ORIGINAL RESEARCH ARTICLE

Moleculr Psychitry (1999) 4, 163 172 1999 Stockton Press All rights reserved 1359 4184/99 $12.00 ORIGINAL RESEARCH ARTICLE Environment nd vulnerbility to mjor psychitric illness: cse control study of erly prentl loss in mjor depression, bipolr disorder nd schizophreni O Agid 1,2, B Shpir 2,3, J Zislin 3, M Ritsner 4, B Hnin 5, H Murd 6, T Troudrt 5, M Bloch 1, U Heresco-Levy 2,3 nd B Lerer 1,2 1 Biologicl Psychitry Lbortory, Dept of Psychitry, Hdssh Hebrew University Medicl Center; 2 Dept of Psychitry, Hebrew University Hdssh Medicl School; 3 Herzog Hospitl; 4 Tlbieh Hospitl; 5 Eitnim Kfr Shul Mentl Helth Center; 6 Dept of Sttistics, Hebrew University, Jeruslem, Isrel The current focus on identifying genes which predispose to psychitric illness shrpens the need to identify environmentl fctors which interct with genetic predisposition nd thus contribute to the multifctoril custion of these disorders. One such fctor my be erly prentl loss (EPL). The puttive reltionship between erly environmentl stressors such s prentl loss nd psychopthology in dult life hs intrigued psychitrists for most of this century. We report cse control study in which rtes of EPL, due to prentl deth or permnent seprtion before the ge of 17 yers were evluted in ptients with mjor depression (MD), bipolr disorder (BPD) nd schizophreni (SCZ), compred to individully mtched, helthy control subjects (MD-Control, 79 pirs; BPD-Control, 79 pirs; SCZ-Control, 76 pirs). Loss of prent during childhood significntly incresed the likelihood of developing MD during dult life (OR = 3.8, P = 0.001). The effect of loss due to permnent seprtion (P = 0.008) ws more striking thn loss due to deth, s ws loss before the ge of 9 yers (OR = 11.0, P = 0.003) compred to lter childhood nd dolescence. The overll rte of EPL ws lso incresed in BPD (OR = 2.6, P = 0.048) but there were no significnt findings in ny of the subctegories of loss. A significntly incresed rte of EPL ws observed in schizophreni ptients (OR = 3.8, P = 0.01), prticulrly before the ge of 9 yers (OR = 4.3, P = 0.01). Comprison of psychosocil, medicl nd clinicl chrcteristics of subjects with nd without history of EPL, within the lrger ptient groups from which the mtched smples were drwn (MD, n = 136; BPD, n = 107; SCZ, n = 160), yielded few significnt findings. Among the controls (n = 170), however, subjects who hd experienced EPL, reported lower incomes, hd been divorced more frequently, were more likely to be living lone, were more likely to smoke or hve smoked cigrettes nd reported more physicl illness (P = 0.03 0.001). Long term neurobiologicl consequences of erly environmentl stressors such s mternl deprivtion hve been extensively studied in mny niml species. Recently, enduring chnges in hypothlmic-pituitry-drenl xis function, including corticotrophin relesing fctor gene expression, hve received prticulr ttention. Anlogous processes my be implicted in the effect of EPL on humn vulnerbility to psychopthology, vi ltertions in responsiveness to stress. Genetic predisposition my influence the degree of susceptibility of the individul to the effects of erly environmentl stress nd my lso determine the psychopthologicl entity to which the individul is rendered vulnerble s consequence of the stress. Keywords: bipolr disorder; environment; genes; mjor depression; prentl deth; prentl loss; prentl seprtion; schizophreni; stress Introduction Although dvnces in moleculr technology hve stimulted vigorous serch for genes which predispose to mjor psychitric disorders, it is widely ccepted tht these disorders re multifctoril nd tht environmentl fctors ply pivotl role. The nt- Correspondence: Professor B Lerer, Dept of Psychitry, Hdssh Hebrew University Medicl Center, PO Box 12000, Jeruslem 91120, Isrel. E-mil: lerer cc.huji.c.il Received 8 June 1998; revised nd ccepted 12 August 1998 ure of this role is not well understood nd specific fctors hve yet to be definitively identified. In considering environmentl fctors which ply role in the pthogenesis of disorder, it is importnt to differentite between those which render the individul vulnerble to the disorder nd those which precipitte its onset. Events or experiences which ct s vulnerbility or risk fctors my be temporlly distnt from the ppernce of clinicl symptomtology. Assocition of fctor with vulnerbility to n illness is not necessrily direct nd the reltionship my be medited by intervening fctors. Erly prentl loss (EPL) is n

