Distinguishing characteristics of subjects with good and poor early outcome in the Edinburgh High-Risk Study

Background ‘High-risk’ studies of schizophreniahave the potential to clarify the pathogenesis of schizophrenia.Here, results of extreme outcome groups in the Edinburgh High-RiskStudy are presented.

Aims To compare groups of good and poor outcome from the Edinburgh High-Risk Study and clarify the nature of the change from thestate of vulnerability to that of developing psychosis.

Method The recruitment procedure is described. Good and pooroutcome are defined. These groups are compared in terms ofgenetic liability and of baseline and change in neuropsychologyand neuroanatomy.

Results Demographic characteristics and genetic liability donot differ between the groups. The good outcome group performbetter at baseline in some neuropsychological tests, but thereis little neuroanatomical difference. The poor outcome groupshow consistently impaired memory function and a tendency toreduction in temporal lobe size.

Conclusions In genetically predisposed subjects, the changefrom vulnerability to developing psychosis may be marked bya reduced size and impaired function of the temporal lobe.

INTRODUCTION

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INTRODUCTION

The biological basis of schizophrenia is poorly understood althoughgenetic factors are known to be important. Individuals whodevelop schizophrenia may have abnormalities of language (Jones et al, 1994),behaviour (Done et al, 1994) and motor development(Walker et al, 1994) in childhood, but whether these featuresrepresent a vulnerability to schizophrenia or are precursorsof the disorder is unclear. ‘High-risk’ studiesof individuals at enhanced risk of developing schizophreniacould potentially clarify this but have mainly concerned individualsidentified in infancy as the children of mothers with schizophreniaand thus extend for decades (Asarnow, 1988; Cornblatt & Obuchowski, 1997).The Edinburgh High-Risk Study (Byrne etal, 1999; Hodges et al, 1999; Lawrie et al, 1999, 2001a, b; Cosway et al, 2000; Johnstone et al, 2000; Miller et al,2001, 2002) differs from others as the subjects have beenrecruited as young adults who will pass through the periodof maximum risk of developing schizophrenia during the planned10 years of the study. The investigation concerns young peopleaged between 16 and 25 years at ascertainment (when they wereconsidered well) who have at least two close blood relativeswith schizophrenia. A total of 229 such young people were identifiedand 162 of them have so far provided data. They were compared with 34 age-and gender-matched well young people, with no familyhistory from the same communities (Hodges et al 1999; Johnstone et al, 2000),and 36 age-matched subjects with first episodesof schizophrenia. The numbers in the control and first-episodegroups were chosen to reflect the number of high-risk subjectseventually predicted to develop schizophrenia (approximately30 individuals). The study has now been in progress for morethan 6 years and some results have been presented (Byrne etal, 1999; Lawrie et al, 1999, 2001a,b; Miller et al, 2001, 2002). This report compares those individuals from within thehigh-risk sample who so far have achieved the best and theworst outcomes.

METHOD

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METHOD

Case ascertainment
The methods of the study have been described in detail in earlierpapers. Essentially, subjects were assessed, at ascertainmentand every 18 months until they develop schizophrenia or reachthe age of 30 years, in terms of the following variables: (a)psychopathology as determined by the Present State Examination(PSE; Wing et al, 1974); (b) structural magnetic resonanceimaging (MRI) (Lawrie et al, 1999, 2001a); and (c) an extensiveprogramme of neuropsychological tests (Byrne et al, 1999). In addition, assessments of social function, personality andbehaviour and life events were made (Hodges et al, 1999; Milleret al, 2001, 2002).

