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Twin Research (2000) 3, 28–32 © 2000 Macmillan Publishers Ltd All rights reserved 1369–0523/00 $15.00 www.nature.com/tr
Li feti me pr eval ence of mood and anxi ety di sor der s i n tw i n pai r s di scor dant for schi zophr eni a M i chael J Lyons1,2,3,4, Jonathan Huppert 1, Rosemary Toomey 2,3,4, Rebecca Harl ey 1, Jack Gol dberg5,6, Seth Ei sen 7,8, Wi l l i am True7,9, Stephen V Faraone2,3 and M i ng T Tsuang2,3,4 1
Department of Psychology, Boston University Harvard Medical School Department of Psychiatry at Massachusetts Mental Health Center, Boston, MA 3 Harvard Institute of Psychiatric Epidemiology and Genetics, Boston, MA 4 Department of Psychiatry, Brockton VA, Brockton, MA 5 Department of Epidemiology, University of Illinois School of Public Health, Chicago, IL 6 Hines VA Cooperative Studies Program Coordinating Center, Hines, IL 7 Research and Medical Service, St Louis, MO 8 Department of Medicine, Washington University, St Louis, MO 9 School of Public Health, St Louis University, St Louis, MO, USA 2
Ther e have been l ong questi ons about the r el ati onshi p of schi zophr eni a to other mental di sor der s. Li feti me DSM -I I I -R di agnoses of mood and anxi ety di sor der s i n tw i ns w i th cl i ni cal l y di agnosed schi zophr eni a (n = 24) and thei r non-affected co-tw i ns (n = 24) w er e compar ed w i th tw i ns fr om pai r s w i thout schi zophr eni a (n = 3327) usi ng a sampl e fr om the Vi etnam Er a Tw i n Regi str y. Schi zophr eni c pr obands had si gni fi cantl y el evated r ates of al l i ncl uded di sor der s (bi pol ar di sor der, major depr essi on, dysthymi a, gener al i zed anxi ety di sor der, pani c di sor der, and PTSD) compar ed w i th contr ol s (P < 0.01). The odd r ati os compar i ng co-tw i ns of schi zophr eni c pr obands w i th contr ol s w as gr eater than thr ee for ever y di sor der, but di d not attai n stati sti cal si gni fi cance. A si mi l ar patter n w as obser ved w hen anal yses w er e r estr i cted to onl y monozygoti c tw i ns (n = 12). Consi stent w i th other studi es, schi zophr eni cs appear ed to have hi gher r ates of a r ange of mental di sor der s. Our r esul ts suggest that schi zophr eni a per se r epr esents a r i sk factor for other psychi atr i c di sor der s, but the absence of si gni fi cantl y el evated r i sk among non-schi zophr eni c co-tw i ns suggested that fami l y envi r onmental and/or geneti c factor s that contr i bute to r i sk of schi zophr eni a do not i ncr ease the r i sk of mood and anxi ety di sor der s to the same extent that the r i sk of these other di sor der s i s i ncr eased by the pr esence of schi zophr eni a. Twin Research (2000) 3, 28–32. Keyw or ds: schi zophreni a, tw i ns, di scordant, mood di sorders, anxi ety di sorders
I ntr oducti on The nature of the rel ati onshi p, i f any, betw een schi zophreni a and other mental di sorders has been an enduri ng i ssue i n the fi el d of psychopathol ogy. Di sti ngui shi ng betw een dementi a praecox (schi zophreni a) and mani c-depressi ve i l l ness i s regarded as a central achi evement of Kraepel i n,1 w ho i s general l y credi ted w i th ori gi nati ng modern psychi atri c nosol ogy. Others, such as Crow,2 have argued that the di sti ncti on betw een schi zophreni a and affecti ve i l l ness i s i ncorrect. A l though di sti ngui shi ng betw een schi zophreni a and affecti ve i l l ness has been the majori ty vi ew,3 Tayl or 4 sel ecti vel y revi ew ed Correspondence: M i chael J Lyons PhD, Psychol ogy Department, Boston Uni versi ty, 64 Cummi ngton Street, Boston, M A 02215, USA . Tel : (617)353 3820; Fax: (508)586 6791; E-mai l : ml
[email protected] Recei ved 26 M arch 1999; revi sed 28 Jul y 1999; accepted 17 A ugust 1999
