Section of Developmental Psychiatry, Division of Psychiatry, University of Nottingham, E Floor, South Block, Queen's Medical Centre, Nottingham NG7 2UH, UK.
Correspondence: Tel/fax: 0115 970 9946; e-mail: Chris.hollis{at}nottingham.ac.uk
Declaration of interest C.H. was funded by the Medical Research Council.
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ABSTRACT |
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Aims To examine the evidence for a specific association between premorbid impairment and child- and adolescent-onset schizophrenia, and whether specific continuities exist between premorbid impairments and psychotic symptom dimensions.
Method Retrospective case note study of 110 first-episode child- and adolescent-onset psychoses (age 10-17 years). DSMIIIR diagnoses derived from the OPCRIT algorithm showed 61 with schizophrenia (mean age 14.1 years) and 49 with other non-schizophrenic psychoses (mean age 14.7 years).
Results Premorbid social impairment was more common in early-onset schizophrenia than in other early-onset psychoses (OR 1.9, P=0.03). Overall, impaired premorbid development, enuresis and incontinence during psychosis were specifically associated with the negative psychotic symptom dimension.
Conclusions Premorbid social impairments are more marked in child-and adolescent-onset schizophrenia than in other psychoses. There appears to be developmental continuity from premorbid impairment to negative symptoms.
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INTRODUCTION |
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METHOD |
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The second stage involved a detailed chart review of the 196 screen-positive cases. The selection criterion was the unequivocal evidence of at least one psychotic symptom according to the Research Diagnostic Criteria (RDC) (Spitzer et al, 1978). Of these 196 cases, 23 had missing case notes or insufficient clinical detail to determine with confidence the presence or absence of psychotic symptoms; 58 were confirmed as non-psychotic after examination of the case records; and 5 had a diagnosis of autism in the absence of an RDC psychotic symptom. The remaining 110 cases constituted the child- and adolescent-onset psychosis sample for this study.
Measures
Clinical and demographic information was extracted from the patients'
medical records using a structured coding sheet specifically designed for the
study. The quality of case-note information recorded by Maudsley Hospital
psychiatry trainees was uniformly high and followed the guidelines on
obtaining and recording clinical information produced by the Maudsley Hospital
and Institute of Psychiatry (Goldberg,
2002). To minimise potential bias and to avoid inferential
impressions, items were rated only if the case notes contained explicit
positive statements concerning the patient's status.
Rating of psychopathology
Psychopathological characteristics were rated from medical records using
the Operational Criteria (OPCRIT) checklist for psychotic illness, version
3.31 (McGuffin et al,
1991). This comprises a checklist of 90 items constructed from
operational criteria for the major psychiatric classifications and a suite of
computer programs which allow psychopathological data to be entered, edited
and diagnoses to be generated according to each set of diagnostic criteria.
The OPCRIT system has been shown to have good reliability for DSM-III-R
diagnoses (American Psychiatric
Association, 1987) using the 90-item checklist (=0.73)
(Williams et al,
1996). The concurrent validity of OPCRIT DSM-III-R diagnoses has
been established with good to excellent agreement with consensus best-estimate
diagnoses (Craddock et al,
1996).
Other ratings during the first psychotic episode
Data were collected on psychotropic medication exposure and the occurrence
of urinary incontinence during the first psychotic episode.
Obstetric complications
Obstetric complications were recorded on the LewisMurray scale
(Lewis et al, 1989)
using a summary score of 0, absent; 1, equivocal; 2, definite.
Premorbid behaviour and development
Premorbid behaviour and development were recorded using three scales: the
General Developmental Scale, the Childhood Behaviour Scale and the Premorbid
Adjustment Scale. Ratings were made from patient case-note information.
