The Aetiology of Schizophrenia

Sherine Thomas

« Psychiatry

Schizophrenia - a review by Dr Ben Green

Introduction

Schizophrenia is a severely debilitating neuropsychiatric disorder characterised by ‘disturbances of thought, auditory hallucinations and multiple delusions’ (1). At times, people with schizophrenia have an accurate view of reality and function well in daily life, and at other times, they lose touch with reality, and are not able to care for themselves in even the most basic ways.

Estimates of prevalence of schizophrenia in different countries range from 0.2-2.0%. Geographical comparisons of the prevalence of schizophrenia show differences between countries. These differences may be due to the different definitions of schizophrenia that have been used. An average incidence rate of 28.1/100,000 per year has been estimated from past studies, and it appears to be fairly stable across a wide range of cultures, climates and ethnic groups. Studies of lifetime risk of schizophrenia estimate a risk of less than 1% (3).

The symptoms and prevalence of schizophrenia are very similar across many different cultures, so it is thought that biological factors strongly influence the development of schizophrenia. There is a lot of evidence to suggest that schizophrenia is genetically transmitted although, genetics do not explain who will get the disorder. There is also a lot of evidence of structural and functional abnormalities in the brains of people with schizophrenia.

A Medline search was carried out in order to find all the recent and relevant articles on the possible biological aetiology of schizophrenia.

Genetic Contribution to Schizophenia

What is the genetic evidence?

Family, twin and adoption studies have suggested that genetics play a major role in the transmission of schizophrenia. Irwing Gottesman compiled over 40 studies in order to work out the risks of developing schizophrenia, of people with different familial relationships to the schizophrenic person.

Two classes of relatives have especially high risks of developing schizophrenia. These are the offspring of two schizophrenic parents and a monozygotic (MZ) co-twin of a schizophrenic. Apparently, people who share the greatest number of genes with the people who have schizophrenia, have an increased risk of developing schizophrenia themselves.

Gottesman and Shields reviewed the results of 5 twin studies looking for concordance rates for schizophrenia (4). It was found that in MZ twins there was a concordance rate of 35-58% compared with dizygotic (DZ) twin rates that ranged from 9-26%. They also found a concordance rate in MZ twins of 75-91% when the sample was restricted to the most severe form of schizophrenia (5). The milder forms of schizophrenia had concordance rates of 17-33% suggesting that there may be greater genetic loading with severe forms of schizophrenia. The twin studies have all assumed that the shared environmental effects for MZ and DZ twins are equal which may be incorrect.

Environmental factors could influence the development of schizophrenia but, adoption studies support the genetic theory of transmission. In 1994, a study looked at schizophrenia in the biological and adoptive relatives of schizophrenic adoptees, and compared this to a demographically matched group of control adoptees (6). In the sample of adoptees with chronic schizophrenia, the disorder was found exclusively in their biological relatives and not their adoptive relatives. The prevalence of the disorder was 10 times higher in the biological relatives of the schizophrenic adoptees than in the biological relatives of the control group. These studies make a clear case for the involvement of genetics in schizophrenia.

Modes of Transmission.

Since the concordance rate among MZ twins is not 100% and people can apparently carry the genotype for schizophrenia without ever developing the disease, there probably is not a single dominant gene for schizophrenia.

One model of transmission that has been suggested is the single gene model with incomplete penetrance. Penetrance is the probability of manifesting a trait given a particular genotype e.g. penetrance is either 1 or 0 for dominant or recessive traits(7).

Another model of transmission is the polygenic model which suggests that the ‘liability to develop the disorder’ is continuously distributed within the population (8). Only those individuals whose liability exceeds a certain threshold show symptoms of the disorder. This model is appealing because it could explain why concordance in twins increases with severity of illness and why the risk of schizophrenia increases with the number of relatives affected. Resolving the mode of inheritance of schizophrenia is complicated. Studies using genetic models have not been able to exclude either the single gene or polygenic models. This is most probably due to the problems in defining the schizophrenic phenotype.

Schizophrenia Loci.

