The aetiology of schizophrenia: Genetic and environmental risk factors for schizophrenia.
- Familial–genetic risk
- Adoption studies
- Twin studies
- What is the range of the clinical phenotype transmitted?
- Molecular genetics
- Genetic models
- Biological abnormalities in the relatives of schizophrenics
- Environmental factors
- Pre- and perinatal complications
- Childhood risk factors
- Social and geographic risk factors
- Life events
- Drug abuse
- Risk factors, age of onset, and outcome
- The risk factor model
- Gene–environment interaction
- The implications
- The risk factor model
After many years of fruitlessly seeking a single cause for schizophrenia, sometimes sarcastically termed ‘the search for the schizococcus', almost all researchers have come to the conclusion that there is no single cause. Instead, they have concluded that, like other disorders such as ischaemic heart disease and diabetes mellitus, schizophrenia results from the cumulative effects of a number of risk factors. These may be crudely divided into the familial–genetic and the environmental.
The most powerful risk factor for schizophrenia is having a relative afflicted with the disorder. Numerous studies have shown that the lifetime risk for broadly defined schizophrenia increases from about 1 per cent in the general population to about 10 per cent in first-degree relatives of patients with schizophrenia and to 48 per cent in those with two parents with the disorder. (1) However, familial aggregation does not prove that a condition is genetically transmitted; speaking in French also runs in families!
Most children inherit their genes and their family culture from the same set of parents. However, since adoptees do not, adoption studies offer the opportunity of separating the effects of the two. In the first study of schizophrenia, Heston and Denney (2) demonstrated that five out of 47 children of schizophrenic mothers who were adopted away within a few days of their birth, later developed schizophrenia compared with none out of 50 adoptees with no family history of schizophrenia. Similar findings were reported from the Danish–American Study of Rosenthal et al.(3) who found that a significantly higher proportion of the adopted-away offspring of schizophrenic parents from Copenhagen were classified as having schizophrenia or ‘borderline schizophrenia', than were control adoptees. This study originated the concept of the schizophrenia spectrum disorder, which has come to include not only frank schizophrenia but also schizophreniform disorder, as well as schizotypal and possibly paranoid personality disorder.
In an extension of the Danish–American collaboration, Kety et al. (4) took all schizophrenic adoptees in Denmark as their starting point, and then examined their biological and adoptive relatives; unlike the earlier adoption studies this one also used operational definitions of the schizophrenia spectrum conditions. Fully 23.5 per cent of the biological first-degree relatives of schizophrenic adoptees received a schizophrenia spectrum diagnosis compared with only 4.7 per cent of the biological relatives of normal control adoptees; the adoptive relatives of both groups of adoptees had very low rates of spectrum disorders.
Finally, Wender et al. (5) studied the grown-up children of normal individuals who, by mischance, had been placed with an adoptive parent who later developed schizophrenia. Thankfully, these unfortunate adoptees did not themselves show an increased risk of the disorder. Thus, adoption studies consistently indicate that the familial aggregation of schizophrenia is determined by individuals inheriting genes from someone with the disorder (or a related spectrum condition) rather than any effect of the intrafamilial culture (e.g. being brought up by a parent with schizophrenia).
Twin studies have come to the same conclusion. Gottesman, (1) who reviewed the literature, calculated the average probandwise concordance rate for broadly defined schizophrenia in monozygotic twins to be 46 per cent, compared with 14 per cent in dizygotic twins. This difference has been taken to be a reflection of the fact that while monozygotic twins share all their genes, dizygotic twins share, on average, only 50 per cent. Further evidence of the effect of heredity comes from the evidence that the concordance rate in 12 pairs of monozygotic twins who were reared apart was 58 per cent. (1)
The above twin studies preceded the introduction of operational definitions of schizophrenia. When studies with such definitions were carried out, the rates for both monozygotic and dizygotic twins were both lower but the disparity between the two remained. Thus, in the latest and largest study, which examined 108 consecutive pairs of twins seen at the Maudsley Hospital in London, Cardno et al. (6) reported probandwise concordance rates for DSM-IIIR schizophrenia of 42.6 per cent in monozygotic twins and 0 per cent in dizygotic twins.
