Cognition, inflammation and related risk factors in suicide attempts

DOCTORAL THESIS COGNITION, INFLAMMATION AND RELATED RISK FACTORS IN SUICIDE ATTEMPTS JESSICA FERNÁNDEZ SEVILLANO SUPERVISOR: ANA MARÍA GONZÁLEZ-PINTO ARRILLAGA VITORIA-GASTEIZ, 2022 (cc)2022 JESSICA FERNÁNDEZ SEVILLANO (cc by-nc 4.0) A i, mamá, que luchas e he oicamen e con a el COVID-19 pa a i i y celeb a mis log os. Du an e u ba alla eché de menos con a e los a ances de es e abajo, pe o aho a puedes e el esul ado de mi es ue zo. Ese que ú me enseñas e. G acias. AGRADECIMIENTOS Con es as líneas quie o exp esa mi econocimien o a mi di ec o a de esis, Ana González- Pin o, po las opo unidades de ap endizaje que me ha o ecido du an e es os años como in es igado a en salud men al. G acias a odas aquellas compañe as del equipo de in es igación que han compa ido en algún momen o mis inquie udes y me han dado ue zas y a odos los p o esionales del se icio de Psiquia ía del Hospi al Uni e si a io A aba. Además, quie o ag adece a odos los co-au o es que han colabo ado con sus apo aciones, abajo y dedicación pa a que es e abajo sea posible. Y po supues o, a odos los olun a ios pa icipan es cuya apo ación ha sido indispensable pa a ealiza es a esis y que an o me han enseñado no sólo como cien í ica, sino a ni el humano. Mi especial ag adecimien o a mi amilia y pa eja. A mis pad es, Ca los y Azucena, po que cualquie log o de mi ida es y se á siemp e de ellos ambién. G acias a los dos po es a a mi lado y apoya me en mi p oyec o de ida pe sonal y p o esional. Sois incondicionales. A mi abuelo An onio, po deci me que me quie e siemp e que iene ocasión y a mi abuela Ma iluz po es a o gullosa de mí simplemen e po se quien soy. Y a Igo , po su sen ido del humo que me ayuda a oma me las cosas menos en se io y po compa i el camino con se enidad haciendo más lige as mis p eocupaciones. También, a Diego, mi compañe o de d amas y anécdo as a a és del iempo y la dis ancia. Po úl imo, una b e e mención ca iñosa a las masco as que han con ibuido a mi salud men al en los momen os de abajo más in enso: Koki o, K yp o y Andy. A odas las pe sonas, las que es án y las que es u ie on, que de alguna mane a han sido pa e de es a me a que ya es una ealidad. FINANCIAL SUPPORT The au ho o his hesis has been a bene icia y o he P edoc o al Fellowship P og amme o he Basque Go e nmen and has ecei ed inancial suppo o an in e na ional s age om he Men al Heal h Ne wo king Biomedical Resea ch Cen e (CIBERSAM) o he Ins i u e o Heal h Ca los III (ISCIII). This wo k has de i ed om esea ch p ojec s suppo ed by he Ins i u e o Heal h Ca los III [g an numbe PI15/00789 (co- inanced by he Eu opean Regional De elopmen Fund (ERDF) / Eu opean Social Fund ‘In es ing in you u u e’], he Basque Go e nmen [g an numbe 2017111104] and he Uni e si y o he Basque Coun y [g an numbe 321218ELCY]. ACKNOWLEDGMENTS The au ho wan s o acknowledge he Men al Heal h Ne wo king Biomedical Resea ch Cen e (CIBERSAM), he Ins i u e o Heal h Ca los III, he Basque Go e nmen , he Uni e si y o he Basque Coun y (UPV/EHU) and Bioa aba Resea ch Ins i u e. ABBREVIATIONS 3. MANUSCRIPTS: OBJECTIVES, MATERIALS AND METHODS, RESULTS _________________________________________________________ 65 3.1. MANUSCRIPT 1: SUICIDAL BEHAVIOUR AND COGNITION: A SYSTEMATIC REVIEW WITH SPECIAL FOCUS ON PREFRONTAL DEFICITS_ ____________________________________________________________ 67 3.2. MANUSCRIPT 2: COGNITION IN RECENT SUICIDE ATTEMPTS: ALTERED EXECUTIVE FUNCTION __________________________________ 82 3.3. MANUSCRIPT 3: INFLAMMATION BIOMARKERS IN SUICIDE ATTEMPTS AND THEIR RELATION TO ABUSE, GLOBAL FUNCTIONING AND COGNITION _________________________________________________ 90 4. DISCUSSION ________________________________________________ 97 5. CONCLUSIONS ____________________________________________ 107 6. CURRENT AND FUTURE PRODUCTION DERIVED FROM THIS THESIS __________________________________________________________ 111 6.1. VITAMIN D AS A PREDICTOR OF SUICIDE ATTEMPTS AND GLOBAL FUNCTIONING ___________________________________________________ 113 6.2. C-REACTIVE PROTEIN (CRP) IN SUICIDAL BEHAVIOUR AND THE LINK TO COGNITIVE PERFORMANCE ______________________________ 117 6.3. TELEMEDICINE-BASED SUICIDE PREVENTION _______________ 120 7. REFERENCES _____________________________________________ 123 8. ANNEX 1: MANUSCRIPTS ___________________________________ 159 FIGURES AND TABLES FIGURES Figu e 1. Age-s anda dized suicide a es (pe 100.000 popula ion) in 2019. ___________ 25 Figu e 2. Age-s anda dized suicide a es in he wo ld by sex in 2019. _______________ 26 Figu e 3. Global suicides by age and coun y income le el, 2019. __________________ 26 Figu e 4. Suicide da a in Spain in 2020. ______________________________________ 27 Figu e 5. Numbe o suicides in Spain by e i o y in 2020. ______________________ 28 Figu e 6. Dis ibu ion o suicide by sex and e i o y in Euskadi, 2020.______________ 28 Figu e 7. The hema opoie ic cell di e en ia ion. _______________________________ 47 Figu e 8. Dis ibu ion o majo lymphoid issues o he lympha ic sys em. ___________ 48 Figu e 9. The h ee lines o de ence o he immune sys em. ______________________ 48 Figu e 10. S uc u e o he WAIS: indexes and sub es s. _________________________ 69 Figu e 11. PRISMA Flow cha . ___________________________________________ 72 Figu e 12. Mean (SD) IL-6 plasma concen a ions in each g oup. __________________ 96 TABLES Table 1. Summa y o main suicide isk ac o s. ________________________________ 29 Table 2. Ea ly heo ies o suicidal beha iou . _________________________________ 38 Table 3. Main s udies o cy okines in suicide a emp s. __________________________ 56 Table 4. Main cha ac e is ics and esul s o a icles included in he e iew. ___________ 74 Table 5. Pe o mance on each neu opsychological domain classi ied by diagnosis. _____ 76 Table 6. Sample dis ibu ion acco ding o diagnosis, ime o he a emp and symp oms. 81 Table 7. Cogni i e domains and neu opsychological es s employed. _______________ 84 Table 8. Demog aphic and clinical a iables.__________________________________ 87 Table 9. Pe o mance on each cogni i e domain by g oupa. ______________________ 88 Table 10. Mul iple eg ession o neu opsychological pe o mancea._________________ 88 Table 11. E ec sizes o being emale on execu i e unc iona. _____________________ 89 Table 12. Demog aphic, clinical and cogni i e a iables. _________________________ 94 Table 13. In lamma ion pa ame e s ac oss g oups. _____________________________ 96 Table 14. Re e ence le els o 25-hyd oxy i amin D ___________________________ 115 Table 15. Main s udies o CRP in suicide a emp s. ____________________________ 119 1. INTRODUCTION 21 1.1. SUICIDE: EVOLUTION OF ITS CONCEPTUALIZATION. The e ymology o he e m suicide comes om he La in suicidium; sui, in e e ence o sel and -cidium, conce ning he e b caede e o o kill. Fi s eco ds o he e m, which was coined by Pie e F ançois Guyo Des on aines, da e back o he mid-XVII cen u y (Be olo e & Wasse man, 2021; Mesones, 2014) bu nuances and conno a ions ega ding he concep ha e e ol ed wi hin he his o ical, sociological and cul u al con ex as i is b ie ly de ailed below: The i s manusc ip alluding o suicide is an Ancien Egyp ian poem app oxima ely da ed in 2200 B.C. named The dispu e be ween a man and his Ba (soul), a dialogue be ween a man who wishes o be dead and his soul which con inces him o emain ali e (Moleón & Moleón, 2022). A ha ime suicide was conside ed a con enien solu ion o a oid excessi e pain o disg ace (Mesones, 2014). Delibe a e dea h s a s o be ejec ed in he Ancien G eece excep o some au ho ized suicides mean o p ese e honou o a oid humilia ion. Philosophe s ques ioned he eedom behind suicide om di e en poin s o iew: o S oics, Epicu eans and Cynics suicide was a ee app op ia e choice, in con as o o he g ea hinke s’, like Pla o and A is o eles, ideas. Simila ly, despi e being a condemnable ac in Rome, suicide could be allowed o hose wi h a men al diso de —insanus e u iosus in he Roman Law— and o uppe -class ci izens when honou , pa io ism, disease o digni y we e he cause o suicide (Mesones, 2014; Moleón & Moleón, 2022). I was no un il he Ancien Age ha suicide was ex emely ili ied and s igma ized. Al hough he Bible — wi h 9 e e ences in he Old Tes amen and 1 in he New Tes amen — does no condemn suicide, Ch is ians ega ded i as an un o gi able sin and ho i ic c ime ha caused ex-communica ion om he chu ch and b u al punishmen s o a emp e s (And és, 2015; Mesones, 2014; Moleón & Moleón, 2022; Picazo, 2017). In addi ion o his eligious ou look, demonological concep s p e ailed du ing he Middle Age. Suicide was an unmen ionable sin p oduc o he de il and, o his eason, euphemisms we e o en employed o e e o his beha iou . Those who died by suicide we e bu ied in non-consec a ed g ound wi h a s ake in he ches o p e en hei soul om esusci a ing (Mesones, 2014; Moleón & Moleón, 2022). 22 Suicide was g adually dec iminalized in he Mode n Age (XV-XVIII) hanks o some philosophe s, such as Da id Hume, and he scien i ic knowledge. Suicide was unde s ood as a equen a emp o soo he he ex eme su e ing o he melancholic as Robe Bu on desc ibed i in The Ana omy o Melancoly (1621) (And és, 2015; Moleón & Moleón, 2022). In his cen u y, al hough suicide was no longe a punishable c ime, he s igma was linked o madness and men al diso de s emaining nega i e conno a ions (Picazo, 2017). In he XIX cen u y, while Roman icism exal ed he psychological pain and suicide as he sel -exp ession o eedom, he concep o madness in suicide con inued o be discussed. Philippe Pinel in his T ai é medico-philosophique su l’aliéna ion men ale (1801) posed ha suicide is gene ally caused by melancholia bu also by ad e si y o physical pain (Moleón & Moleón, 2022). La e , Jean-É ienne Esqui ol in Maladies men ales (1838) a gued ha suicide is always a symp om, no an illness i sel , o a men al diso de which could also be p o oked by passions and edium (Picazo, 2017). The s igma o he a emp e and hei amilies we e no longe ela ed o he e il bu connec ed o a men al diso de ins ead. I is no ewo hy ha in his cen u y Johann W. Goe he published The So ows o Young We he (1774) causing he We he E ec , ha is, he massi e imi a ion o he suicide ollowing he me hod desc ibed in he no el (Mesones, 2014). In he XX cen u y suicide was no longe a c iminal ac ion bu he con lic emained; hinke s like Albe Camus and Jean-Paul Sa e opposed o suicide bu o he s like Ka l Jaspe s, philosophe and psychia is , conside ed suicide as he only possible ou come o an unbea able si ua ion ha would o he wise a nish he indi idual (Moleón & Moleón, 2022). In his cen u y, suicide was i s s udied om a Social Sciences pe spec i e. Émile Du kheim, con inced ha social and no indi idual ac o s igge suicide, de eloped a sociological app oach o suicide in his wo k Le Suicide: É ude de Sociologie (1897). Acco ding o his au ho , suicide could be al uis ic (sac i ice o he common good), egois ic (indi idualis ac wi hou he conside a ion o he impac on he socie y), a alis (inadap a ion and su e ing caused by he socie y) and anomic (du ing social c isis mos ulne able indi iduals a e a ec ed by he con ex ) depending on he g ade o social in eg a ion o he indi idual and social ules (Gine e al., 2016; Mesones, 2014; Moleón & Moleón, 2022). Ano he ele an au ho o his pe iod was Edwin Shneidman known as he a he o Suicidology, a e m he coined. He claimed o psychology he s udy and p e en ion o suicide as he ound psychological pain o psychache was a he co e o his beha iou . He was he ounde o he Suicide P e en ion Cen e in 23 Los Angeles wi h he i s elephone helpline o suicide p e en ion, he Ame ican Associa ion o Suicidology and he Suicide, he Li e-Th ea ening Beha iou Jou nal. He also c ea ed he psychological au opsy in 1962 o analyse Ma ilyn Mon oe’s dea h (Mesones, 2014). Con empo a ily, F eud s udied suicide and he i s ega ded i as a sel -di ec ed agg ession ha a oids agg ession owa d o he s (Moleón & Moleón, 2022). La e , in Beyond he Pleasu e P inciple (1922) he posed ha suicide was an exp ession o he dea h d i e (Thana os) ha coexis s in con inuous con lic wi h he li e d i e (E os) in e e y indi idual (Mesones, 2014), being he i s au ho o desc ibe he ambi alence behind suicide (Gine e al., 2016). Ka l Menninge , ex ended he ideas o F eud ca ego izing suicide in o h ee basic o : wish o kill (being unable o kill he objec o age, he kills himsel ), wish o be killed (due o guil and shame) and wish o be dead (as a need o escaping om su e ing) (Moleón & Moleón, 2022). Fi s endea ou s o ope a ionally de ine and ca ego ize suicide we e made in his pe iod. The Cen e o Disease con ol p oposed suicide as dea h as a esul o an in en ional, sel -in lic ed ha m and he Wo ld Heal h O ganiza ion (WHO) de ined a suicide a emp as he ac wi h a non a al ou come which he deceased, knowing o expec ing a a al ou come, had ini ia ed and ca ied ou wi h he pu pose o p o oking he changes he desi ed (Gine e al., 2016). Classi ica ions o suicidal beha iou a ose in his cen u y, being he mos ou s anding he one o Ma is e al (1992) who ca ego ized i in o h ee axes: Axis I – beha iou (idea ion, a emp o suicide), Axis II – (le hali y, in en ionali y, ci cums ances, me hod, sex, age, ace, ma i al s a us and occupa ion) and Axis III – (subs ance abuse, p e ious sel -mu ila ion o ea ing diso de s); he classi ica ion o Dieks a (1992) composed wi h h ee ca ego ies: suicide, suicide a emp s o pa asuicide and he classi ica ion o O’Ca oll (1996) —suicidal idea ion, beha iou ela ed o suicide, comple ed suicide, sel -in lic ed wounds and beha iou s wi h he in en ion o dying— which was la e used o elabo a e he Columbia Classi ica ion Algo i hm o Suicide Assessmen (C-CASA) (Gine e al., 2016). 24 Nowadays, acco ding o Gine (2016) suicidal beha iou is unde s ood as a spec um o ac ions and hough p ocesses. The cu en de ini ion o he e m acco ding o he 5 h e sion o he Diagnos ic and S a is ical Manual o Men al Diso de s (DSM-5) (Ame ican Psychia ic Associa ion, 2013) is he ac o in en ionally causing one’s own dea h, including a e e ence o he in en ion ha was lacking in i s e ymology and which b oadens he concep o a psychological dimension. The WHO now in eg a es in o he concep a ange o beha iou s ha include hinking abou suicide (o idea ion), planning o suicide, a emp ing suicide and suicide i sel (Wo ld Heal h O ganiza ion [WHO], 2014). Suicidal idea ion is de ined in he DSM-5 as hough s abou sel - ha m, wi h delibe a e conside a ion o planning o possible echniques o causing one’s own dea h which may esul in a suicide a emp , a sel -ini ia ed sequence o beha iou s by an indi idual who, a he ime o he ini ia ion, expec ed ha he se o ac ions would lead o his o he own dea h (Ame ican Psychia ic Associa ion, 2013). Acco ding o DSM-5 (Ame ican Psychia ic Associa ion, 2013), a suicide a emp could be classi ied by i s iolence —o e doses a e conside ed non- iolen whe eas jumping, gunsho , wounds and hanging a e iolen — by i s le hali y wi h high-le hali y a emp s equi ing medical hospi aliza ion and by he deg ee o planning e sus impulsi eness. I is no ewo hy ha acco ding o Oquendo e al. (2003) a suicide a emp is conside ed as such ega dless o he ac ual ha m o me hod; howe e , i would no be conside ed a suicide a emp i he indi idual is dissuaded by ano he o changes his o he mind be o e ini ia ing he beha iou (Ame ican Psychia ic Associa ion, 2013). In chap e 23 o he cu en classi ica ion o he In e na ional Classi ica ion o Diseases, ICD-11 (Wo ld Heal h O ganiza ion, 2019) —o icially in e ec since Janua y 2022 he e is a ca ego iza ion based on he ana omical egion inju ed o he ex e nal agen employed; o example: inju ies o he neck, inju ies o w is o hand o ha m ul e ec s o subs ances. Each diagnosis is subdi ided acco ding o he in en ionali y and o who in lic ed he inju y; in he case o suicide, i would be ca ego ized as sel -ha m speci ied by he me hod employed: o example, by all o jump, by exposu e o an objec , by imme sion o alling in o he wa e , by a h ea o b ea hing, by exposu e o ha m ul e ec s o subs ances. Howe e , his classi ica ion sys em is based on he mos ob ious physical ea u e o he de imen o he psychological aspec s ha unde lie suicidal beha iou (Be olo e & Wasse man, 2021). In chap e 21 o ICD-11 (Wo ld Heal h O ganiza ion, 2019) suicide idea ion, suicide a emp and suicidal beha iou can also be classi ied in o he ambiguous ca ego y o abno mal symp oms, signs o clinical ou comes unclassi iable elsewhe e (Anseán, 2021). 25 1.2. EPIDEMIOLOGY OF SUICIDE Nowadays, suicidal beha iou is a majo heal h conce n wo ldwide ha ep esen s a leading ac o o mo ali y associa ed wi h disabili y and unc ional impai men and which causes app oxima ely 800.000 casual ies pe yea in he wo ld ( esul ing in one dea h e e y 30 seconds wi h mo e han 20 suicide a emp s behind e e y suicide (WHO, 2021). Acco ding o he WHO (2021), suicide is he cause o dea h o one in e e y 100 dea hs (1.3%) wi h highe mo ali y han he Human Immunode iciency Vi us (HIV), mala ia, b eas cance , wa and homicide. The mos equen me hods wo ldwide include handing, pes icide sel - poisoning and i ea ms; gene ally, women op o sel -poisoning and males i ea ms and hanging (Anseán, 2014). In compa ison o he global a e age (9.0 pe 100.000), A ica (11.2 pe 100.000), Eu ope (10.5 pe 100.000) and Sou h-Eas Asia (10.2 pe 100.000) had highe a es o suicide (WHO, 2021) (Figu e 1). Globally suicide a es (Figu e 2) a e highe , mo e han wice, in males han in emales —12.6 pe 100.000 males; 5.4 pe 100.000 emales— bu women ha e 3 imes mo e a emp s (Anseán, 2021; Moleón & Moleón, 2022; WHO, 2021). Low-and middle- income coun ies sha ed o e 77% o he global suicides in 2019, bu be e suicide su eillance and da a ga he ing a e needed in hose egions in o de o comp ehend he scope o he p oblem (WHO, 2021). Figu e 1. Age-s anda dized suicide a es (pe 100.000 popula ion) in 2019. Re ie ed om WHO, 2022. 32 1.2.2. CLINICAL FACTORS ▪ P io Suicide A emp : The s onges isk ac o o suicide is ha ing a p io au oly ic a emp (Bos wick e al., 2016) which implies 25-40 imes mo e isk o suicide (WHO, 2022), pa icula ly 6 mon hs a e he a emp (Vuagna e al., 2019) bu also 32 yea s la e (P obe -Linds öm e al., 2020). ▪ Psychopa hology: App oxima ely, 80-98% o suicide a emp e s had a men al diso de , as well as he 90% o suicide casual ies, as e ealed by psychological au opsies (Moleón & Moleón, 2022). The mos common como bid diagnosis —one ou o wo suicide a emp e s— is majo dep ession diso de (MDD) (Na ío & Villo ia, 2014), which en ails 20 imes mo e isk o suicide (Ge e al., 2020). MDD diagnosis c i e ia acco ding o DSM-5 (Ame ican Psychia ic Associa ion, 2013) a e summa ized below: A. Fi e (o mo e) o he ollowing symp oms ha e been p esen du ing he same 2-week pe iod and ep esen a change om p e ious unc ioning: a leas one o he symp oms is ei he (1) dep essed mood o (2) loss o in e es o pleasu e. No e: Do no include symp oms ha a e clea ly a ibu able o ano he medical condi ion. 1. Dep essed mood mos o he day, nea ly e e y day, as indica ed by ei he subjec i e epo (e.g., eels sad, emp y, hopeless) o obse a ion made by o he s (e.g., appea s ea ul). (No e: In child en and adolescen s, can be i i able mood). 2. Ma kedly diminished in e es o pleasu e in all, o almos all, ac i i ies mos o he day, nea ly e e y day (as indica ed by ei he subjec i e accoun o obse a ion). 3. Signi ican weigh loss when no die ing o weigh gain (e.g., a change o mo e han 5% o body weigh in a mon h), o dec ease o inc ease in appe i e nea ly e e y day. (No e: In child en, conside ailu e o make expec ed weigh gain.). 4. Insomnia o hype somnia nea ly e e y day. 5. Psychomo o agi a ion o e a da ion nea ly e e y day (obse able by o he s, no me ely subjec i e eelings o es lessness o being slowed down). 6. Fa igue o loss o ene gy nea ly e e y day. 33 7. Feelings o wo hlessness o excessi e o inapp op ia e guil (which may be delusional) nea ly e e y day (no me ely sel - ep oach o guil abou being sick). 8. Diminished abili y o hink o concen a e, o indecisi eness, nea ly e e y day (ei he by subjec i e accoun o as obse ed by o he s). 9. Recu en hough s o dea h (no jus ea o dying), ecu en suicidal idea ion wi hou a speci ic plan, o a suicide a emp o a speci ic plan o commi ing suicide. B. The symp oms cause clinically signi ican dis ess o impai men in social, occupa ional, o o he impo an a eas o unc ioning. C. The episode is no a ibu able o he physiological e ec s o a subs ance o o ano he medical condi ion. No e: C i e ia A-C cons i u e a majo dep essi e episode. Majo dep essi e episodes a e common in bipola diso de bu a e no equi ed o he diagnosis o bipola diso de . D. The occu ence o he majo dep essi e episode is no be e explained by schizoa ec i e diso de , schizoph enia, schizoph eni o m diso de , delusional diso de , o o he speci ied and unspeci ied schizoph enia spec um and o he psycho ic diso de s. E. The e has ne e been a manic episode o a hypomanic episode. MDD can be classi ied as a single/ ecu en episode and acco ding o i s se e i y: mild, mode a e, se e e, wi h psycho ic ea u es, in pa ial emission and in ull emission. I can be speci ied as ollows: wi h anxious dis ess, wi h mixed ea u es, wi h melancholic ea u es, wi h mood-cong uen psycho ic ea u es, wi h mood- incong uen psycho ic ea u es and wi h ca a onia. MDD can onse a any age, bu pa icula ly a pube y wi h a peak in he 20s. I s cou se is a iable: some indi iduals a ely expe ience emission while o he s expe ience many yea s wi h ew o no symp oms. Episode du a ion, psycho ic ea u es, p ominen anxie y, pe sonali y diso de s and symp om se e i y p edic lowe eco e y a es. Episodes a e mo e ecu en in hose pa ien s wi h p io se e e episodes, his o y o mul iple episodes and younge indi iduals. 