Genetic marker studies can greatly improve the prospect of detecting a major gene effect. A study published in 1998, conducted a genome wide search for evidence of loci linked to schizophrenia (1). Genetic maps were constructed for each chromosome using genotype data. The genome wide search did not find evidence for a major genetic loci for schizophrenia but, it did find 12 chromosomes that had one statistically significant region at a 5% level (1, 2, 4, 5, 8, 10, 11, 12, 13, 14, 16 and 22) and 2 of these chromosomes had statistical significance to a 1% level (13 and 16).

From these results, it seems unlikely that one major locus exists for schizophrenia. It could be that schizophrenia belongs to a class of complex disorders that have a genetic predisposition. This could be due to more than one gene that could produce illnesses independently in different families or, genes that act together to cause illnesses in susceptible people. Only 70 families were used in this study which is a small sample size so more studies looking for schizophrenia susceptibility loci are needed.

Neuropathology of Schizophrenia.

It is believed that there is something different about the workings of the brain in people with schizophrenia. It is only since the introduction of positron emission tomography (PET scans), computer axial tomography (CT scans) and magnetic resonance imaging (MRI), that the structure and function of the brain has been examined in detail. A number of brain-imaging and post-mortem studies have shown that abnormal brain morphology and physiology appear to be involved in the development of schizophrenia.

Limbic system.

Limbic and paralimbic regions are highly organised regions of the brain and are involved in association and integration functions. If there is a structural and functional deficit in this region, it will cause associative and integrative problem, as are experienced by schizophrenic patients. These problems lead to distorted interpretations of reality. The hippocampus and amygdala are the key features in sensory interpretation and processing, and comparing past and present experiences. They also control the basic drives and emotions that are generated in the neuronal networks of the septum hypothalamus complex (13). In addition to disturbed sensory information processing, limbic pathology could explain the dyscontrol syndrome of basic drives and emotions that are seen in schizophrenic patients. ‘There is a particularly strong association between the left temporolimbic pathology and the positive symptoms of schizophrenia’ (14) so, it appears that the limbic system pathology is involved in the pathology of schizophrenia.

Using neuropathology to find an aetiology.

Investigation of the glial cells is one of the strategies used in the study of the aetiology of schizophrenia. The brain tissue responds to progressive brain disease, infections and acute brain lesions by a process known as gliosis. Astrocytes respond to these insults by developing hyperplasia and proliferation of cell bodies and fibres.

The immature brain is not capable of reactive gliosis. Gliosis would not be observed with developmental disturbances or inherited variations. It is associated with pathological events occurring after the second trimester of pregnancy. The absence of gliosis in a structurally changed brain region is compatible with a fixed, very early prenatal or genetic pathology.

Ten controlled quantitative studies found no evidence of gliosis in the medial temporal lobe gyrus or the mediodorsal thalamus of schizophrenic patients (13). However, cell loss and cytoarchitectural changes occurred in these regions. These studies show that the anatomical abnormalities that were found, seem to reflect disorders of brain development.

Another way of studying the aetiology of schizophrenia is to use neuropathology to investigate cortical architecture. Abnormal architectural arrangements of single nerve cells, cell clusters or cortical layers are strong indicators of disturbed early brain development. Abnormal cell clusters have been found, more frequently in the left hemisphere of schizophrenic patients, but these abnormalities are not as extensive as in other disorders of cortical development like developmental dyslexia (11).

Studies of cerebral asymmetry are also used to study the aetiology of schizophrenia. In the normal brain, there is a structural asymmetry which includes larger right frontal and temporal lobes. Several CT and MRI studies suggest that in schizophrenia, the normal structural asymmetry is absent, and left temporal horn and left ventricular enlargement have been reported (11 & 15).

Some facts have been established about the neuropathology of schizophrenia. The disorder is associated with ventricular enlargement and decreased cortical volume (16). This could have a number of causes including brain injury due to birth injury, head injury, viral infection, deficiencies in nutrition or genetic abnormalities. Evidence against a genetic cause for this neuropathology has come from twin studies. MZ twins who are discordant share the same genetic make-up but only the twin with schizophrenia has a low prefrontal activity and/or ventricular enlargement (17).

