Division of Psychiatry, University of Edinburgh, Edinburgh, UK
Correspondence: Professor Eve C. Johnstone, Division of Psychiatry, University of Edinburgh, Kennedy Tower, Royal Edinburgh Hospital, Morningside Park, Edinburgh EH10 5HF, UK. E-mail: Norma.Brearley{at}ed.ac.uk
Funding detailed in Acknowledgements.
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ABSTRACT |
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Aims To determine premorbid variables distinguishing high-risk people who will go on to develop schizophrenia from those who will not.
Method A high-risk sample of 163 young adults with two relatives with schizophrenia was recruited. They and 36 controls were serially examined. Baseline measures were compared between those who did develop schizophrenia, a well control group, a well high-risk group and high-risk participants with partial or isolated psychotic symptoms.
Results Of those at high risk, 20 developed schizophrenia within
2 years. More experienced isolated or partial psychotic symptoms.
Those who developed schizophrenia differed from those who did not on social
anxiety, withdrawal and other schizotypal features. The whole high-risk sample
differed from the control group on developmental and neuropsychological
variables.
Conclusions The genetic component of schizophrenia affects many more individuals than will develop the illness, and partial impairment can be found in them. Highly significant predictors of the development of schizophrenia are detectable years before onset.
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INTRODUCTION |
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METHOD |
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The EHRS examined the pathogenesis of schizophrenia by addressing the hypothesis that individuals from the high-risk sample who eventually develop schizophrenia would, at ascertainment and long before the development of psychosis, differ from high-risk individuals who do not develop schizophrenia and also from the well control group, in terms of the clinical and neurobiological assessments used. We predicted that, although the high-risk sample as a whole would differ from the control groups in terms of these indices, those who went on to develop schizophrenia would show more marked differences than those who did not. Previous comparisons between this high-risk sample and the two control groups have shown differences in clinical, psychopathological, psychological, neurological, developmental and imaging variables (Hodges et al, 1999; Johnstone et al, 2000; Lawrie et al, 2001a,b; Miller et al, 2002a; Byrne et al, 2003). One of the central comparisons to be addressed in this data-set is the comparison in terms of baseline data of those who have and those who have not gone on to develop schizophrenia. We are now in a position to examine this issue.
Derivation of the sample
The study began in 1994. High-risk individuals aged 1625 years with
no history of serious psychiatric problems were identified throughout Scotland
on the basis that they had at least two first- or second-degree relatives
affected with schizophrenia (Hodges et
al, 1999). Participants for the well control group were
recruited from the social network of the high-risk individuals themselves;
they had no personal or family history of psychotic illness, but could have a
family history of other psychiatric illness and otherwise were as similar to
the high-risk participants as possible
(Hodges et al, 1999).
Participants for the first-episode case group were recruited from local
hospitals and were balanced group-wise for age with the high-risk individuals.
Both control groups were planned to consist of approximately 35 persons each,
the maximum number of the high-risk sample predicted to develop
schizophrenia.
Plan of the study and assessments used
The plan for the period 19941999 was to assess all participants at
ascertainment in terms of clinical features, neuropsychology and brain
structure as determined by structural magnetic resonance imaging (MRI). People
in the first-episode control group were assessed only on ascertainment; for
clarity, findings in these individuals have been omitted from this report,
although their baseline data have been presented elsewhere (Lawrie et
al,
2001a,b;
Byrne et al, 2003). In
the high-risk and the well control groups psychopathological assessments were
repeated every 18 months. The baseline clinical measures included assessments
of childhood behavioural traits (Miller
et al, 2002a), schizotypal features (Miller
et al,
2002b,c),
and the neurodevelopmental variables of minor physical anomalies and
neurological soft signs (Lawrie et
al, 2001b), ocular hypertelorism
(Boyes et al, 2001),
dermatoglyphics (Langsley et al,
2004) and substance use
(Miller et al, 2001).
Mental state was assessed at entry and at all the follow-up points by the
Present State Examination (PSE; Wing
et al, 1974), and from this we derived the following
five-point psychopathological scale
(Johnstone et al,
2000): 0, no psychotic or neurotic symptoms; 1, neurotic symptoms
only; 2, partially held psychotic symptoms; 3, definite but isolated and/or
transient psychotic symptoms; 4, schizophrenia diagnosed by ICD10
(World Health Organization,
1992) and PSE (CATEGO S+ or O+). Psychotic illness of a
non-schizophrenic type is not covered by the scale, but it did not occur.
