Switching to Vortioxetine in Patients with Poorly Tolerated Antidepressant-Related Sexual Dysfunction in Clinical Practice: A 3-Month Prospective Real-Life Study.

Ci a ion: Mon ejo, A.L.; Sánchez- Sánchez, F.; De Ala cón, R.; Ma ías, J.; Co és, B.; Ma os, C.; Ma ín-Pin o, T.; Ríos, P.; González-Ga cía, N.; Acos a, J.M. Swi ching o Vo ioxe ine in Pa ien s wi h Poo ly Tole a ed An idep essan -Rela ed Sexual Dys unc ion in Clinical P ac ice: A 3-Mon h P ospec i e Real-Li e S udy. J. Clin. Med. 2024,13, 546. h ps:// doi.o g/10.3390/jcm13020546 Academic Edi o : Ana Adan Recei ed: 28 No embe 2023 Re ised: 13 Janua y 2024 Accep ed: 16 Janua y 2024 Published: 18 Janua y 2024 Copy igh : © 2024 by he au ho s. Licensee MDPI, Basel, Swi ze land. This a icle is an open access a icle dis ibu ed unde he e ms and condi ions o he C ea i e Commons A ibu ion (CC BY) license (h ps:// c ea i ecommons.o g/licenses/by/ 4.0/). Jou nal o Clinical Medicine A icle Swi ching o Vo ioxe ine in Pa ien s wi h Poo ly Tole a ed An idep essan -Rela ed Sexual Dys unc ion in Clinical P ac ice: A 3-Mon h P ospec i e Real-Li e S udy Angel L. Mon ejo 1,2,3,* , F oilán Sánchez-Sánchez 4, Rubén De Ala cón2, Juan Ma ías 2, Benjamin Co és2, Claudia Ma os 2, Tomás Ma ín-Pin o 2, Peñi as Ríos 5, Ne ea González-Ga cía6and JoséMa ía Acos a 3 1Nu sing School, Uni e si y o Salamanca, A . Donan es de Sang e SN, 37004 Salamanca, Spain 2Se icio de Psiquia ía, Hospi al Uni e si a io de Salamanca, 37007 Salamanca, Spain; ubenala [email p o ec ed] (R.D.A.); [email p o ec ed] (J.M.); [email p o ec ed] (B.C.); [email p o ec ed] (C.M.); [email p o ec ed] (T.M.-P.) 3Ins i u o de In es igación Biomédica de Salamanca (IBSAL), Paseo de San Vicen e SN, 37007 Salamanca, Spain; [email p o ec ed] 4Cen o de Salud Xà i a, Xà i a, 46800 Valencia, Spain; [email p o ec ed] 5Hospi al Uni e si a io Cáce es, 10004 Cáce es, Spain; [email p o ec ed] 6S a is ical Depa men , Uni e si y o Salamanca, 37004 Salamanca, Spain; ne ea_gonzalez_ga [email p o ec ed] *Co espondence: [email p o ec ed]; Tel.: +34-639-754-620 Abs ac : T ea men -eme gen sexual dys unc ion (TESD) is one o he mos equen and pe sis en ad e se e ec s o an idep essan medica ion. Sexual dys unc ion (SD) seconda y o SSRIs occu s in >60% o sexually ac i e pa ien s and >80% o heal hy olun ee s, wi h his causing ea men discon inua ion in >35% o pa ien s. Howe e , his ac o is a ely add essed in ou ine examina ions, and only 15–30% o hese e en s a e spon aneously epo ed. A s a egy o swi ching o a di e en non-se o one gic an idep essan could in ol e a isk o elapse o clinical wo sening due o a lack o se o one gic ac i i y. Vo ioxe ine appea s o ha e less impac on sexual unc ion due o i s mul imodal mechanism o ac ion. No s udies ha e been published on he e ec i eness o swi ching o o ioxe ine in pa ien s wi h poo ly ole a ed long- e m an idep essan - ela ed SD in na u alis ic se ings. S udy objec i es: To de e mine he e ec i eness o swi ching o o ioxe ine due o SD in a ou ine clinical p ac ice se ing. Me hodology: obse a ional p agma ic and na u alis ic s udy o de e mine he e ec i eness o he swi ch o o ioxe ine (mean dosage 13.11 ± 4.03) in 74 pa ien s aged 43.1 ± 12.65 (54% males) a isk o discon inuing ea men due o sexual dys unc ion. The PRSexDQ*- SALSEX scale (*Psycho opic-Rela ed Sexual Dys unc ion Ques ionnai e) was applied a wo momen s: baseline isi and a e 3 mon hs o ollow-up. Resul s: global Sexual Dys unc ion (SD) measu ed wi h he SALSEX scale dec eased signi ican ly be ween he baseline isi (10.32; SD 2.73) and he ollow-up isi (3.78; SD 3.68), p< 0.001. The e was a signi ican imp o emen (p< 0.001) a he endpoin including dec eased libido, delay o o gasm, ano gasmia and a ousal di icul ies in bo h sexes. A e swi ching o o ioxe ine, 83.81% o pa ien s expe ienced an imp o emen in sexual unc ion (43.2% el g ea ly imp o ed). Mos pa ien s (83.3%) who swi ched o o ioxe ine con inued ea men a e he ollow-up isi . A o al o 58.1% o pa ien s showed an imp o emen in dep essi e symp oms om he baseline isi . Conclusion: swi ching o o ioxe ine is an e ec i e and eliable s a egy o ea pa ien s wi h poo ly ole a ed p e ious an idep essan - ela ed sexual dys unc ion in eal-li e clinical se ings. Keywo ds: sexual dys unc ion; an idep essan ; o ioxe ine; dep ession; sexuali y 1. In oduc ion An idep essan s a e equen ly associa ed wi h sexual dys unc ion (SD), pa icula ly SSRI se o one gic agen s, dual-ac ion d ugs, and clomip amine [ 1 ]. O he d ugs wi h J. Clin. Med. 2024,13, 546. h ps://doi.o g/10.3390/jcm13020546 h ps://www.mdpi.com/jou nal/jcm J. Clin. Med. 2024,13, 546 2 o 17 di e en mechanisms o ac ion appea o cause ewe sexual ad e se e ec s (mi azapine, bup opion, moclobemide). Un o una ely, he eal incidence o SD is unde es ima ed, and speci ic ques ionnai es mus be used. Spon aneous epo ing o his ad e se e ec is a ound 15–20%, while eal igu es exceed 60–80% [ 2 , 3 ]. The p oblem is signi ican and i is closely associa ed wi h ea men d opou , pa icula ly in he case o long- e m ea men s, and has a nega i e impac on he quali y o li e o pa ien s and hei pa ne s [4]. Vo ioxe ine (VOR) seems o ha e a be e p o ile in e ms o SD, al hough mos da a comes om clinical ials wi h egis a ion pu poses ha may ha e some me hodological limi a ions, such as he dep essi e popula ion examined and sho - e m da a [ 5 ]. SD a es a y be ween 0.9% and 45%, depending on he s udy me hodology. Since he se o one gic mechanism o ac ion seems o be closely linked wi h he e iology and pa hogenesis o dep ession [ 6 ], d ugs inc easing se o onin a ailabili y a e gene ally associa ed wi h high a es o SD, as his neu o ansmi e is e y closely in ol ed wi h inhibi ion o sexual unc ion, impulsi i y, and appe i e, among o he s. The physiopa hogenic mechanisms o hese phenomena appea o be mul i ac o ial and complex [ 7 ]. One mechanism is he inc ease in ci cula ing se o onin and he ac i a ion o se o onin 5-HT2A ecep o s, which could a ec o gasmic unc ion and sexual in e es . E ec ile dys unc ion appea s o be caused by changes in ni ic oxide unc ioning and ac i a ion o pe iphe al ad ene gic ecep o s. Managemen o SD has been a emp ed using a ious app oaches [ 8 ]: wai ing o spon aneous emission, dose educ ion, o swi ching o ano he d ug wi h a lowe p o ile o impac on sexual unc ioning, o use o “an ido es” such as sildena il o o he simila compounds [ 4 , 9 ]. Gi en he high a es o sexual dys unc ion nowadays, which a e usually le unadd essed by clinicians, and i s impac on pa ien s’ quali y o li e and ea men discon inua ion (es ima ed a o e 35%), his p oblem mus be di ec ly in es iga ed in all pa ien s who ecei e an idep essan s. In he las 10 yea s, a e y signi ican inc ease has been obse ed in he numbe o publica ions add essing his opic, and ising a es o SD ha e been de ec ed wi h he use o speci ic ques ionnai es [ 10 – 12 ], compa ed o he ini ial es ima es ob ained om spon aneous pa ien epo s. Ini ial da a on he incidence o SD ob ained e ospec i ely anged widely: be ween 5% and 75% depending on he s udy me hodology used. In p e ious s udies using he alida ed ques ionnai e Psycho opic-Rela ed Sexual Dys unc ion Ques ionnai e (PRSexDQ-SALSEX) [ 10 ], he mean incidence o SD wi h SSRIs and dual-ac ion agen s was 62.9–80% among sexually ac i e pa ien s [ 3 , 13 ]. Ne e heless, only 14–40% o hese pa ien s spon aneously epo ed any dys unc ion in ei he males o emales. Women li ing wi h psychia ic illness conside sexuali y o be an impo an pa o hei quali y o li e [14]. An Ame ican g oup led by Ani a Clay on (Uni e si y o Vi ginia) also used a speci ic ques ionnai e, he Changes in Sexual Func ion Ques ionnai e (CSFQ) [ 12 ]. A e sc eening a popula ion sample wi h inclusion and exclusion c i e ia, hei esul s we e simila o he Spanish se ies, and con ibu ed da a on he low p e alence o bup opion-associa ed SD, which was shown o be lowe han 10% [ 15 ]. Su p isingly, epo s om medical eco ds o se o one gic an idep essan use ob ained h ough he esul s o egis a ion clinical ials e e o a e y low incidence o SD (2–16%) [ 16 ]. These di e ences in incidence compa ed o hose ob ained in eal clinical p ac ice a e due o he lack o use o speci ic ques ionnai es o measu e sexual dys unc ion and a e based on spon aneous communica ion om pa ien s. The PRSexDQ-SALSEX ques ionnai e analyzes he ollowing a iables on a scale o se e i y o equency: (1) lowe libido; (2) delayed o gasm/ejacula ion; (3) absen o - gasm/ejacula ion; (4) e ec ile/ aginal lub ica ion dys unc ion; and (5) pa ien ’s ole abili y o sexual dys unc ion and isk o discon inuing ea men . The au ho and he wo king g oup ha e published nume ous s udies ha use his me hod o e alua e equency o SD, isk o discon inua ion, impac on quali y o li e, s udies in heal hy olun ee s, clinical managemen p ocedu es, and global e iew s udies, such as ha in Wo ld Psychia y 2018 [4]. J. Clin. Med. 2024,13, 546 3 o 17 The ques ionnai e has been ansla ed in o mul iple languages, including F ench, English, I alian, Ge man, Po uguese, G eek, Swedish, Finnish, Polish, and Japanese, and has ecen ly also been alida ed in Manda in Chinese. Al hough SD is a common side e ec o all SSRIs and dual-ac ion d ugs, he highes a es ha e been epo ed wi h pa oxe ine o se e al easons: i s powe ul se o one gic ac ion, i s e ec on inc easing p olac in and inhibi ing ni ic oxide, and i s g ea e an icholin- e gic e ec . The mos common p oblems a e educed desi e and delay in achie ing o gasm. E ec ile dys unc ion is less common, al hough a es associa ed wi h pa oxe ine, ci alop am, and enla axine a s anda d he apeu ic doses we e a ound 30–40%. Absen o gasm o ejacula ion is clea ly he mos poo ly ole a ed side e ec in pa ien s o bo h gende s. In con as , he a es o SD caused by mi azapine, bup opion, and agomela ine a e lowe han hose o SSRIs [ 1 ], due o hei di e en mechanisms o ac ion: mi aza- pine blocks pos synap ic 5-HT2 ecep o s ( he s imula ion o which has been closely ela ed wi h he de elopmen o ejacula ion and o gasm changes); bup opion has a dopamine gic/ad ene gic ac ion; and agomela ine is a mela onin ecep o agonis and HT2C an agonis . The e appea o be di e ences be ween gende s. Males o e 40 yea s o age gene ally ole a e SD wo se han emales [ 3 ], bu his is no obse ed in younge indi iduals, and a leas one hi d o pa ien s conside ed discon inuing ea men o his eason. In con as , o he pa ien s, such as hose wi h p ema u e ejacula ion, accep ed hei SD well: he delay in achie ing ejacula ion expe ienced a e s a ing an idep essan ea men “no malized” hei ejacula o y ime. Su eys conduc ed in la ge pa ien se ies epo discon inua ion igu es be ween 41.7% and 50.8% [14]. In clinical p ac ice, doc o s a e o en unawa e and