previ ous research and i denti fi ed a number of studi es that do not support the di sti ncti on. One approach to assessi ng the rel ati onshi p betw een schi zophreni a and other di sorders i s to exami ne w hether they co-occur i n the same i ndi vi dual s at rates that exceed w hat w oul d be expected by chance. In an epi demi ol ogi cal study, Bl and et al 5 demonstrated el evated odds rati os (above 10) for schi zophreni a and mani c epi sode, major depressi ve epi sode, obsessi ve compul si ve di sorder, phobi a, pani c, substance abuse/ dependence, and any DSM III di agnosi s usi ng l i feti me preval ence. Robi ns and Regi er 6 reported data from the Epi demi ol ogi c Catchment A rea (ECA ) study demonstrati ng el evated odds rati os (above 10) for schi zophreni a and mani a, depressi on, somati zati on, pani c, obsessi ve compul si ve di sorder, and phobi as usi ng 12-month preval ences, and that 91% of al l pati ents w i th schi zophreni a or schi zophreni form di sorder had some other addi ti onal l i feti me di agnosi s. Kessl er 7 reported data from the Nati onal Comorbi di ty Study (NCS)
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demonstrati ng el evated odds rati os (above 10) for non-affecti ve psychoses (schi zophreni a, schi zoaffecti ve, schi zophreni form, atypi cal psychosi s, del usi onal di sorders, and psychoti c di sorder NOS), and major depressi on, bi pol ar I, general i zed anxi ety di sorders, and pani c di sorder accordi ng to DSM -III R cri teri a and usi ng 12-month preval ences. He al so reported that 93% of al l peopl e w i th nonaffecti ve psychoses have some other di sorder duri ng thei r l i feti me. In concl usi on, there appear to be el evated preval ences of comorbi d major depressi ve epi sodes, pani c di sorder, and bi pol ar di sorders i n peopl e di agnosed w i th schi zophreni a across epi demi ol ogi cal studi es. There are several al ternati ve mechani sms that mi ght be responsi bl e for the observed comorbi di ty betw een schi zophreni a and these other mental di sorders.8 One possi bi l i ty i s an overl ap betw een the envi ronmental and/ or geneti c factors that make an i ndi vi dual vul nerabl e to schi zophreni a and vul nerabl e to these other di sorders. The exami nati on of non-schi zophreni c rel ati ves presents the opportuni ty to determi ne i f i ndi vi dual s w ho share geneti c and envi ronmental characteri sti cs w i th the schi zophreni c proband al so di spl ay an el evated ri sk for the other di sorders, even i n the absence of schi zophreni a. Kendl er et al 9 revi ew ed studi es eval uati ng ri sk for vari ous mental di sorders i n rel ati ves of schi zophreni cs. They reported fi ve studi es show i ng no i ncreased ri sk of affecti ve i l l nesses, tw o demonstrati ng an i ncreased ri sk, and one show i ng a decreased ri sk for affecti ve i l l nesses i n the rel ati ves of i ndi vi dual s w i th schi zophreni a. They al so reported four studi es demonstrati ng no i ncreased ri sk for anxi ety di sorders, and one study reporti ng decreased ri sk. Si nce Kendl er et al’s revi ew, w e have i denti fi ed four addi ti onal fami l y studi es usi ng DSM -III-R or RDC cri teri a;3,9,10,11 three studi es reported no i ncreases i n ri sk for affecti ve i l l ness or anxi ety di sorders i n rel ati ves of schi zophreni cs, w hi l st the fourth (M ai er) found an el evated ri sk for uni pol ar depressi on, but not bi pol ar di sorder among fi rst-degree rel ati ves. Fi nal l y, a study of tw i ns di scordant for schi zophreni a reported that none of 27 probands and thei r co-tw i ns evi denced any any other A xi s I di sorder.12 If the same geneti c and/ or fami l y envi ronmental factors that i mpart ri sk for schi zophreni a al so i mpart ri sk for other mental di sorders found to be co-morbi d w i th schi zophreni a, then the non-schi zophreni c co-tw i ns of schi zophreni cs mi ght be parti cul arl y i nformati ve because they shared the same fami l y envi ronment w i th thei r schi zophreni c tw i n and share ei ther 50% of thei r geneti c materi al w i th the schi zophreni c tw i n i n the case i f di zygoti c (DZ) tw i ns or 100% of thei r geneti c materi al i n the case of monozygoti c (M Z) tw i ns. In thi s paper w e report our
fi ndi ngs based on pai rs of tw i ns di scordant for schi zophreni a from the Vi etnam Era Tw i n Regi stry.
