Boulougouris et al, 2013

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Experimental Brain Research

ISSN 0014-4819

Exp Brain Res

DOI 10.1007/s00221-013-3669-z

Serotonergic modulation of suicidal behaviour: integrating preclinical data with

clinical practice and psychotherapy

Vasileios Boulougouris, Ioannis

Malogiannis, George Lockwood, Iannis

Zervas & Giuseppe Di Giovanni



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Exp Brai ResDOI 10.1007/s00221-013-3669-z

SEROtOnIn

Serotonergic modulation of suicidal behaviour: integrating

preclinical data with clinical practice and psychotherapy

Vasileios Boulougouris · Ioannis Malogiannis ·

George Lockwood · Iannis Zervas ·

Giuseppe Di Giovanni

Received: 6 May 2013 / Acceped: 30 July 2013© Spriger-Verlag Berli Heidelberg 2013

wih persoaliy disorders), aimig o ivie he reader o

iegrae some aspecs o he eurobiology o huma sui-cidal behaviour io a model o suicide ha ca be used ia cliical ecouer.

Keywords Suicide · Serooi · 5-Ht2 recepors ·5-HttLP · Serooi rasporer · Schema herapy ·Borderlie persoaliy disorder

Introduction

Suicide is receivig icreasig aeio worldwide, wih

may couries developig aioal sraegies or preve-io. Suicide accous or almos 2 % o deahs worldwide,ad aemped suicide is more reque ha compleed sui-cide, wih a prevalece o 3.5 % (Suomie e al. 2004).the deiio o suicidal behaviours ecompasses a broadcosellaio o heerogeeous eiies dierig o oly imaiesaio, bu also i heir backgroud (Coure e al.2004).

Forms o suicidaliy iclude suicidal ideaios, impul-sive suicide aemps wih low lehaliy, highly lehal ailedsuicide aemps ad compleed suicide (Body e al. 2000)ad ivolve he ieio o die ad he lehaliy o mehod(Body e al. 2000). the aure o he suicidal ac mayrage rom impulsive o careully premediaed ad romaggressive/puiive or viole o o-viole or passive.

Suicide ca eiher be aemped or compleed, alhougha overlap has bee oed give ha abou wo-hirdso suicide vicims have made oe or more prior suicideaemp(s), ad o-viole suicide aempers requelychage heir suicide mehod rom o-viole o vio-le (Rihmer 2007). Aemped suicide is a sel-damagigac aimed a edig oe’s lie resulig i ailed suicide

Abstract May sudies have provided impora ior-

maio regardig he aaomy, developme ad uc-ioal orgaizaio o he 5-Ht sysem ad he aleraiosi his sysem ha are prese wihi he brai o he sui-cidal paie. there is also a growig ieres i geeicacors associaed wih suicide, sice hese may lead ohe emergece o persoaliy rais ha prove o be log-erm predicors o suicidal behaviour. this review willocus o preseig he scieic lieraure o he role o he serooergic sysem i suicidal behaviour as well asdysucioal aiudes ad persoaliy rais associaedwih he suicidal paie. the associaio o he serooirasporer gee, he 5-Ht2 recepors ad is meabolie

5-hydroxyidoleaceic acid wih suicidal behaviour adaimal models ha may capure he complexiy o sui-cidal behaviour will be discussed. Fially, he relaioshipbewee eurobiological models ad psychoherapeuicierveios or suicide preveio will be cosidered wiha ocus o Schema therapy (a approach ha has showparicular promise i he reame o suicidal idividuals

V. Boulougouris (*) · I. Malogiais · I. ZervasGreek Sociey o Schema therapy, Ahes, Greecee-mail: [email protected]

V. Boulougouris · I. Malogiais · I. Zervas1s Deparme o Psychiary, Egiiio Hospial,Ahes Medical School, Ahes, Greece

G. LockwoodSchema therapy Isiue Midwes, Kalamazoo,MI, USA

G. Di GiovaiDeparme o Physiology ad Biochemisry,Faculy o Medicie ad Surgery, Uiversiy o Mala,Vallea, Mala



Exp Brai Res

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ad suicide gesure. Failed suicide, provoked by a srogie o die, ivolves careul plaig ad a highly lehalmehod, whereas suicide gesure (usually provoked by aierpersoal cofic) ivolves less preparaio ad lesslehal mehods wih low ie o die (Ma 1998).

the grea diversiy o suicidal behaviours refecs heirassociaio wih a rage o disorders. these iclude major

depressive disorder (MDD), subsace-relaed disordersad persoaliy disorders, icludig borderlie persoaliydisorder (BPD). Comorbidiy amog hese disorders adbewee hese disorders ad suicide behaviour is commo(Body e al. 2000; Dumais e al. 2005a, b). Suicide adaemped suicide are complex behaviours. A large um-ber o proximal ad disal risk acors have bee ideied(Hawo ad va Heerige 2009) which ca be caego-rized io explaaory models aimig o udersad suicidalidividuals ad aciliae suicide risk assessme. the moswidely acceped risk acors or suicidal behaviour ivolvepsychiaric–psychological ad socioecoomic acors,

while he biological, eurochemical ad geeic coribu-ios o suicidaliy have o ye bee as ully elucidaed.

O a eurobiological level, dysucio o he seroo-ergic sysem has bee show o be implicaed i a umbero psychiaric aficios icludig MDD, BPD ad suicide(Oquedo ad Ma 2000; Borolao e al. 2013; Di Gio-vai e al. 2008). May sudies have provided imporaiormaio regardig he aaomy, developme ad uc-ioal orgaizaio o he 5-Ht sysem ad he aleraiosi his sysem ha are prese wihi he brai o he sui-cidal paie (Padey 2013). O a psychoherapeuic level,early models have ideied key deermias operaig

durig he developme o disorders or behavioural prob-lems. Several have ocused o, amog oher acors, hecogiive ad emoioal characerisics o depressio adpersoaliy disorders. this cocepual approach ad heempirical research moivaed by such models have led osigica isighs io hese disorders (Igram ad Luxo2005; nador e al. 2009).

Our aim is o review he scieic lieraure o he co-ribuio o he serooergic sysem o suicidal behaviouras well as o dysucioal aiudes ad persoaliy raisassociaed wih he suicidal paie. Alhough we will dis-cuss daa rom sudies ivesigaig boh suicide compleersad aempers ierchageably, we ackowledge ha hesewo pheoypes are likely o oly parly share uderly-ig aeiological ad eurobiological mechaisms (tureckie al. 2012). the associaio o he 5-hydroxyidoleaceicacid (5-HIAA), he 5-Ht2A/2C recepors ad he serooirasporer promoer regio (5-HttLPR) polymorphismad suicidal behaviour alog wih aimal models will bediscussed. Fially, he relaioship bewee eurobiologi-cal models ad psychoherapeuic ierveios or sui-cide preveio will be discussed wih a ocus o Schema

therapy (a approach ha has show paricular promise ihe reame o suicidal idividuals wih persoaliy disor-ders), aimig o ivie he reader o iegrae some aspecso eurobiology o huma suicidal behaviour io a modelo suicide ha ca be used i a cliical ecouer.

Serotonergic function in suicide

Cerebral spial fuid 5-hydroxyidoleaceic acid i suicidalbehaviour

Give he iaccessibiliy o he huma brai, iiial sud-ies o he biology o suicidal behaviour ad developmeo biomarkers ocused o peripheral issues such as cer-ebrospial fuid (CSF), urie, plaeles ad serum. Iiialevidece or he ivolveme o 5-Ht i suicide semmedrom digs o low CSF 5-hydroxyidoleaceic acid(5-HIAA) levels i depressed suicide aempers ad i he

brai sems o compleed suicides (Asberg 1997; Asberge al. 1976; Baki e al. 1984; Carlsso e al. 1980; Maad Maloe 1997; Placidi e al. 2001; Roy e al. 1986;träskma e al. 1981). Alhough he lik bewee low CSF5-HIAA ad suicidaliy has bee debaed (Roggebache al. 2002), sigicaly lower levels o CSF 5-HIAA havealso bee repored i a mea-aalysis o CSF meaboliesudies i subjecs who made prior suicide aemps adhose who subsequely commied suicide (Leser 1995).Furher ivesigaio o he relaioship bewee CSF5-HIAA ad preroal (PFC) 5-Ht has show a posiivecorrelaio bewee he wo i auopsied subjecs (Saley

e al. 1985). I addiio, more rece sudies have showha suicide aempers exhibi a blued release o prolac-i i respose o admiisraio o efuramie, a measureo 5-Ht aciviy (Dulchi e al. 2001; Duval e al. 2001;Maloe e al. 1996; Ma 1995; Padey 1997; Weiss adCoccaro 1997).

