Division of Psychiatry, University of Edinburgh
Correspondence: D.G.Cunningham Owens, University of Edinburgh, Division of Psychiatry, Kennedy Tower, Royal Edinburgh Hospital, Morningside Terrace, Edinburgh EH10 5HF, UK.Tel: 0131 537 6267; fax: 0131 537 6291; e-mail: david.owens{at}ed.ac.uk
Declaration of interest None. Funding detailed in Acknowlegements.
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ABSTRACT |
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Aims To compare pre-illness symptomatology in patients at high risk of schizophrenia who progress to illness with that of high-risk subjects who remain well and with normal controls.
Method Using Present State Examination (PSE) data, symptomatic scales were devised from participants of the Northwick Park Study of first-episode schizophrenia and scores were compared on the first and last PSEs of participants of the Edinburgh High Risk Study.
Results At entry, when still well, high-risk individuals who subsequently became ill (mean time to diagnosis 929 days; s.e.=138 days) scored significantly higher onsituational anxiety, nervous tension, depression, changed perceptionand hallucinationsthan those remaining well and normal controls, who did not differ. With illness onset, affective symptomatology remained high but essentially stable.
Conclusions In genetically predisposed individuals, affective and perceptual disorders are prominent before any behavioural or subjective change that usually characterises the shift to schizophrenic prodrome or active illness.
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INTRODUCTION |
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Background
There are three strands to the literature on pre-illness features
associated with schizophrenia. First, it has been well established that in
childhood and the years before evidence of schizophrenia emerges, individuals
differ from normal controls on a range of measures, including psychological
test performance and patterns of behaviour
(Baum & Walker, 1995;
Jones, 1997). Such findings
frequently are regarded as evidence that schizophrenia is a disorder of
neuro-development that arises early but in some way is compensated until the
typical age of clinical onset in young adulthood
(Murray & Lewis, 1987;
Weinberger, 1987). Second,
using retrospective patient and third-party accounts, it has been shown that
psychopathology of various kinds can precede the emergence of diagnosable
illness by months or years (Chapman,
1966; Hafner et al,
1995). Some authors have concluded that the psychotic shift is
driven by affective change, either anxiety or depression
(Birchwood & Iqbal, 1998; Garety et al, 2001),
whereas others have concluded that affective change itself is consequent upon
disturbances in either cognition or perception
(Chapman, 1966), something that
would be difficult to determine with even detailed retrospective techniques.
Third, greater emphasis has been given recently to minor psychotic or
psychotic-like phenomena such as referential ideas, perceptual disturbances
and magical thinking, in an attempt to determine the point at which early
treatment, especially with antipsychotic drugs, would be appropriate
(McGlashan & Johannessen,
1996; McGorry,
1998; McGorry et al,
2002; Woods et al,
2003).
Although the onset of schizophrenia can be very acute, it is often more gradual and the point at which symptomatology could be regarded as predictive or prodromal, rather than representative of the early features of illness itself, is often far from clear (Beiser et al, 1993). Prospective population-based studies utilising the controlled and masked assessment of prepsychotic states would be impractical, but the possibility of such assessment has arisen within the context of the Edinburgh High Risk Study of schizophrenia.
The purpose of the present study is to relate initial symptomatic assessments of the high-risk participants and controls to those characteristic of patients already ill with a first episode of schizophrenia, with a view to considering whether non-psychotic symptoms are secondary to developing psychosis and to define the characteristics of the pre-illness state in high-risk individuals who eventually progress to an acute schizophrenic illness.
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METHOD |
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The first-episode controls were seen only once, at the point of their initial assessment, but the high-risk participants and the well controls were seen every 18 months and assessed in psychopathological, neuropsychological and imaging terms (Johnstone et al, 2005).
The instrument chosen for assessing the presence of psychopathology was the 9th edition of the Present State Examination (PSE; Wing et al, 1974), conducted at entry and at each follow-up. This had been chosen because of its reliability in providing a standardised diagnosis that would be used, along with ICD10 (World Health Organization, 1993), to classify those high-risk individuals who developed a formal schizophrenic illness and who thereby had reached the end of their participation in the study. The PSE is a very detailed instrument giving a standardised assessment of a wide range of symptomatology and therefore would be helpful in evaluating the extent of any psychopathology shown by the high-risk participants and controls.
