madman
Super Moderator
Persistent sexual dysfunction after SSRI withdrawal: a scoping review and presentation of 86 cases from the Netherlands (2021)
Katherine Chinchilla Alfaro, Florence van Hunsel & Corine Ekhart
Abstract
Background: Sexual dysfunction is highly prevalent worldwide. A specific form is persistent sexual dysfunction after SSRI withdrawal. We conducted a systematic literature review in order to characterize factors related to post SSRI sexual dysfunction (PSSD) and analyzed spontaneous reports of persistent sexual dysfunction reported to the Netherlands Pharmacovigilance Center Lareb.
Research Design and Methods: A systematic literature review was conducted following the PRISMAScR guidelines. In addition, reports of PSSD submitted to the Netherlands Pharmacovigilance Center Lareb between 1992 and 2021 were analyzed.
Results: A total of 237 articles were retrieved through the search and 33 articles were selected for inclusion in this review, in accordance with the inclusion criteria. Information regarding the characteristics of the condition, its clinical management, patient characteristics, and impact of PSSD is presented. A total of 86 reports of persistent sexual dysfunction were analyzed. The longest case was a patient with PSSD for 23 years. The main symptoms were: loss or decreased libido (n = 53), erectile dysfunction (n = 23) and anorgasmia (n = 5).
Conclusions: PSSD impact includes sexual, psychological, and social consequences. Little is known about the mechanisms underlying PSSD and no effective treatment exists. It is necessary to increase recognition of PSSD among prescribers and improve its management at the clinical level.
1. Introduction
Sexual dysfunction (SD) is defined as disorders in sexual desire and/or in the psychophysiological changes associated with the sexual response cycle [1]. The etiology of sexual dysfunction is multifactorial, encompassing biological, psychological, relational, and sociocultural factors. Chronic illnesses, such as vascular disease, diabetes mellitus, neurological disease, and malignancy, can impact sexual function. Aging itself is associated with decreased sexual function. However, similar symptoms can also be caused by different groups of drugs, e.g. anticholinergics, cardiovascular and antihypertensive medications, hormonal preparations, or psychotropics [2,3]. Sexual dysfunction can take many forms, not only erectile dysfunction or low libido but also pain, discomfort, and orgasm or ejaculation disorders [4]. Sexual dysfunction is common in both sexes. Studies show that the prevalence is between 10% and 52% in men, versus 25% and 63% in women. The widespread of these values is due to differences in criteria, methods, and definitions between the studies [2,3,5]. Sexual dysfunction is still a ‘taboo,’ which usually makes people who suffer from it feel ashamed to talk about it with caregivers and family members [4].
Selective serotonin reuptake inhibitors (SSRIs) are known to cause sexual adverse drug reactions (ADRs). SSRI-induced sexual ADRs are associated with an increase in the amount of serotonin in the synaptic cleft, which has stimulating effects on the postsynaptic 5HT2A receptors, which are associated with sexual ADRs [6]. SSRIs can affect any phase of the four phases of the sexual response cycle: sexual desire (libido), arousal (male erection, female lubrication), orgasm and ejaculation, and the recovery phase (resolution) [7].
The sexual response requires the interaction of multiple neurotransmitters and hormones that balance excitatory and inhibitory pathways [8] Dopamine, norepinephrine, melanocortin, and oxytocin are known to have an excitatory effect at different stages of sexual response while serotonin, endocannabinoids, and opioids serve to inhibit these pathways [8,9]. Therefore, the increase of serotonin levels during the treatment with SSRIs tilts this balance toward inhibition. The high concentration of serotonin downregulates dopamine neurotransmission by affecting dopamine secretion and recapture [10]. In addition, high serotonin levels can regulate proopiomelanocortin neurons output, inhibit melanocortin receptors (MC4) and diminish the function of norepinephrine in the sexual response [11]. These changes in neurotransmitter levels explain how the sexual response is affected during the use of SSRIs, and are usually reversible [6,12].