Ratings required that clear behavioural descriptions or developmental data
existed in the records. In the case of discrepancies, positive
clear symptoms took precedence over negative statements, and symptoms recorded
at the time they were observed took precedence over those recollected. Not all
items could be completed for every patient. A decision was taken not to
prorate scores but to record data as missing if less than half of the items in
the scale were completed. Where doubt remained concerning the onset of
symptoms, ratings were always made for the highest level of
premorbid functioning.
General Developmental Scale. The General Developmental Scale (GDS) is a composite scale constructed specifically for this study, to record early childhood developmental delays and neurodevelopmental problems. Seven areas are assessed: motor milestones, language milestones, impaired social development, reading problems, neurodevelopmental problems, enuresis and encopresis (see Appendix for details of items and scoring).
Childhood Behaviour Scale. The Childhood Behaviour Scale (CBS) is a modified form of the Premorbid Schizoid and Schizotypal Scale described by Foerster et al (1991). It contains ten items covering the following areas: social isolation, social aloofness, separation or social anxiety, unusual stereotyped interests and preoccupations, deviant social communication or comprehension, quality of affect, suspiciousness and sensitivity, thought content and beliefs, deviant speech, and antisocial behaviour. In order to avoid rating prodromal symptoms, the premorbid period was defined as ending 1 year before the onset of psychotic symptoms. Where doubt remained about the onset of prodromal symptoms, the highest level of premorbid functioning was recorded (see Appendix for details of items and scoring).
Premorbid Adjustment Scale. In the Premorbid Adjustment Scale (PAS; Cannon-Spoor et al, 1982) premorbid was defined as the period ending 1 year before the onset of overt psychosis. In this study, the childhood to 11 years section of the PAS was completed. The original PAS uses a seven-point scale (0, normal; 6, severely impaired). In this study, scores were collapsed into three categories (0, normal/above average; 1, mild impairment; 2, severe impairment). Individual items were social withdrawal (as defined by avoidance of social interaction and social contexts), peer relationships, scholastic performance, social and behavioural adaptation to school, and interests or hobbies.
IQ measures
Scores of IQ based on the Wechsler Intelligence Scale for Children
Revised (WISCR; Wechsler,
1974) were available for 64 out of 110 (58%) of the baseline
sample.
Reliability of premorbid data
The premorbid measures (GDS, CBS and PAS) were constructed or modified
specifically for this study and were of unknown reliability. In a random
sample of 25 cases, information on premorbid development and behaviour were
extracted from the case notes and ratings made by a second experienced child
psychiatrist (Karmen Slaveska), who remained blind to psychopathological data
and diagnoses. For the three scales, the intraclass correlations (r)
were uniformly high: GDS, r=0.91 (95% CI 0.81-0.96); CBS,
r=0.91 (95% CI 0.81-0.96); PAS, r=0.97 (95% CI 0.94-0.99).
For all three measures, random and observer error accounted for less than 10%
of the observed variance in scores.
Analyses
Factor analysis
Twenty items were selected from the OPCRIT checklist, reflecting the main
psychotic and affective symptoms and signs (see
Table 2). Manic and depressive
symptoms were each entered as the sum of the individual items for mania and
depression. Of the items included, the median number of non-zero (0 indicating
absence of symptom or sign) items was 32.5% (range 12-84%). Initial unrotated
factors were extracted by principal components analysis. Factors with an
eigenvalue greater than 1 were then subjected to a varimax rotation. Finally,
regression factor scores were produced for each case and saved for further
analyses.
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Univariate analyses
Comparisons were made between schizophrenia and other psychoses.
Categorical data were analysed using a chi-squared test of significance and a
continuity (Yates') correction. Categorical rx2 tables with
ordered categories were analysed using the 2 test for linear
trend. Fisher's exact test was used when expected cell numbers were less than
5. For continuous variables, Student's t-test was used when
assumptions of normality and homogeneity were met; when these assumptions were
violated we used non-parametric tests such as the MannWhitney
U test (corrected for ties). All reported tests of significance are
two-sided.