When the study was designed, it had been predicted that those destined to develop schizophrenia would show a range of prodromal symptoms, which were likely initially to be non-specific in nature but would be followed by the emergence of referential ideas, magical thinking, etc., as much of the recent literature has suggested. It had been anticipated that those who were not going to develop schizophrenia within the study period would be little different from the normal controls, with both groups showing some non-psychotic symptomatology.
These predictions were not altogether borne out. Clinical symptoms of all kinds occurred in high-risk participants and controls but all were more marked in the high-risk individuals, in whom symptoms increased with the passage of time. Possibly psychotic phenomena such as referential ideation and magical thinking occurred in many more of the high-risk individuals than were ever anticipated to develop schizophrenia and considerable degrees of anxiety and depression were found in the high-risk sample at the outset, long before those individuals had developed psychotic features. The CATEGO diagnostic programme (for the PSE) was not helpful in the assessment of this because it does not give emphasis to non-psychotic symptomatology not scoring as severe.
At the outset, when designing the study, we were conscious of the need to limit the number of assessments in order not to over-burden the participants and thereby reduce the likelihood of their persisting in the programme. In retrospect, we regret that no well-established psychopathological rating scale sensitive to change, such as the Positive and Negative Syndrome Scale (PANSS; Kay et al, 1987), was included in the design. In view of the findings that the study has produced, it seems important, however, to attempt to unlock some of the trends that the data suggest. Consequently, we sought to develop a rating scale from the PSE using data from a large alternative sample to which we had access. This comprised the admission PSEs of the 229 individuals assessed for the Northwick Park Study of first episodes of schizophrenia (Crow et al, 1986; Johnstone et al, 1986) who received a diagnosis of schizophrenia. These assessments were conducted within 2 weeks of admission for a first psychotic illness and often were done within the first week, before antipsychotic treatment had been instituted.
From this data-set we derived 12 severity scales rating situational anxiety, nervous tension, depression, mania, overactivity, disorganisation, changed perception, hallucinations, disorder of possession of thought, delusional construction, outside control and negative symptoms. The derivation and details of these scales are shown in the Appendix. Comparing the scores derived from patients with an already established first episode of schizophrenia (and hence exhibiting those features inherently part of the acute syndrome) with those of the participants of the Edinburgh High Risk Study at entry and over time, we were able to provide an analysis of baseline phenomena and their evolution, with an attempt to identify those that may be harbingers of illness.
Analysis
The PSE data on participants entering the Edinburgh High Risk Study were
available at entry on 175 individuals, divided into 127 high-risk participants
who remained well through follow-up, 21 who developed a first formal
schizophrenic illness (i.e. high-risk ill participants) and 27 normal
controls. One-way analyses of variance (ANOVAs) were run, comparing these
three groups and the Northwick Park first-episode patients on all the
log-transformed symptom scales. Follow-up planned comparisons, not assuming
equal variances, compared the 21 high-risk ill participants with the other
Edinburgh High Risk Study groups and also to the Northwick Park patients.
Non-parametric KruskalWallis tests also were run and in all cases they
confirmed the overall parametric findings. Possible gender effects were
examined, using 2-tests to assess group composition and
two-way ANOVAs to search for interaction effects. A separate comparison was
made of the Northwick Park patients with high-risk participants who fell ill
and were assessed at the time of illness onset. A second analysis
examined changes in symptoms between the first and last assessments for the
Edinburgh High Risk Study participants. This was attempted using
repeated-measure ANOVAs, with group (high-risk ill, high-risk well and
control) as a between-participants variable.
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RESULTS |
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In the last two columns of Table 1, high-risk participants who fell ill are compared at the time of their illness with the Northwick Park patients. The mean scores of the high-risk group are now similar to those of the Northwick Park patients. Only two significant differences remain: on situational anxiety the high-risk participants scores are higher and on delusional construction they are lower than the Northwick Park patients.
The groups were similar in gender composition (controls, 40.7% female;
high-risk well, 53.5%; high-risk fell ill, 42.9%; Northwick Park, 41.4%;
2=5.1, NS). No significant interactions between gender and
group were discovered on any of the scales.
Scores were calculated for each group from their entry PSE and the last PSE conducted. Because the high-risk sample was drawn from all over Scotland, formal PSEs were available only at illness onset on 19 of those who became unwell. Results are shown in Fig. 1. As would be anticipated, psychotic symptomatology covered by disorganisation, hallucinations, disorder of possession of thought, delusional construction and outside control increased significantly in those who became formally ill, as did negative features (time, group and interaction terms all significant, P<0.001), and significant deterioration also was evident in changed perception. No significant changes occurred in the other participant groups, who continued to hold to low and stable symptomatic levels. On the other hand, situational anxiety, nervous tension and depression remained high in those who fell ill, significantly more so than in the controls and high-risk participants remaining well.