There have been methodological problems that have hampered the progress of neuropathological studies. These problems include, difficulties with tissue acquisition, inconsistent tissue handling and inadequate and improper comparison groups (13). These issues need to be addressed in order to shed light on the neuropathology of schizophrenia.

Neurodevelopmental models.

Epidemiological and neuropathological studies seem to indicate that pathogenic processes early in life culminate in the development of schizophrenia. The neurodevelopmental hypothesis states that the origins of schizophrenia are in abnormal brain development and that the pathology originates in the middle stage of intrauterine life (18).

An earlier timing for the pathology of schizophrenia can be ruled out since abnormalities in the structure of the cerebral cortex would be expected if neurogenesis were affected. The absence of gliosis can be taken to mean that the changes must have occurred prior to the third trimester (13). However, this hypothesis is weak because a) gliosis is difficult to recognise and b) the cytoarchitectural changes that have been found have not been proven to be a feature of schizophrenia (19). Overall however, the cytoachitectural abnormalities and the lack of gliosis appear to be indicative of neurodevelopmental problems rather than a neurodegenerative process.

Obstetric complications.

Many epidemiological studies have observed an association between obstetric complications during intrauterine life and schizophrenia. In 1999, a cohort study was published (20). It set out to study sets of risk factors representing three different aetiological mechanisms that could lead to schizophrenia. These were, malnutrition during fetal life, extreme prematurity , and hypoxia and ischaemia. Malnutrition during fetal life could lead to a reduction in the supply of nutrients, such as oxygen, iodine, glucose and iron, which could impair development of the CNS. This may contribute to the development of schizophrenia. The study supports the theory of an association between obstetric complications and schizophrenia. There was evidence of increased risk associated with all three aetiological mechanisms. Pre-eclampsia was the strongest individual risk factor. Some of the factors that were looked at may not have been good indicators of the conditions they were defined as representing (i.e. small for gestational age to indicate malnutrition) therefore further studies need to be undertaken in this field.

Other researchers have also examined the relationship between obstetric complications and adult ventricular size. It has been found that obstetric complications appear to be predictive of increased ventricular size in adults, particularly in schizophrenia (20). Other studies have reported earlier onset of schizophrenia in patients with a history of obstetric complications (21 & 22).

Obstetric insults do not equate with cerebral damage. Several variables probably interact in order for obstetric insults to lead to schizophrenia. These would include the site of any lesions, the timing of the injury and the presence of any genetic predisposition to schizophrenia.

Viral Infections.

Evidence for the involvement of infectious diseases in the aetiology of schizophrenia first came from the ‘season of birth effect’. People born during the winter months appear to have a higher risk of developing schizophrenia. This is thought to be due to exposure to viruses during development. Epidemiological studies have shown high rates of schizophrenia among people whose mothers were exposed to the influenza virus while pregnant (23). The second trimester is a crucial period for the development of the CNS of the fetus. Disruption of brain development in this phase could cause the major structural deficits that are found in the brains of some people with schizophrenia. The mechanism of how a viral infection could lead to schizophrenia is unknown. Further studies are needed to look into this.

Brain maturation and the onset of schizophrenia.

There is a long latent period between early cerebral insults and the appearance of schizophrenia. The explanation for this could be due to the fact that brain development continues throughout childhood and adolescence. Myelination continues into adolescence, and there is some evidence that the deleterious effects of damaged neurones may not become apparent until they myelinate (8). It has been suggested that synaptic elimination in adolescence may underlie the emergence of psychotic symptoms. Hormonal and sexual maturity during adolescence have also been thought to contribute to the onset of schizophrenia, but very few studies have looked into this.

All of these theories that try to explain the long latency between cerebral insults and the appearance of schizophrenia, assume that the structural abnormalities seen in the brains of schizophrenic people, can be regarded as ‘vulnerability markers’ that can lead to the development of schizophrenia during stress and the vulnerable time between puberty and old age (13).

The neurodevelopmental hypothesis can only account for a minority of cases of schizophrenia. Most of the evidence in support of this theory is circumstantial, but the neuropathological findings in the brains of schizophrenics fits in well with this theory.

