Post-SSRI sexual dysfunction
Post-SSRI sexual dysfunction (PSSD) is a name given to a reported iatrogenic sexual dysfunction caused by the previous use of selective serotonin reuptake inhibitor (SSRI) antidepressants. While apparently uncommon, it can last for months, years, or sometimes indefinitely after the discontinuation of SSRIs. It may represent a specific subtype of SSRI discontinuation syndrome. This condition has not been well-established or studied in the field of medicine.
One or more of the following sexual symptoms attributed to PSSD after the discontinuation of SSRIs include:
- Decreased libido
- Impotence or reduced vaginal lubrication
- Difficulty initiating or maintaining an erection or becoming aroused
- Persistent sexual arousal syndrome despite absence of desire
- Muted, delayed or absent orgasm (anorgasmia)
- Reduced or no experience of pleasure during orgasm (ejaculatory anhedonia)
- Premature ejaculation
- Weakened penile, vaginal or clitoral sensitivity
- Genital anesthesia
- Loss or decreased response to sexual stimuli
The true prevalence of PSSD has yet to be determined, although published calls have been made for post-marketing epidemiological studies. It is known that SSRIs can cause various types of sexual dysfunction. Initial studies found that such side effects were reported in less than 10% of patients. When doctors have specifically asked about treatment-emergent sexual difficulties, some have found that they are present in up to 60% of patients. Spontaneous reporting methods are believed to result in lower reporting rates than targeted questions, either due to recall bias or stigma regarding sexual dysfunction.
While sexual dysfunction can be common while taking SSRIs, the problem of persistent dysfunction after discontinuation does not appear to be as frequent, or at least not as well-known. Onset of sexual problems often occurs during, and sometimes after, extended SSRI use but there have been reports of rapid onset as well. It appears as though the majority of people regain their sexual function after stopping SSRIs, but some do not, and are faced with the persistent symptoms of post-SSRI sexual dysfunction (PSSD). In one study in which patients with SSRI-induced sexual dysfunction were switched to the dopaminergic antidepressant amineptine, 55% still had at least some type of sexual dysfunction after six months compared to 4% in the control group treated with amineptine alone. In recent placebo controlled double-blind studies testing the efficacy of SSRIs for treating premature ejaculation, it has been noted that the ejaculation-delaying effect of the medications may last for months after discontinuation in a percentage of the trial participants.
Three cases of hyposexuality following SSRI use and a fourth case describing genital anesthesia following SSRI use were described in 2006. A fifth case of similar findings was published in late 2007. In early 2008, three more cases were published in the Journal of Sexual Medicine, selected from a Yahoo Group composed of over 3500 PSSD sufferers. There have also been several published cases of Persistent Genital Arousal Disorder (PGAD) and premature ejaculation that start and last long after withdrawal from SSRIs. These symptoms are quite different from, and should not be confused with, hypersexuality.
Surveillance and reporting
To establish, monitor, and regulate causation of PSSD in individual patients, one approach in use by consulation-liaison psychiatrists is to assay measurable parameters of patient health (hormone levels, sexual functioning) with a survey or laboratory tests before and after administering a psychiatric drug, based on individual patient concern regarding each of the listed side effects. If PSSD develops, a correlation can be established between assay results and PSSD, guiding further treatment for the individual patient and others. A lack of education on drug side effects and the presence of clinical depression in a patient who is a candidate for antidepressant therapy can combine to reduce the patient's ability to advocate for tests. Calls have been made for better informed consent regarding the possibility of permanent sexual dysfunction when prescribing SSRIs to potential patients. Post-administration reporting of side effects may provide useful data for development of new drugs and better inform patients of their risks. In The United States, adverse effects are reported with FDA forms, 3500 for optional use (patients can self-report using this form), and 3500A, for mandatory reporting.
It is currently not known what causes PSSD. Fluoxetine (Prozac), the prototypical SSRI, is classified as a reproductive toxin by the Center for the Evaluation of Risks to Human Reproduction (CERHR), an expert panel at the National Institute of Environmental Health Sciences at the National Institutes of Health.
Experiments with rodents have shown that chronic treatment with SSRIs at a young age results in permanently decreased sexual behavior that persists into adulthood and is similar to PSSD. These studies found reductions in both the rate-limiting serotonin synthetic enzyme, tryptophan hydroxylase, in dorsal raphe and in serotonin transporter (SERT) expression in the cortex. It also appears as though PSSD might be transgenerationally inherited, at least in rodents, since maternal exposure to fluoxetine impairs sexual motivation in adult male mice. It is not known whether these findings in rodents recapitulates the human condition, but the long term neurobehavioral consequences may be similar.