5-Ht recepor i suicidal behaviour

Wih regard o 5-Ht recepor dysucio i suicide adaggressio, he mos sudied have bee he 5-Ht1, 5-Ht2 subypes (Borolao e al. 2013; Paariello e al. 2011). Wewill ocus o 5-Ht2 recepors ha have bee implicaedi a wide variey o codiios icludig obesiy, axiey,depressio, obsessive compulsive disorder, schizophreia,migraie ad erecile dysucio (Di Giovai e al. 2008,2011).

5-Ht2A recepor i suicidal behaviour

I vivo euroimagig echiques provide a grea oppor-uiy o urher elucidae he lik bewee adverse



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eviromeal codiios, biomarkers ad he sympomsor rais implicaed i suicidal behaviour. Early evidecesuggess ha icreased 5-Ht2A recepor bidig i he pre-roal corex, specically Brodma area 9, cosiueshe mos cosise pos-morem biological abormaliy o suicide (Arago e al. 1990, 1992; Ma e al. 1986; Sock-meier e al. 1997; turecki e al. 1999; Padey e al. 2002;

Sockmeier 2003). Alhough hese abormaliies wererepored as aleraios i 5-Ht2 recepor bidig, i seemsas i hese sudies ivesigaed 5-Ht2A recepors as ligadbidig o 5-Ht2C recepors (Hoyer e al. 1986). I addi-io, he mRnA o 5-Ht2B recepors has low expressiolevels i corex (Schmuck e al. 1994). Give ha hesedigs were repored i sudies i which diagosis o he suicide vicim was uresriced ogeher wih he co-sisecy oed bewee hose sudies wih depressed admedicaio-ree suicide vicims (Hrdia e al. 1993; Yaese al. 1990), quesios are raised cocerig he exe owhich his dig is associaed wih a specic diagosis,

a sympom cluser associaed wih suicide or represeeda biomarker o suicidal ideaio. Alhough he aoreme-ioed dig was oed i sudies o vicims who com-mied suicide by viole meas (Arago e al. 1990; Aroraad Melzer 1989; Ma 1996; Hrdia e al. 1993), i wasuclear how his abormaliy could be liked wih symp-omaology or persoaliy rais. A rece auopsy sudyhas proposed ha suicide vicims dyig by viole measexhibied greaer plaig o suicide or a predisposiioowards aggressive behaviour (Dumais e al. 2005a, b).Sice i is much easier o recrui subjecs wih specicdiagoses i vivo, mos euroimagig sudies o 5-Ht2A

recepors ocused upo hree diagosic areas i relaio o5-Ht2A recepors: MDD, BPD ad aisocial persoaliydisorder (APD).

MDD ad preroal 5-Ht2A bidig i suicidal behaviour

neuroimagig sudies o 5-Ht2A recepors i depressedad healhy samples seem o be icosise wih he pos-morem digs as may o hese bewee-group compari-sos repored a regioal decrease i 5-Ht2A bidig, whichcould probably be aribued o selecive serooi reupakeihibior (SSRI) reame (Dhaee e al. 1992; Biver e al.1997; Aar-Levy e al. 1999; Miu e al. 2004; va Heer-ige e al. 2003; Audeaer e al. 2001). Sice hese iiialsudies sampled people wih rece aidepressa rea-me, he iiial impressio was ha regioal 5-Ht2A bid-ig eded o be reduced i MDD. However, urher sudieso depressed subjecs o beig i aidepressa reameailed o reveal ay diereces compared o healhy co-rols (Meyer e al. 1999; Melzer e al. 1999). Specically,Meyer e al. (1999) sampled medicaio-ree (>6 mohs)subjecs wih o comorbid psychiaric aficios, i he

mids o a major depressive episode (MDE) rom earlyose MDD ad by applyig [18F]seoperoe, a very goodradioligad or imagig 5-Ht2A recepors, o dierece ipreroal corex 5-Ht2A bidig was oud as comparedo healhy corols.

the icosisecy bewee sudies o suicide vicimsad euroimagig sudies o MDEs could be aribued o

he presece o a subgroup o subjecs wih MDEs whohave he biological abormaliy repored i suicide vicims(e.g. low exracellular serooi). 5-Ht2A recepor desiyhas a iverse relaioship wih exracellular serooilevels, i.e. he desiy o 5-Ht2A recepors i he corexicreases aer chroic serooi depleio ad decreasesaer chroically raisig exracellular serooi (O’Regae al. 1987; todd e al. 1995). the sympom used o ide-iy his subgroup was he elevaed pessimism (dysuc-ioal aiudes) observed durig MDEs. there is a modeslevel o dysucioal aiudes i healh, which icreases oa variable exe durig depressive episodes (Simos e al.

1986; Fava e al. 1994). Greaer pessimism durig MDEsis a impora sympom ha coribues o he geeraioo sad mood ad is argeed by cogiive herapy as wellas SSRI reame (Simos e al. 1986; Fava e al. 1994).Icreasig exracellular serooi aer admiisraio o iraveous d-efuramie is associaed wih a srog shii dysucioal aiudes owards opimism i healhy idi-viduals (Meyer e al. 2003). this argues ha amog hemay roles o serooi, oe o hem is o modulae dys-ucioal aiudes i humas. Boh he aerior cigu-lae corex ad dorsolaeral ad medial PFC paricipae iucios relaed o opimism ad pessimism (Sharo e al.

2007; Mierschihaler e al. 2008; Ellio e al. 2002).A srog correlaio has bee observed bewee he

severiy o dysucioal aiudes (pessimism) ad eleva-io i corex 5-Ht2A bidig poeial, refecig specicbidig relaive o ree ad o-specic bidig (BPnD).Moreover, corex 5-Ht2A BPnD was sigicaly elevaedi subjecs wih MDE ad severe pessimism (Meyer e al.2003). there was a srog, sigica correlaio beweeseveriy o pessimism ad preroal corex 5-Ht2A BPnD.I a separae sudy o a large sample o healhy subjecs,wo persoaliy aces relaed o pessimism (vulerabiliyad axiey) were also posiively correlaed wih prero-al corex, emporal corex ad le isula 5-Ht2A BPnD (Frokjaer e al. 2008).

the ivesigaios correlaig severiy o dysucioalaiudes wih greaer 5-Ht2A BPnD (Meyer e al. 2003) arehighly cosise wih pos-morem ivesigaios repor-ig greaer 5-Ht2A recepor desiy i he preroal cor-ex o suicide vicims. Fiy per ce o suicide vicimssuer rom MDD (Robis e al. 1959). the dysucioalaiudes scale (DAS) is highly correlaed wih hopeless-ess measured wih he Beck Hopelessess Scale (Cao



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e al. 1999; norma e al. 1988). Give ha hopelessessis a risk acor or suicide (Beck e al. 1985, 1989), i isplausible ha ivesigaios o suicide vicims reporigicreased 5-Ht2A BPnD sampled depressed subjecs wih agreaer severiy o pessimism.

Persoaliy disorders (BPD/APD) ad preroal 5-Ht2A

bidig i suicidal behaviour

BPD ad APD cosiue wo oher psychiaric codi-ios o which he sudies o suicide vicims have ocused(Barraclough e al. 1974; Robis e al. 1959; Brodsky e al.1997). 5-Ht2A bidig i medicaio-ree BPD paiesshowed o dierece i he preroal corex (Meyer e al.2003); however, a icrease i 5-Ht2A bidig i he hip-pocampus was oud (Solo e al. 2007). 5-Ht2A bidigi aggressive idividuals revealed o group dierece iay regio, bu a age ieracio such ha 5-Ht2A bidigeded o icrease cosiderably more wih age i idividu-

als wih aggressio (Meyer e al. 2008). this age-relaedeec migh represe a idex o diereial chage ipyramidal cell loss, sice mos 5-Ht2A recepors are oudi apical dedries o pyramidal cell euros ad he pa-er o loss o pyramidal cells maches he loss i 5-Ht2A recepors wih age (Jacobs e al. 1997; Jakab ad Goldma-Rakic 1998; Saaa e al. 2004). Greaer 5-Ht2A receporbidig has also bee repored recely i he orbioro-al corex o impulsively aggressive persoaliy disorderedidividuals (Rosell e al. 2010). However, his digshould be reaed wih cauio as paricipas were osubjeced o urie screeig or subsace abuse, a codi-

io commoly comorbid wih aggressio. Such subsacesmay bias 5-Ht2A recepor bidig (Bubar ad Cuigham2008). Cosequely, amog he ivesigaios o 5-Ht2A bidig, here is suppor or icreased bidig i older idi-viduals wih aggressio hroughou he corex ad i heorbioroal corex i people wih aggressio.

the evidece o greaer 5-Ht2A desiy i he PFC o suicide vicims i pos-morem sudies should be rei-erpreed hrough he prism o diagosic ad sympom-specic digs rom euroimagig sudies o 5-Ht2A bidig. MDD wih high levels o pessimism is associaedwih greaer preroal corex 5-Ht

2A

bidig. Hal o hesuicide vicims have MDD ad hopelessess (highly corre-laed wih pessimism), which is associaed wih heigheedrisk o suicide (Beck e al. 1985, 1989; Cao e al. 1999).the diagosis o BPD does o coribue o he d-ig o greaer preroal corex 5-Ht2A desiy i suicidevicims sice o chage i preroal 5-Ht2A BPnD wasoud (Meyer e al. 2003; Solo e al. 2007). I hose wihaggressive behaviour, a subgroup o subjecs older haage 34 show a similar eurobiological dig ad wouldbe expeced o also coribue o he origial digs o

greaer preroal 5-Ht2A desiy i suicide vicims (Meyere al. 2008; Rosell e al. 2010).

