Show Summary Details
Page of

Epidemiology of schizophrenia 

Epidemiology of schizophrenia
Chapter:
Epidemiology of schizophrenia
Author(s):

Assen Jablensky

DOI:
10.1093/med/9780199696758.003.0075
Page of

PRINTED FROM OXFORD MEDICINE ONLINE (www.oxfordmedicine.com). © Oxford University Press, 2016. All Rights Reserved. Under the terms of the licence agreement, an individual user may print out a PDF of a single chapter of a title in Oxford Medicine Online for personal use (for details see Privacy Policy and Legal Notice).

Subscriber: null; date: 17 September 2019

Introduction

Epidemiological research into schizophrenia aims to answer four essential questions.

  • What is the ‘true’ population frequency of the disorder in various populations and how is it distributed across the various groups within populations?

  • Do the incidence, manifestations, and course of schizophrenia vary in relation to factors of the physical and social environment?

  • Who is at risk and what forces determine or influence the risk of developing schizophrenia?

  • Can the answers to the above questions help explain what causes the disorder and how to prevent it?

The hallmark of the epidemiological method (see Chapter 2.7) is the referral of a measure (numerator) of the occurrence of a disorder, or of any associated characteristics, to a population base (denominator), such as person-years at risk. The epidemiological study of diseases usually proceeds from a description of its frequency and associations (establishing rates of occurrence) to testing hypo-theses about risk factors and causes by analysing ratios between rates.

Schizophrenia has been studied extensively from an epidemiological perspective since Kraepelin(1) introduced the concept of dementia praecox in 1896. In the first half of the twentieth century, epidemiological research into schizophrenia took two divergent paths. While European studies tended to focus on population distributions and genetic risks, North American researchers investigated the social ecology of the disorder. A variety of methods were explored and successfully applied by the pioneers of psychiatric epidemiology, and the contours of the epidemiological map of schizophrenia in Europe and North America were effectively laid down between the two World Wars. The early studies were carried out by dedicated researchers who often spent months or years collecting data ‘door-to-door’ in small communities. Close knowledge of the respondents, access to multigenerational records from the local parish registers, and the cooperation of the community resulted in studies that remain landmarks of psychiatric epidemiology (Table 4.3.5.1).

Table 4.3.5.1 Historical landmarks in the epidemiology of psychoses

Author

Method

Target population

Case-finding

Assessment

Koller (1895)(2)

The first epidemiological case- control study of psychoses

Probands with psychoses (n = 287) and non-psychiatric controls (n = 370)

Records of psychiatric hospitals and clinics

Genealogical inquiry

Luxenburger (1928)(3)

Twin concordance/discordance analysis; sampling design

Monozygotic and dizygotic twin pairs

Census of inpatients; search of birth registers for twin births

Emphasis on reliability of diagnosis: ‘definite’ and ‘probable’

Brugger (1931)(4)

Census (door-to-door survey)

Area in Thuringia, population 37 561

Records and key informants consulted to detect ‘suspected’ cases

Personal examination of ‘suspected’ cases and of a control sample

Klemperer (1933)(5)

Birth cohort study

Random sample (n = 1000) from all births in Munich, 1881–90

Attempted tracing of all cohort members, 44% successfully traced

Personal examination or key informant interview (271 examined)

Ödegaard (1946)(6)

Cumulative national case register

Entire population of Norway

Registration of all first- admissions 1926–35 (n = 14 231)

Statistical analysis of hospital diagnoses and records

Essen-Möller et al. (1956);(7) Hagnell (1966)(8)

Census followed by repeated follow-up surveys

Rural community, initial population 2550 (+1013 new residents in the course of follow-up)

Complete census; tracing of migrants

Personal examination (and re-examination) of all residents

During the last several decades, the scope of epidemiological studies of schizophrenia has expanded to include populations in Asia, Africa, and South America about which little had been known previously. The World Health Organization (WHO) International Pilot Study of Schizophrenia and its successor, the WHO 10-country epidemiological study(9,10) were the first systematic investigations of the comparative incidence, clinical manifestations, and course of schizophrenia in both developing and developed countries. The WHO programme was an impetus for similar studies in India, China, the Caribbean, and Australia. Two major studies of psychiatric morbidity in the United States, the Epidemiological Catchment Area project,(11) and the National Comorbidity Survey,(12) generated data on the prevalence of DSM-III/IIIR schizophrenia and related disorders in representative population samples. In the 1980s and 1990s, epidemiological studies increasingly utilized existing large databases such as cumulative case registers or birth cohorts to test hypotheses about risk factors, and began to include methods of genetic epidemiology. There is a current tendency towards integrating epidemiological approaches with other types of aetiological research in schizophrenia. This predicts an important role for epidemiology in the era of molecular biology of mental disorders.

Epidemiological methods and instruments in the study of schizophrenia

The measurement of the prevalence, incidence, and disease expectancy of schizophrenia depends critically on the sensitivity of the case-finding method (i.e. its capacity to identify all affected persons in a given population) and the availability of a diagnostic instrument or procedure that selects ‘true’ cases (i.e. those corresponding to an established clinical concept).

Case-finding

Case-finding designs fall into three broad groups: case detection in clinical populations, door-to-door surveys of population samples or whole communities, and birth cohort studies. Each method has its advantages and limitations.

While case-finding through the mental health services provides a relatively easy access to a substantial proportion of all persons with schizophrenia, the cases in treatment may not be fully representative of all individuals with the disorder. Bias related to gender, marital status, socio-economic factors, culture, or ethnicity are known to affect the probability of being in treatment at a given time in a given setting, and generalizations about schizophrenia from hospital or clinic samples are liable to error. Some of the deficiencies of case-finding through service contacts are avoided in cumulative national or regional psychiatric case registers, which cover large well-defined populations and can be linked to other population databases (e.g. birth records). This makes registers efficient research instruments in low-incidence disorders such as schizophrenia.

Surveys involve accounting for every person at risk within a defined community or a population sample in terms of either being or not being a case. Face-to-face interviews (and follow-up) of all residents in defined communities has been a feature of some high-quality research, especially in the Scandinavian countries. However, since the size of the populations surveyed in this way is limited, the number of detected cases of schizophrenia is usually too small to generate stable estimates of epidemiological parameters. Surveys of large populations involve two basic designs: a single-phase survey of a probability sample drawn from the general population, and a two-phase survey where a validated screening test is first applied to the entire population and only those scoring as screen-positive proceed to a full assessment. In the instance of schizophrenia, logistics dictates a choice between assessing large numbers less rigorously and investigating a smaller sample in greater depth. In the absence of a simple and valid screening procedure for schizophrenia, such as a biological or psychological test, the advantages of the two-phase survey may be offset by poor sensitivity or specificity of the screening device which is usually a questionnaire or checklist.

The study of birth cohorts at ages when their members have passed through the greater part of the period of risk for onset of schizophrenia is usually done by direct interviewing or by analysing available case register data. Well-characterized birth cohorts are among the best tools for the study of the incidence of schizophrenia and associated risk factors. However, even in settings where the population is stable and mortality and morbidity are adequately monitored, the size of birth cohorts with prospectively collected data may not be sufficient for conclusive epidemiological inferences.

All this suggests that there is no single ‘gold standard’ of case-finding for schizophrenia that could be applied across all possible settings, and the assets and liabilities of particular case-finding procedures need to be evaluated in the context of each study. This makes the detailed reporting of case-finding methods a mandatory prerequisite for an ‘evidence-based’ epidemiology of schizophrenia.

Diagnosis

Variation in diagnostic concepts and practices always explains a proportion of the variation in the results of schizophrenia studies, especially if they involve different populations or different periods. Until the 1960s, the diagnostic rules used in epidemiological research were seldom explicitly stated. In the late 1960s, the WHO International Pilot Study of Schizophrenia(10) examined diagnostic variation in schizophrenia across nine countries by comparing the diagnoses made by psychiatrists using a semi-structured clinical interview with diagnostic classification by a computer algorithm(13) utilizing the same interview data. The results demonstrated that in the majority of settings psychiatrists were using comparable diagnostic concepts in the Kraepelin–Bleuler tradition. The introduction of explicit diagnostic criteria and rules with the consecutive editions of DSM and the WHO's ICD-10 improved further the reliability of diagnosis but did not resolve all diagnostic issues with implications for epidemiology. While ICD-10 and DSM-IV tend to agree well on the core cases of schizophrenia, they agree less well on the classification of atypical or milder cases. Such differences may be less important in clinical practice but they present a problem for epidemiological and genetic studies. By providing more restrictive criteria for schizophrenia, both classifications aim to identify clinically similar cases and to minimize false-positive diagnoses. This is not an unequivocal advantage for epidemiology. Applying such criteria at case-finding may result in the rejection of potential cases which fail to meet the full set of criteria at initial assessment. Therefore it is desirable to develop less restrictive screening versions of the DSM and ICD criteria for epidemiological research.

