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).
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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.
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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.
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