Multivariate analyses
The strength of association between individual premorbid variables and
diagnostic status was assessed using logistic regression. Odds ratios were
adjusted for gender, social class, ethnicity and catchment-area status. The
strength of association between premorbid functioning and symptom dimensions
was assessed using multiple regression analysis. Continuous premorbid
variables (GDS, CBS, PAS items) were treated as dependent variables and
regressed onto the six symptom dimensions (regression factor scores) entered
simultaneously into the regression model. Premorbid variables (GDS and CBS)
were log transformed to remove skewness. Logistic regression was used to
assess the association between symptom dimensions and dichotomous
developmental variables found in Table
4, plus the variable urinary incontinence while
psychotic. Standardised regression coefficients (ß) and odds
ratios (OR) were adjusted for gender, social class and catchment-area
status.
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RESULTS |
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Psychotic symptom dimensions: factor analysis of OPCRIT items
Table 2 shows the frequency
and factor analysis of the 20 main OPCRIT psychopathology items. Six factors
had eigenvalues greater than 1, accounting for 60.3% of the total variance.
Regression factor scores for each dimension were approximately normally
distributed (mean of zero with unit standard deviation).
Premorbid functioning and diagnosis
Table 3 shows that DSM-III-R
schizophrenia was associated with higher (more deviant) scores on each of the
three premorbid scales.
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Table 4 presents the frequency of perinatal and developmental problems for schizophrenia and non-schizophrenic psychoses. Delays in the onset of urinary continence and broadly defined premorbid social impairments were significantly more common in DSM-III-R adolescent-onset schizophrenia. Delays in language milestones, reading and neurodevelopmental disorders were also more common in those with a diagnosis of schizophrenia, although none of these associations reached statistical significance at the 5% level. There was no difference between the diagnostic groups in the rates of obstetric complications, encopresis or delays in motor development.
IQ measures
Full-scale IQ was measured during the index assessment using the
WISCR on 37 out of 61 (61%) of the schizophrenia group and 27 out of 48
(56%) of those with non-schizophrenic psychoses. Full-scale IQ was
significantly lower in the schizophrenia group (mean 79.5, s.d. 14.6)
v. the non-schizophrenia group (mean 90.4, s.d. 17.9; t=2.7,
P=0.009). The IQ scores for both groups were distributed normally,
with no evidence for a low-IQ subgroup. For those with a diagnosis of
schizophrenia, 26 (70%) had IQ scores within the normal range (70-130); the
remainder fell into the category of mild mental retardation or
learning disability (50-69). Of those with non-schizophrenic psychosis, 25
(93%) fell within the normal 70-130 IQ range, with only 2 cases (7%) falling
into the category of mild learning disability (Fisher's exact test,
P=0.03).
Symptom dimensions and premorbid functioning
Table 5 shows the
associations (standardised regression coefficients and odds ratios) between
premorbid variables and symptom dimensions. The negative
syndrome was specifically associated with impaired premorbid
functioning (measured on the GDS, CBS and PAS), premorbid enuresis and urinary
incontinence during the psychotic episode. In contrast, both the
depression and mania symptom dimensions were
associated with relatively better premorbid functioning within the sample.
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DISCUSSION |
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Factor analysis revealed six psychotic symptom dimensions: negative symptoms; disorganisation; two positive symptom factors; mania; and depression. The negative symptom dimension was specifically associated with premorbid impairment. Both the manic and depressive symptom dimensions were associated with better premorbid functioning. Negative symptoms were specifically associated with enuresis (late onset of urinary continence) and the occurrence of urinary incontinence during the first psychotic episode.