A specific form of sexual dysfunction is post-SSRI sexual dysfunction (PSSD) [13]. With PSSD the sexual difficulties occur after discontinuation of SSRIs or while taking SSRIs and persist after discontinuation. It is under-recognized and can be debilitating both psychologically and physically. Prevalence and incidence are both currently unknown, and also the risk of PSSD among patients taking SSRIs [14]
The validation of sexual ADRs in the case of PSSD is difficult because the dysfunction extends or emerges after withdrawal. The first reports of PSSD in Britain date back to 1991 [15], but it was not until 2006 that the term PSSD was coined [16]. The evidence of the persistence of sexual dysfunction after the discontinuation of SSRIs is supported by the number of case reports that have become available through time [12,16,17]. This led the Pharmacovigilance Risk Assessment Committee (PRAC) to recommend adding a warning regarding PSSD in the summary of the product characteristics and the patient leaflet of SSRIs [18].
It is important to gain more insight into PSSD for healthcare professionals to be able to better inform patients. Better recognition of the condition, identifying pathophysiological mechanisms, and potential treatments are needed. We conducted a systematic literature review in order to characterize factors related to PSSD. Furthermore, spontaneous reports of adverse events of persisting sexual dysfunction reported to the Netherlands Pharmacovigilance Center Lareb were characterized.
3. Results
3.1. Selections of sources of evidence for the review
3.2. Narrative summary
PGAD is rather an entity of its own that groups a series of hyperactive symptoms.
3.2.1. PSSD presentation
The most commonly reported symptoms of PSSD are loss of libido and sexual drive, erectile dysfunction, week or pleasureless orgasms, genital anesthesia, and anorgasmia (Figure 2). The most characteristic symptom of this condition is genital anesthesia, which is not reported by patients who suffer SD as a consequence of depression or another psychological condition [23–25].
3.2.2. SSRI and characteristics of use
Figure 2 lists the SSRIs that have been associated with PSSD. Citalopram, paroxetine, fluoxetine, and sertraline are the most frequently mentioned through the literature, however, any SSRI should be held suspicious in the onset and endurance of sexual dysfunctions.
3.2.3. Diagnostics
3.2.4. Impact and personal statement of symptoms
3.2.5. Physiopathology
Initially, during the treatment with SSRIs, the blockage of the serotonin transporters causes the acute increase of serotonin levels that in return activates 5-HT1A and 5-HT1B autoreceptors. These autoreceptors decrease the firing rate of the serotonergic neural pathway, which decreases the release of serotonin into the synaptic cleft.
As the autoreceptors desensitize, the presence of serotonin no longer inhibits the activity of the neurons and there is an increase in the serotonin levels in the synaptic cleft. Some of the serotonin cell bodies in the central nervous system that arise from the raphe nuclei project to the mesolimbic dopamine system, where they inhibit the dopamine pathways. In addition, serotonin projections to the spine can inhibit erection, vaginal lubrication, ejaculation, and orgasm [44,45]
These mechanisms help explain the SD during the use of SSRI, nonetheless, the pathological mechanisms behind PSSD are still mostly unknown [23,34,38,46]. The root cause might be a combination of these potential theories [39]. The different hypotheses found in the literature are mentioned below.
3.2.5.1. Endocrinal and neurochemical imbalance.
The increase of serotonin in the central and peripheral nervous system causes several neurochemical changes that play important roles in the sexual response, including an increase in prolactin levels, blockage of A1-adrenergic receptors, a decrease in dopamine, and oxytocin, and a decrease in nitric oxide synthesis [16,23,39,41]. Serotonin receptors are also involved in the negative feedback regulation of the hypothalamic-pituitary-testicular axis, leading to a decrease in testosterone and therefore causing imbalances in the sexual response cycle [24,38,39,47]
These imbalances help explain the SSRI effect on the sexual response, nevertheless, it is not yet known why these levels do not return to normal in some patients after withdrawal.
3.2.5.2. Ion channels
It is speculated that the mechanisms underpinning genital anesthesia could be associated with transient receptor potential (TRP) ion channel transduction disturbances [4,14,36,39]. TRP ion channels can respond to multiple stimuli, including temperature [36,39]. At the same time, the temperature is important for sensitivity; glans tactile receptors are more sensitive when the penis surface is warm. All SSRIs have effects on sodium currents and evidence shows that serotonin relates to TRPs thermal transduction to the spinal cord [4,14], yet the exact interaction between peripheral serotonin and TRPs causing the genital anesthesia in PSSD is unknown [36].
