In 2019 the European Medicines Agency (EMA) acknowledged that sexual dysfunction can persist after treatment with serotonergic antidepressants has been discontinued and asked for product labels to be updated accordingly: “Selective serotonin reuptake inhibitors (SSRIs)/serotonin norepinephrine reuptake inhibitors (SNRIs) may cause symptoms of sexual dysfunction. There have been reports of long-lasting sexual dysfunction where the symptoms have continued despite discontinuation of SSRIs/SNRI.” [Special warnings and precautions for use – EMA]
The condition has been described in the literature for many years as post-SSRI sexual dysfunction (PSSD). While cases of PSSD have been reported since the 90s, it took great efforts to get the regulators to acknowledge the condition. Reports of adverse effects to regulators are generally anonymized, lessening their credibility and the ability to establish causality. The psychiatrist David Healy shares that he and his colleagues sent the EMA “84 named patient reports and contact emails and 32 letters from doctors to confirm the patient’s identity, their treatment with an SSRI and the lack of a competing explanation for their difficulties. The European Medicines Agency were told we were offering them the possibility to cross-examine patients or their doctors to establish causality.” (Healy, 2020)
The core features of PSSD are genital numbing, loss of or difficulty with orgasm, and loss of libido. Non-sexual symptoms such as anhedonia, apathy, and blunted affect are also frequently present as part of the syndrome. Often the sexual dysfunction is experienced during treatment and then persists despite discontinuation. But in many cases the sexual dysfunction is not experienced, or is experienced in a mild form, during treatment and only becomes prominent once treatment is stopped. It is often protracted and appears to be permanent in some cases. A similar syndrome has also been described with the use of finasteride and retinoids. Diagnostic criteria by expert consensus (Healy, et al. 2022) have set a threshold of sexual problems persisting for 3 months or more for it be classified as PSSD.
PSSD is slowly receiving more attention from the medical community, and several comprehensive reviews have been published in the academic literature. In addition, there have been renewed efforts by those affected by this condition to raise awareness about it. A picture campaign by the PSSD network displays some harrowing testimonials (see here), such as:
“Every aspect of the person that I once was has been stripped away. I am living a fate worse than death and there is nothing that anyone can do to help me. I am a PSSD sufferer.”
“I lost my sexuality, my creativity & my sense of self. I have been reduced to nothing. A commonly prescribed SSRI ruined my life & future.”
“15 years ago I was chemically castrated. No one cares!”
“Every aspect of the person that I once was has been stripped away. I am living a fate worse than death and there is nothing that anyone can do to help me. I am a PSSD sufferer.”
Nonetheless, awareness of this iatrogenic condition remains extremely limited, and from informal discussions, it appears to me that majority of my psychiatrist and physician colleagues are unaware of it. This lack of awareness leads to emotional and epistemic harm. A study on the experiences of patients with PSSD and their interactions healthcare professionals reported: “While some had received support and validation of their condition, many described a number of difficulties including a lack of awareness or knowledge about PSSD, not being listened to, receiving unsympathetic or inappropriate responses, and a refusal to engage with the published medical literature.” (Healy, et al. 2019)
There are some excellent discussions in the literature about clinical features and hypothesized mechanisms, so I will refer readers to the following articles for details.
From a clinical standpoint, PSSD appears to raise difficult questions about medical decision-making. Given the lack of systematic research, the actual prevalence of persistent sexual side effects after stopping SSRIs/SNRIs is basically unknown. Estimates range from it being a very rare adverse effect to its prevalence being in double digits. In informal discussions many psychiatrist colleagues with several decades of experience of prescribing antidepressants report having never seen a case of PSSD. Others disagree; experts such as David Healy think the condition is much more common but mostly goes unrecognized. The scientifically honest answer is that we don’t know for sure. Milder forms of PSSD are likely to be much more common than severe and enduring forms.
Even if the severe and enduring forms are rare (say, affecting between 1 in 10,000 and 1 in 1,000 people), that’s still a large number of people across the world (13% of US adults were on antidepressants during the years 2015-2018), and medicine in general does a terrible job with uncommon and rare adverse effects when it comes to informed consent. When was the last time a physician prescribed you a commonly used medication and discussed rare adverse effects? Even when rare adverse effects are shared, they are often mentioned in a manner disconnected from decision-making, brought up to minimize legal liability, with little discussion of how this information ought to influence clinical decisions.
Even when rare adverse effects are shared, they are often mentioned in a manner disconnected from decision-making, brought up to minimize legal liability, with little discussion of how this information ought to influence clinical decisions.
