Altough is uncommon PSSD is a very serious problem,that harshly impact quality of life.
What is PSSD?
PSSD is a iatrogenic sexual disfunction syndrome,caused by previous SSRI treatment, it can last for months or years after the discontinuation of SSRIs
SSRI are the newest class of antidepressant which function only blocking the reuptake of serotonin without theoretically affecting other neurotransmitter circuits.
Blocking the SERT there is an increase of the level of extracellular serotonin avalaible to bind to the post-synaptical receptors
The mechanism of action remains unknown but there are two hypothesis
The monoamine theory:an increased level of serotonin causes downregulation of 5HT1A autorecereptor thus leading to an increased firing rate of the neurons.
This theory is somewhat incomplete because it can't explain why the therapeutic role of antidepressant is delayed by weeks,or even month from the onset of treatment,instead of following serotonin level which is raised in minutes or hours after the molecule arrives in the brain.
The BDNF theory:an increased level of serotonine can indirectly affect the level of BDNF an important neurotrophic factor,this can explain why the action is delayed,it has to build up new synapses and circuits before taking action.
Sexual side-effect during treatment with antidepressant are condition well known and studied,the peculiarity of PSSD is that the sexual side effect persists after the discontinuation of the SSRI.
The drugs that are more frequently used in impotence like sildenafil,tadalafil,vardenafil,seems to be useless in PSSD patients,PSSD seems to have no therapy.
This clinical condition is uncommon and often not recognized,homewer recently this syndrome is officially recognised by LAREB the Netherlands Pharmacovigilance Centre, the equivalent of italian AIFA,and the more famous american FDA.
In the american label of prozac it is clearly written "symptoms of sexual dysfunction occasionally persist after discontinuation of fluoxetine treatment '',so we can infere that the company is well aware of this syndrome and want to be protected against any class action.
Paper related PSSD,in Lareb site:
Some features of PSSD
1)PSSD can start during treatment and continue after discontinuation of the drug
2)both male and female can be afflicted
3)every SSRI and SNRI drug can cause the syndrome
4)can last for months or years,indefinitely
5)can be caused by the same SSRI that previously was not correlated with any side-effect
6)can be caused by few doses of SSRI
Often the patient with PSSD does not report a normal impotence,but a specifical impotence characterized by genitals anesthesia,a particular condition where not only there is a lack of sexual desire,difficulty to get aroused and reach an orgasm,but also an insensibility of the skin to tactile stimulus.
The symptoms of PSSD have different gravity and can include:
1)Muted, delayed or absent orgasm (anorgasmia)
4)Difficulty initiating or maintaining an erection or becoming aroused
6)Impotence or reduced vaginal lubrication
8)Weakened penile, vaginal or clitoral sensitivity
9)Reduced or no experience of pleasure during orgasm (ejaculatory anhedonia)
The cause of PSSD is unknown but there are several hypothesis
Circuits of low sexual desire
1)The epigenetic mutation hypothesis
It is well known that SSRI antidepressant downregulates 5HT1A increasing serotoninergic trasmission,it has been shown that chronic treatment with fluoxetine causes persistent downregulation of 5 HT1A.
This persistent modification is probably correlated with epigenetic modifications,which can result in different gene expression,chromatine remodeling, especially through gene silencing by DNA methylation,due to increased expression of the methyl binding proteins MeCP2 andMBD1 .
The production of MECP2 e MBD1 is accompanied with enhanced HDAC2 mRNA synthesis, and decreased amount of histone H3 deacetylase,the modifications are detected in three serotonin projection areas : the caudate-putamen, the frontal cortex, and the dentate gyrus of the hippocampus .
MDB1,MECP2 AND HDAC2 are proteins involved in the complex mechanism of action of fluoxetine and other SSRI.
A permanent treatment with SSRI can have positive impact on several diseases like depression,anxiety,obsessive compulsive syndrome altering gene expression,but can also cause reduced fertility and persistent sexual dysfunction.
Another paper finds evidence of epigenetic mutation during treatment of fluoxetine of the same protein Mecp2 methyl-CpG-binding protein 2 silencing the histone deacetylase,the effect is observated in the same three serotonin projection areas, the caudate-putamen, the frontal cortex, and the dentate gyrus subregion of hippocampus.
Recently a team investigates the effects on sexual behaviour in mice caused by chronic treatment with fluoxetine,they discover that not only the mice that receive fluoxetine have reduced sexual dysfunction but also their progeny.
The mothers are treated daily with 7.5 mg/kg daily of fluoxetine during pregnancy and lactation,male pups are find to have reduced sexual motivation,that is a common side-effect of fluoxetine.
They do not found difference in plasmatic testosterone concentration and testis, epididymis, seminal vesicle and pituitary wet weights,homewer they find a desrease in sexual incentive on the sexual incentive motivation test.
This research does not demonstrates epigenetic modification,but suggests that permanenent impairment of sexual skills caused by SSRI antidepressants is more than a theory.
It is also suggested that SSRI are not safe in pregnancy.