unable o manage he appea ance o hese side e ec s. This app oach would a oid he possibili y o pa ien s discon inuing ea men , pa icula ly among hose who equi e i in he long e m. Wi h ega ds o clinical managemen , he ea men o SD caused by an idep essan s has no been examined using con olled and ex ensi e s udies. Scan da a a e a ailable o guide clinicians on he mos app op ia e choice in each case, and no con olled clinical ials ha e been pe o med in his a ea. In he ELIXIR s udy [ 17 ] clinicians we e asked abou hei ea men choice in cases o SD due o an idep essan s. The esul s indica ed ha mos psychia is s op ed o no in e en ion, and p e e ed o wai o spon aneous emission, and a small pe cen age chose o swi ch ea men o o add an an ido e. In Spain, [ 3 ] a clinical s udy wi h mo e han 2000 pa ien s ound a a e o SD o o e 80% in pa ien s who we e ecei ing SSRIs o dual-ac ion agen s. Spanish doc o s op ed o wai o spon aneous emission in 25% o cases o swi ched o bup opion o agomela ine in 30% o cases. Resul s we e be e o agomela ine (80% educ ion in SALSEX sco es) [ 18 , 19 ]. The use o PDE5 inhibi o s such as sildena il, o weekend d ug holidays, was e y a e. The main objec i e o his s udy is o analyze whe he swi ching o ano he an ide- p essan wi h a di e en mechanism o ac ion is use ul in clinical p ac ice, educing he equency o sexual dys unc ion and main aining an idep essan e icacy a e swi ching. The expe ience in ou coun y shows ha while pa ien s wi h a leas 3 mon hs ollowing can bene i om swi ching o o he non-se o one gic an idep essan s in o de o imp o e SD, hey can be a isk o clinical de e io a ion o dep essi e elapses in one in h ee cases. The e o e, new he apeu ic al e na i es mus be ound. In he absence o me a-analyses and speci ically designed clinical ials, he ecommenda ions ob ained om analyzed da a om published s udies sugges di e en le els o e idence including swi ching o ano he an idep essan (agomela ine, bup opion o mi azapine), weekend d ug holidays (use ul in he absence o o gasm), and PD5Inhibi o s, among o he s. Due o he lack o an e ec i e ea men wi h a o able, pe sis en esul s in an ide- p essan ea men -eme gen SD, newe p oduc s wi h di e en mechanisms o ac ion ha could ha e less e ec on sexual unc ioning mus be explo ed. One o hem is o ioxe ine, which has a mul imodal mechanism o ac ion on di e en ecep o s, wi h ull agonis e ec J. Clin. Med. 2024,13, 546 4 o 17 on 5-HT1A, pa ial an agonism on 5-HT1B, and an agonis e ec s on 5HT1D, 5-HT3 and 5-HT7, in addi ion o displaying dopamine gic, ad ene gic, his amine gic, and choline gic e ec s. Gi en he lack o cu en e idence ega ding his opic, speci ic s udies in ou- ine clinical p ac ice and in ca e ully selec ed popula ions a e equi ed o con i m hese p elimina y da a. 2. S udy Ra ionale Vo ioxe ine is a ecen ly de eloped an idep essan wi h a no el mechanism o ac ion. Da a om clinical ials o egis a ion pu poses sugges a neu al, o e en bene icial, e ec on sexual unc ioning in dep essi e pa ien s ecei ing o ioxe ine [ 20 , 21 ], which has since been p o ed again in a ecen phase IV andomized s udy [ 22 ]. A swi ching s udy showed ha o ioxe ine is a sa e and e ec i e swi ch he apy o ea ing SSRI-induced sexual dys unc ion in adul s wi h well- ea ed MDD [ 23 ]. Also, imp o emen in sexual dys unc ion wi h o ioxe ine o esci alop am may be in luenced by p io SSRI usage, sex, age ( ≤ 45 yea s, women), and his o y o one o h ee majo dep essi e episodes [ 24 ]. Fo example, a ecen s udy in pos menopausal ansi ion women obse ed less an idep essan - induced SD wi h o ioxe ine when compa ed o pa oxe ine [ 25 ], al hough he exac dose was no speci ied. Howe e , o e all limi ed da a ha e been published o da e ega ding he e ec s o his an idep essan on sexual unc ioning. Vo ioxe ine, wi h his no el mechanism o ac ion, could ha e some implica ions o less sexual dys unc ion. In a ecen andomized, double-blind ial wi h o ioxe- ine (15–20 mg/day), ea men -eme gen sexual dys unc ion symp oms we e no signi i- can ly di e en e sus placebo using he ASEX Scale [ 26 ]. In an open-label, lexible-dose (2.5–10 mg/day), 52-week ex ension s udy ha e alua ed he long- e m sa e y and ole a- bili y o o ioxe ine, he a e o ad e se e en s ela ed o sexual dys unc ion was low [ 27 ]. Mo eo e , a ecen p ospec i e epidemiological s udy shows ha emales (bu no males) ea ed wi h o ioxe ine p esen ed be e sexual unc ion han hose ea ed wi h SSRIs o Duals and a lowe isk o sexual dys unc ion [28]. In a ecen e iew [ 29 ], au ho s s a ed ha o ioxe ine is well ole a ed, bu is as- socia ed wi h signi ican ly inc eased sexual dys unc ion a a dosage o 20 mg; howe e , o ioxe ine was shown o imp o e p e ious- ea men -eme gen sexual dys unc ion in pa ien s wi h well- ea ed MDD o a g ea e deg ee han esci alop am. These s udies show some limi a ions when s udying his opic, such as lack o a con ol g oup wi h sexually ac i e pa ien s in a na u alis ic se ing, so u he speci ic s udies a e needed. The e o e, he aim o his s udy is o de e mine he equency and in ensi y o sexual dys unc ion (SD) a e swi ching o o ioxe ine om ano he an idep essan due o TESD. 3. S udy Objec i es 3.1. P ima y Objec i e • To analyze he e ec i eness o he an idep essan swi ch s a egy o o ioxe ine o he imp o emen o sexual dys unc ion (measu ed as o al SALSEX sco e) a e 3 mon hs o ollow-up in pa ien s wi h poo ole ance o isk o ea men discon inua ion ( he isk o discon inua ion is de ined as a sco e ≥2 in i em 5 o he SALSEX). 