Predicting Schizophrenia: Findings from the Edinburgh High-Risk Study
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BRITISH JOURNAL OF PSYCHIATRY (2005),(2005),186,18^25 186, 18^25 Predicting schizophrenia: findings schizophrenia. Two models of inheritance were considered, predicting that from 200 from the Edinburgh High-Risk Study individuals aged 16–24 years 19 and 29 persons, respectively, would develop schizophrenia within 10 years. The actual EVE C. JOHNSTONE, KLAUS P. EBMEIER, PATRICK MILLER, number would depend upon the ages of DAVIDG.C.OWENSandSTEPHENM.LAWRIEDAVID G. C. OWENS and STEPHEN M. LAWRIE the individuals in the sample and the rela- tive frequencies of the stronger and weaker patterns of inheritance, but it appeared rea- sonable to predict that from 200 such high- risk individuals 20 would develop schizo- phrenia within 10 years. It is, of course, Background The hypothesis that Direct evidence for a neurodevelopmental the case that some individuals from the fa- schizophrenia is neurodevelopmental was origin of schizophrenia can only be acquired milies who have illnesses of very early onset by comparing individuals at risk with might be excluded and some might become investigatedininvestigated in a prospective study of normal controls before illness onset, and ill later, but the purpose of our study was young people with a postulated10^15% following both groups through the period not to acquire every case but to acquire suf- risk for the development of schizophrenia. of risk until the psychosis does or does ficient numbers for adequate comparisons. not develop. Several prospective studies There is little work sufficiently similar to Aims To determined e te r min e premorbidp r e m o r b i d have identified high-risk individuals as provide a basis for adequate power calcula- variables distinguishing high-risk people infants on the grounds that their mothers tions, but imaging was an important part of who will go on to develop schizophrenia had schizophrenia (for review, see Tarrant our considerations, and the study by Sud- from those who will not. & Jones,&Jones,1999). These studies encountered dathdath et aletal (1990) of monozygotic twins pro- difficultiesdifficultiesresulting from the 20-year inter- vided clear findings on 15 discordant pairs. MethodMethod Ahigh-risksampleof163A high-risk sample of163 val before the participants entered the We aimed, therefore, to acquire a high-risk period of maximum risk (Asarnow, 1988; sample ofsampleof200 persons (Johnstone et aletal,, young adults with two relatives with Cornblatt & Obuchowski, 1997). The 2000). Controlgroups comprised well schizophrenia was recruited.They and 36 Edinburgh High-Risk Study (EHRS) young people and individuals in the first controls were serially examined.Baseline (Lawrie(Lawrie et aletal, 1999; Johnstone et aletal, 2000),2000) episode of schizophrenia who did not have measures were compared betweenthose is a development of such work. It investi- a family risk of the disorder. who did develop schizophrenia, a well gates individuals at enhanced risk because The EHRS examined the pathogenesis they have two or more affected relatives. of schizophrenia by addressing the controlcontrolgroup, group, a wellwellhigh-risk high-risk group and These individuals were identified at age hypothesis that individuals from the high- high-risk participants with partial or 16–24 years as they entered the period of risk sample who eventually develop schizo- isolated psychotic symptoms. maximum risk andwere followed over 10 phrenia would, at ascertainment and long years, by whichtime most of those destined before the development of psychosis, differ ResultsResults Ofthose at high risk, 20 to develop schizophrenia would have done from high-risk individuals who do not 11 developed schizophrenia within 2//22 years. so.so. developdevelopschizophreniaschizophrenia and also from the More experienced isolated or partial well controlgroup, in terms of the clinical and neurobiological assessments used. We psychotic symptoms.Those who METHOD predicted that, although the high-risk developed schizophrenia differed from sample as a whole would differ from the those who did not on social anxiety, The purpose of the Edinburgh High-Risk control groups in terms of these indices, withdrawalandother schizotypalfeatures. Study is to determine the features that those who went on to develop schizo- The whole high-risk sample differed from distinguish high-risk individuals who go phrenia would show more marked differ- on to develop schizophrenia from those ences than those who did not. Previous the control group on developmental and who do not, and to compare relevant comparisons between this high-risk sample neuropsychological variables. variables in affected and unaffected and the two control groups have shown members of the high-risk sample with differences in clinical, psychopathological, Conclusions The genetic componentof matched controls. We sought to acquire a psychological, neurological, developmental schizophrenia affects manymore sample of young people aged 16–24 years and imaging variables (Hodges et aletal,, individualsthanwilldeveloptheillness,individuals