A similar research is conducted with another SSRI citalopram,develops in the same way exposing to citalopram,neonatal rats and giving similar conclusions,the rats exposed neonatally have their sexual behaviour impaired.
Homewer the research-team does not suggest epigenetic mutation but focus on receptor 5HT1A an 5HT1B desensitisation.
Sexual side effect are linked to specifical type of cytochrome specifically cyp2d6 and cyp2c19 are two sub-types that gives a poor metabolizer state thus increasing the likelyhood of sexual side effect.
2)Impact on dopaminergic system
Chronic treatment with SSRI considerably reduce the firing on the dopamine neurons in the rat ventral tegmental area
The mesolilmbic circuit is deeply involved in the perception of pleasure and sexual motivation,an increase in serotoninergic trasmission can inhibite dopamine neurons in ventral tegmental area.Dopamine seems to play an important role in sexual arousal,and SSRI interfere with dopaminergic system.,the serotonin and dopamine systems modulate numerous brain functions and are implicated in the pathophysiology of affective, anxiety, and movement disorders.
Both systems interact by mutually innervating brain regions/circuits and reciprocally modulating each other. This serotonin-dopamine interaction plays a critical role in the action of antidepressant drugs.
Serotonin selective reuptake inhibitors (SSRIs) for example, block serotonine transporter (5-HTT) function to increase serotonine signaling, but may also induce side effects typically associated with reduced dopamine signaling, such as anhedonia, apathy, reduced libido, akathisia, and extrapyramidal motor symptoms . These side effects can lead to discontinuation even when treatment is efficacious.
Serotonin neurons of the dorsal and median raphe nuclei densely innervate dopaminergic nuclei and their projection areas
In mouse and rat, the densest afferent serotonin innervation is present in the substantia nigra pars compacta and pars reticulata both integral parts of the basal ganglia .
The dopaminergic neurons project to the striatum and provide dopaminergic modulatory input into the direct and indirect pathways of the basal ganglia. The SNP is the main output region of the basal ganglia and contains mostly gabaergic neurons projecting to the thalamus and the SNC .
The latter projection provides feedback inhibition to dopaminergic activity
3)Impact on melanocortin hypotalamic system
SSRI are used in bulimia,it is well known that SSRI can reduce hunger and promotes hypophagia.
Proopiomelanocortin neurons play a role in regulation of food intake,hunger and sexual behaviour.
Melanocortins do not only affect coloring of the skin but also regulate sexual behavior including penile erection, sexual motivation, and, in the female rat the secretion of sexual attractant
This can explain why sunlight may increase sexual drive also in human being...
a-MSH and ACTH are believed to act downstream from dopamine and oxytocin in the hypothalamic proerectile centers adjacent to the third ventricle.
a-MSH and ACTH are believed to act downstream from dopamine and oxytocin in the hypothalamic proerectile centers adjacent to the third ventricle.
Evidence of this function are based on several experimental findings,a MC4R selective substance augments erectile activity in wild type mice but not in MC4R knock-out mice, copulatory behavior is enhanced by administration of a selective MC4R agonist and is diminished in mice lacking Mc4r .
Real Time PCR demonstrates presence of MCR4 not only in central nervous system but also in the pelvic ganglion (major autonomic relay center to the penis) and in nerve fibers and mechanoreceptors in the glans of the penis.
These data implicate the MC4R in the modulation of penile erectile function and provide evidence that MC4R-mediated proerectile responses may be activated through neuronal circuitry in spinal cord erectile centers and somatosensory afferent nerve terminals of the penis.
Serotonin can regulate POMC neurons output,especially inhibiting melanocortin MC4 receptor via 5HT2a and 5 HT2c receptors.
4)desensitisation and downregulation of 5ht1a and 5ht1b
SSRI block reuptake of serotonine,this results in raising serotonine level that bind 5HT1A
The chronic stimulation of 5HT1A results in downregolation,as a consequence firing rate is increased.
Treatment with fluoxetine impair sexual behaviour and results in marked reduction in the number of non-contact penile erections in sexually experienced male rats.
It is observed that antagonists of 5HT1A molecules WAY-101405 or WAY-100635,coadministrated with fluoxetine reverse sexual-side effect in mice.
Withdrawal of WAY-100635 causes the reinstatement of the previous impairment of sexual behaviour.
A permanent downregulation of 5HT1A that is recognised as one of action mechanism of SSRI can result in a permanent impotence.
Post fluoxetine treatment there is a desensitization of 5ht1a hypotalamic receptor,this lead to a persisting oxytocin and ACTH release from hypotalamus,mediated by 5HT1A.
A persisting reduction of ACTH level can be positive in depression-anxiety management where there is abnormal high level of cortisol,the stress-hormone,but can also disrupt sexual behaviour.
Other studies pointed out that 5ht1a receptor can interfere with testosterone plasma level,altough 5HT1B do not affect hormonal level.
In PSSD homewer there is no clear evidence of reduced testosterone level,or other hormonal modification..
Hormone levels can be easily checked by routine laboratory test so hormonal deficit-imbalance can easily been observated.
Hormonal imbalance can be observed during treatment with SSRI but not strictly correlate with PSSD.