What is the range of the clinical phenotype transmitted?
The fact that an individual can have the same genes as their schizophrenic co-twin but have a better than evens chance of remaining non-psychotic indicates that it is not schizophrenia per se which is inherited but rather a susceptibility to it. Further evidence in support of this comes from a study which showed that the offspring of the identical but well co-twins of schizophrenic individuals have a risk of the disorder similar to that of the offspring of the affected. (7) Thus the predisposition is transmitted without being expressed as schizophrenia.
As noted earlier, sometimes the predisposition may be expressed as non-psychotic spectrum disorders. In addition, family studies show that relatives of schizophrenic patients also have an excess of other psychotic conditions such as schizoaffective disorder, atypical and schizophreniform psychoses, and affective psychosis with mood-incongruent delusions. Thus, the clinical phenotype transmitted encompasses a range of psychotic conditions, as well as schizotypal personality disorder.
Within schizophrenia, researchers have asked whether the classical Kraepelinian subtypes are differentially inherited. The results have in general been negative which is not surprising since clinicians know that an individual patient can appear predominantly hebephrenic on one admission and schizoaffective on another. However, there has been a consensus that paranoid schizophrenia is less familial than other types and is associated with a lower monozygotic twin concordance.
Recently, it has been shown that schizophrenic symptoms can be summarized as three main factors: delusions and hallucinations (reality distortion), negative symptoms (psychomotor poverty), and disorganization or positive thought disorder. (8,9) Is schizotypal personality particularly closely related to one of these three core syndromes? Mata et al.(10) showed that schizotypal personality scores in non-psychotic relatives were significantly correlated with the presence of delusions and hallucinations in the probands; indeed, they were also correlated with premorbid schizoptypal traits in the childhood of the probands. Thus, it seems that certain families transmit schizotypal traits which manifest themselves in childhood; some family members remain schizotypal throughout life but in others this deviant personality type is then compounded by other (genetic or environmental) factors so that the individual passes a threshold for the expression of delusions and hallucinations.
For more than 20 years researchers have been using molecular techniques to seek the gene or genes that predispose to schizophrenia. The first technique to be used was that of linkage in which large families with several members affected with schizophrenia are studied to try and find a genetic marker that cosegregates with the disease. Unfortunately, to date no single gene or indeed region has been unequivocally implicated in susceptibility to schizophrenia. Rather, linkage studies suggest that no gene can exist which increases the risk of schizophrenia by more than a factor of 3 but that there may be a number of susceptibility genes. Findings suggest that some of these may lie within ‘hot spots' on chromosomes 22, 6, or 13 (reviewed by Kirov and Murray (11).
The second approach, that of association studies, takes a gene that is suspected of involvement in the pathogensis of the disorder (e.g. a gene involved in dopamine metabolism) and then compares the frequency of its various alleles in a series of individuals with schizophrenia as opposed to a control group. Some candidate gene studies imply a weak effect of the D3 dopamine and 5-HT2A receptor genes as well as the HLA locus on chromosome 6.(12)
Other studies have noted that patients in successive generations tend to develop frank schizophrenia at ever earlier ages. This process of ‘anticipation' occurs in a number of neurological conditions in which an excess number of trinucleotide repeats occurs, and increases with succeeding generations; some claim that the same occurs in schizophrenia but most studies do not (see Kirov and Murray (11)).
Thus, both statistical and molecular studies indicate that schizophrenia cannot be explained by the inheritance of a single major gene. In any case, such simple Mendelian inheritance would be hard to square with the persistence of schizophrenia in the population. Since people with schizophrenia tend to reproduce less frequently than the rest of the population, one would have expected that a single major gene with such damaging consequences would have been selected out of the gene pool.
The evidence is compatible with oligogenic inheritance (a small number of genes involved) but the most popular model is the polygenic model which postulates that a number of genes of small effect are involved. Further support for this model comes from the fact that the risk to an individual increases with the number of affected relatives(1) and also with the finding of Cardno et al.(6) that the monozygotic concordance rate is higher for those twins who had an early rather than late onset of psychosis.