Points 2 and 3 are combined within this study and participants are referred to
as having had psychotic or possibly psychotic symptoms.
The neuropsychological test battery (Byrne et al, 1999) consisted of tests of general IQ, attention, motor speed, executive function, verbal learning and memory. Brain structure was assessed (Whalley et al, 1999) by MRI scanning on a 1 T Magnetom scanner (Siemens, Erlangen, Germany). In addition to these measures, we assessed the degree of genetic liability of the high-risk participants by both categorical and continuous methods (Lawrie et al, 2001a). From 1999 to 2004 the assessments were continued every 18 months, with the addition of functional MRI.
The principal purpose of this study is twofold. First, we wished to determine variables that at baseline (i.e. at initial ascertainment assessment) distinguish between high-risk individuals who will fall ill with schizophrenia, and those who will not do so but who will or will not show psychotic or possibly psychotic symptoms. To do this, we selected all the variables from our previous studies (Lawrie et al, 2001a,b; Miller et al, 2001, 2002a,b,c; Byrne et al, 2003; Langsley et al, 2004) that at baseline either distinguished high-risk individuals from well controls beyond the P<0.01 level of significance, or distinguished high-risk individuals who experienced psychotic symptoms at an early stage from those who did not (P<0.01) (see Table 1). We retested these variables to assess the usefulness of each one in making the distinctions described. The sample retested consisted of all the participants with whom we were still in regular contact. We predicted that there would be a gradation in the effects, from high-risk individuals who fall ill followed by high-risk individuals with psychotic symptoms only, high-risk individuals without psychotic symptoms and well controls, in that order. Our second aim was to describe, for the first time, some of the characteristics of the high-risk participants who became ill with schizophrenia.
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RESULTS |
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The updated results reported here concern 173 participants (from both the high-risk and the well control groups) with whom we remain in regular contact. Of these, 27 were members of the well control group, none of whom has developed schizophrenia. The high-risk group was divided into high risk without psychotic or possibly psychotic symptoms ever by July 2003 (n=66), high risk with psychotic or possibly psychotic symptoms by July 2003 (n=60) and high risk ill by July 2003 (n=20). Occasionally the high risk ill participants were classified as ill at their planned review, but as might be expected most developed schizophrenia between assessments and were admitted to a local service. Consultants in the areas from which these patients came were collaborators in the project. They and the high-risk participants themselves, and their families, knew that we wished to be informed of any deterioration. Through their cooperation we were able to obtain PSE ratings shortly after admission for treatment of the first psychotic episode for 18 of 20 participants. All those rated fulfilled the PSE CATEGO criteria for schizophrenia and paranoid psychoses and all 20 fulfilled ICD10 criteria for schizophrenia.
We were unable to obtain follow-up data on 10 (6%) of the high-risk group and 9 controls (25%).
Twenty-seven variables assessed at baseline met our criteria for initial inclusion set out above. Baseline scores for each of these were subjected to one-way analysis of variance (ANOVA) (with log transformations where warranted) within our sample of 173 participants divided as above. These ANOVAs were followed up by three planned comparisons:
Table 1 sets out these variables, indicates the earlier results that justified their inclusion and gives the mean values and the significance levels for the ANOVAs overall.
On this basis the Structural Interview for Schizotypy (SIS; Miller et al, 2002b) social withdrawal score, the SIS total score and the Rust Inventory of Schizotypal Cognitions (RISC; Miller et al, 2002c) distinguish the high-risk group who fall ill from high-risk subjects who do and do not develop psychotic symptoms. Although results of the Rey Auditory Verbal Learning Test (RAVLT) total are just significant (Table 1), it is the behavioural measures that clearly separate high-risk participants who will become ill from the other two high-risk groups. Statistically significant separation of those who will become ill from the controls is, however, additionally achieved on a number of psychological tests, on measures of childhood behaviour, on the developmental measures of ocular hypertelorism and dermatoglyphic variables, and on left thalamic volume.
