madman
Super Moderator
ABSTRACT
Introduction: Post-SSRI sexual dysfunction (PSSD) is an iatrogenic syndrome, the underlying neurobiological mechanisms of which are unclear. Symptom onset follows the cessation of serotonergic antidepressants i.e. Selective Serotonin and Norepinephrine reuptake inhibitors (SSRIs, SNRIs), and Tricyclic antidepressants (TCA’s). PTSD symptoms include genital anesthesia, erectile dysfunction, and orgasmic/ejaculatory anhedonia, and should be differentiated from depression-related sexual dysfunction. Recently, accumulated data of numerous case reports suggest additional non-sexual symptoms including, anhedonia, apathy, and blunted effect. PSSD gained official recognition after the European medical agency concluded that PSSD is a medical condition that persists after discontinuation of SSRIs and SNRIs.
Objective: To review possible underlying neurobiological mechanisms of this syndrome, update information on the pathophysiology, present a list of potential risk factors and discuss potential management options for PSSD.
Methods: Extensive literature review on the main symptom patterns of this disorder was undertaken using PubMed. It includes introductory explications of relevant neurobiology with the objective of generating a hypothesis.
Results: Precipitating factors for PSSD include previous exposure to certain drugs, genetic predisposition, psychological stress, or chemical stressful reaction to antidepressants along with pre-existing medical conditions affecting neuroplasticity. Different theories have been proposed to explain the pathophysiology of PSSD: epigenetic gene expression, dopamine-serotonin interactions, serotonin neurotoxicity, and hormonal changes. The diagnosis of PSSD is by excluding all other etiologies of sexual dysfunction. Treatment is challenging, and many strategies have been suggested without definitive outcomes. We offer the contours of a future neurobiological research agenda and propose several underlying mechanisms for the various symptoms of PSSD which could be the foundation for a future treatment algorithm.
Conclusion: There is a need for well-designed neurobiological research in this domain, as well as in the prevalence, pathophysiology, and treatment of PSSD. Practitioners should be alert to the distinctive features of PSSD. Misdiagnosing this syndrome might lead to harmful Sexual Medicine Reviews.
INTRODUCTION
Sexual Dysfunction (SD) is often without a clear cause, but may be linked to lifestyle factors such as smoking, exposure to environmental factors (eg, heavy metals), deleterious mental states (anxiety or stress), pathological conditions (i.e. major depressive disorder, hypertension, diabetes) and medication side-effects, such as those of the widely used selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs).1,2
Depression is strongly associated with SD as part of the core depressive syndrome, in which sexual function may be diminished or absent. In both sexes, decreased sexual desire in depression is the most prominent symptom, and dysfunctions of sexual arousal and orgasm may also occur. There may also be a bi-directional relationship between depression and SD.3 However, the treatment of depression with SSRI antidepressants is itself an independent cause of SD, despite improvement of, and recovery from, the depression, as long as the treatment endures.4−6 Over time, it emerged that SSRI-induced sexual dysfunction may persist following cessation of SSRI treatment.7−9 This condition has been termed post-SSRI Sexual Dysfunction (PSSD). The syndrome is characterized by a wide array of symptoms that may persist for variable periods or even indefinitely. The core symptoms of PSSD are genital anesthesia, loss of pleasure derived from genital stimulation, pleasure-less or weak orgasms (anhedonic orgasm), decreased sex drive, erectile dysfunction (ED), premature ejaculation, diminished vaginal lubrication, and diminished tactile sensitivity of nipples.10 Genital anesthesia appears to be uniquely and distinctively associated with PSSD; this phenomenon emerges in literature searches for PSSD symptoms but not in searches for SD symptoms common in depression. Furthermore, accumulated data of hundreds of case reports that were published in recent years, suggest that there are also non-sexual symptoms including, but not limited to, anhedonia, apathy, and blunted affect.11,12 In the year 2020 the British Medical Journal (BMJ) has also recognized PSSD as an important and distinct syndrome.13 PSSD has also been described as a cause of substantial and prolonged suffering, with devastating effects on quality of life that lead to significant loss of function, culminating in suicide attempts or even successful suicides in several anecdotal cases.14 No rational or consistent treatment has been found for this disorder. It is imperative for clinicians to be aware of non-sexual symptoms and to be able to differentiate between PSSD-associated SD and depression-related SD, as each of their symptoms can be quite distinctive with a few symptoms overlapping. We highlight these differences in this manuscript and propose a number of presumed risk factors that we have commonly encountered while reviewing cases of PSSD.