164 intriguing exmple of puttive environmentl vulnerbility fctor for psychitric illness which hs recently become focus of renewed interest becuse of niml studies which hve demonstrted long-term neurobiologicl effects of mternl deprivtion, prticulrly in regrd to hypothlmic-pituitry-drenl xis (HPA) function. 1 5 EPL is by no mens novel focus of interest in psychitry. The possible reltionship between loss of prent during childhood nd psychopthology in dult life hs intrigued psychitrists for lmost 100 yers. In his seminl pper, Mourning nd Melncholi, Freud 6 suggested tht erly loss of loved object renders the individul vulnerble to depression when loss is gin experienced in lter life. The dynmic mechnisms whereby erly object loss predisposes to the lter development of neurosis were expnded upon by other psychonlytic uthors 7 nd in the context of ttchment theory. 8 These hypotheses stimulted numerous efforts to empiriclly determine whether ptients suffering from depression hve indeed experienced EPL to greter extent thn ptients with other psychitric disorders nd psychologiclly helthy individuls. The role of EPL in other dignostic ctegories hs been considered to considerbly lesser extent. Although the erly literture on EPL in reltion to depression is voluminous, it is for the most prt difficult to interpret when pplying contemporry dignostic pproches nd empiricl reserch stndrds. Underscoring this difficulty, two reviews published in 1980 9,10 reched dimetriclly opposite conclusions regrding the ssocition of prentl deth in childhood with dult depression, even though they were bsed on the sme body of literture. While Lloyd 9 concluded tht the evidence supported n ssocition, Crook nd Eliot 10 took the position tht the observed ssocition ws spurious nd ws n rtifct of methodologicl error nd filure to ccount for confounding vribles. A number of resons underlie the difficult in estblishing whether dult psychopthology is ssocited with higher thn norml rtes of EPL in childhood. 10 12 (i) A primry difficulty hs been the definition of EPL. Although most erlier studies focused on prentl deth, others included seprtion nd mny did not clerly distinguish the type of loss. The definition of seprtion hs been prticulrly problemtic, rnging from permnent seprtion to periods of 3 months or less. The upper ge limit of subjects t the time of the loss hs generlly been 15 17 yers, but this definition hs lso been vrible, further complicting comprtive evlution. (ii) A second source of confusion hs been the criteri used for psychitric dignosis. Most of the erlier studies did not use opertionl dignostic criteri or ccepted clssifictions. Therefore, it is lmost impossible to estblish dignostic prllels between syndromes such s mjor depression (MD), s currently defined, nd the ctegories used in erlier studies. In ddition, mny erly studies did not seprte bipolr (BP) nd unipolr depression. (iii) A third difficulty reltes to the control groups to which rtes of EPL in psychitric ptients hve been compred. As noted by number of uthors, 10 12 controls should idelly be mtched to the ptient group for ge, gender, socio-economic sttus of the fmily of origin nd ge of the prents t the birth of the subject (lthough some of these mtching criteri re very difficult to implement in prctice). Mny other fctors could influence the likelihood of prentl deth or seprtion. These include ethnic origin which impcts upon vulnerbility to certin diseses nd is relted to socioeconomic sttus, nd degree of dmixture of ntiveborn nd immigrnt fmilies of origin in the ptient nd control groups. Studies which exmined the prevlence of EPL in ptients with depression hve been of three types: () comprisons of EPL rtes (usully due to deth) in depressed ptients with those in the generl popultion s reflected in census figures nd dt from insurnce compnies; (b) comprisons between depressed ptients nd control groups either psychitric ptients with dignoses other thn depression or medicl ptients of vrious types serving s psychitriclly helthy control group; (c) studies bsed on smples recruited from the community, by dvertising for volunteers or by epidemiologicl smpling, in which EPL rtes in cses of depression re compred to non-cses or psychopthology is determined in subjects who hve experienced EPL compred to subjects who hve not. Becuse of the methodologicl discrepncies nd weknesses outlined bove, comprison between studies, even within the vrious clsses, is difficult. Nevertheless, certin overll trends cn be identified: (1) As reviewed by Lloyd, 9 mny erlier studies, prticulrly those which used census figures or nonoptimlly mtched generl prctice ptients for comprison, 13 15 showed n excess of erly prentl deth mong depressed ptients. More rigorous comprisons with medicl controls hve tended not to find significnt difference, 16 18 with exceptions. 