3.2. Seconda y Objec i es □ To s udy he indi idual ole ance and isk o ea men discon inua ion using he PSRSexDQ-SALSEX ques ionnai e a baseline and o he endpoin . □ To de e mine di e ences in SD be ween males and emales a baseline and o he endpoin . □ To de e mine di e ences in SD be ween di e en age g oups a baseline and o he endpoin . □ To de e mine di e ences in SD be ween di e en le els o se e i y o dep ession a baseline and o he endpoin . □ To de e mine di e ences in SD be ween di e en dosages o o ioxe ine (10–20 mg). J. Clin. Med. 2024,13, 546 5 o 17 4. Me hodology 4.1. Design This is a na u alis ic, p ospec i e, p agma ic, open-label, one-g oup s udy design in a ou ine clinical p ac ice se ing, measu ing he ou comes o an idep essan swi ching o o ioxe ine in pa ien s wi h p e ious an idep essan - ela ed poo ly ole a ed SD. 4.2. S udy Subjec s 4.2.1. Sample Size Calcula ion To analyze he e ec i eness o he an idep essan swi ch s a egy o o ioxe ine o he imp o emen o sexual dys unc ion, and conside ing he equency o SD o di e en an idep essan s in p e ious s udies, he sample size necessa y o he di e ence be ween p opo ions was calcula ed. Assuming a 95% con idence le el and a powe o 80%, acco d- ing o da a om p e ious s udies in which he p opo ion o pa ien s wi h SD on SSRIs was 70% and 45% on dual-ac ion d ugs [ 2 , 3 ], and based on ecen s udies wi h he same design, he equi ed sample size is 124 pa ien s, wi h a sample size o 62 male and 62 emale pa ien s in each g oup in o de o obse e possible gende di e ences. 4.2.2. Inclusion C i e ia □ Pa ien s who showed a leas mode a e in ensi y in hei o al SALSEX sco e, wi h a sco e ≥6 (including ≥2 in i em 5, ole ance o sexual dys unc ion). □ Pa ien s wi h no mal sexual unc ion p io o aking an idep essan s (no mal sexual unc ion was de ined as an absence o habi ual dys unc ions o su icien in ensi y o cause subjec i e discom o in he pa ien in he a eas o desi e, o gasm o sexual a ousal ha would equi e specialized a en ion, wi h p e ious egula , sa is ac o y sexual and/o au oe o ic p ac ices). □ Sexually ac i e pa ien s ea ed wi h an an idep essan o a leas 2 mon hs. This ime equi emen was included o a oid alse nega i es, as some symp oms do no appea un il a e his pe iod (loss o sexual desi e o e ec ile/ aginal lub ica ion dys unc ion). □ P e ious an idep essan - ela ed sexual dys unc ion. Pa ien s we e swi ched o o - ioxe ine only i he e we e symp oms o sexual dys unc ion ha we e conside ed associa ed wi h he p e ious an idep essan . □ T ea men exclusi ely wi h an idep essan s used wi hin app o ed label (including SSRIs, SNRIs). Combined ea men wi h benzodiazepines a low clinical doses was pe mi ed (less han 20 mg clo azepa e o equi alen ). □ Pa ien s wi h a leas pa ial esponse wi h a maximum sco e on he Clinical Global Imp ession Scale o Dep ession (CGI-D) ≤3-mild dep ession. 4.2.3. Exclusion C i e ia □ SD p io o s a ing adminis a ion o he an idep essan . (Only a mild dec ease in libido be o e s a ing an idep essan ea men was pe mi ed, as his is conside ed a symp om o dep ession i sel , al hough wo sening o libido because o ea men was conside ed as an ad e se e ec .) □Combina ion o he an idep essan wi h an ipsycho ic d ugs o mood s abilize s. □ Use o ho mones o any o he medica ion wi h known capaci y o in e e e in sexual e- la ionships (an iepilep ic d ugs, H2 an agonis s, ecen in oduc ion o con acep i es as concomi an he apy, β-blocke s, opia es, and an ihype ensi e d ugs). □Medically signi ican in e cu en diseases clea ly a ec ing sexual unc ion. 4.2.4. Swi ching P ocedu es Swi ching om p e ious an idep essan he apy (SSRI, SNRI) was unde aken wi h no ab up in e up ions. Doses we e inc eased up o 10 mg/day du ing he i s week and, ollowing a na u alis ic design, an inc ease up o 15–20 mg/day o o ioxe ine was allowed a e he i s week. P e ious an idep essan s we e simul aneously g adually ape ed down by hal ing he dose o he i s week be o e comple e wi hd awal. J. Clin. Med. 2024,13, 546 6 o 17 4.2.5. Si es All pa ien s we e a ended by psychia is s wo king in Salamanca’s (Spain) comple e ou pa ien ne wo k, which comp ises i e ou pa ien uni s in o al. 4.3. Va iables 4.3.1. P ima y Va iable □ The Se e i y o global SD was measu ed using he SALSEX o al sco e (sco ing om 0 = no sexual dys unc ion o 15 = maximum sexual dys unc ion) a baseline and o he endpoin . The se e i y o each indi idual dimension o sexual unc ioning ( educed sexual desi e, delay o o gasm, ano gasmia, and a ousal di icul ies such as e ec ile dys unc ion o aginal lub ica ion) was measu ed wi h a Like scale (0 = no SD; 3 = maximum SD ) o he i ems 1–4 o he SALSEX ques ionnai e a baseline and a endpoin isi . 4.3.2. Seconda y Va iables □ To s udy he indi idual accep ance o SD and isk o ea men discon inua ion, we used he sco e o i em 5 o he SALSEX ques ionnai e (0 = no isk o discon inua ion; 3 = maximum isk) a baseline and a endpoin isi . □To de e mine di e ences in SD ha a ied ac oss he se e i y o dep ession we used he Clinical Global Imp ession-Imp o emen (CGI-I) scale o dep ession, and he CGI-S o sexual unc ioning a baseline and a endpoin isi . 