*PSSD Biological Plausibility, Development, and Occurrence
Symptoms
It is important to differentiate between depression-related SD symptoms and those of PSSD. Among all symptoms of SD, some seem to be more associated with PSSD rather than with depression.10,15,16,30 In the absence of a depressive syndrome, PSSD-related symptoms are as follows:
-Genital Anesthesia & Decreased Tactile Sensitivity of Nipples
-Absent or Diminished Sexual Desire
-Erectile Dysfunction & Diminished Vaginal Lubrication
-Flaccid Penile Glans
-Anorgasmia, Premature Ejaculation, and Ejaculatory Anhedonia
*Diagnosis & Treatment of PSSD
*Presumed Risk Factors of PSSD Genetic Predisposition
-Chemical Stressors
-Psychological Stressors
-Previous Exposure to Finasteride & Isotretinoin
-First-Time Use of Antidepressants Without PSSD Sequelae
-Maladaptive Neuroplastic Change
-MTHFR Gene Variants (C677T and A1298C)
-Substance Abuse & Combination With Antidepressants
CONCLUSION
In this manuscript, we review post-SSRI sexual dysfunction (PSSD) in terms of its biological plausibility, occurrence, symptoms, and presumed risk factors. We propose that pre-existing factors and previous drug use are implicated in the triggering of PSSD and its persistent nature. Upon cessation of SSRI therapy, depressive illness may re-emerge, therefore it is of importance to note the difference between depression-related sexual dysfunction and PSSD-associated sexual dysfunction, as highlighted in this manuscript, when attempting to diagnose PSSD. There is a paucity of data on the frequency, incidence, prevalence, onset, course and outcomes, comorbidity, demographics, and risk factors of this syndrome, arising from the discontinuation of such a ubiquitous class of medications (SSRIs). Some of the hypotheses raised here may have an impact on the understanding of the long-term effects and pharmacological mechanisms of medications affecting the central nervous system (CNS). The concept, that essential pharmacological treatment may lead to long term post-continuation adverse effects, should be taken into clinical consideration. PSSD is now a new, important example of that. As it is slowly gaining its recognition as a prevalent syndrome, improved knowledge may offer new insights into the prevention and treatment of this condition. General epidemiological studies in the domain of PSSD might be especially revealing and useful.
We present this information hoping it may be useful for aiding future research into possible risk factors, causes, and potential treatments of this syndrome.
Introduction: Post-SSRI sexual dysfunction (PSSD) is an iatrogenic syndrome, the underlying neurobiological mechanisms of which are unclear. Symptom onset follows the cessation of serotonergic antidepressants i.e. Selective Serotonin and Norepinephrine reuptake inhibitors (SSRIs, SNRIs), and Tricyclic antidepressants (TCA’s). PTSD symptoms include genital anesthesia, erectile dysfunction, and orgasmic/ejaculatory anhedonia, and should be differentiated from depression-related sexual dysfunction. Recently, accumulated data of numerous case reports suggest additional non-sexual symptoms including, anhedonia, apathy, and blunted effect. PSSD gained official recognition after the European medical agency concluded that PSSD is a medical condition that persists after discontinuation of SSRIs and SNRIs.
Objective: To review possible underlying neurobiological mechanisms of this syndrome, update information on the pathophysiology, present a list of potential risk factors and discuss potential management options for PSSD.
Methods: Extensive literature review on the main symptom patterns of this disorder was undertaken using PubMed. It includes introductory explications of relevant neurobiology with the objective of generating a hypothesis.
Results: Precipitating factors for PSSD include previous exposure to certain drugs, genetic predisposition, psychological stress, or chemical stressful reaction to antidepressants along with pre-existing medical conditions affecting neuroplasticity. Different theories have been proposed to explain the pathophysiology of PSSD: epigenetic gene expression, dopamine-serotonin interactions, serotonin neurotoxicity, and hormonal changes. The diagnosis of PSSD is by excluding all other etiologies of sexual dysfunction. Treatment is challenging, and many strategies have been suggested without definitive outcomes. We offer the contours of a future neurobiological research agenda and propose several underlying mechanisms for the various symptoms of PSSD which could be the foundation for a future treatment algorithm.
Conclusion: There is a need for well-designed neurobiological research in this domain, as well as in the prevalence, pathophysiology, and treatment of PSSD. Practitioners should be alert to the distinctive features of PSSD. Misdiagnosing this syndrome might lead to harmful Sexual Medicine Reviews.