than will develop the illness, and and considered to be well at ascertainment, 1999; Johnstone et aletal, 2000; Lawrie et aletal,, partial impairment can be found in them. who each had at least two first- or second- 20012001aa,,bb; Miller;Miller et aletal, 2002,2002aa; Byrne;Byrne et aletal,, degree relatives with schizophrenia. To 2003). One of the central comparisons to Highly significant predictors ofthe determine the number of high-risk indivi- be addressed in this data-set is the development of schizophrenia are duals that we would need to study in order comparison in terms of baseline data of detectable years before onset. to achieve a number who would become ill those who have and those who have adequate for relevant comparisons, we not gone on to develop schizophrenia. Declaration of interest None. considered data on age at onset from We are now in a position to examine this Funding detailed in Acknowledgements. 235 families multiply affected with issue.issue. 1818 Downloaded from https://www.cambridge.org/core. 27 Sep 2021 at 03:02:27, subject to the Cambridge Core terms of use. PREDICTING SCHIZOPHRENIA Derivation of the sample Organization, 1992) and PSE (CATEGO some data and 156 provided complete data The study began in 1994. High-risk indivi- S+ or O+). Psychotic illness of a non-schizo- by closure of the recruiting period of the duals aged 16–25 years with no history of phrenic type is not covered by the scale, but programme in July 1999. There were 36 serious psychiatric problems were identified it did not occur. Points 2 and 3 are com- participants in the well control group. At throughout Scotland on the basis that they bined within this study and participantspantspartici ascertainment the mean age of the high-risk had at least two first- or second-degree rela- are referred to as having had psychotic oror group was 21.19 years (s.d.¼2.97) and it tives affected with schizophrenia (Hodges possibly psychotic symptoms. comprised 77 men and 79 women. The well et aletal, 1999). Participants for the well con- The neuropsychological test battery control group’s mean age was 21.17 years trol group were recruited from the social (Byrne(Byrne et aletal, 1999) consisted of tests of (s.d.(s.d.¼2.37) and there were 17 men and 19 network of the high-risk individuals them- general IQ, attention, motor speed, execu- women. On social class, however, the selves; they had no personal or family tive function, verbal learning and memory. samples did differ significantly, with 19 history of psychotic illness, but could have Brain structure was assessed (Whalley etet (53%) of the control group having fathers a family history of other psychiatric illness alal, 1999) by MRI scanning on a 1 T in non-manual occupations against only and otherwise were as similar to the high- Magnetom scanner (Siemens, Erlangen, 46 (29.5%) of the high-risk group 22 risk participants as possible (Hodges et aletal,, Germany). In addition to these measures, ((ww ¼6.9, Fisher’s exact test PP¼0.011).0.011). 1999). Participants for the first-episode we assessed the degree of genetic liability The updated results reported here case group were recruited from local hospi- of the high-risk participants by both catego- concern 173 participants (from both the tals and were balanced group-wise for age rical and continuous methods (Lawrie et aletal,, high-risk and the well control groups) with with the high-risk individuals. Both control 20012001aa). From 1999 to 2004 the assess- whom we remain in regular contact. Of groups were planned to consist of approxi- ments were continued every 18 months, these, 27 were members of the well control mately 35 persons each, the maximum with the addition of functional MRI. group, none of whom has developed schizo- number of the high-risk sample predicted The principal purpose of this study is phrenia. The high-risk group was divided to develop schizophrenia. twofold. First, we wished to determine into ‘high risk without psychotic or possibly variables that at baseline (i.e. at initial psychotic symptoms ever by July 2003’ Plan of the study and assessments ascertainment assessment) distinguish be- ((nn¼66), ‘high risk with psychotic or poss- usedused tween high-risk individuals who will fall ibly psychotic symptoms by July 2003’ The plan for the period 1994–1999 was to ill with schizophrenia, and those who will ((nn¼60) and ‘high risk ill by July 2003’ assess all participants at ascertainment in not do so but who will or will not show ((nn¼20). Occasionally the ‘high risk ill’ terms of clinical features, neuropsychology psychotic or possibly psychotic symptoms. participants were classified as ill at their and brain structure as determined by struc- To do this, we selected all the variables planned review, but – as might be ex- tural magnetic resonance imaging (MRI). from our previous studies (Lawrie et aletal,, pected – most developed schizophrenia People in the first-episode control group 20012001aa,,bb; Miller;Miller et aletal, 2001, 2002aa,,bb,,cc;; between assessments and were admitted to were assessed only on ascertainment; for ByrneByrne et aletal, 2003; Langsley et aletal, 2004) that a local service.