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Guided by two university librarians, we did preliminary searches in PubMed, Embase, Biosis, Zoological Records, Web of Science and PsycINFO in order to identify the most relevant search criteriaand databases. We did our final searches in PubMed and Embase. PubMed is the biggest database ofmedical animal studies; two other big databases of animal studies are Embase and Web of Science. Wechose Embase because of its good search options, map terms, and its inclusion of many European andpharmacological journals not found in PubMed. We excluded PsycINFO, Web of Science, Biosis andZoological Records, as it has never been shown that it adds anything to search in multiple databases,compared to searching only two and track references in the included articles.We searched the two databases for selective serotonin reuptake inhibitors and serotonin
norepinephrine reuptake inhibitors (SNRIs) combined with sexual dysfunction and animal usingappropriate subheadings.
2.1. Search strategy
2. Methods
different studies [5, 6, 11~13]. A study of 1,022 patients who all had a normal sex life before they startedon antidepressants found sexual dysfunction in 59% of the patients [6] on direct questioning; only 20%reported such effects spontaneously [6]. The weighted average occurrence of sexual problems for thefive most commonly used drugs was: 57% experienced decreased libido; 57% experienced delayedorgasm or ejaculation; 46% experienced no orgasm or ejaculation; and 31% experienced erectiledysfunction or decreased vaginal lubrication [2]. About 40% of the patients considered their sexualdysfunction unacceptable [6].
There is concern that the sexual harms might persist after discontinuation of therapy. Two studieswith three cases each reported on persistent sexual dysfunction long after discontinuation of SSRls [14,15]. Another paper listed 120 cases of enduring sexual dysfunction following drug treatment reportedto RxISK.org, and 101 of these were related to SSRIs and similar drugs [16]. The length of treatmentprior to the dysfunction ranged from 3 days to 15 years, and in many instances these problems firstoccurred when treatment was stopped [16]. In the internet community, [email protected],with over 3500 members, patients also complain about sexual problems that persist long after the endof therapy.The persistent effects of SSRls on sexuality have been little studied in humans, and patients might
not associate them with a drug they no longer take. Animal studies suggest that SSRls might causepermanent sexual dysfunction after ending SSRl exposure at an early age [17~21]. Unfortunately,the methodological quality of animal studies is generally poor [22~24]. The National Centre for theReplacement, Refinement and Reduction of Animals in Research (NC3Rs; http://www.nc3rs.org.ukl).a UK government sponsored organization, found that most studies did not use randomization (87%)or blinding (86%) [22].Initiatives have been undertaken to promote the use of similar standards for systematic reviews of
animal studies as those used in Cochrane reviews of human studies, e.g. The Collaborative Approachto Meta-analysis and Review of Animal Data from Experimental Studies (CAMARADES; www.Camarades.info) and the Systematic Review Centre for Laboratory animal Experimentation researchgroup (SYRCLE; www.umcn.nllResearchlDepartments/cdllSYRCLE).
Systematic reviews of animal studies could make significant contributions to healthcare [25] andcould also identify biasing factors in these studies [26, 27]. We have not found any systematic reviewsof sexual dysfunction in animal studies after early exposure to SSRls and therefore decided to performour own.
A.L. Simonsen et al. I Persistent sexual dysfunction after early exposure to SSRls2
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3.4.1. Binary dataAll studies with binary data had used rats treated prenatally or neonatally, assessed as adults. They
examined the effect of citalopram or fluoxetine at different concentrations [17, 20, 21, 31, 36, 39]. Forrats exposed to SSRls compared with those exposed to placebo, we found a higher risk of no mountingbehaviour (RR=0.73; 95% CI=0.62-0.86; 5 studies, with 106 rats in the SSRI groups and 54 in theplacebo groups), (Fig. 1), no intromission behaviour (RR=0.74; 95% CI = 0.60-0.92; 4 studies, with106versus 53 rats) (Fig. 2), and no ejaculation behaviour (RR=0.49, 95% CI = 0.24-1.00; 3 studies,with 92 versus 42 rats) (Fig. 3).
3.4. Quantitative data synthesis
The general quality of the included studies was poor. Only 4 studies reported use of randomisation,but gave no further explanation [34, 37, 38, 40]; which makes allocation concealment unclear in allstudies. All studies used placebo control groups and were therefore blinded; four mentioned explicitlythe use of blinded outcome assessment [31,34, 37,39]. Nine articles had no conflictsof interest section;in the remaining 5 studies, the authors declared to have no conflict of interest [17, 20, 21, 34, 35].One study didn't mention funding [38], two studies were funded by pharmaceutical companies [32,40] whereas the remaining 11 studies were publicly funded. Ten studies did not mention whether anyanimals were excluded; in two studies, animals were excluded if they had no sexual activity [19, 21];one study did not mention the reasons why some animalswere excluded [18]; and one studymentionedthat no animals were excluded [32].