5-Ht2A recepors i aggressio ad suicide

Impulsive ad aggressive rais are posulaed o be paro he diahesis or suicidal behaviour (Ma e al. 1999).

High levels o aggressive behaviour have bee associaedwih suicidal behaviour, especially lehal suicide aemps.Impulsive behaviour has bee show o be highly relaedo o-aal suicide aemps (Oquedo e al. 2004). Asmeioed earlier, low levels o 5-Ht have bee implicaedi impulsive violece ad aggressio i sudies icludiglow CSF 5-HIAA i idividuals wih a lieime hisory o aggressive behaviour wih persoaliy ad oher psychi-aric disorders (Brow ad Goodwi 1986; Saley e al.2000). Low levels o 5-Ht have also bee associaed wiha blued prolaci respose o serooi-releasig ageefuramie i persoaliy disorder paies (Coccaro

e al. 1989, 1995). Icreased levels o 5-Ht2A receporbidig correlaed wih aggressive behaviour i persoal-iy ad oher psychiaric disorder paies (McBride e al.1994; Coccaro e al. 1989). A role or serooergic ucioi aggressive ad o a lesser exe, impulsive behaviour,is well documeed (Rydig e al. 2006; Cogdo e al.2008), cosise wih observaios ha low SERt bid-ig associaed wih suicide appears o be coceraed ihe veromedial PFC ad aerior cigulae regios, whichplay a role i mediaig ihibiio ad resrai (Aragoe al. 1995; Ma e al. 2000). However, usig pos-morembrai issue, plaeles, ad DnA rom suicide compleers

ad aempers has o provided uequivocal evidece ora pre-emie role or he SERt i he pahophysiology o suicide (Purselle ad nemero 2003).

5-Ht2C recepors i aggressio ad suicide

Despie he iese research o 5-Ht2C recepors show-ig is pivoal ivolveme i diere europsychiaricdisorders, oly recely has he rs selecive agois lor-caseri (Beliviq, Area Pharmaceuical) advaced iohe cliic, i was approved i 2013 by FDA or he rea-me o obesiy (Berlie ad Hurre 2013). this paradoxi-cal siuaio is due o he lack o selecive pharmacologicalools capable o overcomig he high degree o homologyamog 5-Ht2 recepors ad, above all, he complexiyo 5-Ht2C sigallig. Ideed, he 5-Ht2C recepor is heoly kow G proei-coupled recepor (GPCR) subjeco a orm o pos-rascripioal modicaio kow asRnA ediig (Di Giovai e al. 2006). this is a processi which specic adeosie residues are covered o io-sie resulig i ucioal recodig o he mRnA ha cageerae up o 24 diere proei isoorms wih disic



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ucioal properies. Pos-morem, aimal ad pharmaco-logical sudies have suggesed ha 5-Ht2C recepor adheir alered RnA ediig is ivolved i he pahophysiol-ogy o meal disorders icludig aggressio ad suicide,alhough resuls remai icosise (Paariello e al. 2011;Borolao e al. 2013; Di Giovai e al. 2006, 2011). Forisace, a icreased desiy o preroal corex 5-Ht2CR

mRnA (Padey e al. 2006) ad diereces i pre-mRnAediig o hese recepors bewee corol subjecs adsuicidal vicims have bee oud (Gurevich e al. 2002;Dracheva e al. 2008). Cosisely, ull edied 5-Ht2CRrecepor mice displayed ehaced axiey-like behaviouri respose o he preereial 5-Ht2C agois, m-chloro-pheylpiperazie (mCPP; Di Giovai e al. 2000), i hesocial ieracio es ad icrease i reezig behaviours ireacio o a iaely aversive ulrasoic simulus (Marie al. 2013). these auhors suggesed ha ehaced 5-Ht2C recepor ediig hrough iererece rom aleraive splic-ig would lead o a deci o rucaed recepors ha or-

mally exer a domia egaive eec o he addressig o he ull-legh 5-Ht2C recepor proei o he membrae(Mari e al. 2013). Moreover, i is kow ha he pharma-cological simulaio o 5-Ht2C recepors reduces aggres-sive resposes ad ehaces he display o submissivebehaviour (Rosezweig-Lipso e al. 2007; Dekeye e al.2012; Harvey e al. 2012). these eecs, however, mayresul rom a geeral ehaceme i social axiey causedby drugs acig a 5-Ht2C recepors capable o iduc-ig paic aack i humas (Charey e al. 1987). Ideed,icreased euroedocrie ad axiey resposes o mCPPwere observed i some idividuals wih MDD (Ghaziuddi

e al. 2000). I addiio, a icreased i respose o mCPPi cerebral blood fow o le roal o idividuals carry-ig he 5-Ht2C-Cys-23-Ser polymorphism i he 5-Ht2C codig regio was observed (Kuh e al. 2004). I co-ras, mos sudies ailed o ideiy sigica associa-ios amog polymorphisms o his recepor ad suicidalaemps (Zhag e al. 2008; turecki e al. 2003; Serreie al. 2007, 2009; Arias e al. 2001), compleed suicide(Seulj e al. 2004), he severiy o suicidal behaviours (DeLuca e al. 2008; Di Giovai e al. 2011; Paariello e al.2011) or suicide risk ad deliberae sel-harm (Pooley e al.2003). O he oher had, he laes available sudy deeceda sigica associaio bewee compleed suicide ad hevarias o 5-Ht2C-Cys-23-Ser polymorphism bu o hemuaio G-995A (promoer regio) i he 5-Ht2C o Slo-veia suicide vicims (Videic e al. 2009).

Sice 5-Ht2C recepors are preereially expressed oGABAergic iereuros (Serras e al. 2005; Boohmae al. 2006; Liu e al. 2007; Di Giovai e al. 2001), heirhyperaciviy ad/or icrease desiy/ediig lead o aicrease i he GABAergic ucio i areas such as heroal corex, oher limbic srucures ad he raphé uclei

deermiig a decrease i 5-Ht urover see i aggres-sio ad suicide (Borolao e al. 2013; Oquedo ad Ma2000).

Serooi rasporer imagig ad pos-morem sudieso suicide vicims

I addiio o he pos-morem sudies o serooi ras-porer (5-Htt) bidig i depressio (wih or wihoucocurre suicide), decreased 5-Htt bidig has beerepored i he veral preroal corex associaed wih sui-cide, idepede o diagosis (Ma e al. 2000; Aragoe al. 1995). Compariso bewee suicide vicims wih ahisory o depressio ad suicide vicims wihou a hisoryo depressio yielded sigicaly lower 5-Htt bidig iveral preroal corex i he suicide vicims (Ma e al.2000). Addiioally, boh groups o suicide vicims hadlower veral preroal corex 5-Htt bidig as comparedo o-suicide corols.

Furher euroimagig ivesigaios have ideied hecodiios associaed wih decreased global 5-Htt bid-ig describig a regio-specic paer ha maches a pre-domia lower level o veral preroal corex bidig(Meyer e al. 2001, 2004). Global reducios i 5-Httbidig may be observed ollowig aidepressa rea-me (Meyer e al. 2001, 2004; Suhara e al. 2003), i all/ wier seaso relaive o sprig/summer (Praschak-Riedere al. 2005), as well as ollowig ecsasy abuse, wherea reducio i 5-Htt bidig seems o be selecivelyaecig corical regios icludig he sriaum ad mid-brai (McCa e al. 2005; Selvaraj e al. 2009). A similar

regio-specic eec has bee recely repored i sudieswih paies suerig rom obsessive–compulsive disor-der (OCD) where he lowes 5-Htt bidig was oed iveral preroal corex (Masumoo e al. 2010; Reimolde al. 2007). Give ha subsace abuse ad axiey disor-ders are correlaed wih higher risk or suicide, i could beargued ha ecsasy abuse ad OCD could coribue o hedimiished veral preroal corex 5-Htt bidig i sui-cide compleers (Ma e al. 2000).