Instruments

The diagnostic instruments used in surveys which involve interviewing fall into two categories: fully structured interviews such as the Diagnostic Interview Schedule (DIS)(12) and the Composite International Diagnostic Interview (CIDI)(14) both written to match exactly the diagnostic criteria of DSM-IIIR/IV and ICD-10, and semi-structured interview schedules such as the Present State Examination (PSE)(13) and the Schedules for Clinical Assessment in Neuropsychiatry (SCAN),(15) which cover a broad range of psychopathology and elicit data that can be processed by alternative diagnostic algorithms.

The DIS/CIDI type of instrument is reliable and capable of generating standard diagnoses of common mental disorders in a single-phase survey design. Its clinical validity in schizophrenia is less certain because symptoms may not be reported accurately or impairment may be underestimated by the respondent. In contrast, the PSE/SCAN allows a greater amount of psychopathological data to be elicited in a flexible clinical interview format, but its use in epidemiological studies presupposes availability of clinically trained interviewers. While SCAN and other similar interviews are suitable as second-stage diagnostic instruments, there is still a need for a relatively simple and effective screening procedure for case-finding of schizophrenia in field surveys.

Persons, place, time: descriptive epidemiology of schizophrenia

The epidemiological description of schizophrenia draws on extensive evidence available today on its frequency, age, and sex distribution in relatively large populations or geographical areas. Less than complete information is available on variations in its epidemiological characteristics that may be found in unusual or isolated populations, or on the temporal trends in its occurrence.

Prevalence, incidence, and disease expectancy

(a) Prevalence

Prevalence provides an estimate of the number of cases per 1000 persons at risk present in a population at a given time or over a defined period. Point prevalence refers to the ‘active’ (i.e. symptomatic) cases on a given date, or within a brief census period. Since asymptomatic cases (e.g. persons in remission) will be missed in a point prevalence survey, it is useful to supplement the assessment of the present mental state with an enquiry about past episodes of the disorder to obtain a lifetime prevalence index. In schizophrenia, which tends to a chronic course, estimates of point and lifetime prevalence will be closer to each other than in remitting illnesses.

An overview of selected prevalence studies of schizophrenia spanning nearly seven decades is presented in Table 4.3.5.2. The studies differ in many aspects of methodology but the majority of them feature a high intensity of case-finding. Several studies are repeat surveys in which the original population was reinvestigated following an interval of 10 or more years (the resulting consecutive prevalence figures are indicated by arrows).

Table 4.3.5.2 Selected prevalence studies of schizophrenia

Author

Country

Population

Method

Prevalence per 1000 population at risk

Brugger (1931)(4)

Germany

Area in Thuringia (n =37 561); age 10+

Census; interview of sample

2.4

Strömgren (1938)(17); Bøjholm and Strömgren (1989)(18)

Denmark

Island population (n = 50 000)

Census interviews; repeat census

3.9→3..3

Böök (1953);(19) Böök et al. (1978)(20)

Sweden

Genetic isolate (n = 9000); age 15–50

Census interviews; repeat census

9.5→17.0

Essen-Möller et al. (1956);(7) Hagnell (1966)(8)

Sweden

Community in Southern Sweden

Census interviews; repeat census

6.7→4.5

Lin et al. (1989)(21)

Taiwan

Population sample

Census interviews; repeat census

2.1→1.4

Crocetti et al. (1971)(22)

Croatia

Sample of 9201 households

Census based on hospital records and interviews

5.9

Dube and Kumar (1972)(23)

India

Four areas in Agra (n = 29 468)

Census based on hospital and clinic records

2.6

Rotstein (1977)(24)

Russia

Population sample (n = 35 590)

Census based on hospital and clinic records

3.8

Keith et al. (1991)(25)

USA

Aggregated data across five ECA sites

Sample survey; interviews

7.0 (point) 15.0 (lifetime)

Jeffreys et al. (1997)(26)

UK

London health district (n = 112 127)

Census; interview of sample (n = 172)

5.1

Kebede et al. (1999)(27)

Ethiopia

25 districts of Addis Ababa (n = 2 228 490)

Screening by self-report questionnaire, interviews of sample (n = 2042)

7.0 (point) 9.0 (lifetime)

Jablensky et al. (2000)(28)

Australia

Four urban areas (n = 1 084 978)

Census, screen for psychosis; interviews of sample (n = 980)

3.1–5.9 (point)a 3.9–6.9 (period, one year)b

Waldo et al. (1999)(29)

Micronesia

Island of Kosrae Genetic isolate

Screen of hospital records, interviews

6.8 (point)

Arajärvi et al. (2005)(30)

Finland

Birth cohort (n = 14 817) Genetic isolate

Case register data; interviews of 55% of register cases

15.0 (lifetime) 19.0c (lifetime)

Wu et al. (2006)(31)

USA (California)

Medicaid/Medicare health insurance data

20% random sample of insured subjects

5.1 (period, 1 year)

Perälä et al. (2007)(32)

Finland

National sample (n = 8028)

Screen for psychosis, interviews of sample; register and case note data also used

10.0 (lifetime) 22.9d (lifetime)

aAll psychoses.

bSchizophrenia and other non-affective psychotic disorders.

cSchizophrenia spectrum disorders.

dNon-affective psychotic disorders.

The majority of studies have produced point prevalence estimates in the range 2.1 to 7.0 per 1000 population at risk and lifetime prevalence of schizophrenia in the range 15.0 to 19.0 per 1000. The figures are not uniformly standardized, and should be compared with caution because of demographic differences between populations related to factors such as age-specific mortality and migration. A systematic review of 188 studies in 46 countries, published between 1965 and 2002,(16) estimated the median value for point prevalence at 4.6 per 1000 persons and for lifetime prevalence at 7.2 per 1000.

Certain populations and groups deviate markedly from the central tendency. Strikingly high prevalence of schizophrenia (two to three times the national or regional average) has been found in geographically and genetically isolated populations, including small communities in Northern Sweden and Finland, and several Western Pacific islands (see Table 4.3.5.2). At the other extreme, a virtual absence of schizophrenia and a high rate of depression have been claimed for the Hutterites of South Dakota, a Protestant sect whose members live in close-knit endogamous communities sheltered from the outside world.(33) Negative social selection for schizoid individuals who fail to adjust to the lifestyle of the majority and eventually migrate without leaving progeny has been suggested (but not definitively proven) as an explanation. Results of two surveys in Taiwan,(21) separated by 15 years, point to a falling prevalence of schizophrenia (from 2.1 to 1.4 per 1000) in the context of major socio-economic change and an overall increase in total mental morbidity in the population.

The question about the extent of true variation in the prevalence of schizophrenia across populations has no simple answer. Methodological differences among studies, related to sampling, case-finding, and diagnostic assessment are likely to account for a good deal of the observed variation. As an example, the high mean prevalence rate of DSM-III schizophrenia reported from the Epidemiologic Catchment Area study in the United States(25) is difficult to reconcile with inconsistencies, such as a 13-fold difference in the rates for age group 18–24 years across the various sites of the survey. One possible reason is that the principal diagnostic instrument of the survey (DIS), administered by lay interviewers, may produce both false-positive and false-negative diagnoses of schizophrenia in a number of cases. Similarly, computer-generated diagnoses of ‘non-affective psychosis’ in the National Comorbidity Survey,(12) based on a version of the CIDI administered by lay interviewers, were found to agree poorly with clinicians’ diagnoses when a subsample of the respondents were re-interviewed over the telephone.(34)

Notwithstanding such caveats in the interpretation of survey findings, the prevalence rates are fairly similar in the majority of studies, though certain specific populations clearly deviate from the modal value. Even in those instances, however, the magnitude of the deviation is modest compared with the 10- to 30-fold dif-ferences in prevalence observed in other multifactorial diseases (e.g. diabetes, ischaemic heart disease, multiple sclerosis) across populations.

