respondents.

Shortly after discontinuing treatment with a serotonin reuptake inhibitor, 15% of respondents experienced a decrease in the severity of symptoms of sexual dysfunction. Symptom severity was unchanged for 32% of respondents and 54% reported new or worsening symptoms. Over time, these persistent symptoms improved, to some degree, in 45% of respondents, remained constant for 13%, and worsened for 24%. When asked to rate the impact of PSSD on quality of life, 59% reported it had an extremely negative effect and 23% reported the impact was very negative (Table 5). Only one person reported a somewhat positive effect.

Respondents have sought treatment for PSSD from different specialists in the medical field and alternative health services. Treatment options offered by psychiatrists and urologists were used by 26% and 27% of respondents, respectively. Other medical specialties included family medicine/internal medicine, neurology, and different types of therapists (e.g., psychologists, sexologists). Respondents tried different medications, vitamins, supplements, and counseling without clear success. Some individuals reported trying different combinations of potentially hazardous and illicit substances such as psilocybin and methamphetamine to treat symptoms without significant improvement. Due to the small sample size, a statistical analysis of the efficacy of different treatments was not possible.

This retrospective survey characterizes the symptoms of PSSD and the profoundly negative impact this condition has on quality of life. PSSD can develop after less than one week of treatment with a serotonin reuptake inhibitor, with previous studies and written responses to our survey indicating that persistent sexual dysfunction can occur after just one dose of a serotonin reuptake inhibitor [16]. After discontinuing treatment with a serotonin reuptake inhibitor, disease course varies with 45% of respondents reporting some improvement and 37% experiencing continued or worsening symptoms. Individuals with PSSD have tried a variety of different medications and therapies to alleviate symptoms. Our study did not find evidence to support any consistently effective treatments for PSSD.

Previous studies have reported that symptoms associated with PSSD are not limited to changes in sexual function [11,14]. Our study found that at least one non-sexual symptom was reported in 70% of cases. In written answers, individuals with PSSD reported new diagnoses of depression, anxiety, and post-traumatic stress disorder as a result of their condition. There were also reports of past suicide attempts, current suicidal ideation, and knowledge of friends or loved ones with PSSD who had ended their lives. A concerning theme among written responses is a willingness to experiment with potentially harmful and illicit substances to treat symptoms of PSSD. One man reported that he had spent over $80,000 and traveled to multiple countries in an unsuccessful attempt to find relief from the symptoms of PSSD.

Limited awareness of PSSD among medical providers was referenced as a contributor to feelings of anger, frustration, and hopelessness in the open-ended portion of the survey. Many respondents reported negative encounters with medical professionals who had never heard of PSSD or dismissed symptoms of sexual dysfunction as a result of persistent depression. The majority of patients with PSSD were not counseled regarding symptoms of sexual dysfunction that could occur while taking an SSRI.

Though the prevalence of PSSD is unknown, it is possible that this condition is rare, as there are relatively few reported cases. Antidepressants, after all, are very commonly prescribed with 12.7% of teens and adults reporting antidepressant use in the last 30 days [17]. It is also possible that PSSD is more prevalent than the number of current case reports due to significant underreporting of this condition. Patient hesitancy to bring up symptoms of sexual dysfunction is well documented and may contribute to a low detection rate of PSSD in the general population [15]. Previous studies have indicated that some individuals with PSSD choose not to discuss their condition with their doctor as they do not think their doctor will not help [18]. A lack of awareness of PSSD may also lead both patients and providers to attribute sexual dysfunction to persistent depression without considering the potential impact of serotonin reuptake inhibitor use.

When compared to tricyclic antidepressants (TCAs), SSRIs are often considered to have a better safety profile [19]. It is difficult to determine the impact that PSSD will have on the overall safety profile of SSRIs as so little is known about incidence or prevalence of this condition. Given the inability to determine who may develop PSSD and the lack of effective treatment options, it is recommended that prescribers of serotonin reuptake inhibitors discuss this condition with patients prior to initiation of treatment. Currently, the majority of mental health care services are provided in the primary care setting [20,21]. In the United States, primary care providers and psychiatrists write 65% and 27% of the prescriptions for SSRIs, respectively [22]. Increased awareness of PSSD among these specialties is needed to improve the informed consent process when discussing with patients the risks and benefits of treatment with a serotonin reuptake inhibitor.

There are several limitations to this study. The use of surveys distributed to web based PSSD support groups selects for individuals who proactively seek help online. The trajectory and severity of this condition varies greatly between individuals and surveys of support groups may capture only the most severe or treatment resistant cases. Retrospective studies may be subject to recall bias and may not account for compounding variables when assessing treatment efficacy. Some respondents did not answer all questions in this survey. Due to an inability to determine why a question was left blank, the total number of respondents (n = 239) was used when calculating the frequency of specific answers to survey questions. This may lead to a slight underestimation in the frequencies of different symptoms and experiences due to nonresponses. Further research is needed to determine the pathophysiology of PSSD and its relationship to other discontinuation syndromes.