Furher experimeaio suppors he hypohesis ha5-Htt bidig i impulsiviy, as well as oher maladap-ive behaviours relaed o risk or suicide, is associaedwih 5-Htt bidig reducio. Sudies o early maeralseparaio i peer-reared rhesus mokeys (a aimal modelwhich will be discussed i aoher secio o his review),who laer exhibied aggressive ad impulsive behaviour,have repored loss o 5-Htt bidig resriced i areasicludig he midbrai, halamus, caudae, puame adaerior cigulae corex, bu o he preroal corex(Ichise e al. 2006). neuroicism, a persoaliy rai whichmay ivolve impulsiviy, has bee posiively correlaedwih halamic 5-Htt bidig (takao e al. 2007) ad



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egaively associaed wih opeess o values, he laer o which has show a egaive correlaio wih 5-Htt bid-ig i subcorical regios (Kalbizer e al. 2009). Aggres-sio has also bee liked wih low levels o 5-Htt bid-ig i he aerior cigulae corex (Frakle e al. 2005) buwih greaer 5-Htt bidig i brai sem o people wihBPD (Koch e al. 2007). the degree o which hese bid-

ig chages ake place i he preroal corex cao beassessed due o he radioracig mehods uilized i hesesudies. neuroimagig sudies o 5-Htt bidig i impul-siviy ad relaed codiios have o provided evidececormig he veral preroal corex paer o 5-Httbidig loss repored by pos-morem sudies argeig hisspecic regio (Ma e al. 2000; Arago e al. 1995).

Serooi rasporer i persoaliy rais likedwih suicide

Geeic sudies ocusig o 5-Ht-relaed gees i search o

geeic markers o suicide sugges ha he 5-Ht rasporerlegh polymorphic regio (5-HttLPR) polymorphismo he serooi rasporer gee is srogly relaed o sui-cide (Cosaza e al. 2013; Goda e al. 2011). the shor(s) allele o he 5-HttLPR is associaed wih reduced sero-oi rasporer (5-Htt) proei availabiliy ad ucio(Cali ad Lesch, 2007) compared wih he log (L) orm.the presece o a leas oe s allele has bee proposedas a predicor o suicidal behaviour (Body e al. 2006).Cosiderig he diere suicidal pheoypes, icludiga review o relaed mea-aalyses, he s allele seems o beassociaed wih impulsive ad aggressive suicidal behav-

iours ad compleed suicide (Body e al. 2000) ad vio-le (Bayle e al. 2003; Bellivier e al. 2000; Coure e al.2001) as well as repeaed suicide aemps (Coure e al.2004). A rece mea-aalysis suggess ha 5HttLPR adhe RS1800532 (rypopha hydroxylase varia) polymor-phisms are sigicaly associaed wih suicide aemps,bu o associaed wih compleed suicides (Clayde e al.2012).

the presece o he s allele o he 5HttLPR has beeassociaed wih he developme o BPD (ni e al. 2006).A rece sudy has show ha amog a broad rage o psychiaric disorders, paies wih BPD are a paricu-larly high risk or suicide compleio (Qi 2011) makigup 9–33 % o he oal umber (Pompili e al. 2005). twomea-aalyses (Samual ad Widiger 2008; Saulsma adPage 2004) have oud cosise high posiive correla-ios bewee various measures o BPD ad euroicism asdeed ad measure by he nEO PI-r (Cosa ad McCrae1995). I ac, BPD has he sroges ad mos cosisecorrelaio wih euroicism amog he persoaliy dis-orders wih BPD havig sigica correlaios wih allsix o is aces. thus, euroicism ca be see as a core

rai uderlyig BPD (Samual ad Widiger 2008; Sauls-ma ad Page 2004). neuroicism is amog he rais hacosisely have bee associaed wih suicide ideaio,aemps ad complee suicide (Brezo e al. 2006). Lesche al. (1996) oud a sigica correlaio bewee he sallele ad euroicism. this ivesigaio ispired maysubseque aemps a replicaio. the resuls have bee

icosise wih sudies supporig (Goda e al. 2009)ad o supporig (Willis-Owe e al. 2005) his d-ig. the majoriy o hese sudies were uderpowered,wih sample sizes beig small relaive o wha is eededo draw coclusios based o he small eec size haca be aribued o a sigle gee. two sudies ha wereadequaely powered (Willis-Owe e al. 2005; terracciaoe al. 2009) did o d a correlaio, however, severalmea-aalyses did (Schika e al. 2004; Se e al. 2004;Muao e al. 2005). the laer wo ivesigaios clariedha dig a correlaio was depede upo he mehodo mea-aalysis beig used. Geeic variaios oher ha

hose associaed wih 5-HttLPR have bee explored bu odae, aer a decade o eor, o ohers have bee oud ocorrelae wih euroicism, uderscorig he imporace o he lik bewee he wo (Cali 2008). Primaes who carryhe homologue o he s allele express pheoypic eaureso euroicism (e.g. icreased axiey ad reduced socialieracio; Hariri 2006).

Aoher lie o ivesigaio has looked a he possi-biliy ha he s allele is o isel correlaed wih egaiveaec bu ieracs wih adversiy, leadig o euroicismor such saes as depressio or axiey i he ace o ega-ive lie eves. these sudies were also iiially leadig

o icosise digs. A rece large-scale, highly pow-ered sudy (Middeldorp e al. 2010) ad wo mea-aalyses(Muao e al. 2009; Risch e al. 2009) cocluded ha hes allele did o moderae he ieracio bewee egaivelie eves ad euroicism. However, Uher ad McGu(2009) have show ha he mehod o assessme o evi-romeal adversiy led o hese egaive resuls. Whesel-repor measures were used, o moderaig eec wasoud, bu whe deailed ierview-based measures wereused, he s allele was ideed oud o have a moderaigeec. this moderaig eec has bee clearly demo-sraed i o-huma primaes (rhesus macaques). Iaprimaes who were deprived o adequae maeral care(i.e. peer raised) ad who carried he s allele maiesedheigheed axiey ad depressio, reduced egagemei play, greaer aggressio ad icreased alcohol cosump-io relaive o L allele carriers (Champoux e al. 2002;Meaey 2001; nelso e al. 2009). Moher rearig elimi-aed he diereces bewee he wo groups. Sudies hahave demosraed his ieracio i humas have oudha childre who carried he s allele who were exposed oemoioal ad or physical abuse showed icreased levels



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o axiey, depressio ad corisol secreio (Caspi e al.2003; Sei e al. 2008; taylor e al. 2006). Huma iaswho carry he s allele ad who experiece poor childrear-ig codiios are more likely o develop a egaive emo-ioal emperame (Auerbach e al. 2001). Idividualsdiagosed wih BPD or APD almos always suer romsevere childhood adversiy. the ieracio bewee hese

adverse experieces ad he s allele is demosraed by hedig ha he relaive risk o developig BPD or APD hasbee show o icrease by a acor o 2 or each shor allelehe idividual carries (Guderso ad Lyos-Ruh 2008).

I is impora o oe ha he impac o he s allele goesbeyod a ifuece o axiey ad depressio. I has beeassociaed wih bipolar ad uipolar aecive disorder,OCD, eaig disorders, aeio-deci/hyperaciviy dis-order, eurodegeeraive disorders ad o paricular impor-ace i relaio o he curre discussio, suicide (Murphyad Lesch 2008). the s allele has bee oud o be asso-ciaed wih geeral impulsiviy i he coex o a broad

rage o emoioally evocaive siuaios whe he idivid-ual has bee exposed o adverse eviromes i childhood.the combiaio o greaer impulsiviy ad heigheed lev-els o emoioal pai associaed wih he s allele × child-hood adversiy ieracio sreghes he lik wih suici-daliy. this combiaio is refeced i he sigica adcosise egaive correlaio oud bewee he Cosci-eiousess scale o he nEO PI-r ad BPD ad he srogposiive correlaios bewee euroicism ad BPD (Sam-ual ad Widiger 2008; Saulsma ad Page 2004). negaivescores o he Coscieious scale refec diculies wihresrai ad impulse corol.