34 Many bipola pa ien s debu wi h one o mo e dep essi e episodes and a la ge p opo ion o pa ien s who ini ially appea o ha e MDD will p o e, in ime, o ins ead ha e a bipola diso de . Bo h bipola and unipola dep essions a e a high- isk ac o s o suicide as 80% o dep essi e pa ien s ha e au oly ic idea ion while 14- 50% will a emp suicide (Na ío & Villo ia, 2014). ▪ D ug abuse: App oxima ely 35% o a emp e s ha e a p e ious alcohol in ake be o e a emp ing suicide (Bo ges e al., 2017). Besides, p io subs ance use diso de s linked o smoking, alcohol, cannabis, cocaine, amphe amine and polysubs ance abuse we e associa ed o suicide isk (Ami i & Behnezhad, 2020; A moon e al., 2021). ▪ Soma ic illness, pain and unc ional impai men : Ch onic diseases, unc ional impai men and pain a e associa ed wi h ele a ed suicidal isk. Some illnesses such as neu ological illness (Cos anza e al., 2020), cance (Cala i e al., 2021), mul iple scle osis (Lewis e al., 2017) and ib omyalgia (Le ine & Ho esh, 2020) ha e been ela ed o a highe suicide. Likewise, unc ional impai men (Fässbe g e al., 2016; Lu z & Fiske, 2018) and ch onic pain (Racine, 2018) ha e been ela ed o suicidali y. ▪ Sleep diso de s: Acco ding o he me analysis o Ha is e al. (2020) sleep diso de s —mainly insomnia and nigh ma es— wi hou a psychopa hological con ex in ol e a sligh ly highe isk o suicide idea ion and a emp s. 35 1.2.3. PSYCHOLOGICAL FACTORS ▪ Pe sonali y ai s: Impulsi i y, especially in men (C oss e al., 2011; G issom & Reyes, 2019), hos ili y-agg ession and anxie y-neu o icism a e he main ai s ha ha e been associa ed wi h suicidal beha iou (Bi e al., 2017; Tu ecki e al., 2019). Conce ning hos ili y-agg ession ai , li e ime agg essi e beha iou has also been linked o suicide (Bui on e al., 2018; Ha ley e al., 2018). ▪ Sel -es eem: Low sel -es eem (Macalli e al., 2021; Nguyen e al., 2019) and sel - c i icism (O’Neill e al., 2021) ha e been co ela ed wi h suicidal beha iou . Pa icula ly, lowe sco es on social and amilia dimensions o sel -es eem a e associa ed wi h suicide (Pe o e al., 2018). ▪ Social suppo : A any age o he li espan social isola ion and seclusion a e associa ed wi h suicide (Cala i e al., 2019). Besides, suicides a e mo e equen in hose wi hou o sp ing (Qin & Mo ensen, 2003). ▪ Hopelessness and Reasons o Li ing: Hopelessness is as ly desc ibed as a isk ac o o suicide idea ion, a emp s and dea h ( Ribei o e al., 2018). Indi iduals wi h ew easons o li ing a e a inc eased isk o de eloping suicidal hough s and a emp ing suicide (B üde n e al., 2018). ▪ S ess ul li e e en s: acciden s, diagnosis o wo sening o a se e e illness, be ea emen , judicial p ocesses, unwan ed ab up i al changes, unwan ed p egnancy o abo ion, amongs o he s ess ul ele an e en s, inc ease he p obabili y o suicide, especially in he sho e e m (Howa h e al., 2020). ▪ Childhood / Adul abuse: Childhood and adul abuse —physical, sexual, emo ional and negligence— including school (Zabo skis e al., 2019) and wo kplace bullying (Leach e al., 2020), ha e been widely epo ed as high- isk ac o s o suicidal beha iou (Ásgei sdó i e al., 2018; Bjö kens am e al., 2017; Thompson e al., 2019). ▪ A achmen s yles: Insecu e a achmen is a isk ac o o suicidal idea ion and beha iou (G een e al., 2020) in youngs e s (Yang e al., 2021), adul s (Zo ea e al., 2021) and he elde ly (Oon-A om e al., 2019). 36 ▪ Coping skills: Coping is he way a pe son aces and o e comes s esso s. The e a e wo ypes o coping skills: 1) p oblem-based skills (sea ch help, sel -ins uc ion, posi i e e-e alua ion, sea ch o al e na i e ac ions), which a e o ien ed o inding a solu ion, and 2) emo ional-based skills (e asi e dis ac ion, a oidance, p epa ing o he wo s , emo ional discha ge, esigned accep ance) ocusing in he pe son’s eelings wi hou add essing he p oblem (Baz a shan e al., 2014). Emo ional-based coping skills a e associa ed wi h suicidal beha iou while posi i e p oblem-based coping skills ha e a p o ec i e ole agains suicide (Ho wi z e al., 2018; Lew e al., 2019). ▪ Neu opsychological pe o mance: Pe o mance on se e al neu ocogni i e domains has been associa ed wi h suicidal beha iou . As his is a co e aspec o his hesis, his ac o will be explained in de ail in u he sec ions o his documen . 37 1.2.4. BIOLOGICAL FACTORS ▪ Gene ics and epigene ics: Obse a ion o amilial agg ega ion o suicide has been desc ibed in la ge coho s (Tidemalm e al., 2011). Twin and adop ion s udies suppo 30-50% o he i abili y; 17-36% when co ec ed by he ansmission o psychia ic diso de s (Lu z e al., 2017). Gene ic s udies ha e ound mo e han 200 genes associa ed wi h suicide (Sokolowski e al., 2015) wi h inconsis en esul s. Genome-wide- associa ion s udies (GWAS), which in ol e scanning comple e se s o Deoxy ibonucleic Acid (DNA) —genome— o ind possible a ia ions —single nucleo ide polymo phisms (SNPs, also called snips) — ha e been conduc ed in ela ion o suicide poin ing o a numbe o signi ican polymo phisms. Al hough esul s on he s udy o gene ics in suicide a e p omising, hey a e likely o accoun only o a e y small p opo ion o ulne abili y (Sokolowski e al., 2015). Genes can be in luenced by epigene ic p ocesses, ha is, he iming and exp ession o genes adjus o he social, physical and biological con ex . As many o hese ac o s di ec ly o indi ec ly a ec suicidal beha iou , epigene ic egula ion is likely a key con ibu o o suicidali y mainly h ough DNA me hyla ion and his one modi ica ions (Labon é e al., 2013; Schneide e al., 2015; Tu ecki, 2014). ▪ Neu o ansmi e s: The unc ion o se o onin, no ad enaline, dopamine, glu ama e and gamma-aminobu y ic acid (GABA) neu o ansmi e sys ems has been ound o be dis up ed in suicide, including abno mali ies in hei ecep o s, anspo e s and syn hesis pa hways (Fu czyk e al., 2013; Oquendo e al., 2014; Sudol & Mann, 2017; Wisłowska-S anek e al., 2021). ▪ In lamma ion and s ess esponse The in lamma o y and he igh ly ela ed s ess esponses a e al e ed in suicide. As he link be ween in lamma ion and suicide is a co e aspec o his hesis, a desc ip ion o he mechanisms in ol ed and e idence on he ma e will be p o ided in de ail in u he sec ions o his documen . 38 1.4. THEORETICAL MODELS OF SUICIDAL BEHAVIOUR Suicide is a highly complex and mul i ace ed phenomenon ha esul s om he in e play o many con ibu ing and acili a ing a iables men ioned in he p e ious sec ion o his documen , ha is, he in e ac ion be ween biological, sociodemog aphic, sociocul u al, clinical and psychological ac o s. Al hough many suicide isk ac o s ha e been iden i ied, how o why some o hem in e play is no clea ye (O’Conno & Nock, 2014). Many heo e ical models ha e been p oposed o explain suicidal beha iou by a ending o some o se e al o hese ac o s. Ea lie heo ies o suicidal beha iou (Table 2) ocused on indi idual psychological ac o s bu did no accoun o why mos people wi h hese ea u es do no a emp suicide (O’Conno & Po zky, 2018). Table 2. Ea ly heo ies o suicidal beha iou . Model Au ho s Basic p emise o suicide isk Cubic model o suicide Shneidman (1985) Unbea able psychological pain Suicide as escape om sel Baumeis e (1990) F us a ed goals wi h p o ound sel -blame and he need o escape om in e nal nega i e a ec . Dialec ical beha iou he apy Linehan (1993) Emo ion dys egula ion unde psychological pain. In luence o biological and social ac o s. Cogni i e beha iou al model o suicidali y Beck e al. (1990) The in e p e a ion and pe cep ion o s esso s a e cen al o unde s and emo ional impac . Emphasis on cogni i e aspec s: hopelessness. Adap ed om (O’Conno & Nock, 2014). 39 A e wa ds, plen y o models ha e ied o ace his limi a ion, being he s ess-dia hesis model one o he mos ou s anding nowadays which poses ha suicide depends on he in e ac ion be ween ulne abili y ac o s and s esso s. The i s s ess-dia hesis model in suicide was p oposed by Scho e and Clum (1987). Acco ding o he au ho s, impai ed social p oblem-sol ing ac s as a dia hesis o a ulne abili y ac o ele a ing suicide isk in he p esence o s ess. A e wa ds, he clinical dia hesis-s ess model was de eloped by Mann e al. (1999), which pos ula ed ha psychological c isis o psychia ic diso de s in combina ion wi h impulsi e and agg essi e ai s as ulne abili y ac o s will esul in suicidal beha iou . The con empo a y s ess-dia hesis model in eg a es he biopsychosocial app oach esul ing in a much b oad pe spec i e in which he in e play o biological (gene ics, neu obiology, men al diso de ), psychological and social ulne abili y ac o s inc ease suicide isk unde s ess (Na ío & Villo ia, 2014; O’Conno & Nock, 2014). Taking in o conside a ion his in eg a i e pe spec i e, in his hesis we explo e he ole o some psychological (neu opsychological pe o mance, childhood auma, agg essi e beha iou ) and biological (in lamma ion) dia hesis o ulne abili y ac o s ha inc ease he isk o suicide a emp s. 40 1.5. NEUROPSYCHOLOGICAL PERFORMANCE IN SUICIDE Neu opsychology is he b anch o science conce ned wi h he s udy o he psychological p ocesses o he ne ous sys em ela ed o beha iou , emo ion and cogni ion bo h unde pa hological and no mal condi ions (Ame ican Psychia ic Associa ion, 2022). Cogni i e unc ion is a b oad e m ha e e s o he men al p ocesses in ol ed in he acquisi ion o knowledge, manipula ion o in o ma ion and easoning and can be classi ied in o majo cogni i e domains— pe cep ion, mo o skills and cons uc ion, a en ion, memo y, language and execu i e unc ion— and subdomains depending on hei unc ion (Ha ey, 2019). Neu opsychological e alua ion measu es and assess he indi idual pe o mance on hese cogni i e domains and o he ela ed cogni i e abili ies using s anda dized psychome ic ins umen s ha can be domain-speci ic o gene alized including se e al domains (Kiely, 2014). Howe e , he e a e some di icul ies and limi a ions in he classi ica ion domains and subdomains: 1) a la ge numbe o di e en heo e ical models cause 2) inconsis encies and a ia ions in classi ica ions as 3) some p ocesses may belong o di e en domains o e en 4) p ocesses a e named and de ined di e en ly by each au ho esul ing in a 5) con e gence and o e lap o cons uc s in neu opsychological es s (Ha ey, 2019). As suicide —bo h idea ion and a emp s— implies beha iou , emo ion and cogni ion, knowledge om psychology and neu opsychology can o e ele an insigh s o he unde s anding o his mul i ac o ial complex phenomenon. Due o he ac ha psychology is specialized in explaining human beha iou —unde s ood as bo h obse able (beha iou display) and unobse able ( hough s, emo ions)— and neu opsychology seeks o un eil he cogni i e p ocesses behind i , an in e es ing app oach ga he ing his knowledge opens o he ield o suicidology: he s udy o he link be ween suicide and cogni ion. 41 1.2.5. RELEVANT NEUROPSYCHOLOGICAL DOMAINS IN SUICIDE Since his doc o al hesis ocuses on he neu opsychological pe o mance in suicidal a emp s, an obse able beha iou , he ollowing pa ag aphs in oduce ele an cogni i e domains ela ed o beha iou planning, o ganisa ion and display ha ha e been selec ed o be assessed in he manusc ip s o his hesis: execu i e unc ion, a en ion, wo king memo y and p axis. 1.2.5.1. EXECUTIVE FUNCTION Execu i e unc ion is a se o complex highe -o de cogni i e p ocesses ha a y in hei de ini ion, and classi ica ion be ween he ple ho a o heo e ical models ha ha e been p oposed h oughou he his o y o neu opsychology. Lu ia was he i s au ho o desc ibe a p oposal o he cogni i e p ocesses in ol ed in his domain bu i was no un il 1982 ha Lezak coined he e m execu i e unc ion (T ápaga e al., 2018). Un il oday, he complex concep ualiza ion o execu i e unc ion emains con o e sial and he e is no ag eemen be ween au ho s abou a unique de ini ion and classi ica ion o he p ocesses in ol ed. Despi e he lack o consensus, is widely accep ed ha execu i e unc ion —mos ly associa ed wi h he on al lobe unc ions o he b ain (Blázquez-Alisen e e al., 2012)— is he cogni i e domain esponsible o he planning, implemen a ion, o ganiza ion, coo dina ion, moni o ing and di ec ing hough and beha iou allowing he indi idual o adap and espond o he en i onmen (Kiely, 2014; T ápaga e al., 2018), including bo h ex e nal (e.g., si ua ional demands, s imuli) and in e nal in o ma ion (e.g., hough s, memo ies) o he indi idual (Po ellano, 2018). Execu i e unc ion is necessa y o se a goal, choose be ween a ailable al e na i es, es ima e and p edic possible ou comes and selec , o ganize, ini ia e and modi y he plan/cou se o ac ion (Po ellano, 2018). 48 Figu e 8. Dis ibu ion o majo lymphoid issues o he lympha ic sys em. Re ie ed om Del es e al., 2017. The de ensi e eac ion o he immune sys em is e med he in lamma o y o immune esponse which can be di e en ia ed in o (1) inna e, na u al o nonspeci ic and (2) adap a i e, acqui ed o speci ic (Figu e 9). Figu e 9. The h ee lines o de ence o he immune sys em. The immune sys em is composed o h ee le els o de ence: 1) physical ba ie s o skin and mucosa, 2) he inna e and 3) he adap a i e immune esponses. Re ie ed om Del es e al., 2017. 49 The inna e esponse is he mos p imi i e and he i s line o de ence in he o ganism. I is a apid esponse ha does no need p io expe ience o wo k and ha will eac alike on u u e occasions (Abbas e al., 2022). Cells in ol ed in his esponse des oying pa hogens (Del es e al., 2017) a e: ▪ Neu ophils ▪ Eosinophils ▪ Monocy es: mac ophages. ▪ Na u al kille ▪ Mas ocy es ▪ Basophils ▪ Pla ele s In o de o espond agains a h ea , he inna e esponse cells need a pa hogen iden i ica ion mechanism. Fo his pu pose, hese cells ha e Pa e n Recogni ion Recep o s (PRR) ha can ecognize Pa hogen-Associa ed Molecula Pa e ns (PAMPs), in o he wo ds, ecep o s ha can iden i y molecules o pa hogens. PRR also ecognize Damage-Associa ed Molecula Pa e ns (DAMPs) which indica e he issula damage in he a ec ed loca ion o he body (Abbas e al., 2022; Del es e al., 2017). Once PAMPs and DAMPs a e de ec ed, he in lamma o y esponse a oids he p oli e a ion o he pa hogen and s imula es damaged issue epai : 1) asodila ion and edema in he a ec ed loca ion o a ac inna e immune cells, 2) blood coagula ion o impede pa hogen dissemina ion, 3) pa hogen deli e y h ough he lympha ic sys em o he ganglia whe e adap a i e esponse s a s (Pa ham, 2021). The adap a i e esponse is he second line o de ence in he o ganism; slowe bu speci ic and wi h immunological memo y which con e s enhanced esis ance agains epea ed in ec ions. This esponse can be classi ied as cellula o humo al media ed by T lymphocy es o B lymphocy es, espec i ely. In he adap a i e esponse, he ha m ul elemen is iden i ied by he ecogni ion o he an igens o pa hogens, molecules loca ed in he pa hogen cell su ace and which ac i a e he speci ic immune esponse (Abbas e al., 2022; Fainboim & Ge ne , 2013). 50 Howe e , T and B lymphocy es di e in how hey ecognize an igens. Fi s , T Cell Recep o s in he T lymphocy es and B Cell Recep o s in he B lymphocy es cell memb anes in e ac wi h a small egion o he an igen named epi ope o he an igenic de e minan . In he case o T lymphocy e esponse, his in e ac ion is no enough o ecognize he an igen. Epi opes a e p esen ed o he An igen-P esen ing Cells (ACPs) whe e hey bind o he Majo His ocompa ibili y Complex (MHC), a complex o med by p o eins ha a e p esen on he su ace o all cells cha ac e izing hem as belonging o he o ganism o a oid he immune sys em a ack. When he an igenic de e minan binds o he MHC in he ACP he la e is iden i ied as an ou side by he T lymphocy e h ough i s ecep o . Once he h ea is p ope ly iden i ied, cy o oxic CD8+ kille and CD4+ helpe T cells ca y ou he immune esponse (Abbas e al., 2022; Fainboim & Ge ne , 2013) In he humo al esponse, con a y o cellula esponse, B lymphocy es a e able o di ec ly ecognize he an igenic de e minan h ough B Cell Recep o s ini ia ing he syn hesis o speci ic an ibodies ha will bind o he an igen o ming he an igen-an ibody complex (Ag- Ab) whose unc ion is o neu alize he oxici y o an igens and ac i a e he esponse o o he immune cells esponse. Once he pa hogen is elimina ed, he immuni y esponse de elops long- e m p o ec ion agains he same h ea hanks o T and B memo y lymphocy es ha emain ale and in case o u u e in ec ions o he same pa hogen, hey will be ackled as e and mo e e ec i ely (Abbas e al., 2022; Fainboim & Ge ne , 2013; Pa ham, 2021). 1.2.7.1. CYTOKINES Cy okines a e small p o eins sec e ed by cells o bo h inna e and adap a i e esponse — mainly mac ophages and helpe T cells— which a e esponsible o he egula ion o di e se biological unc ions in he immune esponse: hey con ol he g ow h and ac i i y o o he immune cells, hei signals allow he cell communica ion in he in lamma o y esponse and coo dina e he ansi ion om inna e o adap a i e esponse (Kany e al., 2019). Cy okines a e pleio opic ( he same cy okine has many di e en e ec s o unc ions), edundan (mul iple cy okines ha e he same e ec ), an agonis ic (some cy okines a e inhibi ed by o he s) and can be induc ed in cascade (ampli ied p oduc ion o a cy okine). These p ope ies allow an en i e ne wo k o immune cells o wo k wi h a ela i ely small numbe o cy okines (So ia e al., 2018). Cy okines may ac in he si e whe e hey a e loca ed (au oc ine ac ion), in nea by cells (pa ac ine ac ion) o in dis an cells (endoc ine ac ion). 51 Cy okines can be as ly classi ied as chemokines, in e leukins (IL), lymphokines, in e e ons (IFN), and umou nec osis ac o (TNF) (So ia e al., 2018): ▪ Chemokines a e a ype o cy okines in cha ge o he chemo axis, cell mo emen p omo ed by chemical messages, o ce ain immune ha mus a el o he a ec ed si e. Up o da e, abou 50 chemokines ha e been iden i ied. ▪ In e leukins (IL) a e p oduced mainly by leucocy es and play an impo an ole in he p oli e a ion, mig a ion, ma u a ion, ac i a ion and di e en ia ion o immune cells. Cu en ly, o e 43 membe s o his supe amily ha e been iden i ied (IL-1 o IL-43). ▪ In e e ons (IFN) an i i al agen which ac i a es na u al kille , mac ophages and T lymphocy es. ▪ Tumou Nec osis Fac o s (TNF) a e a g oup o p o eins ha kill o inhibi umou cells and hey a e in ol ed in se e al physiological and pa hological p ocesses. Mos sounding examples a e TNF-α and TNF-β which a e po en media o s in he in lamma o y esponse. Cy okines can also be classi ied by hei in lamma o y ole as p o-in lamma o y (IL-1α/β, TNF-α/β, IL-2, IL-6, IL-11, IL-18, IFN-γ) o an i-in lamma o y (IL-4, IL-10) (Ach yes e al., 2020; Himme ich e al., 2019; Kany e al., 2019; Se a ini e al., 2020). Ne e heless, his classi ica ion is no clea as pa hway in e ac ions and cy okine combina ions can con ibu e o a ious and di e en physiological e ec s. Besides, some cy okine can change hei in lamma o y esponse by being p o-in lamma o y o an i-in lamma o y depending on he si ua ion o he o ganism. Since cy okines ha e such po en e ec s, hei ac ion mus be limi ed o a oid he pa hogenic e ec s o a cy okine o e dose, ha is, he ac i a ion o cy okines has o be egula ed o a oid inapp op ia e esponses ha would be de imen al o heal h. Dys egula ion o cy okine sec e ion and hei consequen signalizing ne wo k is an impo an componen o pa hological diseases like heuma oid a h i is o sys emic lupus e y hema osus (Moul on & Tsokos, 2016). 52 1.2.7.2. IMMUNE SYSTEM – CENTRAL NERVOUS SYSTEM INTERACTION Despi e being adi ionally ega ded as independen sys ems, bo h he immune sys em and he Cen al Ne ous Sys em (CNS) a e in e ela ed which implies ha psychological and beha iou al ac o s can in luence he immune sys em and ice e sa (So ia e al., 2018). Classical s udies on psychoneu oimmunology like Ade y Cohen’s (1975) showed ha he immune esponse could be condi ioned o ce ain s imuli, including s esso s, and he e o e i was p o en i s connec ion o he CNS p ocesses. The immune sys em in e ac s bidi ec ionally wi h he CNS h ough he same molecula language shaped by neu o ansmi e s, neu opep ides, ho mones and cy okines, in addi ion o he in e ac ion wi h he hypo halamic-pi ui a y-ad enal (HPA) axis, esul ing in he up egula ion and/o down egula ion o he immune esponse. 1.2.7.2.1. THE STRESS RESPONSE AND HPA AXIS Unde a physical and/o psychological s esso , he ini ial u gen esponse o he o ganism is immedia ely media ed by he sympa he ic-ad enal-medulla y sys em (SAM) which acili a es he s a e o ale ness in he body by he elease o ad enaline and no ad enaline om he ad enal medulla. As a esul , body changes like pupila and b onchial dila a ion and hea a e inc ease allow a as igh o ligh esponse. Immedia ely a e , he HPA axis ac i a es and eleases he co ico opin- eleasing ho mone (CRH) in o he bloods eam. This ho mone s imula es he libe a ion o he ad enoco ico opic ho mone (ACTH) by he pi ui a y gland. ACTH hen a els o he ad enal co ex leading o he elease o glucoco icoids like co isol ha os e he a o emen ioned igh o ligh esponse by inc easing blood p essu e and glucose a ailabili y o p o ide skele al muscles wi h mo e ene gy and down egula ing non-essen ial unc ions such as ep oduc ion o sleep (Abbas e al., 2022). I main ained o e ime, hese physiological changes mean o enhance su i al can be ex emely ha m ul o he o ganism. Fo his eason, h ough a nega i e eedback glucoco icoids hemsel es ac as a con ol mechanism ha ensu es he HPA axis is es ained causing a educ ion o he ACTH elease. Du ing ch onic s ess, his con ol sys em ails and co isol is o e p oduced. O e ime, immune cells exp ess ewe ecep o s o co isol and desensi ize o i s an i-in lamma o y e ec s causing ch onic in lamma ion (Gje s ad e al., 2018). 