3.2.5.3. Neurotoxicity
Serotonergic neurotoxicity might also play a role in PSSD. High serotonin levels in the peripheral nerves can lead to axonal damage [38]. In a similar way, 3,4- methylenedioxymethamphetamine (ecstasy) can stimulate the release and inhibit the reuptake of serotonin and is associated with SD long after stopping its use. In this case, axonal damage is involved [23–25,34,38,39] The potency of 3,4- methylenedioxymethamphetamine is probably the cause of neurogenic sexual impairment, whereas in PSSD individual vulnerability may play a prominent role [25].
3.2.5.4. Epigenetic changes
Epigenetic changes’ input to PSSD has been increasingly recognized [16,23,24,39,48]. SSRIs can trigger epigenetic changes that cause a persistent downregulation of 5-HT1A receptors which has been linked to the regulation of sexual motivation. Csoka and Szyf [48] indicate that the persistent desensitization of the receptor, even after withdrawal could be a result of gene expression alterations, specifically DNA methylation due to increased expression of methyl-binding proteins. These epigenetic changes have been observed in three areas of the brain: the frontal cortex, the dentate gyrus of the hippocampus, and the caudate-putamen [39,48].
3.2.5.5. Other hypotheses
Some authors point out that just as there are reports of SSRIs causing extrapyramidal effects such as bradykinesia, rigidity, akathisia, and acute dystonia which can persist after drug discontinuation, PSSD could be caused by mechanisms similar to those of extrapyramidal effects but in an area of the brain responsible for sexual function [16,47].
Lastly, PSSD could be related to genetic polymorphisms in genes related to the glutamatergic system of depressed patients [23] or with structural changes in brain regions involved in sexual response. The use of paroxetine for obsessive-compulsive disorder has caused a significant reduction in the left amygdala volume of adolescent patients [16].
3.2.6. Treatment
There is currently neither consensus on the treatment nor protocols for the management of PSSD. See Figure 2 for the separate treatment of PSSD and PGAD.
3.2.7. Knowledge gaps
The knowledge gaps identified through this review can be grouped into two big areas; those aimed for a better understanding of the syndrome and its dimensions, and the second area comprehends improvements in patient management. Many authors agree that more research is needed for a better understanding of physiopathology and to identify effective treatment [4,24,31–33,47].
3.3. Reports submitted to the Netherlands Pharmacovigilance Center Lareb
4. Discussion
5. Limitations
One of the most important limitations this study presents is that multiple terms can be used to describe the condition under study. The term PSSD or PGAD is not included in the MedDRA terminology. Before it was grouped as a syndrome, some publication names and keywords could have referred to more general aspects like ‘antidepressants’ or to more specific conditions like ‘erectile dysfunction or ‘anejaculation.’ This creates a limitation regarding the scope of the keywords selected for this study.
This same term limitation is present in the report's database search. Hence, it is not possible to exclude that there could be more reports of persistent SD after SSRI withdrawal. The PGAD report included in this study is a confirmed report by individual analysis of the case.
In addition, studies not available at the time of the search through one of the search engines used for this review were not included. The cross-reference check aims to reduce the impact of this limitation yet, some relevant studies could have evaded our search. Other articles meeting the inclusion criteria were not included because they escaped the publication time ranges or the language limitations of this review.
6. Conclusions
The symptoms of PSSD frequently have mixed physical and psychological components and have a very high impact on the quality of life of those who experience it. There is some evidence of pharmacological and non-pharmacological management of the symptoms but the outcome is very variable. For some patients, the symptoms disappear with time but for some others, PSSD may persist for decades.
The ethnic origin and country were frequently not reported and no studies were able to draw any conclusion on these variables or on gender-based differences. The reason why PSSD occurs is not yet known, but it probably has a multifactorial cause. Theories explaining the relation between SSRI exposition and disturbances in the TRP channels transduction and epigenetic changes seem to have the most attention among the articles reviewed. Nevertheless, further research is needed to fully understand the underlying mechanisms.
One of the most frequent difficulties patients face is dealing with their practitioners because some of them do not believe their patients or underestimate the impact PSSD has on their patients’ lives. We expect to contribute to these difficulties by providing some clarity to all the different aspects presented in this review.