Family studies also show that the relatives of probands with an early onset have a higher morbid risk of psychosis than the relatives of late-onset patients. (13) These findings are compatible with the idea that schizophrenia is in part a developmental disorder and that some of the susceptibility genes may be involved in the control of neurodevelopment.(14)
Biological abnormalities in the relatives of schizophrenics
Relatives have been examined for some of the biological abnormalities which are found in their schizophrenic kin. Thus, in the Maudsley Family Study, Sharma et al. (15,16) carried out magnetic resonance imaging (MRI) scans on families with several members affected with schizophrenia. Both the schizophrenic members and those unaffected relatives who appeared to be transmitting the liability to the disorder (so-called obligate carriers) showed larger lateral ventricles than controls as well as loss of the normal cerebral asymmetry. This latter finding gives some support to Crow's (17) hypothesis that an abnormality in the genetic control of the development of normal asymmetry contributes to schizophrenia.
In the same Maudsley Family Study, the non-psychotic relatives exhibited other neurophysiological abnormalities such as an excess of delayed P300 event-related potentials; their prevalence was not as high as in the patients themselves but higher than in normal controls. (18) Those patients who showed an excess of saccadic distractability errors tended to have relatives with the same eye-tracking abnormalities. (19) The schizophrenic patients and their well relatives from these multiply affected families also showed more integrative neurological abnormalities than controls. (20)
These findings suggest that what is being transmitted is not genes for schizophrenia per se but rather genes for a variety of characteristics (e.g. schizotypal personality, enlarged lateral ventricles, loss of cerebral asymmetry, delayed P300, integrative neurological abnormalities, etc.) which increase the risk of schizophrenia. Individuals can inherit these characteristics without being psychotic; perhaps schizophrenia only ensues when an individual inherits a number of such endophenotypic abnormalities and passes a critical threshold of risk. (21)
It is evident from the above that genes exert a probabilistic rather than a deterministic effect on the development of schizophrenia; environmental risk factors appear to be necessary for the disease to become manifest in many, if not all, cases. (22) But what are these environmental risk factors?
Pre- and perinatal complications
More than 20 studies have shown that patients suffering from schizophrenia are more likely to have a history of pre- or perinatal complications (collectively termed obstetric complications) than are healthy subjects from the general population, patients with other psychiatric disorders, and their own healthy siblings. (23) Some of the studies which reported these findings were based upon interviews with patients' mothers asking them to recall their pregnancies; such interviews are obviously open to distortion by loss of, or faulty, memory. However, similar findings have been reported by studies examining data collected in obstetric records at the time of birth of patients and controls. (24) A further assessment of the epidemiological studies of obstetric complications as risk factors for schizophrenia is given in this article: The epidemiology of schizophrenia.
Of course, it is possible that the excess obstetric complications in schizophrenia may be the consequence of some pre-existing abnormality. Since the fetus plays an active role in the normal progress of pregnancy and labour, fetal impairment induced by earlier abnormality may itself result in some perinatal complications. Also some studies have shown that women with schizophrenia who become pregnant tend to have more obstetric complications, possibly owing to their behaviour during pregnancy, for example smoking and not attending antenatal visits.
The term of ‘obstetric complications' covers a broad range of obstetric events. A recent international collaboration therefore gathered data on more than 700 schizophrenics and a similar number of controls to see whether the general association could be explained by one or two specific complications; low birth weight, prematurity, and resuscitation at birth were particularly increased in the schizophrenics; (23) other complications that have been implicated include retarded fetal growth and rhesus incompatability. Thus, a common characteristic of most of the obstetric complications implicated is that they increase the risk of hypoxia.