4.4. Da a Collec ion and Analysis 4.4.1. Measu emen Scales PRSexDQ-SALSEX Ques ionnai e The SALSEX ques ionnai e o he E alua ion o Psycho opic-Rela ed Sexual Dys unc- ion was used o measu e and e alua e he p e alence and se e i y o SD ( alida ed in 2008 by Mon ejo e al. [ 10 ] in a popula ion wi h dep essi e diso de s). This ques ionnai e was adminis e ed a baseline and du ing he ollow-up pe iod (wi hin 3 mon hs o he ini ial isi ). I is included in an annex a he end o his pape . The SALSEX ques ionnai e is mean o be adminis e ed du ing a di ec clinical in e iew o collec in o ma ion on whe he ea men - ela ed SD is de ec ed, and i i is p esen , o no e whe he he pa ien epo ed he SD spon aneously o no . The deg ee o SD is e alua ed acco ding o 4 i ems, o each o he possible mani es a ions o SD: (1) sexual desi e; (2) delayed o gasm; (3) absen o gasm; (4) e ec ion-lub ica ion. A i h i em e alua es he accep ance o SD, i p esen . Each o hese i ems is sco ed be ween 0 (no p oblem) and 3 (maximum in ole ance). The p esence and se e i y o SD is e alua ed acco ding o he o al sco e and indi idual i em sco es o he ques ionnai e, using he ollowing c i e ia: # No SD: To al sco e o 0 o 1, only i i em 1 is e alua ed as a sligh loss o libido (which is equi alen o a sco e o 1 on ha i em). # SD p esen : To al sco e o 2–15, o o al sco e o 1 i any i em excep i em 1 (desi e) is sco ed 1. □ Mild SD: 1–5 poin s, p o ided no i em sco es ≥ 2 poin s and i em 5 ( ole abili y) is no >1. □ Mode a e SD: 6–10 poin s, p o ided ha no i em sco es ≥ 3 poin s, o <6 poin s i any i em = 2 and p o ided ha i em 5 ( ole abili y) is no >2. □ Se e e SD: 11–15 o <11 poin s i any i em = 3 o whene e i em 5 ( ole abili y) = 3. Clinical Global Imp ession Scale, se e i y subscale, applied o sexual dys unc ion (CGI-S- SD) o assess he DS se e i y a baseline Clinical Global Imp ession Scale, imp o emen subscale, applied o sexual dys unc ion (CGI-I-SD) o assess he clinical e ec i eness o he in e en ion, adminis e ed in he ollow-up isi (pe o med wi hin 3 mon hs o he baseline isi ) J. Clin. Med. 2024,13, 546 7 o 17 Clinical Global Imp ession Scale, se e i y subscale (CGI-S), applied o he psychia ic disease o which he an idep essan ea men is adminis e ed, o assess se e i y a baseline Clinical Global Imp ession Scale, imp o emen subscale (CGI-I), o assess he clinical e ec i eness o he in e en ion, adminis e ed in he ollow-up isi (pe o med wi hin 3 mon hs o he baseline isi ) Ad e se E en s Assessmen s Ad e se e en s (including p e- ea men ad e se e en s) had o be eco ded on an Ad e se E en Fo m. The in es iga o had o p o ide in o ma ion on he ad e se e en , p e e ably wi h a diagnosis, o a leas wi h signs and symp oms; s a and s op da es (and s a and s op ime i he ad e se e en las ed less han 24 h); se e i y; causal ela ionship o he IMP; ac ion aken; and ou come. I he ad e se e en was no ela ed o he IMP, an al e na i e e iology had o be eco ded, i a ailable. I he ad e se e en was an o e dose, he na u e o he o e dose had o be s a ed ( o example, medica ion e o , acciden al o e dose, o in en ional o e dose). I he ad e se e en was se ious, his had o be indica ed on he Ad e se E en Fo m. The sponso /in es iga o had o comply wi h all na ional ules and egula ions conce ning he epo ing o Se ious Ad e se E en s as de ined in he ICH GCP guidelines and o wa d a copy o any such epo s o Lundbeck, and o epo all AE/ADRs o Lundbeck immedia ely. ICH. 4.4.2. Visi s In o ma ion was collec ed on wo isi s: □Baseline isi (V1): ea men ini ia ion swi ch i p omp ed by poo ly ole a ed SD; □ Visi 2 (V2) conduc ed wi hin 3 mon hs o ollow-up a e swi ching an idep essan a baseline isi . 4.4.3. T ea men Pa ien s swi ched ea men s only i he clinician and/o he pa ien conside ed ha some ea men modi ica ion was necessa y o imp o e SD due o he use o he cu en an idep essan , which was eplaced by o ioxe ine wi h he pa ien ’s consen . 4.4.4. E hical and Legal Conside a ions Pa ien In o ma ion In o med consen was ob ained om he pa ien , and he physician in ol ed he pa ien and his/he pa ne in he s udy, since hei collabo a ion was deemed essen ial. Con iden iali y Collec ion, p ocessing, and ans e o s udy da a we e conduc ed in compliance wi h he p o isions o he Spanish O ganic Law 15/1999 on Pe sonal Da a P o ec ion. All in o ma ion on he iden i y o pa icipa ing pa ien s was ea ed as con iden ial o all pu poses. The iden i y o he pa ien s was no o be disclosed o sha ed, excep when necessa y o hei ea men , e alua ion, ollow-up, and sa e y. The pa ien was iden i ied in he da a collec ion o ms wi h a pa ien numbe . The collec ed da a we e en e ed in a da abase ollowing a p ocedu e ha ensu ed o al dissocia ion be ween hese da a and he iden i y o he pa ien . 5. Da a Analysis 5.1. E alua ion C i e ia and Da a Managemen Case epo o ms (CRFs) we e indi idually e iewed o ensu e ha all da a had been collec ed o o he wise a eason had been p o ided. Nume ical alues we e assigned o he open ex ields, pa icula ly o ad e se eac ions. Inco ec and incomple e CRFs, and hose ha had no been comple ed acco ding o he p o ocol we e ejec ed o e u ned o he co esponding in es iga o o e iew and co ec ion. J. Clin. Med. 2024,13, 546 8 o 17 CRF da a conside ed alid was en e ed in a da abase c ea ed o his pu pose wi h app op ia e sa e y measu es and in e nal cohe ence ules, a e which any cases wi h anomalous o inconsis en alues we e e iewed. 