Aetiology
4.3.6.1 Genetic and environmental risk factors for schizophrenia
R. M. Murray
D. J. Castle
One thing that is certain about the aetiology of schizophrenia is that there is no single cause. This might reflect the fact that the schizophrenia construct itself is heterogeneous, such that specific subtypes might in the future be found to have specific causes. But it is more useful at this stage of our knowledge to conclude 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, though there are clearly interactions between the two.
Familial–genetic risk
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 one per cent in the general population to about 10 per cent cent in first-degree relatives of patients with schizophrenia and to close to 50 per cent in those with two parents with the disorder.(1) However, familial aggregation does not prove that a condition is genetically transmitted; to look at this issue we need to turn to adoptee and twin studies.
Adoption studies
Adoptee studies offer the opportunity of separating the effects of familiality from genetics. In the first such study of schizophrenia, Heston and Denney(2) demonstrated that five out of 47 children of mothers with schizophrenia 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 parents with schizophrenia 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 adoptees in Denmark who had schizophrenia and 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 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.
schizophrenia spectrum conditions. Fully 23.5 per cent of the biological first-degree relatives 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, and found that they were at no 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
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 reflects that while monozygotic twins share all their genes, dizygotic twins share, on average, only half. 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. Cardno et al.(6) examined 108 consecutive pairs of twins seen at the Maudsley Hospital in London, and 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 co-twin with schizophrenia 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 individuals with schizophrenia carry a risk of the disorder similar to that of the offspring of the affected twin.(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 people with schizophrenia also show an increased risk 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 and paranoid personality. Within schizophrenia, researchers have asked whether different 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. Also, very late onset schizophrenia (late paraphrenia) appears to carry less genetic loading than early-onset types.
It has been repeatedly 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 predisposition is compounded by other (genetic or environmental) factors so that the individual passes a threshold for the expression of delusions and hallucinations.
Genetic models
From the data reviewed above, we can conclude 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 most parsimonious is a polygenic model which postulates that a number of genes of small effect are involved. Support for this model comes from the fact that the risk to an individual increases with the number of affected relatives(1) and also that the monozygotic concordance rate is higher for those twins who had an early rather than late onset of psychosis.(6)
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.(11) 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.(12)
Molecular genetic studies
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 co-segregates with the disease. Two decades of linkage studies suggest that no gene can exist which increases the overall risk of schizophrenia by more than a factor of around three, and that, therefore, there are likely to be a number of susceptibility genes of small effect. This is the mode of transmission for other chronic disorders such as diabetes and hypertension, and, as with these disorders, the genetic basis of schizophrenia is beginning to be unravelled. In the past few years, findings from linkage studies have led on to detailed mapping studies of certain chromosomal
regions which have in turn implicated specific genes. Those for which there is most evidence currently are neuregulin and dysbindin.
regions which have in turn implicated specific genes. Those for which there is most evidence currently are neuregulin and dysbindin.
Neuregulin(13): An association between schizophrenia and a multi marker haplotype (a pattern of DNA within a gene) of Neuregulin 1 (NRG1) on chromosome 8p21–22 was found in an Icelandic sample in 2002 and soon replicated in a Scottish population. Subsequently, neuregulin has been implicated in other studies although the exact haplotype has varied in the different studies.
Dysbindin: Also in 2002, Straub et al.(14) reported, in Irish families, association between schizophrenia and several SNPs (single nucleotide polymorphisms) and multimarker haplotypes spanning the gene encoding dystrobrevin-binding protein 1 (DTNBP1), or dysbindin, located at chromosome 6p22.3. Some but not all other studies have replicated this association.
Another way of identifying susceptibility genes is through the study of chromosomal rearrangements. Thus, Blackwood, et al.(15) reported that a large Scottish pedigree showed strong evidence for linkage between a balanced chromosomal translocation (1, 11) (q42;q14.3) (two portions of the different chromosomes swapping positions with each other) and a broad phenotype consisting of schizophrenia, bipolar disorder, and recurrent depression. This translocation caused the disruption of a gene, termed disrupted in schizophrenia 1 (DISC1). Subsequent studies have examined DISC1 in Finnish and US samples, and have suggested that it may be a susceptibility gene for both schizophrenia and bipolar disorder.