INTRODUCTION
Sexual Dysfunction (SD) is often without a clear cause, but may be linked to lifestyle factors such as smoking, exposure to environmental factors (eg, heavy metals), deleterious mental states (anxiety or stress), pathological conditions (i.e. major depressive disorder, hypertension, diabetes) and medication side-effects, such as those of the widely used selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs).1,2
Depression is strongly associated with SD as part of the core depressive syndrome, in which sexual function may be diminished or absent. In both sexes, decreased sexual desire in depression is the most prominent symptom, and dysfunctions of sexual arousal and orgasm may also occur. There may also be a bi-directional relationship between depression and SD.3 However, the treatment of depression with SSRI antidepressants is itself an independent cause of SD, despite improvement of, and recovery from, the depression, as long as the treatment endures.4−6 Over time, it emerged that SSRI-induced sexual dysfunction may persist following cessation of SSRI treatment.7−9 This condition has been termed post-SSRI Sexual Dysfunction (PSSD). The syndrome is characterized by a wide array of symptoms that may persist for variable periods or even indefinitely. The core symptoms of PSSD are genital anesthesia, loss of pleasure derived from genital stimulation, pleasure-less or weak orgasms (anhedonic orgasm), decreased sex drive, erectile dysfunction (ED), premature ejaculation, diminished vaginal lubrication, and diminished tactile sensitivity of nipples.10 Genital anesthesia appears to be uniquely and distinctively associated with PSSD; this phenomenon emerges in literature searches for PSSD symptoms but not in searches for SD symptoms common in depression. Furthermore, accumulated data of hundreds of case reports that were published in recent years, suggest that there are also non-sexual symptoms including, but not limited to, anhedonia, apathy, and blunted affect.11,12 In the year 2020 the British Medical Journal (BMJ) has also recognized PSSD as an important and distinct syndrome.13 PSSD has also been described as a cause of substantial and prolonged suffering, with devastating effects on quality of life that lead to significant loss of function, culminating in suicide attempts or even successful suicides in several anecdotal cases.14 No rational or consistent treatment has been found for this disorder. It is imperative for clinicians to be aware of non-sexual symptoms and to be able to differentiate between PSSD-associated SD and depression-related SD, as each of their symptoms can be quite distinctive with a few symptoms overlapping. We highlight these differences in this manuscript and propose a number of presumed risk factors that we have commonly encountered while reviewing cases of PSSD.
*PSSD Biological Plausibility, Development, and Occurrence
Symptoms
It is important to differentiate between depression-related SD symptoms and those of PSSD. Among all symptoms of SD, some seem to be more associated with PSSD rather than with depression.10,15,16,30 In the absence of a depressive syndrome, PSSD-related symptoms are as follows:
-Genital Anesthesia & Decreased Tactile Sensitivity of Nipples
-Absent or Diminished Sexual Desire
-Erectile Dysfunction & Diminished Vaginal Lubrication
-Flaccid Penile Glans
-Anorgasmia, Premature Ejaculation, and Ejaculatory Anhedonia
*Diagnosis & Treatment of PSSD
*Presumed Risk Factors of PSSD Genetic Predisposition
-Chemical Stressors
-Psychological Stressors
-Previous Exposure to Finasteride & Isotretinoin
-First-Time Use of Antidepressants Without PSSD Sequelae
-Maladaptive Neuroplastic Change
-MTHFR Gene Variants (C677T and A1298C)
-Substance Abuse & Combination With Antidepressants
CONCLUSION
In this manuscript, we review post-SSRI sexual dysfunction (PSSD) in terms of its biological plausibility, occurrence, symptoms, and presumed risk factors. We propose that pre-existing factors and previous drug use are implicated in the triggering of PSSD and its persistent nature. Upon cessation of SSRI therapy, depressive illness may re-emerge, therefore it is of importance to note the difference between depression-related sexual dysfunction and PSSD-associated sexual dysfunction, as highlighted in this manuscript, when attempting to diagnose PSSD. There is a paucity of data on the frequency, incidence, prevalence, onset, course and outcomes, comorbidity, demographics, and risk factors of this syndrome, arising from the discontinuation of such a ubiquitous class of medications (SSRIs). Some of the hypotheses raised here may have an impact on the understanding of the long-term effects and pharmacological mechanisms of medications affecting the central nervous system (CNS). The concept, that essential pharmacological treatment may lead to long term post-continuation adverse effects, should be taken into clinical consideration. PSSD is now a new, important example of that. As it is slowly gaining its recognition as a prevalent syndrome, improved knowledge may offer new insights into the prevention and treatment of this condition. General epidemiological studies in the domain of PSSD might be especially revealing and useful.
We present this information hoping it may be useful for aiding future research into possible risk factors, causes, and potential treatments of this syndrome.
