Epidemiology and risk factors

Epidemiology and risk factors

HISTORY, AETIOLOGY AND EPIDEMIOLOGY Epidemiology and risk factors What’s new? • The incidence of schizophrenia is increasing in certain areas Mary ...

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HISTORY, AETIOLOGY AND EPIDEMIOLOGY

Epidemiology and risk factors

What’s new? • The incidence of schizophrenia is increasing in certain areas

Mary Cannon

• Men are at greater risk of developing schizophrenia

Mary Catherine Clarke

• Cannabis use in early adolescence is associated with a significant increase in risk for later psychosis, particularly in those who are genetically vulnerable • Many environmental risk factors for schizophrenia appear to be operating during prenatal life

Who develops schizophrenia? Age and sex distribution: the age at onset of schizophrenia is usually defined as the age at onset of psychotic symptoms or the age at first hospitalization. The peak age at onset of schizophrenia is in early adulthood (between 15 and 35 years of age), but onset can also occur in childhood or old age. The mean age of onset for males is 3–4 years earlier than that for females. Peak age of onset for males is between 15 and 30 years, while females have a bimodal age of onset distribution with a peak between the ages of 20 and 35 and a second, smaller peak after the age of 45 (Figure 1).

migrants have a 4.5-fold increased risk.3 There is a greater effect size for migrants from areas where the majority of the population have black skin colour. The hospital admission rate for schizophrenia among migrants is higher in the host country than in the country of origin, implicating factors occurring principally after migration. It has been suggested that the same environmental factors are acting on the minority as on the majority group, but the former are less protected against them; minority populations are not at increased risk of developing psychotic disorders in situations where they become majority populations. Immigrants from poor countries have a 3-fold increased risk of developing schizophrenia compared to immigrants from affluent countries, implying that factors associated with improved living conditions, industrialization or urbanization are involved.3 More specifically, infection, vitamin deficiency and drug abuse have all been suggested as contributory factors but there is no strong evidence to support these links. The finding of an increased risk of schizophrenia among the siblings of secondgeneration Afro-Caribbean patients suggests a gene–environment interaction effect.

Sex differences in incidence rates: until now, the accepted wisdom has been that males and females were equally at risk of developing schizophrenia. However, recent meta-analytic reviews have shown that the incidence of schizophrenia is actually higher among men with a median male/female rate ratio of 1.40. This increased risk among males remains significant even when potentially confounding factors such as age bias, criterion bias and hospital admission bias are controlled for.1,2 There is as yet no satisfactory explanation for this sex difference. Social class: individuals with a diagnosis of schizophrenia tend to be clustered in the lower socioeconomic groups. However, this relationship is not causal, as schizophrenic patients at birth have the same socioeconomic distribution as the general population. A steep decline in social status accompanies the illness and is evident even before the clinical onset.

Distribution of age at first admission for schizophrenia in males and females

Ethnicity and immigration status: there is now robust evidence from systematic reviews that first-generation migrants have a 2.7-fold increased risk of developing schizophrenia and second-generation

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Percentage

Female Male

Mary Cannon is Consultant Psychiatrist at Beaumont Hospital, Dublin, Ireland and Senior Lecturer in Psychiatry with the Royal College of Surgeons in Ireland. She trained at University College Dublin and at the Institute of Psychiatry and the Maudsley Hospital, London, UK. Her main area of research is the developmental epidemiology of psychiatric disorders, particularly early risk factors for schizophrenia.

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0 12–14 15–19 20–24 25–29 30–34 35–39 40–44 45–49 50–54 55–59

Age group Note the bimodal age at onset pattern for females. (Adapted from Häfner et al. Br J Psychiatry 1993; 162: 316–22)

Mary Catherine Clarke is a Postdoctoral Research Fellow at the Department of Psychiatry, Royal College of Surgeons in Ireland. She has a PhD in neuropsychology from Trinity College Dublin, Ireland.

