Data Based Medicine Americas Ltd. The undersigned submits this petition to request the Commissioner of Food and Drugs to immediately require the addition of boxed warnings, warnings, precautions, and highlights of prescribing information to the product label for all serotonin reuptake inhibitor SSRI and serotonin-norepinephrine reuptake inhibitor SNRI products, including branded and generic formulations.
These include, but are not limited to, citalopram Celexadesvenlafaxine Pristiqduloxetine Cymbaltaescitalopram Lexaprofluoxetine Prozacparoxetine Paxilsertraline Zoloftvenlafaxine Effexorand vortioxetine Trintellix. Require the immediate revision of all SSRI and SNRI product labels including branded and generic formulations to warn of serious and severe risks, as follows:.
This was first established in healthy volunteer phase 1 trials in the s. Current product labeling warns of disturbances to sexual functioning, but these warnings are insufficient. The ability of a serotonin reuptake inhibitor to reduce genital sensation was identified as far back as A study investigated the use of clomipramine as a possible treatment for premature ejaculation [ 1 ].
Post ssri sexual dysfunction celexa testing was used to assess penile sensory threshold before and after treatment. While clomipramine is classed as a tricyclic antidepressant, it is a potent serotonin reuptake inhibitor.
The current was then decreased until it could no longer be perceived. This second figure was taken as a measurement of penile sensory threshold. The study found that the drug had increased penile sensory threshold from Ina similar study involving fluoxetine found an increase in penile sensory threshold from 4. The fluoxetine study also had the benefit of a control group placebo for whom penile sensory threshold remained unchanged. In addition, there were multiple case reports of genital anesthesia during the s linked to each of the major SSRIs [ 3—9 ], including one that involved reduced nipple sensitivity [ 8 ].
These date from toand involve the use of sertraline, and paroxetine. Clinical experience suggests that almost everyone who takes an SSRI or SNRI experiences a degree of reduced genital sensitivity, often occurring within 30 minutes of taking the first dose.
In this sense, almost everyone taking a serotonin reuptake inhibitor has altered sexual functioning. Despite this, and the fact there is an indication for a serotonin reuptake inhibitor for premature ejaculation based on this effect ie. This has never been properly investigated. Pre-medication sexual functioning baselines are rarely taken; there are no queries in any standard sexual functioning instruments related to genital numbness or orgasmic anhedonia; there is rarely any follow-up, and no-one has systematically asked whether the sexual side effects have resolved — or if anyone has, the data has not been published.
Ina case report from Bolton et al appeared in the medical literature describing a year-old male with persistent sexual side effects following treatment with sertraline [ 10 ]. Sexual dysfunction had emerged early in treatment, which was continued for around four or five "Post ssri sexual dysfunction celexa." Symptoms of genital anesthesia, pleasureless orgasm, delayed orgasm, and loss of libido had persisted for six years after withdrawal of the drug.
The subject was in no doubt that sertraline was responsible, and the authors of the case report acknowledged having been torn, but they tentatively opted for a psychodynamic interpretation of the ongoing symptoms because they found nothing in the literature at that time to support the notion of enduring SSRI sexual side effects.
However, they noted that an enduring pharmacological effect could not be ruled out as an alternative explanation. Three case reports followed from Csoka and Shipko [ 11 ]. She noted that these are
Post ssri sexual dysfunction celexa typical features of sexual dysfunction, and are not associated with conditions for which antidepressants are prescribed.
The article also drew attention to a study by Montejo et al which inadvertently appeared to discover evidence of post-treatment changes to sexual function [ 13 ]. A group of patients who were experiencing sexual side effects on an SSRI were switched to the dopaminergic antidepressant, amineptine.
InKauffman and Murdock reported the case of a year-old female who developed genital anesthesia, diminished orgasmic intensity, difficulty achieving orgasm, and a substantial decrease in libido within days of starting citalopram [ 14 ]. All of these difficulties remained essentially unchanged after discontinuation of the drug, with the subject continuing to experience low libido, minimal genital tactile sensation, and orgasmic dysfunction.
Physical and psychological testing did not reveal a cause. Inthree more cases persistent sexual dysfunction following SSRIs were reported by Csoka et al. A review article published by Bahrick in the same year highlighted the significance of two large placebo controlled studies into the use of SSRIs as a treatment for premature ejaculation [ 16 ].
The studies by Safarinejad and Hosseini [ 17 ], and by Arafa and Shamloul [ 18 ], found that the ejaculation-delaying effects of citalopram and sertraline, respectively, persisted for a significant number of participants at 3- and 6-month follow-up after the drugs had been withdrawn. A similar study by Safarinejad involving escitalopram has since been published with the same "Post ssri sexual dysfunction celexa" [ 19 ].
A study by Tanrikut et al which aimed to investigate the effects of paroxetine on sperm also assessed sexual function before, during, and after the five-week treatment period [ 20 ].
Of note, SSRIs have been shown to have adverse effects on semen quality and sperm DNA fragmentation, which may be detrimental to male fertility [ 21—24 ]. There were published calls for epidemiological studies Post ssri sexual dysfunction celexa investigate the prevalence of PSSD, from Kauffman in [ 25 ], and from Farnsworth and Dinsmore in [ 26 ].