Katherine Chinchilla Alfaro, Florence van Hunsel & Corine Ekhart
Abstract
Background: Sexual dysfunction is highly prevalent worldwide. A specific form is persistent sexual dysfunction after SSRI withdrawal. We conducted a systematic literature review in order to characterize factors related to post SSRI sexual dysfunction (PSSD) and analyzed spontaneous reports of persistent sexual dysfunction reported to the Netherlands Pharmacovigilance Center Lareb.
Research Design and Methods: A systematic literature review was conducted following the PRISMAScR guidelines. In addition, reports of PSSD submitted to the Netherlands Pharmacovigilance Center Lareb between 1992 and 2021 were analyzed.
Results: A total of 237 articles were retrieved through the search and 33 articles were selected for inclusion in this review, in accordance with the inclusion criteria. Information regarding the characteristics of the condition, its clinical management, patient characteristics, and impact of PSSD is presented. A total of 86 reports of persistent sexual dysfunction were analyzed. The longest case was a patient with PSSD for 23 years. The main symptoms were: loss or decreased libido (n = 53), erectile dysfunction (n = 23) and anorgasmia (n = 5).
Conclusions: PSSD impact includes sexual, psychological, and social consequences. Little is known about the mechanisms underlying PSSD and no effective treatment exists. It is necessary to increase recognition of PSSD among prescribers and improve its management at the clinical level.
1. Introduction
Sexual dysfunction (SD) is defined as disorders in sexual desire and/or in the psychophysiological changes associated with the sexual response cycle [1]. The etiology of sexual dysfunction is multifactorial, encompassing biological, psychological, relational, and sociocultural factors. Chronic illnesses, such as vascular disease, diabetes mellitus, neurological disease, and malignancy, can impact sexual function. Aging itself is associated with decreased sexual function. However, similar symptoms can also be caused by different groups of drugs, e.g. anticholinergics, cardiovascular and antihypertensive medications, hormonal preparations, or psychotropics [2,3]. Sexual dysfunction can take many forms, not only erectile dysfunction or low libido but also pain, discomfort, and orgasm or ejaculation disorders [4]. Sexual dysfunction is common in both sexes. Studies show that the prevalence is between 10% and 52% in men, versus 25% and 63% in women. The widespread of these values is due to differences in criteria, methods, and definitions between the studies [2,3,5]. Sexual dysfunction is still a ‘taboo,’ which usually makes people who suffer from it feel ashamed to talk about it with caregivers and family members [4].
Selective serotonin reuptake inhibitors (SSRIs) are known to cause sexual adverse drug reactions (ADRs). SSRI-induced sexual ADRs are associated with an increase in the amount of serotonin in the synaptic cleft, which has stimulating effects on the postsynaptic 5HT2A receptors, which are associated with sexual ADRs [6]. SSRIs can affect any phase of the four phases of the sexual response cycle: sexual desire (libido), arousal (male erection, female lubrication), orgasm and ejaculation, and the recovery phase (resolution) [7].
The sexual response requires the interaction of multiple neurotransmitters and hormones that balance excitatory and inhibitory pathways [8] Dopamine, norepinephrine, melanocortin, and oxytocin are known to have an excitatory effect at different stages of sexual response while serotonin, endocannabinoids, and opioids serve to inhibit these pathways [8,9]. Therefore, the increase of serotonin levels during the treatment with SSRIs tilts this balance toward inhibition. The high concentration of serotonin downregulates dopamine neurotransmission by affecting dopamine secretion and recapture [10]. In addition, high serotonin levels can regulate proopiomelanocortin neurons output, inhibit melanocortin receptors (MC4) and diminish the function of norepinephrine in the sexual response [11]. These changes in neurotransmitter levels explain how the sexual response is affected during the use of SSRIs, and are usually reversible [6,12].