Neurochemistry

The dysfunction of several neurotransmitter systems like dopamine, 5-hydroxytryptamine (5-HT; Serotonin)and glutamate are thought to play a part in schizophrenia.

Dopamine.

Dopaminergic overactivity is thought to be involved in schizophrenia for several reasons. Firstly, drugs that reduce the levels of dopamine in the brain also tend to reduce the positive symptoms of schizophrenia (neuroleptics). Secondly, drugs like amphetamines that increase the levels of dopamine, also increase the psychotic symptoms of schizophrenia (24). PET scan studies have also found more neuronal receptors for dopamine in some areas of the brains of people with schizophrenia.

There is some controversy about this finding. It has been found that people treated with neuroleptics, had an increased striatal volume that was thought to be due to neuroleptics causing a functional hyperactivity of the striatum, leading to hypertrophy. Since the striatum contains a large number of dopamine receptors, the use of neuroleptics could account for the higher dopamine receptor density in the brains of schizophrenics (25). But further studies have found increased striatal dopamine receptor activity in medication-free patients (26). There are different types of dopamine receptors therefore identifying the site of dysfunction in the dopaminergic system is difficult.

Regional cerebral blood flow studies have shown dysfunction in the dorso-lateral prefrontal cortex (DLPFC) in schizophrenics. Dysfunction of the dopamine systems in this region has been implicated in schizophrenia. Reduced levels of dopamine in the prefrontal cortex have been linked to impaired metabolism, therefore a lesion in the prefrontal cortex, or the afferent neurones to the prefrontal cortex in schizophrenics, could lead to reduced dopamine function and therefore to the negative symptoms of schizophrenia (26).

Dopamine hyperactivity seems to lead to the positive symptoms of schizophrenia and dopamine underactivity to the negative symptoms therefore, there appears to be inverse levels of cortical-subcortical dopaminergic function. Animal studies have shown that dopamine underactivity in one part of the brain can be accompanied by dopamine overactivity in another part of the brain . ‘If this exists in humans, then a lesion that affects the prefrontal dopamine projection and/or their connections could account for both mesocortical underactivity and mesolimbic overactivity’ (26).

Dopamine systems respond to stress but if there is a lesion that disrupts these systems, the individual may be physiologically incapable of making the appropriate cognitive responses to stressful situations. The pattern of abnormalities seen in schizophrenia, suggests some sort of disturbance of connectivity within and between the hippocampus, prefrontal cortex and the dorsal thalamus. This could mean that there is a disruption between the mesolimbic system and the prefrontal cortex so, normal feedback mechanisms would not work. Therefore dopamine activity in the mesolimbic system would be unmediated, which could lead to overactivity and psychosis during stressful periods (26).

It has been suggested that the dopamine system has a peak activity during early adulthood which could explain the time of onset of schizophrenia.

5-HT.

5-HT is thought to be involved in schizophrenia because the hallucinogen LSD is a 5-HT agonist. It has been found that in schizophrenia, there is a reduced number of 5-HT2A receptors and an increase in the number of 5-HT1A receptors in the frontal cortex (13). Both of these changes were seen in the post-mortems of unmedicated patients. These changes were not seen in PET scans of younger unmedicated patients suggesting that these abnormalities may emerge during the course of the illness. Several hypothesis have been offered in order to explain the involvement of 5-HT in schizophrenia including, alterations in the trophic role of 5-HT in neurodevelopment and impaired interactions between 5-HT and dopamine.

Glutamate.

Phencyclidine is a non-competitive antagonist of the NMDA (N-methyl-D-aspartate) type of glutamate receptor, and it produces a psychosis similar to schizophrenia. This is the reason that glutamatergic dysfunction is thought to be involved in schizophrenia. There is evidence that in the medial temporal lobe, glutamatergic markers are decreased and there is reduced expression of non-NMDA subtypes of glutamate receptor (13), but different patterns are seen in other brain regions.

Mechanisms that have been proposed to explain glutamatergic involvement in schizophrenia centre on its interaction with dopamine, and a developmental abnormality of connections within the brain (14).There is still no clear picture of the neurochemical features of schizophrenia or their role in the pathogenesis of the disorder. It is difficult to interpret many of the neurochemical abnormalities seen in schizophrenia so more sophisticated analysis are needed.