3.3. Quality assessment
All 14 studies were published in English from 2006 to 2013. All studies used an SSRI, most commonly fluoxetine or citalopram, and all had a placebo treated control group. In 7 studies, the drug wasgiven subcutaneously [17, 19,20,31,36,38,39], in 6 orally [18,21,32,34,35,40] and 1 intraperitoneally [37]. The animals were treated in the prenatal period in 3 studies [18, 35, 38], in the neonatalperiod in7 studies (between day 1and 21) [17, 19,20,31,34,36,39], in one study inboth the prenataland neonatal period [21], in the adolescent period in 2 studies (between days 33 and 62) [32, 37] andas adults (8 weeks old) in one study [40]. All studies assessed sexual behaviour in adults, which wererodents in all studies: 12 used rats (5 Long-Evans rats, 5 Wistar rats, 2 Sprague Dawley rats) and 2used mice (lC57 BL/6N mice and 1Swiss mice) [18,19]. The size of experimental and control groupsvaried from 5 to 22.
3.2. Study characteristics
In our searches, we identified 154 citations; 145 in PubMed and 9 additional ones in Embase. Weexcluded 140 for various reasons: not an SSRI or SNRI, no follow-up period without drug, not ananimal study, not measuring sexual behaviour.We excluded two more studies; one because it was notbased on mammals but on fruit flies (Drosophila melanogaster) and another because the female miceassessed were hormonally primed. We found two additional studies from other sources. This gave usa total of 14 animal studies for our systematic review [17-21, 31, 32, 34-40].
3.1. Result of the searches
3. Results
A.L. Simonsen et al. / Persistent sexual dysfunction after early exposure to SSRls4
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Itwas a strength that the included studies were similar in many ways; all used rodents, most animalswere treated in the prenatal or neonatal period and were assessed as adults, most studies assessed theeffect of citalopram or ftuoxetine, and all of them studied SSRls. Compared to studies in humans, therisk of introducing bias after the randomisation is lower, i.e. there are usually no potentially distortingfactors such as concomitantmedication, concurrent illnesses, or differential exposure to environmentalfactors due to the effects of the experimental drug [41]. Itwas a strength that all studies were placebocontrolled, which suggests that outcome assessment was blinded, as there would otherwise be nogood reason to blind the treatments. Another strength was that only two studies were funded bypharmaceutical companies (these reported more positive results for the drugs than other studies).
4.1. Study strengths and limitations
4. Discussion
below. The data rather consistently showed permanent impairment of sexual function in terms ofnumber of or average rates of mounting, intromission and ejaculation (Tables 1-3) and time to firstmounting, intromission and ejaculation (Tables 4-6). Trials sponsored by the drug industry tended toshow markedly different results than other trials, in some cases reporting an improvement in sexualfunction while other trials showed an impairment.For the number of or average rates of intromission and ejaculations, one study, which did not find
significant differences, provided no data [35]. For time to firstmounting, one study found a significantincreased latency when comparing citalopram 20mg/kg to control, but not for 10 and 5mg/kg, butprovided no data [20].For time to intromission, two studies found no significant difference butprovidedno data [17, 20]; and for time to ejaculation, one study provided no data [20].
6 A.L. Simonsen et al. / Persistent sexual dysfunction after early exposure to SSRls
Table 1Mean number or rate of mountings at longest follow-up
Experimental Control
Study Treatment/cone. Total Mean Mean Total
Chan, 2009 [40] PAR/l0 mg/kg 12 8,1 12 12de Jong T, 2006 [32] PAR/iS mg/kg 16
~: I7,6
~: Ide Jong T, 2006 [32] FLUV/30 mg/kg 16 7,6Gouvea, 2008 [18] FLX/7,Smg/kg 9 4,9 5,6 7Harris, 2011 [20] CTM/20 mg/kg 11 9 31 16Harris, 2011 [20] CTM/l0 mg/kg is 9,4 31 16Harris, 2011 [20] CTM/5 mg/kg 16 18 31 16
Maciag, 2006 B [36] CTM/5 mg/kg 5 35 49 5Maciag, 2006 C [39} CTM/5 mg/kg 14 24 46 11Olivier, 2011 [35} FLX/12mg/kg 9 1,2 0,92 11Rayen I, 2013 [34] FLX/5mg/kg 10 5,3 8,7 10Soga T, 2012 [19} CTM/l0 rng/kg 15 20 43 15
The boxes indicate that the data comes from the same control group. Chan and de long were sponsoredby a drug company, all other studies in the table were public funded [32,40].