There are physiological changes while on SSRIs. It has been postulated that drugs can exert epigenetic effects.
Changes include reduced hypothalamic-pituitary-testis axis (HPTA) function, decreased testosterone levels, reduced sperm counts, which showed marked improvement after discontinuation and reduced semen quality with damaged sperm DNA, which is reversible after discontinuation.
Treatment with fluoxetine (Prozac) has been shown to cause persistent desensitization of 5HT1A receptors after removal of the SSRI in rats. These long-term adaptive changes in 5-HT receptors, as well as more complex, global changes, are thought to be mediated through alterations of gene expression. Some of these gene expression changes are a result of altered DNA structure caused by chromatin remodeling, specifically epigenetic modification of histones and gene silencing by DNA methylation due to increased expression of the methyl binding proteins MeCP2 and MBD1. Altered gene expression and chromatin remodeling may also be involved in the mechanism of action of electroconvulsive therapy (ECT).
Because described gene expression changes are complex, and can involve persistent modifications of chromatin structure, it has been suggested that SSRI use can result in persistently altered cerebral gene expression leading to compromised catecholaminergic neurotransmission and neuroendocrine disturbances, However, without detailed neuropsychopharmacological, pharmacogenomic and toxicogenomic research, the definitive cause remains unknown.
Relationship to "chemical imbalance" theory
Some critics of SSRIs claim that the widely-disseminated television and print advertising of SSRIs promotes an inaccurate message, oversimplifying what these medications actually do. Much of the criticism stems from questions about the validity of claims that SSRIs work by correcting chemical imbalances. Without tools to accurately measure neurotransmitter levels and to allow for continuous monitoring during treatment, it remains difficult to know if one is correctly targeting a deficient neurotransmitter (i.e. correcting an imbalance) or reaching a desirable level of a particular neurotransmitter. It has been argued that without this knowledge for each patient, SSRIs can actually cause chemical imbalances and abnormal brain states. One possible mechanism is by inhibition of dopaminergic neurotransmission, resulting in described persistent sexual dysfunction.
Antipsychotics are also known to cause sexual dysfunction that is similar to PSSD, especially because of their antagonist effects on D2 dopamine receptors, as well as H1, α1 and α2 antagonism. Finasteride, which is used to treat male pattern baldness and benign prostatic hypertrophy, has also been found to cause persistent sexual dysfunction in a subset of patients that are treated with the drug.
There is no known cure for PSSD, mostly because its etiology is still poorly understood. Possible treatment options for SSRI-induced sexual dysfunction have been reviewed theoretically. However, there has been a lack of randomized, placebo-controlled, double-blind trials of potential treatments. Of those that have been done, there is evidence for the following management strategies: for erectile dysfunction, the addition of a PDE5 inhibitor such as sildenafil; for decreased libido, possibly adding or switching to Wellbutrin (Bupropion); and for overall sexual dysfunction, switching to nefazodone.
According to a survey of psychiatrists, Bupropion is the drug of choice for the treatment of SSRI-induced sexual dysfunction, although this is not an FDA-approved indication. Thirty-six percent of psychiatrists preferred switching patients with SSRI-induced sexual dysfunction to bupropion, and 43 percent favored the augmentation of the current medication with bupropion. A higher dose of bupropion (minimum 300 mg) may be necessary: a randomized study with 31 subjects that utilized a lower dose (150 mg) once daily failed to find a significant difference between bupropion, sexual therapy or combined treatment, while a subsequent study with 234 subjects and employing Bupropion SR 150 mg twice daily did show a significant improvement of sexual function.
Some other off-label prescriptions include pramipexole, ropinirole, yohimbine and possibly other molecules increasing the dopamine blood levels, though there have been no double blind placebo-controlled trials to show their efficacy. The chemical cabergoline, which is an agonist of D2 receptors, which in turn decreases prolactin, has fully restored orgasm in 1/3rd of anorgasmic subjects, and partially restored orgasm in another 1/3rd of subjects. 
Most studies of sexual dysfunction have been done in men, though some studies done in women have shown benefit from bupropion (at doses >300 mg/d) or Olanzapine (>5 mg/d). There has been 1 study showing possible benefit in orgasmic function with sildanefil, though no change in desire or arousal.
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