(b) Incidence

The incidence rate (an estimate of the annual number of first-onset cases in a defined population per 1000 persons at risk) is of greater interest for the study of risk factors than prevalence since it represents the so-called force of morbidity (the probability of disease occurrence) in a given population, and is closer in time to the action of antecedent or precipitating factors. The estimation of incidence depends critically on the ability to determine reliably the point of onset of the disorder. In the case of schizophrenia, the long prodromal period and the fuzzy boundary between premorbid state and onset of psychosis make this particularly difficult. In the absence of an objective biomarker of the disease, onset is usually defined as the point in time when clinical manifestations become recognizable and diagnosable according to specified criteria. The first hospital admission, which has been used as a proxy for disease onset in many studies, is not a robust indicator because of the variable time lag between the earliest appearance of symptoms and the first-admission across treatment facilities and settings. A better approximation is provided by the first-contact, i.e. the point at which any psychiatric, general medical, or alternative ‘helping’ agency is accessed by symptomatic individuals for the first time. A limitation common to both first-admission and first-contact studies is that they produce rates of ‘treated’ incidence and miss symptomatic cases that do not present for assessment or treatment. This limitation can be overcome by periodically repeated door-to-door surveys of the same population or by longitudinal cohort studies (though both are difficult to mount for reasons of cost and logistics).

Table 4.3.5.3 summarizes the essential features of 12 selected incidence studies of schizophrenia. Studies using a ‘broad’ definition of schizophrenia (ICD-8 or ICD-9) estimate about three-fold difference in the variation of rates, in the range from 0.17 to 0.57 per 1000 population per year, for first-admissions or first contacts. Studies using more stringent criteria, such as the Research Diagnostic Criteria (RDC),(121) DSM-IV, ICD-10, or Catego S+,(13) have reported incidence rates two to three times lower than those based on ‘broad’ criteria. A systematic review of data from some 160 studies from 33 countries, published between 1965 and 2001,(35) yielded a median value of 0.15 and mean value of 0.24 per 1000, with a five-fold range of the rates and a tendency for more recent studies to report lower rates.

Table 4.3.5.3 Selected incidence studies of schizophrenia

Author

Country

Population

Method

Rate per 1000

Ödegaard (1946)(6)

Norway

Total population

First-admissions 1926–35 (n = 14 231)

0.24 (Hospital diagnoses)

Walsh (1969)(36)

Ireland

City of Dublin (n = 720 000)

First-admissions

0.57 (males, ICD-8); 0.46 (females, ICD-8)

Murphy and Raman (1971)(37)

Mauritius

Total population (n = 257 000)

First-admissions

0.24 (Africans); 0.14 (Indian Hindus); 0.09 (Indian Moslems)

Lieberman (1974)(38)

Russia

Moscow district (n = 248 000)

Follow-back of prevalent cases

0.20 (males) 0.19 (females)

Helgason (1977)(39)

Iceland

Total population

First-admissions (case register)

0.27 (ICD-8)

Lin et al. (1989)(21)

Taiwan

Three communities (n = 39 024)

Door-to-door survey

0.17 (‘Bleulerian’ criteria)

Castle et al. (1991)(40)

UK

London (Camberwell)

First-admissions (case register)

0.25 (ICD-9); 0.17 (RDC); 0.08 (DSM-III)

Rajkumar et al. (1993)(41)

India

Area in Madras (n = 43 097)

Door-to-door survey and key informants

0.41 (ICD-9)

Wig et al. (1993)(42)

India

A rural area (n = 1 036 868) and an urban area (n = 348 609) in Northern India

Case-to-case finding and key informants

0.38 (urban, ICD-9); 0.09 (urban, Catego S+); 0.44 (rural, ICD-9); 0.12 (rural, Catego S+)

Brewin et al. (1997)(43)

UK

Nottingham

Two cohorts of first contacts (1978–80 and 1992–94)

0.25→0.29 (All psychoses, ICD-10); 0.14→0.09 (ICD-10 schizophrenia)

Mahy et al. (1999)(44)

Barbados

Total population (n = 262 000)

First contacts; PSE interviews; Catego

(0.32 ICD-9); (0.28 Catego S+)

Bresnahan et al. (2000)(45)

USA (California)

Birth cohort (n = 12 094)

Case register study; cumulative risk by age 38

0.93 (males, DSM-IV) 0.35 (females, DSM-IV)

Considering the methodological differences among individual studies, generalizing about the incidence of schizophrenia from pooled data may be problematic. To date, the only investigation that has applied a uniform design and common research tools to generate directly comparable incidence data for different populations is the WHO 10-country study.(9) Incidence counts in the WHO study were based on first-in-lifetime contacts with any ‘helping agency’ within defined areas (including traditional healers in the developing countries) which were monitored over a 2-year period. Potential cases and key informants were interviewed by clinicians using standardized instruments, and the timing of onset was ascertained for the majority of the patients. In 86 per cent of the 1022 patients the onset of diagnostic symptoms of schizophrenia was within the year preceding the first-contact, and therefore the first-contact incidence rate was adopted as a reasonable approximation to the ‘true’ onset rate. Two definitions of ‘caseness’, dif-fering in the degree of specificity, were used to determine incidence: a ‘broad’ clinical definition comprising ICD-9 schizophrenia and paranoid psychoses, and a more restrictive definition of PSE/Catego S+(13) ‘nuclear’ schizophrenia manifesting with Schneiderian first-rank symptoms. The rates for eight of the catchment areas are shown in Table 4.3.5.4.

Table 4.3.5.4 Incidence rates per 1000 population, age 15–54, for a ‘broad’ and a ‘narrow’ case definition of schizophrenia (WHO 10-country study)

Country

Area

‘Broad’ definition (ICD-9)

‘Narrow’ definition (CATEGO S+)

Male

Female

All

Male

Female

All

Denmark

Aarhus

0.18

0.13

0.16

0.09

0.05

0.07

India

Chandigarh (rural area)

0.37

0.48

0.42

0.13

0.09

0.11

Chandigarh (urban area)

0.34

0.35

0.35

0.08

0.11

0.09

Ireland

Dublin

0.23

0.21

0.22

0.10

0.08

0.09

Japan

Nagasaki

0.23

0.18

0.20

0.11

0.09

0.10

Russia

Moscow

0.25

0.31

0.28

0.03

0.03

0.02

United Kingdom

Nottingham

0.28

0.15

0.22

0.17

0.12

0.14

United States of America

Honolulu

0.18

0.14

0.16

0.10

0.08

0.09

(Taken from Report of the international pilot study of schizophrenia, WHO 10-country study, © World Health Organization, www.who.int)

The differences between the area rates for ‘broadly’ defined schizophrenia (0.16–0.42 per 1000) were significant (p < 0.001) but those for ‘nuclear’ schizophrenia were not, suggesting that the frequency of this diagnostic subgroup varies less across different populations. No differences were found between cases meeting only ‘broad’ ICD-9 criteria and the Catego S+ cases with regard to age at onset, or 2-year course and outcome. Therefore it is unlikely that ‘nuclear’ and ‘broad’ schizophrenia define two different clinical illnesses.

Replications of the design of the WHO 10-country study, including its research procedures and instruments, have been carried out with very similar results in India, the Caribbean, and the United Kingdom (Table 4.3.5.3).

(c) Disease expectancy (morbid risk)

This is the probability (expressed as a percentage) that an individual born into a particular population will develop the disease if he or she survives the period of risk for that disease. In the instance of schizophrenia the period of risk is usually defined as 15 to 54 years. If age- and sex-specific incidence rates are known, disease expectancy can be estimated directly by a summation of the age-specific rates within the period of risk. Alternatively, disease expectancy can be estimated indirectly from prevalence data.

The estimates of disease expectancy produced by a number of studies are fairly consistent across populations and over time. Excluding outliers, such as the northern Swedish isolate,(19,20) they vary about five-fold; in the WHO study, they range from 0.59 per cent (Aarhus) to 1.8 per cent (Chandigarh, rural area) for ICD-9 schizophrenia and from 0.26 per cent (Honolulu) to 0.54 per cent (Nottingham) for Catego S+ ‘nuclear’ schizophrenia. The frequently cited modal estimate of lifetime disease expectancy for broadly defined schizophrenia at around 1 per cent seems to be consistent with the evidence.