A third approach, that of association studies, takes a gene that is suspected of involvement in the pathogenesis of the disorder and compares the frequency of its various alleles in a series of individuals with schizophrenia as opposed to a control group without schizophrenia. One such gene is the catecholamine O-methyl transferase (COMT) gene which has been extensively investigated because of its role in dopamine metabolism, especially in the prefrontal cortex.(16, 17) A mis-sense mutation (incorrect unit in the genetic code) generates a valine to methionine substitution at codon 158 (Val158Met), producing an unstable enzyme with reduced degradation of dopamine. The evidence that this polymorphism is in itself a susceptibility gene is uncertain but as we shall see later, it may compound other risk factors for schizophrenia.
Neuregulin, dysbindin, and DISC 1 are the most replicated putative susceptibility genes for schizophrenia but other plausible candidate genes identified by linkage and follow-up studies such as G72 (D–amino acid oxidase activator, DAOA), have been suggested. G72 and several of the other putative risk genes appear to carry not only an increased risk of schizophrenia but also of bipolar disorder, and are thus congruent with the results of a twin study which suggested substantial genetic overlap between the two major psychoses.
Nevertheless, none of the above genes can yet be said to be 100 per cent proven as a cause of schizophrenia since there remain inconsistencies between the specific risk alleles and haplotypes among studies. It is unlikely that there is a simple relationship between carrying one risk allele and developing schizophrenia. Rather, an individual may need to carry a number of risk genes and be exposed to several environmental risk factors. In such a dynamic multifactorial model, several genes of small effect interact with each other and with time-specific exposure to environmental risk factors contribute to both the onset and outcome of schizophrenia.
Biological abnormalities in the relatives of people with schizophrenia
Relatives have been examined for some of the biological abnormalities which are found in their kin with schizophrenia. Thus, in the Maudsley Study of families multiply affected with schizophrenia, both the members with schizophrenia and those unaffected relatives who appeared to be transmitting the liability to the disorder (so-called obligate carriers) showed larger lateral ventricles than controls.(18, 19) McDonald et al.(20) went on to show that such families transmit a grey matter pattern that shows deficits in frontal and temporal areas and that the greater the genetic liability, the greater the deficit.
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 unaffected controls.(21) Those patients who showed an excess of saccadic distractability errors tended to have relatives with the same eye-tracking abnormalities.(22) The patients with schizophrenia and their well relatives from these multiply affected families also showed more integrative neurological abnormalities than controls.(23)
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, grey matter deficit, delayed P300, integrative neurological abnormalities) which may increase the risk of schizophrenia or at least be markers thereof. 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.(24)
Advancing paternal age in non-familial schizophrenia
An interesting finding first noted over 30 years ago is that schizophrenia is commoner in those whose fathers were old at the time they were born. One of the largest studies to demonstrate this comes from Sipos et al.(25) who studied the risk of schizophrenia in 7 54 330 people born in Sweden. The overall hazard ratio for developing schizophrenia increased with each 10 year increase in paternal age. This association between paternal age and schizophrenia has been repeatedly shown to be present in those with no family history of the disorder, but not in those with a positive family history. This stronger association between paternal age and schizophrenia in people without a family history raises the possibility that accumulation of de novo mutations in paternal sperm with ageing contributes to the risk of schizophrenia.