Conclusion.

Biological theories of schizophrenia have focused on genetics and, structural and functional abnormalities in the brain.

Family, twin and adoption studies indicate an important genetic contribution to the aetiology of schizophrenia. It appears that a ‘liability to develop’ the disorder is what is inherited rather than a certainty of getting it. Studies are being carried out in order to detect and locate genes contributing to schizophrenia.

People with schizophrenia tend to show lowered functioning in the prefrontal areas of the brain and enlarged ventricles suggesting atrophy in parts of the brain. These changes cannot be seen in all patients. There is no evidence of a specific pathological characteristic common to all patients with schizophrenia. Most studies seem to agree that many patients appear to suffer from a disorder of early brain development. A developmental defect alone cannot explain the course of the disease or how the symptoms are made worse under stress. Several theories have offered an explanation for the long latency between disturbances in brain development and the onset of symptoms. These include synaptic elimination during adolescence and late myelination in the frontal cortex. However, many more studies need to be carried out to investigate these theories.

There is evidence for the involvement of neurotransmitters in the disorder, but no clear picture has been made. It appears unlikely that dysfunction of any single neurotransmitter system could account for a disorder as complex as schizophrenia. It is also unlikely that the pathology that has been found would only affect one neurotransmitter system. More studies are needed to look at the role of neurotransmitters in schizophrenia.

It has been suggested that schizophrenia is a misconnectivity or disconnectivity syndrome which affects the organisation of neurones in the brain, but more studies are needed to determine the likelihood of this hypothesis.

The DLPFC has been understudied in the past. It is important that any future investigations into the DLPFC analyse both anatomical and neurochemical changes on the same brains so that the relationship between these two factors can be seen. Methodological problems have limited studies into the possible aetiology of schizophrenia but many of these problems are being overcome by modern technology. Studies have also been limited by the subtlety of the target pathology. Many theories of possible aetiology have come from previous studies so, with more research, more light could be shed onto an aetiology for schizophrenia.

Currently, the Clinical Brain Disorders branch of the National Institute of Mental Health, are studying the molecular abnormalities in the schizophrenic brain. They are mainly studying the cortical-striatal circuitry and the hippocampal-entrohinal connections in humans, as well as determining the molecular changes occurring in the brains of animals with neonatal damage of the hippocampus or prefrontal cortex in order to determine animal models of schizophrenia (27).

Clinically, schizophrenia is heterogeneous and this may point to heterogeneous aetiology. It seems that genetics, neurodevelopmental problems, neurochemistry and abnormal connectivity, as well as psychosocial stressors probably all contribute to developing the typical clinical pictures of schizophrenia.

References.

1. Shaw SH, Kelly M, Smith AB, Shields G, Hopkins PJ, Loftus J, Laval SH, Vita A, Dehert M, Cardon LR, Crow T, Sherrington R, Delisi LE. A Genome-wide search for Schizophrenia Susceptibility Genes. American Journal of Medical Genetics 1998 Sept; 81(5): 364-376.

2. Nolen-Hoeksema S. Abnormal Psychology, 1st ed. McGraw-Hill: 1998.

3. Torrey EF. Prevalence Studies in Schizophrenia. British Journal of Psychiatry 1987; 150: 598-608.

4. Gottesman II, Shields J. A Critical review of recent adoption, twin and family studies of schizophrenia: Behavioural genetics perspectives. Schizophrenia Bulletin 1976; 2: 360-401.

5. Gottesman II, Shields J. Schizophrenia, the epigenetic puzzle. New York: Cambridge university press, 1982.

6. Kety SS, Wender PH, Jacobsen B, Ingaham LJ, Jansson L, Faber B, Kinney DK. Mental illness in the biological and adoptive relatives of schizophrenic adoptees. Archives of General Psychiatry 1994 June; 51: 442-455.

7. O’Rourke DH, Gottesman II, Saurez BK, Rice J, Reich T. Refutation of the single locus model in the aetiology of schizophrenia. American Journal of Human Genetics 1982; 33: 630-649.

