Department of Social Medicine, University of Bristol
Division of Psychiatry, University of Bristol
Department of Epidemiology, Karolinska Institute, Stockholm, Sweden
Division of Psychiatry, University of Bristol
Department of Epidemiology, Karolinska Institute, Stockholm, Sweden
Correspondence: David Gunnell, Department of Social Medicine, University of Bristol, Canynge Hall, Whiteladies Road, Bristol BS8 2PR, UK. Tel: 0117 928 7253; fax: 0117 928 7204; e-mail: D.J.Gunnell{at}bristol.ac.uk
See editorial, pp.
276277, this issue.
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ABSTRACT |
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Aims To investigate whether this association is due to the influence of prenatal and early childhood exposures on both intellectual development and the risk of schizophrenia.
Method Cohort of 197 613 Swedish male conscripts with linked birth, census and hospital admission data together with five measures of verbal and non-verbal intellectual performance recorded at conscription.
Results 109 643 subjects had complete data; over a mean 5-year follow-up, 60 developed schizophrenia and 92 developed other non-affective psychoses. Poor scores for each of the five tests were associated with 3- to 14-fold increased risk of psychosis, particularly schizophrenia. Controlling for birth-related exposures, including birth weight, and parental education did not attenuate these associations.
Conclusions Poor intellectual performance at 18 years of age is associated with early-onset psychotic disorder. Associations do not appear to be confounded by prenatal adversity or childhood circumstances, as indexed by parental education.
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INTRODUCTION |
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METHOD |
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Record linkage
Information on the study sample was obtained from a linkage between the
Swedish medical birth registry, the military service conscription registry,
the population and housing censuses of 1970 and 1990 and the Swedish
in-patient discharge register (up to 31 December 1997). Hospital admissions
were coded using ICD-9 and, for more recent years, ICD-10.
Disease outcomes
We examined associations with all non-affective, non-drug-related psychoses
(ICD-9 295, 297-299; ICD-10 F20-F29). We categorised the participants into two
groups: those admitted with a diagnosis of schizophrenia (ICD-9 295; ICD-10
F20); and those admitted with a diagnosis of non-affective, non-schizophrenic
psychosis (ICD-9 297-9; ICD-10 F21-F29). Although the latter category included
those diagnosed using ICD-9 as having psychoses with origin specific to
childhood (ICD-9 code 299), only one subject fell into this category.
As this person was found to be well at the conscription medical and had no
record of previous psychiatric admissions, we included this subject among our
adult-onset psychoses.
To minimise misclassification of diagnosis, if subjects were admitted on more than one occasion, we used the latest diagnosis, assuming this to be the most accurate. The non-schizophrenic, non-affective group comprised patients with non-schizophrenic psychotic disorders not thought to be due to substance misuse or to be affective in origin. This group of diagnoses therefore included people who received a diagnosis of paranoid states or other non-organic psychoses; we excluded affective psychoses seeing that in ICD-9 this grouping also includes subjects with endogenous depression whose aetiology may be different. Although schizoaffective disorders are coded differently in ICD-10 (as F25) rather than within the schizophrenia (ICD-9 295) grouping in ICD-9, there were no cases of this disorder, coded using ICD-10, in our data-set.
Ethical approval for the study was obtained from the Karolinska Institute research ethics committee.
Risk factors investigated
As part of the conscription process each young man undergoes a standard
examination of physical health, intellectual capacity and psychological
function. The physical examination includes measures of height and weight. The
tests of intellectual function have been described in detail else-where
(David et al, 1997;
Jiang et al, 1999;
Otto, 1976;
Nilsson et al, 2001)
but complete information is unavailable as they are considered classified
military material. The fullest description is given by David et al
(1997). In brief, there are
four basic tests: technical/mechanical skills with mathematical/physics
problems; logic/general intelligence test; a verbal test detecting synonyms;
and a test of visuo-spatial/geometric perception. We included one further test
in this analysis: a test for the potential suitability of the conscript to be
an officer, the score for which was based on a loosely structured interview
with a psychologist.
Testing is carried out in six regional conscription centres. Central training and instruction of the psychologists who carry out the tests, and the use of a standard manual, help to ensure consistency (Nilsson et al, 2001). Results from the five tests are standardised against data from previous years to give each subject a score from 1 to 9 for each scale (David et al, 1997). Low scores indicate poor intellectual functioning.
We investigated the association of each of these measures of intellectual performance with subsequent hospital admission with a diagnosis of psychosis. These associations were examined in age-adjusted statistical models, in models with additional adjustment for growth in utero and in models with further adjustment for markers of adverse events at or after birth (see below).