the vas majoriy o his research has bee coducedwihi he diahesis-sress ramework ad, as a resul, haso examied hese ieracios rom he vaage poi o wha is called he diereial suscepibiliy or “plasiciyhypohesis” (Belsky ad Pluess 2009). the diahesis-sressmodel ocuses solely o he egaive impac sress ca havewhe impigig o a area o vulerabiliy. the plasiciyhypohesis suggess ha some idividual diereces calead o bad oucomes i he ace o adversiy or very goodoucomes i he coex o eriched eviromes. Mea-phorically wha was viewed as a source o ragiliy adas operaig like glass i he ace o a soe is ow seeas somehig more like clay ha ca orm a deep impres-sio or he beer or worse. Lookig a he impac o bohposiive ad egaive lie eves o he lik bewee he sallele ad euroicism would allow or a examiaio o he ull scope o is poeially moderaig eec. O heposiive side, carriers o wo shor alleles have bee oudo have more pulviar euros (Youg e al. 2007). Pulvi-ar euros are ivolved i he processig o visual sigalsse o he limbic sysem via a subcorical roue. More eu-ros mea a sroger coecio ad may be associaed

wih a greaer capaciy o deec he emoioal coex o a evirome. Shor allele carriers express greaer sym-paheic reaciviy whe observig aoher perso receiv-ig a shock (Crisa e al. 2009), suggesig a possible liko a greaer capaciy or empahy. I aoher sudy, i wasoud ha seeig a avourie perso led o sigicalyhigher amygdala aciviy i shor allele carriers suggesig

a higher reward value o posiive ierpersoal experiece(Masuagaa e al. 2010). Homberg ad Lesch (2011) havereviewed he may cogiive ad emoioal advaages hacorrespod o he greaer sesiiviy ad emoioal respo-siveess ha has bee correlaed wih he s allele. theyhypohesize ha hese advaages may couerbalaceor compleely ose he disadvaages ad may also be acoribuor o some o he icosise digs reerred oabove.

Workig rom he same premise, Pluess e al. (2010)sudied he ieracio bewee egaive ad posiive lieeves i relaio o euroicism i idividuals homozy-

gous or s alleles ad L alleles. Cosise wih he plas-iciy hypohesis, hey oud ha hose wih s alleles whoexperieced more egaive lie eves had higher eu-roicism scores ad hose experiecig more posiive lieeves had lower euroicism scores. those wih L alleleshad cosise scores o euroicism regardless o he um-ber o posiive or egaive lie eves. thus, euroicismmay be a more sable rai or hose wih he L allele adless so or hose wih a s allele. I also may be ha hosewih s alleles are more likely o be egaively impaced by aoxic childhood, develop maladapive schemas ad exhibia behavioural ad aecioal paer ha will be associ-

aed wih higher euroicism scores. As oed above, wekow ha s allele carriers are more likely o develop BPDwhe exposed o oxic eviromes. this greaer degreeo resposiveess o he evirome is refeced i hedig ha huma ad primae s allele carriers have beeoud o be more resposive a res i may corical sies(Cali 2008).

Aoher sudy supporig he plasiciy hypohesiswas coduced by Aypa ad va der Does (2010). theyasked 250 uiversiy sudes abou experieces o emo-ioal abuse i childhood. Emoioal abuse is a requelyrepored occurrece amog paies suerig rom BPD.Cogiive reaciviy o sad mood was assessed usig heLeide Idex o Depressio Sesiiviy Scale. this meas-ures habiual egaive cogiive paers ad yields scoresha remai high eve whe sympoms are low ad husoverlaps sigicaly wih he oio o a early mala-dapive schema described i he las secio o his review(4. Bridging neurobiological models with clinical psycho-

therapy). the resuls cormed he plasiciy hypohesis.Shor allele carriers whose scores were very low o a meas-ure o childhood emoioal abuse had exremely low scores



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o he measure o cogiive vulerabiliy o depressioad exremely high scores whe hey repored high scoreso measures o abuse. Log allele carriers had moderaescores o maer wha level o abuse hey repored. Puaoher way, he shor allele carriers were able o bee armore rom a good childhood ha he log allele carriers.I is impora o oe ha while hese rece digs are

iriguig, replicaio wih a well-powered sudy is eededo corm or reue hese observaios. I is esimaed ha asample size over 1,000 will be eeded o have 80 % powera a sigicace level o p = 0.50 (Muao e al. 2009).

O a eural level, a mea-aalysis oud a cosisecorrelaio bewee he s allele ad greaer amygdala reac-iviy o may orms o egaive simuli relaive o euralcues. this icluded aces expressig ear ad ager, adegaive scees ad words (Cali ad Lesch 2007; Hariri2006). the sregh o his correlaio was abou six imesgreaer ha ha oud o sel-repor measures. thus, iappears ha whe variables closer o he geeic level

(edopheoypes) are sudied, he liks are sroger hahose oud o he pheoypic level (e.g. hose assessedby he nEO PR-r). Huma s allele carriers have also beeoud o have icreased aerior cigulae aciviy, espe-cially i respose o social hrea (Jah e al. 2010; Wayad taylor 2010). this reaciviy was associaed wihgrealy icreased corisol secreio.

the L allele ad he associaed ecie serooergicucioig may lead o greaer sel-reliace wih moreaecive regulaio occurrig wihi oe’s ow syapses.the s-allele, associaed wih less ecie serooergicucioig, may lead o a adapive sraegy ha draws

more o deep ad eriched ogoig aachmes o regulaeaec. We could view his as emphasizig regulaio acrossa “social syapse”. this is a geeic variaio ha goesdeep io our pas as a species ad, ieresigly, humasad rhesus macaques are he oly wo species which havei. Humas ad rhesus macaques are kow as he “weed”species sice boh prolierae wherever hey are placed ihe world. I seems ha boh adapive sraegies (sel-reli-ace ad srog aachmes) are impora o he collecivewhole i boh o hese species ad ha he laer fourishesi supporive ad ururig ierpersoal eviromes adleads o cosiderable emoioal suerig icludig despairad suicidal behaviour i oxic ierpersoal coexs.

Animal models of suicide

Aimal models are ormidable ools o ivesigae heaeiology o a illess, is course, poeial reame(Collado ad Serrao 2010; Lazas e al. 2010) ad he eu-robiology o associaed behaviour (McKiey 2001). nocovicig aimal models o suicide have bee developed

o dae, alhough may researchers have ried o ideiysuicide i o-huma species i he aural seig (Prei2007). A rage o suicidal behaviour i aimals has beeclaimed. For example, aimals i capiviy or separaedrom heir maser have bee repored o sarve o deahvoluarily (Prei ad Mioo 2005; Ramsde ad Wilso2010) or exhibi sel-desrucive behaviours (Crawley e al.

1985); ucorolled axiey provokig siuaios icludigisolaio, separaio ad coeme have bee repored oresul i sel-edagerig behaviours i primaes (Kraemerad Clarke 1990; tieebacher e al. 2005); mokeys ireared isolaio showed higher risk o sel-edageredbehaviour i adulhood (Crawley e al. 1985). this laerdig parallels he impac o childhood abuse or egleco he risk o suicide i humas (Evas e al. 2005; Brodskyad Saley 2008). However, he degree o which such sel-edagerig behaviours i aimals resemble sel-harmigbehaviour i humas is debaable.

While modellig suicidal behaviour i aimals ails o

reproduce he role o will ad ieio i suicide mecha-ics, curre aimal models are makig a eor o orge aigher lik by sudyig each sep alog he chai o behav-iours leadig o suicide i humas (or review o aimalmodels o suicide, see Prei 2011). Amog he several dis-ic aimal models o suicide, leared hopelessess admaeral deprivaio seem o be paricularly promisig.

As discussed earlier, hopelessess ad pessimism aremajor cogiive acors or suicide, ad hopelessess perse has emerged as a predicor o suicide aemp ad com-pleio i cliical samples (Beck e al. 1985). the learedhelplessess paradigm (Seligma 1972) is cosidered as

a aalog o huma hopelessess (Krisha ad nesler.2008). these sudies have ivolved series o iescapableelecried oo shocks as aversive simuli, aer which asubgroup o aimals sops ay aemp o escape. Follow-ig reesig aer some delay, some aimals ry o escapeagai, while ohers ideiely exhibi despairlike behav-iour, ailig o escape. Alhough his model oers goodace validiy, as may sympoms i humas (weigh loss,sleep disurbaces, disored percepio o pleasure, ec.)ca be modelled i aimals oce leared helplessess hasesablished, is ecological validiy (i.e. correspodece wiha real siuaio i humas) is poor as he model uilizespaiul simuli o produce helplessess. Ieresigly, allaidepressas are eecive i reversig he helplessesswihi 3–5 days o admiisraio, compared o a 2–3 weekdelay i humas.

turig o he maeral deprivaio model, i has beeoud ha early adverse lie eves (i.e. childhood abuseor eglec) ad disruped pareig are associaed wih aicreased risk or psychopahology ad suicidal behaviouri adolescece ad adulhood (Agerbo e al. 2002; Lu e al.2008; A e al. 2009). Maeral deprivaio (Lovic e al.