Environmental factors
It is evident from 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.(26) 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.(27) 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 recall bias. However, similar findings have been reported by studies examining data collected in obstetric records at the time of birth of patients and controls.(28) Indeed a meta-analysis of large epidemiologically sophisticated studies which used contemporary records confirmed that there is modest but consistent effect of obstetric complications.(29)
are healthy subjects from the general population, patients with other psychiatric disorders, and their own healthy siblings.(27) 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 recall bias. However, similar findings have been reported by studies examining data collected in obstetric records at the time of birth of patients and controls.(28) Indeed a meta-analysis of large epidemiologically sophisticated studies which used contemporary records confirmed that there is modest but consistent effect of obstetric complications.(29)
Of course, it is possible that the excess obstetric complications in schizophrenia may be the consequence of some pre-existing abnormality. Since the foetus plays an active role in the normal progress of pregnancy and labour, foetal 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 ‘obstetric complications’ covers a broad range of obstetric events. An international study on 700 schizophrenic patients and a similar number of controls found that low birth weight, prematurity, and resuscitation at birth were particularly increased in the schizophrenic patients;(27) other complications that have been implicated include retarded foetal 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.(30) 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;(31,32) furthermore, those twins who have been subjected to the most severe perinatal difficulties have the largest ventricles and smallest hippocampi.(33)
Similarly, Stefanis et al.(34) compared hippocampal volume in three groups, viz, schizophrenia patients with affected relatives but with no personal history of obstetric complications; schizophrenia patients with no affected relatives but who had a history of significant obstetric complications; and normal controls. Hippocampal volume was normal in the first schizophrenia 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.
Season of birth and maternal exposure to infection
Many studies have shown (in the Northern Hemisphere at least) that people born in late winter and spring are slightly more likely than expected to later develop schizophrenia. 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.(35) One study(36) reported an association between the presence of antibodies to the influenza virus in first trimester blood, but not during the other trimesters. The possibility that prenatal exposure to rubella may have a similar risk-increasing effect for schizophrenia has been raised, and a significant association has been reported with serologically-documented rubella exposure in gestation(37) Some studies have implicated other infectious agents such as herpes simplex, cytomegalovirus and toxoplasmosis, but there is as yet no consensus as to whether these findings are replicable or not.
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; and
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.
(a) High-risk studies
Studies of the offspring of mothers with schizophrenia, the so-called ‘high-risk studies’, show that between a quarter to a half show some deviation from normal in terms of their early development (reviewed by Davies et al.(40)) 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.(41) 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 two years of life.
(b) Follow-back studies
High-risk studies have been criticized on the basis that they are unrepresentative because only a minority of people who develop schizophrenia have a mother with the same illness. Therefore, a separate set of studies of representative groups of patients with schizophrenia have used 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.(42) The findings are not specific to schizophrenia, being
reported also in the early development of some children who later manifest an affective psychosis.(43)
reported also in the early development of some children who later manifest an affective psychosis.(43)
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.(44, 45)
Another source of material mapping early development has been childhood home videos, which have been reviewed by researchers ‘blind’ to whether the individual later manifested schizophrenia.(46) 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 two years of age.
(c) Cohort studies
Cohort studies have 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.(47) compared those who later manifested schizophrenia (n = 40), affective psychosis (n = 35), and neurotic illness (n = 79) with each other as well as with 1 914 randomly selected individuals with no history of mental illness. At age seven 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.(48) determined that 30 out of 4 746 individuals had, in adulthood, developed schizophrenia. This group was 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. Perhaps the most influential of all the cohort studies has been the Dunedin Birth Cohort Study, which followed the development of 1 037 children through the ages of 3 to 15 years, and assessed them again at the ages of 18, 21, and 26 years.(49) This study found that poorer motor development, poorer receptive language, and a lower IQ all increased the risk of subsequently developing schizophreniform disorder by age 26 years. The Dunedin cohort additionally provided evidence that a proportion of children who develop schizophrenia are already experiencing ‘quasi-psychotic’ phenomena by age 11 years.(50) These phenomena include beliefs that people are reading their minds or following or spying on them, or they are already hearing voices. Children with strong evidence of quasi-psychotic symptomatology were up to 16-times more likely to develop schizophreniform disorders by the age of 26 years; making these phenomena some of the most powerful early predictors of later psychosis.
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.
Social and geographic risk factors
Recent dogma about schizophrenia has held that the incidence does not vary by time or place, even though such an occurrence would have made schizophrenia unique among diseases! Now this curious belief has been disproved by a raft of studies. In particular, a systematic review by McGrath et al.(50) concluded that the incidence of schizophrenia shows prominent worldwide variation (up to five-fold), and that it is about 40 per cent greater in men than women.