(d) Associations with age and sex

Schizophrenia may have its onset at any age—in childhood as well as past middle age—although the vast majority of onsets fall within the 15 to 54 years of age interval. Onsets in men peak steeply in the age group 20 to 24 years; thereafter the rate of inception remains more or less constant at a lower level. In women, a less prominent peak in the age group 20 to 24 years is followed by another increase in incidence in age groups older than 35. While the age-specific incidence up to the mid-thirties is significantly higher in men, the male-to-female ratio becomes inverted with age, reaching 1:1.9 for onsets after age 40 and 1:4 or even 1:6 for onsets after age 60. There seems to be no real ‘point of rarity’ between the symptomatology of late-onset schizophrenia and schizophrenia of an early onset.

The sex differences in mean age at onset are unlikely to be an invariant biological characteristic of schizophrenia. For example, within families carrying high-genetic risk (two or more affected members), no significant differences in age at onset have been found between male and female siblings with schizophrenia. In some populations (e.g. India and China) the male predominance in the frequency of onsets in the younger age groups is attenuated or even inverted.(46,47)

The question of whether the total lifetime risks for men and women are about the same, or different, has not been answered definitively. In the WHO 10-country study, the cumulated risks for males and females up to the of age 54 were found to be approximately equal. Scandinavian studies which followed up population cohorts into very old age (over 80) reported a higher cumulated lifetime risk in women than in men.(48)

Male–female differences have been described in relation to the premorbid history (better premorbid functioning in women), the occurrence of brain abnormalities (more frequent in men), course (a higher percentage of remitting illness episodes and shorter hospital stay in women), and outcome (higher survival rate in the community, less disability in women). However, there is no unequivocal evidence of consistent sex differences in the symptom profiles of schizophrenia, including the frequency of positive and negative symptoms. Generally, the sex differences described in schizophrenia are more likely to result from normal sexual dimorphism in brain development, as well as from gender-related social roles, rather than from sex-specific aetiological factors.

Fertility, mortality, and comorbidity

(a) Fertility

Earlier studies reported low fertility in both men and women diagnosed with schizophrenia. The mean number of children fathered by men with schizophrenia in Sweden was 0.9, and the average number of live births over the entire reproductive period of women treated for schizophrenia in Norway between 1936 and 1975 was 1.8, compared with 2.2 for the general female population.(49) Yet this phenomenon is neither universal nor consistent over time. In the WHO 10-country study,(9) the fertility of women with schizophrenia in India did not differ from that of women in the general population within the same age groups and geographic areas. Although men with schizophrenia continue to be reproductively disadvantaged, the fertility of women with schizophrenia has increased over the last decades and this trend is likely to be sustained as a result of deinstitutionalization and the greater number of people with mental disorders being able to live in the community.

(b) Mortality

Excess mortality associated with schizophrenia has been well documented by epidemiological studies on large cohorts. National case register data for Norway, 1926–1941 and 1950–1974, indicate that, while the total mortality of psychiatric patients was decreasing, the relative mortality of patients with schizophrenia remained unchanged at a level higher than twice that of the general population.(6) Similar findings have been reported from other European countries and North America, with standardized mortality ratios of 2:6 or higher for patients with schizophrenia, which corresponds to about 20 per cent reduction in life expectancy. A meta-analysis of 18 studies(50) estimated a crude mortality rate of 189 deaths per 10 000 population per year and a 10-year survival rate of 81 per cent. Mortality among males was significantly higher than among females, and the difference was primarily due to an excess in suicides and accidents. Unnatural causes apart, the leading causes of death among schizophrenia patients are similar to those in the general population, with the exception of a significantly lower than expected cancer morbidity and mortality, especially for tobacco-related malignancies in males with schizophrenia.(51) This puzzling phenomenon has been replicated by several case register and record linkage studies(52,53) and does not appear to be an artifact. Its causes remain unknown, though protective effects of both genes and antipsychotic pharmacological agents have been proposed.

The single most common cause of death among schizophrenia patients at present is suicide (aggregated standardized mortality ratios 9.6 for males and 6.8 for females) which accounts for 28 per cent of the excess mortality in schizophrenia.(54) The suicide rate in schizophrenia patients is at least equal to, or may indeed be higher, than the suicide rate in major depression. In China, the relative risk of suicide in individuals with schizophrenia compared to those without has been estimated at 23.8.(47) Several risk factors, relatively specific to schizophrenia, have been suggested: being young and male, experiencing multiple relapses and remissions, comorbid substance use, awareness of the deteriorating course of the condition, and loss of faith in treatment. Data from successive patient cohorts in Denmark,(55) United Kingdom,(56) and Australia(57) suggest an alarming trend of increasing mortality in first- admission patients with schizophrenia. In the Danish study,(55) the 5-year cumulated standardized mortality ratios increased from 5.30 (males) and 2.27 (females) between 1971 and 1973 to 7.79 (males) and 4.52 (females) between 1980 and 1982. Particularly striking was the standardized mortality ratio of 16.4 for males with schizophrenia in the first year after diagnosis. In the Australian study,(57) suicide risk was highest in the first 7 days after discharge from inpatient care. These trends seem to parallel the significant reductions in the number of psychiatric beds. Whether the increases in suicide mortality are associated with the shift in the management of schizophrenia from hospital to community care remains to be established.

(c) Comorbidity: physical disease

There is significant comorbidity in schizophrenia, comprising: (i) common medical problems and diseases that affect schizophrenia patients more frequently than attributable to chance; and (ii) certain rare conditions or abnormalities which tend to co-occur with the disorder.

Physical disease is common but tends to be seriously undetected and underdiagnosed. Between 46 per cent and 80 per cent of inpatients with schizophrenia, and between 20 per cent and 43 per cent of outpatients, have been found in different surveys to have concurrent medical illnesses.(58) Persons with schizophrenia, and especially those who are homeless or injection drug users, are at increased risk for potentially life-threatening communicable diseases, such as HIV/AIDS, hepatitis C, and tuberculosis.(59,60) Among the chronic non-communicable diseases, patients with schizophrenia have significantly higher than expected rates of epilepsy, diabetes, arteriosclerosis, and ischaemic heart disease.(61–63) Obesity and the concomitant metabolic syndrome involving insulin resistance are becoming increasingly common problems in schizophrenia patients.(64) Although a high incidence of diabetes in schizophrenia patients had been described long before the introduction of neuroleptic treatment, a contributing role for some of the second-generation antipsychotic agents has not been ruled out.

Some rare genetic or idiopathic disorders, such as metachromatic leucodystrophy, acute intermittent porphyria, and coeliac disease, as well as dysmorphic features such as high-steepled palate, malformed ears and other minor physical anomalies have also been reported to co-occur with schizophrenia.(65,66) On the other hand, several studies have found a lower than expected rate of rheumatoid arthritis in schizophrenia patients.(67)

(d) Comorbidity: substance abuse

Substance abuse is at present by far the most common associated health problem among patients with schizophrenia(68) and may involve any drug of abuse or a polydrug combination. It seems, however, that the addictive use of cannabis, stimulants, and nicotine is disproportionately high among schizophrenia patients and may be linked to the underlying neurobiology of the disorder.(69,70) In a nationwide sample of patients with psychotic disorders in Australia,(28) a lifetime diagnosis of comorbid drug abuse, or dependence was made in 36.3 per cent of males and 15.7 per cent of females with schizophrenia (compared to 3.1 per cent and 1.3 per cent respectively in the general population). In addition to poor prognosis of schizophrenia in patients with heavy cannabis use,(71) a systematic review of published data on cannabis exposure and the onset of schizophrenia(72) concluded that early use increased the risk of psychosis in a dose-related manner, especially in persons at high genetic risk of schizophrenia. Similarly, stimulants tend to exacerbate acute psychotic symptoms in over 50 per cent of schizophrenia patients.(73) The prevalence of cigarette smoking among schizophrenia patients is, on the average, two to three times higher than in the general population,(74) but the evidence regarding any adverse effects of nicotine use on the onset and course of schizophrenia is equivocal. A population cohort study(75) found that smoking at ages 18–20 was associated with a lower risk of schizophrenia in later life and could have a specific neuroprotective effect independent of its overall harmful impact on health.