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2001; Gozalez e al. 2001) i rodes has bee used as amodel o huma disruped pareig. Sudies have showha maeral separaio leads o a icrease i he ypicalmarkers o sress (Walker e al. 1991) ad o reduced aciv-iy o he mai ihibiory eurorasmiers i he brai(newpor e al. 2002). Moreover, emale osprig separaedrom heir mohers showed aberra maeral care i adul-

hood (Lovic e al. 2001; Gozalez e al. 2001). Maerallydeprived mokeys exhibied depressive-like sympoms dur-ig developme, icludig low CSF oradrealie coce-raios (Kraemer e al. 1991), icreased sel-admiisraioo alcohol (Fahlke e al. 2002) ad sel-edagerig behav-iour (Kraemer ad Clarke 1990; tieebacher e al. 2005).All o hese digs led suppor o he ace ad predicivevalidiy o his model regardig he mai correlaes o majordepressio [i.e. comorbidiy wih alcohol abuse (Gra adHarord 1995) ad icreased risk o sel-harmig behaviour(Ags e al. 2005; todo e al. 2008)].

Give he diculies i aimal modellig, a iermedi-

ae pheoype i he aimal mus be specically esed orvalidiy ad reliabiliy (Geyer ad Markou 1995; Boulou-gouris e al. 2009). Isolaig ad sudyig releva edo-pheoypes will also be impora. this will ivolve a ocuso iermediae ad behavioural markers proximal o gees(Goesma ad Gould 2003). A umber o ivesigaorshave begu his process ocusig o rhesus macaques. thispopulaio is o paricular imporace i aimal modelligsice hey share over 98 % o heir geeic maerial wihhumas, ad as meioed above, rhesus macaques areliked wih humas i erms o a umber o key geeicpolymorphisms. Sice rhesus macaques’ early develop-

me ivolves a srog, exclusive, uique ad edurigbod bewee moher ad ia ha has a high degree o overlap wih Bowlby’s (1969) characerizaio o humamoher–ia aachme, his work has direc relevace ohe maeral deprivaio model.

Peer-oly (PO) rearig (maerally deprived) has beeoud o lead o mokeys ha, a a pheoypic level, arehighly axious, aggressive ad impulsive ad o a eu-roedocrie (HPA) level exhibi more exreme resposeso social separaio (Suomi 1997; Demer e al. 2012).they have lower levels o CSF 5-HIAA coceraiosha moher-reared mokeys rom early iacy o laeradulhood (Shao e al. 2005; Higley ad Suomi 2011)ad have sigicaly diere peripheral measures o eurorophic acors nGF ad BDnF (Cirulli e al. 2009)ad as adolesces ad youg aduls cosume sigicalymore alcohol ha heir moher-reared couerpars duriga “happy hour” siuaio (Higley e al. 1991; Fahlke e al.2002). neuroimagig sudies have also show he PO-reared mokeys o dier sigicaly i brai ucio adsrucure (Doude e al. 1995; Ichise e al. 2006; Spiellie al. 2009). Fially, major diereces have bee oud i

geome-wide expressio i leucocyes bewee PO-rearedad moher-reared mokeys (Cole e al. 2012). Depriva-io o adequae maeral care clearly has prooud ega-ive cosequeces or rhesus mokeys a pheoypic levelsas well as euroedocrie oupu, eurorasmier meab-olism, brai srucure ad ucio ad eve geome-wideexpressio. these cosequeces are liked o risk acors

associaed wih suicide (e.g. high emoioal reaciviy,aggressio, impulsiviy ad icreased alcohol cosumpio).

Sudies o his populaio examiig he ieraciobewee maeral deprivaio ad geeic polymorphismshave led o several dramaic discoveries ha coribue oaimal models o suicidal behaviour ad have a bearig opreveio ad reame. these discoveries, i lie wihhe plasiciy hypohesis described above, have demo-sraed ha whe mokeys bor wih so-called risk alleles[such as he shor allele o he 5-Htt or he less ucio-ally ecie MAOA allele, i addiio o polymorphismsi he coricorophi releasig acor (CRH) 2A gee,

he europepide Y (nPY) gee ad he mu opioid recep-or gee] are deprived o adequae maeral care, heydevelop he rage o egaive cosequeces oulied abovebu whe mokeys wih hese less ecie varias haveormal moherig o oly do hey develop ormally bui some ways (e.g. cosumig less alcohol durig happyhours) ucio beer ha heir L allele couerpars.thus, hese alleles seem o be a risk acor i deprivigor harsh eviromes ad a proecive acor i beevo-le eviromes (Suomi 2011). the poeial bees o hese less ecie varias are mos likely uderappreci-aed a prese due o he ac ha hese sudies, excep or

oe ha will be discussed laer, have o bee assessig heimpac excepioally good moherig over ad above or-mal moherig has o hese polymorphisms. the plasiciyhypohesis would predic ha hese alleles have evolved ia way ha capializes o his dierece.

While edopheoypes, such as hose discussed above,have bee proposed as physiological ad behaviouralmarkers ad impora gee × evirome ieraciosideied ha relae o suscepibiliy o a psychiaric dis-order (Hizema 2000; nesler ad Hyma 2010), edo-pheoypes or each lik i he suicidal behaviour chaihave ye o be ideied. Claricaio o cliical ad psy-choherapeuic models o suicidal behaviour is a prereq-uisie or he implemeaio o valid ad reliable aimalmodels.

Bridging neurobiological models with clinical

psychotherapy

Diere aspecs o suicidaliy ha have bee associaedwih serooergic modulaio have bee he arge o several



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psychoherapeuic approaches. Hopelessess ca be co-cepualized as a relaively sable schema icorporaig eg-aive expecaios cocerig he uure. Several echiqueshave bee developed as a par o cogiive behaviouralherapy (CBt) i order o challege ad modiy egaivecore belies. Problem-solvig echiques cosiue paro CBt as well. Boh cogiive herapy (Rush e al. 1982)ad problem-solvig raiig (Salkovskis e al. 1990) havebee oud o reduce hopelessess. Dialecical behavioural

herapy (DBt) is a orm o CBt developed by Lieha orhe reame o paies wih BPD ad suicidal behaviour.Accordig o Lieha e al. (1993), BPD is primarily a dys-ucio o he emoio regulaio sysem which resulsrom biological irregulariies combied wih cerai dys-ucioal eviromes, as well as rom heir ieracioad rasacio over ime. Paies wih BPD experieceedurig aversive saes wih impulsive, suicidal behavioursappearig o be behavioural soluios o iolerably paiulemoios (Lieha e al. 1993). the eeciveess o DBt ireducig suicidal behaviour has bee demosraed by Lie-ha e al. (1991) who oud ha a group o BPD paies

who received DBt (1) had ewer icideces o parasuicidead less medically severe parasuicides, (2) were more likelyo say i idividual herapy ad (3) had ewer ipaiepsychiaric days, i compariso wih a reame as usualgroup. A he iiial 6-moh ollow-up, DBt subjecs hadsigicaly less parasuicidal behaviour, less ager adbeer sel-repored social adjusme. A he al 6-mohollow-up, DBt subjecs were oud o have sigicalyewer psychiaric ipaie days ad beer ierviewer-raedsocial adjusme (Lieha e al. 1993).

Schema therapy (St) is a iegraive psychoherapyha combies elemes o cogiive-behavioural, aach-me, objec relaios, psychodyamic ad emoio-ocused models. St was developed by Jerey Youg orhe reame o people wih chroic characerologicalproblems ad has bee oud o be a eecive reameor paies wih BPD (Farrell e al. 2009; Giese-Blooe al. 2006; nador e al. 2009).

the cosruc o a early maladapive schema (EMS)

is ceral o St. A EMS is deed as a broad, pervasivelie heme or paer comprised o memories, emoios adcogiios regardig oesel ad oe’s relaioship wihohers developed durig childhood or adolescece adelaboraed hroughou oe’s lieime ad dysucioal oa sigica degree. Suicidal risk ad behaviour could becocepualized aroud he EMS ad schema modes. O heull rage o 18 EMS which have bee deed (table 1),he oes (based o cliical observaios) ha are cosis-ely associaed wih he mos iese paiul aec adgreaes risk o suicidal behaviour are hose ivolvig dis-coecio ad rejecio (e.g. he emoioal deprivaio,social exclusio, misrus/abuse, ad abadome sche-mas), especially whe hey have bee developed early ichildhood. this is clearly liked o he maeral deprivaioaimal model o suicide described i he previous secio.