19 Lck of ssocition of deth of prent in childhood with dult depression is prticulrly true of studies which employed n epidemiologicl pproch. 20 22 (2) Differences between depressed ptients nd controls with regrd to seprtion experiences (of vrible length) hve tended to become more definitive s the methodologicl rigor of cse control studies hs incresed 18,23 nd re reltively consistent finding in epidemiologiclly bsed smples. 20 22 (3) There is trend for loss of mother to be more ssocited with depression thn loss of fther, 19,24 but this finding is not consistent. 20,23 (4) Loss in erly childhood hs been reported to be of greter pthogenic significnce thn loss in lter childhood nd dolescence 24,25 but this ws not observed in ll studies. 20 (5) Loss in femles, 19 prticulrly of mother, 23 my be more ssocited with lter development of depression thn loss in mles. However, mny

influentil studies of EPL hve encompssed exclusively femle smples 21,20,24 nd studies which exmined exclusively mle popultions hve lso found n ssocition of loss with depression. 26 Controlled dt on the role of EPL in psychitric disorders other thn depression re less redily vilble. Abrhms nd Whitlock 27 did not observe n incresed rte of EPL (seprtion nd deth combined) in their mnic depressive ptients compred to medicl controls nor did Ro 28 who compred much smller smples of mnic depressives, rective depressives nd first ttck depressives for prentl deth before the ge of 12. Wytt nd Nicholl 29 reported n incresed incidence of erly prentl deth in ptients with schizophreni but erlier studies did not find such n ssocition. 16,30 In their twin study, Kendler et l 20 found tht seprtion from prent before the ge of 17 significntly incresed the risk for generlized nxiety disorder, pnic disorder nd phobi s well s depression. Deth of prent ws significntly ssocited with phobi nd pnic disorder. These findings re comptible with those of nother lrge epidemiologicl study in regrd to pnic but not generlized nxiety disorder 31 nd differ from those of Tennnt et l 32 who found tht seprtion from prent in childhood preferentilly predisposed to depressive nd not nxiety disorder. It is cler from the bove brief review tht mny spects of the role of EPL s risk fctor for psychitric illness remin open nd tht methodologicl issues re of pivotl importnce in ddressing them. We report cse control study in which rtes of EPL due to prentl deth or seprtion (resulting from the prent permnently leving the home) before the ge of 17 yers, were compred in ptients with mjor depression (MD), bipolr disorder (BPD) nd schizophreni (SCZ) to individully mtched helthy control subjects. In ddition, psychosocil, medicl nd clinicl chrcteristics of subjects with nd without history of EPL were compred within ech dignostic group. On the bsis of the literture, the following hypotheses could be tested: (1) ll three disorders would be chrcterized by incresed rtes of EPL reflecting non-specific role of loss s risk fctor for psychitric illness but the ssocition would be strongest for MD; (2) seprtion from prent would be more strongly ssocited with dult psychopthology, prticulrly depression, thn the deth of prent; (3) loss of mother would be more significnt thn loss of fther; (4) loss t n erly ge would be more significnt s risk fctor thn loss in lter childhood nd dolescence; nd (5) EPL would be of greter pthogenic significnce in femles thn in mles. Mterils nd methods Subjects Ptients with MD, BPD nd SCZ were recruited from consecutive dmissions to the prticipting hospitls nd consecutive visits to the follow-up clinics of the sme centers. Psychitriclly helthy control subjects were rndomly recruited from prticipnts in the ctivities of neighborhood community centers in the sme res s the hospitls on series of evenings nd from cross section of the stff of the Hdssh Hebrew University Medicl Center (including clericl nd mintennce workers) or their immedite fmilies. All subjects gve written informed consent for the study which hd been pproved by the Helsinki Committee (Internl Review Bord) of the Hdssh Hebrew University Medicl Center s prt of multi-center, composite reserch protocol on vulnerbility fctors for psychitric illness. Becuse of the minimlly invsive nture of the reserch protocol, refusl to prticipte did not exceed 3%. Ptients underwent detiled clinicl interview by one of the investigtors, which included the Structured Clinicl Interview for Axis I DSM-III-R Disorders (SCID). (A pilot version of the Hebrew version, ultimtely updted to DSM-IV, ws used.) 33 Dignoses were estblished by consensus of two psychitrists ccording to DSM-III-R criteri. 