Post-SSRI sexual dysfunction

Post-SSRI sexual dysfunction (PSSD) [Bahrick AS. " [http://www.division55.org/Tablet/Vol7No3.pdf Post SSRI Sexual Dysfunction.] " American Society for the Advancement of Pharmacotherapy Tablet 2006; 7:2-10.] 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.

Symptoms

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
* Priapism
* Damaged DNA within Sperm causing infertility [http://www.newscientist.com/channel/sex/mg19926754.500-antidepressants-may-harm-male-fertility.html] .

Prevalence

The true prevalence of PSSD has yet to be determined, although published calls have been made for post-marketing epidemiological studies [Kauffman, RP. " [http://www.primarypsychiatry.com/aspx/articledetail.aspx?articleid=1479 Persistent Sexual Side Effects after Discontinuation of Psychotropic Medications] " Primary Psychiatry. 2008;15:24.] .

Initial underestimation of the incidence of sexual side-effects

It is widely 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 these 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 some have found that they are present in up to 60% [Zajecka J, Mitchell S, Fawcett J. "Treatment-emergent changes in sexual function with selective serotonin reuptake inhibitors as measured with the rush sexual inventory" Psychopharmacol. Bull. 1997;33:755-60. PMID 9493488.] 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. [Balon, R. "SSRI-associated sexual dysfunction" Am J Psychiatry. 2006;163:1504-1509. PMID 16946173.]

tudy data

While sexual dysfunction can be fairly 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. However, emerging evidence suggests that such persistence may in fact be fairly common and has been heretofore overlooked for a variety of reasons [Bahrick AS " [http://www.bentham-open.org/pages/contentb.php?TOPSYJ/2008/00000001/00000001 Persistence of Sexual Dysfunction Side Effects after Discontinuation of Antidepressant Medications: Emerging Evidence.] " The Open Psychology Journal. 2008;1:42-50.] . 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. [Montejo AL, Llorca G, Izquierdo JA, Carrasco JL, Daniel E, Perez-Sola V, Vicens E, Bousono M, Sanchez-Iglesias S, Franco M, Cabezudo A, Rubio V, Ortega MA, Puigdellivol M, Domenech JR, Allue B, Saez C, Mezquita B, Galvez I, Pacheco L, de Miguel E. "Sexual dysfunction with antidepressive agents. Effect of the change to amineptine in patients with sexual dysfunction secondary to SSRI." Actas Esp Psiquiatr. 1999;27:23-34. PMID 10380144.] In recent placebo controlled double-blind studies testing the efficacy of SSRIs for treating premture ejaculation, it has been noted that the ejaculation-delaying effect of the medications may last a long time after discontinuation in a large percentage of the trial participants [Safarinejad MR, Hosseini SY. "Safety and efficacy of citalopram in the treatment of premature ejaculation: a double-blind placebo-controlled, fixed dose, randomized study." Int J Impot Res. 2006;18:164-9. PMID 16107866.] [ Arafa M, Shamloul R. "Efficacy of sertraline hydrochloride in treatment of premature ejaculation: a placebo-controlled study using a validated questionnaire." Int J Impot Res. 2006;18:534-8. PMID 16554853.] [Safarinejad MR. "Safety and efficacy of escitalopram in the treatment of premature ejaculation: a double-blind, placebo-controlled, fixed-dose, randomized study." J Clin Psychopharmacol. 2007;27:444-50. PMID 17873675] . Another study by the Cornell Medical Center in New York suggests that use of SSRI's damages fertility by causing damage to the DNA in the sperm.

It should be noted that persistent side effects are rarely reported by clinical trials. However, this could be attributed to the fact that trials are normally terminated on or before completion of treatment, which may have led to gross bias.