53 1.2.7.2.2. NEUROINFLAMMATION: THE INFLAMED MIND Mic oglia a e b ain cells ha egula e b ain de elopmen , main enance o neu onal ne wo ks and neu oplas ici y and epai . Fu he mo e, hey a e he inna e immune esponse o he b ain. Unde s ess and ha m ul s imuli, hese cells su e unc ional and mo phological changes which igge an in lamma o y cascade os e ed by cy okines, chemokines, seconda y messenge s and eac i e oxygen species in he b ain. This cen al in lamma ion is ampli ied esul ing in he a ac ion o pe iphe ic in lamma o y media o s in o he b ain (DiSaba o e al., 2016). Unde no mal condi ions, he p oduc s o he immune sys em do no physically pene a e in o he b ain hanks o he p o ec ion o he blood-b ain ba ie (BBB). Howe e , unde a neu oin lamma o y s a e he pe meabili y o his ba ie can be comp omised and pe iphe ic in lamma o y p oduc s can en e he CNS enhancing neu oin lamma ion (DiSaba o e al., 2016). Neu oin lamma ion causes neu o oxici y, synap ic dys unc ion and has been implica ed in neu odegene a i e diseases like Alzheime ’s disease (Kwon & Koh, 2020), Pa kinson’s disease (Kouli e al., 2020), Mul iple Scle osis (Va asou e al., 2022), and ischemic s oke (Lian e al., 2020). 54 1.2.8. INFLAMMATION HYPOTHESIS IN SUICIDE Vulne abili y ac o s such as gene ic p edisposi ion, p ena al and childhood expe iences and s ess ul li e e en s, amongs o he s, can esul in a dys egula ed immune esponse wi h an unbalance be ween p o-in lamma o y and an i-in lamma o y cy okines, blun ed HPA axis ac i i y and neu oin lamma ion. As he immune sys em communica es wi h he CNS and e en i s in lamma o y p oduc s can espass a comp omised BBB, in lamma ion can ha e de imen al e ec s on he b ain unc ions including he syn hesis, elease and eup ake o neu o ansmi e s —se o onin, glu ama e and GABA— ul ima ely a ec ing neu oci cui s ha egula e emo ion and beha iou which con ibu es o he e iopa hogenesis o psychia ic diso de s and suicide (Mille , 2020). The ollowing pa ag aphs con ain an explana ion o some ele an in lamma ion bioma ke s in he li e a u e conce ning suicide. 1.2.8.1. CYTOKINES IN SUICIDAL BEHAVIOUR The pa hophysiology o suicidal beha iou has been linked o a disbalance be ween IL-2, IL- 6, TNF-α and IL-4 (Table 3), causing b ain unc ion al e a ions wi h implica ions o emo ion, mo i a ion and beha iou which may inc ease suicide isk (B undin e al., 2017; Cou e e al., 2016; Vasupan aji e al., 2021). Acco ding o se e al sys ema ic e iews and me a-analyses (Black & Mille , 2015; Ducasse e al., 2015; Ganança e al., 2016; Se a ini e al., 2020), IL-6 is he cy okine mos consis en ly associa ed wi h suicidal beha iou . Ou o he 17 main s udies in he li e a u e (Table 3), 8 desc ibe ele a ed le els o IL-6 in ce eb ospinal luid (Bay-Rich e e al., 2013; Lindq is e al., 2009, 2011), plasma (Janelidze e al., 2011) and se um (P iya e al., 2016) o non- a al a emp e s and pos -mo em issue o a al suicide a emp e s (Hoyo-Bece a e al., 2013; Pandey e al., 2012, 2018). In addi ion, IL-6 migh play a ole in suicide isk as some s udies epo highe le els o hese cy okines in pa ien s wi h suicidal idea ion (Ach yes e al., 2020; Dolsen e al., 2020; Ka lo ić e al., 2012; Kea on e al., 2019; Ma inez e al., 2012; O’Dono an e al., 2013). Al hough many s udies show ele a ed IL-6 in suicide (González-Cas o e al., 2021), some indings do no suppo his ela ionship (Co yell e al., 2018, 2020; Dolsen e al., 2020; Eidan e al., 2019; Gabbay e al., 2009; Isung e al., 2012; Jha e al., 2020; Tonelli e al., 2008; Va gas e al., 2013) o ound lowe ed concen a ions in suicide a emp e s (Kim e al., 2008). 55 The ole o TNF-α in suicide has also been esea ched. Ou o he 13 main s udies ha measu e his cy okine in suicide (Table 3), 4 ind highe plasma concen a ions o non- a al a emp e s (Janelidze e al., 2011) and in he pos -mo em b ain issue o suicide casual ies (Pandey e al., 2012, 2018). Simila ly o IL-6, he e a e some s udies (Co yell e al., 2018, 2020; Dolsen e al., 2020; Hoyo-Bece a e al., 2013; Huang & Lee, 2007; Jha e al., 2020; Lindq is e al., 2009; Tonelli e al., 2008; Va gas e al., 2013) ha do no ind di e ences on TNF-α le els o desc ibe an opposi e ela ionship wi h lowe concen a ions in suicide a emp e s (Gabbay e al., 2009). Rega ding IL-2, some s udies (Nässbe ge & T äskman-Bendz, 1993) epo inc eased le els in suicide a emp e s in opposi ion o o he au ho s (Janelidze e al., 2011; Kim e al., 2008) ha desc ibe dec eased le els in suicide and o he s udy o Ro henhäusle e al. (2006) wi h no di e ences be ween g oups. Conce ning IL-4, Tonelli e al. (2008) epo ele a ed IL-4 le els in he pos -mo em p e on al co ex o suicide ic ims. Con a y o hese au ho s, Kim e al. (2008) and Jha e al. (2020) ind lowe IL-4 plasma le els in suicide a emp e s and Gabbay e al. (2009) do no ind any di e ences be ween g oups. Al hough he e is compelling e idence sugges ing a connec ion be ween suicide and cy okines, he e a e con adic o y esul s ha indica e ha he in lamma ion mechanisms in ol ed in his complex beha iou a e ye o be explo ed. Besides, he implica ion o cy okines in he pa hophysiology and symp om se e i y o MDD wi hou suicide has also been epo ed (Dowla i e al., 2010; Enache e al., 2019; Felge & Lo ich, 2013; Himme ich e al., 2019; Köhle e al., 2017; Lop es i e al., 2014; Mille , 2020; Raison e al., 2006; Ting e al., 2020; Valkano a e al., 2013; Young e al., 2014) making i necessa y o explo e he speci ic al e a ions ela ed o suicide o be eligible as a bioma ke . The e o e, compa isons o he cy okine p o ile be ween dep essed suicide a emp e s, dep essed non-a emp e s and heal hy con ols may shed ligh on he unde s anding o he speci ic in lamma ion p o ile exclusi ely implica ed in suicidal beha iou . As only 5 (Eidan e al., 2019; Gabbay e al., 2009; Huang & Lee, 2007; Janelidze e al., 2011; Kim e al., 2008) ou o he 20 main s udies analysed in his sec ion (Table 3) employ his ho ough me hodological design, he e is ample oom o u u e s udies ha del e in o he opic ollowing his s a egy. 56 Table 3. Main s udies o cy okines in suicide a emp s. AUTHORS SUBJECTS SAMPLE IL-2 / IL2-R IL-4 IL-6 NASSBERGER AND TRASKMAN-BENDZ, 1993 SA HC Plasma IL-2R SA>HC* - - - ROTHENHÄUSLER ET AL., 2006 MDD SA HC Plasma IL-2R SA=HC - - - HUANG & LEE, 2007 MDD SA MDD NSA HC Plasma - - - SA=NSA=HC KIM ET AL., 2008 MDD SA MDD NSA HC Plasma SA<NSA* SA<HC* NSA<HC* SA=NSA SA<NSA* - TONELLI ET AL., 2008 SC HC Pos -mo em issue - SC> HC* SC=HC SC=HC GABBAY ET AL., 2009 MDD SA MDD NSA HC Plasma - SA=NSA=HC SA=NSA=HC SA<NSA* LINDQVIST ET AL., 2009 SA HC CSF - - SA>HC* SA=HC JANELIDZE ET AL., 2011 MDD SA MDD NSA HC Plasma SA<NSA* SA<HC* - SA>NSA* SA>HC* SA>NSA* SA>HC* ISUNG ET AL., 2012 SA HC CSF - - SA=HC - PANDEY ET AL., 2012 SC HC Pos -mo em issue - - SC>HC* SC>HC* HOYO-BECERRA ET AL., 2013 SC HC Pos -mo em issue - - SC>HC* SC=HC VARGAS ET AL., 2013 SA HC Plasma - - SA=NSA SA=NSA TNF-α 57 Composed om Black & Mille , 2015; Ducasse e al., 2015; Ganança e al., 2016; Miná e al., 2015; Se a ini e al., 2020. SA: Suicide a emp e s SC: Suicide comple e s NSA: Non-suicide a emp e s wi h a psychia ic diso de SI: Suicidal Idea ion HC: Heal hy con ols MDD: Majo dep ession diso de CSF: Ce eb ospinal Fluid * signi ican di e ences BAY-RICHTER ET AL., 2015 SA HC CSF - - SA>HC* SA=HC PRIYA ET AL., 2016 SA HC Se um - - SA>HC* - CORYELL ET AL., 2018 MDD SA MDD NSA Plasma - - SA=HC SA=HC PANDEY ET AL., 2018 SC HC Pos -mo em issue - - SA>HC* SA>HC* EIDAN ET AL., 2019 MDD SA MDD NSA HC Plasma - - SA=NSA - CORYELL ET AL., 2020 MDD SA MDD NSA Plasma - - SA=NSA SA=NSA DOLSEN ET AL., 2020 MDD / Anxie y SA MDD /Anxie y NSA Plasma - - SA=NSA SA=NSA JHA ET AL., 2020 MDD SA+SI MDD- isk NSA HC Plasma SA+SI= MDD- isk NSA=HC SA+SI < NSA* SA+SI < HC* SA+SI= MDD- isk NSA=HC SA+SI= MDD- isk NSA=HC 64 • To compa e childhood auma and ecen s ess ul li e e en s o MDD pa ien s wi h a ecen suicide a emp , MDD pa ien s wi h his o y o suicide a emp , MDD non- a emp e s and heal hy con ols (Manusc ip 2). ▪ To analyse he cy okine p o ile in ecen and dis an suicide MDD a emp e s in compa ison o MDD non-a emp e s and heal hy con ols (Manusc ip 3). ▪ To explo e he ela ionship be ween cy okines and child/adul abuse, li e ime agg essi e beha iou , global unc ioning and cogni ion (a en ion) (Manusc ip 3). 3. MANUSCRIPTS: OBJECTIVES, MATERIALS AND METHODS, RESULTS 67 3.1. MANUSCRIPT 1: SUICIDAL BEHAVIOUR AND COGNITION: A SYSTEMATIC REVIEW WITH SPECIAL FOCUS ON PREFRONTAL DEFICITS (Fe nández-Se illano e al., 2021a) (Annex 1). 3.1.1. OBJECTIVES • To ga he upda ed and homogenized e idence on neu opsychological p e on al de ici s ela ed o beha iou o ganiza ion and display in suicide a emp s by compa ing psychia ic pa ien s wi h a suicide a emp wi h non-a emp e s ha sha e he same diagnosis. • To analyse which cogni i e al e a ion is mo e linked o suicide a emp s in each men al diso de . • To compa e he neu opsychological pe o mance o a emp e s and non-a emp e s ocusing on cu en psychia ic symp oms and he ime o he a emp ( ecen /dis an ). 3.1.2. MATERIALS AND METHODS A sys ema ic li e a u e sea ch, om 2000 o 2020 was pe o med on Ma ch 30 h 2020 using Medline (Pubmed), Web o Science, SciELO Ci a ion Index, PyscIn o, PsycA icles and Coch ane Lib a y da abases. Medical subjec heading (MESH) e ms and ee- e ms suicide, suicidal beha io and suicidal beha iou we e combined wi h he e ms execu i e unc ion, wo king memo y, p e on al dys unc ion, cogni i e con ol, execu i e pe o mance and he ollowing e ms ela ed o speci ic neu opsychological es s: Iowa Gambling Tes , IGT, Wisconsin Ca d So ing Tes , WCST, Con olled O al Wo d Associa ion Tes , COWAT, Weschle Adul In elligence Tes , WAIS, S oop Colou -Wo d Tes , SCWT, Con inuous Pe o mance Tes , CPT, T ail Making Tes and TMT. The es s included we e selec ed o being classical measu es used in neu opsychological assessmen which can p o ide e idence on he unc ioning o cogni i e domains ela ed o beha iou planning, o ganiza ion and display: 68 ▪ Iowa Gambling Tes , IGT (Becha a e al., 1994). The IGT measu es decision-making by using 100 ca ds di ided in o ou ca d decks (A, B, C, D ha he pa icipan has o choose om wi h he consequence o winning o losing money wi h each ca d. Pa icipan s s a he game wi h $2000 and ha e o make he mos p o i possible wi hou p e iously knowing ha isk decks (A/B) b ing highe bene i s bu also highe losses and, in e sely, low- isk decks (C/D) de i e lowe p o i s bu also lowe penal ies. ▪ Wisconsin Ca d So ing Tes , WCST (Hea on, 1981). The WSCT measu es execu i e unc ion wi h wo mazes o 64 ca ds each. Each ca d has h ee ypes o a ibu es: shape ( iangle, s a , c oss, ci cle), colou ( ed, blue, g een and yellow) and numbe (one, wo, h ee o ou elemen s). The ask consis s o ca ego izing he ca ds ollowing one o he h ee possible a ibu es. Howe e , only he e alua o knows which a ibu e should be ollowed and gi es cons an eedback (w ong /co ec ) o he pa icipan a e each esponse. When 10 co ec esponses a e accumula ed he e e ence a ibu e changes wi hou any wa ning o he pa icipan . ▪ Con olled O al Wo d Associa ion Tes , COWAT (Ben on e al., 1994; Bu iel e al., 2004). The COWAT, also known as FAS depending on he e sion, measu es e bal luency by gi ing 1 minu e o he pa icipan o name as many wo ds as possible beginning wi h a gi en le e (usually C, F, L o also F, A, S; depending he e sion used). Success ul e ie al equi es execu i e unc ion componen s o wo k, such as se -shi ing and sel - moni o ing. ▪ S oop Colou Wo d Tes , SCWT (S oop, 1935). The SCWT consis s o h ee asks in which subjec s a e equi ed o ead h ee di e en ables as as as possible. The i s wo asks a e he cong uous condi ion: in he i s condi ion he pa icipan has o ead a lis o colou names p in ed in black ink and in he second, he pa icipan s ha e o say he name o he colou o he ink used o p in each elemen on a lis o un eadable cha ac e s (XXX). In he hi d ask, also e e ed o as he colou -wo d condi ion, he names o colou s a e p in ed wi h an inconsis en ly cong uen and incong uen colou ink and pa icipan s a e equi ed o name he colou 69 o he ink while a oiding naming he wo ds w i en. SCWT may be used o measu e mul iple cogni i e unc ions anging om cogni i e inhibi ion o a en ion, p ocessing speed, cogni i e lexibili y and wo king memo y (Sca pina & Tagini, 2017). ▪ Con inuous Pe o mance Tes , CPT (Conne s, 1994). The CPT assesses sus ained a en ion and isual igilance in scanning and concen a ing on some s imulus. Du ing 14 minu es and 360- ial adminis a ion, pa icipan s a e equi ed o push he spaceba when any le e appea s, excep he le e X. ▪ T ail Making Tes , TMT (B own & Pa ing on, 2012). The TMT can be used o measu e se e al cogni i e abili ies anging om isual a en ion o ask shi ing, cogni i e lexibili y and p ocessing speed. I consis s o wo pa s (A and B) ha should be pe o med in he sho es ime possible: in he i s pa , pa icipan s a e asked o connec consecu i ely 25 do s a ending o he numbe w i en inside hem; in he second pa , pa icipan s a e ins uc ed o connec he do s in o de al e na ing le e and numbe s as in 1-A-2-B-3-C. ▪ Weschle Adul In elligence Scale, WAIS (Wechsle , 1955, 2008, 2012). O iginally published in 1955 (Wechsle , 1955), he WAIS has been e ised un il he ou h e sion in 2008 (Wechsle , 2008) o measu e in elligence by using 15 sub es s (Figu e 10) ha assess di e en cogni i e domains and ha ca ego ized in o ou indexes: e bal comp ehension, pe cep ual easoning, wo king memo y and p ocessing speed. Figu e 10. S uc u e o he WAIS: indexes and sub es s. Re ie ed om D ozdick e al., 2013. 70 Eligibili y c i e ia A e sc eening, eco ds ha me he ollowing inclusion c i e ia we e included in his e iew: 1) Published in English o Spanish language. 2) Pe o med a leas one o he ollowing neu opsychological es s: Iowa Gambling Tes , Wisconsin Ca d So ing Tes , Con olled O al Wo d Associa ion Tes , Weschle Adul In elligence Tes (any o he sub es s), S oop Colou -Wo d Tes , Cogni i e Pe o mance Tes and T ail Making Tes . 3) Compa ed suicide a emp e s e sus non-a emp e s. 4) In ol ed pa ien s o e 18 yea s old o disca d neu ode elopmen e ec s o cogni i e unc ioning. 5) In ol ed pa ien s in bo h g oups diagnosed wi h he same men al diso de acco ding o he Diagnos ic and S a is ical Manual o Men al Diso de s o /and he In e na ional Classi ica ion o Diseases in hei di e en e sions depending on he da e o publica ion o he eco ds. 6) Con e ence and mee ing abs ac s, e iews, me a-analyses and pilo s udies we e excluded. Da a collec ion and ex ac ion PRISMA-P (Mohe e al., 2015) checklis and low-cha we e used o ensu e he quali y o his sys ema ic e iew. The quali y o he s udies included was assessed independen ly by 4 e iewe s using he online C i ical App aisal Tools o he Basque O ice o Heal h Technology Assessmen (López de A gumedo e al., 2017). This ool allows esea che s o collec and ex ac summa ized da a o each o he s udies (Da a ex ac ed: Au ho s, yea o publica ion, diagnosis, cu en symp oma ology, ime o a emp , neu opsychological es used and esul s) and a es he quali y o pape s as poo , medium o high acco ding o a comp ehensi e checklis abou he objec i e o he s udy, esea ch ques ion, me hodological aspec s (es ima ion o sample size, diagnos ic c i e ia, inclusion/exclusion c i e ia o pa icipan s, eliable ins umen s o measu emen , con ol o con ounding ac o s, 71 minimiza ion o possible bias), esul s, conclusions, ex e nal alidi y and con lic o in e es s a emen . In his e iew, only medium and high-quali y pape s we e included. Any disag eemen be ween e iewe s was sol ed by discussion. 3.1.3. RESULTS O he 1153 pape s iden i ied (Figu e 11), 17 s udies me he inclusion c i e ia and we e selec ed o his e iew. A o al o 63 ull- ex a icles we e excluded: 13 o no ha ing a con ol g oup (pa ien s wi h he same diagnosis bu no suicidal beha iou ), 10 o using di e en neu opsychological es s om hose es ablished as eligibili y c i e ia, 4 did no p o ide any da a on diagnosis, 8 included pa ien s less han 18 yea s old, 23 we e excluded o eco d ype (con e ence abs ac , mee ing abs ac , e ision, pilo s udy), 4 we e excluded o he language o publica ion and 1 was excluded o sco ing low quali y acco ding o he online C i ical App aisal Tools o he Basque O ice o Heal h Technology Assessmen . Acco ding o his c i e ia, 14 s udies included we e o high-quali y and 3 o medium quali y. 72 Figu e 11. PRISMA Flow cha . 1.885 pa ien s diagnosed wi h a men al illness comp ise he o al sample o his e iew, o whom 840 had a emp ed suicide and 1.045 had ne e a emp ed suicide. Ou o he 17 s udies in his e iew, 11 ound neu opsychological de ici s in a sample o 685 a emp e s compa ed o 814 non-a emp e s (n = 1499). O he 6 s udies, comp ising 155 a emp e s and 231 non-a emp e s (n = 386), did no ind hese di e ences. 73 Rega ding he clinical p o ile, ou o he 17 eco ds selec ed, 4 (Adan e al., 2017; Koca ü k e al., 2015; Nangle e al., 2006; Ve ma e al., 2016) assessed 373 pa ien s ha had been diagnosed wi h schizoph enia o schizoa ec i e diso de . The es 13 s udies (Deisenhamme e al., 2018; Gilbe e al., 2011; Go lyn e al., 2013; Ho e al., 2018; Jollan e al., 2013; Keilp e al., 2008, 2013, 2014; King e al., 2000; Malloy-Diniz e al., 2009; McGi e al., 2012; Olié e al., 2015; Richa d-De an oy e al., 2012) assessed he neu opsychological unc ioning o 1512 pa ien s wi h an a ec i e diso de . Conce ning he ime o he suicide a emp , only 3 s udies (Deisenhamme e al., 2018; King e al., 2000; Richa d-De an oy e al., 2012) a e based on ecen suicide a emp s, whe eas he es 14 s udies ocused on li e ime his o y o p e ious suicide beha iou . Table 4 p o ides he main cha ac e is ics and esul s o he s udies included in he e iew. Fo p ac ical easons, he esul s ob ained we e classi ied in o i e neu opsychological domains as ollows: Execu i e unc ion, decision-making, a en ion, cons uc ional p axis and wo king memo y. As some o he es s included measu e di e en cogni i e p ocesses and could be classi ied in o di e en domains, he c i e ia used o he ca ego iza ion o esul s was made acco ding o he mos common objec i e o he au ho s using hose measu es and in a way ha enabled esul s compa ison. Speci ically, execu i e unc ion was measu ed wi h he WSCT (Hea on, 1981). Decision-making was conside ed an independen dimension o execu i e unc ion as he s udies included in his e iew assessed sepa a ely wi h he IGT (Becha a e al., 1994). A en ion was measu ed wi h he TMT (B own & Pa ing on, 2012), SCWT (S oop, 1935) and CPT (Conne s, 1994) sco es. Al hough S oop In e e ence and TMT- pa B sco es could be also classi ied in o he execu i e unc ion domain his was no he objec i e o he majo i y o he s udies. Cons uc ional p axis and wo king memo y we e measu ed using he WAIS Block Design sub es and Digi sub es espec i ely (Wechsle , 1955, 2008, 2012) (Table 5). 80 ound mo e e o s in SCWT (U = 118.5; p = 0.03) and TMT-B (U = 98; p = 0.005) in ecen suicide a emp e s (n = 20) han non-a emp e pa ien s (n = 20). In acco dance wi h hese esul s, Ve ma e al. (2016) assessed a en ion in 175 pa ien s diagnosed wi h schizoph enia o schizoa ec i e diso de using TMT. Resul s indica e ha pa ien s wi h li e ime suicide in en had a poo e pe o mance in TMT-A ( = 1.965, p = 0.026) and TMT-B (X2173=2.282, p = 0.012) when compa ed o non-a emp e s, who ook mo e ime o comple e bo h asks. In e es ingly, Nangle e al. (2006) epo ed a signi ican ly be e abili y o con ol and shi a en ion in schizoph enic pa ien s wi h a p e ious his o y o suicidal beha iou (n = 28) measu ed wi h TMT Pa -B compa ed o non-a emp e s (n = 50) wi h he same diagnosis ( = 2.06; p < 0.05). Cons uc ional p axis and wo king memo y Weschle Adul In elligence Tes (WAIS) Block Design sub es was used by Adan e al. (2017), Nangle e al. (2006) and King e al. (2000) o assess cons uc ional p axis bu he e was no di e ence be ween g oups. The same happened wi h he WAIS Digi sub es o measu ing wo king memo y in he s udies conduc ed by Adan e al. (2017), Gilbe e al. (2011) and Keilp e al. (2013). The e o e, esul s indica e ha hese wo domains may no be al e ed in pa ien s who ha e a emp ed suicide. Diagnosis, cu en psychia ic symp oms and ime o he a emp Schizoph enia Pa ien s diagnosed wi h schizoph enia and p e ious his o y o suicidal beha iou showed a poo e pe o mance in execu i e unc ion (Adan e al., 2017; Koca ü k e al., 2015) compa ed o pa ien s wi h schizoph enia who had ne e a emp ed suicide. Con adic o y and insu icien esul s we e ound ega ding a en ion as a emp e s ou pe o med non- a emp e s in one s udy (Nangle e al., 2006) and ice e sa in ano he (Ve ma e al., 2016) (Table 6). 