34 Control subjects underwent detiled clinicl interview nd 60% lso underwent semi-structured interview. Further informtion ws obtined from ll subjects using the Hebrew University Dtbse Questionnires (HUD-Q) which were developed for the project nd consist of structured questionnires, filled in by the exminer, which cover the following res: (i) personl bckground nd demogrphic fetures including informtion on ethnicity, immigrtion, eduction, occuption nd income; (ii) pst nd recent significnt life events including erly prentl loss; (iii) psychitric history including previous hospitliztions, tretment history, length nd qulity of remissions nd suicide ttempts; (iv) medicl history including detils of significnt physicl illness; nd (v) fmily history of mentl illness encompssing first degree reltives. Altogether, 136 ptients with MD, 107 with BPD, 160 with SCZ nd 170 norml controls were recruited for the study. Mtching procedure In ccordnce with the cse control design of the study, ptients were mtched to control subjects on one to one bsis nd blind to EPL sttus. The mtching criteri were: (i) ge (±5 yers); (ii) gender; (iii) ethnic origin (Ashkenzi/Non-Ashkenzi Jews). Subjects with prents of different ethnic origins were not included. Emphsis ws plced on ethnicity becuse of the reltionship between ethnicity nd socio-economic levels in Isrel (lower socio-economic level of non- Ashkenzi fmilies of origin); (iv) immigrtion sttus ccording to four ctegories: ntive born Isreli, immigrnt before the ge of 9 yers, 9 16 yers nd 17 yers nd over. We did not hve sufficient informtion to ccurtely mtch the subjects ccording to socio-economic sttus of the fmily of origin prior to the loss event. However, mtching for ethnicity nd immigrtion sttus could be expected to prtilly contribute to mtching for socio-economic sttus of the fmily of 165

166 origin. Becuse of the uniquely trumtic nture of the Nzi holocust experience, subjects who were resident in Europe during the period they were t risk for prentl loss, were excluded from the mtching. According to the mtching criteri, control subject ws sought for ech ptient without regrd to EPL sttus. The mtching procedure yielded 79 MD-Control pirs, 79 BPD-Control pirs nd 76 SCZ-Control pirs. Becuse of the extensive mtching criteri, these numbers were smller thn we hd originlly intended on the bsis of preliminry power nlyses. Controls were used more thn once in the mtching process but the composition of the control groups for ech dignostic ctegory ws different depending on the mtching. Altogether, 131 controls were used for the mtching process. Anlyses of rtes of EPL were conducted seprtely for ech of the dignostic groups. Definition of EPL EPL ws defined s the loss of prent before the subject reched the ge of 17 yers due to (i) deth or (ii) seprtion resulting from prent permnently leving the home nd residing elsewhere. The definition of seprtion did not require tht there be no contct between the subject nd the prent but did clerly stipulte tht the prent ws no longer resident in the home from the time of the seprtion. Cses in which prent left the home for vrible period(s) but returned before the subject reched the ge of 17 yers, were excluded. In cses where the subject lost both prents before the ge of 17, the ptient-control pir ws excluded from those nlyses in which the nture of the loss could not be clerly ctegorized, such s the gender of prent lost, loss of prent due to deth vs seprtion (unless the cuse of loss ws the sme for both prents) or the ge-group in which the subject ws t the time of the loss of the prent (except if both losses occurred while the ptient ws in the sme ge group). Tble 1 summrizes the brekdown of the subjects ccording to the mtching vribles by dignostic groups. Tble 2 summrizes the clinicl bckground detils of the ptients. Sttisticl nlysis Since ptients nd controls were individully mtched, the mtched pirs were the pproprite unit of nlysis rther thn the individul subjects. 35,36 Mntel-Henszel odds rtio estimtes, pproprite for mtched pirs, were clculted for the prticulr dignosis in the presence reltive to the bsence of EPL (including specific sub-ctegories of EPL). In this mtched pirs nlysis only pirs in which one of the subjects experienced the event (EPL) nd the other did not, re tken into ccount; pirs in which both or neither experienced the event re excluded. 35 Significnce levels of the odds rtios were estblished by McNemr s test using the exct binomil distribution. 