Case Reports

Published Reports

The first three cases of typical hyposexuality caused by PSSD were published in May 2006,Csoka AB, Shipko S. " [http://content.karger.com/ProdukteDB/produkte.asp?Doi=91777 Persistent sexual side effects after SSRI discontinuation.] " Psychother Psychosom 2006;75:187-8. PMID 16636635.] A fourth case was published soon after [Bolton JM, Sareen J, Reiss JP. " [http://www.informaworld.com/smpp/content~content=a748909592~db=all~order=page Genital anaesthesia persisting six years after sertraline discontinuation.] " J. Sex Marital Ther. 2006;32:327-30. PMID 16709553.] and a fifth case was published in late 2007 [Kauffman RP, Murdock A. " [http://www.bentham-open.org/pages/content.php?TOWHJ/2007/00000001/00000001/1TOWHJ.SGM Prolonged Post-Treatment Genital Anesthesia and Sexual Dysfunction Following Discontinuation of Citalopram and the Atypical Antidepressant Nefazodone.] " The Open Women’s Health Journal. 2007;1:1-3.] . In early 2008, three more cases were published [Csoka AB, Bahrick AS, Mehtonen O-P. " [http://www.blackwell-synergy.com/doi/abs/10.1111/j.1743-6109.2007.00630.x Persistent Sexual Dysfunction after Discontinuation of Selective Serotonin Reuptake Inhibitors (SSRIs).] " J Sex Med. 2008; 5:227-33.] in the Journal of Sexual Medicine, selected from a Yahoo Group comprised of over [http://health.groups.yahoo.com/group/SSRIsex/ 1700 PSSD sufferers] . There have also been several published cases of Persistent Genital Arousal Disorder (PGAD) [Goldmeier D, Leiblum SR. "Persistent genital arousal in women - a new syndrome entity" Int J STD & AIDS 2006; 17:215-6. PMID 16595040.] [Goldmeier D, Bell C, Richardson D. "Withdrawal of selective serotonin reuptake inhibitors (SSRIs) may cause increased atrial natriuretic peptide (ANP) and persistent sexual arousal in women?" J Sex Med. 2006;3:376. PMID 16490037.] [Leiblum SR, Goldmeier D."Persistent genital arousal disorder in women: case reports of association with anti-depressant usage and withdrawal."J Sex Marital Ther. 2008;34:150-9 PMID 18224549.] and premature ejaculation [Adson DE, Kotlyar M. " [http://www.theannals.com/cgi/content/abstract/37/12/1804 Premature ejaculation associated with citalopram withdrawal.] " Ann Pharmacother. 2003;37:1804-6. PMID 14632589.] that start and last long after withdrawal from SSRIs. These symptoms are quite different from, and should not be confused with, hypersexuality.

urveillance and Reporting

To establish, monitor, and regulate causation of PSSD in individual patients, one approach in use by [http://www.psychosomaticmedicine.org/cgi/content/full/63/6/896 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, [https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm 3500] for optional use (patients can self-report using this form), and 3500A, for mandatory reporting.

Cause

It is currently not known precisely what causes PSSD. Unaware of the possibility of these long-lasting effects, most physicians automatically attribute them to psychological causes.

Fluoxetine (Prozac), the prototypical SSRI, is classified as a reproductive toxin [Hines RN, Adams J, Buck GM, Faber W, Holson JF, Jacobson SW, Keszler M, McMartin K, Segraves RT, Singer LT, Sipes IG, Williams PL. " [http://cerhr.niehs.nih.gov/chemicals/fluoxetine/fluoxetine_monograph.pdf NTP-CERHR Expert panel report on the reproductive and developmental toxicity of fluoxetine.] "NIH Publication No. 05-4471. 2004;1-211.] 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.