81 Table 6. Sample dis ibu ion acco ding o diagnosis, ime o he a emp and symp oms. A ec i e diso de s n = 1512 Recen a emp 59 symp oma ic Dis an a emp 313 eu hymic 350 symp oma ic Ne e a emp ed 345 eu hymic 445 symp oma ic Schizoph enia n = 373 Dis an a emp 118 symp oma ic Ne e a emp ed 255 symp oma ic A ec i e diso de s In 7 s udies (Jollan e al., 2013; Keilp e al., 2008, 2013, 2014; McGi e al., 2012; Olié e al., 2015; Richa d-De an oy e al., 2012) cogni i e pe o mance was epo ed o be poo e in a ec i e pa ien s wi h suicide compa ed o clinically-simila pa ien s wi hou suicidal beha iou , while 5 s udies (Deisenhamme e al., 2018; Gilbe e al., 2011; Go lyn e al., 2013; Ho e al., 2018; King e al., 2000) did no ind di e ences be ween g oups. Acco ding o Richa d-De an oy e al. (2012), cu en ly symp oma ic pa ien s who had ecen ly a emp ed suicide had a poo e pe o mance in a en ion compa ed o non- a emp e s. Howe e , o he au ho s ound no di e ences in a en ion (King e al., 2000), execu i e unc ion (King e al., 2000) and decision-making (Deisenhamme e al., 2018) in cu en ly dep essed a emp e s compa ed o clinically-ma ched non-a emp e s. Fu he mo e, cu en ly symp oma ic pa ien s wi h a his o y o suicide a emp had poo e ou comes in a en ion (Keilp e al., 2008, 2013) and execu i e unc ion (McGi e al., 2012) bu exhibi ed simila decision-making pe o mance (Go lyn e al., 2013; Ho e al., 2018) when compa ed o pa ien s wi h a ec i e symp oms wi hou a his o y o suicide a emp . Finally, eu hymic pa ien s wi h his o y o suicidal beha iou had wo se decision-making (Jollan e al., 2013), a en ion (Keilp e al., 2014; Olié e al., 2015) and execu i e unc ion (Keilp e al., 2014) compa ed o eu hymic non-a emp e s. None heless, he s udy by Gilbe e al. (2011) conduc ed wi h a simila sample epo ed no di e ences on he cogni i e pe o mance be ween g oups (Table 5). 82 3.2. MANUSCRIPT 2: COGNITION IN RECENT SUICIDE ATTEMPTS: ALTERED EXECUTIVE FUNCTION (Fe nández-Se illano e al., 2021b) (Annex 1). 3.2.1. OBJECTIVES • To compa e he neu opsychological pe o mance o MDD pa ien s wi h a ecen suicide a emp , MDD pa ien s wi h his o y o suicide a emp , MDD non-a emp e s and heal hy con ols on he ollowing cogni i e domains: wo king memo y, p ocessing speed, decision-making, execu i e unc ion, and a en ion. • To compa e childhood auma and ecen s ess ul li e e en s o MDD pa ien s wi h a ecen suicide a emp , MDD pa ien s wi h his o y o suicide a emp , MDD non- a emp e s and heal hy con ols 3.2.2. MATERIALS AND METHODS Pa icipan s 96 pa icipan s we e ec ui ed om he Psychia y Depa men o he A aba Uni e si y Hospi al—San iago. All pa ien s we e diagnosed wi h MDD acco ding o DSM-5 (Ame ican Psychia ic Associa ion, 2013) c i e ia and we e ecei ing psychopha macological ea men o hei condi ion. The sample was ca ego ized in o he ollowing g oups: 20 dep essed pa ien s who we e hospi alized a e a ecen suicide a emp (≤ 30 days), 33 pa ien s wi h a pas suicide a emp du ing hei li e ime and hospi alized o MDD episodes, 23 pa ien s wi hou his o y o suicidal a emp s and hospi alized o MDD episodes and 20 heal hy con ols wi h no pe sonal o amily his o y o men al illness ma ched by age and sex wi h he e e ence g oup, ha is, he ecen suicide a emp g oup. Suicide a emp was de ined as a sel -ini ia ed sequence o beha iou s by an indi idual who, a he ime o he ini ia ion, expec ed ha he se o ac ions would lead o his o he own dea h (DSM-5; Ame ican Psychia ic Associa ion, 2013). The exclusion c i e ia o he h ee g oups including pa ien s we e: p esence o psycho ic symp oms and o he como bid psychia ic diso de s wi h he excep ion o obacco use 83 diso de , acu e in ec ions, neu ological illness, in ellec ual disabili y, demen ia, o ganic diseases ha comp omise cogni i e unc ioning, and cogni i e synd omes. In addi ion o his, he exclusion c i e ia o heal hy con ols included ei he pe sonal o a amily his o y o majo psychia ic diso de s. All pa icipan s we e be ween 18 and 65 yea s old and had signed an in o med consen . This s udy was app o ed by he Euskadi E hics Commi ee and was conduc ed acco ding o he Decla a ion o Helsinki (Wo ld Medical Associa ion, 2013). P ocedu e and Measu es A e ec ui men and signa u e o he in o med consen , each pa icipan had an in e iew wi h a psychologis o sociodemog aphic da a collec ion and clinical assessmen . Sociodemog aphic a iables included sex, age, educa ion le el, ma i al s a us and economic s a us. Clinical assessmen included he numbe o p e ious a emp s, age o index a emp o suicide a emp e g oup, he numbe o p e ious dep essi e episodes and psychia ic medica ion o all pa ien g oups. Fo all pa icipan s he assessmen included a d ug in ake egis y ca ego izing he consump ion o each d ug as use / abuse / dependence. Besides, dep essi e symp om se e i y was assessed using he 17-i em Spanish e sion o he Hamil on Dep ession Ra ing Scale (HDRS) (Bobes e al., 2003; Hamil on, 1967), a s uc u ed ins umen widely used in he psychia ic ield (Failde e al., 2013; González-O ega e al., 2015; Heal h Quali y On a io, 2017) ha o e s a quan i a i e measu e o he se e i y o dep essi e symp oms in a clinical popula ion acco ding o he c i e ia o he e alua o who conduc s he clinical in e iew. Each i em has be ween h ee and i e possible esponses wi h 0–2 o 0–4 sco es, espec i ely, and he o al sco e anges om 0 o 52. The 17-i em Spanish e sion has good eliabili y, wi h a C onbach's α o 0.72, and alidi y wi h a co ela ion wi h o he scales o dep essi e symp oms (Mon gome y–Asbe g and Beck's Dep ession In en o y) anging om 0.8 o 0.9. Recen (6 mon hs) s ess ul e en s we e measu ed in all pa icipan s using he Spanish e sion o he Lis o Th ea ening Expe iences (LTE) (B ugha & C agg, 1990; Mo ico e al., 2013), a 12-i em b ie ques ionnai e wi h yes/no esponses ega ding pe sonal, ela ional, inancial, and heal h p oblems. This ques ionnai e has a high es – e es eliabili y (κ = 0.61– 0.87) and is a alid and eliable measu e o s ess ul e en s in men al heal h, speci ically in dep ession (OR = 1.64–2.57) (Mo ico e al., 2013), which has been p e iously used in s udies 84 wi h psychia ic popula ions (Casey e al., 2006; Ce illa e al., 2007; Dalga d e al., 2006; Powe s e al., 2013). Childhood abuse and neglec o pa icipan s we e assessed wi h he Spanish e sion o he Childhood T auma Ques ionnai e—Sho Fo m (CTQ-SF) (Be ns ein & Fink, 1998; He nandez e al., 2013), a sel -adminis e ed 28-i em ques ionnai e wi h i e Like esponses (ne e , a ely, some imes, o en, and always) ha has been ex ensi ely used (B us enghi e al., 2019; De i e al., 2019; Gu ié ez e al., 2015; Lee e al., 2015; Li e al., 2014; Xie e al., 2018) o e alua e he mal ea men dimensions ha we e de ec ed in he o iginal ac o ial analysis o cons uc alidi y (Be ns ein & Fink, 1998): emo ional (C onbach's α = 0.87): physical (C onbach's α = 0.89) and sexual (C onbach's α = 0.94) abuse and physical (C onbach's α = 0.66) and emo ional (C onbach's α = 0.83) neglec (He nandez e al., 2013). Besides, he pa icipan s unde wen a neu opsychological assessmen using s anda dized ins umen s ha e alua e he ollowing cogni i e domains: wo king memo y, p ocessing speed, decision-making, execu i e unc ion, and a en ion. The es and measu es used in each domain (Table 7) we e adap ed om p e ious exis ing li e a u e on cogni i e assessmen in men al diso de s (Be na do e al., 2013; Cues a e al., 2015). A desc ip ion o each ins umen can be ound in he me hods sec ion o Manusc ip 1 abo e. Table 7. Cogni i e domains and neu opsychological es s employed. Wo king memo y WAIS-IV A i hme ic: o al sco e WAIS-IV Digi o al sco e (Wechsle , 2008, 2012) P ocessing speed WAIS-IV Symbol Sea ch: o al sco e WAIS-IV Coding o al sco e (Wechsle , 2008, 2012) Decision-making IGT: o al money sco e (Becha a e al., 1994) Execu i e unc ion WSCT: ca ego ies, e o s, pe se e a i e e o s (Hea on, 1981) SCWT: in e e ence sco e (Golden, 2001; S oop, 1935) FAS Tes : o al co ec answe s (Ben on e al., 1994; Bu iel e al., 2004) A en ion SCWT: Colou Wo d sco e (Golden, 2001) 85 S a is ical Analyses S a is ical analyses we e pe o med using IBM SPSS S a is ics 25 and R 2.5.1. wi h he help o an expe biomedical s a is ician. Da a we e checked o Gaussian dis ibu ion. Compa isons be ween g oups ega ding he sociodemog aphic and clinical a iables we e pe o med wi h ANOVA ollowed by Bon e oni pos -hoc es ing o con inuous a iables and chi-squa e o ca ego ical a iables. Fo he analyses o cogni i e pe o mance, measu es selec ed om each es (Table 7) we e ga he ed in o he co esponding cogni i e domain ha is e alua ed and he ob ained sco es we e ans o med in o a e age z-sco es. Backwa d mul iple eg essions we e pe o med adjus ing o he ollowing con ounding a iables: age, sex, economic s a us, educa ion, ma i al s a us, d ug consump ion ( obacco, cannabis, and alcohol), and se e i y o dep essi e symp oms acco ding o he HDRS. In each model, only signi ican con ounde s (p<0.05) we e included. 3.2.3. RESULTS Sociodemog aphic and clinical a iables The e we e no signi ican di e ences be ween g oups ega ding sociodemog aphic a iables (Table 8). In he ecen a emp g oup, 35% o pa ien s we e ec ui ed a e an index a emp , 40% o pa ien s ea emp ed o he second ime, and 60% o pa ien s had mo e han wo ea emp s. In he li e ime a emp g oup, 6.3% o pa ien s had a emp ed suicide once, 34.4% wice, and 59.3% mo e han wice. Rega ding psychia ic medica ion, he majo i y had simila psychopha macological ea men as 94% we e unde poly he apy consis ing o an idep essan s and benzodiazepines, whe eas 6% o pa ien s we e unde mono he apy o ei he o hose medica ions. In addi ion o ha ing simila medica ion p o iles, he se e i y o dep essi e symp oms was equally dis ibu ed ac oss pa ien g oups. Bon e oni pos -hoc analyses e ealed ha all pa ien g oups had signi ican ly highe sco es o dep essi e symp oms measu ed by he HDRS han heal hy con ols (p < 0.01 in each compa ison), bu wi h no di e ence be ween pa ien g oups. Besides, heal hy con ols had ewe s ess ul e en s in he las 6 mon hs han each o he pa ien g oups (p < 0.05 in each compa ison), wi h no di e ence be ween pa ien g oup. Also, pos -hoc analyses o he CTQ-SF sco es indica e g ea e gene al auma (p = 86 0.003), emo ional abuse (p = 0.003), emo ional negligence (p = 0.006), and physical negligence (p = 0.009) in pa ien s wi h a his o y o suicide a emp s in compa ison o heal hy con ols. Besides, pa ien s wi h ecen suicide a emp s epo ed highe sco es o childhood sexual abuse (p = 0.038) han heal hy con ols. The e we e no o he signi ican di e ences be ween g oups ega ding auma and abuse. 87 Table 8. Demog aphic and clinical a iables. Recen a emp e s (n=20) Li e ime a emp e s (n=33) Dep essed non-a emp e s (n=23) Heal hy con ols (n=20) S a is ical con as (p) Sex, n(%) Female Male 13 (65%) 7 (35%) 26 (78.8%) 7 (21.2%) 18 (78.3%) 5 (21.7%) 14 (70%) 6 (30%) X2 =1.617; p=0.656 Age, mean (SD) 44.70 (8.785) 44.45 (12.765) 50.57 (9.926) 44.58 (9.221) F(3,91) = 1.842; p=0.145 Educa ion le el, n(%) P ima y Seconda y P epa a o y Uni e si y 2 (10%) 7 (35%) 5 (25%) 6 (30%) 6 (18.2%) 11 (33.3%) 9 (27.3%) 7 (21.2%) 5 (21.7%) 7 (30.4%) 6 (26.1%) 5 (21.7%) 0 (0%) 6 (30%) 4 (20%) 10 (50%) X2 =9.886; p=0.360 Economic s a us, n(%) Low Medium High 7 (38.9%) 9 (50%) 2 (11.1%) 10 (37%) 11 (40.7%) 6 (22.3%) 10 (50%) 10 (50%) 0 6 (33.3%) 9 (50%) 3 (16.7%) X2 =5.61; p=0.468 P e ious suicide a emp s, mean (SD) 1.47 (1.87) 2.34 (2.04) - - =-1.52; p=0.1 Age o index a emp , mean (SD) 33.55 (11.91) 31.83 (15.35) - - =0.42; p=0.67 P e ious dep essi e episodes, mean (SD) 2.60 (2.90) 7.50 (9.81) 2.38 (1.59) - F(2,47) =2.16; p>0.05 Dep ession se e i y (HDRS), mean (SD) 15.50 (7.23) 17.87 (6.54) 14.36 (8.93) 1.60 (2.09) F(3,89) = 25.741; p<0.01 Recen s ess ul e en s (LTE), mean (SD) 2.80 (1.70) 2.53 (2.11) 2.56 (1.90) 0.5 (1.15) F(3,91) = 7,281; p<0.01 CTQ o al, mean (SD) 57 (25.63) 64.1 (21.66) 52.57 (23.06) 38.15 (7.12) F(3,80) = 4.54; p<0.05 CTQ emo ional abuse, mean (SD) 11.15 (6.63) 13.19 (6.16) 10.38 (6.08) 7.57 (2.90) F(3,82) =3.112; p<0.05 CTQ physical abuse, mean (SD) 8.80 (4.93) 8.13 (5.02) 8.10 (5.73) 6.21 (2.36) F(3,82) =0.813; p=0.49 CTQ sexual abuse, mean (SD) 10 (7.48) 8.81 (5.58) 6.14 (2.15) 5.07 (0.27) F(3,82) =3.789; p<0.05 CTQ emo ional negligence, mean (SD) 10.2 (5.02) 14.13 (6.07) 10.67 (5.94) 8.08 (1.85) F(3,80) =4.736; p<0.05 CTQ physical negligence, mean (SD) 11.55 (2.58) 13.06 (3.18) 11.68 (3.48) 9.93 (1.90) F(3,83) =3.770; p<0.05 HDRS: Hamil on Dep ession Ra ing Scale. LTE: Lis o Th ea ening Expe iences. CTQ: Childhood T auma Ques ionnai e. 88 Pe o mance on Cogni ion The sco es on he i e domains included in his s udy a e p esen ed in Table 9. Table 9. Pe o mance on each cogni i e domain by g oupa. aDa a a e p esen ed as means and s anda d de ia ions. All alues a e z-sco es. Fo compa isons, backwa d s epwise mul iple eg essions we e pe o med adjus ed by signi ican con ounde s (age, sex, economic s a us, educa ion le el, ma i al s a us, dep ession se e i y and subs ance consump ion) wi h heal hy con ols as he e e ence g oup. Heal hy con ols pe o med signi ican ly be e in p ocessing speed, decision-making and a en ion han all pa ien g oups, wi h no di e ences be ween hem (Table 10). Table 10. Mul iple eg ession o neu opsychological pe o mancea. aDa a a e p esen ed as adjus ed B coe icien s assuming heal hy con ols as he e e ence g oup. * p<0.05; ** p<0.001 Recen a emp e s (n=20) Li e ime a emp e s (n=33) Dep essed non-a emp e s (n=23) Heal hy con ols (n=20) Wo king memo y -0.577 (0.822) -0.825 (0.867) -0.798 (0.845) 0 (0.784) P ocessing speed -1.002 (0.821) -1.403 (1.444) -1.306 (1.411) 0 (0.944) Decision making -0.772 (1.089) -0.726 (1.053) -0.873 (0.889) 0 (1.000) Execu i e unc ion -0.191 (0.256) 0.066 (0.484) 0.070 (0.530) 0.021 (0.313) A en ion -0.910 (0.770) -1.025 (0.667) -0.913 (0.646) 0.046 (0.781) Ve bal memo y Wo king memo y P ocessing speed Decision making Execu i e unc ion A en ion Recen A emp e s -0.176 -0.113 -1.065* -0.829* -0.229 -0.604* Li e ime A emp e s -0.292 -0.221 -1.416** -0.664* 0.068 -0.577* Dep essed Non-A emp e s -0.174 -0.313 -1.050* -0.782* 0.072 -0.567* 89 As he main objec i e o his s udy was o de e mine he cogni i e di e ences be ween ecen suicide a emp e s and cu en non-suicidal dep essed pa ien s, he e e ence g oup o adjus ed eg essions was a e wa ds changed o ecen a emp e s. The esul s yielded signi ican di e ences in he execu i e unc ion domain. Bo h li e ime a emp e s and dep essed non-a emp e s had signi ican ly highe sco es in his domain in compa ison o ecen a emp e s (B = 0.296, p = 0.019, and B= 0.301, p = 0.028, espec i ely); ha is, ecen suicide a emp e s had poo e pe o mance on execu i e unc ion. Howe e , he e we e no signi ican di e ences be ween g oups in he es o he cogni i e domains. Fu he analyses showed ha he e was an in e ac ion be ween g oup (dep essed ecen a emp e s, dep essed (Table 11) li e ime a emp e s, and dep essed non-a emp e s) and sex on execu i e pe o mance. Acco ding o hese esul s, women wi h ecen a emp s had sligh ly be e sco es on execu i e unc ion han males. Howe e , in he es o he g oups, men ou pe o med women, especially in dep essed non-a emp e pa ien s, wi h a la ge e ec size indica ing a s ong in e ac ion be ween sex and g oup. Table 11. E ec sizes o being emale on execu i e unc iona. a Adjus ed o po en ial con ounde s b E ec size is in e p e ed as mean (s anda d de ia ion) di e ences be ween emales and males on he execu i e unc ion. Femaleb Recen A emp e s 0.088 (-0.301, 0.478) Li e ime A emp e s -0.239 (-0.624, 0.146) Dep essed Non-A emp e -0.663 (-1.134, -0.192) Heal hy Con ols -0.189 (-2.058, 1.680) 96 Table 13. In lamma ion pa ame e s ac oss g oups. Recen a emp e s (01) (n=20) (mean;SD) Dis an a emp e s (02) (n=33) (mean;SD) Dep essed non- a emp e s (03) (n=23) (mean;SD) Heal hy con ols (04) (n=20) (mean;SD) S a is ical con as (p) E ec Size Bon e oni Pos Hoc Tes IL-2 77.66 (70.72) 59.89 (54.46) 52.64 (35.15) 70.52 (48.68) F(3,89)=0.91;p=0.44 0.03 01=02=03=04 IL-2R 124.11 (30.29) 141.29 (32.32) 136.43 (55.00) 135.00 (40.31) F(3,89)=0.71;p=0.55 0.02 01=02=03=04 IL-4 1.84 (1.47) 3.73 (7.22) 1.60 (0.68) 2.29 (0.50) F(3,89)=1,32;p=0.27 0.04 01=02=03=04 IL-6 5.94 (3.49) 5.90 (2.72) 5.41 (2.42) 3.60 (1.64) F(3,89)=3.69;p=0.01 0.11 01>04 02>04 TNF-α 43.74 (14.41) 45.74 (20.96) 44.41 (13.09) 39.21 (11.55) F(3,89)=0.67; p=0.57 0.00 01=02=03=04 Figu e 12. Mean (SD) IL-6 plasma concen a ions in each g oup. *p < 0.05 signi ican di e ences in compa ison o con ols. 5.94 (3.49)* 5.90 (2.72)* 5.41 (2.42) 3.6 (1.64) 0 1 2 3 4 5 6 7 RE CENT AT T E MPTERS LIFETIME AT T E MPTERS DEPRESSED NON - AT T E MPTERS HEALT HY CONTROLS IL-6 (PG/ML PLASMA) 4. DISCUSSION The i s main inding in his hesis is ha indi iduals who ha e a emp ed suicide ha e some neu opsychological al e a ions ha a e speci ic o suicide and no a ibu able o an unde lying psychia ic diso de (Manusc ip 1 and Manusc ip 2). P e ious s udies (Keilp e al., 2001; Ma zuk e al., 2005; McGi e al., 2012; Wes heide e al., 2008) and se e al sys ema ic e iews and me a-analyses epo neu opsychological al e a ions in suicide a emp e s (Hube e al., 2019; Jollan e al., 2011; Richa d-De an oy e al., 2012, 2014, 2016) bu cogni i e unc ioning is also impai ed in a high p opo ion o pa ien s wi h a men al diso de wi hou suicidal beha iou (Allo e al., 2016; Baune e al., 2014; Chak aba y e al., 2016; G ü zne e al., 2019; MacQueen & Memedo ich, 2017; Nakagome, 2017; Solé e al., 2017; Somme eld e al., 2016; Zhou e al., 2017). Since cogni i e de ici s a e p esen bo h in suicidal beha iou and men al illness, his aises he ques ion whe he he cogni i e pe o mance in suicide a emp e s is diagnosis-dependen o i he e may be some al e a ions speci ically ela ed o he a emp . In o de o add ess his inqui y, h oughou his hesis he me hodology employed was designed o con ol he possible e ec o a psychia ic diso de by compa ing clinically simila suicide a emp e s and suicide non-a emp e s. The e o e, he di e ences obse ed in cogni i e pe o mance a e mo e a ibu able o suicidal beha iou han o he men al diso de i sel . Rega ding he al e ed cogni i e domains in he Manusc ip 1 pa ien s wi h schizoph enia o an a ec i e diso de ha ha e a emp ed suicide ( ecen o dis an ) ha e wo se a en ion pe o mance han non-a emp e pa ien s wi h he same diagnosis and simila psychia ic symp oms. Besides, execu i e unc ion is al e ed in cu en ly symp oma ic a emp e s diagnosed wi h schizoph enia (Adan e al., 2017; Koca ü k e al., 2015) and possibly in cu en ly symp oma ic a emp e s diagnosed wi h an a ec i e diso de (McGi e al., 2012). In con as , inconclusi e da a has been ound ega ding decision-making and no di e ences a e ound in cons uc ional p axis and wo king memo y. Mos o he s udies in his e iew include dis an suicide a emp s; he e o e, di e ences be ween g oups sugges ha cogni i e al e a ions a e p esen long a e he a emp which migh be a isk ac o o e-a emp s; howe e , hese al e a ions ha e no necessa ily been p esen in he pe iod o ime when he a emp occu ed. In his sense, s udies in ol ing ecen a emp s could help o analyse he cogni i e pe o mance closely ela ed o a suicide a emp . 99 In ela ion o his, Manusc ip 2 gi es e idence ha ecen suicide a emp s a e linked o al e a ions on he execu i e unc ion. In his s udy, dep essed pa ien s wi h a suicide a emp in he las 30 days ha e signi ican ly poo e pe o mance on execu i e unc ion han dis an dep essed a emp e s and dep essed non-a emp e s. Al e a ions on his cogni i e domain ha e al eady been desc ibed in pa ien s wi h a his o y o suicide a emp (Adan e al., 2017; Keilp e al., 2001, 2008, 2013, 2014; McGi e al., 2012; Richa d-De an oy e al., 2012) and in dep essed pa ien s wi hou suicidal beha iou (Keilp e al., 2013; Somme eld e al., 2016), especially in hose wi h poo ea men esponse (Cas ellano e al., 2020), bu o he bes o ou knowledge, his is he i s s udy ha compa es ecen , dis an and ne e a emp e s diagnosed wi h MDD and heal hy con ols. Besides, ou esul s show ha sex has an in luence on he execu i e unc ion o ecen suicidal a emp e s. The sligh ly be e pe o mance o women in ecen a emp g oup migh be linked o highe impulsi i y sco es ound in men in p e ious s udies (C oss e al., 2011; G issom & Reyes, 2019) which would imply a highe endency o hink and beha e wi hou less planning, e o de ec ion, cogni i e lexibili y and inhibi o y con ol (Jiménez e al., 2016), ha is, a poo e pe o mance in cogni i e p ocesses ha a e unde execu i e unc ion con ol. Acco ding o his, men would be mo e p one o make unadap a i e impulsi e choices unde demanding o s ess ul e en s which could inc ease he isk o high le hali y o a al suicide a emp s. None heless, i is ema kable ha dep essed non-a emp e men ha e a signi ican ly be e execu i e unc ion pe o mance. This may be due o he ac ha cogni i e symp oms ela ed o dep ession, such as umina ion and hypochond ia, a e mo e se e e in women (Ma cus e al., 2005) wi h a g ea e impac on hei unc ionali y (Rieche - Rössle , 2010). Apa om psychological ac o s, he e a e also biological di e ences such as, sex ho mones (Gil ay e al., 2012; Kumsa e al., 2014), dys egula ion o he HPA axis (Zagni e al., 2016) and in lamma o y pa ame e s (Labaka e al., 2018) ha make dep ession mo e ad e se o women. 