Strengths and limitations of the methodology
The study is based on a large consecutive series of first-episode child-
and adolescent-onset psychoses collected over an 18-year period. The sample
design allows premorbid functioning to be contrasted between schizophrenia and
other early-onset psychotic disorders. It also allows symptom dimensions to be
examined across a broad range of psychoses rather than within a single
diagnostic group. The choice of a first-episode sample means that associations
between premorbid functioning and psychopathology are not confounded by
outcome. The quality of the case notes was high, with the majority containing
contemporaneous descriptions of child development and behaviour (e.g. school
and health reports) in addition to retrospective parental accounts obtained at
the index episode. The OPCRIT method of rating psychopathology is well suited
to case-note ratings and has been demonstrated to have good reliability and
validity. Data on premorbid functioning was collected blind to OPCRIT
diagnostic status, with high interrater reliability, suggesting that a
surprisingly high degree of precision was possible when rating these
high-quality case notes. Premorbid developmental and social functioning was
recorded and analysed as both composite scores and individual items, to reduce
the possibility of spurious chance associations with multiple comparisons.
There are several limitations in the study design. First, a single person made the case-note ratings of both premorbid functioning and psychopathology. This introduces the possibility of information bias i.e. premorbid ratings could have been influenced by knowledge of diagnosis and symptoms, or diagnostic ratings could have been influenced by premorbid data. The first possibility seems unlikely, as a second, independent, rater achieved a high level of agreement with the main rater when assessing premorbid functioning blind to both symptoms and diagnosis. Although the main rater was clearly aware of symptoms recorded in the case notes, neither rater knew the OPCRIT-derived DSM-III-R diagnosis when rating premorbid data. There was no difference between the diagnostic groups in the amount of case-note information available on premorbid development. Although the Maudsley case records were extremely detailed, the secondary rating of chart data collected by a large number of different examining psychiatrists is likely to have introduced considerable random error into the ratings. Given this caveat, the observed association between premorbid impairments and schizophrenia and the specific continuity with negative symptoms was impressive, and may in fact underestimate true effects. Second, the low incidence of child- and adolescent-onset psychoses necessitated retrospective case ascertainment and limited the available sample size. The sample size necessitated the grouping together of non-schizophrenic psychoses and provided limited power to detect small effects associated with individual developmental variables. Birth cohort studies identifying adult-onset psychoses have larger control groups and greater power to detect small effects of individual developmental variables (Jones et al, 1994; Cannon et al, 2002). Power was also reduced by the necessity of using categorical ratings of what are in reality continuous developmental variables. Finally, it seems unlikely that premorbid impairments identified in this study simply represent prodromal psychotic symptoms: first, the rating of the premorbid period was based on the highest level of functioning from early childhood, and second, the premorbid period excluded the 12 months prior to the onset of psychosis.
What do the results mean?
The results of this study suggest that the premorbid phenotype of child-
and adolescent-onset schizophrenia can be distinguished from other early-onset
psychoses by a higher rate of premorbid impairments, particularly affecting
the domains of social development and the onset of urinary continence.
However, in this study premorbid motor impairments and obstetric complications
fail to distinguish between schizophrenia and other early-onset psychoses. In
other words, impaired sociability (similar to concepts of
schizoid personality and schizotypy) may provide the clearest
distinction between the developmental phenotype of schizophrenia and
precursors of other psychoses. The occurrence of social and language
impairments in non-schizophrenic psychoses indicates that they are not
diagnosis-specific although the magnitude of the association seems to
be greater in schizophrenia. The evidence of a specific continuity between
premorbid impairments and negative symptoms suggests possible developmental
continuity at the level of symptom dimensions.
Several rather different mechanisms may underlie the association between developmental impairment and psychosis. First, general developmental delay, reflected in late milestones, low premorbid IQ and broad cognitive impairments, could reduce the threshold for the expression of all forms of psychosis in a non-specific way, with only the magnitude of effect being greater for schizophrenia. Hence, non-specific developmental delay could act as a continuous independent risk factor for a broad range of psychopathological outcomes, including psychosis. Second, impaired premorbid sociability may be a more direct expression of genetic vulnerability to schizophrenia. However, premorbid social impairment could be a developmental precursor of the negative symptom dimension rather than of schizophrenia per se. The links between negative symptoms, enuresis and urinary incontinence during psychotic episodes suggest that these symptoms might result from a common neural mechanism, possibly involving aspects of prefrontal cortical function.