Suicidal behaviour, as disic rom risk, could cocep-ualize i erms o schema modes. there are our disicypes: child modes, maladapive copig modes, maladap-ive pare modes ad a healhy adul mode (table 2). thechild modes (Vulerable, Agry, Impulsive/Udisciplied,Coeed) are oes ha humas come io he world

Table 1 Domais ad earlymaladapive schemas (EMS)o schema herapy [ake adadaped rom Lockwood adPerris (2012)]

Disconnection and rejection

typically arises rom pareig ha is deached, cold,rejecig, wihholdig, explosive, upredicable or abusive

Misrus/abuseDeeciveess/shameEmoioal deprivaioSocial isolaio/alieaioEmoioal ihibiioAbadome/isabiliy; primary

Impaired autonomy and performance

typically arises rom pareig ha is uderor overproecive, emeshed ad does o helpo build compee ucioig ouside o he amily

Vulerabiliy o harm ad illessDepedece/icompeeceEmeshme/udeveloped sel Abadome/isabiliy; secodarySubjugaioFailure

Extreme conscientiousness

typically arises rom pareig ha is based o codiioalapproval, is corollig, emphasizes saus ad appearace,or emphasizes rigid rules ad expecaios abouperormace ad/or ehical behaviour

Sel-sacriceUreleig sadards

Impaired limits

typically arises rom pareig ha is permissive,overidulge, ails o provide srucure ad direcio

ad/or impars a sese o superioriy

EilemeIsucie sel-corol



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wih ad have close parallels o he child emoioal sys-ems ha have bee ideied i mammalia brais (ear,paic, rage, seekig ad play; Paskeep 1998). the Vuler-able Child mode, i he case o idividuals who have su-ered pareal eglec ad/or abuse, is characerized by aogoig sese o deprivaio ad/or abuse ad is labelledhe Deprived/Abadoed or Abused Child mode. theDeprived/Abadoed/Abused Child mode is he oe moscommoly drivig suicidal behaviour. Each mode is see ashavig characerisic sigs ad sympoms, is ow ucioad as requirig is ow sraegies o be eecively reaed.the Deprived/Abadoed/Abused Child mode is charac-erized by eediess, raic eors o avoid abadome,cligig, a idealized view o ururers ad eeligs o

depressio, loeliess, hopelessess, despair, ear, paic,worhlessess ad vicimizaio. the idividual eels help-less o ge heir eeds me or d proecio. Oe o hemai sraegies whe his mode is acivaed ad suicidalrisk is high is o coec o, sooh, reassure ad proec he“Vulerable Child” par o he paie ad provide eoughogoig coac (wih he herapis or sigica ohers)or he crisis o be weahered ad core eeds or coec-io o be me. this mode ad hese sraegies have closeparallels o he aoremeioed aimal models ivolvighe ceral role o maeral deprivaio i suicidal risk.two oher modes, he Deached Proecor (oe o he mala-dapive copig modes) ad he Puiive Pare (oe o hemaladapive pare modes) are also ivolved wih suicidal

Table 2 Descripio o he schema modes o schema herapy [ake ad adaped rom Youg e al. (2003)]

Child modes

Ivolve eelig, hikig ad acig i a “childlike” maer

Vulnerable child (icludig abadoed, abused, humiliaed, or loely ypes) Feels overwhelmed by paiul eeligs, e.g. axiey, depressio,grie, shame/humiliaio, or loeliess

Angry child Feels ad expresses ucorolled ager or rage i respose o perceived or real misreame, abadome, humiliaio, or rusra-io; oe eels reaed ujusly. Acs like a child hrowig a emper arum

Impulsive, undisciplined child “Was wha he was whe he was i”. Cao olerae he rusraio o limis

Maladaptive parent modes

Ivolve ieralized dysucioal pare “voices”

Punitive/critical parent Ieralized, criical or puishig pare voice; harsh criicism direced owards he sel; eeligs such as shame, guil orsel-loahig

Demanding parent Urealisically high expecaios; Pushy, corollig, demadig

Maladaptive coping modes

Ivolve maladapive aemps o proec sel rom pai

Avoidance modes

Detached protector Emoioal deachme used as proecio rom paiul eeligs; uaware o eeligs; eels “ohig”; appears emoioally

disa, fa, or roboic; avoids geig close o oher peopleDetached self-soother/self-stimulator Uses repeiive, “addicive”, compulsive or sel-simulaig behaviours o calm ad soohe himsel; uses

pleasurable or exciig sesaios o disace himsel rom paiul eeligs

Angry protector A “wall o ager” used o keep ohers a a sae disace; ager is more corolled ha i Agry Child mode

Surrender mode

Compliant surrenderer Gives io real or perceived demads/expecaios o ohers see as more powerul i a axious aemp o avoid pai/ ge eeds me

Over-compensator modes

Self-aggrandizer Feels superior, special or powerul; looks dow o ohers; sees he world i erms o “op dog” ad “boom dog”; shows o or acs i a sel-impora, sel-aggradizig maer; cocered abou appearaces raher ha eeligs or real coac wih ohers

Bully/attacker Uses hreas, iimidaio, aggressio, coercio, realiaio o ge wha he was; assers his domia posiio; eels sadisicpleasure i aackig ohers

Con man/manipulator Cos, lies or maipulaes o achieve goals; vicimizes ohers; seeks o escape puishme

Predator Focuses o elimiaig hreas, rivals, obsacles or eemies i a cold, ruhless ad calculaig maerOver-controller (Paraoid ad obsessive–compulsive) Focuses aeio, rumiaes ad exercises exreme corol i aemp o proec sel

rom perceived or real hreas paraoid ypes ry o locae/ucover hidde hreas; obsessive ypes use order, repeiio, or riual

Healthy adult mode

Serves as a “execuive ucio” i which he healhy adul par urures ad proecs he vulerable loely child, ses limis or he agry childad bales or moderaes he maladapive copig modes so helpig o mee he child’s emoioal eeds



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risk bu ivolve a sese o sel ha oher aimals ad eveprimaes do o have. While hese may be uique o Homosapies, he mos impora ad ceral acor i he devel-opme ad resoluio o suicidal risk ivolves he Vuler-able Child mode; oe we share wih all oher mammals.

All o he EMS (excep or Eileme/Gradiosiy adSel-Sacrice) have show sigica correlaios wih he

emperame dimesio “egaive aeciviy” ad he rai“euroicism” i child, adolesce ad adul samples (Muris2006; thimm 2010; Rijkeboer ad de Boo 2010). As me-ioed above, cosise ad srog correlaios have beeoud bewee various measures o BPD ad euroicism.Cosise wih his dig, i is observed cliically hawhe BPD paies ll ou he Youg Schema Quesio-aire (Youg 2005), a sel-repor iveory use o assessEMS, hey almos always score highly o almos all 18 o he schemas makig up he iveory.

negaive aeciviy ad axiey proeess (precursorso euroicism i adulhood) are associaed wih greaer

pareal eeds o he child (Va de Boom ad Hocksma1994). A prospecive sudy ha ocused o he issue o how o bes pare a eedy child ad ha leds suppor ohe plasiciy hypohesis i relaio o euroicism ad hes allele was coduced by Suomi (1997). the sudy ives-igaed he developmeal oucome o isucie, ormalad excepioally good pareig o ia rhesus macaquemokeys wih boh ormal ad “euroic” emperames.Oe o he digs was ha ia mokeys wih or-mal emperame raised by iadequae pares (i.e. peers)developed behavioural ad physiological characerisics o euroic ias raised by ormal pares. Ia mokeys

wih a euroic emperame raised by ormal mohersdeveloped decis i early exploraio, exaggeraed sar-le resposes o mior sressors ad a less secure aach-me ad were more likely o remai a he boom o hedomiace hierarchy. Ieresigly, ia mokeys wiha euroic emperame raised by pares wih excepio-ally good pareig skills (i.e. beig oably lovig, urur-ig ad paie; qualiies ha are kow o be esseial oreecive St) expressed a eve beer developmeal rajecory ha ias wih a ormal emperame raised byormal pares. For example, hey explored heir eviro-me more, displayed less behavioural disurbace durigweaig, had a uusually secure aachme, rose o admaiaied op posiios i he domiace hierarchy adbecame highly ururig pares hemselves. the develop-meal rajecory o ormal ias raised by excepioallygood pares was he same as ha whe raised by ormalpares so he exra ururace seemed o make o dier-ece. Beig a prospecive sudy wih primaes, i allowedor corol o all releva variables hroughou he periodo ivesigaio, makig coclusios abou causaliy morereliable ha eve he mos ighly corolled prospecive

sudies possible wih humas. We hereore view hissudy as a srikig example o he poeial advaages o a resposive ad armaive sace owards he eeds o paies wih a emperame characerized by euroicism,egaive aeciviy ad icreased risk o suicidal behavioursuch as hose diagosed wih BPD.