M ater i al s and methods Parti ci pants w ere 6744 men from the Vi etnam Era Tw i n (VET) Regi stry, w hi ch has been descri bed el sew here.13 Of 10 300 el i gi bl e i ndi vi dual s, 8169 (79.7% ) w ere successful l y i ntervi ew ed by tel ephone fol l ow i ng the granti ng of i nformed consent. Thi s procedure for obtai ni ng i nformed consent w as approved by our uni versi ty’s i nsti tuti onal revi ew board. The mean age of parti ci pants w as 44.6 years. Subjects w ere i ntervi ew ed usi ng the Di agnosti c Intervi ew Schedul e Versi on III Revi sed (DIS-III-R), w hi ch yi el ded DSM -III-R di agnoses of mood and anxi ety di sorders. The psychosi s secti on w as not admi ni stered because w e expected a l ow rate of schi zophreni a i n the overal l sampl e and bel i eved that the tel ephone format di d not l end i tsel f to the opti mal i denti fi cati on of schi zophreni a. The presence of schi zophreni a i n probands w as based on cl i ni cal di agnoses obtai ned from the Department of Veterans A ffai rs Pati ent Treatment Fi l es (PTF). The PTF, a central i zed computeri zed abstract of i n-pati ent hospi tal i zati ons, i s mai ntai ned by the Department of Veterans A ffai rs and i ncl udes Internati onal Cl assi fi cati on of Di sease (ICD) di agnosti c codes. Di agnosti c codes w ere assi gned at the l ocal hospi tal by trai ned personnel . The absence of schi zophreni a i n the non-schi zophreni c co-tw i ns w as based on the absence of a PTF di agnosi s and a negati ve response to a sel f-report questi onnai re admi ni stered to Regi stry members by the Nati onal Heart, Lung and Bl ood Insti tute (NHLBI). The PTF i denti fi ed 12 monozygoti c (M Z) and 12 di zygoti c (DZ) tw i n pai rs i n w hi ch one tw i n had ICD-defi ned schi zophreni a and the other tw i n had not. In 23 of these 24 pai rs, the non-schi zophreni c co-tw i n responded to the NHLBI questi onnai re that he w as not schi zophreni c. In one pai r, the nonschi zophreni c co-tw i n di d not respond to the NHLBI survey.