Inthe US Prozac product information [ 27 ] was amended to warn that:. The findings were subsequently published in the medical literature by Ekhart and van Puijenbroek [ 29 ]. The drugs involved were paroxetine, sertraline, venlafaxine, citalopram, fluoxetine, fluvoxamine, and escitalopram. Fifteen reports came from consumers, with the remainder from general practitioners, a pharmacist, and a pharmaceutical company. There were 13 male subjects and six Post ssri sexual dysfunction celexa, aged from 20 to 59 years.
Duration of treatment ranged from 9 days to 10 years, and the time since stopping the drug and still experiencing sexual side effects ranged from two months to two years. Also inStinson authored a qualitative study on the impact of persistent sexual side effects of selective serotonin reuptake inhibitors after discontinuing treatment [ 31 ].
Four male and five female PSSD sufferers were assessed, aged from 22 to 59 years.
The drugs involved were citalopram, escitalopram, fluoxetine, paroxetine, and sertraline. Symptoms included genital anesthesia, orgasmic anhedonia, anorgasmia, erectile dysfunction, and hypoactive desire.
Six of the subjects reported having the condition for over a year since stopping the medication, with the longest being three years and nine months. InHogan et al published a study of cases of enduring sexual dysfunction, including 90 involving serotonin reuptake inhibitors.
Also inWaldinger et al. A year-old male developed penile anesthesia and scrotum hypesthesia on paroxetine which persisted after stopping the drug. He had attempted to assess the level of insensitivity by applying Tiger Balm to his penis, but felt nothing except a vague sensation over his scrotum. A small degree of tactile sensitivity was regained following treatment with low-power laser irradiation, though there was no improvement in sexual responsiveness.
InBen-Sheetrit et al published a study of possible cases of PSSD including 23 high-probability cases from an online survey [ 34 ]. There were 19 male subjects and four female, aged from 21 to 47 years, all whom had normal scores on depression and anxiety scales, and did not have confounding conditions, medications, or addictive substance use.
The shortest duration of treatment was 4 days of sertraline.
The longest time since stopping an SSRI and still experiencing sexual side effects was 16 years. The subject had no concurrent physical illness, no medication or recreational drug use, and was free of affective symptoms.
The authors concluded that the previous use of paroxetine was the most likely cause. A letter available on request from Dr. Of these, indicated that the sexual dysfunction persisted after discontinuation of the drug, and in cases it was unknown whether the reaction continued after the drug was withdrawn. In Februarya review article about PSSD by Coskuner et al raised concerns about the possibility of long-term sexual consequences for people exposed to SSRIs during pregnancy or at a young age [ 38 ].
In MayHealy et al published a study of cases of enduring sexual dysfunction of which were after the previous use of serotonin reuptake inhibitors [ 39 ]. Treatment with fluoxetine has been shown to cause persistent desensitization of 5-HT1A receptors after removal of the SSRI in rats [ 40 ]. Rodent studies have shown that treatment with SSRIs at a young age resulted in permanently decreased sexual behavior in adulthood [ 41—43 ], including the presence Post ssri sexual dysfunction celexa long-term neurological changes [ 41 ].
Maternal exposure to fluoxetine was also found to impair sexual motivation in adult male mice [ 44 ]. InSimonsen et al published a systematic review of 14 animal studies measuring sexual behavior after
Post ssri sexual dysfunction celexa of treatment with SSRIs [ 45 ]. PGAD is a condition involving an uncontrollable and relentless feeling of physiological arousal in the genitals, but without any accompanying feeling of sexual desire.
It is the mirror image of PSSD.
The use of SSRIs or SNRIs, and often their withdrawal, has consistently been reported as one of the triggers of the condition, which can endure for years after the medication has been discontinued. Desperate women with PGAD have resorted to treatment with clitoridectory, pudendal nerve ablation, electroconvulsive therapy ECTand other drastic measures. The condition was first described by Leiblum and Nathan inand was originally called persistent sexual arousal syndrome PSAS [ 46 ].
Later that year, Goldmeier and Leiblum noted that within a small study group consisting of physicians and PGAD sufferers, several people had reported that their unprovoked genital arousal began when an SSRI was discontinued [ 49 ].
InMahoney and Zarate described a year-old female who developed unrelenting and unwanted sensations of genital arousal when her dose of Post ssri sexual dysfunction celexa was increased [ 50 ].
These sensations remitted upon Post ssri sexual dysfunction celexa the dose. All five cases involved female subjects. In four of the cases, development of the condition was specifically linked to withdrawal of the drug [ 51 "Post ssri sexual dysfunction celexa." InEibye and Jensen reported the case of a year-old woman who developed PGAD upon withdrawal of paroxetine [ 53 ].
A variety of treatments were tried including ECT, but with only temporary improvement. The aforementioned paper from Healy et al included six reports of PGAD linked to the previous use of serotonin reuptake inhibitors [ 39 ]. FDA updated the product information for finasteride products in to warn of persisting sexual side effects after discontinuation of treatment, with further warnings added in [ 56 ]. A similar post-treatment sexual dysfunction following isotretinoin has been reported in the literature [ 32, 39 ].
In SeptemberHealy wrote to all companies producing serotonin reuptake inhibitors, drawing their attention to the existence of these problems on medicines that have originated with them. Some explored the issue of seeking further details on the patients, but have not followed up on this.