A oucome sudy i which St was compared o ras-

erece ocused herapy (tFP) i he reame o BPDproduced digs cosise wih hose discussed above(Giese-Bloo e al. 2006). St was oud o be wice aseecive as tFP ad led o a sigica reducio i allBPD maiesaios ad relaed psychopahology iclud-ig suicidal risk ad behaviour. St also had a sigicalylower dropou rae. I is worh oig ha St was silloud o be wice as eecive eve whe corollig orhe lower dropou rae. this sreghes he greaer impaco St o suicidal behaviour ad risk sice i reaiedmore paies who would oherwise be le a higher riskad more quickly ad eecively reduced suicidal behav-

iour ad oher BPD sympomaology i he paies haremaied i he sudy. the Schema therapiss i he sudywere seleced ad raied wih a ocus o beig warm adhighly ururig i respose o he BPD paie’s ieseaec ad eeds or soohig. this ivolved he herapissmakig direc coac wih he paie’s Vulerable Childmode ad providig emoioal urimes such as sooh-ig, reassurace, validaio, udersadig ad praise,alog wih empahic limis whe eeded. the experi-eces are see as beig ieralized ad hereby buildighe healhy adul par o he paie. tFP herapiss, o heoher had, ocused o he adul par o heir paies, help-

ig hem gai a beer isigh io he aure o heir eedsad eeligs ad hrough his, lear how o beer oleraepaiul aec ad sel-sooh. A key dierece beweehese wo approaches, ad bewee St ad almos all oherherapies icludig DBt, is capured i his disiciobewee he ieralizaio o “oher-soohig” ad rai-ig i “sel-soohig”. the ormer ivolves he assumpioha he abiliy o sel-sooh will grow spoaeously ou o graiyig depedecy eeds. the laer ivolves a belie ha direcly graiyig paies’ logigs o be soohedad urured will do he opposie—impede ad udermiehe developme o he capaciy o sel-sooh. noably, heururig mokey pares were operaig o he basis o ieralizaio o oher-soohig. We do o ecessarilysee his as a dierece bewee good ad bad. For childrewih less sesiive emperames, here appears o be liledierece bewee ormal ad excepioally lovig par-eig ad may youg childre ad paies wih eiheremperame ca be raied o sel-sooh. Moreover, a largeperceage o he paies reaed wih tFP derived sigi-ca bee. We believe, however, ha providig raiigi sel-soohig i respose o hese early core emoioal



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eeds could aciliae he developme o compulsive sel-reliace ad risks promoig deachme rom sel ad oh-ers as a meas o copig wih iese aec. this ca resuli idividuals wih more sesiive aures (e.g. s allelecarries) o havig ull access o he urimes ha allowhem o fourish. St seems o be especially eecive i isabiliy o capialize o he plasiciy associaed wih he s

allele ad more sesiive emperames, icludig paieswih BPD, ad i so doig, o more eecively reduce orelimiae suicidal risk ad behaviour.

the imporace o “oher-soohig” i relaio o BPDis see i he hird sigica correlaio (i he egaivedirecio) bewee his diagosis ad he Agreeableessscale o he nEO PI-r (Samual ad Widiger 2008; Sauls-ma ad Page 2004). this refecs he grea diculy o hose diagosed wih BPD o rus ad ge alog wih oh-ers. the laer, i combiaio wih he iese emoioalsuerig BPD paies edure, leaves hem cu o rom hesoohig ad resposiveess hey eed, hus allig back o

compulsive sel-reliace. the paies i he Giese-Blooe al. (2006) sudy aribued a large par o St eecive-ess o he exe he herapis acively reached ou o orma coecio wih, ad be resposive ad soohig o, heirvulerable or “child side”. this was also believed o be amajor acor i he lower dropou rae.

the nEO PI-r neuroicism, Coscieiousess adAgreeableess scales were all oud o correlae wih BPD.the combiaio o correlaios o hese hree dimesiosis uique o BPD. the sregh o he correlaio wih eu-roicism is also ceral. While, or example, APD also cor-relaes sigicaly i a egaive direcio wih Agreeable-

ess ad Coscieiousess, i correlaes egaively raherha posiively wih euroicism. the correlaios oudwih BPD overlap well wih he mode model ha orms aceral ramework or he St approach o his disorder. Stviews BPD as made up o our disic modes: he Vuler-able Child, Agry/Impulsive Child, Deached Proecor adPuiive Pare modes. the Vulerable Child mode is asso-ciaed wih reacios such as ear, axiey, sadess, loe-liess ad hopelessess ad hus has a clear lik o eu-roicism. the Agry/Impulsive Child mode correspodswih low Coscieiousess sice he laer is associaedwih diculies wih resrai ad impulse corol. theDeached Proecor mode is characerized by diculyrusig ohers ad a edecy owards ierpersoal vigi-lace ad keepig a emoioal disace orm oesel adohers. this paer is cosise wih wha is deed aslow Agreeableess. the Puiive Pare mode (a criical/ puiive aspec o he sel) geeraes eeligs such as lowsel-eseem, sel-loahig, shame ad guil ad is clearlyliked o euroicism wih a ocus o he ieral aciv-iy hrough which hese eeligs are geeraed. this over-lap leds suppor o he mode model as a comprehesive

ramework wih which o orgaize he key dimesios o aBPD paie’s ucioig ad o is emphasis o he Vul-erable Child mode as he core o he reame process.I addiio o he “oher-soohig” aspec o St (a key ele-me o a process called “limied repareig”), he modemodel was see by he paies i he sudy as beig oe o he mos helpul eaures o he reame.

the resuls o his sudy were replicaed by nador e al.(2009) i a secod large-scale rial o St i he reameo BPD esig o see i St could be successully imple-meed i regular reame seigs. A radomized corolrial o Group St i compariso wih reame as usual ihe reame o BPD oud Group St o be sigicalymore eecive ad o have a sigicaly lower dropourae (Farrell e al. 2009). the resuls o hese sudies wereas srog as or sroger ha he Giese-Bloo e al. (2006)sudy suggesig ha St shows cosiderable promise asa approach o decrease he risk ad icidece o suicidalbehaviour.

Ledig suppor o he hypohesized lik bewee rhesusmacaques, humas ad euroicism discussed above ador he previous discussio o aimal models o suicide isha ac ha aimals, ad especially primaes such as rhe-sus macaques, exhibi idividual diereces i behaviourha mirror mos o he major emperame dimesios ichildhood ad Big Five persoaliy rais i aduls (Wei-sei e al. 2008). Oly eorul corol (Coscieious-ess) is o widely evide i oher species, alhough i cabe observed i chimpazees.

Conclusions

I has bee argued ha, rom a eurobiological perspecive,suicidal behaviour is relaed o ucioal abormaliiesi specic brai regios ha have bee associaed wih aperso’s experiece o he coiuiy o sel, goal seig,decisio makig ad emoio regulaio. Biological suicideresearch has largely ocused o low serooi urover. Icurre eurobiologically iormed models, geeic predis-posiio ad adverse childhood experieces (i.e. biologicalad psychosocial acors) are hough o ierac durig hedevelopmeal years, eveually resulig i he maiesa-io o eurobiological ad cliical acors associaed wihsuicidal behaviour. Cliically, hese characerisics appearo be relaed o rais such as impulsiviy ad aggressio,hopelessess ad impaired problem-solvig capaciies.

Emergig sudies o he aure o he geeic poly-morphisms ha uderlie hese abormaliies sugges haa paradigmaic shi is uoldig ha sheds a ew adbrigher ligh o wha has bee viewed sricly i erms o he eurobiology o vulerabiliy. I appears ha may o hose who have less ecie serooergic sysems suer



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he mos ad who are a he greaes risk o suicide suergrealy i oxic ad deprivig eviromes ad bee hemos rom highly ururig eviromes. these idividu-als may i ac have a especially srog capaciy or deepad meaigul relaioships, ad St seems o be espe-cially well suied o capializig o hese sreghs, allow-ig hese idividuals o move beyod copig ad reduced

suicidal risk o livig rich ad deeply coeced lives.the developmes i he eld o eurosciece are ow

leadig o a deeper ad more precise udersadig o howad why approaches such as St are especially eecive ihe reame o suicidal risk. the coiuig iegraio o psychoherapeuic models wih eurobiological cocepshas he poeial o help build o hese early successes ado lead o he developme o beer herapies or suicidalidividuals. I is coceivable ha i he uure, euroimag-ig sudies will help o ideiy which reames are eec-ive i icreasig resiliece o sressul experieces aeroe or several suicide aemps. neurobiological perspec-

ives o udersadig are o coradicio o paie-ori-eed models o suicide.

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