36 One sided P vlues were used (P 0.05) becuse the direction of the hypothesis ws known beforehnd. Where pproprite, Bonferonni correction for multiple Tble 1 Mtched chrcteristics of the ptient-control pirs MD-CON BPD-CON SCZ-CON (n = 79) (n = 79) (n = 76) Age MD BPD SCZ (Men ± s.d.) 50.7 ± 14.4 48.5 ± 17.4 42.5 ± 12.3 CON CON CON 49.3 ± 15.0 47.2 ± 17.0 41.7 ± 13.4 Gender Mle 24 28 36 Femle 55 51 40 Ethnicity Ashkenzi 47 40 37 Non- 32 39 39 Ashkenzi Age t immigrtion 8 yrs 2 3 4 9 16 yrs 6 7 5 17 yrs 37 24 16 Isreli born 34 45 51 Number of mtched pirs in ech ctegory. Tble 2 Clinicl fetures of the ptient smples mtched to controls MD BPD SCZ (n = 79) (n = 79) (n = 76) Age t first depressive 39.3 ± 16.2 31.1 ± 14.0 episode Age t first psychitric 38.5 ± 16.3 29.4 ± 13.2 20.7 ± 8.0 tretment Age t first psychitric 42.0 ± 15.0 31.4 ± 14.9 22.5 ± 8.3 hospitlistion Age t first mnic 31.0 ± 14.9 episode Number of depressive 0.4 ± 0.3 0.4 ± 0.6 episodes,b Number of mnic 0.4 ± 0.3 episodes,b Number of psychitric 0.5 ± 0.5 0.5 ± 0.6 0.4 ± 0.4 hospitlistions,b Fmily history of psychitric illness c Affective disorder d 19 (25.0) 16 (21.1) 8 (10.5) Schizophreni e 3 (3.9) 4 (5.3) 17 (22.4) Any psychitric 25 (32.9) 21 (27.6) 25 (32.9) disorder Men ± s.d. b Per yer since first illness episode. c Number of subjects (%). d Including schizoffective minly ffective. e Including schizoffective minly schizophrenic. testing ws pplied with overll set t 0.05. To compre subjects with nd without history of EPL within the dignostic groups, ctegoricl vribles were nlyzed by the Chi-squre or Fisher exct test nd ordinl vribles by the Wilcoxon-Mnn Whitney test (since

Tble 3 Rtes of EPL in ptients with mjor depression, bipolr disorder nd schizophreni nd their mtched control groups MD (n = 79) CON (n = 79) BPD (n = 79) CON (n = 79) SCZ (n = 76) CON (n = 76) 167 No. Rte No. Rte No. Rte No. Rte No. Rte No. Rte Any EPL 23 29.1 6 7.6 14 17.7 6 7.6 17 22.4 6 7.9 Type of EPL Deth 15 19.2 6 7.6 12 15.2 5 6.3 11 14.5 4 5.3 Permnent seprtion 7 9.0 0 0 2 2.5 1 1.3 6 7.9 2 2.6 Prent lost Mother only 7 8.9 1 1.3 4 5.1 2 2.5 7 9.2 3 3.9 Fther only 11 13.9 5 6.3 8 10.1 4 5.1 10 13.2 3 3.9 Both prents 5 6.3 0 0 2 2.5 0 0 0 0 0 0 Age t loss b 8 yrs 11 14.3 1 1.3 5 6.4 2 2.5 14 13.4 4 5.3 9 16 yrs 10 13.0 5 6.3 8 10.3 4 5.1 3 3.9 2 2.6 Subjects flling into more thn one ctegory due to loss of both prents from different cuses, excluded (MD, n = 1). b Subjects flling into more thn one ctegory due to loss of both prents in different ge groups, excluded (MD, n = 2; BP, n = 1). the dt for most of the continuous vribles were not normlly distributed). For the nlyses within groups, two-sided P vlues were pplied (P 0.05). Group vribles re presented s men ± stndrd devition (s.d.). Results Tble 3 shows the rtes of EPL due to deth or permnent seprtion from prent in the three dignostic groups compred to their respective mtched controls nd Tbles 4 6 the sttisticl nlyses. The proportion of the MDD ptients who hd experienced loss of prent due to deth or permnent seprtion before the ge of 17 ws 29.1%, compred to 7.6% of their mtched control subjects (OR = 3.8, P = 0.001). The rte of EPL mong the BP ptients ws lso higher thn mong their controls, t borderline level of signifi- cnce (17.7% vs 7.6%, OR = 2.6, P = 0.048). The rte of EPL mong the schizophrenic ptients ws significntly higher thn mong their controls (22.4% vs 7.9%; OR = 3.8, P = 0.01). Considering the rte of EPL in the MD nd control groups ccording to different ctegories of loss (Tbles 3, 4), there ws significnt excess of EPL due to permnent seprtion from prent (P = 0.008) but not due to deth (OR = 2.5, P = 0.039, not significnt fter correction). (Subjects who lost one prent due to deth nd the other due to seprtion were excluded from this nlysis.) Considering the gender of the prent, loss of mother ws more frequent in the ptients with MD thn their controls but this difference ws not significnt fter correction (OR = 7.0, P = 0.035) while the difference for loss of fther did not pproch significnce (OR = 2.2, P 0.1). (This nlysis did not include ptient-control pirs in which one of the sub- Tble 4 EPL in ptients with mjor depression sttisticl significnce vs mtched controls No. pirs Pirs with EPL Pirs with EPL Odds rtio P vlue MD+/CON CON+/MD Any EPL 79 23 6 3.8 0.001* Type of EPL Deth 71 15 6 2.5 0.039 Permnent seprtion 57 7 0 0.008* Prent lost Mother 58 7 1 7.0 0.035 Fther 66 11 5 2.2 0.1 Both 55 5 0 0.03 Age t loss 8 yrs 62 11 1 11.0 0.003* 9 16 yrs 65 10 5 2.0 0.1 Comprison in ech subctegory limited to ptient-control pirs mnifesting the specified ctegory of loss vs no EPL. Also, where relevnt, pirs which could not be ssigned to ctegory due to loss of both prents, were excluded (see footnotes 1 nd 2 to Tble 3). *Significnt fter correction for multiple testing ( k = 0.025, djusting for two comprisons, k = 0.017 djusting for three comprisons).