In 1939, Faris and Dunham(52) 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.(53) This effect was 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(54) 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(55) 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(56) reported fathers of schizophrenia patients to be themselves over-represented in lower socio-economic groups. However, Jones et al.(48) 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.(57) 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.(58) 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.(59) It is now generally accepted that the incidence is higher amongst those brought up in urban areas, and that the larger the town, and the longer the individual has lived in the city, the greater the risk. The exact mechanisms underlying this effect remain unclear.
Immigration
Since the classic study of Odegaard in 1932,(60) many studies have reported that migrants are at increased risk of schizophrenia. A recent meta-analysis of 18 studies of migrants from different backgrounds confirmed a weighted mean relative risk for firstgeneration migrants of 2.7 (95 per cent CI 2.3–3.2) and for second generation migrants, 4.5 (95 per cent CI 1.5–13.1). Risk was higher for migrants from lower socio-economic countries, and for black people moving into predominantly white societies.(61)
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.(62)This is in the absence of any increased risk to Caribbeans who remain in the West Indies.(63) The increase is striking. The large and sophisticated AESOP study of three English cities demonstrated a ninefold increase in the incidence of schizophrenia among African Caribbeans, and a six-fold increase among those of African origin.(64) Boydell et al.(65) further demonstrated that migrants were especially vulnerable if relatively isolated in localities where their own ethnic group were in a small minority. 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 alone. Furthermore, there is a marked increased risk in the siblings but not the parents of this second generation;(63) this suggests an environmental effect operating particularly upon this second generation.
British-born counterparts.(62)This is in the absence of any increased risk to Caribbeans who remain in the West Indies.(63) The increase is striking. The large and sophisticated AESOP study of three English cities demonstrated a ninefold increase in the incidence of schizophrenia among African Caribbeans, and a six-fold increase among those of African origin.(64) Boydell et al.(65) further demonstrated that migrants were especially vulnerable if relatively isolated in localities where their own ethnic group were in a small minority. 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 alone. Furthermore, there is a marked increased risk in the siblings but not the parents of this second generation;(63) 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. The findings relating to skin colour potentially support the notion of perceived or real discrimination being an important variable. Other work suggests that people in certain migrant communities are particularly likely to be exposed to risk-increasing factors such as childhood adversity (e.g. parental separation) and adult social exclusion.
Life events
Brown and Birley(66) 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 study of Bebbington et al.(67) 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 or 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.(67) 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. It is clear, though, that family interventions aimed at reducing levels of expressed emotion can be effective in reducing relapse rates in the individual.
Drug abuse
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.(68)
Whether illicit substances actually cause schizophrenia has been very contentious. The most robust methodology to consider this issue is a cohort design, and a number of such studies have now investigated whether premorbid exposure to cannabis is associated with an increased later risk of schizophrenia. Arseneault et al.(69) reviewed these studies and concluded that cannabis could be considered a cumulative casual factor in some cases of schizophrenia, operating in consort with other predisposing factors to ‘tip the scales’ in some individuals who might not otherwise have manifested the disorder. This literature needs to be seen in the light of the fact that the vast majority of people who use cannabis do not develop schizophrenia, and the majority of cases of schizophrenia are not caused by cannabis; it has been estimated that the population attributable fraction for cannabis and schizophrenia is of the order of 5 per cent to 8 per cent.
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.(70, 71) 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. On balance, though, it seems reasonable to conclude that illicit substances make the longitudinal course of illness worse, and that patients with schizophrenia should be strongly advised to seek help to cease such behaviours.
Risk factors, age of onset, and outcome
Individuals who have been exposed to certain 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;(11) similarly, those twin pairs in which the schizophrenia has an early onset show the highest monozygotic concordance.(6)
Schizophrenia patients with an early age at onset of psychosis are also more likely than those with later onset to have had a history of exposure to obstetric complications,(72) while those who showed childhood deficits such as low IQ also tend to have an early onset.(45) Schizophrenia patients who abuse cannabis have also recently been shown to have an earlier onset than those who do not.
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: Gene–environment interaction
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.
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(26) 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.(73) Obstetric complications also appear to interact with, and compound, a genetic liability; the offspring of parents with schizophrenia are more likely to develop increased ventricular size following obstetric complications.
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