Lower level of testosterone during SSRI have been observed in small studies,and there is no clear evidence of the relationship between SSRI and sexual steroids.
It has been shown alterations in semen parameters and infertility wich both correlate with a changed hormonal enviroment.
Homewer this modifications can't be blamed for all the symptoms of PSSD such as genital anesthesia,and complete lack of libido.
It is also to be cleared the role of prolactine in relation to serotonin,especially through dopamine inhibition as mentioned above.
Patient with depression frequently express chronic pain,and SSRI and antidepressant are used as painkiller as they can raise pain threshold,this is due to an increasing serotonergic trasmission.especially in rafe nucleus.
It is well known that c fibers have a key role in nociception but recenntly new findings evidence the role of c fibers in the perception of pleasure,Olausson demonstrated the existence of this kind of unmyelinated fibers that can detect pleaseant stimuli,as serotonergic trasmission can block pain stimuli it can block pleasure stimuli too.
Genital anestesthesia is a strange symptom,relatevely uncommon in normal impotence,more common in PSSD,this suggest not only changing in brain or hypothalamus,but also in raphe nucleus.
The raphe nucleus has a dense serotonergic innervation which can be responsible for stopping pain impulse,as C fibers do not only transmit pain,but are also responsible for the trasmission of pleasant stimuli,an empowerment of serotonergic trasmission can both blockade pain and pleasure stimuli via the raphe serotonergic inhibition.
This can explain genital anesthesia,total insensibility of the genital area to tactile stimuli.
Considering that many of the patients with PSSD have clinical depression the first thing that can be done is switching to another antidepressant with low sexual-side effects like mirtazapine or nefazodone.
Especially mirtazapine can alleviate sexual symmptoms as it binds to alpha 2 receptor like yohimbine, a powerful alkaloyd with aphrodisiac effect,nefazodone can cause priapism,it is an alpha1 and 5ht2a blocker.
In relation to the dopamine hypothesis it has been suggested the use of bupropione an antidepressant that act both inhibiting the reuptake of dopamine and norepinefrine.
Another dopaminergic drug which can be used are cabergoline ropinirole and pramipexole,due to their binding to D2 receptors,cabergoline and bupropione can both increase sexual drive but not overcome the PPSD whole problem.
A new kind approach to sexual side effect are the sythetic melanocortins like melanotan and PT-141,which can raise sexual desire,homewer both peptides are not yet approved by FDA because they can cause hyperthension.
Classic treatment like sildenafil and other PDE5 inhibitors can sometimes improve the mechanics of sex but not the sexual anhedonia experienced by the patients.
In order to regain sensitivity in the genital area it has been used donezepil a procolinergic drug that act inhibiting acetylcolinesterase,thus increasing general perception and sensitivity.
A similar ,but not pharmacological approach is used by a team that used low power laser stimulation to the area with aneshesia
The purpose of this paper is not only to inform about an unknown syndrome related to a common type of drugs widespread in the world,and commonly prescribed, but also to point out how deeper a single drug can interfere with human homeostasis,and how persisting this changes can be.
Medical studies attest PSSD:
1) Persistent sexual side effect after discontinuation, Antonei B. Csoka, Stuart Shipko, 2006
2) Genital anesthesia persisting six years after sertraline discontinuation, Bolton JM, Sareen J, Reiss JP, 2006
3) Post SSRI Sexual Dysfunction, Audrey Bahrick, 2006
4),Persistent sexual side effect after discontinuation of selective serotonin reuptake inhibitors Antonei Csoka, Audrey Bahrick, Olli-Pekka Mehtonen, 2008
5)Persistent Sexual Dysfunction after Discontinuation of Selective Serotonin Reuptake InhibitorsPersistence of Sexual Dysfunction Side Effects after Discontinuation of Antidepressant Medications: Emerging Evidence , Audrey S. Bahrick, 2008
6)Persistent sexual dysfunction in genitourinary medicine clinic attendees induced by selective serotonin reuptake inhibitors, Farnsworth KD, Dinsmore WW, 2009
7)The impact of persistent sexual side effects of selective serotonin reuptake inhibitors after discontinuing treatment: a qualitative study , Rebecca Diane Stinson, 2013
8)Does sexual dysfunction persist upon discontinuation of selective serotonin reuptake inhibitors? , G.C. Ekhart, E.P. van Puijenbroek, 2014
9) One hundred and twenty cases of enduring sexual dysfunction following treatment, Hogan C, Le Noury J, Healy D, Mangin D, 2014
10)Penile anesthesia in post SSRI sexual dysfunction (PSSD) responds to low-power laser irradiation: A case study and hypothesis about the role of transient receptor potential (TRP) ion channels , Waldinger MD, van Coevorden RS, Schweitzer DH, Georgiadis J, 2014
11)Post-SSRI Sexual Dysfunction: Clinical Characterization and Preliminary Assessment of Contributory Factors and Dose-Response Relationship , Ben-Sheetrit J, Aizenberg D, Csoka AB, Weizman A, Hermesh H., 2015