Animal studies

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. [Maciag D, Simpson KL, Coppinger D, Lu Y, Wang Y, Lin RC, Paul IA. "Neonatal Antidepressant Exposure has Lasting Effects on Behavior and Serotonin Circuitry." Neuropsychopharmacology. 2006;31:47-57. PMID 16012532.] [de Jong TR, Snaphaan LJ, Pattij T, Veening JG, Waldinger MD, Cools AR, Olivier B. "Effects of chronic treatment with fluvoxamine and paroxetine during adolescence on serotonin-related behavior in adult male rats." Eur Neuropsychopharmacol. 2006;16:39-48. PMID 16107310.] 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 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 [Gouvêa TS, Morimoto HK, de Faria MJ, Moreira EG, Gerardin DC. "Maternal exposure to the antidepressant fluoxetine impairs sexual motivation in adult male mice." Pharmacol Biochem Behav. 2008 Apr 4. [Epub ahead of print] PMID 18457868] .It is not known whether PSSD in rodents exactly recapitulates the human condition, but the long term neurobehavioral consequences are very similar. [Maciag D, Coppinger D, Paul IA. "Evidence that the deficit in sexual behavior in adult rats neonatally exposed to citalopram is a consequence of 5-HT(1) receptor stimulation during development." Brain Res. 2006;1125:171-5. PMID 17101120.]

Epigenetic effects

Long-term alterations in gene expression may result from disturbances in 5-HT neurotransmission in the brain. [Hansen HH, Mikkelsen JD. "Long-term effects on serotonin transporter mRNA expression of chronic neonatal exposure to a serotonin reuptake inhibitor." Eur J Pharmacol. 1998;352:307-15. PMID 9716368.] For example, chronic treatment with fluoxetine (Prozac) has been shown to cause persistent desensitization of 5HT1A receptors even after removal of the SSRI. [Raap DK, Garcia F, Muma NA, Wolf WA, Battaglia G, van de Kar LD. "Sustained desensitization of hypothalamic 5-Hydroxytryptamine1A receptors after discontinuation of fluoxetine: inhibited neuroendocrine responses to 8-hydroxy-2-(Dipropylamino)Tetralin in the absence of changes in Gi/o/z proteins." J Pharmacol Exp Ther. 1999;288:561-7. PMID 9918559.] 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. [Faure C, Ouissame MF, Nasser H. "Long-term adaptive changes induced by serotonergic antidepressant drugs." Expert Rev Neurother. 2006;6:235-45. PMID 16466303. ] [Palotas M, Palotas A, Puskas LG, Kitajka K, Pakaski M, Janka Z, Molnar J, Penke B, Kalman J. "Gene expression profile analysis of the rat cortex following treatment with imipramine and citalopram." Int J Neuropsychopharmacol. 2004;7:401-13. PMID 15315716.] [Kalman J, Palotas A, Juhasz A, Rimanoczy A, Hugyecz M, Kovacs Z, Galsi G, Szabo Z, Pakaski M, Feher LZ, Janka Z, Puskas LG. "Impact of venlafaxine on gene expression profile in lymphocytes of the elderly with major depression--evolution of antidepressants and the role of the "neuro-immune" system." Neurochem Res. 2005;30:1429-38. PMID 16341940.] [Yamada M, Yamada M, Higuchi T. "Antidepressant-elicited changes in gene expression: remodeling of neuronal circuits as a new hypothesis for drug efficacy." Prog Neuropsychopharmacol Biol Psychiatry. 2005;29:999-1009. PMID 15975701.] [Boehm C, Newrzella D, Herberger S, Schramm N, Eisenhardt G, Schenk V, Sonntag-Buck V, Sorgenfrei O. "Effects of antidepressant treatment on gene expression profile in mouse brain: cell type-specific transcription profiling using laser microdissection and microarray analysis." J Neurochem. 2006; 97 Suppl 1:44-9. PMID 16515540.] Some of these gene expression changes are a result of altered DNA structure caused by chromatin remodeling, [Hyman SE. "Even chromatin gets the blues." Nat Neurosci. 2006;9:465-6. PMID 16568101.] [Newton SS, Duman RS. "Chromatin Remodeling: A Novel Mechanism of Psychotropic Drug Action (Relates to article by Cassel, et al. FastForward 2 May 2006)". Mol Pharmacol. 2006;70:440-3. PMID 16728645.] specifically epigenetic modification of histones [Tsankova NM, Berton O, Renthal W, Kumar A, Neve RL, Nestler EJ. "Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action." Nat Neurosci. 2006;9:519-25. PMID 16501568.] and gene silencing by DNA methylation due to increased expression of the methyl binding proteins MeCP2 and MBD1. [Cassel S, Carouge D, Gensburger C, Anglard P, Burgun C, Dietrich JB, Aunis D, Zwiller J. "Fluoxetine and cocaine induce the epigenetic factors MeCP2 and MBD1 in adult rat brain." Mol Pharmacol. 2006;70:487-92. PMID 16670375.] Altered gene expression and chromatin remodeling are also involved in the mechanism of action of electroconvulsive therapy (ECT). [Altar CA, Laeng P, Jurata LW, Brockman JA, Lemire A, Bullard J, Bukhman YV, Young TA, Charles V, Palfreyman MG. "Electroconvulsive seizures regulate gene expression of distinct neurotrophic signaling pathways." J Neurosci. 2004;24:2667-77. PMID 15028759.] [Tsankova NM, Kumar A, Nestler EJ. "Histone modifications at gene promoter regions in rat hippocampus after acute and chronic electroconvulsive seizures." J Neurosci. 2004;24:5603-10. PMID 15201333.]