100 Addi ionally, neu opsychological assessmen esul s e eal ha all dep essed pa ien s wi h simila dep ession se e i y pe o m signi ican ly wo se han heal hy con ols in p ocessing speed, decision making and a en ion bu wi h no di e ence be ween g oups. Consis en wi h p e ious li e a u e (Alexopoulos e al., 2015; Chak aba y e al., 2016; Co ena e al., 2016; Keilp e al., 2008), his inding sugges s ha hese al e a ions a e associa ed wi h MDD being di e en om hose speci ically associa ed wi h ecen suicide a emp s and he e o e each condi ion would be ela ed o a di e en cogni i e p o ile. Acco ding o ou esul s, a en ion and execu i e unc ion migh be al e ed in suicide a emp s. A en ional dys unc ion in e e es wi h he abili y o p ocess and in e p e in o ma ion o espond o si ua ional demands. Execu i e unc ion encompasses mul iple cogni i e p ocesses ha o ches a e hough and beha iou (Gläsche e al., 2012; Mille & Cohen, 2001) including esponse inhibi ion, ask-shi ing and he cons an upda e o he wo king memo y as s a ed in he comp ehensi e model p oposed by Miyake e al. (2000). O he au ho s also inco po a e planning, decision making, wo king memo y and e o de ec ion among i s unc ions (Gläsche e al., 2012; Mille & Cohen, 2001). The pe o mance on bo h cogni i e domains is subjec ed o he in luence o indi idual ac o s, such as emo ional egula ion, pe sonali y ai s and e en auma ic e en s (G issom & Reyes, 2019; Le ne e al., 2015; Phelps e al., 2014) . De ici s on hese p ocesses can lead o dys egula ion o emo ion, hough s and ac ions (B edemeie & Mille , 2015) which migh con ibu e o conside ing suicide as a solu ion unde c i ical ci cums ances (Richa d- De an oy e al., 2014). In addi ion, hese al e a ions may also inc ease in e pe sonal di icul ies inc easing he isk o a emp ed suicide (Jollan e al., 2007). Ano he ele an inding in his esea ch is ha indi iduals ha ha e a emp ed suicide ha e in lamma ion al e a ions (Manusc ip 3). Ou esul s in Manusc ip 3 sugges ha suicide is accompanied by a sys emic in lamma o y esponse as IL-6 cy okine plasma concen a ion is ele a ed in bo h ecen (las 30 days) and dis an dep essed suicide a emp e s. This is in acco dance wi h se e al s udies ha ind ele a ed IL-6 in ce eb ospinal luid (Bay-Rich e e al., 2015; Lindq is e al., 2011), plasma (Ami ai e al., 2020; Isung e al., 2014; Janelidze e al., 2011; Kea on e al., 2019; P iya e al., 2016) and gene and p o ein exp ession ela ed o IL-6 in pos -mo em issue o suicide a emp e s (Hoyo-Bece a e al., 2013; Pandey e al., 2012). 101 I is no ewo hy ha in ou s udy his cy okine p og essi ely dec eases om i s highes le els in ecen suicide a emp e s o dis an a emp e s, non-a emp e s and heal hy con ols, espec i ely sugges ing a dose-e ec ole o IL-6 in suicidal beha iou . Al hough no s a is ically signi ican , IL-6 concen a ions o dep essed non-a emp e s show a endency o be highe han heal hy con ols, in consonance wi h p e ious s udies ha obse e mo e in lamma ion in dep essi e pa ien s (Colasan o e al., 2020; Liu e al., 2017; Ting e al., 2020). Howe e , as his s udy s a i ies dep essi e pa ien s acco ding o hei suicidal p o ile in o sepa a e g oups, possible di e ences be ween non-suicidal dep essi e pa ien s and heal hy subjec s migh be mo e sub le han hose obse ed in s udies ha include dep essi e pa ien s in o he same g oup ega dless o hei suicidal his o y. Despi e IL-6 being one o he cy okines mos equen ly associa ed wi h suicide (Black & Mille , 2015; Ducasse e al., 2015; Ganança e al., 2016; Se a ini e al., 2020), o he s udies desc ibe no di e ences wi h non-a emp e s (Co yell e al., 2018, 2020; Dolsen e al., 2020; Eidan e al., 2019; Gabbay e al., 2009; Isung e al., 2012; Jha e al., 2020; Tonelli e al., 2008; Va gas e al., 2013), hus, i s ole in suicidal beha iou is ye o be elucida ed. The mechanisms by which cy okines in luence suicide isk a e no clea bu he e is e idence o hei immunomodula ing ole in he CNS (Bo sini e al., 2015; Cou e e al., 2016; Dunn, 2006) a ec ing emo ion, cogni ion and beha iou . In ac , a eas o he b ain ha o ches a e and egula e hese h ee psychological p ocesses, such as hypo halamus, hippocampus, locus coe uleus and p e on al co ex, a e densely popula ed wi h cy okine ecep o s (Jeon e al., 2019). Hence, dys egula ed con inual syn hesis o IL-6 has a pa hological e ec which may esul in he de elopmen o psychia ic condi ions (Tanaka e al., 2014) and inc eased suicide isk (B undin e al., 2017). Acco ding o he p ospec i e s udy o Ba y e al. (2016) pa ien s wi h highe le els o in lamma ion ha e a h ee- old ele a ed isk o u u e suicide dea h, sugges ing ha in lamma ion is p eceded and implica ed in suicide a emp s. Compa isons be ween g oups on IL-2, IL2-R, IL-4 and TNF-α do no yield signi ican esul s and li e a u e on hese pa ame e s emains con adic o y. Rega ding IL-2 and IL2-R, Janelidze e al. (2011) and Kim e al. (2008) desc ibe lowe IL-2 concen a ions in suicide a emp e s in compa ison o pa ien s wi hou a suicide a emp and heal hy con ols while Nässbe ge & T äskman-Bendz (1993) epo inc eased IL-2 soluble ecep o (IL-2R) plasma concen a ions in suicide a emp e s, al hough Ro henhäusle e al. (2006) do no ind hese di e ences. Conce ning IL-4 le els, he e a e s udies ha desc ibe an inc ease in suicide 102 a emp s (Tonelli e al., 2008), o he s a dec ease (Jha e al., 2020; Kim e al., 2008) and he one o Gabbay e al. (2009) wi h no di e ences be ween g oups. Rega ding TNF-α, in he s udy o Janelidze e al. (2011) dep essed suicide a emp e s ha e highe plasma le els han dep essed non-a emp e s and heal hy con ols. Simila ly, Pandey e al. (2012, 2018) ind mo e concen a ion o TNF-α in he b ain o adolescen s who died by suicide. Howe e , he e a e s udies desc ibing an opposi e ela ionship (Gabbay e al., 2009) and o he s ha do no suppo any connec ion (Co yell e al., 2018, 2020; Dolsen e al., 2020; Hoyo-Bece a e al., 2013; Huang & Lee, 2007; Jha e al., 2020; Lindq is e al., 2009; Tonelli e al., 2008; Va gas e al., 2013). The las impo an inding in his in es iga ion is ha hese in lamma o y and cogni i e al e a ions a e in e ela ed and associa ed o o he psychological isk ac o s in ecen suicide a emp s (Manusc ip 2 and Manusc ip 3). In lamma ion and cogni ion a e linked acco ding o he esul s in he Manusc ip 3 in which highe IL-6 le els a e associa ed o lowe sco es on a en ion, he mos clea ly al e ed cogni i e domain in suicide a emp s acco ding o he sys ema ic e iew in he Manusc ip 1. As p e iously men ioned in his documen , cy okines can media e cogni ion due o hei e ec on he CNS mechanisms and a eas ela ed o cogni ion (Jeon e al., 2019; Wilson e al., 2002) causing cogni i e al e a ions ha in e e e wi h in o ma ion p ocessing, in e p e a ion and beha iou al esponse inc easing suicide isk (La a e al., 2015; Szan o, 2017). Rega ding psychological isk ac o s, in Manusc ip 2 ecen suicide a emp e s epo mo e child sexual abuse han he es o he g oups. Dis an suicide a emp e s epo mo e gene al auma, emo ional abuse and negligence and, in gene al, all pa ien s had mo e ecen s ess ul e en s han heal hy con ols. The accumula ing e ec o ecen s ess ul e en s (Howa h e al., 2020) and p e ious his o y o childhood mal ea men ele a es he isk o suicide in adul li e (Bahk e al., 2017; Jiménez-T e iño e al., 2019; Zelazny e al., 2019). In Manusc ip 3 esul s gi e e idence o he link be ween in lamma ion and auma in ecen suicide a emp . Highe IL-6 concen a ions we e independen ly linked o adul physical abuse and lowe global unc ioning sco es. In addi ion, highe le els o IL-4 we e associa ed o his o y o child physical abuse and his o y o child agg essi e beha iou . Nume ous s udies ha e linked suicide wi h childhood and adul abuse (Ca a aca-Sánchez e al., 2019; 103 Co yell e al., 2020; Ha ley e al., 2018; Salokangas e al., 2019; Thompson e al., 2019). In e es ingly, a ecen s udy ela es suicide isk o IL-6 pheno ypes and childhood ad e si y (Schiweck e al., 2020). Fu he mo e, hese ad e se expe iences can ha e de imen al e ec s on cogni ion as desc ibed by se e al au ho s. In he s udy o Zelazny e al. (2019) highe sco es on execu i e unc ion p o ec om suicide in indi iduals wi h childhood mal ea men . Ca alho e al. (2020) ind a poo e pe o mance on he execu i e unc ion o mal ea ed child en in compa ison o non-mal ea ed child en and acco ding o he s udy o Dannehl e al. (2017) hese di e ences a e also p esen in adul s wi h his o y o childhood ad e si y, especially in hose wi h physical abuse and neglec . All in all, ad e se li e e en s, e en long ime a e , can dys egula e he immune sys em as a esponse o a s ess ul auma ic s imulus esul ing in highe le els o in lamma o y pa ame e s (B undin e al., 2017; Lippa d & Neme o , 2020) which can a ec cogni i e pe o mance (Jeon e al., 2019; Wilson e al., 2002) inc easing suicide isk. In conclusion, ou esul s gi e e idence on he speci ic cogni i e and in lamma ion al e na ions in suicide a emp s and hei mu ual in e play and associa ion wi h o he ulne abili y ac o s ha inc ease he suicidal isk. As cogni i e pe o mance can be ained and imp o ed (Salag e e al., 2017), cogni i e sc eening and s imula ion may be p oposed as a s a egy o suicide p e en ion in a isk pa ien s. Fu u e s udies a e needed o iden i y possible di e ences be ween sex in each cogni i e domain o a mo e pe sonalized app oach and o a be e unde s anding o ea ly de ec ion ulne abili y ac o s ha may enable us o p e en suicide in a isk pa ien s. Fu he mo e, he in lamma ion mechanisms in ol ed in his complex beha iou a e ye o be explo ed. Unde s anding he ole o in lamma ion in suicide and iden i ying po en ial bioma ke s o his mul i ac o ial phenomenon emains a challenge o psychia y. Al hough he e is g owing e idence o he neu oin lamma ion hypo hesis o suicide, mo e esea ch is needed o cla i y inconsis en da a ound in li e a u e. Fu u e s udies in ol ing in lamma ion and suicide may ocus on measu ing he e ec o psychological p o ec i e ac o s and con inue he esea ch on he biological mechanisms in ol ing he immune esponse. Finally, deepe knowledge on he in e play o biological and clinical aspec s in MDD pa ien s wi h suicide a emp s would enable no el and pe sonalized ea men op ions and he de elopmen o mo e e ec i e p e en i e in e en ions. 104 Limi a ions The esea ch conduc ed on his hesis has he ollowing limi a ions ha should be men ioned: - In he Manusc ip 1 only s udies published in English o Spanish be ween he yea s 2000 and 2020 we e included in he sys ema ic e iew and g ey li e a u e was excluded. In addi ion, due o he sca ci y o s udies ha in ol e non-a emp e clinically-ma ched con ol g oup, he numbe o a icles and sample o pa ien s in his sys ema ic e iew was limi ed. Thus, u he s udies a e needed o cla i y he cogni i e domains ha a e al e ed in subjec s wi h suicidal beha iou . Rega ding execu i e unc ion esul s we e con adic o y, he e o e i is necessa y o con i m hese indings in u u e in es iga ions as we endea ou in Manusc ip 2. Ano he limi a ion o his e iew is he neu opsychological ba e y de ined as eligibili y c i e ia, which had o be educed o widely-used ins umen s bu , as a esul , we disca ded he e ogeneous da a om o he es s and cogni i e domains. - In he Manusc ip 2 he e a e a numbe o limi a ions. Recen and pas auma e en s we e assessed using sel -adminis e ed and sel - epo ed scales in MDD pa ien s who can be biased when epo ing his in o ma ion. As mo e women ecen ly a emp ed suicide han men, sex- ela ed di e ences on execu i e unc ion ound in ecen a emp e s mus be in e p e ed wi h cau ion and u he con i ma o y s udies a e ad isable. Mo eo e , some ac o s ha ha e been desc ibed in he li e a u e as po en ially in luencing suicidal beha iou in majo dep ession, such as anxie y (Mi e e al., 2013) o mixed symp oms (Popo ic e al., 2015), we e no assessed. - In he Manusc ip 3 al hough gene al sample was no small, each g oup sample size was no la ge o clus e compa isons. Howe e , his ho ough me hodological design composed by ou g oups ha di e en ia es ecen and dis an suicide a emp e s was c ucial o ob ain speci ic ou comes o clinically di e en g oups. Recen and dis an auma e en s we e assessed using a s anda dized p o ocol bu in o ma ion could be biased when epo ing his in o ma ion. Pa ien s wi h o he psychia ic condi ions and subs ance use diso de we e excluded om he s udy in o de o con ol signi ican in e ac ions wi h in lamma ion, which may esul in a less 105 ep esen a i e popula ion o a - isk pa ien s. Due o hei heal h s a us, pa ien s wi h suicidal a emp s in ol ing ex emely se e e inju ies we e no ec ui ed du ing he i s mon h a e he a emp . Thus, he sample o ecen a emp e s is less ep esen a i e ega ding his me hod. Some ac o s ha could po en ially in luence ou esul s, such as he p esence o anxie y, mixed symp oms, BMI and psychopha macological ea men we e no assessed. Indi idual bioma ke s o in lamma ion we e measu ed ins ead o ull pa hway in ol ing ecep o s and ansduc ion mechanisms. 113 This hesis is a inal p oduc ga he ing he e o s o he las yea s, bu i is no he end o ou in e es on suicidal beha iou . As esea ch is an ali e pa h, hese indings and he challenges aced on he clinical p ac ice lead o u he ques ions and inqui ies ha encou age us o con inue esea ching in o his opic. In his sec ion, p elimina y esul s o cu en and u u e p oduc ion ha has de i ed om his hesis a e b ie ly p esen ed. 6.1. VITAMIN D AS A PREDICTOR OF SUICIDE ATTEMPTS AND GLOBAL FUNCTIONING 6.1.1. BACKGROUND Ano he p omising bioma ke o suicide a emp s is i amin D, an indi ec measu e o he in lamma o y s a e o he o ganism. Amongs o he signi ican unc ions in he o ganism, i amin D has immunomodula ing p ope ies by egula ing he p oduc ion, di e en ia ion and unc ion o cy okines (Bo ges e al., 2011; Guillo e al., 2010; Yin & Ag awal, 2014). In ac , i has been desc ibed an in e se associa ion be ween i amin D and IL-6 le els (Liu e al., 2011) and low le els o i amin D ha e been associa ed wi h ch onic in lamma o y diseases such as mul iple scle osis, as hma, in lamma o y bowel disease and au oimmune heuma ic diseases (Piędel e al., 2021; Yin & Ag awal, 2014; Zheng e al., 2016). The e o e, i amin D can be an indi ec measu e o he in lamma o y s a e o he o ganism. Many s udies gi e e idence o he link be ween suicide and i amin D (G ude e al., 2014; Ta iq e al., 2011; Umhau e al., 2013; Fond e al., 2018; Gokalp, 2020; Kim e al., 2020; Pos olache e al., 2020; Wei e al., 2021; Yagci & A ci, 2021) and MDD (Anglin e al., 2013; Ju e al., 2013; Köhnke e al., 2020; Manzanos e al., 2020; Ronaldson e al., 2020; She chand e al., 2018; Spedding, 2014). In o de o be eligible as a suicide bioma ke , i amin D le els should be speci ically di e en in dep essed pa ien s wi h a suicide a emp han in dep essed non-a emp e s. Fo his eason, compa ing dep essed suicide a emp e s, dep essed non- a emp e s and heal hy con ols could shed ligh on he ole o his i amin in ela ion o suicide. 114 6.1.2. METHOD Pa icipan s 110 pa icipan s we e ec ui ed om he Psychia y Depa men o he A aba Uni e si y Hospi al – San iago om he yea 2018 o 2020. The sample (n=110) was composed o 52 dep essed pa ien s ha had ecen ly a emp ed suicide (<30 days), 23 dep essed pa ien s wi hou a li e ime his o y o suicide a emp s and 35 heal hy olun ee s ha we e in i ed o pa icipa e h ough a public ad e isemen in he hospi al. All pa ien s had been diagnosed wi h MDD acco ding o DSM-5 (Ame ican Psychia ic Associa ion, 2013) be o e he s udy and we e unde psychopha macological ea men o hei condi ion. Suicide a emp s we e de ined as sel -ini ia ed sequence o beha iou s by an indi idual who, a he ime o he ini ia ion, expec ed ha he se o ac ions would lead o his o he own dea h (DSM-5; Ame ican Psychia ic Associa ion, 2013). Pa ien s wi h a diagnosis o a psycho ic diso de we e no eligible o his s udy. Exclusion c i e ia o all pa icipan s included subs ance use diso de excep obacco, neu ological o /and neu odegene a i e illness, se e e o ganic disease, sys emic au oimmune disease, acu e in ec ions, being unde ecen (las week) an i-in lamma o y ea men and i amin D supplemen a ion (las yea ). Besides, heal hy con ols wi h pe sonal o amily his o y o se e e psychia ic diso de s and/o suicide a emp s we e no included in he s udy. P ocedu e and Measu es All pa ien s we e in e iewed o sociodemog aphic and clinical da a ga he ing by an expe ienced psychologis . Clinical a iables included psychopha macological ea men , dep ession se e i y and global unc ioning. The se e i y o dep essi e symp oms was assessed by he Spanish e sion o he Hamil on Dep ession Ra ing Scale (HDRS) (Bobes e al., 2003; Hamil on, 1967) and he Global Assessmen o Func ioning scale (GAF) was used o measu e global unc ioning (Ame ican Psychia ic Associa ion, 2013). Heal hy olun ee s we e only in e iewed o sociodemog aphic da a ga he ing. Besides, all pa icipan s had a 10mL enous blood ex ac ion o se um 25-hyd oxy i amin D analysis. Seasonali y da a was ga he ed o egis e he season o he yea when he blood ex ac ion was conduc ed on each pa icipan . A he hospi al labo a o y Alini y i 25-OH Vi amin D Reagen Ki (08P45) was employed o quan i y se um 25-OH i amin D le els and e e ence le els we e ca ego ized as in Table 14. 115 Table 14. Re e ence le els o 25-hyd oxy i amin D De icien < 10 ng/mL Subop imal 10 - 30 ng/mL Op imal 30 -100 ng/mL Toxic >100 ng/mL 6.1.3. PRELIMINARY RESULTS The sample was composed o 102 pa icipan s, 46 dep essed pa ien s who had ecen ly a emp ed suicide (<30days), 22 non-a emp e dep essed pa ien s and 34 heal hy con ols. The e we e no di e ences ega ding sex (X2(2,102)=0.12; p=0.94) and age (F(2,99)=2.35; p=0.10) be ween g oups and dep ession se e i y ( (63)=0.98; p=0.33) be ween pa ien g oups. Pa ien s wi h a suicide a emp (M=53.88, SD=11.11) had signi ican ly lowe global unc ioning sco es ( =-3.75; p=0.001) han dep essed non-a emp e pa ien s (M=69.33, SD=15.84). Al hough he majo i y o pa icipan s had 25-hyd oxy- i amin D unde op imal concen a ion (30ng/mL), de icien le els (<10ng/mL) we e only egis e ed in he suicidal a emp e g oup wi h a 91.3% o pa ien s unde he op imal concen a ion. One-way ANOVA e ealed signi ican di e ences (F(2,99)=11.39; p<0.001) be ween g oups ega ding 25-hyd oxy- i amin D le els. Speci ically, acco ding o Bon e oni Pos Hoc es , dep essed ecen suicide a emp e s had signi ican ly lowe le els o i amin D in compa ison o non-a emp e dep essed pa ien s (p<0.001, 95% C.I.= -21.32, -6.41) and heal hy con ols (p=0.03, 95% C.I.= -14.73, -1.72), whe eas he e we e no di e ences be ween non-a emp e dep essed pa ien s and heal hy con ols (p=0.11). These di e ences emained signi ican a e ANCOVA compa isons con olling o s a ionali y (F(2,99)=9.86; p<0.001) in all g oups and o psychopha macological ea men (F(68)=21.54; p<0.001) in pa ien g oups whose pa icipan s we e mos ly p esc ibed a combina ion o SSRI/SNRI an idep essan and benzodiazepines (45.6%). The odds o a emp ing suicide in he whole sample (bo h g oups o pa ien s wi h dep essi e episodes and heal hy con ols) we e app oxima ely 7 imes highe wi h subop imal i amin D le els (<30 ng/mL), OR=6.79 (95% CI: 2.14, 21.62) and inc eased o almos 9 imes conside ing only pa ien s (a emp e s and dep essed non-a emp e s) in he sample, OR=8.75 (95% CI: 2.33, 32.93). 116 In pa ien s, Vi amin D le els did no co ela e wi h dep ession se e i y ( =-0.18; p=0.16) bu co ela ed posi i ely wi h global unc ioning sco es ( =0.30, p=0.02). Fu he mo e, backwa d mul iple eg ession e ealed ha i amin D le els we e a p edic o o global unc ionali y sco es (B=0.03; p=0.02) wi hou any signi ican in luence o o he possible co a iables (i.e, sex, age, dep ession se e i y) included in he i s s ep o he model bu emo ed a e wa ds o no being subsequen ly signi ican . 6.1.4. CONCLUSIONS In his s udy, pa ien s wi h a ecen dep essed suicide a emp ha e lowe le els o i amin D han dep essed non-a emp e s and heal hy con ols. As he se e i y o dep ession is simila in bo h pa ien g oups, he di e ences obse ed on i amin D le els be ween hese g oups could no be a ibu ed o he men al diso de . In addi ion, in his s udy i amin D p edic s suicide isk as he odds o a emp ing suicide in he whole sample a e app oxima ely 7 imes highe wi h subop imal (30ng/mL) i amin D le els and o he dep essed sample exclusi ely he odds o a emp ing suicide a e almos 9 imes highe wi h subop imal i amin D le els. In line wi h ou esul s, o he s udies ha e also ound ha low i amin D le els inc ease he isk o suicide bu hey ei he lack a pa ien con ol g oup o con ol he possible e ec o he diagnosis (Gokalp, 2020; Wei e al., 2021; Yagci & A ci, 2021) o include di e en diagnosis in he a emp e g oup (Gokalp, 2020; G ude e al., 2014; Umhau e al., 2013; Yagci & A ci, 2021). A possible explana ion o he link be ween he isk o an a emp and i amin D may be due o i s immunomodula ing e ec s on he in lamma o y esponse which, in u n, has been widely desc ibed o be associa ed o suicide (Ba y e al., 2016; Boko e al., 2021; B undin e al., 2015; Ducasse e al., 2015; Ganança e al., 2016; Kea on e al., 2019). Vi amin D can also p edic he global unc ioning o dep essi e pa ien s. This inding sugges s ha he neu omodula ing unc ions o i amin D in he b ain (Anjum e al., 2018; Lee e al., 2021; Mo ello e al., 2020) migh ha e a wide ole in beha io and emo ion, a ec ing he global pe o mance in daily li e a eas such as employmen , social li e, sel -ca e and leisu e. As disabili y (Ma low e al., 2021) has been associa ed wi h suicide isk, global unc ioning sco es migh be an indi ec measu e ha could help clinicians o es ima e he isk o a suicide a emp and he bu den o disease caused by a men al diso de . 