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DISCUSSION |
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The PSE is an extensive instrument comprising 140 elicited and observed
mental state phenomena, most of which are recorded as continuous variables
along a range of absent/mild/severe,
and it proved a relatively straightforward matter to construct the 12 scales
with high coefficients (see below and Appendix). In many ways they are
similar to other measures of mental state and would be expected to be
reliable, valid, sensitive to change and inclusive. The PANSS now has been
incorporated into the study and the new PSE scales will be compared with these
ratings at completion.
The 12 scales were derived from one of the largest samples of patients with first-episode schizophrenia to which the PSE was applied on admission (i.e. the North-wick Park sample). These patients were early in the course of their florid illness and for the most part only briefly exposed or not exposed at all to psychotropic medications. Because the PSE applies to the previous 4 weeks, it is unlikely that medication or other factors relating to admission significantly altered the ratings in this sample, which may be taken as generally representative of the illness in its acute state. This sample was preferable to the first-episode patients participating in the Edinburgh High Risk Study, in view of its much larger size and the fact that the Edinburgh patients mainly had been exposed to significant antipsychotic drug treatment, sometimes for months, by the time their PSEs were conducted.
The concept of schizophrenia has not changed radically in the 20 years separating the two studies, and the PSE remains a valid instrument. However, different raters were involved in the two studies, raising the question of reliability. Both E.C.J. and D.G.C.O. conducted PSEs in both studies and did the great majority in the second phase of the Edinburgh High Risk Study. In addition, for many years they ran a PSE training course, the first such course to be approved outside the Institute of Psychiatry. Research colleagues all received their clinical training in the same institutions as those in which the principal authors worked a factor known to improve reliability (Kendell, 1975) and in addition underwent similar PSE training.
Thus, notwithstanding its limitations, we believe that the material presented here is reliable and valid.
Pre-illness symptomatology
This study shows that high levels of non-specific, affective symptoms are
evident in patients with first-episode schizophrenia substantially before the
onset of psychosis and that these separate those high-risk individuals
destined to develop schizophrenia from the other high-risk individuals who
remain well. These non-specific abnormalities remain essentially stable over
time (and in most instances by time we mean more than 2 years),
both in those who progress to illness and in those remaining well, despite a
non-significant tendency for situational anxiety to diminish and
depression to exacerbate in those who progress to illness. These
results suggest that such non-specific affective symptomatology is not merely
secondary to emerging psychosis but is more fundamental to the illness process
that it antedates. Furthermore, entry scores comprising situational
anxiety were significantly higher in those destined to progress to
psychosis than in the sample who had been diagnosed with a first episode of
schizophrenia (the North-wick Park sample), supporting the view that
anxiety-type phenomena may partially remit as psychotic features escalate.
Although this study cannot address the question of whether a greater risk
accrues from anxiety (Garety et
al, 2001; Turnbull &
Bebbington, 2001) or depression
(Birchwood & Iqbal, 1998), a key role for anxiety is in keeping with other results from the Edinburgh
High Risk Study, in which the best predictors of illness from mothers
accounts recorded on the Childhood Behaviour Checklist
(Achenbach et al,
1991) were withdrawn and deviant behaviour, which includes anxiety
and depression (Miller et al,
2002). Using different measures, participants in the Israeli
high-risk study who subsequently progressed to a schizophrenic-spectrum
diagnosis were found to have had higher pre-illness levels of anxiety assessed
at age 16 years (Kugelmass et al,
1995). Thus, anxiety phenomena may be an inherent part of the
pathophysiological process mediating the schizophrenic syndrome.
The more specific symptomatology associated with pre-illness states relates to perceptual abnormalities and comprises both distortions and deceptions. Although changed perception and hallucinations were found in normal controls and high-risk participants who remained well, hallucinations in particular were infrequent but were more evident at entry in those who progressed to illness. Abnormalities of thought form and content did not differ significantly between the groups at entry. Group scores were very low and these features were found only in those destined to become ill. Together they comprised the major changes associated with formal illness development.
Premorbid or prodromal?
In the high-risk population, the mean time to illness onset was 929 days
(s.e.=138). Because it has been reported that prodromal symptomatology can be
present for many years prior to formal diagnosis
(Hafner et al, 1999),
this raises the question of what type of phenomenology the high-risk
participants who fell ill were exhibiting at entry premorbid or
prodromal.