168 Tble 5 EPL in ptients with bipolr disorder sttisticl significnce vs mtched controls No. pirs Pirs with EPL Pirs with EPL Odds rtio P vlue BPD+/CON CON+/BPD Any EPL 79 13 5 2.6 0.048 Type of EPL Deth 76 11 5 2.2 0.1 Permnent seprtion 62 2 0 Prent lost Mother 65 3 2 1.5 0.1 Fther 71 8 3 2.7 0.1 Both 65 2 0 Age t loss 8 yrs 66 4 1 4.0 0.1 9 16 yrs 72 8 4 2.0 0.1 Comprison in ech subctegory limited to ptient-control pirs mnifesting the specified ctegory of loss vs no EPL. Also, where relevnt, pirs which could not be ssigned to ctegory due to loss of both prents, were excluded (see footnotes 1 nd 2 to Tble 3). Tble 6 EPL in ptients with schizophreni sttisticl significnce vs mtched controls No. pirs Pirs with EPL Pirs with EPL Odds rtio P vlue SCZ+/CON CON+/SCZ Any EPL 76 15 4 3.8 0.01* Type of EPL Deth 68 9 2 4.5 0.033 Permnent seprtion 63 6 2 3.0 0.1 Prent lost Mother 63 6 1 6.0 0.06 Fther 67 9 3 3.0 0.073 Both 55 0 0 Age t loss 8 yrs 71 13 3 4.3 0.011* 9 16 yrs 58 2 1 2.0 0.1 Comprison in ech subctegory limited to ptient-control pirs mnifesting the specified ctegory of loss vs no EPL. Also, where relevnt, pirs which could not be ssigned to ctegory due to loss of both prents, were excluded (see footnotes 1 nd 2 to Tble 3). *Significnt fter correction for multiple testing ( k = 0.025 djusting for two comprisons, k = 0.017 djusting for three comprisons). jects hd lost both prents.) Although there were no MD-control pirs in which the control hd lost both prents compred to five with the opposite finding, the difference (P = 0.03) ws not significnt fter correction. Considering the ge t which the loss occurred (due to deth or permnent seprtion), there ws significnt excess of EPL in the MD ptients compred to their controls before the ge of 9 yers (OR = 11.0, P = 0.003). In the ge group 9 16 yers, loss ws not significntly more frequent mong the MDD ptients. (Subjects who lost both prents while in different ge ctegories were excluded from this nlysis.) Among the BP ptients, there ws no significnt excess of EPL in ny of the ctegories of loss compred to their mtched controls (Tbles 3, 5). Among the schizophreni ptients, EPL due to deth ws more frequent thn mong their controls but this difference ws not significnt fter correction (OR = 4.5, P = 0.033; Tbles 3, 6) nd there ws trend for loss of mother (OR = 6.0, P = 0.06). EPL before the ge of 9 yers ws significntly more frequent mong the schizophreni ptients thn their mtched controls (OR = 4.3, P = 0.011). To exmine whether the effects of EPL were specific to gender, rtes were exmined seprtely in femlefemle nd mle-mle ptient-controls pirs. Among femles, the overll rte of EPL ws significntly higher in MD (OR = 5.33, P = 0.002; 55 pirs) nd BPD (OR = 3.67, P = 0.029; 51 pirs), while in schizophreni trend ws observed (OR = 4.0, P = 0.055; 40 pirs). Among mles, the smller number of pirs limits the vlidity of the nlysis. There were no significnt differences in MD (OR = 2.33, P = 0.17; 24 pirs) or BPD (OR = 1.0, P = 0.68; 28 pirs) or schizophreni

(OR = 3.50, P = 0.09; 36 pirs). There were insufficient numbers to conduct nlyses of the sub-ctegories of loss in either gender. To exmine the reltionship between EPL nd demogrphic nd clinicl vribles within groups, ll the subjects recruited in ech ctegory (including those not mtched) were used for the nlysis. Subjects with history of EPL due to deth or seprtion were compred to those with no loss. Exmintion of the vribles used for mtching (ge, gender, ethnicity nd ge t immigrtion) reveled no significnt difference between subjects with nd without history of EPL in the groups s whole. In the clinicl groups, virtully no significnt differences were observed on ny of the bckground (ge, gender, mritl history, eduction, income, physicl helth, cigrette smoking) nd clinicl vribles (ge t onset of illness, first psychitric tretment nd first hospitliztion, number of illness episodes nd number of hospitliztions corrected for illness durtion). However, MD ptients with EPL hd been divorced significntly more frequently (20% vs 5.6%, P = 0.034) nd BP ptients with history of EPL hd ttempted suicide more often (45.5% vs 20.4%, P = 0.032). There ws no significnt difference in fmily history of ffective disorder, schizophreni or ny other psychitric disorder (in first degree reltives) between ptients with or without history of EPL in ny of the dignostic groups. Alcohol use ws miniml or bsent mong the ptients nd controls nd none hd ny history of drug buse. In the control group, n interesting series of differences ws observed between subjects with nd without history of EPL. Subjects with history of EPL reported lower incomes (71.4% vs 22.2%, P = 0.031), hd more physicl illness (45.8% vs 15.1%, P = 0.012), hd substntilly stronger lifetime history of cigrette smoking (81.3% vs 36.4%, P = 0.001), hd been divorced more frequently (33.3% vs 9.0%, P = 0.037) nd were more likely to be living lone (81.3% vs 43.6%, P = 0.009). Discussion The results of this study indicte tht loss of prent during childhood increses the likelihood of developing MD during dult life by fctor of 3.8 (P = 0.001). The effect of loss due to seprtion ws significntly more striking thn loss due to deth, s ws loss during erly childhood (less thn 9 yers) compred to lter childhood nd dolescence. Although not significnt in this nlysis, loss of mother hd stronger effect thn loss of fther in ptients with MD, s did loss of both prents. The overll rte of EPL ws lso incresed in BPD, t mrginl level of significnce but there were no significnt findings in ny of the sub-ctegories of loss. A significntly incresed rte of EPL ws observed in SCZ ptients, prticulrly before the ge of 9 yers, with mrginl significnce level for loss due to deth nd trend for loss of mother. Selection bis nd indequte mtching of ptient nd control groups hve been serious criticisms of previous studies which compred EPL in psychitric ptients nd helthy controls. 