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across the world for narrowly defined schizophrenia, with rates ranging between only 7 and 14 per 100,000 (Figure 2).6 The study concluded that the rates for narrowly defined schizophrenia are the same worldwide, but the confidence intervals for these estimates were wide and there may not have been sufficient statistical power to detect differences. The incidence rates for broadly defined schizophrenia did vary significantly between countries (ranging from 16 to 42 per 100,000), with rates for centres in the developing world about twice as high as those in the developed world.

Is the incidence of schizophrenia decreasing? The incidence of schizophrenia is about 10–20 new cases per 100,000 population per year, but there is a relatively wide range in incidence rates worldwide. Register-based studies from the USA and Europe have reported a significant decline of approximately 40% in first admissions with schizophrenia since the mid-1960s. However, recent studies highlight methodological problems with these previous studies and indicate that the incidence of schizophrenia is actually increasing in certain areas. A significant increase in the incidence of schizophrenia in south-east London has been found and a previously reported decline in incidence of schizophrenia in south-west Scotland between 1979 and 1998 has been shown to be attributable to a change in diagnostic practices.4,5

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Within-country variation: the risk of schizophrenia has repeatedly been observed to be higher in urban than in rural areas (Figure 3).7 Recent work has shown that urban birth and upbringing are associated with an increased risk of developing schizophrenia in adulthood in a dose–response fashion – i.e. the risk of schizophrenia increases with duration of urban dwelling as a child. No convincing mechanism has emerged by which ‘urbanicity’ may translate into risk for psychosis.8 Urban compared to rural living is associated with greater facilitation of the transmission of infections, greater exposure to pollution and stress (e.g. neighbourhood noise) and increased health risk behaviours, like smoking, drinking and substance misuse. These environmental risk factors may make individuals more susceptible to developing psychosis by affecting early brain development and/or cognitive schemata. Wider social forces, such as discrimination or exclusion, may be at play here but are notoriously difficult to study.

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Seasonal variation of births in schizophrenia

Geographical variation in the incidence of schizophrenia Between-country variation: the World Health OrganIzatIon (WHO) 10-country study found little variation between centres

Incidence rates from the WHO multi-centre study

Incidence/100,000/year

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Schizophrenic patients have a 5–8% excess of births during the winter and spring months (January to April) in the northern hemisphere compared with the general population. There is some evidence that patients with a ‘deficit’ form of schizophrenia (i.e. mainly negative symptoms) exhibit a summer birth excess, a finding that provides support for heterogeneity within the diagnosis of schizophrenia. The reason for seasonal variation in births is not known.

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Adjusted relative risk of schizophrenia in Denmark according to place of birth

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Capital Suburb of capital

Du bl in Ho no lu lu M os co w Na ga sa ki No tti Ch n an gh di am ga rg h Ch ur an ba di n ga rg h ru ra l

Aa rh us

Incidence/100,000/year

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Provincial city Provincial town Rural area*

Incidence rates, with 95% confidence limits, of a narrowly defined schizophrenia and b broadly defined schizophrenia from eight centres in the WHO determinants of outcome study. Note the apparently higher incidence of broadly defined schizophrenia in the developing world centres (Chandigargh). (Adapted from Jablensky et al., 1992)6

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Relative risk (95% Cl) *Rural areas are used as the reference category. (Adapted from Mortensen et al., 1999)7

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Heritability of schizophrenia

The influence of early-onset cannabis use on adult psychosis is moderated by the COMT genotype

Family, twin and adoption studies provide strong evidence for a genetic component to schizophrenia, but the size and nature of the genetic contribution is still debated. Heritabilities of 80% have been proposed, but it is apparent that schizophrenia depends on a complex interaction of genetic and environmental risk factors. Risk genes for schizophrenia have now been found, but the effect sizes are small and such genes are also common in the general population.9 It is likely that a substantial proportion of the heritability of schizophrenia may be accounted for by gene–gene interactions or gene–environment interactions.