A specific form of sexual dysfunction is post-SSRI sexual dysfunction (PSSD) [13]. With PSSD the sexual difficulties occur after discontinuation of SSRIs or while taking SSRIs and persist after discontinuation. It is under-recognized and can be debilitating both psychologically and physically. Prevalence and incidence are both currently unknown, and also the risk of PSSD among patients taking SSRIs [14]
The validation of sexual ADRs in the case of PSSD is difficult because the dysfunction extends or emerges after withdrawal. The first reports of PSSD in Britain date back to 1991 [15], but it was not until 2006 that the term PSSD was coined [16]. The evidence of the persistence of sexual dysfunction after the discontinuation of SSRIs is supported by the number of case reports that have become available through time [12,16,17]. This led the Pharmacovigilance Risk Assessment Committee (PRAC) to recommend adding a warning regarding PSSD in the summary of the product characteristics and the patient leaflet of SSRIs [18].
It is important to gain more insight into PSSD for healthcare professionals to be able to better inform patients. Better recognition of the condition, identifying pathophysiological mechanisms, and potential treatments are needed. We conducted a systematic literature review in order to characterize factors related to PSSD. Furthermore, spontaneous reports of adverse events of persisting sexual dysfunction reported to the Netherlands Pharmacovigilance Center Lareb were characterized.
3. Results
3.1. Selections of sources of evidence for the review
3.2. Narrative summary
PGAD is rather an entity of its own that groups a series of hyperactive symptoms.
3.2.1. PSSD presentation
The most commonly reported symptoms of PSSD are loss of libido and sexual drive, erectile dysfunction, week or pleasureless orgasms, genital anesthesia, and anorgasmia (Figure 2). The most characteristic symptom of this condition is genital anesthesia, which is not reported by patients who suffer SD as a consequence of depression or another psychological condition [23–25].
3.2.2. SSRI and characteristics of use
Figure 2 lists the SSRIs that have been associated with PSSD. Citalopram, paroxetine, fluoxetine, and sertraline are the most frequently mentioned through the literature, however, any SSRI should be held suspicious in the onset and endurance of sexual dysfunctions.
3.2.3. Diagnostics
3.2.4. Impact and personal statement of symptoms
3.2.5. Physiopathology
Initially, during the treatment with SSRIs, the blockage of the serotonin transporters causes the acute increase of serotonin levels that in return activates 5-HT1A and 5-HT1B autoreceptors. These autoreceptors decrease the firing rate of the serotonergic neural pathway, which decreases the release of serotonin into the synaptic cleft.
As the autoreceptors desensitize, the presence of serotonin no longer inhibits the activity of the neurons and there is an increase in the serotonin levels in the synaptic cleft. Some of the serotonin cell bodies in the central nervous system that arise from the raphe nuclei project to the mesolimbic dopamine system, where they inhibit the dopamine pathways. In addition, serotonin projections to the spine can inhibit erection, vaginal lubrication, ejaculation, and orgasm [44,45]
These mechanisms help explain the SD during the use of SSRI, nonetheless, the pathological mechanisms behind PSSD are still mostly unknown [23,34,38,46]. The root cause might be a combination of these potential theories [39]. The different hypotheses found in the literature are mentioned below.
3.2.5.1. Endocrinal and neurochemical imbalance.
The increase of serotonin in the central and peripheral nervous system causes several neurochemical changes that play important roles in the sexual response, including an increase in prolactin levels, blockage of A1-adrenergic receptors, a decrease in dopamine, and oxytocin, and a decrease in nitric oxide synthesis [16,23,39,41]. Serotonin receptors are also involved in the negative feedback regulation of the hypothalamic-pituitary-testicular axis, leading to a decrease in testosterone and therefore causing imbalances in the sexual response cycle [24,38,39,47]
These imbalances help explain the SSRI effect on the sexual response, nevertheless, it is not yet known why these levels do not return to normal in some patients after withdrawal.
3.2.5.2. Ion channels
It is speculated that the mechanisms underpinning genital anesthesia could be associated with transient receptor potential (TRP) ion channel transduction disturbances [4,14,36,39]. TRP ion channels can respond to multiple stimuli, including temperature [36,39]. At the same time, the temperature is important for sensitivity; glans tactile receptors are more sensitive when the penis surface is warm. All SSRIs have effects on sodium currents and evidence shows that serotonin relates to TRPs thermal transduction to the spinal cord [4,14], yet the exact interaction between peripheral serotonin and TRPs causing the genital anesthesia in PSSD is unknown [36].