117 These esul s highligh he po en ial p edic i e alue o i amin D in ela ion o suicide, a cos -e ec i e objec i e bioma ke ha could wa n clinicians when handling an hypo i aminosis D, specially, in MDD pa ien s. Thus, i could be bene icial o include i amin D in he blood- es p o ocol o psychia ic ca e uni s, ein o cing i s use wi h pa ien s a - isk o suicide and conside ing i s supplemen a ion in hose pa ien s unde op imal le els. 6.2. C-REACTIVE PROTEIN (CRP) IN SUICIDAL BEHAVIOUR AND THE LINK TO COGNITIVE PERFORMANCE 6.2.1. BACKGROUND CRP is a p o ein ound in he blood ha se es as a ma ke o in lamma ion. Ci cula ing CRP le els inc ease du ing acu e in lamma ion ( he i s 4-24 hou s) as i s syn hesis is igge ed mos ly by he elease o IL-6 in esponse o a pa hogen (El Ayadi e al., 2018). Thus, CRP is an in lamma ion bioma ke which is a easie o ob ain han cy okine concen a ion and al eady a ailable in clinical p ac ice. Fo his eason, many s udies ha e explo ed he link be ween CRP and suicidal beha iou gi ing e idence o ele a ed le els in suicide a emp s (Table 15) (Aguglia e al., 2019, 2020; Cáceda e al., 2018; Cou e e al., 2015; Ekinci & Ekinci, 2017; Gambi e al., 2005; Gibbs e al., 2016; Loas e al., 2016; Oh e al., 2019; P iya e al., 2016) and suicidal idea ion (Chang e al., 2017; De Be a dis e al., 2013; Ka lo ić e al., 2012; O’Dono an e al., 2013; Pa k & Kim, 2017). Howe e , some con adic o y esul s also eme ge om s udies ocusing on CRP and suicidal beha iou inding no associa ion be ween hem (da G aça Can a elli e al., 2015; Dolsen e al., 2020; Ducasse e al., 2015; Kim e al., 2019; Peng e al., 2018; Va gas e al., 2013; Ven o p e al., 2015); hus, u he s udies a e needed o cla i y he associa ion o CRP and suicidal beha iou . 118 6.2.2. METHOD 1102 pa ien s ea ed o a majo dep essi e episode in he U gence e Pos -U gence Psychia ique Uni a he Mon pellie Uni e si y Hospi al con o med his sample. 678 had a emp ed suicide and 424 we e non-a emp e pa ien s. Exclusion c i e ia we e any in lamma o y diso de , cu en ea men wi h an ibio ics o an i-in lamma o y medica ions, incapable o e usal o pa icipa e in he s udy. Clinical expe s (psychia is s and psychologis s) conduc ed sociodemog aphic, clinical (CTQ) and cogni i e (D2 Tes , Na ional Adul Reading Tes -NART) da a ga he ing. Blood ex ac ions we e conduc ed o CPR measu emen . 6.2.1. PRELIMINARY RESULTS Non-adjus ed di e ences be ween g oups e ealed ha pa ien s wi h a suicidal a emp ha e mo e emo ional ( =3.702; p=0.000), physical ( =3.076; p=0.002) and sexual ( =2.837; p=0.005) abuse. Besides, hey had a poo e pe o mance on he ollowing a en ion sco es: D2 P ocessed I ems sco e ( =-3.234; p=0.001), D2 e o pe cen age ( =2.203; p=0.028) D2 p ocessed-e o s ( =-3.502; p=0.000) and di e ences emained signi ican a e con olling o age and in elligence (IQ). Rega ding in lamma ion, hese pa ien s had signi ican ly highe CPR le els ha dep essed non-a emp e s ( =-3.519; p=0.000). Backwa d mul iple eg essions e ealed ha a suicide a emp was less p obable wi h a be e a en ion pe o mance (B=-0.003; p=0.001) con olled o sex in he model. Besides, he odds o a emp ing suicide we e 1.16 highe when CRP inc eased one uni (Exp(B)=1.16; C.I.=1.067-1.261). Fu he mo e, a be e pe o mance on a en ion (D2 P ocessed sco e) was p edic ed by lowe CRP le els (B=5.270; p=0.000) adjus ed o age, suicide idea ion and IQ. 6.2.1. CONCLUSIONS The CRP could be a po en ial cos -e ec i e bioma ke o suicide ha is an indi ec measu e o he in lamma o y s a e in he o ganism. Acco ding o hese esul s, CRP is ele a ed in suicide a emp e s and ela es o hei cogni i e pe o mance on a en ion domain. As CRP can be easily ob ained in a blood es , u u e s udies a e needed o conside i s implemen a ion in he cu en T ea men as Usual in psychia ic ca e uni s. 119 Table 15. Main s udies o CRP in suicide a emp s. AUTHOR SUBJECTS SAMPLE CRP GAMBI ET AL.,2005 MDD SA MDD NSA Se um SA>NSA* VARGAS ET AL., 2013 SA HC Plasma SA=HC COURTET ET AL., 2015 MDD SA MDD NSA Se um SA>NSA* DA GRAÇA CANTARELLI ET AL., 2015 Mood Diso de s SA Mood Diso de s NSA Se um SA=NSA DUCASSE ET AL., 2015 BD SA BD NSA Se um SA=NSA VENTORP ET AL., 2015 MDD SA MDD NSA HC Plasma SA=NSA=HC GIBBS ET AL., 2016 SA SI NSA Se um SA>SI>NSA LOAS ET AL., 2016 Mood Diso de / Anxie y SA Mood Diso de / Anxie y NSA Se um SA>NSA* PRIYA ET AL., 2016 SA HC Se um SA>HC* EKINCI ET AL., 2017 MDD SA MDD NSA HC Se um SA>NSA* SA>HC* CÁCEDA ET AL., 2018 MDD ND Posi i e co ela ion wi h he numbe o SAs PENG ET AL., 2018 MDD SA MDD NSA Se um SA=NSA AGUGLIA ET AL., 2019 SA NSA Se um SA>NSA* KIM ET AL., 2019 MDD SA MDD SI Plasma SA=SI OH ET AL., 2019 MDD SA MDD NSA ND SA>NSA* AGUGLIA ET AL., 2020 SA SA e-a emp Se um SA e-a emp > SA* DOLSEN ET AL., 2020 MDD/Anxie y SA MDD/Anxie y NSA Plasma SA=NSA Composed om Chen e al., 2020; Miola e al., 2021. SA: Suicide a emp e s NSA: Non suicide a emp e s wi h a psychia ic diso de SI: Suicidal Idea ion HC: Heal hy con ols MDD: Majo dep ession diso de BD: Bipola diso de ND: No da a * signi ican di e ences 120 6.3. TELEMEDICINE-BASED SUICIDE PREVENTION 6.3.1. BACKGROUND One o he main isk ac o s o comple ed suicide is p e ious his o y o suicide a emp s (Bos wick e al., 2016) wi h 25-40 imes mo e isk o suicide (WHO, 2022). Telemedicine can o e con inuous suppo o a - isk pa ien s which migh educe he a e o ea emp s (Ceb ià e al., 2013; Exb aya e al., 2017; Mille e al., 2017) bu u he esea ch is needed o assess i s e icacy. Suicide p e en ion emains a challenge and should be a ge ed o a - isk popula ion such as pa ien s wi h a p e ious a emp . Hospi al con ex p o ides a g ea oppo uni y o implemen p e en i e in e en ions o educing suicide isk as many pa ien s a i e a Eme gency Se ices when a emp s occu and can en ol in pos -discha ged ollow- up p og ammes. The objec i e o his s udy is o assess he e icacy o a 5 (Week 1, Mon h 1, Mon h 3, Mon h 6, Mon h 12) elephone calls ollow-up in e en ion on he delay o suicide e-a emp s in a g oup o pa ien s wi h a ecen suicide a emp (las mon h) in compa ison o a g oup o pa ien s wi h a ecen suicide a emp wi hou a elephone ollow- up. 6.3.2. METHOD 140 pa ien s we e ec ui ed om he Psychia y Depa men o he A aba Uni e si y Hospi al – San iago sho ly a e (less han a mon h) isi ing he eme gency se ice due o a suicide a emp . 70 pa ien s, in addi ion o he T ea men as Usual (TAU) ecei ed, ag eed o oll-up in a 5 (Week 1, Mon h 1, Mon h 3, Mon h 6, Mon h 12) elephone calls ollow-up in e en ion a ge ed o educe suicide isk and conduc ed by a ained nu se. Ano he 70 pa ien s only ecei ed TAU as con ol g oup. All pa ien s we e in e iewed o sociodemog aphic and clinical da a ga he ing by an expe ienced psychologis . 6.3.3. PRELIMINARY RESULTS The sample was composed by 89 women (63.3%) and 51 men (36.4%) wi h a mean age o 46.37 (SD=12.69). The mos equen me hod o a emp ing suicide was d ug poisoning (89.3%) ollowed by de enes a ion (5.7%), cu s (3.6%), hanging (0.7%) and i eguns (0.7%). Adhe ence o he elemedicine p og amme in he in e en ion g oup was mos ly excellen wi h a 51.5% o pa ien s comple ing 4-5 o he 5 phone calls p og ammed, 26.5% comple ed 2-3 phone calls and 22.1% had a low adhe ence wi h only comple ing one phone call. The in ensi y o suicide idea ion measu ed by Columbia-Suicide Se e i y Ra ing Scale dec eased 121 signi ican ly om he i s phone call o he las ( =2.46; p=0.02). Rega ding he main objec i e, he elemedicine in e en ion showed signi ican e icacy on elapse delay ( =2.204; p=0.03). Besides, a e 12 mon hs o ollow-up pa ien s on he elemedicine p og amme (X=0.37; SD=0.81) had signi ican ly less elapses ( =-1.978; p=0.05) han pa ien s wi h TAU (X=0.67; SD=0.99). 6.3.4. CONCLUSIONS The elemedicine-based suicide p e en ion p og amme has been e ec i e in delaying and educing suicide a emp s. Besides, i has educed he suicide idea ion in ensi y and has achie ed an excellen adhe ence in mos o he pa ien s. This is a cos -e ec i e in e en ion ha can be easily implemen ed in he psychia ic ca e uni o p e en suicide e-a emp s. 128 Be na do, M., Bioque, M., Pa ellada, M., Ruiz, J. S., Cues a, M. J., Lle ena, A., Sanjuán, J., Cas o-Fo nieles, J., A ango, C., & Cab e a, B. (2013). Assessing clinical and unc ional ou comes in a gene–en i onmen in e ac ion s udy in i s episode o psychosis (PEPs). Re is a de Psiquia ía y Salud Men al (English Edi ion), 6(1), 4–16. h ps://doi.o g/10.1016/j. psmen.2012.11.001 Be ns ein, D. P., & Fink, L. (1998). Childhood T auma Ques ionnai e: A e ospec i e sel - epo manual San An onio,. The Psychological Co po a ion. Be olo e, J. M., & Wasse man, D. (2021). De elopmen o de ini ions o suicidal beha iou s: F om suicidal hough s o comple ed suicides. In D. Wasse man (Ed.), Ox o d Tex book o Suicidology and Suicide P e en ion (2nd ed., pp. 87–91). Ox o d Uni e si y P ess. Bi, B., Liu, W., Zhou, D., Fu, X., Qin, X., & Wu, J. (2017). Pe sonali y ai s and suicide a emp s wi h and wi hou psychia ic diso de s: Analysis o impulsi i y and neu o icism. BMC Psychia y, 17(1), 294. h ps://doi.o g/10.1186/s12888-017-1453- 5 Bjö kens am, C., Kosidou, K., & Bjö kens am, E. (2017). Childhood ad e si y and isk o suicide: Coho s udy o 548 721 adolescen s and young adul s in Sweden. BMJ (Clinical Resea ch Ed.), 357, j1334. h ps://doi.o g/10.1136/bmj.j1334 Black, C., & Mille , B. J. (2015). Me a-Analysis o Cy okines and Chemokines in Suicidali y: Dis inguishing Suicidal Ve sus Nonsuicidal Pa ien s. Biological Psychia y, 78(1), 28–37. h ps://doi.o g/10.1016/j.biopsych.2014.10.014 Blázquez-Alisen e, J. L., González-Rod íguez, B., & Paúl-Laped iza, N. (2012). E aluación neu opsicológica. In J. Ti apu Us á oz, M. Rios Lago, & F. Maes ú Un u be (Eds.), Manual de neu opsicología (2nd ed., pp. 33–56). Vigue a. Bobes, J., Bulbena, A., Luque, A., Dal-Ré, R., Balles e os, J., & Iba a, N. (2003). E aluación psicomé ica compa a i a de las e siones en español de 6, 17 y 21 í ems de la Escala de alo ación de Hamil on pa a la e aluación de la dep esión. Medicina Clínica, 120(18), 693–700. h ps://doi.o g/10.1016/S0025-7753(03)73814-7 Bohn, D. K. (2003). Li e ime physical and sexual abuse, subs ance abuse, dep ession, and suicide a emp s among Na i e Ame ican women. Issues in Men al Heal h Nu sing, 24(3), 333–352. h ps://doi.o g/10.1080/01612840305277 Boko , J., Su o i, S., To ok, D., Gal, Z., Eszla i, N., Gyo ik, D., Baksa, D., Pe schne , P., Se a ini, G., Pompili, M., Ande son, I. M., Deakin, B., Bagdy, G., Juhasz, G., & Gonda, X. (2021). In lamed Mind: Mul iple Gene ic Va ian s o IL6 In luence Suicide Risk Pheno ypes in In e ac ion wi h Ea ly and Recen Ad e si ies in a Linkage Disequilib ium-Based Clumping Analysis. F on ie s in Psychia y, 12, 1855. h ps://doi.o g/10.3389/ psy .2021.746206 Bo ges, G., Che pi el, C. J., O ozco, R., Ye, Y., Mon ei o, M., Hao, W., & Benegal, V. (2017). A dose– esponse es ima e o acu e alcohol use and isk o suicide a emp . Addic ion Biology, 22(6), 1554–1561. h ps://doi.o g/10.1111/adb.12439 129 Bo ges, M. C., Ma ini, L. A., & Roge o, M. M. (2011). Cu en pe spec i es on i amin D, immune sys em, and ch onic diseases. Nu i ion (Bu bank, Los Angeles Coun y, Cali .), 27(4), 399–404. h ps://doi.o g/10.1016/j.nu .2010.07.022 Bo sini, A., Zunszain, P. A., Thu e , S., & Pa ian e, C. M. (2015). The ole o in lamma o y cy okines as key modula o s o neu ogenesis. T ends in Neu osciences, 38(3), 145–157. h ps://doi.o g/10.1016/j. ins.2014.12.006 Bos wick, J. M., Pabba i, C., Geske, J. R., & McKean, A. J. (2016). Suicide A emp as a Risk Fac o o Comple ed Suicide: E en Mo e Le hal Than We Knew. Ame ican Jou nal o Psychia y, 173(11), 1094–1100. h ps://doi.o g/10.1176/appi.ajp.2016.15070854 B edemeie , K., & Mille , I. W. (2015). Execu i e unc ion and suicidali y: A sys ema ic quali a i e e iew. Clinical Psychology Re iew, 40, 170–183. h ps://doi.o g/10.1016/j.cp .2015.06.005 B own, G. L., Goodwin, F. K., Ballenge , J. C., Goye , P. F., & Majo , L. F. (1979). Agg ession in humans co ela es wi h ce eb ospinal luid amine me aboli es. Psychia y Resea ch, 1(2), 131–139. h ps://doi.o g/10.1016/0165-1781(79)90053-2 B own, R. R., & Pa ing on, J. E. (2012). Sho A icles and No es: The In elligence o he Na co ic D ug Addic : The Jou nal o Gene al Psychology: Vol 26, No 1. The Jou nal o Gene al Psychology, 26(1942), 175–179. B üde n, J., S ähli, A., Gysin-Mailla , A., Michel, K., Reisch, T., Jobes, D. A., & B odbeck, J. (2018). Reasons o li ing and dying in suicide a emp e s: A wo-yea p ospec i e s udy. BMC Psychia y, 18, 234. h ps://doi.o g/10.1186/s12888-018-1814-8 B ugha, T. S., & C agg, D. (1990). The Lis o Th ea ening Expe iences: The eliabili y and alidi y o a b ie li e e en s ques ionnai e. Ac a Psychia ica Scandina ica, 82(1), 77–81. h ps://doi.o g/10.1111/j.1600-0447.1990. b01360.x B undin, L., B yle a, E. Y., & Thi ama a Rajamani, K. (2017). Role o In lamma ion in Suicide: F om Mechanisms o T ea men . Neu opsychopha macology: O icial Publica ion o he Ame ican College o Neu opsychopha macology, 42(1), 271–283. h ps://doi.o g/10.1038/npp.2016.116 B undin, L., E ha d , S., B yle a, E. Y., Ach yes, E. D., & Pos olache, T. T. (2015). The ole o in lamma ion in suicidal beha iou . Ac a Psychia ica Scandina ica, 132(3), 192–203. h ps://doi.o g/10.1111/acps.12458 B us enghi, F., Mezze i, F. A. F., Di Sa no, C., Giulie i, C., Mo e i, P., & To o ella, A. (2019). Ea ing Diso de s: The Role o Childhood T auma and he Emo ion Dys egula ion. Psychia ia Danubina, 31(Suppl 3), 509–511. Bui on, V., Ha ley, C. M., Pe i , J. W., Ha ke ich, C., & Sha p, C. (2018). Agg essi e Beha io s and Suicide Idea ion in Inpa ien Adolescen s: The Mode a ing Roles o In e nalizing Symp oms and S ess. Suicide & Li e-Th ea ening Beha io , 48(5), 580–588. h ps://doi.o g/10.1111/sl b.12375 130 Bu iel, Y., Casano a, J. P., Rodés, E., Fombuena, N. G., & Böhm, P. (2004). Fluencia e bal. Es udio no ma i o pilo o en una mues a española de adul os jó enes (20 a 49 años). Neu ología: Publicación o icial de la Sociedad Española de Neu ología, 19(4), 153–159. Cáceda, R., G i in, W. S. T., & Delgado, P. L. (2018). A p obe in he connec ion be ween in lamma ion, cogni ion and suicide. Jou nal o Psychopha macology (Ox o d, England), 32(4), 482–488. h ps://doi.o g/10.1177/0269881118764022 Cala i, R., Fe a i, C., B i ne , M., Oasi, O., Olié, E., Ca alho, A. F., & Cou e , P. (2019). Suicidal hough s and beha io s and social isola ion: A na a i e e iew o he li e a u e. Jou nal o A ec i e Diso de s, 245, 653–667. h ps://doi.o g/10.1016/j.jad.2018.11.022 Cala i, R., Filipponi, C., Mansi, W., Casu, D., Pe iani, G., Gen ile, G., Tambuzzi, S., Zoja, R., Fo na o, M., Lopez-Cas oman, J., & Madeddu, F. (2021). Cance diagnosis and suicide ou comes: Umb ella e iew and me hodological conside a ions. Jou nal o A ec i e Diso de s, 295, 1201–1214. h ps://doi.o g/10.1016/j.jad.2021.08.131 Ca a aca-Sánchez, F., Igna ye , Y., & Mund , A. P. (2019). Associa ions be ween childhood abuse, men al heal h p oblems, and suicide isk among male p ison popula ions in Spain. C iminal Beha iou and Men al Heal h: CBMH, 29(1), 18–30. h ps://doi.o g/10.1002/cbm.2099 Ca alho, J. N., Renne , A. M., Dona , J. C., de Mou a, T. C., Fonseca, R. P., & K is ensen, C. H. (2020). Execu i e unc ions and clinical symp oms in child en exposed o mal ea men . Applied Neu opsychology. Child, 9(1), 1–12. h ps://doi.o g/10.1080/21622965.2018.1497989 Casey, P. R., Dunn, G., Kelly, B. D., Bi kbeck, G., Dalga d, O. S., Leh inen, V., B i a, S., Ayuso-Ma eos, J. L., Dow ick, C., & ODIN G oup. (2006). Fac o s associa ed wi h suicidal idea ion in he gene al popula ion: Fi e-cen e analysis om he ODIN s udy. The B i ish Jou nal o Psychia y: The Jou nal o Men al Science, 189, 410–415. h ps://doi.o g/10.1192/bjp.bp.105.017368 Cas ellano, S., To en , C., Pe alia, M. C., Godos, J., Can a ella, R. A., Ven imiglia, A., De Vi o, S., Pla ania, S., Gua ne a, M., Pi one, C., D ago, F., Vie a, E., Di Nuo o, S., Popo ic, D., & Ca aci, F. (2020). Clinical and Neu ocogni i e P edic o s o Func ional Ou come in Dep essed Pa ien s wi h Pa ial Response o T ea men : One Yea Follow-Up S udy. Neu opsychia ic Disease and T ea men , 16, 589–595. h ps://doi.o g/10.2147/NDT.S224754 Ceb ià, A. I., Pa a, I., Pàmias, M., Escayola, A., Ga cía-Pa és, G., Pun í, J., La edo, A., Vallès, V., Ca e o, M., Oli a, J. C., Hege l, U., Pé ez-Solà, V., & Palao, D. J. (2013). E ec i eness o a elephone managemen p og amme o pa ien s discha ged om an eme gency depa men a e a suicide a emp : Con olled s udy in a Spanish popula ion. Jou nal o A ec i e Diso de s, 147(1–3), 269–276. h ps://doi.o g/10.1016/j.jad.2012.11.016 131 Ce illa, J. A., Molina, E., Ri e a, M., To es-González, F., Bellón, J. A., Mo eno, B., Luna, J. D., Lo en e, J. A., Mayo al, F., King, M., Naza e h, I., PREDICT S udy Co e G oup, & Gu ié ez, B. (2007). The isk o dep ession con e ed by s ess ul li e e en s is modi ied by a ia ion a he se o onin anspo e 5HTTLPR geno ype: E idence om he Spanish PREDICT-Gene coho . Molecula Psychia y, 12(8), 748– 755. h ps://doi.o g/10.1038/sj.mp.4001981 Chak aba y, T., Hadjipa lou, G., & Lam, R. W. (2016). Cogni i e Dys unc ion in Majo Dep essi e Diso de : Assessmen , Impac , and Managemen . Focus: Jou nal o Li e Long Lea ning in Psychia y, 14(2), 194–206. h ps://doi.o g/10.1176/appi. ocus.20150043 Chang, C.-C., Tzeng, N.-S., Kao, Y.-C., Yeh, C.-B., & Chang, H.-A. (2017). The ela ionships o cu en suicidal idea ion wi h in lamma o y ma ke s and hea a e a iabili y in unmedica ed pa ien s wi h majo dep essi e diso de . Psychia y Resea ch, 258, 449– 456. h ps://doi.o g/10.1016/j.psych es.2017.08.076 Colasan o, M., Madigan, S., & Ko czak, D. J. (2020). Dep ession and in lamma ion among child en and adolescen s: A me a-analysis. Jou nal o A ec i e Diso de s, 277, 940–948. h ps://doi.o g/10.1016/j.jad.2020.09.025 Coneje o, I., Lopez-Cas oman, J., Gine , L., & Baca-Ga cia, E. (2016). Sociodemog aphic An eceden Valida o s o Suicidal Beha io : A Re iew o Recen Li e a u e. Cu en Psychia y Repo s, 18(10), 94. h ps://doi.o g/10.1007/s11920-016-0732-z Conne s, C. K. (1994). The Conne s Con inuous Pe o mance Tes . Mul i-Heal h Sys ems. Co yell, W., Wilcox, H., E ans, S. J., Pandey, G. N., Jones-B ando, L., Dicke son, F., & Yolken, R. (2018). Agg ession, impulsi i y and in lamma o y ma ke s as isk ac o s o suicidal beha io . Jou nal o Psychia ic Resea ch, 106, 38–42. h ps://doi.o g/10.1016/j.jpsychi es.2018.09.004 Co yell, W., Wilcox, H., E ans, S. J., Pandey, G. N., Jones-B ando, L., Dicke son, F., & Yolken, R. (2020). La en in ec ion, in lamma o y ma ke s and suicide a emp his o y in dep essi e diso de s. Jou nal o A ec i e Diso de s, 270, 97–101. h ps://doi.o g/10.1016/j.jad.2020.03.057 Cos anza, A., Ame io, A., Aguglia, A., Escelsio , A., Se a ini, G., Be a delli, I., Pompili, M., & Amo e, M. (2020). When Sick B ain and Hopelessness Mee : Some Aspec s o Suicidali y in he Neu ological Pa ien . CNS & Neu ological Diso de s D ug Ta ge s, 19(4), 257–263. h ps://doi.o g/10.2174/1871527319666200611130804 Co ena, C., B anco, L. D., Kochhann, R., Shansis, F. M., & Fonseca, R. P. (2016). Quali y o li e, unc ioning and cogni ion in bipola diso de and majo dep ession: A la en p o ile analysis. Psychia y Resea ch, 241, 289–296. h ps://doi.o g/10.1016/j.psych es.2016.04.102 Cou e , P., Gine , L., Seneque, M., Guillaume, S., Olie, E., & Ducasse, D. (2016). Neu oin lamma ion in suicide: Towa d a comp ehensi e model. The Wo ld Jou nal o Biological Psychia y: The O icial Jou nal o he Wo ld Fede a ion o Socie ies o Biological Psychia y, 17(8), 564–586. h ps://doi.o g/10.3109/15622975.2015.1054879 132 Cou e , P., Jaussen , I., Gen y, C., Dupuy, A. M., Guillaume, S., Ducasse, D., & Olié, E. (2015). Inc eased CRP le els may be a ai ma ke o suicidal a emp . Eu opean Neu opsychopha macology: The Jou nal o he Eu opean College o Neu opsychopha macology, 25(10), 1824–1831. h ps://doi.o g/10.1016/j.eu oneu o.2015.05.003 C oss, C. P., Copping, L. T., & Campbell, A. (2011). Sex di e ences in impulsi i y: A me a- analysis. Psychological Bulle in, 137(1), 97–130. h ps://doi.o g/10.1037/a0021591 Cues a, M. J., Sánchez-To es, A. M., Cab e a, B., Bioque, M., Me chán-Na anjo, J., Co ipio, I., González-Pin o, A., Lobo, A., Bombín, I., de la Se na, E., Sanjuan, J., Pa ellada, M., Saiz-Ruiz, J., Be na do, M., & PEPs G oup. (2015). P emo bid adjus men and clinical co ela es o cogni i e impai men in i s -episode psychosis. The PEPsCog S udy. Schizoph enia Resea ch, 164(1–3), 65–73. h ps://doi.o g/10.1016/j.sch es.2015.02.022 da G aça Can a elli, M., Na din, P., Bu on, A., Eid , M. C., Godoy, L., Fe nandes, B. S., & Gonçal es, C.-A. (2015). Se um iglyce ides, bu no choles e ol o lep in, a e dec eased in suicide a emp e s wi h mood diso de s. Jou nal o A ec i e Diso de s, 172, 403–409. h ps://doi.o g/10.1016/j.jad.2014.10.033 Dalga d, O. S., Dow ick, C., Leh inen, V., Vazquez-Ba que o, J. L., Casey, P., Wilkinson, G., Ayuso-Ma eos, J. L., Page, H., Dunn, G., & ODIN G oup. (2006). Nega i e li e e en s, social suppo and gende di e ence in dep ession: A mul ina ional communi y su ey wi h da a om he ODIN s udy. Social Psychia y and Psychia ic Epidemiology, 41(6), 444–451. h ps://doi.o g/10.1007/s00127-006-0051-5 Dannehl, K., Rie , W., & Eu eneue , F. (2017). Childhood ad e si y and cogni i e unc ioning in pa ien s wi h majo dep ession. Child Abuse & Neglec , 70, 247–254. h ps://doi.o g/10.1016/j.chiabu.2017.06.013 De Be a dis, D., Con i, C. M., Ma ini, S., Se oni, N., Mosche a, R. S., Ca ano, A., Valche a, A., Iase oli, F., Fo na o, M., Pe na, G., Di Io io, G., Ma ino i, G., Niolu, C., Si acusano, A., & Di Giannan onio, M. (2013). C-Reac i e P o ein Le el and i s Rela ionship wi h Suicide Risk and Alexi hymia among Newly Diagnosed, D ug- Naï e Pa ien s wi h Non-A ec i e Psychosis. Eu opean Jou nal o In lamma ion, 11(1), 215–221. h ps://doi.o g/10.1177/1721727X1301100120 de No eña, D., & Maes ú, F. (2012). Neu opsicología de la memo ia. In J. Ti apu Us á oz, M. Rios Lago, & F. Maes ú Un u be (Eds.), Manual de neu opsicología (2nd ed., pp. 189– 218). Vigue a. Deisenhamme , E. A., Schmid, S. K., Kemmle , G., Mose , B., & Delaze , M. (2018). Decision making unde isk and unde ambigui y in dep essed suicide a emp e s, dep essed non-a emp e s and heal hy con ols. Jou nal o A ec i e Diso de s, 226, 261– 266. h ps://doi.o g/10.1016/j.jad.2017.10.012 Del es, P. J., Ma in, S. J., Bu on, D. R., & Roi , I. M. (2017). Roi ’s essen ial immunology (13 h edi ion). Wiley Blackwell. 