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,Csoka AB, Shipko S. "Persistent sexual side effects after SSRI discontinuation." Psychother Psychosom 2006;75:187-8. PMID 16636635.] such as decreased testosterone levels [Cohen AJ. " [http://www.priory.com/psych/sexdys.htm Antidepressant-Induced Sexual Dysfunction Associated with Low Serum Free Testosterone.] " Psychiatry Online 1999.] and reduced sperm counts. [Tanrikut C, Schlegel PN. "Antidepressant-associated changes in semen parameters." Urology. 2007;69:185.e5-7. PMID 17270655.] However, without detailed neuropsychopharmacological, pharmacogenomic and toxicogenomic [Szyf M. " [http://www.ingentaconnect.com/content/ben/cpg/2004/00000002/00000004/art00006 Toward a Discipline of Pharmacoepigenomics.] " Current Pharmacogenomics 2004;2:357-377.] 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 and deceiving the public. [Lacasse JR, Leo J. " [http://medicine.plosjournals.org/archive/1549-1676/2/12/pdf/10.1371_journal.pmed.0020392-S.pdf Serotonin and Depression: A Disconnect between the Advertisements and the Scientific Literature.] " PLoS Medicine 2005;2:e392.] 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 difficult 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. [Moncrieff J, Cohen D. " [http://medicine.plosjournals.org/archive/1549-1676/3/7/pdf/10.1371_journal.pmed.0030240-p-S.pdf Do Antidepressants Cure or Create Abnormal Brain States?] " PLoS Medicine 2006;3:e240.] One possible mechanism is by inhibition of dopaminergic neurotransmission, [Damsa C, Bumb A, Bianchi-Demicheli F, Vidailhet P, Sterck R, Andreoli A, Beyenburg S. "Dopamine-dependent" side effects of selective serotonin reuptake inhibitors: a clinical review." J Clin Psychiatry. 2004;65:1064-8. PMID 15323590.] resulting in described persistent sexual dysfunction. This may suggest possible treatment options, reviewed theoretically in 2002. [ Keltner NL, McAfee KM, Taylor CL. "Mechanisms and treatments of SSRI-induced sexual dysfunction." Perspect Psychiatr Care. 2002 Jul-Sep;38(3):111-6. PMID 12385082.]

Other drugs

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.

References

External links

* [http://www.psas.nl/ Persistent Sexual Arousal Syndrome] "Language: Dutch and English" - PSAS may be a link to withdrawal from Selective Serotonin Reuptake Inhibitors.