5.2. E alua ion C i e ia Cases ejec ed due o se ious inconsis encies o inco ec o incomple e da a we e no e alua ed. All pa ien s we e o be desc ibed in he pa icipan ’s biodemog aphic cha ac e is ics sec ion, indica ing he o al numbe o pa ien s included, he o al numbe o pa ien s excluded o who had discon inued ea men ea ly (along wi h he eason), and he o al numbe o e aluable pa ien s. Pha maco igilance assessmen was based on all ec ui ed pa ien s, excep o hose cases ejec ed due o inco ec da a o hose who did no e u n o any isi a e baseline. E alua ions Pe o med Gene al cha ac e is ics o pa ien s included in he s udy, including biodemog aphic da a and hei psychia ic diagnosis, we e desc ibed. The p ima y analysis was con-duc ed by desc ibing he pe cen age o pa ien s who had SD du ing p e ious ea men and a e swi ching o o ioxe ine wi h hei espec i e con idence in e als. To al SALSEX sco e, equency, and in ensi y o each i em o he SALSEX (i ems 1–5) was compa ed a endpoin s. baseline. Tes ing o he hypo hesis was conside ed signi ican when he co esponding p- alue was less han 5% ( α = 0.05) o wo- ailed es s. All ope a ions we e pe o med on PC- ype compa ible compu e s, p o ec ed by s ic measu es con olling access and quali y, using he SPSS package, e sion 23.0 o Windows o a subsequen e sion. Measu es o cen al endency and dispe sion o quan i a i e a iables we e de- e mined h oughou he s udy. No mali y o dis ibu ion o con inuous a iables was es ed using he Kolmogo o -Smi no es o one sample, so ha he da a we e sub- sequen ly analyzed based on he esul s ob ained. The desc ip i e analysis included ca ego ical quali a i e a iables measu ed using equencies and pe cen ages. Fo he in e en ial s a is ical analysis, es ing o he hypo hesis was e alua ed using he app op ia e pa ame ic es o a iables wi h no mal dis ibu ion, o non-pa ame ic es s o hose wi h non-no mal dis ibu ion. Th oughou he s udy, i was o in e es o examine di e ences be ween he pa ien g oups in he cha ac e is ics e alua ed. When expe imen al da a we e measu ed using con inuous scales ha ollow a no mal dis i- bu ion, he app op ia e p ocedu e was he S uden ’s es o wo independen samples. I hese scales did no ha e a no mal dis ibu ion, a non-pa ame ic Mann–Whi ney U es was used. I he di e ence o means was o be s udied be ween mo e han wo g oups, he co esponding pa ame ic o non-pa ame ic es was used. Pea son’s chi-squa ed es o independence and Fishe ’s exac es we e used o compa e independence be ween ca ego ical a iables. 6. P ojec De elopmen S ages The s udy was conduc ed in he Depa men o Psychia y o he Hospi al Uni e - si a io de Salamanca, wi h he pa icipa ion o 10 in es iga o s om 5 men al heal h ou pa ien uni s loca ed in Salamanca, which p o ides ca e o a popula ion close o 300,000 inhabi an s. The s udy was pe o med in h ee phases be ween July 2019 and Sep embe 2022. Rec ui men was delayed due o COVID-19. All adminis a i e pe missions, including submission o he p o ocol o quali ica ion by he Spanish Agency o Medicines, ag eemen om he Resea ch E hics Commi ee o he Salamanca Heal h A ea, and ag eemen om he Go e nmen o Cas ile and Leon we e ob ained in 2019. An in es iga o s’ mee ing was held in Janua y 2020 o an explana ion o he p o ocol, s anda diza ion o p ocedu es, aining, and p ac ical adminis a ion o he SALSEX ques ionnai e o educe in e -in es iga o a iabili y. The collec ion o baseline J. Clin. Med. 2024,13, 546 9 o 17 sociodemog aphic da a was ob ained and included in he CRF, as well as all selec ion c i e ia, p esence and se e i y o he psychia ic disease (measu ed using he CGI-S scale), p esence and se e i y o SD (measu ed wi h he SALSEX ques ionnai e and he CGI-S-SD), and andomized he apeu ic s a egy o an idep essan swi ch o he managemen o SD associa ed wi h an idep essan ea men . Clinical ollow-up o pa ien s wi h SD de ec ed a he baseline isi included he measu emen , wi hin 3 mon hs o baseline, o he e ec i eness o he in e en ion using he SALSEX scale (lowe sco es indica e imp o emen ), and a Clinical Global Imp ession- Imp o emen o dep ession (CGI-IDep) and o sexual unc ioning (CGI-ISex) a e in e - en ion. A de e mina ion o he numbe o pa ien s wi hd awing om he s udy due o lack o e icacy, ad e se e ec s o loss o ollow-up was pe o med. 7. Resul s 103 pa ien s ea ed wi h an an idep essan who had poo ly ole a ed sexual dys unc- ion a e ini ia ion o ea men and who me he inclusion and exclusion c i e ia o he p o ocol we e swi ched o o ioxe ine. The esponse o he SALSEX scale was analyzed in 74 pa ien s om whom da a we e ob ained a he ollow-up isi (3 mon hs a e he baseline). 29 ou o 103 pa ien s (28.15%) we e los o he s udy wi h no da a a Visi 2. Clinical and sociodemog aphic cha ac e is ics o pa ien s swi ched o o ioxe ine a e showed in Table 1. Table 1. Clinical and sociodemog aphic cha ac e is ics o pa ien s swi ched o o ioxe ine. n= 74 Age (yea s) 43.1 ±12.65 <30, n(%) 14 (18.9) 30–40, n(%) 21 (28.4) 40–50, n(%) 17 (23.0) >50, n(%) 22 (29.7) Gende (Males), n(%) 40 (54.1) Gende (Females), n(%) 34 (45.9) Du a ion o ea men (mon hs) (Baseline) 19.53 ±37.27 Du a ion o ea men (mon hs) (Follow-up) 3.21 ±1.17 Dosage (mg/d) (Follow-up) 13.11±4.03 SALSEX To al Sco e a Baseline 10.32 ±2.73 SALSEX To al Sco e a Follow-up 3.78 ±3.68 7.1. P e ious An idep essan T ea men a Baseline A baseline, pa ien s wi h sexual dys unc ion we e aking enla axine 6.8%, mean dosage 177 mg/day ± 73.02; esci alop am 25.7%, 14.74 mg/day ± 3.90; ci alop am 5.4%, 23.75 mg/day ± 7.50; pa oxe ine 9.5%, 22.86 mg/day ± 7.56; se aline 18.9%, 78.57 mg/day ±37.80; luoxe ine 8%, 23.33 mg/day ± 8.17; duloxe ine 10.8%, 67.50 mg/day ±21.21; clomip amine 4.1%, 75.00 mg/day ± 0.000 and des enla axine 10.8%, 78.57 mg/day ±56.70 (Figu e 1). 