133 De i, F., Shahwan, S., Teh, W. L., Sambasi am, R., Zhang, Y. J., Lau, Y. W., Ong, S. H., Fung, D., Gup a, B., Chong, S. A., & Sub amaniam, M. (2019). The p e alence o childhood auma in psychia ic ou pa ien s. Annals o Gene al Psychia y, 18, 15. h ps://doi.o g/10.1186/s12991-019-0239-1 Dieks a, R. F. (1992). Epidemiology o suicide: Aspec s o de ini ion, classi ica ion and p e en i e policies. In P. C epe , G. Fe a i, S. Pla , & M. Bellini (Eds.), Suicidal beha iou in Eu ope ecen esea ch iindings (pp. 15–45). John Libey. DiSaba o, D. J., Quan, N., & Godbou , J. P. (2016). Neu oin lamma ion: The de il is in he de ails. Jou nal o Neu ochemis y, 139 Suppl 2, 136–153. h ps://doi.o g/10.1111/jnc.13607 Dolsen, M. R., P a he , A. A., Lame s, F., & Penninx, B. W. J. H. (2020). Suicidal idea ion and suicide a emp s: Associa ions wi h sleep du a ion, insomnia, and in lamma ion. Psychological Medicine, 1–10. h ps://doi.o g/10.1017/S0033291720000860 Dowla i, Y., He mann, N., Swa d age , W., Liu, H., Sham, L., Reim, E. K., & Lanc ô , K. L. (2010). A Me a-Analysis o Cy okines in Majo Dep ession. Biological Psychia y, 67(5), 446–457. h ps://doi.o g/10.1016/j.biopsych.2009.09.033 D ozdick, L. W., Holdnack, J. A., Weiss, L. G., & Zhou, X. (2013). O e iew o he WAIS– IV/WMS–IV/ACS. In J. A. Holdnack, L. W. D ozdick, L. G. Weiss, & G. L. I e son (Eds.), WAIS-IV, WMS-IV, and ACS. Ad anced Clinical In e p e a ion (pp. 1–73). Academic P ess. h ps://doi.o g/10.1016/B978-0-12-386934-0.00001-8 Dubois, T., Reynae , C., Jacques, D., Lepiece, B., Pa igny, P., & Zdanowicz, N. (2018). Immuni y and psychia ic diso de s: Va iabili ies o immuni y bioma ke s a e hey speci ic? Psychia ia Danubina, 30(Suppl 7), 447–451. Ducasse, D., Jaussen , I., Guillaume, S., Azo in, J. M., Belli ie , F., Belzeaux, R., Bouge ol, T., E ain, B., Ga d, S., Hen y, C., Kahn, J. P., Leboye , M., Lo us, J., Passe ieux, C., Cou e , P., Olié, E., & FondaMen al Ad anced Cen e s o Expe ise in Bipola Diso de s (FACE-BD) Collabo a o s. (2015). Inc eased isk o suicide a emp in bipola pa ien s wi h se e e obacco dependence. Jou nal o A ec i e Diso de s, 183, 113–118. h ps://doi.o g/10.1016/j.jad.2015.04.038 Ducasse, D., Olié, E., Guillaume, S., A é o, S., & Cou e , P. (2015). A me a-analysis o cy okines in suicidal beha io . B ain, Beha io , and Immuni y, 46, 203–211. h ps://doi.o g/10.1016/j.bbi.2015.02.004 Dunn, A. J. (2006). E ec s o cy okines and in ec ions on b ain neu ochemis y. Clinical Neu oscience Resea ch, 6(1–2), 52–68. h ps://doi.o g/10.1016/j.cn .2006.04.002 Du heil, F., Aube , C., Pe ei a, B., Damb un, M., Mous a a, F., Me millod, M., Bake , J. S., T oussela d, M., Lesage, F.-X., & Na el, V. (2019). Suicide among physicians and heal h-ca e wo ke s: A sys ema ic e iew and me a-analysis. PloS One, 14(12), e0226361. h ps://doi.o g/10.1371/jou nal.pone.0226361 134 Eidan, A. J., Al-Ha moosh, R. A., & Al-Ama ei, H. M. (2019). Es ima ion o IL-6, INFγ, and Lipid P o ile in Suicidal and Nonsuicidal Adul s wi h Majo Dep essi e Diso de . Jou nal o In e e on & Cy okine Resea ch: The O icial Jou nal o he In e na ional Socie y o In e e on and Cy okine Resea ch, 39(3), 181–189. h ps://doi.o g/10.1089/ji .2018.0134 Ekinci, O., & Ekinci, A. (2017). The connec ions among suicidal beha io , lipid p o ile and low-g ade in lamma ion in pa ien s wi h majo dep essi e diso de : A speci ic ela ionship wi h he neu ophil- o-lymphocy e a io. No dic Jou nal o Psychia y, 71(8), 574–580. h ps://doi.o g/10.1080/08039488.2017.1363285 El Ayadi, A., He ndon, D. N., & Finne y, C. C. (2018). Bioma ke s in Bu n Pa ien Ca e. In D. N. He ndon (Ed.), To al bu n ca e (Fi h edi ion, pp. 232–235). Else ie . El Mundo. (2021, No embe 12). Año I del Co id: Réco d his ó ico de suicidios. h ps://www.elmundo.es/espana/2021/11/12/618d7d7021e a0875b8b45 7.h ml Enache, D., Pa ian e, C. M., & Mondelli, V. (2019). Ma ke s o cen al in lamma ion in majo dep essi e diso de : A sys ema ic e iew and me a-analysis o s udies examining ce eb ospinal luid, posi on emission omog aphy and pos -mo em b ain issue. B ain, Beha io , & Immuni y, 81, 24–40. h ps://doi.o g/10.1016/j.bbi.2019.06.015 Euesden, J., Danese, A., Lewis, C. M., & Maughan, B. (2017). A bidi ec ional ela ionship be ween dep ession and he au oimmune diso de s – New pe spec i es om he Na ional Child De elopmen S udy. PLoS ONE, 12(3), e0173015. h ps://doi.o g/10.1371/jou nal.pone.0173015 Eus a . (2021, July 29). Suicidios de la C.A. de Euskadi po g upos de edad, e i o io his ó ico y sexo. h ps://www.eus a .eus/elemen os/ele0000000/suicidios-de-la-ca-de-euskadi-po - g upos-de-edad- e i o io-his o ico-y-sexo/ bl0000007_c.h ml Exb aya , S., Coud o , C., Gou don, X., Gay, A., Se os, J., Pelle , J., T ombe -Pa io , B., & Massoub e, C. (2017). E ec o elephone ollow-up on epea ed suicide a emp in pa ien s discha ged om an eme gency psychia y depa men : A con olled s udy. BMC Psychia y, 17(1), 96. h ps://doi.o g/10.1186/s12888-017-1258-6 Failde, I., Dueñas, M., Agüe a-O íz, L., Ce illa, J. A., Gonzalez-Pin o, A., & Mico, J. A. (2013). Fac o s associa ed wi h ch onic pain in pa ien s wi h bipola dep ession: A c oss-sec ional s udy. BMC Psychia y, 13, 112. h ps://doi.o g/10.1186/1471-244X- 13-112 Fainboim, L., & Ge ne , J. (2013). In oducción a la inmunología humana. Médica Paname icana. Fässbe g, M. M., Cheung, G., Cane o, S. S., E langsen, A., Lapie e, S., Lindne , R., D ape , B., Gallo, J. J., Wong, C., Wu, J., Dube s ein, P., & Wæ n, M. (2016). A sys ema ic e iew o physical illness, unc ional disabili y, and suicidal beha iou among olde adul s. Aging & Men al Heal h, 20(2), 166–194. h ps://doi.o g/10.1080/13607863.2015.1083945 FDA-NIH Bioma ke Wo king G oup. (2016). BEST (Bioma ke s, Endpoin S, and o he Tools) Resou ce. Food and D ug Adminis a ion (US). h p://www.ncbi.nlm.nih.go /books/NBK326791/ 135 Felge , J. C., & Lo ich, F. E. (2013). In lamma o y cy okines in dep ession: Neu obiological mechanisms and he apeu ic implica ions. Neu oscience, 246, 199–229. h ps://doi.o g/10.1016/j.neu oscience.2013.04.060 Fe nández-Se illano, J., González-Pin o, A., Rod íguez-Re uel a, J., Albe ich, S., Gónzalez- Blanco, L., Zo illa, I., Velasco, Á., López, M. P., Abad, I., & Sáiz, P. A. (2021a). Suicidal beha iou and cogni ion: A sys ema ic e iew wi h special ocus on p e on al de ici s. Jou nal o A ec i e Diso de s, 278, 488–496. h ps://doi.o g/10.1016/j.jad.2020.09.044 Fe nández-Se illano, J., Albe ich, S., Zo illa, I., González-O ega, I., López, M. P., Pé ez, V., Vie a, E., González-Pin o, A., & Saíz, P. (2021b). Cogni ion in Recen Suicide A emp s: Al e ed Execu i e Func ion. F on ie s in Psychia y, 12, 701140. h ps://doi.o g/10.3389/ psy .2021.701140 Fe nández-Se illano, J., González-O ega, I., MacDowell, K., Zo illa, I., López, M. P., Cou e , P., Gabilondo, A., Ma ínez-Cengo i abengoa, M., Leza, J. C., Sáiz, P., & González-Pin o, A. (2021c). In lamma ion bioma ke s in suicide a emp s and hei ela ion o abuse, global unc ioning and cogni ion. The Wo ld Jou nal o Biological Psychia y, 0(0), 1–11. h ps://doi.o g/10.1080/15622975.2021.1988703 Fond, G., Fauge e, M., Fage -Agius, C., Ce molacce, M., Richie i, R., Boye , L., & Lancon, C. (2018). Hypo i aminosis D is associa ed wi h nega i e symp oms, suicide isk, ago aphobia, impai ed unc ional emission, and an idep essan consump ion in schizoph enia. Eu opean A chi es o Psychia y & Clinical Neu oscience, 04, 04. h ps://doi.o g/10.1007/s00406-018-0932-0 Fundación Española pa a la P e ención del Suicidio. (2022, Ma ch 1). Obse a o io del Suicidio en España 2020. Fu czyk, K., Schu o á, B., Michel, T. M., Thome, J., & Bü ne , A. (2013). The neu obiology o suicide—A Re iew o pos -mo em s udies. Jou nal o Molecula Psychia y, 1(1), 2. h ps://doi.o g/10.1186/2049-9256-1-2 Gabbay, V., Klein, R. G., Gu man, L. E., Babb, J. S., Alonso, C. M., Nishawala, M., Ka z, Y., Gai e, M. R., & Gonzalez, C. J. (2009). A P elimina y S udy o Cy okines in Suicidal and Nonsuicidal Adolescen s wi h Majo Dep ession. Jou nal o Child and Adolescen Psychopha macology, 19(4), 423–430. h ps://doi.o g/10.1089/cap.2008.0140 Gambi, F., De Be a dis, D., Campanella, D., Ca ano, A., Sepede, G., Salini, G., Sco ano, B., Spinella, S., Con i, C. M., La Ro e e, R., Valche a, A., Mancini, E., Ceddia, D., Ma chionni, L., Calcagni, E., Co ellessa, C., Sale no, R. M., & Fe o, F. M. (2005). A Re ospec i e E alua ion o he In lamma o y Ma ke C-Reac i e P o ein (CRP), Choles e ol and High-Densi y Lipop o eins in Pa ien s wi h Majo Dep ession: P elimina y Findings. Eu opean Jou nal o In lamma ion, 3(3), 127–134. h ps://doi.o g/10.1177/1721727X0500300304 Ganança, L., Oquendo, M. A., Ty ka, A. R., Cisne os-T ujillo, S., Mann, J. J., & Suble e, M. E. (2016). The ole o cy okines in he pa hophysiology o suicidal beha io . Psychoneu oendoc inology, 63, 296–310. h ps://doi.o g/10.1016/j.psyneuen.2015.10.008 136 Ga cía, A. (2018). E aluación neu opsicológica de las unciones ejecu i as. Sín esis. Ga cía-Nie o, R., Pa a U ibe, I., Palao, D., Lopez-Cas oman, J., Sáiz, P. A., Ga cía-Po illa, M. P., Saiz Ruiz, J., Ibañez, A., Tiana, T., Du án Sind eu, S., Pe ez Sola, V., de Diego- O e o, Y., Pé ez-Cos illas, L., Fe nández Ga cía-And ade, R., Saiz-González, D., Jiménez A ie o, M. A., Na ío Acos a, M., Gine , L., Guija, J. A.,…,Baca-Ga cía, E. (2012). P o ocolo b e e de e aluación del suicidio: Fiabilidad in e examinado es. Re is a de Psiquia ía y Salud Men al, 5(1), 24–36. h ps://doi.o g/10.1016/j. psm.2011.10.001 Ge, F., Jiang, J., Wang, Y., Yuan, C., & Zhang, W. (2020). Iden i ying Suicidal Idea ion Among Chinese Pa ien s wi h Majo Dep essi e Diso de : E idence om a Real- Wo ld Hospi al-Based S udy in China. Neu opsychia ic Disease and T ea men , 16, 665– 672. h ps://doi.o g/10.2147/NDT.S238286 Gibbs, H. M., Da is, L., Han, X., Clo hie , J., Eads, L. A., & Caceda, R. (2016). Associa ion be ween C- eac i e p o ein and suicidal beha io in an adul inpa ien popula ion. Jou nal o Psychia ic Resea ch, 79, 28–33. h ps://doi.o g/10.1016/j.jpsychi es.2016.04.002 Gilbe , A. M., Ga no, J. L., B aga, R. J., Shaya, Y., Goldbe g, T. E., Malho a, A. K., & Bu dick, K. E. (2011). Clinical and cogni i e co ela es o suicide a emp s in bipola diso de : Is suicide p edic able? The Jou nal o Clinical Psychia y, 72(8), 1027–1033. h ps://doi.o g/10.4088/JCP.10m06410 Gil ay, E. J., En e , D., Zi man, F. G., Penninx, B. W. J. H., an Pel , J., Spinho en, P., & Roelo s, K. (2012). Sali a y es os e one: Associa ions wi h dep ession, anxie y diso de s, and an idep essan use in a la ge coho s udy. Jou nal o Psychosoma ic Resea ch, 72(3), 205–213. h ps://doi.o g/10.1016/j.jpsycho es.2011.11.014 Gine , L., Guija, J. A., Roo , C. W., & Baca-Ga cia, E. (2016). Nomencla u e and De ini ion o Suicidal Beha io . In P. Cou e (Ed.), Unde s anding Suicide: F om diagnosis o pe sonalized ea men (pp. 3–17). Sp inge . Gje s ad, J. K., Ligh man, S. L., & Spiga, F. (2018). Role o glucoco icoid nega i e eedback in he egula ion o HPA axis pulsa ili y. S ess (Ams e dam, Ne he lands), 21(5), 403– 416. h ps://doi.o g/10.1080/10253890.2018.1470238 Gläsche , J., Adolphs, R., Damasio, H., Becha a, A., Rud au , D., Calamia, M., Paul, L. K., & T anel, D. (2012). Lesion mapping o cogni i e con ol and alue-based decision making in he p e on al co ex. P oceedings o he Na ional Academy o Sciences, 109(36), 14681–14686. h ps://doi.o g/10.1073/pnas.1206608109 Gokalp, G. (2020). The associa ion be ween low i amin D le els and suicide a emp s in adolescen s. Annals o Clinical Psychia y: O icial Jou nal o he Ame ican Academy o Clinical Psychia is s, 32(2), 106–113. Golden, C. (2001). Tes de Colo es y palab as S oop. TEA Ediciones. 137 González-Cas o, T. B., To illa-Zá a e, C. A., López-Na áez, M. L., Genis-Mendoza, A. D., & Juá ez-Rojop, I. E. (2021). In e leukin-6 Le els in Se um, Plasma, and Ce eb al Spinal Fluid in Indi iduals wi h Suicide Beha io : Sys ema ic Re iew and Me a- Analysis wi h Me a-Reg ession. Jou nal o In e e on & Cy okine Resea ch: The O icial Jou nal o he In e na ional Socie y o In e e on and Cy okine Resea ch, 41(7), 258–267. h ps://doi.o g/10.1089/ji .2020.0265 González-O ega, I., Albe ich, S., Echebu úa, E., Aizpu u, F., Millán, E., Vie a, E., Ma u e, C., & González-Pin o, A. (2015). Subclinical Dep essi e Symp oms and Con inued Cannabis Use: P edic o s o Nega i e Ou comes in Fi s Episode Psychosis. PLoS ONE, 10(4). h ps://doi.o g/10.1371/jou nal.pone.0123707 González-Pin o, A., & Fe nández-Se illano, J. (2020). Bioma cado es en dep esión y suicidio. In M. Na ío Acos a & V. Pé ez Sola, Dep esión y suicidio (pp. 137–146). Weca e-u. Heal hca e Communica ion G oup. Go lyn, M., Keilp, J. G., Oquendo, M. A., Bu ke, A. K., & Mann, J. J. (2013). Iowa Gambling Task pe o mance in cu en ly dep essed suicide a emp e s. Psychia y Resea ch, 207(3), 150–157. h ps://doi.o g/10.1016/j.psych es.2013.01.030 G een, J., Be y, K., Danquah, A., & P a , D. (2020). The ole o psychological and social ac o s in he ela ionship be ween a achmen and suicide: A sys ema ic e iew. Clinical Psychology & Psycho he apy, 27(4), 463–488. h ps://doi.o g/10.1002/cpp.2445 G issom, N. M., & Reyes, T. M. (2019). Le ’s call he whole hing o : E alua ing gende and sex di e ences in execu i e unc ion. Neu opsychopha macology: O icial Publica ion o he Ame ican College o Neu opsychopha macology, 44(1), 86–96. h ps://doi.o g/10.1038/s41386-018-0179-5 G ude , C., Malm, J., Wes in, A., & B undin, L. (2014). Suicidal pa ien s a e de icien in i amin D, associa ed wi h a p o-in lamma o y s a us in he blood. Psychoneu oendoc inology, 50, 210–219. h ps://doi.o g/10.1016/j.psyneuen.2014.08.016 G ü zne , T. M., Sha ma, A., Lis uno a, L., Ba olo ic, M., Weisb od, M., & Roesch-Ely, D. (2019). Neu ocogni i e pe o mance in pa ien s wi h dep ession compa ed o heal hy con ols: Associa ion o clinical a iables and emission s a e. Psychia y Resea ch, 271, 343–350. h ps://doi.o g/10.1016/j.psych es.2018.11.047 Guillo , X., Seme ano, L., Saidenbe g-Ke manac’h, N., Falga one, G., & Boissie , M.-C. (2010). Vi amin D and in lamma ion. Join Bone Spine, 77(6), 552–557. h ps://doi.o g/10.1016/j.jbspin.2010.09.018 Gu ié ez, B., Bellón, J. Á., Ri e a, M., Molina, E., King, M., Ma s on, L., To es-González, F., Mo eno-Küs ne , B., Mo eno-Pe al, P., Mo ico, E., Mon ón-F anco, C., GildeGómez-Ba agán, M. J., Sánchez-Celaya, M., Díaz-Ba ei os, M. Á., Vicens, C., de Dios Luna, J., Naza e h, I., & Ce illa, J. (2015). The isk o majo dep ession con e ed by childhood mal ea men is mul iplied by BDNF and SERT gene ic ulne abili y: A eplica ion s udy. Jou nal o Psychia y & Neu oscience: JPN, 40(3), 187– 196. h ps://doi.o g/10.1503/jpn.140097 144 Lewis, V. M., Williams, K., KoKo, C., Woolmo e, J., Jones, C., & Powell, T. (2017). Disabili y, dep ession and suicide idea ion in people wi h mul iple scle osis. Jou nal o A ec i e Diso de s, 208, 662–669. h ps://doi.o g/10.1016/j.jad.2016.08.038 Li, X.-B., Liu, J.-T., Zhu, X.-Z., Zhang, L., Tang, Y.-L., & Wang, C.-Y. (2014). Childhood auma associa es wi h clinical ea u es o bipola diso de in a sample o Chinese pa ien s. Jou nal o A ec i e Diso de s, 168, 58–63. h ps://doi.o g/10.1016/j.jad.2014.06.017 Lian, L., Zhang, Y., Liu, L., Yang, L., Cai, Y., Zhang, J., & Xu, S. (2020). Neu oin lamma ion in Ischemic S oke: Focus on Mic oRNA-media ed Pola iza ion o Mic oglia. F on ie s in Molecula Neu oscience, 13, 612439. h ps://doi.o g/10.3389/ nmol.2020.612439 Liepmann, H. (1900). Das K ankhei sbild de Ap axie (mo o ische asymbolie). Mona ssch i Fü Psychia ie Und Neu ologie, 8, 182–197. Lindq is , D., Janelidze, S., E ha d , S., T äskman‐Bendz, L., Engs öm, G., & B undin, L. (2011). CSF bioma ke s in suicide a emp e s – a p incipal componen analysis. Ac a Psychia ica Scandina ica, 124(1), 52–61. h ps://doi.o g/10.1111/j.1600- 0447.2010.01655.x Lindq is , D., Janelidze, S., Hagell, P., E ha d , S., Samuelsson, M., Min hon, L., Hansson, O., Bjö kq is , M., T äskman-Bendz, L., & B undin, L. (2009). In e leukin-6 is ele a ed in he ce eb ospinal luid o suicide a emp e s and ela ed o symp om se e i y. Biological Psychia y, 66(3), 287–292. h ps://doi.o g/10.1016/j.biopsych.2009.01.030 Linehan, M. M. (1993). Cogni i e-beha io al ea men o bo de line pe sonali y diso de . Guil o d P ess. Lippa d, E. T. C., & Neme o , C. B. (2020). The De as a ing Clinical Consequences o Child Abuse and Neglec : Inc eased Disease Vulne abili y and Poo T ea men Response in Mood Diso de s. The Ame ican Jou nal o Psychia y, 177(1), 20–36. h ps://doi.o g/10.1176/appi.ajp.2019.19010020 Liu, C. S., Adib a , A., He mann, N., Gallaghe , D., & Lanc ô , K. L. (2017). E idence o In lamma ion-Associa ed Dep ession. Cu en Topics in Beha io al Neu osciences, 31, 3– 30. h ps://doi.o g/10.1007/7854_2016_2 Liu, L. C. Y., Voo s, A. A., an Veldhuisen, D. J., an de Vee , E., Belonje, A. M., Szymanski, M. K., Silljé, H. H. W., an Gils , W. H., Jaa sma, T., & de Boe , R. A. (2011). Vi amin D s a us and ou comes in hea ailu e pa ien s. Eu opean Jou nal o Hea Failu e, 13(6), 619–625. h ps://doi.o g/10.1093/eu jh /h 032 Loas, G., Dalleau, E., Lecoin e, H., & Yon, V. (2016). Rela ionships be ween anhedonia, alexi hymia, impulsi i y, suicidal idea ion, ecen suicide a emp , C- eac i e p o ein and se um lipid le els among 122 inpa ien s wi h mood o anxious diso de s. Psychia y Resea ch, 246, 296–302. h ps://doi.o g/10.1016/j.psych es.2016.09.056 145 López de A gumedo, M., Re i iego, E., Gu ié ez, A., & Bayón, J. C. (2017). Ac ualización del Sis ema de T abajo Compa ido pa a Re isiones Sis emá icas de la E idencia Cien í ica y Lec u a C í ica (Pla a o ma FLC 3.0). In o mes de E aluación de Tecnologías Sani a ias: OSTEBA, p. 145. Minis e io de Sanidad, Se icios Sociales e Igualdad. Se icio de E aluación de Tecnologías Sani a ias del País Vasco. Lop es i, A. L., Make , G. L., Hood, S. D., & D ummond, P. D. (2014). A e iew o pe iphe al bioma ke s in majo dep ession: The po en ial o in lamma o y and oxida i e s ess bioma ke s. P og ess in Neu o-Psychopha macology & Biological Psychia y, 48, 102–111. h ps://doi.o g/10.1016/j.pnpbp.2013.09.017 Lu ia, A. R. (1975). Vnimanie y Pamia . Ediciones de la Un i e sidad de Moscú. Lu z, J., & Fiske, A. (2018). Func ional disabili y and suicidal beha io in middle-aged and olde adul s: A sys ema ic c i ical e iew. Jou nal o A ec i e Diso de s, 227, 260–271. h ps://doi.o g/10.1016/j.jad.2017.10.043 Lu z, P.E., Mechawa , N., & Tu ecki, G. (2017). Neu opa hology o suicide: Recen indings and u u e di ec ions. Molecula Psychia y, 22(10), 1395–1412. h ps://doi.o g/10.1038/mp.2017.141 Lyons, B. H., Wal e s, M. L., Jack, S. P. D., Pe osky, E., Blai , J. M., & I ey-S ephenson, A. Z. (2019). Suicides Among Lesbian and Gay Male Indi iduals: Findings F om he Na ional Violen Dea h Repo ing Sys em. Ame ican Jou nal o P e en i e Medicine, 56(4), 512–521. h ps://doi.o g/10.1016/j.amep e.2018.11.012 Macalli, M., Na a o, M., O i, M., Tou nie , M., Thiébau , R., Cô é, S. M., & Tzou io, C. (2021). A machine lea ning app oach o p edic ing suicidal hough s and beha iou s among college s uden s. Scien i ic Repo s, 11(1), 11363. h ps://doi.o g/10.1038/s41598-021-90728-z MacQueen, G. M., & Memedo ich, K. A. (2017). Cogni i e dys unc ion in majo dep ession and bipola diso de : Assessmen and ea men op ions. Psychia y and Clinical Neu osciences, 71(1), 18–27. h ps://doi.o g/10.1111/pcn.12463 Malloy-Diniz, L. F., Ne es, F. S., Ab an es, S. S. C., Fuen es, D., & Co êa, H. (2009). Suicide beha io and neu opsychological assessmen o ype I bipola pa ien s. Jou nal o A ec i e Diso de s, 112(1–3), 231–236. h ps://doi.o g/10.1016/j.jad.2008.03.019 Mann, J. J., Wa e naux, C., Haas, G. L., & Malone, K. M. (1999). Towa d a clinical model o suicidal beha io in psychia ic pa ien s. The Ame ican Jou nal o Psychia y, 156(2), 181– 189. h ps://doi.o g/10.1176/ajp.156.2.181 Manzanos, I., Ma ino, P., Audisio, E., & Bone , J. (2020). Vi amin D: Be ween he B igh ness o he sun and he Da kness o Dep ession. Re is a Colombiana De Psiquia ia (English Ed.), S0034-7450(20)30086-X. h ps://doi.o g/10.1016/j. cp.2020.08.002 146 Ma cus, S. M., Young, E. A., Ke be , K. B., Ko ns ein, S., Fa abaugh, A. H., Mi chell, J., Wisniewski, S. R., Balasub amani, G. K., T i edi, M. H., & Rush, A. J. (2005). Gende di e ences in dep ession: Findings om he STAR*D s udy. Jou nal o A ec i e Diso de s, 87(2–3), 141–150. h ps://doi.o g/10.1016/j.jad.2004.09.008 Ma is, R. W., Be man, A. L., Mal sbe g, J. T., & Yu i , R. I. (1992). Assessmen and p edic ion o suicide. Guil o d. Ma low, N. M., Xie, Z., Tanne , R., Jo, A., & Ki by, A. V. (2021). Associa ion Be ween Disabili y and Suicide-Rela ed Ou comes Among U.S. Adul s. Ame ican Jou nal o P e en i e Medicine, 61(6), 852–862. h ps://doi.o g/10.1016/j.amep e.2021.05.035 Ma inez, J. M., Ga akani, A., Yehuda, R., & Go man, J. M. (2012). P oin lamma o y and ‘ esiliency’ p o eins in he CSF o pa ien s wi h majo dep ession. Dep ession and Anxie y, 29(1), 32–38. h ps://doi.o g/10.1002/da.20876 Ma ín-Ven u a, J. L., Blanco-Colio, L. M., Tuñón, J., Muñoz-Ga cía, B., Mad igal-Ma u e, J., Mo