Geographical and cultural variation

To date, no population or culture has been identified in which schizophrenic illnesses do not occur. Also, there is no strong evidence that the incidence of schizophrenia is either uniform, or varies widely across populations, provided that the populations being compared are large enough to minimize the effects of small-area variation. The evidence that specific psychosocial or cultural factors play an aetiological role in schizophrenia is also inconsistent.(76) However, there are well-replicated findings of variations in the course and outcome of schizophrenia across populations and cultures that involve, above all, a higher rate of symptomatic recovery and a lower rate of social deterioration in traditional rural communities. Data supporting this conclusion were provided by the WHO studies(9) which found a higher proportion of recovering or improving patients in developing countries such as India and Nigeria than in the developed countries. Sampling bias (e.g. a higher percentage of acute-onset schizophreniform illnesses of good prognosis among Third World patients) was not a likely explanation. A better outcome in the developing countries was found in patients with various modes of onset, and the initial symptoms of the disorder did not distinguish good-outcome from poor- outcome cases. What causes such differences in the prognosis of schizophrenia remains largely unknown. The follow-up in the WHO studies demonstrated that the outcome of paranoid psychoses and affective disorders was also better in the developing countries. Such a general effect on the outcome of psychiatric disorders may result from psychosocial factors, such as availability of social support networks, non-stigmatizing beliefs about mental illness, and positive expectations during the early stages of psychotic illness, as well as from unknown genetic or ecological (including nutritional) factors influencing brain development.

The disease and disability burden of schizophrenia

According to WHO estimates(77,78) no less than 25 per cent of the total ‘burden of disease’ in the established market economies is at present attributable to neuropsychiatric conditions. Measured as proportion of the disability-adjusted life-years (DALYs) lost, schizophrenia, bipolar affective disorder, and major depression together account for 10.8 per cent of the total, i.e. they inflict on most communities losses that are comparable to those due to cancer (15 per cent) and higher than the losses due to ischaemic heart disease (9 per cent).

An epidemiological perspective on risk factors and antecedents

Studies on clinical samples suggest a great variety of putative risk factors in schizophrenia. As clinical samples are rarely representative and often vulnerable to bias, epidemiological evidence helps in evaluating the significance of such conjectures. Genetic and environmental risk factors are considered further in Chapter 4.3.6.1.

Genetic risk: necessary and sufficient?

Family aggregation of schizophrenia is at present the only epidemiologically well-established risk factor for the disorder, with a relative risk for first-degree relatives of persons with schizophrenia in the range from 9 to 18. Allowing for diagnostic variation, the risk estimates generated by different studies are similar and suggest a general pattern of descending risk as the proportions of shared genes between any two individuals decrease.(79,80) Although heritability (commonly estimated at about 80 per cent) provides the basis for the search of specific genes and gene networks involved in schizophrenia causation, the extent to which genetic vulnerability alone is necessary and sufficient to produce the disorder remains unclear. While an environmental contribution to the aetiology of schizophrenia is highly plausible, the evidence in support of it is inferential, typically proceeding from the observation that the concordance for schizophrenia in monozygotic twins (sharing 100 per cent of their genes) is only about 50 per cent. The majority of investigators now agree that genes and environments should be studied jointly and three models of conjunction have been proposed(81):

  • The effects of predisposing genes and environmental factors are additive and increase the risk of disease in a linear fashion;

  • Genes modulate the sensitivity of the brain to environmental insults;

  • By fostering certain personality traits and associated behaviour, genes influence the likelihood of an individual's exposure to stressful environments.

Epidemiological research into possible environmental contributions to the causation of schizophrenia focuses on three main areas: pre- and perinatal brain damage, factors affecting neurodevelopment from infancy to late adolescence, and factors of the social and urban ecology. (See also Chapter 4.3.6.1)

Factors maintaining the incidence of schizophrenia in populations

Since the first epidemiological study on the reproduction patterns of people with psychoses,(82) reduced fertility among individuals with schizophrenia has been documented by numerous investigators. Coupled with the evidence that the lifetime risk of the disorder (about 1 per cent) is similar across populations and remains stable over time, the question about factors that sustain the incidence of schizophrenia despite a reduced reproductive fitness. An early hypothesis was proposed in 1964 by Huxley et al.(83) who argued that the high frequency of schizophrenia was evidence of ‘genetic morphism’ (a balanced polymorphism) whereby the low fertility of affected individuals could be compensated for by a higher than average fertility of clinically unaffected ‘cryptoschizophrenic carriers’ who possessed some selective advantage, e.g. resistance to shock, autoimmune disease, or infection. However, attempts to demonstrate such advantage in terms of disease resistance, adaptability to extreme environments, or ability and creativity, have been unsuccessful. Importantly, the selective advantage hypothesis assumed that schizophrenia was a single-gene disorder with low penetrance, whereas the majority of investigators today agree that schizophrenia is a complex polygenic disorder with incomplete or variable expression of the genotype, and widespread locus and allelic heterogeneity. The polygenic model implies that loss of susceptibility alleles resulting from the lower reproductive fitness of affected individuals would have a negligible effect on the overall gene pool in the population. The more recent hypothesis, that de novo germ-line mutations inherited from an ageing father(84) may be responsible for a substantial proportion of incident cases of schizophrenia, is difficult to reconcile with current knowledge that mutation rates for most human genes are within the range of 10−6 to 10−5 per generation, i.e. their contribution to the maintenance of schizophrenia in the population would be insignificant. Considering that both multiple genes and multiple exogenous factors are likely to be involved in the causation of schizophrenia, neither increased fertility in asymptomatic carriers of the risk genes, nor paternal inheritance of germ-line mutations appear to be necessary or sufficient for the persistence of the disorder.

Environmental insults during early development

(a) Season of birth

A 5 per cent to 8 per cent winter–spring excess of schizophrenic births was first described in 1929(85) and since then reported by numerous studies, mostly in the northern hemisphere (southern hemisphere data are less consistent). Though some of these studies did not have the sample size or statistical design needed to definitively prove or rule out a seasonal effect, winter–spring births were associated with a mild but significant increase of the relative risk for schizophrenia (RR = 1.11; CI 1.06–1.18) in a large population cohort from Denmark.(86) Thus, birth seasonality appears to be a robust finding in the epidemiology of schizophrenia,(87) though few biologically plausible and testable causal hypotheses have been advanced to explain it. One of them is the seasonally increased risk of intrauterine exposure to viral infection.

(b) Prenatal exposure to infection

In utero exposure to influenza has been implicated as a risk factor since a report that a significant proportion of adult schizophrenia in Helsinki was associated with presumed second-trimester in utero exposure to the 1957 A2 influenza epidemic.(88) Numerous studies, attempting to replicate the link between maternal influenza and schizophrenia, have since reached conflicting results, with negative findings reported from an increasing number of studies based on large population samples,(89,90) as well as studies including data on schizophrenia risk in the offspring of women with prospectively recorded influenza infection during pregnancy.(91) However, positive association between schizophrenia in the offspring and maternal infection during pregnancy has been reported for rubella(92) and toxoplasmosis(93) and the issue of prenatal infection contributing to schizophrenia risk merits further study.

(c) Pregnancy and birth complications

Maternal obstetric complications, ranging from placental abnormalities in the first trimester of pregnancy to diabetes, pre-eclampsia, perinatal hypoxia, and low birth weight, are widely regarded to be risk factors in schizophrenia. This view is supported by a number of studies of small to moderate size, typically using a case-control design and relying on maternal recall of adverse events during pregnancy.(94) Population-based studies(95,96) using prospectively recorded obstetric data tend to report conflicting or inconclusive results, with generally small effect sizes (odds ratio less than two) for any positive findings.(97) However, several birth cohort studies with long-term follow-up have found significantly increased risk of adult schizophrenia in individuals who had survived severe, mainly hypoxic perinatal brain damage.(98,99) Birth weight (adjusted for gestation) is another factor that may have a complex relationship with schizophrenia risk. A large cohort study in Sweden(100) found a reverse J-shaped association between birth weight and adult schizophrenia, with significant hazard ratios of 7.03 for males of low birth weight (<2500 g) and 3.37 for those of high birth weight (>4000 g). It remains unclear, however, if severe obstetric complications, such as perinatal hypoxia or low birth weight, are capable of raising substantially the risk of schizophrenia in the adult in the absence of increased genetic risk. Maternal schizophrenia is associated with a higher rate of pregnancy complications, including low birth weight,(101) but it is not known if the effects of genetic liability and obstetric complications on schizophrenia risk in the offspring are additive or interactive. It is also possible that genetic predisposition sensitizes the developing brain to lesions resulting from randomly occurring less severe obstetric complications. Such gaps in knowledge or inconsistencies among research findings caution against an unqualified acceptance of obstetric complication as a proven risk factor in schizophrenia. Clarification of their role remains an important priority for epidemiological research.

