Post SSRI sexual dysfunction

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Steven C. Campbell, M.D., Ph.D.

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Overview

Post SSRI Sexual Dysfunction (PSSD)[1] 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.

Prevalence

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%[2] 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[3].

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[4].

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.

Case Reports

The first case of PSSD, long-term premature ejaculation beginning after discontinuation of citalopram, was published in 2003.[5] Three cases of severe hyposexuality caused by PSSD were published in May 2006,[6] and a fifth case was published soon after.[7] A sixth case was published in late 2007[8], and three more cases were published in early 2008[9]. There have also been several published cases of Persistent Genital Arousal Disorder (PGAD) that lasts long after withdrawal from SSRIs.[10][11][12] 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.

Cause

Although fluoxetine (Prozac), the prototypical SSRI, is classified as a reproductive toxin [13] 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[14][15]. 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[16]. Long-term alterations in gene expression may result from disturbances in 5-HT neurotransmission in the brain of the animals.[17]

For example, chronic treatment with fluoxetine (Prozac) has been shown to cause persistent desensitization of 5HT1A receptors even after removal of the SSRI.[18] 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[19][20][21][22][23]. Some of these gene expression changes are a result of altered DNA structure caused by chromatin remodeling,[24][25] specifically epigenetic modification of histones[26] and gene silencing by DNA methylation due to increased expression of the methyl binding proteins MeCP2 and MBD1.[27] Altered gene expression and chromatin remodeling are also involved in the mechanism of action of electroconvulsive therapy (ECT).[28] [29]

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,[6] such as decreased testosterone levels[30] and reduced sperm counts[31]. However, without detailed neuropsychopharmacological, pharmacogenomic and toxicogenomic[32] 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.[33] 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.[34] One possible mechanism is by inhibition of dopaminergic neurotransmission,[35] resulting in described persistent sexual dysfunction. This may suggest possible treatment options, reviewed theoretically in 2002. [36]

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

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  2. 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.
  3. Balon, R. SSRI-associated sexual dysfunction Am J Psychiatry. 2006;163:1504-1509. PMID 16946173.
  4. 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.
  5. Adson DE, Kotlyar M. Premature ejaculation associated with citalopram withdrawal. Ann Pharmacother. 2003;37:1804-6. PMID 14632589.
  6. 6.0 6.1 Csoka AB, Shipko S. Persistent sexual side effects after SSRI discontinuation. Psychother Psychosom 2006;75:187-8. PMID 16636635.
  7. Bolton JM, Sareen J, Reiss JP. Genital anaesthesia persisting six years after sertraline discontinuation. J. Sex Marital Ther. 2006;32:327-30. PMID 16709553.
  8. Kauffman RP, Murdock A. 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.
  9. Csoka AB, Bahrick AS, Mehtonen O-P. Persistent Sexual Dysfunction after Discontinuation of Selective Serotonin Reuptake Inhibitors (SSRIs). J Sex Med. 2008; 5:227-33.
  10. Goldmeier D, Leiblum SR. Persistent genital arousal in women - a new syndrome entity Int J STD & AIDS 2006; 17:215-6. PMID 16595040.
  11. 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.
  12. 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.
  13. Hines RN, Adams J, Buck GM, Faber W, Holson JF, Jacobson SW, Keszler M, McMartin K, Segraves RT, Singer LT, Sipes IG, Williams PL. NTP-CERHR Expert panel report on the reproductive and developmental toxicity of fluoxetine.NIH Publication No. 05-4471. 2004;1-211.
  14. 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.
  15. 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.
  16. 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.
  17. 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.
  18. 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.
  19. Faure C, Ouissame MF, Nasser H. Long-term adaptive changes induced by serotonergic antidepressant drugs. Expert Rev Neurother. 2006;6:235-45. PMID 16466303.
  20. 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.
  21. 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.
  22. 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.
  23. 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.
  24. Hyman SE. Even chromatin gets the blues. Nat Neurosci. 2006;9:465-6. PMID 16568101.
  25. 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.
  26. 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.
  27. 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.
  28. 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.
  29. 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.
  30. Cohen AJ. Antidepressant-Induced Sexual Dysfunction Associated with Low Serum Free Testosterone. Psychiatry Online 1999.
  31. Tanrikut C, Schlegel PN. Antidepressant-associated changes in semen parameters. Urology. 2007;69:185.e5-7. PMID 17270655.
  32. Szyf M. Toward a Discipline of Pharmacoepigenomics. Current Pharmacogenomics 2004;2:357-377.
  33. Lacasse JR, Leo J. Serotonin and Depression: A Disconnect between the Advertisements and the Scientific Literature. PLoS Medicine 2005;2:e392.
  34. Moncrieff J, Cohen D. Do Antidepressants Cure or Create Abnormal Brain States? PLoS Medicine 2006;3:e240.
  35. 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.
  36. 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.

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