Could hypoxic–ischaemic damage be the mechanism that increases the risk of later schizophrenia? Children who were subject to cerebral hypoxia at or before birth show an excess of abnormalities on MRI scan, of minor neurological signs, and of cognitive and behavioural problems, characteristics also found in many preschizophrenic children. (25) As one might predict, studies of monozygotic twins discordant for schizophrenia have shown that the affected twins have larger lateral ventricles and smaller hippocampi than their well co-twins; (26,27) furthermore, those twins who have been subjected to the most severe perinatal difficulties have the largest ventricles and smallest hippocampi. (28)
Similarly, Stefanis et al.(29) compared hippocampal volume in schizophrenics with other affected relatives but no history of obstetric complications, schizophrenics with no affected relatives but a history of significant obstetric complications, and normal controls. Hippocampal volume was normal in the first schizophrenic group but reduced in the second group, implying that it is hypoxic–ischaemic damage rather than genetic predisposition alone that determines decreased hippocampal volume in schizophrenia.
Many studies have shown that more schizophrenic persons are born in late winter and spring than expected; since respiratory viral infections such as influenza tend to occur in autumn and winter, maternal infection might provide the explanation. A number of epidemiological studies have, therefore, addressed the question of whether maternal exposure to influenza during the second trimester of pregnancy is a risk factor for schizophrenia; some but not all studies have suggested that it is.(30) Recently, one study has raised the possibility that prenatal exposure to rubella may have a similar risk-increasing effect for schizophrenia while another implicated maternal malnutrition; (31) neither of these reports has yet been replicated. See also: The epidemiology of schizophrenia for a more cautious assessment of the strength of the evidence that maternal exposure to influenza is a risk factor for schizophrenia.
Childhood risk factors
There is now a wealth of evidence attesting to the fact that a proportion of individuals who later manifest schizophrenia show abnormalities in their early development. The evidence for early developmental abnormalities in schizophrenia come from three main sorts of study:
- high-risk studies in which the offspring of parent(s) with schizophrenia are examined
- follow-back studies where cases of schizophrenia are ascertained, and their early developmental trajectory plotted with the help of history from the individual and family, sometimes also including such evidence as school reports, etc.
- cohort studies, where birth cohorts are followed up prospectively, and individuals who later manifest schizophrenia are compared with the rest of the cohort in terms of their early development.
Studies of the offspring of schizophrenic mothers, the so-called ‘high-risk studies', show that around 25 to 50 per cent show some deviation from normal in terms of their early development (reviewed by Davies et al.(32)). In the neonatal period there is a tendency to hypotonia and decreased cuddliness, in infancy milestones are delayed, in early childhood there is poor motor co-ordination, and in later childhood there are deficits in attention and information processing. Fish et al.(33) followed their cohort of 12 high-risk infants into adulthood. One developed schizophrenia and six showed schizotypal or paranoid personality traits; these authors coined the term ‘pandysmaturation' to describe the abnormalities which included delayed motor milestones in the first 2 years of life.
High-risk studies have been criticised on the basis that they are unrepresentative because only a minority of people who develop schizophrenia have a mother with the same illness. Therefore researchers have carried out studies of reprentative groups of schizophrenic patients which relied on maternal recall to document the early development of adults with schizophrenia; these have shown impairment of cognitive and neuromotor development and interpersonal problems. These findings are more commonly reported in males than females, and tend to be associated with an early onset of illness. (34) The findings are not specific to schizophrenia, being reported also in the early development of some children who later manifest an affective psychosis. (35) Of course, one of the major criticisms of follow-back studies is the likelihood of recall bias. Studies that have avoided this problem include those which have accessed IQ scores assessed prior to illness onset; these have shown that premorbid IQ is, on average, lower in those, particularly males, who later manifest schizophrenia. (36,37)
Another source has been childhood home videos, which have been reviewed by researchers ‘blind' to whether the individual later manifested schizophrenia. (38) In comparison with their healthy siblings, the preschizophrenic children showed higher rates of neuromotor abnormalities (predominantly left-sided) and overall poorer motor skills; the group differences were significant only at age 2 years.