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The boxes indicate that the data comes from the same control group, compared to different treatmentsor different concentrations of the same treatment. Data in the table are given in seconds. Chan and deJong were sponsored by drug companies, all other studies in the table were public funded [32,40].
Acknowledgn
Our resultsthese drugs m.after the patiepermanent har[47-49]. Tbes(these drugs an,
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PAR/l0 mg/kgPAR/15mg/kgFLUV/30mg/kgFLX/10mg/kgFLX/12mg/kgFLX/5mg/kgCTM/l0 mg/kgFLX/7,5mg/kg
Chan,2009 [40]de JongT, 2006 [32]de JongT, 2006 [32}Iniguez, 2010 [37]Olivier, 2011 [35]RayenI, 2013 [34]SogaT, 2012 [19]Vieira, 2012 [21J
TotalMean 4.3. Implicati.Control
MeanTotalTreatment/cone.
Experimental
Study
Table 6Mean latency to first ejaculation at longest follow-up
711101510
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12 229 39 12PAR/l0 mg/kgFLX/7,5mg/kgCTM/5 mg/kgFLX/5 rng/kgCTM/l0 mg/kgFLX/7,5mg/kg
Chan,2009 [40]Gouvea,2008 [18]Maciag, 2006 C [39]RayenI, 2013 [34]SagaT, 2012 [19]Vieira, 2012 [21]
Total Mean Mean Total
Experimental Control
Treatment/cone.Study
Table 5Mean latency to first intromission at longest follow-up. Data in the table are given in seconds. Chan
were sponsored by drug companies, all other studies in the table were public funded [40]
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During OUI
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28215840
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3801790153210531607230
9105141016
12 35 19 12PAR/l0 mg/kgFLX/7,5mg/kgFLX/10mg/kgCTM/5 mg/kgCTM/5 mg/kgFLX/5mg/kgCTM/l0 mg/kg
Chan,2009 [40]Gouvea, 2008 [18]Iniguez, 2010 [37]Maciag, 2006 B [36]Maciag, 2006 C [39]RayenI, 2013 [34]SogaT, 2012 [19]
4.2. InterpreTotal Mean Mean Total
Control
Treatment/cone.
Experimental
Study
There arestudies werewas not c1ea:
Table 4Mean time to first mounting at longest follow-up. Data in the table are given in seconds. Chan
were sponsored by drug companies, all other studies in the table were public funded [40]
AL Simonsen et al. / Persistent sexual dysfunction after early exposure to SSRls8
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[1] Healy D. Let them eat Prozac. New YorkUniversity Press, 2004.(2] Getzsche Pc. Deadly Psychiatry and Organised Denial. People's Press, 2015.[3] RavenM. Depression and antidepressants inAustralia andbeyond - acritical public health analysis.Doctor ofPhilosophy
thesis, Faculty of Arts, University ofWollongong, 2012. http://ro.uow.edu.au/thesis/3686[4] Snoeren EMS, Veening JG, Olivier B, Oosting RS. Serotonin lA receptors and sexual behavior in male rats: A review.
Pharmacology, Biochemistry and Behavior. 2014;121:102-14.[5] Montejo AL, Llorca G, Izquierdo JA, Ledesma A, BousofioM, Calcedo A, Carrasco JL, Ciudad J, Daniel E, Gandara
JDLA, Derecho J, FrancoM, GomezMJ,Macias JA,Martin T,Perez V,Sanchez 1M,Sanchez S,VicensE. SSRl-inducedsexual dysfunction: Fluoxetine, paroxetine, sertraline, and fiuvoxamine in a prospective, multicenter, and descriptiveclinical study of 344 patients. Journal of Sex&Marital Therapy. 1997;23(3):176-94.
(6] Montejo AL, Llorca G, Izquierdo JA, Rico-Villademoros F. Incidence of sexual dysfunction associated with antidepressant agents: A prospective multicenter study of 1022 outpatients. Journal of Clinical Psychiatry. 2001;62(Supp13):10-21.
[7] Montgomery SA,Baldwin DS, Riley A.Antidepressant medications: A review of the evidence for drug-induced sexualdysfunction. Joumal of Affective Disorders. 2002;69: 119-40.
[8] Corona G, Ricca V, Bandini E, Mannucci E, Lotti F, Boddi V,Rastrelli G, Sforza A, Faravelli C, Forti G, Maggi M.Selective serotonin reuptake inhibitor-induced sexual dysfunction. JoumaJ of Sexual Medicine. 2009;6:1259-69.