We hypothesised that intellectually impaired subjects with well-educated parents would be at higher risk of developing psychosis, because such discordance might act as a marker of either impaired neurodevelopment, resulting from complications in utero and early childhood, or of stress arising from conflict between parental aspirations and offspring's intellectual potential (Eaton & Harrison, 2001). We therefore tested for interactions between cognitive function and parental education with regard to the risk of developing psychosis.
Statistical methods
All analyses were carried out in Stata version 6 for PC
(StataCorp, 1996). We used
Cox's proportional hazards models to assess the influence of the factors
listed above on the incidence of schizophrenic and non-affective
non-schizophrenic psychosis. Because of the low number of incident cases of
psychosis and our desire to assess whether associations with intellectual
function were linear, we grouped scores on the nine-point scale for each
measure into three categories (1-3, 4-6 and 7-9) and used those scoring 7-9
(highest ranking on each scale) as the reference category in our models. Tests
for linear and non-linear trends in the association between the test scores
and psychosis were, however, based on the nine-point scale.
In our initial models we examined associations with each intellectual
function scale adjusting only for age. In our subsequent models we controlled
for markers of in-utero and birth exposures. We first controlled for
markers of foetal growth, birth weight (<2500g, 2501-3000g, 3001-3500g,
3501-4000g and >4000g); birth length (as a continuous term); and
gestational age (36, 37-41 and
41 weeks). In our fully adjusted models
we assessed the effect of controlling additionally for: season of birth
(spring, summer, autumn, winter); Apgar score
(Apgar, 1953) at 1 min (
6
or 7+); maternal parity (1, 2 or 3+); Caesarean section birth; maternal age
(
20, 20-24, 25-29, 30-34, 35+ years); head circumference (20-31 cm,
32-34cm, 35-36cm, 37-55cm); uterine atony/prolonged labour; congenital
malformation; and parental education (both parents educated for more than 10
years/only one parent educated for more than 10 years/neither parent educated
for more than 10 years).
To test for non-linearity in the observed associations we added a term for
the explanatory variable squared (quadratic term) to models including a linear
term for this variable. Tests for interaction or non-linearity are based on
likelihood ratio tests comparing models with and without the relevant
explanatory variables. Subjects are censored at the time of first admission,
death or emigration. To investigate whether the associations with intellectual
functioning diminished with increasing duration of follow-up we divided the
follow-up time into two periods (2.9 years and >2.9 years), each
containing half the incident cases. Follow-up ended on 31 December 1997.
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RESULTS |
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The mean age at the time of conscription was 18.2 (range 16.6-21.7) years. Subjects were followed-up for a mean 5.04 (range 0.03-7.83) years after their conscription medical examination. Over this time 60 (0.06%) subjects developed schizophrenia and 92 (0.08%) developed non-affective, non-schizophrenic psychosis. The annual incidence rate of non-affective psychosis was estimated as 0.27 per 1000 person-years and of schizophrenia as 0.11 per 1000 person-years. The mean length of time between conscription examination and hospital admission was 2.78 (range 0.33-6.00) years for schizophrenia and 2.96 (range 0.22-5.92) years for other non-affective psychoses. For all five intellectual function tests, a greater proportion of those who developed psychosis had low scores (1-3) than those who did not (Table 1).
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Age-adjusted and multivariable models
Table 2 presents the
age-adjusted; birth weight-, birth length- and gestational age-adjusted; and
fully adjusted analyses of disease risk in relation to test scores. For
schizophrenia and non-affective non-schizophrenic psychosis, disease risk was
greatly (2- to 14-fold) increased in those scoring 1-3 in each of the tests
compared with those scoring 7-9. Risks were only marginally raised, or in some
cases lower, among those scoring 4-6 compared with those scoring 7-9. Tests
for non-linearity, using the continuous test scores, showed that for most
intellectual test scores the trends were consistent with supralinear increases
in risk with decreasing test results. There were two exceptions to this
general pattern: the association between the schizophrenia and (a) the logic
test, and (b) the test for the suitability for being an officer. Here the
trends were consistent with a linear increase in risk with decreasing test
scores.
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For all measures of intellectual functioning, associations were stronger in relation to schizophrenia. The strongest predictor of risk was the assessment of the subject's suitability for officer status, with a hazard ratio of 12.55 (95% CI 3.85-40.93) among those scoring 1-3 in age-adjusted models. Controlling for birth weight, birth length and gestational age had little effect on these associations.