10 12 The ptient groups for our study were consecutively recruited t number of lrge medicl centers nd my be considered representtive of the popultions under tretment t these centers. They were crefully mtched to control subjects from the sme popultion in terms of ge, gender, ethnic origin nd immigrtion sttus nd possible effects of exposure to the Nzi Holocust were excluded. Thus, the results of our study re unlikely to be due to comprison of unlike popultions mnifesting different bse risk for EPL. Furthermore, the dt were nlyzed by mens of conservtive mtched pirs pproch. Nevertheless, certin potentilly rtifctul resons for difference in rtes of EPL between ptients nd controls were not definitively excluded. We did not directly mtch for socio-economic sttus of the fmily of origin becuse of the difficulty in relibly differentiting between socio-economic sttus before the prentl loss (prticulrly if it occurred erly) nd fter the loss, which could well be consequence thereof. To some extent, this limittion is ddressed by mtching for ethnicity. Although ethnic differences in SES in Isrel re becoming considerbly less prominent, this ws not the cse two or more decdes go. Mtching for immigrtion sttus, long with ethnicity, lso tkes SES into ccount. A further limittion of the study is tht we did not control for ge of the prents t the time of the birth of the child. Surprisingly, informtion in this regrd ws found to be of questionble relibility. Finlly, not ll the control subjects were interviewed by mens of semi-structured instrument. Current psychopthology ws excluded by n extensive clinicl interview which lso ddressed pst history nd fmily history in first degree reltives but lifetime dignoses could hve been missed. However, this would work ginst rther thn in fvor of the hypothesis which we were testing. An importnt question is whether the rtes of EPL which were observed in our control subjects reflect those of the generl popultion in Isrel. We were unble to obtin definitive dt in this regrd. However, n indirect reflection is provided by dt from the Isreli Centrl Bureu of Sttistics 37 concerning the number of Jewish single prent households in Isrel with children under the ge of 16 in which the bsence of one of the prents is due to widowhood or divorce. These figures cnnot be regrded s reflecting the definition of EPL pplied in our study since cses in which prents remrried fter divorce or widowhood, re not reflected. In such cses, EPL, s defined by us, ws experienced by the children. Bering these limittions in mind, the figure ws 3.96% of 427 000 households in 1975, 3.80% of 491 800 in 1980, 4.51% of 540 900 in 1985, 5.33% of 558 850 in 1990 nd 6.9% of 654 400 in 1995. A progressive increse is observed from 1975. Since the numbers re likely to hve been even lower before 1975 (the erliest dte for which figures of this type re vilble), it is unlikely tht EPL rtes in our 169

170 control group represent n underestimtion of the true rte in the popultion. In terms of the hypotheses ddressed by our study, the following conclusions my be drwn. (1) Incresed overll rtes of EPL re observed in MD, BPD nd schizophreni but the finding is most striking in MD followed by schizophreni. The finding in regrd to MD is consistent with the mjority of published studies in which loss is not broken down into ctegories. The literture on BPD 27,28 nd schizophreni 16,29,30 is insufficient for comprison. (2) Ptients with MD mnifest significntly incresed rte of EPL due to permnent seprtion but not due to deth, s observed by number of methodologiclly rigorous cse control 16 18,23 nd epidemiologicl 20 22 studies. (3) As previously reported, 23,24 loss of mother my be more significnt thn loss of fther lthough in our nlysis this observtion ws t trend level only. (4) Loss t n erly ge ( 9 yers) is of greter significnce thn lter loss, s previously observed by Brown et l 24 nd Roy. 25 (5) A specific sensitivity of femles rther thn mles to loss 19 in MD nd BPD, is suggested by our findings but cnnot be regrded s definitive becuse of smple size. A puzzling spect of our findings is the bsence of ny reltionship between EPL nd most of the clinicl chrcteristics of illness which were exmined in the within groups nlyses. Of prticulr interest, there ws no difference in ge t onset between MD nd BP ptients with nd without history of EPL. We hd nticipted tht ptients with EPL would be chrcterized by n erlier onset of illness but this ws not the cse. In schizophreni, there ws lso no difference between ptients with nd without history of EPL in ge t first psychitric tretment nd ge