7.2. SALSEX Scale To al Sco e o Sexual Dys unc ion The o al sco e o Sexual Dys unc ion (SD) measu ed wi h he SALSEX scale ( anging om 0 = no sexual dys unc ion o 15 = s ong SD) a he baseline isi in which pa ien s we e aking an an idep essan was 10.32 (SD 2.73). The o al sco e on he SALSEX scale in he ollow-up isi (3 mon hs a e swi ching o o ioxe ine) was 3.78 (SD 3.68). Highly signi ican di e ences we e ound be ween he global SALSEX sco e a baseline and a e swi ching o o ioxe ine ( = 12.279, p< 0.001). A baseline, 4% o pa ien s had mild sexual dys unc ion (SD) (n= 3), 20.3% o pa ien s had mode a e SD (n= 15) and 75.7% o pa ien s had se e e SD (n= 56). SD was spon aneously epo ed in 47.3% o pa ien s (n= 35), compa ed o 52.7% (n= 39) o whom i was no . J. Clin. Med. 2024,13, 546 16 o 17 6. Able , B.; See inge , A.; Ha mann, A.; G ön, G.; Me zge , C.; Wal e , M.; S ingl, J. Neu al Co ela es o An idep essan - Rela ed Sexual Dys unc ion: A Placebo-Con olled MRI S udy on Heal hy Males Unde Subch onic Pa oxe ine and Bup opion. Neu opsychopha macology 2011,36, 1837. [C ossRe ] 7. Clay on, A.H.; C o , H.A.; Handiwala, L. An idep essan s and Sexual Dys unc ion: Mechanisms and Clinical Implica ions. Pos g ad. Med. 2014,126, 91–99. [C ossRe ] 8. Mon ejo, A.L.; P ie o, N.; de Ala cón, R.; Casado-Espada, N.; de la Iglesia, J.; Mon ejo, L. Managemen S a egies o An idep essan -Rela ed Sexual Dys unc ion: A Clinical App oach. J. Clin. Med. 2019,8, 1640. [C ossRe ] 9. Clay on, A.H.; Alkis, A.R.; Pa ikh, N.B.; Vo a, J.G. Sexual Dys unc ion Due o Psycho opic Medica ions. Psychia . Clin. N. Am. 2016,39, 427–463. [C ossRe ] 10. Mon ejo, A.L.; Rico-Villademo os, F. Psychome ic P ope ies o he Psycho opic-Rela ed Sexual Dys unc ion Ques ionnai e (PRSexDQ-SALSEX) in Pa ien s wi h Schizoph enia and O he Psycho ic Diso de s. J. Sex Ma i al The . 2008,34, 227–239. [C ossRe ] 11. McGahuey, C.A.; Gelenbe g, A.J.; Laukes, C.A.; Mo eno, F.A.; Delgado, P.L.; McKnigh , K.M.; Manbe , R. The A izona Sexual Expe ience Scale (ASEX): Reliabili y and Validi y. J. Sex Ma i al The . 2000,26, 25–40. [C ossRe ] 12. Clay on, A.H.; McGa ey, E.L.; Cla e , G.J. The Changes in Sexual Func ioning Ques ionnai e (CSFQ): De elopmen , Reliabili y, and Validi y. Psychopha macol. Bull. 1997,33, 731–745. 13. Mon ejo, A.L.; Calama, J.; Rico-Villademo os, F.; Mon ejo, L.; González-Ga cía, N.; Pé ez, J. SALSEX Wo king S udy G oup. A Real-Wo ld S udy on An idep essan -Associa ed Sexual Dys unc ion in 2144 Ou pa ien s: The SALSEX I S udy. A ch. Sex. Beha . 2019,48, 923–933. [C ossRe ] [PubMed] 14. Basson, R.; Gilks, T. Women’s sexual dys unc ion associa ed wi h psychia ic diso de s and hei ea men . Womens Heal h 2018, 14, 1745506518762664. [C ossRe ] 15. Clay on, A.H.; Wa nock, J.K.; Ko ns ein, S.G.; Pinke on, R.; Sheldon-Kelle , A.; McGa ey, E.L. A Placebo-Con olled T ial o Bup opion SR as an An ido e o Selec i e Se o onin Reup ake Inhibi o -Induced Sexual Dys unc ion. J. Clin. Psychia y 2004,65, 62–67. [C ossRe ] [PubMed] 16. FDA Selec i e Se o onin Reup ake Inhibi o s (SSRIs) In o ma ion. A ailable online: h ps://www. da.go /d ugs/in o ma ion- d ug-class/selec i e-se o onin- eup ake-inhibi o s-ss is-in o ma ion (accessed on 1 No embe 2023). 17. Bonie bale, M.; Lançon, C.; Tignol, J. The ELIXIR S udy: E alua ion o Sexual Dys unc ion in 4557 Dep essed Pa ien s in F ance. Cu . Med. Res. Opin. 2003,19, 114–124. [C ossRe ] [PubMed] 18. Mon ejo, A.L.; Deakin, J.F.W.; Gailla d, R.; Ha me , C.; Meyniel, F.; Jabou ian, A.; Gab iel, C.; G uge , C.; Klinge, C.; MacFayden, C.; e al. Be e Sexual Accep abili y o Agomela ine (25 and 50 mg) Compa ed o Esci alop am (20 mg) in Heal hy Volun ee s. A 9-Week, Placebo-Con olled S udy Using he PRSexDQ Scale. J. Psychopha macol. 2015,29, 1119–1128. [C ossRe ] 19. Mon ejo, A.L.; P ie o, N.; Te lei a, A.; Ma ias, J.; Alonso, S.; Paniagua, G.; Na al, S.; Pa a, D.G.; Gab iel, C.; Mocaë , E.; e al. Be e Sexual Accep abili y o Agomela ine (25 and 50 mg) Compa ed wi h Pa oxe ine (20 mg) in Heal hy Male Volun ee s. An 8-Week, Placebo-Con olled S udy Using he PRSEXDQ-SALSEX Scale. J. Psychopha macol. 2010,24, 111–120. [C ossRe ] 20. Jacobsen, P.L.; Mahableshwa ka , A.R.; Se enko, M.; Chan, S.; T i edi, M.H. A Randomized, Double-Blind, Placebo-Con olled S udy o he E icacy and Sa e y o Vo ioxe ine 10 mg and 20 mg in Adul s wi h Majo Dep essi e Diso de . J. Clin. Psychia y 2015,76, 575–582. [C ossRe ] 21. Jacobsen, P.L.; Mahableshwa ka , A.R.; Palo, W.A.; Chen, Y.; D agheim, M.; Clay on, A.H. T ea men -Eme gen Sexual Dys unc ion in Randomized T ials o Vo ioxe ine o Majo Dep essi e Diso de o Gene alized Anxie y Diso de : A Pooled Analysis. CNS Spec . 