[9] Breggin PR, Breggin GR. Talking Back to Prozac. e-book. e-reads.com, 2010.[10] Medawar C. Marketing depression and making medicines work. Intemational Journal of Risk & Safety in Medicine.
1997;10:75-126.[II] Williams VSL, Baldwin DS, Hogue SL, Fehnel SE, Hollis KA, Edin HM. Estimating the prevalence and impact of
antidepressant-induced sexual dysfunction in 2 European countries: A cross-sectional patient survey.Journal of ClinicalPsychiatry. 2006;67:204-10.
(12] Osvath P, Fekete S, Voros V, Vitrai J. Sexual dysfunction among patients treated with antidepressants - a Hungarianretrospective study.European Psychiatry. 2003;18:412-4.
[13] Lee KU, Lee YM, Nam 1M,Lee HK, Kweon YS, Lee CT, Jun TY. Antidepressant-induced sexual dysfunction amongnewer antidepressants in a naturalistic setting. Psychiatry Investigation. 2010;7:55-9.
(14] Csoka AB, Bahrick A, Mehtonen OP.Persistent sexual dysfunction after discontinuation of selective serotonin reuptakeinhibitors. Journal of Sexual Medicine. 2008;5:227-33.
[15] Csoka AB, Shipko S. Persistent sexual side effects after SSRI discontinuation. Psychotberapy and Psychosomatics.2006;75:187-8.
[16] Hogan C, Le Noury J, Healy D, Mangin D. One hundred and twenty cases of enduring sexual dysfunction followingtreatment. Intemational Journal of Risk & Safety in Medicine. 2014;26:109-16.
[17] Maciag D, Simpson KL, Coppinger D, Lu Y,WangY,Lin RCS, Paul lA. Neonatal antidepressant exposure has lastingeffects on behavior and serotonin circuitry. Neuropsychopbarmacology. 2006;31(1):47-57.
[18] Gouvea TS, Morimoto HK, de Faria MJSS, Moreira EG, Gerardin DCC. Maternal exposure to the antidepressantfluoxetine impairs sexual motivation in adult male mice. Pharmacology, Biochemistry and Behavior. 2008;90:416-9.
[19] SogaT,WongDW,Putteeraj M, Song KP, Parhar IS. Early-life citalopram-induced impairments in sexual behavior andthe role of androgen receptor. Neuroscience. 2012;225:172-84.
[20] Harris SS, Maciag D, Simpson KL, Lin RCS, Paul lA. Dose-dependent effects of neonatal SSRl exposure on adultbehavior in the rat. Brain Research. 2012;1429:52-60.
[21] Vieira ML, Hamada RY,Gonzaga NI, Bacchi AD, Barbieri M, Moreira EG, Mesquita SDFP, Gerardin DCC. Couldmaternal exposure to the antidepressants fluoxetine and St. John's Wort induce long-term reproductive effects on malerats? Reproductive Toxicology. 2013;35:102-7.
References
This study was carried out without any specific funding at the Nordic Cochrane Centre.
Funding
Authors have declared they have no financial conflicts of interest.
Conflict of interest
A.L. Simonsen et al. / Persistent sexual dysfunction after early exposure to SSRls10
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Pharmacosala MonitorAugust, 201:nNigeria, tand Drugs Areactions in •
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Abstract.BACKGROUevent and a dn:2SeSwhich haOBJECTIVE:je intention te)IETHODS: ..:::d )IovernberRESULTS:Efreponed in 8 tils:- stem adversezse with Cotrir;::gmentation v:our times to c,CO),"CLUSIOesabhsh appro
Received 15NAccepted 7 Jat
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International JDOl IO.3233/.lOS Press[46] EI-Mallakh RS, Gao Y, Jeannie Roberts R. Tardive dysphoria: The role of long term antidepressant use in-inducing
chronic depression. Medical Hypotheses. 2011;76:769-73.[47] Lane RM. SSRI-Induced extrapyramidal side-effects and akathisia: Implications for treatment. Journal ofPsychophar
macology.1998;12(2):192-214.[48] Gerber PE, Lynd LD. Selective serotonin-reuptake inhibitor - induced movement disorders. The Annals of Pharma
cotherapy. 1998;32:692-8.[49] Lee Y, Lin PY, Chang YY, Chong MY, Cheng AT. Antidepressant-induced tardive syndrome: A retrospective epidemi
ological study. Pharmacopsychiatry. 2013;46:281-5.
12 A.L. Simonsen et at. / Persistent sexual dysfunction after early exposure to SSRls