The publication of a number of cohort studies has overcome many of the criticisms of follow-back studies. In an investigation of the 1958 British Perinatal Mortality cohort, comprising 98 per cent of all children ( n = 15 398) born in the United Kingdom in a certain week in March 1958, Done et al. (39) compared those who later manifested schizophrenia (n = 40), affective psychosis (n = 35), and neurotic illness (n = 79) with each other as well as with 1914 randomly selected individuals with no history of mental illness. At age 7 years, teacher ratings showed the preschizophrenic children to have exhibited more social maladjustment than controls; the effect was most marked in boys. The preaffective children differed little from normal controls, whilst the preneurotic children (expressly girls) showed some maladjustment (over- and under-reaction) at age 11 years.
In a similar study of the 1946 British Birth Cohort, Jones et al.(40) determined that 30 out of 4746 individuals had, in adulthood, developed schizophrenia. This group were more likely than the rest of the cohort to show delayed milestones and speech problems, to have a lower premorbid IQ and lower education test scores at ages 8, 11, and 15 years, and to prefer solitary play at ages 4 and 6 years.
Together, such studies provide compelling evidence for a tendency of individuals with schizophrenia to show abnormalities in development which antedate the onset of illness. The findings are compatible with the notion that subtle brain abnormalities (which may be genetically or environmentally mediated, or both) underpin schizophrenia. However, it is also possible that some of the childhood risk factors are independent and act in an additive manner to set individuals on an increasingly deviant trajectory towards schizophrenia. Further information about epidemiological studies linking premorbid impairments and schizophrenia is given in: The epidemiology of schizophrenia.
Social and geographic risk factors
In 1939 Faris and Dunham (41) reported that an excess of individuals with schizophrenia was found in certain deprived inner-city areas. These authors suggested that social isolation in poor deprived parts of the city could precipitate schizophrenia. However, subsequently their results were interpreted as a consequence of social drift, i.e. the idea that individuals with this illness ‘drift' down the social scale. (42) This effect is postulated to result from not only the illness itself but also its prodroma and consequences such as loss of employment and estrangement from family. A related finding is that of lack of upward social mobility in individuals with schizophrenia. For example, Hollingshead and Redlich (43) reported that individuals with schizophrenia to be less likely than expected to attain the socio-economic status of their fathers.
More recently, research has focused on the apparent excess of individuals who later manifest schizophrenia, who actually start life in a setting which appears to increase the subsequent risk of schizophrenia. Kohn (44) stated that ‘... in all probability, lower class families produce a disproportionate number of schizophrenics' but the evidence concerning such ‘social causation' is contradictory. Thus, Turner and Wagenfeld (45) reported fathers of schizophrenia patients to be themselves over-represented in lower socio-economic groups. However, Jones et al. (40) did not find this.
It may be that it is not so much poverty as being born or brought up in a city which increases the risk of the disorder. For example, Lewis et al. (46) found that Swedish conscripts who later manifested schizophrenia were 1.65 times more likely to have been born in urban than rural areas. Similarly, Marcelis et al. (47) reported that birth in an urban area of Holland carried twice the risk of later schizophrenia of birth in a rural area. Similar findings have come from Denmark where those individuals born in Copenhagen appear to have twice the risk of schizophrenia of those born in rural areas. (48) The exact mechanisms underlying this effect remain unclear.
Since the classic study of Odegaard in 1932, (49) many studies have reported that migrants are at increased risk of schizophrenia. There have been many competing explanatory hypotheses, including selective migration, migrant stress, and socio-economic deprivation. A notable example has come from a series of studies of African-Caribbeans resident in the United Kingdom, who show a markedly higher rate of schizophrenia than do their white British-born counterparts. (34,50) This is in the absence of any increased risk to Caribbeans who remain in the West Indies (see Harrison (51)). Of particular interest is that this increased risk also pertains to British-born offspring of Caribbean migrants, discounting an explanation in terms of migration stress. Furthermore, there is a marked increased risk in the siblings but not the parents of this second generation;(52) this suggests an environmental effect operating particularly upon this second generation.