2016,21, 367–378. [C ossRe ] 22. Jacobsen, P.; Zhong, W.; Nomikos, G.; Clay on, A. Pa oxe ine, bu No Vo ioxe ine, Impai s Sexual Func ioning Compa ed Wi h Placebo in Heal hy Adul s: A Randomized, Con olled T ial. J. Sex. Med. 2019,16, 1638–1649. [C ossRe ] [PubMed] 23. Jacobsen, P.L.; Mahableshwa ka , A.R.; Chen, Y.; Ch ones, L.; Clay on, A.H. E ec o Vo ioxe ine s. Esci alop am on Sexual Func ioning in Adul s wi h Well-T ea ed Majo Dep essi e Diso de Expe iencing SSRI-Induced Sexual Dys unc ion. J. Sex. Med. 2015,12, 2036–2048. [C ossRe ] [PubMed] 24. Jacobsen, P.L.; Nomikos, G.G.; Zhong, W.; Cu le , A.J.; A ini o, J.; Clay on, A. Clinical Implica ions o Di ec ly Swi ching An idep essan s in Well-T ea ed Dep essed Pa ien s wi h T ea men -Eme gen Sexual Dys unc ion: A Compa ison be ween Vo ioxe ine and Esci alop am. CNS Spec . 2020,25, 50–63. [C ossRe ] 25. Callega i, C.; Ielmini, M.; Caselli, I.; Lucca, G.; Isella, C.; Diu ni, M.; Pe enon, F.; Poloni, N. Pa oxe ine e sus Vo ioxe ine o Dep essi e Symp oms in Pos menopausal T ansi ion: A P elimina y S udy. Psychopha macol. Bull. 2019,49, 28–43. [PubMed] 26. Mahableshwa ka , A.R.; Jacobsen, P.L.; Se enko, M.; Chen, Y.; T i edi, M.H. A Randomized, Double-Blind, Placebo-Con olled S udy o he E icacy and Sa e y o 2 Doses o Vo ioxe ine in Adul s wi h Majo Dep essi e Diso de . J. Clin. Psychia y 2015,76, 583–591. [C ossRe ] [PubMed] 27. Alam, M.Y.; Jacobsen, P.L.; Chen, Y.; Se enko, M.; Mahableshwa ka , A.R. Sa e y, Tole abili y, and E icacy o Vo ioxe ine (Lu AA21004) in Majo Dep essi e Diso de : Resul s o an Open-Label, Flexible-Dose, 52-Week Ex ension S udy. In . Clin. Psychopha macol. 2014,29, 36–44. [C ossRe ] 28. Sánchez-Sánchez, F.; Ponce-Buj, B.; Mon ejo-González, A.L.; Sipán-Sa ión, Y.; Gimeno-Ma qués, A.; Me ino-Gámez, A. Repe - cusión de o ioxe ina sob e la unción sexual en e a o os an idep esi os [Impac o o ioxe ine on sexual unc ion compa ed o o he an idep essan s]. Seme gen 2023,49, 101997. [C ossRe ] [PubMed] J. Clin. Med. 2024,13, 546 17 o 17 29. Ga nock-Jones, K.P. Vo ioxe ine: A Re iew o I s Use in Majo Dep essi e Diso de . CNS D ugs 2014,28, 855–874. [C ossRe ] 30. Huang, J.; Xie, X.M.; Lyu, N.; Fu, B.B.; Zhao, Q.; Zhang, L.; Wang, G. Agomela ine in he ea men o anhedonia, soma ic symp oms, and sexual dys unc ion in majo dep essi e diso de . F on . Psychia y 2023,14, 1115008. [C ossRe ] 31. Kennedy, S.H.; Riz i, S.; Ful on, K.; Rasmussen, J. A Double-Blind Compa ison o Sexual Func ioning, An idep essan E icacy, and Tole abili y be ween Agomela ine and Venla axine XR. J. Clin. Psychopha macol. 2008,28, 329–333. [C ossRe ] 32. Clay on, A.H.; Reddy, S.; Foch , K.; Musgnung, J.; Fayyad, R. An E alua ion o Sexual Func ioning in Employed Ou pa ien s wi h Majo Dep essi e Diso de T ea ed wi h Des enla axine 50 mg o Placebo. J. Sex. Med. 2013,10, 768–776. [C ossRe ] [PubMed] 33. Dea do , W.J.; G ossbe g, G.T. A Re iew o he Clinical E icacy, Sa e y and Tole abili y o he An idep essan s Vilazodone, Le omilnacip an and Vo ioxe ine. Expe . Opin. Pha maco he . 2014,15, 2525–2542. [C ossRe ] [PubMed] 34. D’Agos ino, A.; English, C.D.; Rey, J.A. Vo ioxe ine (B in ellix): A New Se o one gic An idep essan . Pha m. The . 2015,40, 36. 35. Baldwin, D.S.; Ch ones, L.; Flo ea, I.; Nielsen, R.; Nomikos, G.G.; Palo, W.; Reines, E. The Sa e y and Tole abili y o Vo ioxe ine: Analysis o Da a om Randomized Placebo-Con olled T ials and Open-Label Ex ension S udies. J. Psychopha macol. 2016,30, 242–252. [C ossRe ] 36. De Luca, R.; Bonanno, M.; Manuli, A.; Calab ò, R.S. Cu ing he Fi s Tu o Heal Pos -SSRI Sexual Dys unc ion: A Male Re ospec i e Coho S udy. Medicines 2022,9, 45. [C ossRe ] 37. Kelliny, M.; C oa kin, P.E.; Moo e, K.M.; Bobo, W.V. P o ile o Vo ioxe ine in he T ea men o Majo Dep essi e Diso de : An O e iew o he P ima y and Seconda y Li e a u e. The . Clin. Risk Manag. 2015,11, 1193–1212. [C ossRe ] 38. Takeda A Randomized, Double-Blind, Pa allel G oup, Placebo- and Ac i e-Con olled, Phase 4 S udy E alua ing he E ec o Vo ioxe ine 10 and 20 mg/day s. Pa oxe ine 20 mg/day on Sexual Func ioning in Heal hy Subjec s; clinical ials.go . 2018. A ailable online: h ps://clinical ials.go /s udy/NCT02932904 (accessed on 2 No embe 2023). 39. Ma ingly, G.; B unne , E.; Ch ones, L.; Law ence, D.F.; Simonsen, K.; Ren, H. E ec i eness o Vo ioxe ine o Majo Dep essi e Diso de in Real-Wo ld Clinical P ac ice: US Coho Resul s om he Global RELIEVE S udy. F on . Psychia y 2023,13, 977560. [C ossRe ] 40. McDaniel, B.T.; Co ne , V.; Ca oll, J.; Ch ones, L.; Chudzik, J.; Coch an, J.; Guha, S.; Law ence, D.F.; McCue, M.; Sa key, S.; e al. Real-wo ld clinical ou comes and ea men pa e ns in pa ien s wi h MDD ea ed wi h o ioxe ine: A e ospec i e s udy. BMC Psychia y 2023,23, 938. [C ossRe ] 41. Wa e s, K. The clinical u ili y o newe an idep essan agen s: Unde s anding he ole in managemen o MDD. Men . Heal h Clin. 2022,12, 309–319. [C ossRe ] 42. Li, Y.; Peh son, A.L.; Oos ing, R.S.; Gulinello, M.; Oli ie , B.; Sanchez, C. A s udy o ime- and sex-dependen e ec s o o ioxe ine on a sexual beha io : Possible oles o di ec ecep o modula ion. Neu opha macology 2017,121, 89–99. [C ossRe ] 43. Cowen, P.J. SSRIs in he T ea men o Dep ession: A Pha macological CUL-DE-SAC? In Cu en Topics in Beha io al Neu osciences; Sp inge : Be lin/Heidelbe g, Ge many, 2023. [C ossRe ] Disclaime /Publishe ’s No e: The s a emen s, opinions and da a con ained in all publica ions a e solely hose o he indi idual au ho (s) and con ibu o (s) and no o MDPI and/o he edi o (s). MDPI and/o he edi o (s) disclaim esponsibili y o any inju y o people o p ope y esul ing om any ideas, me hods, ins uc ions o p oduc s e e ed o in he con en .