% with schizophreniform disorder at age 26 years

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No adolescent cannabis use Adolescent cannabis use 10

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Environmental risk factors for schizophrenia

Val/Met

Val/Val

COMT genotype

Birth complications: schizophrenic patients are approximately twice as likely as controls to have experienced one or more of a range of birth complications. Large population-based studies based on birth records show that these complications fall into three main categories: • problems during pregnancy (such as diabetes, bleeding, rhesus incompatibility) • problems with fetal growth and development (e.g. low birth weight, congenital malformations, small head circumference) • hypoxia-related problems.10

Adapted from Caspi et al., 200513

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with an even larger effect size – up to a four-fold increase in risk. The relationship between cannabis use and later schizophrenia is not straightforward, as the majority of early users do not develop later psychotic disorder, and it is likely that other risk factors acting interactively or synergistically may be necessary to produce the final outcome. Evidence of a gene–environment interaction in the aetiology of schizophrenia is supported by the recent finding that, in a birth cohort followed to adulthood, a functional polymorphism in the catechol-O-methyltransferase (COMT) gene interacted with adolescent-onset cannabis use to predict adult psychosis.13 Carriers of the COMT valine158 allele were most likely to exhibit psychotic symptoms and to develop schizophreniform disorder if they used cannabis in adolescence (Figure 4). This is the first evidence to be published of a measured gene–environment interaction in schizophrenia.

Prenatal risk factors for schizophrenia are more difficult to study and evidence comes mainly from ecological studies. Those identified so far include: • prenatal exposure to influenza or rubella • advanced paternal age (over 50 years of age) • rhesus incompatibility • severe nutritional deficiency during the first trimester • prenatal stress (such as loss of spouse during pregnancy). Research is now increasingly looking at the prenatal period as being important for the aetiology of schizophrenia. For example, there is a large and growing literature on the relationship between in utero exposure to infectious agents that are known to disrupt fetal brain development and the risk of adult schizophrenia. Specifically, maternal intake of analgesics due to influenza, maternal exposure to intracellular parasites (taxoplasmosis) and maternal antibody production in response to herpes have all been linked to subsequent development of psychotic illness.

Adverse life events are known to contribute to relapse in schizophrenia, but they may also have a part to play in precipitating onset. Psychosocial stress and adversity, particularly social isolation and alienation, have been suggested as mechanisms underlying the excess of schizophrenia among immigrants discussed above. Prenatal stress has been suggested as a possible mechanism underlying the association between prenatal events such as exposure to infections and experience of catastrophic events (war, tornado, nuclear explosion) with risk of schizophrenia.

Childhood developmental impairment: children who later go on to develop schizophrenia show early motor, language, cognitive, emotional and socio-behavioural developmental abnormalities compared with their peers or siblings. Early motor, language and cognitive impairments (about 0.5 standard deviations below the mean) appear to be specific for schizophrenia-related disorders.11 Emotional and socio-behavioural problems are less specific and are associated with a range of adult psychiatric disorders. Obstetric complications or poor mother–child interaction do not account for these developmental impairments and a genetic explanation is likely.

Conclusion The aetiology of schizophrenia remains a mystery and a number of risk factors, both genetic and non-genetic, appear to interact to increase the risk of schizophrenia. There has been a resurgence of interest in social factors in the aetiology of schizophrenia, but much work remains to be done to characterize precisely the genetic, prenatal and developmental risk factors involved in this complex, chronic disorder. 

Cannabis use: there is now robust replicated evidence that cannabis use is associated with a two-fold increase in the risk of later schizophrenia.12 Cannabis use in early adolescence is associated