The results in context
Previous studies have reported separately on the increased risks of
premorbid impairment in child- and adolescent-onset schizophrenia
(Asarnow et al, 1994;
Hollis, 1995;
Nicholson et al,
2000) and adolescent affective psychoses
(Sigurdsson et al,
1999). However, to date, no study has compared premorbid
functioning in different child- and adolescent-onset psychoses. This study
extends the findings of previous investigations with adult patients that
describe more marked premorbid social impairments in schizophrenia compared
with affective psychoses (Foerster et
al, 1991; Cannon et
al, 1997). However, unlike the reports of Foerster et
al (1991) and Done et
al (1994), in this study
the precursors of psychosis were independent of gender. These findings concur
with Nicholson et al
(2000), who reported that
premorbid impairments in childhood-onset schizophrenia are independent of
gender. The association described here between childhood-onset schizophrenia
and primary enuresis supports the findings of Done et al
(1991) from the 1958 British
birth cohort and Isohanni et al
(1998) from the North Finland
birth cohort, both studies finding an association between delayed onset of
urinary continence and later schizophrenia. The present study also found, in
agreement with Done et al
(1991), that the degree of
cognitive impairment was significantly greater in schizophrenia than in other
psychoses.
The underlying symptom dimensions reported in this study are similar to the pattern described by van Os et al (1996) in adult-onset first-episode psychosis. Few studies have examined symptom dimensions in child- and adolescent-onset psychoses (Maziade et al, 1996; Bunk et al, 1999). Unlike the study by Maziade et al (1996), the present study found a significant association between premorbid functioning and negative symptoms.
Clinical and research implications
The concept of a premorbid or longitudinal phenotype of schizophrenia
raises important questions about developmental mechanisms, as well as the
tantalising possibility of early detection and prevention of psychosis. First,
the premorbid phenotype of schizophrenia as currently conceived in terms of
impaired sociability and developmental impairments lacks both precision and
specificity. Not only does it overlap with premorbid impairments reported in
other psychoses, but also with the clinical features of childhood
developmental disorders such as developmental language disorder,
attention-deficit hyper-activity disorder and autistic spectrum disorders
(Hollis & Taylor, 1997).
Comparisons at the behavioural and neurocognitive levels between children at
high risk of schizophrenia and other developmental disorders
will be needed to identify more specific behavioural or neurocognitive
precursors of schizophrenia. Second, the viability of early detection and
screening depends crucially on whether treatment of the
pre-schizophrenic state can improve outcome. Clearly, much more
fine-grained behavioural and neurocognitive characterisation is required of
the prepsychotic developmental phenotype before screening or early detection
is feasible. It may be more fruitful to look for developmental and
neurocognitive continuities and prediction at the level of symptom dimensions
rather than diagnostic categories.
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Clinical Implications and Limitations |
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LIMITATIONS
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APPENDIX |
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Scoring
Items 1-5: 0, no/absent; 1, equivocal; 2, definite; 9, not known/missing
data.
Items 6-7: 0, no/absent; 1, present; 9, not known/missing data.
The total GDS score has a range from 0 to 12.
Childhood Behaviour Scale
This scale is a modified form of the Premorbid Schizoid and Schizotypal
Scale described by Foerster et al
(1991). Ratings are made for
the premorbid period, age 6-11 years. The premorbid period is defined as
ending 12 months before the onset of the first psychotic symptom. The scale
consists of the following ten items:
The total CBS score has a range from 0 to 20.
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ACKNOWLEDGMENTS |
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Received for publication June 6, 2000. Revision received July 15, 2002. Accepted for publication September 4, 2002.
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