When it comes to rare risks, people – including clinicians and patients – seem to do a poor job of assigning them the right weight. We either underestimate the risk, delegating it to the sort of background risk we accept in daily life (the risk of getting into a fatal car accident, a healthy person’s risk of dying from general anesthesia, etc.) or we overestimate the risk.
It has been reported regarding the psychology of decision-making and rare risks: “Decisions from experience and decisions from description can lead to dramatically different choice behavior. In the case of decisions from description, people make choices as if they overweight the probability of rare events, as described by prospect theory. We found that in the case of decisions from experience, in contrast, people make choices as if they underweight the probability of rare events, and we explored the impact of two possible causes of this underweighting—reliance on relatively small samples of information and overweighting of recently sampled information.” We see the same dynamic play out with regards to PSSD as well.
Many critically-oriented psychiatrists who are convinced that antidepressants have marginal efficacy think that when we take adverse effects such as PSSD into account, the risk-benefit ratio is clinically unacceptable. I am less persuaded on the question of efficacy (see) and it seems unlikely to me that the clinical need for antidepressants will disappear or dramatically diminish anytime soon. To get a better sense of how PSSD might inform clinical decision-making for clinical psychiatrists who do think that antidepressants have clinically meaningful efficacy, I reached out to my psychiatrist friend and colleague Ronald Pies.
Aftab: Based on your understanding of the literature, biological plausibility, and clinical experience, how common do you think this condition is?
Pies: Just as you say, the literature is very clear that we lack sufficient data to determine the actual prevalence of PSSD, and there are many potential confounds that make that determination very difficult. The usual confound cited is the well-known association of sexual dysfunction with major depressive disorder. Most clinicians, in my experience, rarely obtain a baseline (pre-SSRI treatment) assessment of the patient's sexual function/dysfunction. That said, some symptoms of PSSD are simply not known to be complications of depression per se; e.g., genital anesthesia. Then there is the problem of concomitant medication that can provoke sexual dysfunction, such as benzodiazepines, antipsychotics, and many others. In addition, many patients are reluctant to report sexual dysfunction, either during or after use of SSRIs – which might point to under-reporting of PSSD. (And many physicians are hesitant to ask about sexual side effects or dysfunction). All this makes it very hard, if not impossible, to say confidently how common PSSD is. That said, Montejo et al (1999) found that in 55% of individuals switched to a medication that successfully treated depressive symptoms and was not a cause of secondary sexual dysfunction, the initial SSRI-induced sexual dysfunction persisted for at least six months after discontinuing the SSRI. [Actas Esp Psiquiatr. 1999 Jan-Feb;27(1):23-34.]
In my own clinical practice as a psychopharmacology consultant over more than 25 years, I can't recall any cases of PSSD, but that doesn't tell us anything about the actual prevalence of the problem. Given how long the SSRIs have been used, we really have not done a great job in researching this question. I think we have also under-utilized non-serotonergic agents, such as bupropion. [Disclosure: I have no affiliations of any kind with any pharmaceutical companies].
Aftab: While patients are often told about possible sexual adverse effects with SSRI use, the possibility of sexual problems persisting beyond or arising after treatment discontinuation is rarely brought up. Among those who have experienced PSSD, this has been a considerable source of anger. How important is it for clinicians to discuss the possibility of PSSD with patients? (I am also thinking of the reasonable-person standard of informed consent, i.e., that a patient should be informed of all the material risks that would influence a reasonable person in determining whether to consent to treatment.)
Pies: For those who have experienced PSSD and were not informed of the risk, the anger is understandable. First of all, given the high percentage of patients who will experience sexual side effects from standard SSRIs – which may be less common with mirtazapine, and almost non-existent with bupropion – I think it is very important to discuss possible sexual side effects, as part of the informed consent process. And let's remember, this is an ongoing process, not a single warning or a signed form. I think it is also appropriate to inform patients of the possibility of PSSD, while placing this and other side effects in the broader context of the medication’s benefits. (Let's remember that major depression can be a devastating illness, and that we have medications that are safe and effective for this condition).
If patients ask how common PSSD is, I think we need to be frank with them and say that we simply don't know. Neither are there well-established treatments for PSSD, though many “rescue” options have been tried, with varying success.
Aftab: How should clinicians take PSSD into account in their medical decision making when considering the possibility of initiating treatment with SSRIs?
Pies: I think the most important factor to take into consideration is the depressed patient’s pre-treatment sexual functioning. That is, physicians should gather pre-SSRI information regarding any sexual dysfunction, such as diminished libido, anorgasmia, etc. I suspect this is rarely done in primary care settings, and even in most psychiatric practices. It's also important, pre-treatment, to take note of any pre-existing diseases (e.g., diabetes mellitus) or existing medications that may cause or exacerbate sexual dysfunction – and there are many.
