Post SSRI sexual dysfunction
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Steven C. Campbell, M.D., Ph.D.
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Post SSRI Sexual Dysfunction (PSSD) is an iatrogenic type of sexual dysfunction caused directly 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.
One or more of the following sexual symptoms persist or begin after the discontinuation of SSRIs.
- Decreased or absent 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
- Reduced semen volume
It is well known that SSRIs can cause various types of sexual dysfunction. Initial studies found that such side effects occur in less than 10% of patients, but those studies relied on unprompted reporting, so the frequency of such problems was underestimated. In more recent studies, doctors have specifically asked about treatment-emergent sexual difficulties, and found that they are present in up to 60% of patients. Spontaneous reporting methods are believed to result in up to 60% differences in sexual dysfunction rates as compared to rates obtained with systematic inquiry.
However, while sexual dysfunction is obviously very 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 or researched. Onset of sexual problems often occurs during, and sometimes after, extended SSRI use but there have been reports of fairly 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.
It should be noted that persistent side effects are rarely reported by clinical trials because trials are normally terminated on or before completion of treatment, which may have led to gross bias. The true prevalence of PSSD has yet to be determined.
The first case of PSSD, long-term premature ejaculation beginning after discontinuation of citalopram, was published in 2003. Three cases of severe hyposexuality caused by PSSD were published in May 2006, and a fifth case was published soon after. A sixth case was published in late 2007, and three more cases were published in early 2008. There have also been several published cases of Persistent Genital Arousal Disorder (PGAD) that lasts long after withdrawal from SSRIs. These symptoms are quite different from, and should not be confused with, hypersexuality.
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.
Post-administration reporting of side effects provides useful data for development of new drugs and patient decisions. In America, adverse effects are reported with FDA forms, 3500 for optional use (patients can self-report using this form), and 3500A, for mandatory reporting.
The ICD-9 codes used for classifying, diagnosing, and reporting sexual dysfunction are available at Chrisendres.com and other sources.
Although 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, it is currently not known what causes PSSD. Unaware of the possibility of this long-lasting effect, most physicians automatically attribute it to psychological causes. But 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. At the cerebral molecular level there are profound and permanent reductions in both the rate-limiting serotonin synthetic enzyme, tryptophan hydroxylase, in dorsal raphe and in serotonin transporter (SERT) expression in cortex. It is not known whether PSSD in rodents exactly recapitulates the human condition, but the long term neurobehavioral consequences are very similar. Long-term alterations in gene expression may result from disturbances in 5-HT neurotransmission in the brain of the animals.
For example, chronic treatment with fluoxetine (Prozac) has been shown to cause persistent desensitization of 5HT1A receptors even after removal of the SSRI. These long-term adaptive changes in 5-HT receptors, as well as more complex, global changes, are likely 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 are also 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, such as decreased testosterone levels and reduced sperm counts. However, without detailed neuropsychopharmacological, pharmacogenomic and toxicogenomic research, the definitive cause remains unknown.
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 and deceiving the public. 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 is impossible to know if one is correctly targeting a deficient neurotransmitter (i.e. correcting an imbalance), reaching a desirable level, or even introducing too much of a particular neurotransmitter. Thus it has been argued that 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. This may suggest possible treatment options, reviewed theoretically in 2002. 
Antipsychotics are also known to cause sexual dysfunction. Many antipsychotics affect serotonin neurochemistry, much like SSRIs. This could be a possible culprit in sexual dysfunction in such cases. Current antipsychotics predominantly affect dopamine neurochemistry; this can also have an effect on sexual response.
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- PSSD Video
- Persistent Sexual Arousal Syndrome Language: Dutch and English - PSAS may be a link to withdrawal from Selective Serotonin Reuptake Inhibitors.
Cost Effectiveness of Post SSRI sexual dysfunction
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