Resul ts For the purposes of the pri mary data anal yses, subjects w ere di vi ded i nto three groups: a) 24 schi zophreni c probands; b) 24 non-schi zophreni c co-tw i ns of the schi zophreni c probands; and 3) 3327 subjects from pai rs w i thout schi zophreni a. One tw i n w as randoml y sel ected from every pai r i n w hi ch both tw i ns responded and nei ther had schi zophreni a. Odds rati os compared both schi zophreni c Twin Research
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probands and thei r co-tw i ns to control s. Stati sti cal si gni fi cance w as determi ned by a 99% confi dence i nterval that di d not i ncl ude 1. We sel ected the 99% confi dence i nterval rather than the 95% confi dence i nterval to avoi d type I error due to the rel ati vel y hi gh number (24) of i ndi vi dual compari sons carri ed out. Tabl e 1 i ncl udes l i feti me preval ences i n each group and odds rati os compari ng both M Z and DZ schi zophreni c probands and co-tw i ns w i th control s. The odds rati os compari ng parti ci pants w i th schi zophreni a w i th control s w as si gni fi cant for every i ncl uded di sorder. Even the smal l est odds rati o, 7.7 for major depressi on, w as qui te substanti al . To eval uate the possi bi l i ty that schi zophreni a mi ght i ncrease the ri sk of experi enci ng trauma and thus be associ ated w i th el evated rates of PTSD, w e exami ned preval ence of PTSD usi ng onl y subjects w ho reported experi enci ng a qual i fyi ng trauma accordi ng to DSM -III-R. PTSD w as more preval ent among traumati zed i ndi vi dual s (control s = 18.4% ; schi zophreni c probands = 69.2% ; non-schi zophreni c co-tw i ns = 27.3% ), but the onl y si gni fi cant compari son remai ned control s vs schi zophreni c probands. A l though al l the odds rati os compari ng co-tw i ns of
schi zophreni cs w i th control s w as over 2, none reached stati sti cal si gni fi cance. The smal l number of subjects and rel ati ve i nfrequency of psychopathol ogy i n co-tw i ns resul ted i n very broad 99% confi dence i nterval s. The non-affected co-tw i ns from di scordant M Z pai rs are of speci al i nterest because they share al l thei r genes w i th the schi zophreni c proband. Therefore, w e exami ned the 12 M Z co-tw i ns of schi zophreni cs separatel y (see Tabl e 2). Si mi l ar to the resul ts for the combi ned M Z and DZ anal yses, the schi zophreni c M Z probands w ere si gni fi cantl y more l i kel y to have each one of the i ncl uded mental di sorder than w ere control s w i th the excepti on of bi pol ar di sorder. None of the schi zophreni c M Z probands recei ved a di agnosi s of bi pol ar di sorder. Non-schi zophreni c M Z co-tw i ns di d not di ffer si gni fi cantl y from control s for any di sorder. How ever, every odds rati o w as greater than 3. A mong the 24 schi zophreni c probands, fi ve had three or more addi ti onal di sorders, three had tw o, ni ne had one, and seven had no addi ti onal di sorders. A mong the 24 non-schi zophreni c co-tw i ns, three had tw o or three di sorders, three had one, and 18 had no psychi atri c di sorder.
Tabl e 1 Preval ence of mood and anxi ety di sorders i n control s, schi zophreni c probands, and nonschi zophreni c co-tw i ns and odds rati os (w i th 99% confi dence i nterval s) compari ng both M Z and DZ tw i n schi zophreni c probands and thei r co-tw i ns w i th control s Prevalences Disorder
Controls (n = 3327)
MZ & DZ schizophrenic probands (n = 24)
MZ & DZ nonschizophrenic co-twins of probands (n = 24)
Odds ratios (99% confi dence interval) MZ & DZ MZ & DZ schizophrenic nonschizophrenic probands co-twins (n = 24) of probands (n = 24)
M ajor depressi on Dysthymi a Bi pol ar di sorder General i zed anxi ety di sorder Pani c di sorder PTSD
7.7% 1.5% 0.4% 1.0% 1.2% 8.3%
43.5% 12.5% 8.4% 21.7% 12.5% 16.7%