Initial studies sought to ascertain any evidence of developmental disadvantage such as poor maternal nutrition, poor obstetric care, and possible maternal susceptibility to novel viruses. However, these studies have shown that, if anything, African-Caribbean schizophrenic patients in England show less evidence of neurodevelopmental insult than their white counterpart patients. Other research focuses on the possibility that a paranoid reaction to social disadvantage and discrimination may be one factor. Further information about these studies and similar ones from The Netherlands is given in: The epidemiology of schizophrenia.
Brown and Birley (53) reported an excess of life events in the 3 weeks preceding schizophrenic relapse. Further studies were conflicting in their findings, possibly due to methodological problems. The recent study of Bebbington et al. (54) avoided many of the methodological pitfalls, assessing life events in 97 psychotic patients (52 with schizophrenia) and general population controls. There was a significant relationship between life events and onset of relapse of schizophrenia, although it was not as strong as for depressive psychosis. One possibility is that certain types of schizophrenic patients are particularly vulnerable to relapse following adverse life events. For example, Bebbington et al.(54) found females to be particularly prone, whilst van Os et al. (9) found life events to be associated with a less severe good-outcome illness.
There is also evidence that families who exhibit high ‘expressed emotion' (comprising critical comments, hostility, and/or overinvolvement) can provide an environment which enhances the risk of relapse in a family member with schizophrenia. Again, cause and effect are difficult to tease apart. Thus, it is possible that patients with more severe and intractable illnesses may induce more expressed emotion in their relatives.
Numerous studies attest to the fact that illicit substance use is more prevalent in patients with schizophrenia than in the general population; estimates of the prevalence of such comorbidity in individuals with schizophrenia range from 20 to 60 per cent, and are consistently higher than in well controls. (55)
Whether illicit substances actually cause schizophrenia is very contentious. Perhaps the methodologically most sound investigation is the study of Andreason et al., (56) which followed up 45,570 Swedish conscripts and found that a history of cannabis consumption, at 18 years, was positively correlated with a later admission to hospital with schizophrenia. The cohort design and a dose–response effect (heavy users had the highest risk of later schizophrenia) suggest a causal link. However, it might be that those individuals who did manifest schizophrenia in later life were destined to do so in any event, and their premorbid state made them more likely than their peers to use high doses of cannabis.
Similarly, although clinical wisdom suggests that illicit substance use has a negative impact on the longitudinal course of schizophrenia, there are few methodologically sound studies in this area. (57,58) Indeed, even the finding of an excess of use, and the association of such use with a poor longitudinal course, is potentially explicable by confounding factors such as substance abuse by the patients who are more ill.
Why do individuals with schizophrenia use illicit substances? There are two main competing theories: the social affiliation hypothesis, where individuals reportedly use substances in attempt to help them reintegrate socially, and the self-medication hypothesis, where individuals find that use of substances either improves symptoms (e.g. use of amphetamines to counter depression) or alleviates side-effects of neuroleptic medication.
Risk factors, age of onset, and outcome
Individuals who have been exposed to certain of the risk factors for schizophrenia tend have an earlier onset of psychosis than those who have not. Thus, age of onset is earlier in those whose relatives show a high morbid risk of schizophrenia; (13) similarly, those twin pairs in which the schizophrenia has an early onset show the highest monozygotic concordance. (6)
Schizophrenic patients with an early age at onset of psychosis are also more likely than patients with later onset to have had a history of exposure to obstetric complications, (59) while those schizophrenic individuals who showed childhood deficits such as low IQ also tend to have an early onset. (37) Schizophrenic patients who abuse cannabis have also recently been shown to have an earlier onset than those who do not. (58)
If a factor operates to increase the risk of schizophrenia and to bring on its onset, then it is logical to think that if it is still present then it will be associated with a poor outcome. Thus, a family history of schizophrenia, a history of obstetric complication, childhood low IQ, and continued drug abuse are all associated with a poor outcome. On the other hand, those patients who develop psychosis following stressful life-events tend to have a better outcome than those with no such precipitant. (9)
The risk factor model
Thus, one way of construing the aetiology of schizophrenia is to see individuals on a stress-vulnerability continuum in which genetic and environmental factors act in an additive manner until a threshold of liability for expression of psychosis is passed. An individual might, for instance, inherit a schizotypal personality but not develop frank psychosis unless exposed to some cerebral insult which causes cognitive impairment; the sum of the two factors could produce the psychotic illness.