3.2.5.3. Neurotoxicity
Serotonergic neurotoxicity might also play a role in PSSD. High serotonin levels in the peripheral nerves can lead to axonal damage [38]. In a similar way, 3,4- methylenedioxymethamphetamine (ecstasy) can stimulate the release and inhibit the reuptake of serotonin and is associated with SD long after stopping its use. In this case, axonal damage is involved [23–25,34,38,39] The potency of 3,4- methylenedioxymethamphetamine is probably the cause of neurogenic sexual impairment, whereas in PSSD individual vulnerability may play a prominent role [25].
3.2.5.4. Epigenetic changes
Epigenetic changes’ input to PSSD has been increasingly recognized [16,23,24,39,48]. SSRIs can trigger epigenetic changes that cause a persistent downregulation of 5-HT1A receptors which has been linked to the regulation of sexual motivation. Csoka and Szyf [48] indicate that the persistent desensitization of the receptor, even after withdrawal could be a result of gene expression alterations, specifically DNA methylation due to increased expression of methyl-binding proteins. These epigenetic changes have been observed in three areas of the brain: the frontal cortex, the dentate gyrus of the hippocampus, and the caudate-putamen [39,48].
3.2.5.5. Other hypotheses
Some authors point out that just as there are reports of SSRIs causing extrapyramidal effects such as bradykinesia, rigidity, akathisia, and acute dystonia which can persist after drug discontinuation, PSSD could be caused by mechanisms similar to those of extrapyramidal effects but in an area of the brain responsible for sexual function [16,47].
Lastly, PSSD could be related to genetic polymorphisms in genes related to the glutamatergic system of depressed patients [23] or with structural changes in brain regions involved in sexual response. The use of paroxetine for obsessive-compulsive disorder has caused a significant reduction in the left amygdala volume of adolescent patients [16].
3.2.6. Treatment
There is currently neither consensus on the treatment nor protocols for the management of PSSD. See Figure 2 for the separate treatment of PSSD and PGAD.
3.2.7. Knowledge gaps
The knowledge gaps identified through this review can be grouped into two big areas; those aimed for a better understanding of the syndrome and its dimensions, and the second area comprehends improvements in patient management. Many authors agree that more research is needed for a better understanding of physiopathology and to identify effective treatment [4,24,31–33,47].
3.3. Reports submitted to the Netherlands Pharmacovigilance Center Lareb
4. Discussion
5. Limitations
One of the most important limitations this study presents is that multiple terms can be used to describe the condition under study. The term PSSD or PGAD is not included in the MedDRA terminology. Before it was grouped as a syndrome, some publication names and keywords could have referred to more general aspects like ‘antidepressants’ or to more specific conditions like ‘erectile dysfunction or ‘anejaculation.’ This creates a limitation regarding the scope of the keywords selected for this study.
This same term limitation is present in the report's database search. Hence, it is not possible to exclude that there could be more reports of persistent SD after SSRI withdrawal. The PGAD report included in this study is a confirmed report by individual analysis of the case.
In addition, studies not available at the time of the search through one of the search engines used for this review were not included. The cross-reference check aims to reduce the impact of this limitation yet, some relevant studies could have evaded our search. Other articles meeting the inclusion criteria were not included because they escaped the publication time ranges or the language limitations of this review.
6. Conclusions
The symptoms of PSSD frequently have mixed physical and psychological components and have a very high impact on the quality of life of those who experience it. There is some evidence of pharmacological and non-pharmacological management of the symptoms but the outcome is very variable. For some patients, the symptoms disappear with time but for some others, PSSD may persist for decades.
The ethnic origin and country were frequently not reported and no studies were able to draw any conclusion on these variables or on gender-based differences. The reason why PSSD occurs is not yet known, but it probably has a multifactorial cause. Theories explaining the relation between SSRI exposition and disturbances in the TRP channels transduction and epigenetic changes seem to have the most attention among the articles reviewed. Nevertheless, further research is needed to fully understand the underlying mechanisms.
One of the most frequent difficulties patients face is dealing with their practitioners because some of them do not believe their patients or underestimate the impact PSSD has on their patients’ lives. We expect to contribute to these difficulties by providing some clarity to all the different aspects presented in this review.