Clinical significance
We then went on to consider the adequacy of the measures separating the
high-risk group who would become ill from the other two high-risk groups, for
predicting schizophrenia within the high-risk sample as a whole
(Table 2). Each scale is
dichotomised with the cut-off points determined by receiver operating
characteristic analyses (Table
2). Negative predictive power is generally greater than positive,
being as high as 97%, whereas the best positive predictive value is 50%.
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Characteristics of high-risk individuals who fell ill
Twelve men and eight women developed schizophrenia. At ascertainment their
mean age was 20.3 years (s.d.=2.20) for men and 19.6 years (s.d.=2.73) for
women. The mean ages at which they became ill were 22.8 years (s.d.=2.5) for
men and 22.8 years (s.d.=2.50) (women) and the mean length of time between
ascertainment and diagnosis of schizophrenia was 2.4 years (s.d.=1.9) for men
and 3.2 years (s.d.=0.9) for women. There was no significant gender difference
on these variables and no significant difference on age at ascertainment
between these individuals and the high-risk participants who did not become
ill: mean age at ascertainment 21.3 years (s.d.=3.0) for men and 21.4 years
(s.d.=3.0) for women.
According to our classification, at the time of entry (i.e. at baseline), 11 people who fell ill described having or having had some psychotic or possibly psychotic symptoms, and 9 who fell ill did not. Table 3 gives further details, dividing participants who subsequently fell ill according to their symptom status on entry. A preponderance of men who fell ill showed psychotic or possibly psychotic symptoms on entry, whereas the group without such symptoms contained mostly women. Those with such symptoms were older on entry than those without, and there was a slight tendency for those without such symptoms to have a higher proportion of ill parents or siblings.
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DISCUSSION |
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Issues of discrimination and numbers
The idea that people at high risk who will become ill can be clearly
distinguished from those who do not become ill is an oversimplification of
this situation. Psychopathological symptoms short of psychosis occurred in
many more members of the high-risk sample than were ever predicted to develop
schizophrenia. It is extremely unlikely that all the high-risk participants
who have shown psychotic or possibly psychotic symptoms at some stage will
actually develop schizophrenia. If this were to happen, the frequency of the
disorder would be greatly in excess of what is usually reported. Most of the
men, at least, have now passed through the period of highest risk. Moreover,
it has been repeatedly reported that the well-established gender differences
in age at onset of schizophrenia are much less in familial cases
(Hafner et al, 1999).
The Copenhagen High Risk Study (Parnas
et al, 1982; Cannon
et al, 1994), which was similar in design to our study,
identified children of women with a psychotic disorder when the children were
aged between 1019 years in 1962, and followed them up between 1972 and
1974 when they were about 25 years old
(Parnas et al, 1982)
and again between 1986 and 1989 when their mean age was 39 years
(Cannon et al, 1994);
the number of individuals with schizophrenia appeared to increase by four
(from 13 to 17) between the two reports. On the basis of the Copenhagen study
we would not expect more than a few more of our high-risk participants now to
develop schizophrenia. In terms of simple behavioural measures from the SIS
and RISC, the high-risk participants who have become ill
(Table 1) show obvious and
significant differences from those who have not become ill. However, it does
not seem likely that there is a clear separation between these two groups in
terms of developmental measures, as there seems to be a gradient of
impairment.
The strongest discriminators identified in our study between those who fell
ill and the other high-risk participants are found on the RISC and the SIS.
The 26 items of the RISC are designed to measure schizotypal cognitions rather
than overt psychotic symptoms (examples are I never use a lucky
charm and sometimes I get a weird feeling that I am not really
here). The SIS contains several scales, some of which directly measure
near-psychotic symptoms but most of which do not. The elements composing the
social withdrawal factor, which gives the strongest result, concern anxiety
and introversion rather than anything of a psychotic nature
(Miller et al,
2002b). However, the question is raised as to whether the
individuals who later suffered onset of schizophrenia were in the prodromal
phase of the illness on recruitment to the study. There is no easy answer.
Just over half of those who fell ill (Table
3) were in the psychotic or possibly psychotic
symptoms group on entry to the study and some of them progressed to
illness quite soon. Those who had psychotic or possibly psychotic symptoms
were older than those who did not. On the other hand, there was no difference
in the average time between recruitment and illness for those who did and did
not have symptoms on entry according to our classification; this average time
overall was 2 years. Furthermore, although there are indeed highly
significant differences on the RISC and the SIS between those who fell ill and
the other high-risk participants, there is also considerable overlap, i.e.
many of the high-risk group who did not fall ill were just as symptomatic on
entry as any of those who did.