In initiating antidepressant treatment, I think clinicians should also consider greater first use of bupropion, mirtazapine, vilazodone, and vortioxetine, rather than the “traditional” SSRIs like paroxetine, fluoxetine, etc. Bupropion clearly has far fewer sexual side effects than SSRIs, and, in my view, is under-utilized in clinical practice. The other 3 agents (mirtazapine, vilazodone, and vortioxetine) probably have lower rates of sexual side effects compared to traditional SSRIs. However, I am not aware of any published studies looking at rates of PSSD associated with these newer agents. [end quote]
I also reached out to the psychiatrist Jim Phelps, who used this issue as an opportunity to talk about the challenges of informed consent.
Phelps: Well, for starters we could hope that the roughly 50% incidence of sexual dysfunction when starting an antidepressant would be made clear. Then, secondly, we could hope that the potential for severe withdrawal would be made clear, even though we (shamefully, after 30 years) don't know the frequency of that experience. Third, there's the roughly 50% incidence of significant weight gain to be made clear.
Now, after all that, how important is it to invoke the possibility of long-lasting changes in sexual function? Since here again we don't know the frequency, it’s hard to know how strongly to emphasize it. Better to resort to data here than clinical experience – since mine might be highly unrepresentative! [He reported never having encountered a case of PSSD.]
Presuming a willingness to engage in “shared decision-making,” now, after all of the above, we come to the crucial clinical challenge: how can one fairly balance “reasonable informed consent” (i.e. actually presenting significant risks, with our best estimates of their incidence and inviting patients' participation in considering options), with the need to maximize the placebo value of whatever treatment is ultimately decided upon?
In other words: the patient is best served when they leave the encounter strongly believing that the treatment they are about to embark upon is highly likely to help them. How can a clinician steer “informed consent” toward that goal while simultaneously presenting a fair account of a treatment's risks? This is an extremely difficult challenge that gets far too little attention!
Patient advocates are entirely right to call for more truly informed consent. Yet with it, antidepressants start to sound really dubious, don't they? (Even without invoking possible extended difficulty with sexual function). But leaving one’s patient with the impression that the treatment they are about to begin is dubious regarding risks versus benefits directly undercuts the potential value of the medication (at least relative to the value that might have accompanied a presentation that placed less emphasis on risks). [end quote]
Also, the psychiatrist Sanil Rege offers a detailed clinical overview of PSSD in this YouTube video which I will recommend to readers.
My own thinking on this issue is:
Sexual dysfunction after SSRI discontinuation that is enduring or permanent appears to be rare (or at least uncommon) based on clinical experience but likely will be shown to be more common once systematic research is available. It seems essential that sexual side effects are discussed with patients as part of the informed consent process. This is information that I would want to know if I were making a decision about taking an antidepressant, and this is information that patients deserve to know. Given the uncertainty around PSSD, the possibility of protracted sexual dysfunction should be treated similarly to other rare or uncommon adverse effects.
How should this influence medical decision-making? For cases of mild to moderate anxiety or depression, PSSD and other adverse effects shift the balance in favor of non-pharmacological interventions as first-line. Watchful waiting, supportive care, lifestyle and diet changes, exercise, counseling, and various forms of psychotherapy, all these seem preferrable in terms of risk profile (current guidelines already recommend this, but there is a disconnect between practice and recommendations). Even transcranial magnetic stimulation may be offered as a first-line alternative for depression if there are concerns about sexual side-effects. The potential risks associated with antidepressants become more worthwhile if non-pharmacological interventions have failed to offer relief, or if the patient strongly prefers them, or there are good clinical reasons based on prior treatment history, or if severity/chronicity of symptoms warrants combined pharmacological and non-pharmacological treatment. When considering the choice of antidepressants, antidepressants with more favorable sexual profile should be given due consideration.
Second, this warrants greater attention to pre-treatment sexual functioning and history of sexual adverse effects with prior treatments, even if they were mild and tolerable in the past. Sexual adverse effects with on-going treatment should prompt a re-examination of pharmacotherapy agents being used and a consideration of alternatives. Timely recognition and discontinuation may possibly prevent a protracted course. The association of emotional blunting with PSSD may also be relevant here and should be paid attention to.
And third, this suggests a general reassessment of our casual attitudes towards long-term antidepressant maintenance treatment. Longer duration of treatment is a risk factors for many adverse effects. Long-term maintenance treatment should not be the default option; the need for on-going treatment should be continually examined and the risks, both common and rare, should be taken into account by the provider and the patient. There are complex trade-offs involved here and often there is no single correct answer, but that doesn’t take away the need for informed and shared decision-making.