Definition of outcome categories
As previously described (Johnstone et al, 2000), to simplifyconsideration of the psychopathology as determined by PSE,a simplified classification was drawn up on the basis of thePSE profiles whereby a score of 4=Catego S+ together with aclinical diagnosis of schizophrenia; 3=fully rated psychoticsymptom(s) 55-92 and/or fully rated behavioural item(s) 128,129, 135, 136, 137; 2=3, but features partially rated or features49-54 partially or fully rated and/or 108, 109, 118, 125, 126fully and 133 partially or fully rated; 1=none of the above,but any other items fully rated; 0=none of the above. For thepurposes of this study, those with the best outcome were thosewho have never achieved any fully rated score on any psychopathologicalitem at PSE on any occasion of assessment (i.e. they alwaysscored 0 on the study score), and who, in addition, had a recordof sustained employment (or successful study towards employment)at a level higher or at least as high in terms of the Registrar General's ratings (Her Majesty's Stationery Office, 1991) ofsocial class as their parents. Furthermore, at interview theywere noted to have no abnormalities of social presentation and gave an account of unimpaired social performance. Within thecontext of the high-risk study, these individuals are referredto as the ‘perfects’. Those with the worst outcomeshave developed schizophrenia, i.e., they achieved a score of4 on the study score at the last time of assessment and inaddition all fulfilled the diagnostic criteria for schizophreniaaccording to ICD-10 (World Health Organization, 1993).

Comparisons
The ‘perfects’ and the individuals with newly developed schizophrenia were compared in terms of basic demographics,degree of genetic liability, baseline neuropsychology and neuroanatomy,and in those where there were at least two assessments beforedevelopment of illness, change in neuropsychology and changein neuroanatomy. It will be appreciated that whereas most ofthe ‘perfects’ provided at least two assessments the numbers of individuals with newly developed schizophreniawere reduced by the fact that some of them became unwell beforethe second assessment could be carried out.

RESULTS

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RESULTS

There are 24 ‘perfects’, i.e. 13 males and 11 femalesof mean age 21.2 years at ascertainment (range 16-24). Thirteenhigh-risk subjects have developed schizophrenia (8 males and5 females) who at ascertainment were of mean age 20.3 years(range 16-23). This difference in age is not significant.

Genetic liability
Genetic liability was assessed categorically in terms of thenumbers of relatives of first and second degree known to beaffected but this does not, of course, take account of theentire numbers of relatives that the subjects had, and a continuousmeasure of genetic liability was devised by Professor Pak Shamat the Institute of Psychiatry. It has been described by Lawrie et al (2001a) and takes account of the total number of relativesill and well of each subject and their degree of relationshipto the high-risk individual. On this scale, a higher scoreindicates a greater degree of genetic liability. The mean score of the ‘perfects’ was 0.25 (range -0.02 to +0.70)and that of those with new schizophrenia 0.16 (-0.01 to +0.40)but this difference is not significant. In the ‘perfects’,18 had a genetic liability from the maternal side and 6 fromthe paternal. As far as those with new schizophrenia are concerned,six are known to have maternal genetic liability and five paternal.In the remaining two cases, it is possible that the inheritanceis from both sides, but we do not have complete data on both maternal and paternal branches of these families.

Baseline measures
An extensive programme of neuropsychological tests was carriedout at baseline on all entrants to the study and these arecompared between the ‘perfects’ and those withnew schizophrenia. Many of these tests showed no differencesbetween these two groups (Table 1). Differences that werepresent were always in the direction that those who were destinedto develop schizophrenia performed less well (Table 1). Baselinescans were available on 23 of the perfects and 10 of thosedestined to develop schizophrenia. Reasons for non-availabilityinclude pregnancy as well as reluctance to be scanned. Theresults are shown in Table 2. The significant difference inwhole brain relates to the fact that there are more males inthe newly developed schizophrenia group and where correctionis made for gender and height, this difference disappears.

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Table 1 Comparison of baseline neuropsychological test results between the ‘perfects’ and the newly developed schizophrenia group

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Table 2 Whole-brain volumes (cm³) and regional proportions (%), at baseline on the ‘perfects’ and the newly developed schizophrenia group

Differences between first and second assessments
We then examined the relationship between the first and second neuropsychological assessment and compared this between the ‘perfects’ and those of the newly developed schizophreniagroup on whom we had two assessments (eight cases). The significantfindings are shown in Table 3. There is consistently poorerperformance in memory tests in those who will develop schizophreniaand an improvement in function in the Stroop tests in those patients but not in the ‘perfects’. All other testswere non-significant. Similarly, we compared the differencebetween the first and second scan in the ‘perfects’and those with newly developed schizophrenia for whom two scanswere available before they became ill. Most comparisons showedno tendency to significance. In particular, the amygdala—hippocampus,which has shown clear-cut findings such that this is smallestin the control schizophrenia group, next in the generality ofthe high-risk cases and largest in the normal controls (Lawrieet al, 1999, 2001a), showed no tendency to a difference betweenthe ‘perfects’ and those with new schizophrenia.By contrast, there was an apparent difference in the changein temporal lobe size between scans 1 and 2 (see Table 4).This does not achieve significance because of the small numbersand high variance but is of interest.