In a separate analysis, we found a linear association between gestational age-adjusted birth weight and all five measures of intellectual functioning. For every 1000 g increase in birth weight, technical test scores increased by 0.21 (95% CI 0.19-0.23) units, logic scores by 0.22 (95% CI 0.20-0.25), synonym tests by 0.12 (95% CI 0.10-0.15), spatial scores by 0.24 (95% CI 0.22-0.27) and officer status scores by 0.14 (95% CI 0.12-0.16).
In the fully adjusted models, where we controlled for a range of markers for obstetric complications and parental education, disease risk was higher than in the simple age-adjusted models. Addition of the measure of parental education to these multivariable models led to this increased risk, whereas the other factors examined had little effect on the estimates of risk.
Effects of early disease on cognitive function
To assess whether intellectual function may have been affected by early,
pre-diagnostic disease processes (reverse causality) we investigated whether
the strength of the association with intellectual function varied in cases
diagnosed soon after conscription, compared with those admitted to hospital
several years later (Table 3).
For most of the tests examined, associations were some-what weaker in
later-onset than early-onset cases, although confidence intervals were
wide.
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Interactions with parental education
For only one of the test results (spatial perception) was there evidence
that the association with schizophrenia differed depending on parental
education (P for interaction=0.03)
(Table 4). Risk was greatest
among poorly functioning conscripts who had well-educated parents. The hazard
ratio for schizophrenia, based on only 16 cases, was 6.48 (2.53-16.53) in the
low-scoring (1-3) group with the best-educated parents, compared with those
with high intellectual test scores and well-educated parents. Although there
was a significant interaction for only one of the test results, inspection of
Table 4 shows that for all five
tests of intellectual functioning risk of schizophrenia was consistently
greater in the group of poorly functioning conscripts with well-educated
parents.
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There were no significant interactions between intellectual function and parental education with respect to other psychoses. Furthermore, inspection of the hazard ratios in relation to test results and parental education did not show any evidence that low-scoring offspring of well-educated parents were at greater risk than those of less-educated parents (data not shown).
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DISCUSSION |
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Study strengths
We used routinely recorded data on birth-related, parental and adult
exposures, collected before disease onset from a large group of young men from
Sweden. The availability of birth as well as adult measures allowed us to
investigate further the possible causal pathways suggested by David et
al in their analysis of an earlier-born conscript cohort
(David et al, 1997).
The range of test results available for analysis enabled us to determine
whether poor performance is restricted to a particular domain of cognitive
function. As case ascertainment was from a national inpatient register, the
possibility of selection bias was reduced, although it is feasible that
intellectual performance may influence the likelihood of admission.
Study limitations
Our case ascertainment was based on hospital-admitted cases only and used
diagnoses recorded on an administrative database. Studies in the UK, however,
indicate that even in areas with relatively community-oriented services, over
80% of cases are admitted within 3 years of presentation
(Sipos et al, 2001).
Furthermore, analyses of diagnoses recorded on the Swedish in-patient
discharge register indicate that schizophrenia is diagnosed with reasonable
accuracy (David et al,
1997).
Second, our analysis was based on men with illness onset in early adulthood. It is possible that associations seen in males with early-onset schizophrenia may differ from those seen in females and in people with late-onset schizophrenia.
Third, as family history of psychotic disorder was not available we were unable to control for its potential confounding effects in this analysis. It is possible, for example, that the intellectual development of children brought up in a household where one or both parents suffer from psychosis may be impaired. However, only 5-10% of cases are likely to have had an affected parent (Dalman et al, 1999; Mortensen et al, 1999), whereas 30-50% of cases had low scores on the tests of intellectual functioning, making this possible effect unlikely to fully explain the observed associations.
Comparison with other studies
In an earlier analysis of Swedish conscripts examined in 1969-70, linear
associations with IQ were reported which were equally strong in cases of
psychosis occurring soon after conscription and in those occurring 10 or more
years later (David et al,
1997). In our analysis, the associations were generally weaker in
later-onset cases. Similarly, in a cohort of Israeli conscripts followed-up
for 8 years there was some evidence that the strength of association of
measures of cognitive function and behaviour with schizophrenia diminished
over follow-up (Rabinowitz et al,
2000). However, in this Israeli cohort declines were seen for only
one of four measures of cognitive function (Raven's Progressive Matrices) and
one of four measures of behaviour (social functioning)
(Rabinowitz et al,
2000).