t first hospitliztion. There ws lso no difference in fmily history of psychitric disorder (mong first degree reltives) between ptients with nd without history of EPL in ny of the ptient groups. This could hve been consequence of the size of the smples (lthough these were reltively lrge nd no trends were observed) or the fct tht reltives were not directly interviewed. The most intriguing observtion emerging from the within subjects nlysis ws in reltion to the control group. Although free of ny forml personl or fmily psychopthology, control subjects with history of EPL reported lower incomes, hd been divorced more frequently, were more likely to be living lone, were more likely to smoke or hve smoked cigrettes nd hd more physicl illness. Although, not ll these significnt differences would withstnd correction for multiple comprisons, their confluence is strongly suggestive of vlid finding which requires further investigtion. The findings permit the tenttive suggestion tht even in the bsence of overt psychopthology, individuls who hve experienced EPL re more likely to mnifest fetures which could be indictive of neurotic trits thn individuls who hve not experienced EPL. Since our findings support the hypothesis tht EPL increses vulnerbility to MD nd schizophreni, nd possibly BPD, considertion of the mechnisms which might be involved is wrrnted. On the bsis of their twin study, Kendler et l 20 proposed tht seprtion from prent is non-specific vulnerbility fctor for psychitric illness. Our results support this suggestion lthough degree of specificity for MD nd lso for schizophreni, is suggested. An ongoing nd unresolved controversy in the literture is whether it is loss itself tht predisposes to psychopthology or whether loss is merely mrker for other pthogenic fctors in the fmily environment. The ltter view ws strongly dvnced by Tennnt 12 who noted tht prentl deth, lthough ctstrophic experience for the child in the short term, hs been less consistently linked to dult psychopthology thn seprtion from prent (s we too hve observed). Consistent with this view re findings which suggest tht qulity of prentl cre, stbility of home life nd reltionship with the surviving prent re meditors of the pthogenic effect of loss. 38,39 Physicl or sexul buse could lso be more prevlent in home environment disrupted by events leding to nd following prentl seprtion. In our study, we did not obtin dt on these vribles which re very difficult to evlute retrospectively. If erly loss (prticulrly when due to seprtion) is not direct vulnerbility fctor for depressive nd other psychitric disorders in dulthood, it is closely ssocited with fctors which predispose more directly nd cn serve s mrker which is more menble to direct mesurement. Considertion of environmentl fctors which my contribute to vulnerbility is of pivotl importnce in understnding the pthogenesis of complex disorders in which there is genetic component. Applying n lgebric model to the dt of Brown et l, 24 Kendler 40 concluded tht loss of mother could ccount for significnt proportion of the fmilil ggregtion of depression, contributing reltive risk 1.2 1.25. Kendler 40 noted tht this figure should be viewed in the context of n overll reltive risk for depression in close reltives of depressive probnds in the rnge of 2 3. Fmilil ggregtion of EPL could thus ccount for significnt proportion of the observed fmilil ggregtion of depression. Long-term neurobiologicl consequences of mternl seprtion hve been extensively studied in mny niml species. 41 43 Recently, enduring chnges in HPA function hve received prticulr ttention. Rts exposed to erly mternl seprtion, hve been shown to mnifest enhnced HPA responsivity to stress which persists throughout the life of the niml. 2,4 This is ccompnied by incresed corticotrophin relesing fctor (CRF) concentrtions, reduced CRF receptor density in the pituitry 1 nd incresed levels of messenger RNA for CRF in the hypothlmus. 2 Regultion of CRF synthesis is chieved vi negtive feedbck mechnism which involves glucocorticoid nd minerlocorticoid receptors. These receptors were found to be significntly down regulted in dult mle rts which hd been mternlly deprived in infncy 3 nd ltertions in glucocorticoid receptor gene expression were dem-

onstrted in the hippocmpus nd frontl cortex. 2 Not only environmentl stress but lso nturl vritions in mternl cre in infncy were found to influence HPA xis sensitivity to stress nd glucocorticoid messenger RNA expression in dult rts. 5 In non-humn primtes, exposure s infnts to dverse rering conditions ws ssocited with persistently elevted cerebrospinl fluid levels of CRF. 44 Tken together, these findings suggest tht erly life experiences cn significntly influence dult responses to stress in nimls by ffecting brin development. It is conceivble tht nlogous processes my be implicted in the effect of erly prentl loss on humn vulnerbility to psychopthology, vi ltertions in responsiveness to stress. Genetic predisposition my influence the degree of susceptibility of the individul to the effects of erly environmentl stress nd my lso determine the psychopthologicl entity to which the individul is rendered more vulnerble s consequence of the stress. 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