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Table 3 Differences (mean (s.d.)) between first and second neuropsychological assessments in the ‘perfects’ and the newly developed schizophrenia group

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Table 4 Differences between first and second scans in the ‘perfects’ and the newly developed schizophrenia group in terms of volume changes in left and right amygdala—hippocampus and temporal lobes

DISCUSSION

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DISCUSSION

This paper presents preliminary findings concerning a comparisonbetween two extreme subgroups of a much larger study. The conclusionsthat can be drawn are, therefore, tentative. None the less,it is clear that in terms of baseline demographic characteristicsthe two groups are similar and there is no evidence of greatergenetic liability in those who will develop schizophrenia.There are neuropsychological differences at baseline between the two groups, such that the good outcome group perform betterin terms of memory and some, but not all, measures of IQ. Thisis redolent of our previous study of treatment-responsive andtreatment-resistant schizophrenia (Lawrie et al, 1995). Frontal(Hayling test) and cingulate (Stroop test) tasks did not significantly differ between the two groups. The relatively low National AdultReading Test (NART; Nelson, 1982) scores are likely to bebecause of the subjects' youth. At baseline there were essentiallyno neuroanatomical differences between the two groups and this contrasts with the baseline differences we have establishedbetween the high-risk subjects and both normal and schizophreniacontrols (Lawrie et al, 1999). This may well be because ofthe small size of the groups in the current comparison, inthat numbers larger than this are generally required to demonstratedifferences between patients with schizophrenia and normal controls (Lawrie & Abukmeil, 1998). Where we have had theopportunity to assess the subjects twice before illness developsin comparison to the ‘perfects’, those who willdevelop schizophrenia show consistently poor memory function (Table 3). They also show a significant improvement in performanceon the Stroop test, but this is not easy to interpret as itresults from an initially non-significantly poorer performance.

The interest of the impaired memory function that we see beforethe manifestation of psychosis in those destined to developschizophrenia is enhanced by the tendency of these subjectsto show a reduction in temporal lobe size over the same periodbecause, of course, memory function is most localisable tothe temporal lobe. This finding reflects our earlier result (Cosway et al, 2000) of a pre-psychotic decline in memory.We have already shown that the neuropsychological impairmentsin subjects at enhanced risk of schizophrenia are widespreadand affect many more individuals than are likely to developthe condition (Byrne et al, 1999). We suggest that the findingsmay indicate that the feature that marks the change from vulnerabilityto developing psychosis is a reduction in size and impairmentof function of the temporal lobe. Cognitive change seems tobe a precursor and not a consequence of psychosis in people who have schizophrenia.

Clinical Implications and Limitations

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Clinical Implications and...

CLINICAL IMPLICATIONS

Among genetically predisposed subjects, those who will go onto develop schizophrenia do not have greater genetic liabilitythan those who will remain well.
Some individuals with highgenetic liability to schizophreniaare asymptomatic, with highlevels of occupational and socialfunction.
Memory functionmay distinguish between those genetically predisposed individualswho will go on to develop schizophrenia and thosewho will not.

LIMITATIONS

This is an interim analysis of selected subgroups and thus much information from the sample as a whole is not included.
Themembership of the groups is not yet fixed — more subjectswill develop schizophrenia and some of the ‘perfects’may deteriorate.
The number of subjects with two assessmentsbefore illness supervenesis small.

ACKNOWLEDGMENTS

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ACKNOWLEDGMENTS

This study was supported and conducted under the auspices ofthe ethics committees relevant to the districts in which thesubjects lived. We are most grateful to Suheib Abukmeil, MajellaByrne, Bobby Clafferty, Elizabeth Grant, Anne Hodges and JaneMorris who recruited the subjects and conducted some of theassessments, and to Norma Brearley who carefully prepared themanuscript. We greatly appreciate the helpfulness of the subjectsand their extended families, general practitioners and psychiatriststhroughout Scotland.

REFERENCES

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