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REFERENCES 1 Aleman A, Kahn R S, Selten J P. Sex differences in the risk of schizophrenia: evidence from meta-analysis. Arch Gen Psychiatry 2003; 60: 565–71. 2 McGrath J, Saha S, Welham J, El Saadi O, MacCauley C, Chant D. A systematic review of the incidence of schizophrenia: the distribution of rates and the influence of sex, urbanicity, migrant status and methodology. BMC Med 2004; 2: 13. 3 Cantor-Graae E, Selten J P. Schizophrenia and migration: a metaanalysis and review. Am J Psychiatry 2005; 162: 12–14. 4 Boydell J, Van Os J, Lambri M et al. Incidence of schizophrenia in south-east London between 1965 and 1997. Br J Psychiatry 2003; 182: 45–9. 5 Allardyce J, Morrison G, Van Os J, Kelly J, Murray R M, McCreadie R G. Schizophrenia is not disappearing in south-west Scotland. Br J Psychiatry 2000; 177: 38–41. 6 Jablensky A, Sartorius N, Ernberg G et al. Schizophrenia: manifestations, incidence and course in different cultures. A World Health Organization 10-country study. Psychol Med Monograph 1992; Suppl 20. 7 Mortensen P B, Pedersen C B, Westergaard T et al. Effects of family history and place and season of birth on the risk of schizophrenia. N Engl J Med 1999; 340: 603–8. 8 Van Os J. Does the urban environment cause psychosis? Br J Psychiatry 2004; 184: 287–8. 9 Harrison P J, Owen M J. Genes for schizophrenia? Recent findings and their pathophysiological implications. Lancet 2003; 361: 417–19. 10 Cannon M, Jones P B, Murray R M. Obstetric complications and schizophrenia: an historic and meta-analytic review. Am J Psychiatry 2002; 159: 1080–92. 11 Cannon M, Caspi A, Moffitt T E et al. Evidence for early-childhood, pan-developmental impairment specific to schizophreniform disorder: results from a longitudinal birth cohort. Arch Gen Psychiatry 2002; 59: 449–56. 12 Arseneault L, Cannon M, Witton J, Murray R M. Causal association between cannabis and psychosis: examination of the evidence. Br J Psychiatry 2004; 184: 110–17. 13 Caspi A, Moffitt T E, Cannon M et al. Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene x environment interaction. Biol Psychiatry 2005; 57: 1117–27.

(This is the first book dealing solely with the epidemiology of schizophrenia, written by international experts in this area. It covers the social, genetic and developmental epidemiology of schizophrenia and topics of special interest such as violence, mortality and substance misuse.) Stefan M, Travis M, Murray R M. An atlas of schizophrenia. London: Parthenon, 2002. (This colourful, lavishly illustrated book deals with the clinical features, epidemiology, pathogenesis, neurochemistry and treatment of schizophrenia.) Susser E S, Brown A S, Gorman J M, eds. Prenatal exposures in schizophrenia. Washington, DC: American Psychiatric Press, 1999. (A detailed account of prenatal risk factors for schizophrenia such as prenatal infection, rubella incompatibility and prenatal malnutrition.)

Practice points • The incidence of schizophrenia is higher among men than women and among certain ethnic minority groups • Urban birth and upbringing is a risk factor for schizophrenia, but the size of this effect at the individual level is small • Many prenatal and perinatal risk factors for schizophrenia have been identified, but their causal mechanism of action has not been elucidated • A strong link between cannabis use, particularly in adolescence, and later development of schizophrenia has been established • Early motor, language and cognitive developmental impairments appear to be specific to schizophrenia-related disorders, whereas childhood social, emotional and behavioural problems are associated with a wide range of psychiatric disorders in adulthood • Schizophrenia is likely to be due to a complex interaction of genetic and non-genetic risk factors of small effect

FURTHER READING Bark N. Risk factors for schizophrenia and implications for prevention. Int J Ment Health 2000; 29:3, 29:4, 2001; 30:1. (This special three-volume issue covers all known risk factors for schizophrenia, including genetic risk factors, proxy risk factors such as urbanization and season of birth, prenatal and perinatal complications, and later environmental risk factors such as substance abuse and life events.) Castle D, Murray R, eds. Marijuana and madness. Cambridge: Cambridge University Press, 2000. (A comprehensive overview of the neuroscience of marijuana and its impact on mental disorders. The links between cannabis and psychotic disorders are explored in detail). Murray R M, Jones P B, Susser E S, van Os J, Cannon M, eds. The epidemiology of schizophrenia. Cambridge: Cambridge University Press, 2002.

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