Possible clinical applications
The data in Table 2 indicate
that in a sample of high genetic liability, we could use some of the measures
to successfully identify a group who are likely to remain well, and we could
also identify a group in whom the chance of development of schizophrenia was
50%, rather than the approximately 10% risk conveyed by their known familial
high risk. Although replication would be important before this is applied in
clinical practice, and the ethical issues would require careful consideration,
the SIS and the RISC are simple measures that could be widely employed, and it
is possible that this could be helpful for clinicians, parents and
individuals. The findings also have clear implications for the design of
genetic studies, as it is apparent that people at high risk who develop
schizophrenia closely resemble those who develop symptoms short of the
diagnosis. What appears to be inherited is a state of vulnerability rather
than psychosis per se. Other factors would seem to be involved in the
development of florid schizophrenia. Clearly, such findings could be used to
provide a guide to intervention strategies; however, they raise important
questions. Why do not all those with the vulnerability factors become ill?
What can be done to try to retain more individuals in a state in which florid
illness does not occur and functioning remains good, even though abnormalities
can be demonstrated on detailed investigation? Details of the progress of
symptoms in our high-risk sample over the years are the subject of a separate
paper (Owens et al,
2005). These individuals volunteer no complaints, most of them are
in work and, to the casual observer, they do not appear dysplastic or in any
way impaired and are apparently normal young people who for everyday purposes
function well. If they could be held at this stage, their apparent inheritance
of a state of vulnerability to schizophrenia need be no real disadvantage to
them.
Relationship to other research
It is appropriate to consider these findings in relation to the results of
studies that define individuals as being of high risk of schizophrenia on the
basis of symptomatic criteria (e.g.
Klosterkotter et al,
2001) or a combination of familial risk and symptomatic criteria
(Yung et al, 2003,
2004). Such individuals, in
contrast to those in our study, present seeking help for symptoms. Much higher
rates of transition to psychosis (not necessarily schizophrenia) were found
36% over 12 months in the Australian study
(Yung et al, 2004)
and 49.4% over 9.6 years in the Cologne study
(Klosterkotter et al,
2001) and the positive predictive value of certain
variables was greater than we have found here. In the help-seeking samples
described by Yung et al
(2004) and Klosterkotter
et al (2001) it is
evident that the presence of sub-threshold psychotic symptoms was associated
with the later development of psychotic illness, and the suggestion that such
symptoms merit active treatment is reasonably made. In members of our study
sample, who were not seeking care, it is evident that transient and partial
psychotic symptoms and psychotic-like experiences occur in many more people
than might be anticipated to develop schizophrenia. The filmed records of the
PSE interviews show that such symptoms often appear to have been associated
with little distress or functional impairment, and we know that they may be
short-lived and followed by years in which they do not occur at all.
What does this tell us about schizophrenia?
The central finding of our study is that it is the simple behavioural
measures of the SIS and the RISC that provide the best measure of
distinguishing high-risk individuals who will develop schizophrenia from those
who will not. None the less, there are a number of other distinguishing
measures (particularly in terms of neuropsychology) where highly significant
results are obtained, especially on measures of episodic memory. Impairments
in this task are suggestive of temporal lobe dysfunction. We know from the
serial studies in the EHRS that both memory function and temporal lobe volume,
as demonstrated by structural MRI, deteriorate with the passage of time
(Cosway et al, 2000;
Lawrie et al, 2002;
Job et al, 2003) in
those with psychotic or possibly psychotic symptoms. We consider that the
findings of the study as a whole are consistent with the view that
schizophrenia is primarily a disorder of temporal lobe structure and function
which develops slowly over several years. The exact nature of the change that
pushes an individual into psychosis is not clear at this point, but our
continuing studies, particularly of functional imaging, may reveal this.
Final comment
Although imaging is integral to the high-risk study as a whole and is
providing exciting findings, the central features that are presented here do
not depend on advanced technology. We suggest that this study shows that with
a clear hypothesis, a well-characterised sample and an appropriate design,
worthwhile new insights into a common and crippling disorder can be obtained
using simple clinical methods.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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Received for publication January 12, 2004. Revision received August 11, 2004. Accepted for publication August 26, 2004.