In keeping with the possibility that declines in cognitive function before disease onset explain the associations seen in the conscript cohorts described above, the British 1946 birth cohort and the National Collaborative Perinatal Project reported that associations with schizophrenia (Jones et al, 1994) and psychotic symptoms (Kremen et al, 1998) were stronger for cognitive function measures recorded nearer the time of diagnosis. Other studies, however, have reported no deterioration in intellectual function in subjects before development of schizophrenia (Cannon et al, 2000) and have found that non-affected siblings of children who go on to develop schizophrenia have similar deficits in cognitive function (Cannon et al, 2000), indicating a genetic or shared environmental influence on risk. David et al (1997) reported that the single test result most strongly related to risk of schizophrenia was mechanical knowledge (equivalent to the technical test in our analysis). Likewise, of the four specific tests we examined, the strongest associations were seen in relation to the technical test.
Parental education
Our results showed that the risk of schizophrenia was greatest among poorly
functioning conscripts who had well-educated parents. Eaton & Harrison
(2001) have proposed that the
early adult task of formulating a life plan is one of the most complex
cognitive activities a person will ever engage in
(Eaton & Harrison, 2001). Formulating a life plan involves psychological processes of aspiration,
interest and estimation of probability of success, in addition to selecting,
prioritising and balancing complex and subtly different future actions. The
complexity of these cognitive tasks, and the associated psychological strain,
are likely to be accentuated in low-performing children and low-performing
young adults whose parents have higher educational backgrounds and
expectations. Our findings were consistent with this speculation, and merit
replication in other studies.
There are three other possible explanations, however. First, the difference may reflect environmentally induced neuro-developmental insults, with the parents' educational levels indicating the individual's potential rather than actual performance. Second, highly educated parents may be more vigilant and more reactive to the early manifestations of disorder, leading to biased early-case detection. If this is so, the strength of our finding should diminish with longer follow-up of the cohort. Lastly, it is possible that children of more highly educated parents are likely to have higher cognitive function scores and so, in the prodromal stages of schizophrenia, more may move further down the scale of intellectual functioning. In contrast, children of less well-educated parents are more likely to have lower intellectual test scores, and to be in the lowest category for these tests already, and so may not change category to the same degree.
Possible mechanisms underlying observed associations
Our study suggests that pre- and perinatal exposures do not underlie the
association between poor intellectual performance and psychosis. This provides
some evidence against Weinberger's model of fixed lesions acquired in early
life interacting with later brain maturational processes to cause disease
(Weinberger, 1987). Other
factors, such as genetic predisposition or later environmental exposures, may
therefore be independently important. Such factors form part of recently
proposed two- and three-hit models of schizophrenia pathogenesis
(Pearlson, 2000;
Velakoulis et al,
2000) which suggest the importance of additive and interactive
effects of environmental risk factors against a background of genetic
predisposition. It has been suggested, for example, that insufficient synaptic
elimination, synaptic expansion and axonal sprouting in adolescence may be
important in schizophrenia aetiology
(Feinberg 1997); these
processes may be influenced by environmental as well as genetic factors.
The associations we found with intellectual function were not specific to any single test domain, indicating that they reflect global impairment. The strongest impairments previously seen in relation to schizophrenia are for interpersonal skills, speed of thought and executive planning skills (Jones et al, 1994; Diforio et al, 2000; Rabinowitz et al, 2000); these are likely to have been aggregated under the global assessment of suitability to be an officer.
The lack of consistent evidence of a doseresponse effect, together with the observation that associations were generally stronger among cases arising soon after examination, provide some evidence that pre-diagnostic pathophysiological processes may have led to the observed associations. This is consistent with the possibility that rather than being a risk factor for psychosis in its own right, poor test performance may arise as a result of early disease processes (reverse causality). Alternatively, more impaired individuals may succumb sooner to the challenges of independent adult life, so that the risk associated with impairment appears greatest for early-onset cases. Against such an argument is the consistent observation in the literature that the mean age of disease onset is later in females than in males, whereas females reach sexual maturity and independence at an earlier age than males (Eaton, 1988).
Long-term follow-up of this cohort will enable us to investigate some of the issues raised here. In particular, we will be able to determine the extent to which the observed associations with respect to subgroups are maintained in analyses with larger numbers of cases and later-onset cases. In this study poor intellectual functioning strongly predicted future risk of schizophrenia. For some tests over 50% of affected individuals but less than 20% of unaffected individuals scored 1-3, indicating the importance of gaining a greater understanding of the processes lying behind these associations.
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Clinical Implications and Limitations |
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LIMITATIONS
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Received for publication September 5, 2001. Revision received January 16, 2002. Accepted for publication January 17, 2002.
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