eno, J. A., Vega de Céniga, M., & Egido, J. (2009). Bioma cado es en la medicina ca dio ascula . Re is a Española de Ca diología, 62(6), 677–688. h ps://doi.o g/10.1016/S0300-8932(09)71335-1 Ma zuk, P. M., Ha well, N., Leon, A. C., & Po e a, L. (2005). Execu i e unc ioning in dep essed pa ien s wi h suicidal idea ion. Ac a Psychia ica Scandina ica, 112(4), 294– 301. h ps://doi.o g/10.1111/j.1600-0447.2005.00585.x McGi , A., Domb o ski, A. Y., Bu e s, M. A., Cla k, L., & Szan o, K. (2012). De e minis ic lea ning and a emp ed suicide among olde dep essed indi iduals: Cogni i e assessmen using he Wisconsin Ca d So ing Task. Jou nal o Psychia ic Resea ch, 46(2), 226–232. h ps://doi.o g/10.1016/j.jpsychi es.2011.10.001 Mesones, J. E. (2014). El suicidio a lo la go de las his o ia y las cul u as. In A. Anseán (Ed.), Suicidios: Manual de P e ención, In e ención y Pos ención de la Conduc a Suicida (2nd ed., pp. 35–60). Fundación Salud Men al España. Mille , A. H. (2020). Beyond dep ession: The expanding ole o in lamma ion in psychia ic diso de s. Wo ld Psychia y, 19(1), 108–109. h ps://doi.o g/10.1002/wps.20723 Mille , E. K., & Cohen, J. D. (2001). An in eg a i e heo y o p e on al co ex unc ion. Annual Re iew o Neu oscience, 24, 167–202. h ps://doi.o g/10.1146/annu e .neu o.24.1.167 Mille , I. W., Cama go, C. A., A ias, S. A., Sulli an, A. F., Allen, M. H., Golds ein, A. B., Man on, A. P., Espinola, J. A., Jones, R., Hasegawa, K., Boud eaux, E. D., & ED- SAFE In es iga o s. (2017). Suicide P e en ion in an Eme gency Depa men Popula ion: The ED-SAFE S udy. JAMA Psychia y, 74(6), 563–570. h ps://doi.o g/10.1001/jamapsychia y.2017.0678 Miná, V. L., Lace da-Pinhei o, S. F., Maia, L. C., Pinhei o, R. F. F., Mei eles, C. B., de Souza, S. I. R., Reis, A. O. A., Bianco, B., & Rolim, M. L. N. (2015). The in luence o in lamma o y cy okines in physiopa hology o suicidal beha io . Jou nal o A ec i e Diso de s, 172, 219–230. h ps://doi.o g/10.1016/j.jad.2014.09.057 147 Mi e , M., Ayuso-Ma eos, J. L., Sanchez-Mo eno, J., & Vie a, E. (2013). Dep essi e diso de s and suicide: Epidemiology, isk ac o s, and bu den. Neu oscience and Biobeha io al Re iews, 37(10 P 1), 2372–2374. h ps://doi.o g/10.1016/j.neubio e .2013.01.008 Miyake, A., F iedman, N. P., Eme son, M. J., Wi zki, A. H., Howe e , A., & Wage , T. D. (2000). The uni y and di e si y o execu i e unc ions and hei con ibu ions o complex ‘F on al Lobe’ asks: A la en a iable analysis. Cogni i e Psychology, 41(1), 49– 100. h ps://doi.o g/10.1006/cogp.1999.0734 Mohe , D., Shamsee , L., Cla ke, M., Ghe si, D., Libe a i, A., Pe ic ew, M., Shekelle, P., S ewa , L. A., & PRISMA-P G oup. (2015). P e e ed epo ing i ems o sys ema ic e iew and me a-analysis p o ocols (PRISMA-P) 2015 s a emen . Sys ema ic Re iews, 4(1), 1. h ps://doi.o g/10.1186/2046-4053-4-1 Moleón, Á., & Moleón, M. (2022). Suicidio: Una cues ión mul idisciplina . Edi o ial Médica Paname icana, S.A. Mo ello, M., Pie i, M., Zenobi, R., Talamo, A., S ephan, D., Landel, V., Fé on, F., & Mille , P. (2020). The In luence o Vi amin D on Neu odegene a ion and Neu ological Diso de s: A Ra ionale o i s Physio-pa hological Ac ions. Cu en Pha maceu ical Design, 26(21), 2475–2491. h ps://doi.o g/10.2174/1381612826666200316145725 Mo ico, E., Mo eno-Küs ne , B., de Dios Luna, J., To es-González, F., King, M., Naza e h, I., Mon ón-F anco, C., Gilde Gómez-Ba agán, M. J., Sánchez-Celaya, M., Díaz- Ba ei os, M. Á., Vicens, C., Mo eno-Pe al, P., & Bellón, J. Á. (2013). Psychome ic p ope ies o he Lis o Th ea ening Expe iences—LTE and i s associa ion wi h psychosocial ac o s and men al diso de s acco ding o di e en sco ing me hods. Jou nal o A ec i e Diso de s, 150(3), 931–940. h ps://doi.o g/10.1016/j.jad.2013.05.017 Moul on, V. R., & Tsokos, G. (2016). Cy okines. In Sys emic Lupus E y hema osus (pp. 137– 141). Else ie . h ps://doi.o g/10.1016/B978-0-12-801917-7.00017-6 Nähe , A.-F., Rummel-Kluge, C., & Hege l, U. (2019). Associa ions o Suicide Ra es Wi h Socioeconomic S a us and Social Isola ion: Findings F om Longi udinal Regis e and Census Da a. F on ie s in Psychia y, 10, 898. h ps://doi.o g/10.3389/ psy .2019.00898 Nakagome, K. (2017). Cogni i e impai men in psychia ic diso de s. Psychia y and Clinical Neu osciences, 71(5), 293. h ps://doi.o g/10.1111/pcn.12517 Nangle, J.M., Cla ke, S., Mo is, D. W., Schwaige , S., McGhee, K. A., Kenny, N., Mu phy, K., Gill, M., Co in, A., & Donohoe, G. (2006). Neu ocogni ion and suicidal beha iou in an I ish popula ion wi h majo psycho ic diso de s. Schizoph enia Resea ch, 85(1–3), 196–200. h ps://doi.o g/10.1016/j.sch es.2006.03.035 Nässbe ge , L., & T äskman‐Bendz, L. (1993). Inc eased soluble in e leukin‐2 ecep o concen a ions in suicide a emp e s. Ac a Psychia ica Scandina ica, 88(1), 48–52. h ps://doi.o g/10.1111/j.1600-0447.1993. b03412.x 148 Na ío, M., & Villo ia, L. (2014). Fac o es de iesgo en la conduc a suicida. In A. Anseán (Ed.), Suicidios: Manual de P e ención, In e ención y Pos ención de la Conduc a Suicida (2nd ed., pp. 117–194). Fundación Salud Men al España. Nguyen, D. T., W igh , E. P., Dedding, C., Pham, T. T., & Bunde s, J. (2019). Low Sel - Es eem and I s Associa ion Wi h Anxie y, Dep ession, and Suicidal Idea ion in Vie namese Seconda y School S uden s: A C oss-Sec ional S udy. F on ie s in Psychia y, 10. h ps://www. on ie sin.o g/a icle/10.3389/ psy .2019.00698 O’Ca oll, P. W., Be man, A. L., Ma is, R. W., Moscicki, E. K., Tanney, B. L., & Sil e man, M. M. (1996). Beyond he Towe o Babel: A nomencla u e o suicidology. Suicide & Li e-Th ea ening Beha io , 26(3), 237–252. O’Conno , R. C., & Nock, M. K. (2014). The psychology o suicidal beha iou . The Lance Psychia y, 1(1), 73–85. h ps://doi.o g/10.1016/S2215-0366(14)70222-6 O’Conno , R. C., & Po zky, G. (2018). Looking o he Fu u e: A Syn hesis o New De elopmen s and Challenges in Suicide Resea ch and P e en ion. F on ie s in Psychology, 9. h ps://www. on ie sin.o g/a icle/10.3389/ psyg.2018.02139 O’Dono an, A., Rush, G., Hoa am, G., Hughes, B. M., McC ohan, A., Kellehe , C., O’Fa elly, C., & Malone, K. M. (2013). Suicidal idea ion is associa ed wi h ele a ed in lamma ion in pa ien s wi h majo dep essi e diso de . Dep ession and Anxie y, 30(4), 307–314. h ps://doi.o g/10.1002/da.22087 Oh, K. Y., Van Dam, N. T., Douce e, J. T., & Mu ough, J. W. (2019). E ec s o ch onic physical disease and sys emic in lamma ion on suicide isk in pa ien s wi h dep ession: A hospi al-based case-con ol s udy. Psychological Medicine, 1–9. h ps://doi.o g/10.1017/S0033291718003902 Oladunjoye, A. O., Oladunjoye, O. O., Ayeni, O. A., Olubiyi, O., Fuchs, A., Gu ski, J., Yee, M. R., & Espi idion, E. D. (2020). Seasonal T ends in Hospi aliza ion o A emp ed Suicide and Sel -In lic ed Inju y in Uni ed S a es Adul s. Cu eus, 12(10), e10830. h ps://doi.o g/10.7759/cu eus.10830 Olie, E., Seylle , M., Bezia , S., Lo us, J., Belli ie , F., Bouge ol, T., Belzeaux, R., Azo in, J. M., Ga d, S., Kahn, J. P., Passe ieux, C., Leboye , M., E ain, B., Hen y, C., & Cou e , P. (2015). Clinical and neu opsychological cha ac e is ics o eu hymic bipola pa ien s ha ing a his o y o se e e suicide a emp . Ac a Psychia ica Scandina ica, 131(2), 129– 138. h ps://doi.o g/10.1111/acps.12326 O’Neill, C., P a , D., Kilshaw, M., Wa d, K., Kelly, J., & Haddock, G. (2021). The ela ionship be ween sel -c i icism and suicide p obabili y. Clinical Psychology & Psycho he apy, 28(6), 1445–1456. h ps://doi.o g/10.1002/cpp.2593 Oon-A om, A., Wongpaka an, T., Sa hapisi , S., Saisa oey, N., Kun awong, P., & Wongpaka an, N. (2019). Suicidali y in he elde ly: Role o adul a achmen . Asian Jou nal o Psychia y, 44, 8–12. h ps://doi.o g/10.1016/j.ajp.2019.07.014 149 Oquendo, M. A., Halbe s am, B., & Mann, J. J. (2003). Risk ac o s o suicidal beha io : U ili y and limi a ions o esea ch ins umen s. In M. B. Fi s (Ed.), S anda dized E alua ion in Clinical P ac ice (pp. 103–130). Oquendo, M. A., Sulli an, G. M., Sudol, K., Baca-Ga cia, E., S anley, B. H., Suble e, M. E., & Mann, J. J. (2014). Towa d a biosigna u e o suicide. The Ame ican Jou nal o Psychia y, 171(12), 1259–1277. h ps://doi.o g/10.1176/appi.ajp.2014.14020194 Pandey, G. N., Riza i, H. S., Ren, X., Fa eed, J., Hoppens ead , D. A., Robe s, R. C., Conley, R. R., & Dwi edi, Y. (2012). P oin lamma o y cy okines in he p e on al co ex o eenage suicide ic ims. Jou nal o Psychia ic Resea ch, 46(1), 57–63. h ps://doi.o g/10.1016/j.jpsychi es.2011.08.006 Pandey, G. N., Riza i, H. S., Zhang, H., Bhaumik, R., & Ren, X. (2018). Abno mal p o ein and mRNA exp ession o in lamma o y cy okines in he p e on al co ex o dep essed indi iduals who died by suicide. Jou nal o Psychia y & Neu oscience: JPN, 43(6), 376–385. h ps://doi.o g/10.1503/jpn.170192 Pa ham, P. (2021). The immune sys em (Fi h edi ion). W.W. No on & Company. Pa k, R. J., & Kim, Y. H. (2017). Associa ion be ween high sensi i i y CRP and suicidal idea ion in he Ko ean gene al popula ion. Eu opean Neu opsychopha macology, 27(9), 885–891. h ps://doi.o g/10.1016/j.eu oneu o.2017.06.010 Pa ks, R. M., Benne , J. E., Tamu a-Wicks, H., Kon is, V., Toumi, R., Danaei, G., & Ezza i, M. (2020). Anomalously wa m empe a u es a e associa ed wi h inc eased inju y dea hs. Na u e Medicine, 26(1), 65–70. h ps://doi.o g/10.1038/s41591-019-0721-y Peng, R., Dai, W., & Li, Y. (2018). Low se um ee hy oxine le el is co ela ed wi h lipid p o ile in dep essi e pa ien s wi h suicide a emp . Psychia y Resea ch, 266, 111–115. h ps://doi.o g/10.1016/j.psych es.2018.05.059 Pe o , C., Ve a, L., & Go wood, P. (2018). [Poo sel -es eem is co ela ed wi h suicide in en , independen ly om he se e i y o dep ession]. L’Encephale, 44(2), 122–127. h ps://doi.o g/10.1016/j.encep.2016.10.003 Pe e son, C., Sussell, A., Li, J., Schumache , P. K., Yeoman, K., & S one, D. M. (2020). Suicide Ra es by Indus y and Occupa ion—Na ional Violen Dea h Repo ing Sys em, 32 S a es, 2016. MMWR. Mo bidi y and Mo ali y Weekly Repo , 69(3), 57–62. h ps://doi.o g/10.15585/mmw .mm6903a1 Phelps, E. A., Lempe , K. M., & Sokol-Hessne , P. (2014). Emo ion and decision making: Mul iple modula o y neu al ci cui s. Annual Re iew o Neu oscience, 37, 263–287. h ps://doi.o g/10.1146/annu e -neu o-071013-014119 Picazo, J. (2017). El suicidio ac ual. Edi o ial EOS. Piędel, F., Rocka, A., Piwek, M., Jasielski, P. P., Pe i , V., & Rejdak, K. (2021). Co ela ion be ween i amin D and al e a ions in MRI among pa ien s wi h mul iple scle osis. Annals o Ag icul u al and En i onmen al Medicine: AAEM, 28(3), 372–377. h ps://doi.o g/10.26444/aaem/127062 150 Plöde l, M. (2021). Suicide isk o e he cou se o he day, week, and li e. Psychia ia Danubina, 33(3), 438–445. h ps://doi.o g/10.24869/psyd.2021.438 Popo ic, D., Vie a, E., Azo in, J.-M., Angs , J., Bowden, C. L., Mosolo , S., Young, A. H., & Pe ugi, G. (2015). Suicide a emp s in majo dep essi e episode: E idence om he BRIDGE-II-Mix s udy. Bipola Diso de s, 17(7), 795–803. h ps://doi.o g/10.1111/bdi.12338 Po ellano, J. A. (2018). Neu oeduación y unciones ejecu i as. Edi o ial CEPE. h p://public.eblib.com/choice/PublicFullReco d.aspx?p=6777286 Pos olache, T. T., Ak am, F., Lee, E. E., Low y, C. A., S ille , J. W., B enne , L. A., S ee en, E. A., Tu ecki, G., & Dwi edi, Y. (2020). Inc eased b ain i amin D ecep o exp ession and dec eased exp ession o ca helicidin an imic obial pep ide in indi iduals who died by suicide. Jou nal o Psychia ic Resea ch, 125, 75–84. h ps://doi.o g/10.1016/j.jpsychi es.2020.02.027 Powe s, A. D., Gleason, M. E. J., & Ol manns, T. F. (2013). Symp oms o bo de line pe sonali y diso de p edic in e pe sonal (bu no independen ) s ess ul li e e en s in a communi y sample o olde adul s. Jou nal o Abno mal Psychology, 122(2), 469–474. h ps://doi.o g/10.1037/a0032363 P iya, P. K., Rajappa, M., Ka imani, S., Mohan aj, P. S., & Re a hy, G. (2016). Associa ion o neu o ophins, in lamma ion and s ess wi h suicide isk in young adul s. Clinica Chimica Ac a; In e na ional Jou nal o Clinical Chemis y, 457, 41–45. h ps://doi.o g/10.1016/j.cca.2016.03.019 P obe -Linds öm, S., Be ge, J., Wes in, Å., Öjehagen, A., & Pa ulans, K. S. (2020). Long- e m isk ac o s o suicide in suicide a emp e s examined a a medical eme gency in pa ien uni : Resul s om a 32-yea ollow-up s udy. BMJ Open, 10(10), e038794. h ps://doi.o g/10.1136/bmjopen-2020-038794 Qin, P., & Mo ensen, P. B. (2003). The impac o pa en al s a us on he isk o comple ed suicide. A chi es o Gene al Psychia y, 60(8), 797–802. h ps://doi.o g/10.1001/a chpsyc.60.8.797 Racine, M. (2018). Ch onic pain and suicide isk: A comp ehensi e e iew. P og ess in Neu o- Psychopha macology & Biological Psychia y, 87(P B), 269–280. h ps://doi.o g/10.1016/j.pnpbp.2017.08.020 Rai man, J., Cha l on, B. M., A ing on-Sande s, R., Chan, P. A., Rusley, J., Maye , K. H., S ein, M. D., Aus in, S. B., & McConnell, M. (2020). Sexual O ien a ion and Suicide A emp Dispa i ies Among US Adolescen s: 2009-2017. Pedia ics, 145(3), e20191658. h ps://doi.o g/10.1542/peds.2019-1658 Raison, C. L., Capu on, L., & Mille , A. H. (2006). Cy okines sing he blues: In lamma ion and he pa hogenesis o dep ession. T ends in Immunology, 27(1), 24–31. h ps://doi.o g/10.1016/j.i .2005.11.006 151 Rale a, M. (2018). Ea ly Li e S ess: A Key Link be ween Childhood Ad e si y and Risk o A emp ing Suicide. Psychia ia Danubina, 30(Suppl 6), 341–347. Ribei o, J. D., Huang, X., Fox, K. R., & F anklin, J. C. (2018). Dep ession and hopelessness as isk ac o s o suicide idea ion, a emp s and dea h: Me a-analysis o longi udinal s udies. The B i ish Jou nal o Psychia y, 212(5), 279–286. h ps://doi.o g/10.1192/bjp.2018.27 Richa d-De an oy, S., Be lim, M. T., & Jollan , F. (2014). A me a-analysis o neu opsychological ma ke s o ulne abili y o suicidal beha io in mood diso de s. Psychological Medicine, 44(8), 1663–1673. h ps://doi.o g/10.1017/S0033291713002304 Richa d-De an oy, S., Go wood, P., Annweile , C., Olié, J.-P., Le Gall, D., & Beauche , O. (2012). Suicidal beha iou s in a ec i e diso de s: A de ici o cogni i e inhibi ion? Canadian Jou nal o Psychia y. Re ue Canadienne de Psychia ie, 57(4), 254–262. h ps://doi.o g/10.1177/070674371205700409 Richa d-De an oy, S., Olié, E., Guillaume, S., & Cou e , P. (2016). Decision-making in unipola o bipola suicide a emp e s. Jou nal o A ec i e Diso de s, 190, 128–136. h ps://doi.o g/10.1016/j.jad.2015.10.001 Rieche -Rössle , A. (2010). P ospec s o he classi ica ion o men al diso de s in women. Eu opean Psychia y: The Jou nal o he Associa ion o Eu opean Psychia is s, 25(4), 189–196. h ps://doi.o g/10.1016/j.eu psy.2009.03.002 Rios Lago, M., Pe iáñez, J. A., & Rod íguez-Sánchez, J. M. (2012). Neu opsicología de la a ención. In J. Ti apu Us á oz, M. Rios Lago, & F. Maes ú Un u be (Eds.), Manual de neu opsicología (2nd ed., pp. 189–218). Vigue a. Ronaldson, A., A ias de la To e, J., Gaugh an, F., Bakolis, I., Ha ch, S. L., Ho op , M., & D egan, A. (2020). P ospec i e associa ions be ween i amin D and dep ession in middle-aged adul s: Findings om he UK Biobank coho . Psychological Medicine, 1– 9. h ps://doi.o g/10.1017/S0033291720003657 Ro henhäusle , H.-B., S epan, A., & Kap hamme , H.-P. (2006). Soluble in e leukin 2 ecep o le els, empe amen and cha ac e in o me ly dep essed suicide a emp e s compa ed wi h no mal con ols. Suicide and Li e-Th ea ening Beha io , 36(4), 455–466. h ps://doi.o g/10.1521/suli.2006.36.4.455 Salag e, E., Solé, B., Tomioka, Y., Fe nandes, B. S., Hidalgo-Mazzei, D., Ga iga, M., Jimenez, E., Sanchez-Mo eno, J., Vie a, E., & G ande, I. (2017). T ea men o neu ocogni i e symp oms in unipola dep ession: A sys ema ic e iew and u u e pe spec i es. Jou nal o A ec i e Diso de s, 221, 205–221. h ps://doi.o g/10.1016/j.jad.2017.06.034 Salokangas, R. K. R., Luu onen, S., Heinimaa, M., F om, T., & Hie ala, J. (2019). A s udy on he associa ion o psychia ic diagnoses and childhood ad e si ies wi h suicide isk. No dic Jou nal o Psychia y, 73(2), 125–131. h ps://doi.o g/10.1080/08039488.2018.1493748 152 San Sebas ián, M., Edin-Liljeg en, A., & Jonsson, F. (2020). Ru al–u ban di e ences in suicide a emp s and mo ali y among young people in no he n Sweden, 1998–2017: A egis e -based s udy. Scandina ian Jou nal o Public Heal h, 48(8), 794–800. h ps://doi.o g/10.1177/1403494820939018 Sca pina, F., & Tagini, S. (2017). The S oop Colo and Wo d Tes . F on ie s in Psychology, 8, 557. h ps://doi.o g/10.3389/ psyg.2017.00557 Schiweck, C., Claes, S., Van Oudenho e, L., La i , G., Vaessen, T., de Beeck, G. O., Be ghmans, R., Wijkhuijs, A., Mülle , N., A ol , V., D exhage, H., & V ieze, E. (2020). Childhood auma, suicide isk and in lamma o y pheno ypes o dep ession: Insigh s om monocy e gene exp ession. T ansla ional Psychia y, 10(1), 1–12. h ps://doi.o g/10.1038/s41398-020-00979-z Schneide , E., El Hajj, N., Mülle , F., Na a o, B., & Haa , T. (2015). Epigene ic Dys egula ion in he P e on al Co ex o Suicide Comple e s. Cy ogene ic and Genome Resea ch, 146(1), 19–27. h ps://doi.o g/10.1159/000435778 Scho e, D. E., & Clum, G. A. (1987). P oblem-sol ing skills in suicidal psychia ic pa ien s. Jou nal o Consul ing and Clinical Psychology, 55(1), 49–54. h ps://doi.o g/10.1037//0022-006x.55.1.49 Se a ini, G., Pa isi, V. M., Aguglia, A., Ame io, A., Sampogna, G., Fio illo, A., Pompili, M., & Amo e, M. (2020). A Speci ic In lamma o y P o ile Unde lying Suicide Risk? Sys ema ic Re iew o he Main Li e a u e Findings. In e na ional Jou nal o En i onmen al Resea ch and Public Heal h, 17(7), 2393. h ps://doi.o g/10.3390/ije ph17072393 She chand, O., Sapko a, N., Chaudha i, R. K., Khan, S. A., Ba anwal, J. K., Pokh el, T., Das, B. K. L., & Lamsal, M. (2018). Associa ion be ween i amin D de iciency and dep ession in Nepalese popula ion. Psychia y Resea ch, 267, 266–271. h ps://doi.o g/10.1016/j.psych es.2018.06.018 Shneidman, E. S. (1985). Some Though s on G ie and Mou ning. Suicide and Li e-Th ea ening Beha io , 15(1), 51–55. h ps://doi.o g/10.1111/j.1943-278X.1985. b00788.x Sholbe g, M. M., & Ma ee , C. A. (1989). In oduc ion o cogni i e ehabil i a ion: Theo y and p ac ice. Guil o d P ess. Sokolowski, M., Wasse man, J., & Wasse man, D. (2015). An o e iew o he neu obiology o suicidal beha io s as one me a-sys em. Molecula Psychia y, 20(1), 56–71. h ps://doi.o g/10.1038/mp.2014.101 Solé, B., Jiménez, E., To en , C., Reina es, M., Bonnin, C. D. M., To es, I., Va o, C., G ande, I., Valls, E., Salag e, E., Sanchez-Mo eno, J., Ma inez-A an, A., Ca alho, A. F., & Vie a, E. (2017). Cogni i e Impai men in Bipola Diso de : T ea men and P e en ion S a egies. The In e na ional Jou nal o Neu opsychopha macology, 20(8), 670– 680. h ps://doi.o g/10.1093/ijnp/pyx032 153 Somme eld , S. L., Cullen, K. R., Han, G., F yza, B. J., Hou i, A. K., & Klimes-Dougan, B. (2016). Execu i e A en ion Impai men in Adolescen s wi h Majo Dep essi e Diso de . Jou nal o Clinical Child and Adolescen Psychology : The O icial Jou nal o he Socie y o Clinical Child and Adolescen Psychology, Ame ican Psychological Associa ion, Di ision 53, 45(1), 69–83. h ps://doi.o g/10.1080/15374416.2015.1072823 So ia, V., U ibe, J., Sal a -Pujol, N., Palao, D., Menchón, J. M., & Labad, J. (2018). Psiconeu oinmunología de los as o nos men ales. Re is a de Psiquia ía y Salud Men al, 11(2), 115–124. h ps://doi.o g/10.1016/j. psm.2017.07.006 Spedding, S. (2014). Vi amin D and dep ession: A sys ema ic e iew and me a-analysis compa ing s udies wi h and wi hou biological laws. Nu ien s, 6(4), 1501–1518. h ps://doi.o g/10.3390/nu6041501 S oop, J. R. (1935). S udies o in e e ence in se ial e bal eac ions. Jou nal o Expe imen al Psychology, 18(6), 643–662. h ps://doi.o g/10.1037/h0054651 Sudol, K., & Mann, J. J. (2017). Bioma ke s o Suicide A emp Beha io : Towa ds a Biological Model o Risk. Cu en Psychia y Repo s, 19(6), 31. h ps://doi.o g/10.1007/s11920-017-0781-y Szan o, K. (2017). Cogni i e De ici s: Unde app ecia ed Con ibu o s o Suicide. The Ame ican Jou nal o Ge ia ic Psychia y: O icial Jou nal o he Ame ican Associa ion o Ge ia ic Psychia y, 25(6), 630–632. h ps://doi.o g/10.1016/j.jagp.2017.02.012 Tanaka, T., Na azaki, M., & Kishimo o, T. (2014). IL-6 in In lamma ion, Immuni y, and Disease. Cold Sp ing Ha bo Pe spec i es in Biology, 6(10). h ps://doi.o g/10.1101/cshpe spec .a016295 Ta iq, M. M., S ee en, E. A., Smi h, H. A., Sleemi, A., Khabazghaz ini, B., Vaswani, D., & Pos olache, T. T. (2011). Vi amin D: A po en ial ole in educing suicide isk? In e na ional Jou nal o Adolescen Medicine and Heal h, 23(3), 157–165. h ps://doi.o g/10.1515/ijamh.2011.038 Thompson, M. P., King ee, J. B., & Lamis, D. (2019). Associa ions o ad e se childhood expe iences and suicidal beha io s in adul hood in a U.S. na ionally ep esen a i e sample. Child: Ca e, Heal h and De elopmen , 45(1), 121–128. h ps://doi.o g/10.1111/cch.12617 Tidemalm, D., Runeson, B., Wae n, M., F isell, T., Ca ls öm, E., Lich ens ein, P., & Långs öm, N. (2011). Familial clus e ing o suicide isk: A o al popula ion s udy o 11.4 million indi iduals. Psychological Medicine, 41(12), 2527–2534. h ps://doi.o g/10.1017/S0033291711000833 Tie , Q. Q., Finney, J. W., & Moos, R. H. (2006). Recen sexual abuse, physical abuse, and suicide a emp s among male e e ans seeking psychia ic ea men . Psychia ic Se ices, 57(1), 107–113. h ps://doi.o g/10.1176/appi.ps.57.1.107 Ting, E. Y.-C., Yang, A. C., & Tsai, S.-J. (2020). Role o In e leukin-6 in Dep essi e Diso de . In e na ional Jou nal o Molecula Sciences, 21(6), E2194. h ps://doi.o g/10.3390/ijms21062194