Further information about studies of obstetric complications and hypoxic-ischaemic damage as risk factors for schizophrenia can be found in Chapter 4.3.6.1.

Developmental antecedents of schizophrenia

(a) Brain development and neurobehavioural markers

Children at high genetic risk for schizophrenia (i.e. having parents or other first-degree relatives with the disorder) tend to show early signs of aberrant neurodevelopment, including ventricular enlargement on computerized tomography(102) and decreased activation in the prefrontal and parietal regions of the heteromodal association cortex on functional magnetic resonance imaging.(103) Such imaging studies are limited by small sample size and their results may not be generalizable. However, population-based or cohort studies, such as the National Child Development Study in the United Kingdom have demonstrated a higher incidence of abnormal motor and speech development before 2 years of age, and of soft neurological signs (poor motor control, coordination, and balance), non-right handedness and speech defects between ages 2–15.(104)

(b) Cognitive and neurophysiological markers

Deficits in verbal memory, sustained attention and executive functions, as well as abnormalities in event-related brain potentials and oculomotor control(105–107) are common in patients with schizophrenia and antedate the onset of clinical symptoms. They also occur in a proportion of their clinically normal biological relatives, but are rare in control subjects drawn from the general population (see Chapter 4.3.3). Their specificity to schizophrenia needs to be investigated in larger population samples. Should such endophenotypes be validated as biological markers of schizophrenia by epidemiological studies, the power of risk prediction at the level of the individual is likely to increase substantially.

(c) Premorbid intelligence (IQ)

In a cohort study from Sweden,(108) involving a 15-year follow-up of 109 643 men conscripted into the army at age 18 to 20, the individuals who subsequently developed schizophrenia were compared with the rest of the cohort on the performance of IQ-related tests and tasks at the time of conscription. Controlling for potential confounders, the risk of schizophrenia was found to increase linearly with the decrement of IQ. The effect was mainly attributable to poor performance on verbal tasks and tests of reasoning. Similar results have been reported from a study in Israel linking psychometric assessment data of the army draft board with the national psychiatric case register.(109)

Premorbid social impairment

Individuals who develop schizophrenia as adults are more likely to manifest difficulties in social interaction during childhood and adolescence than individuals who do not develop schizophrenia. Among children at increased genetic risk (having a parent with schizophrenia), those who develop schizophrenia as adults have been found to show poorer social competence at age 7 to 12 and more passivity and social isolation in adolescence, as compared to those who do not develop the disorder.(110) The association between early ‘schizoid’ traits and risk of schizophrenia is not restricted to offsprings of parents with schizophrenia. Population-based evidence of early socialization difficulties (school problems, social anxiety, and preference for solitary play) in children who develop schizophrenia as adults is provided by the prospective study of a national birth cohort in the United Kingdom.(104) In the Swedish conscript study,(108) poor social adjustment during childhood and adolescence was significantly more common among those who subsequently developed schizophrenia than among those who did not. It should be noted, however, that the early behavioural traits that tend to be associated with schizophrenia in adult life have low specificity and their predictive value is limited.

Further information about studies of premorbid social impairment can be found in Chapter 4.3.6.1.

The social and family environment

(a) Early rearing environment

Support for an effect of the early rearing family environment on the risk of developing schizophrenia is provided by a study of a Finnish sample of adopted children born to mothers with schizophrenia (a high-risk group) and a control sample of adoptees at no increased genetic risk.(111) Though the rates of adult psychosis or severe personality disorder were significantly higher in the high-risk group compared with the control group, the difference was entirely attributable to a subset of the high-risk children who grew up in dysfunctional or otherwise disturbed adoptive families—a result consistent with a gene-environment model of genetic influence on a person's sensitivity to psychosocial adversity.

(b) The urban environment

Earlier hypotheses that urban environments increase the risk of psychosis, either by contributing to causation (the breeder effect) or by attracting vulnerable individuals (the drift effect), have been revived in the light of recent epidemiological findings suggesting that urban birth is associated with a moderate but statistically significant increase in the incidence of schizophrenia, affective psychoses, and other non-affective psychoses.(112) It remains unclear whether the effect is linked to a factor operating pre- or perinatally, or a factor influencing postnatal development (see also Chapter 4.3.6.1).

(c) Social class

Since the 1930s, numerous studies in North America and Europe have consistently found that the economically disadvantaged social groups contribute disproportionately to the first-admission rate for schizophrenia. Two explanatory hypotheses, of social causation (‘breeder’) and of social selection (‘drift’), were originally proposed.(113) According to the social causation theory, the greater socio-economic adversity characteristic of lower-class living conditions could precipitate psychosis in genetically vulnerable individuals who have a restricted capacity to cope with complex or stressful situations. In the 1960s, this theory was considered to be refuted by a single study(114) which found that the social class distribution of the fathers of schizophrenic patients did not deviate from that of the general population, and that the excess of low socio-economic status among schizophrenic patients was mainly attributable to individuals who had drifted down the occupational and social scale prior to the onset of psychosis. As a result, aetiological research in schizophrenia in recent decades has tended to ignore such ‘macrosocial’ variables. However, the possibility remains that social stratification, socio-economic status, and acculturation stress are contributing factors in the causation of schizophrenia.

(d) Migrants and ethnic minorities

An exceptionally high-incidence rate of schizophrenia (about 6.0 per 1000) has been found in the African–Caribbean population in the United Kingdom.(115,116) The excess morbidity is not restricted to recent immigrants and is higher in the British-born second generation of migrants. Similar findings of nearly four-fold excess over the general population rate have been reported for the Dutch Antillean and Surinamese immigrants in Holland.(117)

The causes of the phenomenon remain obscure. Incidence studies in the Caribbean do not indicate any excess morbidity in the indigenous populations from which migrants are recruited. Explanations in terms of biological risk factors have found little support.(118,122) A finding in need of replication is the significant increase of schizophrenia among the siblings of second-generation African–Caribbean schizophrenia patients compared with the incidence of schizophrenia in the siblings of white patients.(119) Such ‘horizontal’ increase in the morbid risk suggests that an environmental factor may be modifying the penetrance of the genetic predisposition to schizophrenia carried by a proportion of the African–Caribbean population. Psychosocial hypotheses involving acculturation stress, demoralization due to racial discrimination, and blocked opportunities for upward social mobility have been suggested but not yet definitively tested (see also Chapter 4.3.6.1).

Epidemiological issues for the next decade

The unprecedented growth of basic knowledge about the brain and the human genome opens up novel perspectives and opportunities in the study of complex disorders such as schizophrenia, which integrate concepts and tools of genetics, neuroscience, and epidemiology. Several issues with wide implications for future research are already emerging.

Is schizophrenia a single disease or a group of aetiologically distinct disorders?

Schizophrenia is characterized by extensive phenotypic variability and likely genetic heterogeneity. These two factors may be contributing disproportionately to the multitude of research findings that are inconsistent or difficult to replicate and there is increasing concern that the categorical diagnostic concept of schizophrenia may not demarcate a biologically homogeneous entity.(120) The likely existence of different subtypes of the disorder (Bleuler's notion of a ‘group of schizophrenias’) is rarely considered in genetic and other biological research into schizophrenia. Disaggregating a complex phenotype by identifying intermediate (endo-) phenotypes and quantitative traits as covariates has been a successful strategy in the genetic study of disorders such as type I diabetes, asthma, and dementia. While the clinical concept of schizophrenia as a broad syndrome with some internal cohesion and a characteristic course over time is well supported by current epidemiological evidence, its dissection into modular endophenotypes with specific neurocognitive and neurophysiological underpinnings is beginning to be perceived as a promising approach in schizophrenia genetics. The study of endophenotypes cutting across the conventional diagnostic boundaries may reveal unexpected patterns of associations with symptoms, personality traits or behaviours, as well as genetic polymorphisms, providing epidemiology with rich material for hypothesis testing at population level.

Molecular epidemiology of schizophrenia

Notwithstanding the difficulties accompanying the genetic dissection of complex disorders, novel methods of genetic analysis will eventually identify genomic regions, genes, and interacting gene networks underlying the predisposition to schizophrenia. The majority of genes involved are believed to be of small effect, although one cannot exclude the possibility that genes of moderate effects may also be found, especially in relation to the neurophysiological abnormalities associated with schizophrenia. Clarifying the function of such genes will be a complex task. Part of the solution is likely to be found in the domain of epidemiology, since establishing their population frequency and associations with a variety of phenotypic expressions is a prerequisite for understanding their causal role. Thus the molecular epidemiology of schizophrenia is likely to be the next major chapter in the search for its causes and cures.