Assuming such a model in which a number of genes and environmental factors of small effect act additively, then the heritability of schizophrenia can be calculated to be between 66 and 85 per cent (i.e. a high proportion of liability to the disorder is under genetic influence). However, this assumes that the various factors operate additively, and much evidence is against this assumption. Rather, it seems that there is often an interaction between genetic susceptibility and environmental effects.
As van Os and Marcelis (22) point out, it seems that certain individuals exposed to an environmental risk factor have a high risk of developing schizophrenia while others with a different genotype are at low risk.
Thus, the quality of upbringing can interact with genetic predisposition. For example, the Finnish Adoption Study has shown that when the offspring of women with schizophrenia are placed in a well-adjusted family, they have a lower risk of developing a schizophrenia spectrum disorder than if they are placed in a dysfunctional family, i.e the genotype renders the individual susceptible to the adverse effect of an adverse family environment. (60) Obstetric complications also appear to interact with, and compound, a genetic liability; the offspring of schizophrenic parents are more likely to develop increased ventricular size following obstetric complications.
Similarly, there is evidence that individuals with a family loading for schizophrenia may be more susceptible to psychosis following abuse of cannabis. (61) The latter situation may be complicated by the possibility that individuals who inherit a schizotypal personality may be more likely to take drugs such as cannabis to try to alter an unhappy internal mood state, i.e. their genotype renders them more liable to expose themselves to a factor to which they are genetically susceptible.
Having identified various risk factors for schizophrenia, we can proceed to consider the theoretical possibility of reducing the prevalence of certain risk factors and thus reducing the incidence of the disorder. From the point of view of the public health, rare risk factors which have a big effect are much less important than common risk factors of even small effect. Thus, although familial risk has by far the biggest effect, it makes a smaller contribution to the total incidence of the disorder than environmental effects. Therefore, if all cases with an affected first-degree relative could be prevented, we would eliminate only about 10 per cent of the total cases. However, because being born in an urban area is so common, this small effect accounts for a much greater proportion of the population attributable fraction (33 per cent), i.e. if we could bring down the incidence of schizophrenia in cities to that in the countryside, we could theoretically eliminate one-third of all cases of the disorder. Of course, we could only do this if we knew what the critical urban factors were!
The importance of the evidence that early developmental factors are involved in the aetiology of schizophrenia lies in the fact that at least some of these are preventable. For example, advances in antenatal and perinatal care have reduced the frequency, and toxicity, of some obstetric complications. Similarly, vaccination programmes have reduced exposure to some viral infections in pregnancy and childhood. There could be a link between these developments and the decreased incidence of schizophrenia which has been observed in some western countries over recent decades. (62)
Nevertheless, most babies who are exposed to even severe obstetric complications will not later suffer from schizophrenia. Thus, there is at present no sense in attempting to improve antenatal care with the aim of reducing the occurrence of schizophrenia. There is one important exception. It is indisputable that the children of schizophrenic mothers have a higher risk of the disease if they are also exposed to obstetric complications. Therefore those women with schizophrenia who conceive must have the best possible antenatal care during their pregnancy, and steps should be taken to avoid any event (e.g. prolonged labour) which might lead to hypoxic damage to the baby.
The fact that preschizophrenic children show a number of impairments raises the possibility that predisposed individuals could be identified and ‘rescued' by some intervention. Unfortunately, the childhood characteristics of preschizophrenics are non-specific, and their predictive value for the later manifestation of the illness is too low to be of value for any preventative intervention, i.e. many children who show such deviation from normal in terms of early development, do not later manifest schizophrenia, whilst other children who later develop schizophrenia have perfectly ‘normal' early development. Furthermore, any such abnormalities must be seen in the total context of development, and it should be remembered that many such abnormalities are not static, but may be evident at some stages of development and not at others. Thus, with a few exceptions, there is as yet little that can be done systematically to reduce the incidence of schizophrenia.
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