17.4% 4.3% 4.2% 4.3% 4.2% 5.3%
7.7 (2.5–24.1) 8.2 (1.4–41.0) 20.1 (2.0–144.9) 26.0 (5.9–106.7) 10.0 (1.6–50.6) 7.0 (2.1–22.3)
2.1 (0.5–8.8) 2.6 (0.1–27.5) 9.6 (0.3–112.0) 4.3 (0.1–46.1) 3.0 (0.1–32.2) 1.4 (0.2–6.9)
Tabl e 2 Preval ence of mood and anxi ety di sorders i n control s, schi zophreni c probands, and nonschi zophreni c co-tw i ns and odds rati os (w i th 99% confi dence i nterval s) compari ng onl y M Z tw i n schi zophreni c probands and thei r co-tw i ns w i th control s Prevalences Disorder
Controls (n = 3327)
MZ schizophrenic probands (n = 12)
MZ nonschizophrenic co-twins of probands (n = 12)
Odds ratios (99% confi dence interval) MZ MZ schizophrenic nonschizophrenic probands co-twins (n = 12) of probands (n = 12)
M ajor depressi on Dysthymi a Bi pol ar di sorder General i zed anxi ety di sorder Pani c di sorder PTSD
7.7% 1.5% 0.4% 1.0% 1.2% 8.3%
50.0% 25.0% 0.0% 25.0% 16.7% 50.0%
25.0% 8.3% 8.3% 8.3% 8.3% 25.0%
12.0 (2.5–57.1) 12.9 (3.2–127.8) – 33.3 (4.8–200.8) 16.4 (1.6–120.1) 11.1 (3.0–68.0)
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4.0 (0.6–22.3) 6.0 (0.2–68.3) 23.1 (0.7–305.4) 9.1 (0.3–106.9) 7.5 (0.2–86.8) 3.7 (0.6–20.5)
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Di scussi on Subjects w i th schi zophreni a w ere si gni fi cantl y more l i kel y to be di agnosed w i th a range of mood and anxi ety di sorders than control s, w hi l st thei r co-tw i ns w ere not. These resul ts suggest that schi zophreni a per se may be a ri sk factor for mood and anxi ety di sorders, i e schi zophreni a may i mpart a ri sk for the devel opment of other di sorders. How ever, equal l y consi stent w i th the observed pattern i s the possi bi l i ty that the occurrence of an anxi ety or mood di sorder coul d preci pi tate the onset of schi zophreni a i n vul nerabl e i ndi vi dual s. Cassano et al 14 have suggested that observed comorbi di ty mi ght be more arti factual than substanti ve. Symptoms used to arri ve at a di agnosi s of a mood or anxi ety di sorder i n an i ndi vi dual w i th schi zophreni a coul d refl ect nonspeci fi c by-products of psychosi s rather than addi ti onal , di sti nct di sorders. A pparent comorbi di ty mi ght al so refl ect i mpreci se speci fi cati on of symptoms for psychosi s and the other di sorders, as w el l as refl ecti ng the effects of treatment and i nformati on bi as. The absence of si gni fi cantl y el evated ri sk among non-schi zophreni c co-tw i ns suggests that the geneti c and fami l y envi ronmental factors that contri bute to the ri sk of schi zophreni a do not strongl y i nfl uence the ri sk of mood and anxi ety di sorders i n the absence of schi zophreni a. These data are consi stent w i th the vi ew that mood and anxi ety di sorders are not i n a geneti c spectrum w i th schi zophreni a. How ever, these resul ts from the non-schi zophreni c co-tw i ns shoul d be vi ew ed w i th consi derabl e cauti on because, w hi l st none of the odds rati os compari ng non-schi zophreni c co-tw i ns of schi zophreni c probands w i th control s w as stati sti cal l y si gni fi cant, al l w ere greater than 1 and fi ve of the si x w ere greater than 2. When M Z tw i ns al one w ere compared w i th control s, the odds rati os for co-tw i ns w ere hi gher, but not si gni fi cantl y so, than i n the combi ned M Z pl us DZ anal yses. A l though i t i s tempti ng to specul ate about these odds rati os, i t i s i mportant to remember that four of the si x odds rati os that w ere cal cul ated refl ect a si ngl e case of the di sorder among the M Z co-tw i ns and none of the odds rati os i s based on more than three cases among the M Z co-tw i ns. There are several l i mi tati ons of thi s study. Whi l st di agnoses of mood and anxi ety di sorders w ere based on structured di agnosti c i ntervi ew s, the PTF di agnoses of schi zophreni a (al though based on the ICD) w ere not based on standardi zed data col l ecti on methods. A n unknow n number of VET tw i ns may have schi zophreni a, but coul d not be i ncl uded i n thi s study because they never recei ved treatment at a VA faci l i ty. How ever, the chroni c and debi l i tati ng nature of schi zophreni a makes i t more l i kel y that
