There is strong evidence that schizophrenia is a neurodevelopmental disorder. Changes in brain structure have been reported in numerous studies of schizophrenia (Keshavan et al, 2005). One focus of epidemiological studies has been the premorbid state and the definition of factors present during childhood or adolescence which might be associated with later onset of disease. This contrasts with the prodrome, which can be seen as comprising the early manifestations of the onset of disease.
Follow-back studies
It has long been recognised that people who develop schizophrenia may present as ‘odd’ in childhood (Bleuler, 1911). Follow-back studies, although susceptible to recall bias, do suggest a pattern of early abnormal development. Analysis of school reports of people with schizophrenia showed differences in childhood social behaviour (Watt, 1978) in a reconstructed cohort.
Weinberger et al(1980) reported that patients with schizophrenia and computed tomographic changes suggestive of brain atrophy had worse premorbid adjustment in childhood than those without such changes. Later studies by the same group resulted in the development of instruments assessing premorbid personality (Cannon-Spoor et al, 1982). Review of home videos suggested a higher frequency of abnormal neuromotor development in children who went on to develop schizophrenia compared with their siblings without schizophrenia (Walker, 1994).
High-risk populations
Other methods of examining the premorbid state include the use of high-risk populations defined according to family history, attenuated or brief psychotic symptoms and the use of birth cohorts.
Studies of the children of mothers with schizophrenia suggest that early development is frequently abnormal. Fish et al(1992) showed that 6 of 12 high-risk infants showed schizotypal or paranoid personality traits and 1 developed schizophrenia. They also described a pattern of abnormalities seen in the first 2 years of life as ‘pandysmaturation’. Studies have shown some evidence of persistently abnormal motor development in high-risk infants (Erlenmeyer-Kimling et al, 2000) and of a high frequency of soft neurological signs. Davalos et al(2004) demonstrated significant deficits in verbal skills, working memory and inhibition in children at high genetic risk of schizophrenia. Johnstone et al(2005) reported findings from the Edinburgh High Risk Study in which high-risk individuals who developed schizophrenia differed from those who did not on measures of social anxiety, withdrawal and other schizotypal features.
Cohort studies
Cohort studies are less susceptible to recall bias than follow-back studies. Adults with schizophrenia show a greater frequency of problematic social interactions in childhood and adolescence than adults without schizophrenia (Done et al, 1994; Crow et al, 1995; Malmberg et al, 1998). Studies suggest that children who later develop schizophrenia exhibit an increased frequency of speech and language problems, delayed motor milestones, poor motor skills and coordination, lower premorbid IQ, educational difficulties, social anxiety and preference for solitary play (Jones et al, 1994; Malmberg et al, 1998). Cannon et al(2000) found that patients with schizophrenia and their unaffected siblings demonstrated greater cognitive dysfunction during childhood than controls. These deficits in motor and cognitive domains, which are apparent early in life, are consistent with the neurodevelopmental model of schizophrenia.
Neurocognitive and neurophysiological markers
Studies of neurocognitive and neurophysiological markers as possible risk factors for schizophrenia have reported several associations. The deficits are also apparent in some asymptomatic biological relatives of people with schizophrenia (but rare in unrelated controls), which is consistent with Andreasen’s concept of cognitive dysmetria (Andreasen, 1999). They include deficits in sustained attention, event-related brain potentials and saccadic eye movement control. If these reports are replicated in studies with greater power, they could have significant implications for risk prediction.
Monozygotic twins who develop schizophrenia have been reported to have an increased frequency of minor physical abnormalities compared with their non-affected twins, suggesting that abnormalities are present during fetal development (Bracha et al, 1991). Abnormal development may be genetically determined in some instances, but in others will be due to chance events. However, abnormal development does not in itself guarantee the later development of schizophrenia. Random environmental insults (such as birth trauma, infection or Malnutrition) may subsequently act to increase the risk of later development of schizophrenia. Epigenetic mechanisms such as DNA methylation might also play a role.