Interest in the pre-diagnostic phenomena associated with schizophrenia is long-standing but has increased markedly in recent years. Based on the wish to introduce earlier treatment that may have a favourable impact on outcome, attempts have increased to delineate the prodromal phase of illness from both its premorbid characteristics and the features of the florid first psychotic episode. There is a wealth of evidence that schizophrenia is associated with a wide range of premorbid deviations evident in a series of behavioural, neuro-psychological and even brain structural domains observations confirmed in the Edinburgh High Risk Study sample (Lawrie et al, 1999; Cosway et al, 2000). These are essentially stable characteristics that do not necessarily result in disadvantage and are certainly not viewed as clinical phenomena. What is less clear is how the illness prodrome (representing the first shift from the premorbid state towards illness) should be conceived: what features it comprises, how it evolves and where its break points lie between normality and illness. This is an increasingly important question because present conceptualisations of prodrome, essentially derived from retrospective methodologies, have led to the advocacy of early treatment interventions with antipsychotic drugs, often in very young individuals. A significant impact on progression to psychosis has yet to be reported extensively (e.g. McGorry et al, 2002) and it remains unclear that very early interventions do result in better long-term outcomes.
A major problem is the definition of prodrome in the context of schizophrenia, which of necessity is a retrospective concept (Yung & McGorry, 1996; Cornblatt et al, 2001), whose constructs have arisen largely on the basis of interviews with patients already diagnosed and, in more recent work, with their families, supplemented with reference to medical records. Although this methodology may produce systems of assessment that are reliable (Hafner et al, 1999), the sources of bias continue to challenge their validity. Using these methods, current views of the contents of the prodrome do include a prominent place for non-specific symptomatology, including affective features, as reported here.
Chapman, on the basis of patient interviews conducted within 3 years of a first episode, found intense anxiety to be almost invariable and also that perceptual disorders were common, something he placed in a key role in his theory on the origins of florid symptomatology (Chapman, 1966). This also would be compatible with our finding that, on entry, those who eventually became unwell demonstrated higher levels of perceptual abnormalities than the other two Edinburgh High Risk Study groups.
Thus, on this evidence, our high-risk sample destined for illness may indeed have been prodromal at entry. However, no matter how the schizophrenic prodrome is conceptualised, some element of change from a previous state (essentially behavioural, but also subjective) is inherent to the concept (Keith & Matthews, 1991; Hafner et al, 1992; Loebel et al, 1992; Beiser et al, 1993; Yung & McGorry, 1996; Cornblatt et al, 2001). This key criterion did not apply to the participants of the Edinburgh High Risk Study, who were selected specifically on the basis of being well at entry, in both their own and their families eyes. Because these individuals came from families in which at least two members were already affected with schizophrenia, we take this information, especially that from family sources, as sound.
This might suggest that change need not be an inherent part of the schizophrenic prodrome, which if true would make the concept more arbitrary and difficult to pin down clinically than is currently believed. An alternative proposal might be that high levels of affectivity and perceptual aberration can, in a stable behavioural context, represent part of the premorbid state, perhaps the result of a gradual process of adaptation to underlying cognitive deficits.
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APPENDIX |
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The PSE is set out in 20 sections: 17 sections comprising symptomatology elicited by formal questioning; and 3 sections for recording mental state features observed during interview. Within these sections most of the items are rated on one of three anchor points, from absent to severe.
The scales were constructed in four stages.
Stage 1
The starting point lay in six broader groupings of the original 20
sections, corresponding to anxiety, depression,
manic reaction, perceptual disorder,
delusions and negative symptoms, as follows:
Stage 2
In order to determine how many scales could be derived reasonably from
these six groups, an initial principal components analysis, using the scree
test, was carried out on the items within each group. On the basis of these
analyses:
Stage 3
Cronbachs coefficients were calculated for each of the 12
scales and adjustments were made to improve these, where possible, by deleting
some items, moving others and including a few that had not been included
previously.
Stage 4
Cronbachs coefficients for each of the 12 scales were
reassessed in a mixed sample of patients comprising 26 with first-episode
schizophrenia in hospitals local to Edinburgh in 1994, 19 high-risk patients
who fell ill (assessed at the time of their illness) and 98 patients from
Northwick Park with psychoses not classified as schizophrenia.
The details of the final scales derived are set out in Table A1.
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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 February 11, 2004. Revision received September 23, 2004. Accepted for publication September 30, 2004.