8. Bebbington P, McGuffin P. Schizophrenia: the major issues, Heinemann Professional Publishing, 1988.

9. Weinberger DR, Berman KF, Zec RF. Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia: I. Regional cerebral blood flow evidence. Archives of General Psychiatry 1986; 43: 114-125.

10. Ingvar DH, Franzen G. Abnormalities of cerebral blood flow distribution in patients with chronic schizophrenia. Acta Psychiatica Scandinavica 1974; 50: 425-462.

11. Bogerts B. Recent advances in the neuropathology of schizophrenia. Schizophrenia Bulletin 1993; 19(2): 431-445.

12. Bogerts B, Meertz E, Schonfeldt-Bausch R. Basal ganglia and limbic system pathology in schizophrenia. Archives of General Psychiatry 1985 Aug; 42: 784-791.

13. Harrison PJ. The neuropathology of schizophrenia: a critical review of the data and their interpretation. Brain 1999; 122: 593-624.

14. Crow TJ. Schizophrenia as a failure of hemispheric dominance for language. Trends in Neuroscience 1997; 20: 339-343.

15. Crow TJ, Ball J, Bloom SR, Brown R, Bruton CJ, Colter N, Firth CD, Johnstone EC, Owens DG, Roberts GW. Schizophrenia as an anomaly of development of cerebral asymmetry. Archives of General Psychiatry 1989; 46: 1145-1150.

16. Powchik P, Davidson M, Haroutunian V, Gabriel SM, Purohit DP, Perl DP, Harvey PD, Davis KL. Post-mortem studies in schizophrenia. Schizophrenia Bulletin 1998; 24 (3): 325-341.

17. Suddath RL, Christison GW, Torrey EF, Casanova MF. Anatomical abnormalities in the brains of monozygotic twins discordant for schizophrenia. New-England Journal of Medicine 1990; 322: 789-794.

18. Murray RM, Lewis SW. Is schizophrenia a neurodevelopmental disorder? Editorial British Medical Journal 1987; 295: 681-682.

19. Arnold SE, Franz BR, Trojanowski JQ, Moberg PJ, Gur RE. Glial fibrillary acid protein-immunoreactive astrocytosis in elderly patients with schizophrenia and dementia. Acta Neuropathology 1996; 91: 269-277.

20. Dalman C, Allebeck P, Cullberg J, Grunewald C, Koster M. Obstetric complications and the risk of schizophrenia. Archives of General Psychiatry 1999; 56: 234-240.

21. Pearlson GD, Garbacz DJ, Moberg PJ, Ahn HS, DePaulo JR. Symptomatic familial, perinatal and social correlates of complicated computer axial tomography (CAT) changes in schizophrenics and bipolars. Journal of Nervous and Mental disease; 173: 42-50.

22. Verdoux H, Geddes JR, Takei N, Lawrie SM, McCreadie RG, McNeil TF, O’Callaghan E, Stober G, Willinger U, Wright P, Murray RM. Obstetric complications and age at onset in schizophrenia: An international collaborative meta-analysis of individual patient data. American Journal of Psychiatry 1997 Sept; 154 (9): 1220-1227.

23. Kirch DG. Infection and autoimmunity as aetiological factors in schizophrenia: a review and reappraisal. Schizophrenia Bulletin 1993; 19: 355-370.

24. Abi-Dargham A, Gil R, Krystal J, Baldwin RM, Selby JP, Bowers M. Increased striatal dopamine transmission in schizophrenia: conformation in a second cohort. American Journal of Psychiatry 1998; 155: 761-767.

25. Mackay AVP, Iversen LL, Rossor M, Spokes E, Bird E, Arregui A, Creese I, Snyder SH. Increased dopamine and dopamine receptors in schizophrenia. Archives of General Psychiatry 1982; 39: 991-997.

26.Weinberger DR. Implications of normal brain development for the pathogenesis of schizophrenia. Archives of General Psychiatry 1987; 44: 660-668.

27. National Institute of Mental Health web-site.

 

« Psychiatry

First Published April 2000

Schizophrenia - a review by Dr Ben Green

 


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