Such a model, with neurodevelopmental abnormalities providing a substrate on which schizophrenia can occur, would help to explain the concordance rates observed in monozygotic twins, the clinical heterogeneity of schizophrenia and the different phenotypic expression of underlying genetic vulnerability within families. Furthermore, longitudinal imaging studies suggest that anatomical changes occur in the early stages of schizophrenia, which indicates that later neurodevelopmental influences may also be involved in the genesis of the disorder.
Neuroplasticity
There has been recent interest in the possible contribution of neuroplasticity (Frost et al, 2004). Neuroplasticity phenomena result in change in neural structure and function; they are involved in normal brain development and also operate in disease. This approach may help to explain the heterogeneity of schizophrenia (in all domains, including clinical phenotype, treatment response and outcome). The development of different illness phenotypes (which might not require active psychosis) may help to refine our understanding of the neurobiology of the schizophrenia spectrum and allow the development of novel treatment approaches.
Box 4 Non-specific neurodevelopmental precursors of schizophrenia
* Abnormal neuromotor development
* Delayed developmental milestones
* Soft neurological signs
* Neurocognitive deficits (verbal skills, attention, information processing)
* Neurophysiological abnormalities (event-related brain potentials, saccadic eye movement control)
* Poor social adjustment and school performance
Relationship to age at onset
People who develop schizophrenia therefore tend to exhibit a range of often subtle developmental abnormalities, consistent with the neurodevelopmental model of schizophrenia. It is important to note that these risk factors are non-specific (Box 4Go) and their use in predicting the development of schizophrenia is therefore extremely limited at present.
The presence of the risk factors detailed above appears to have some correlation with age at onset of schizophrenia. Age at onset tends to be younger in individuals at a high genetic risk for schizophrenia. Obstetric complications and impaired cognitive functioning may also be associated with earlier disease onset (Verdoux et al, 1997; Tuulio-Henriksson et al, 2004). Similarly a family history of schizophrenia, obstetric complications, low premorbid IQ and ongoing drug misuse all tend to be associated with poorer outcomes.
References
American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders (4th edn). APA.
Andreasen, N. C. (1999) A unitary model of schizophrenia: Bleuler’s “fragmented phrene” as schizencephaly. Archives of General Psychiatry, 56, 781–787.
Asarnow, J. R., Tompson, M. C. & Goldstein, M. J. (1994) Outcome in childhood-onset schizophrenia-spectrum disorders. Schizophrenia Bulletin, 20, 599–617.
Asarnow, J. R., Tompson, M. C. & McGrath, E. P. (2004) Childhood-onset schizophrenia: clinical issues. Journal of Child Psychology and Psychiatry, 45, 180–194.
Bellgrove, M. A, Collinson, S., Mattingley, J. B., et al (2004) Attenuation of perceptual asymmetries in patients with early-onset schizophrenia: evidence in favour of reduced hemispheric differentiation in schizophrenia? Laterality, 9, 79–91.
Berry, N., Jobanputra, V. & Pal, H. (2003) Molecular genetics of schizophrenia: a critical review. Journal of Psychiatry and Neuroscience, 28, 415–429.
Birchwood, M., Todd, P. & Jackson, C. (1998) Early intervention in psychosis. The critical period hypothesis. British Journal of Psychiatry (suppl. 33), 172, 53–59.
Bleuler, E. (1911) Dementia Praecox or the Group of Schizophrenias. Reprinted 1950. International University Press.
Bracha, H. S., Torrey, E. F., Bigelow, L. B., et al (1991) Subtle signs of prenatal maldevelopment of the hand ectoderm in schizophrenia: a preliminary monozygotic twin study. Biological Psychiatry, 30, 719–725.
Eric J. Davies
Eric Davies is Consultant Child and Adolescent Psychiatrist working with the 5 Boroughs Partnership NHS Trust (The Elms, 50 Cowley Hill Lane, St Helens, Merseyside WA10 2AW, UK. Email: eric.davies2@5bp.nhs.uk). He trained at the University of Manchester, where he also completed a PhD on factors related to genetic susceptibility in systemic lupus erythematosus. He has a particular interest in the genetics of schizophrenia and is an Honorary Research Fellow in the Division of Psychiatry at the University of Manchester.