veterans w i th schi zophreni a w i l l recei ve treatment at a VA faci l i ty than w i l l veterans w i th l ess seri ous mental di sorders. Fai l ure to be i denti fi ed i n the PTF as a schi zophreni c i s not strong evi dence that the i ndi vi dual i s not affected. How ever, co-tw i ns w ere cl assi fi ed as non-schi zophreni cs accordi ng to the NHLBI study as w el l as PTF data; i n 23 of 24 pai rs the co-tw i n reported that he had never recei ved a di agnosi s of schi zophreni a. Tw i n pai rs that are di scordant for schi zophreni a may be di fferent from tw i n pai rs that are concordant for schi zophreni a,15 so thi s sampl e may not be representati ve of al l cases of schi zophreni a. The rel ati vel y smal l number of schi zophreni a-di scordant pai rs and l ow preval ences of mood and anxi ety di sorders resul ted i n broad confi dence i nterval s, w hi ch w hi l e not si gni fi cant for compari sons i nvol vi ng non-schi zophreni c co-tw i ns, di d i ncl ude substanti al associ ati ons w i thi n the confi dence i nterval s. The l ack of stati sti cal si gni fi cance i n anal yses i nvol vi ng co-tw i ns, w hi l e not provi di ng evi dence for a fami l i al rel ati onshi p betw een these di sorders and schi zophreni a, shoul d not be vi ew ed as provi di ng strong evi dence agai nst such an associ ati on. The strongest concl usi ons regardi ng these resul ts i nvol ve the si gni fi cantl y el evated rates of mood and anxi ety di sorders among schi zophreni cs; concl usi ons regardi ng co-tw i ns must be vi ew ed as tentati ve. The fact that odds rati os for the other di sorders w ere si gni fi cant for the schi zophreni c tw i ns suggests that havi ng schi zophreni a i s associ ated w i th an i ncreased ri sk of these other di sorders above and beyond any fami l i al vul nerabi l i ty that mi ght be common to schi zophreni a and anxi ety or mood di sorder.
A ck now l edgements Supported by NIH grants DA 04604 and A A 10586 and the Department of Veterans A ffai rs Heal th Servi ces Research and Devel opment Servi ce (Study 992). Department of Veterans A ffai rs Heal th Servi ces and Devel opment Servi ce: Chi ef Research and Devel opment Offi cer, John R Feussner M D; A dmi ni strati ve Offi cer, Janet Gol d. Cooperati ve Studi es i n Heal th Servi ces: Program M anager, Charl es Wel ch III PhD; Heal th Servi ces Research & Devel opment: Deputy Di rector, Shi rl ey M eehan M BA , PhD; Hi nes VA Cooperati ve Studi es Program Coordi nati ng Center, Vi etnam Era Tw i n Regi stry: Di rector, Wi l l i an G Henderson PhD; Regi stry Coordi nator, M ary El l en Vi tek; Programmer, Kenneth Bukow ski ; Stati sti cal A ssi stant, M ary Bi ondi c; Vi etnam Era Tw i n Regi stry A dvi sory Commi ttee: Theodore Col ton ScD, Ral ph Paffenbarger M D, Wal ter Nance M D, M yrna Wei ssman PhD, Roger Wi l l i ams M D. Drs Irvi ng Gottesman and Jag Khal sa al so made Twin Research
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i mportant contri buti ons to the success of thi s study. M ost i mportantl y, the authors w i sh to acknow l edge and thank the members of the Vi etnam Era Tw i n Regi stry for thei r parti ci pati on and cooperati on. They w i l l i ngl y provi ded sensi ti ve i nformati on and consi derabl e ti me i n respondi ng to the survey. Wi thout thei r contri buti on thi s research project w oul d not have been possi bl e.
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