Can schizophrenia be prevented?

The increasing investment in early diagnosis and treatment of first episodes of schizophrenia has raised questions whether people likely to develop schizophrenia can be reliably recognized prior to the onset of symptoms, and whether early pharmacological, cognitive, or social intervention can prevent the development of the disorder. While early diagnosis and timely treatment of symptomatic cases may improve the short- or medium-term outcome, the detection of people at risk with a view to preventative intervention is problematic. Screening young age groups in the population by using predictors such as family history of psychosis, obstetric complications, or abnormal eye tracking is likely to result in multiple false-positive and false-negative results and a generally low positive predictive value. Other candidate risk factors have not been evaluated at all epidemiologically. Problems of reliability of measurement apart, population-based screening will pose huge practical and ethical problems of having to treat a large number of individuals who do not have the disorder and missing many others who eventually will develop the disorder. From an epidemiological point of view, pre-symptomatic detection and preventative intervention in schizophrenia do not appear to be feasible for the time being.

Summary and conclusions

After nearly a century of epidemiological research, essential questions about the nature and causes of schizophrenia still await answers. Two major conclusions stand out.

  • The clinical syndrome of schizophrenia is robust and can be identified in diverse populations, regardless of wide-ranging demographic, ecological, and cultural differences among them. This suggests that a common pathophysiology is likely to underlie the characteristic symptoms of schizophrenia. On balance, the evidence suggests that schizophrenia incidence and disease risk show relatively modest variation at the level of large population aggregates. However, the study of ‘atypical’ populations or pockets of very high or very low frequency of schizophrenia, such as in genetic isolates or minority groups, may provide novel clues to the aetiology and pathogenesis of disorder.

  • No single environmental risk factor of major effect on the incidence of schizophrenia has yet been discovered. Further studies using large samples are required to evaluate potential risk factors, antecedents, and predictors for which the present evidence is inconclusive. Assuming that methodological pitfalls will be avoided by risk-factor epidemiology, and that multiple environmental risk factors of small to moderate effect will eventually be identified, the results will complement those of genetic research which also implicate multiple genes and networks. All this suggests that the key to understanding schizophrenia is likely to be in the unraveling of complex gene-environment interactions.

Further information

Susser, E., Schwartz, S., Morabia, A., and Bromet, E. (eds.) (2006). Psychiatric epidemiology. Searching for the causes of mental disorders. Oxford University Press, Oxford.Find this resource:

    Murray, R.M., Jones, P.B., Susser, E., van Os, J., and Cannon, M. (eds.) (2003). The epidemiology of schizophrenia. Cambridge University Press.Find this resource:

      Hirsch, S.R. and Weinberger, D.R. (eds.) (2003). Schizophrenia (2nd edn). Blackwell Science, Oxford.Find this resource:

      www.schizophreniaforum.org Schizophrenia Research Forum (sponsored by NARSAD, the Mental Health Research Association, through a contract with the National Institute of Mental Health).

      References

      1. Kraepelin, E. (1896). Psychiatrie. Ein Lehrbuch für Studirende und Aerzte. Barth, Leipzig (Reprint: edition 1976 by Arno Press Inc., New York).Find this resource:

        2. Koller, J. (1895). Beitrag zur Erblichkeitsstatistik der Geisteskrankheiten in Canton Zürich. Archiv für Psychiatrie, 27, 269–94.Find this resource:

          3. Luxenburger, H. (1928). Vorläufiger Bericht über psychiatrische Serienuntersuchungen an Zwillingen. Zeitschrift für die gesamte Neurologie und Psychiatrie, 116, 297–326.Find this resource:

          4. Brugger, C. (1931). Versuch einer Geisteskrankenzählung in Thüringen. Zeitschrift für die gesamte Neurologie und Psychiatrie, 133, 252–390.Find this resource:

            5. Klemperer, J. (1933). Zur Belastungsstatistik der Durchschnittsbevölkerung. Psychosehäufigkeit unter 1000 stichprobenmässig ausgelesenen Probanden. Zeitschrift für die gesamte Neurologie und Psychiatrie, 146, 277–316.Find this resource:

            6. Ödegaard, Ö. (1946). A statistical investigation into the incidence of mental disorders in Norway. The Psychiatric Quarterly, 20, 381–401.Find this resource:

            7. Essen-Möller, E., Larsson, H., Uddenberg, C.E., et al. (1956). Individual traits and morbidity in a Swedish rural population. Acta Psychiatrica et Neurologica Scandinavica, (Suppl. 100), 1–136.Find this resource:

              8. Hagnell, O. (1966). A prospective study of the incidence of mental disorder. Svenska Bokforlaget, Lund.Find this resource:

                9. Jablensky, A., Sartorius, N., Ernberg, G., et al. (1992). Schizophrenia: manifestations and course in different cultures. A World Health Organization ten-country study. Psychological Medicine, Monograph Supplement, 20, 1–97.Find this resource:

                10. World Health Organization. (1973). The international pilot study of schizophrenia, Vol. 1. WHO, Geneva.Find this resource:

                  11. Robins, L.N. and Regier, D.A. (eds.) (1991). Psychiatric disorders in America. The Epidemiologic Catchment Area Study. Free Press, New York.Find this resource:

                    12. Kessler, R.C., McGonagle, K.A., Zhao, S., et al. (1994). Lifetime and 12-month prevalence of DSM-IIIR psychiatric disorders in the United States. Results from the National Comorbidity Survey. Archives of General Psychiatry, 51, 8–19.Find this resource:

                    13. Wing, J.K., Cooper, J.E., and Sartorius, N. (1974). The measurement and classification of psychiatric symptoms. Cambridge University Press, Cambridge.Find this resource:

                      14. Robins, L.N., Wing, J., Wittchen, H.U., et al. (1988). The Composite International Diagnostic Interview: an epidemiologic instrument suitable for use in conjunction with different diagnostic systems and in different cultures. Archives of General Psychiatry, 45, 1069–77.Find this resource:

                      15. Wing, J.K., Babor, T., Brugha, T., et al. (1990). SCAN. Schedules for clinical assessment in neuropsychiatry. Archives of General Psychiatry, 47, 589–93.Find this resource:

                      16. Saha, S., Chant, D., Welham, J., et al. (2005). A systematic review of the prevalence of schizophrenia. PLoS Medicine, 2, 413–33. (www.plosmedicine.org)

                      17. Strömgren, E. (1938). Beiträge zur psychiatrischen Erblehre, auf Grund von Untersuchungen an einer Inselbevölkerung. Acta Psychiatrica et Neurologica Scandinavica, (Suppl. 19), 1–86.Find this resource:

                        18. Bøjholm, S. and Strömgren, E. (1989). Prevalence of schizophrenia on the island of Bornholm in 1935 and in 1983. Acta Psychiatrica Scandinavica, 79(Suppl. 348), 157–66.Find this resource:

                          19. Böök, J.A. (1953). A genetic and neuropsychiatric investigation of a North Swedish population (with special regard to schizophrenia and mental deficiency). Acta Genetica, 4, 1–100.Find this resource:

                          20. Böök, J.A., Wettenberg, L., and Modrzewska, K. (1978). Schizophrenia in a North Swedish geographical isolate, 1900–1977: epidemiology, genetics and biochemistry. Clinical Genetics, 14, 373–94.Find this resource:

                          21. Lin, T.Y., Chu, H.M., Rin, H., et al. (1989). Effects of social change on mental disorders in Taiwan: observations based on a 15-year follow-up survey of general population in three communities. Acta Psychiatrica Scandinavica, 79(Suppl. 348), 11–34.Find this resource:

                          22. Crocetti, G.J., Lemkau, P.V., Kulcar, Z., et al. (1971). Selected aspects of the epidemiology of psychoses in Croatia, Yugoslavia, II. The cluster sample and the results of the pilot survey. American Journal of Epidemiology, 94, 126–34.Find this resource:

                          23. Dube, K.V. and Kumar, N. (1972). An epidemiological study of schizophrenia. Journal of Biosocial Science, 4, 187–95.Find this resource:

                          24. Rotstein, V.G. (1977). Material from a psychiatric survey of sample groups from the adult population in several areas of the USSR. Zhurnal Nevropatologii I Psikhiatrii, 77, 569–74 (in Russian).Find this resource:

                          25. Keith, S.J., Regier, D.A., and Rae, D.S. (1991). Schizophrenic disorders. In Psychiatric disorders in America. The Epidemiologic Catchment Area Study (eds. L.N. Robins and D.A. Regier), pp. 33–52. Free Press, New York.Find this resource:

                            26. Jeffreys, S.E., Harvey, C.A., McNaught, A.S., et al. (1997). The Hampstead schizophrenia survey 1991. I. Prevalence and service use comparisons in an inner London health authority, 1986–1991. The British Journal of Psychiatry, 170, 301–6.Find this resource:

                            27. Kebede, D. and Alem, A. (1999). Major mental disorders in Addis Ababa, Ethiopia. I. Schizophrenia, schizoaffective and cognitive disorders. Acta Psychiatrica Scandinavica, 100, 11–7.Find this resource:

                            28. Jablensky, A., McGrath, J., Herrman, H., et al. (2000). Psychotic disorders in urban areas: an overview of the Study on Low Prevalence Disorders. The Australian and New Zealand Journal of Psychiatry, 34, 221–36.Find this resource:

                            29. Waldo, M.C. (1999). Schizophrenia in Kosrae, Micronesia: prevalence, gender ratios, and clinical symptomatology. Schizophrenia Research, 35, 175–81.Find this resource:

                            30. Arajärvi, R., Suvisaari, J, Suokas, J., et al. (2005). Prevalence and diagnosis of schizophrenia based on register, case record and interview data in an isolated Finnish birth cohort born 1940–1969. Social Psychiatry and Psychiatric Epidemiology, 40, 808–16.Find this resource:

                            31. Wu, E.Q., Shi, L., Birnbaum, H., et al. (2006). Annual prevalence of diagnosed schizophrenia in the USA: a claims data analysis approach. Psychological Medicine, 36, 1535–40.Find this resource:

                            32. Perälä, J., Suvisaari, J., Saarni, S.I., et al. (2007). Lifetime prevalence of psychotic and bipolar I disorders in a general population. Archives of General Psychiatry, 64, 19–28.Find this resource:

                            33. Eaton, J.W. and Weil, R.J. (1955). Culture and mental disorder. A comparative study of the Hutterites and other populations. Free Press, Glencoe, IL.Find this resource:

                              34. Kendler, K.S., Gallagher, T.J., Abelson, J.M., et al. (1996). Lifetime prevalence, demographic risk factors, and diagnostic validity of nonaffective psychosis as assessed in a US community sample. Archives of General Psychiatry, 53, 1022–31.Find this resource:

                              35. McGrath, J., Saha, S., Welham, J., et al. (2003). A systematic review of the incidence of schizophrenia: the distribution of rates and the influence of sex, urbanicity, migrant status and methodology. BMC Medicine, 2, 1–22. (www.biomedcentral.com/1741-7015/2/13)

                              36. Walsh, D. (1969). Mental illness in Dublin–first admissions. The British Journal of Psychiatry, 115, 449–56.Find this resource:

                              37. Murphy, H.B.M. and Raman, A.C. (1971). The chronicity of schizophrenia in indigenous tropical peoples. Results of a twelve-year follow-up survey in Mauritius. The British Journal of Psychiatry, 118, 489–97.Find this resource:

                              38. Lieberman, Y.I. (1974). The problem of incidence of schizophrenia: material from a clinical and epidemiological study. Zhurnal Nevropatologii I Psikhiatrii, 74, 1224–32 (in Russian).Find this resource:

                              39. Helgason, L. (1977). Psychiatric services and mental illness in Iceland. Acta Psychiatrica Scandinavica, 53(Suppl. 268), 1–140.Find this resource:

                              40. Castle, D., Wessely, S., Der, G., et al. (1991). The incidence of operationally defined schizophrenia in Camberwell, 1965–1984. The British Journal of Psychiatry, 159, 790–4.Find this resource:

                              41. Rajkumar, S., Padmavati, R., Thara, R., et al. (1993). Incidence of schizophrenia in an urban community in Madras. Indian Journal of Psychiatry, 35, 18–21.Find this resource:

                              42. Wig, N.N., Varma, V.K., Mattoo, S.K., et al. (1993). An incidence study of schizophrenia in India. Indian Journal of Psychiatry, 35, 11–7.Find this resource:

                              43. Brewin, J., Cantwell, R., Dalkin, T., et al. (1997). Incidence of schizophrenia in Nottingham. The British Journal of Psychiatry,171, 140–4.Find this resource:

                              44. Mahy, G.E., Mallett, R., Leff, J., et al. (1999). First-contact incidence rate of schizophrenia on Barbados. The British Journal of Psychiatry, 175, 28–33.Find this resource:

                              45. Bresnahan, M.A., Brown, A.S., Schaefer, C.A., et al. (2000). Incidence and cumulative risk of treated schizophrenia in the prenatal deter-minants of schizophrenia study. Schizophrenia Bulletin, 26, 297–308.Find this resource:

                              46. Murthy, G.V.S., Janakiramaiah, N., Gangadhar, B.N., et al. (1998). Sex difference in age at onset of schizophrenia: discrepant findings from India. Acta Psychiatrica Scandinavica, 97, 321–5.Find this resource:

                              47. Phillips, M.R., Yang, G., Li, S., et al. (2004). Suicide and the unique prevalence pattern of schizophrenia in mainland China: a retrospective observational study. Lancet, 364, 1062–8.Find this resource:

                              48. Helgason, T. and Magnusson, H. (1989). The first 80 years of life. A psychiatric epidemiological study. Acta Psychiatrica Scandinavica, 79(Suppl. 348), 85–94.Find this resource:

                              49. Ödegaard, Ö. (1980). Fertility of psychiatric first admissions in Norway, 1936–1975. Acta Psychiatrica Scandinavica, 62, 212–20.Find this resource:

                              50. Brown, S. (1997). Excess mortality of schizophrenia. A meta-analysis. The British Journal of Psychiatry, 171, 502–8.Find this resource:

                              51. Dupont, A., Jensen, O.M., Strömgren, E., et al. (1986). Incidence of cancer in patients diagnosed as schizophrenic in Denmark. In Psychiatric case registers in public health (eds. S.H. Ten Horn, R. Giel, and W. Gulbinat), pp. 229–39. Elsevier, Amsterdam.Find this resource:

                                52. Dalton, S.O., Mellemkjær, L., Thomassen, L., et al. (2005). Risk for cancer in a cohort of patients hospitalized for schizophrenia in Denmark, 1969–1993. Schizophrenia Research, 75, 315–24.Find this resource:

                                53. Grinshpoon, A., Barchana, M., Ponizovsky, A., et al. (2005). Cancer in schizophrenia: is the risk higher or lower? Schizophrenia Research, 73, 333–41.Find this resource:

                                54. Heilä, H. and Lönnqvist, J. (2003). The clinical epidemiology of suicide in schizophrenia. In The epidemiology of schizophrenia (eds. R.M. Murray, P. Jones, E. Susser, J. van Os, and M. Cannon), pp. 288–314. Cambridge University Press, Cambridge.Find this resource:

                                  55. Mortensen, P.B. and Juel, K. (1993). Mortality and causes of death in first admitted schizophrenic patients. The British Journal of Psychiatry, 163, 183–9.Find this resource:

                                  56. Geddes, J.R. and Juszczak, E. (1995). Period trends in rate of suicide in first 28 days after discharge from psychiatric hospital in Scotland, 1968–92. British Medical Journal, 311, 357–60.Find this resource:

                                  57. Lawrence, D., Holman, C.D.J, Jablensky, A., et al. (2001). Increasing rates of suicide in Western Australian psychiatric patients: a record linkage study. Acta Psychiatrica Scandinavica, 104, 443–51.Find this resource:

                                  58. Jeste, D.V., Gladsjo, J.A., Lindamer, L.A., et al. (1996). Medical comorbidity in schizophrenia. Schizophrenia Bulletin, 22, 413–30.Find this resource:

                                  59. Susser, E., Valencia, E., and Conover, S. (1993). Prevalence of HIV infection among psychiatric patients in a New York City men's shelter. American Journal of Public Health, 83, 568–70.Find this resource:

                                  60. Martens, W.H. (2001). A review of physical and mental health in homeless persons. Public Health Reviews, 29, 13–33.Find this resource:

                                    61. Mortensen, P.B. (2003). Mortality and physical illness in schizophrenia. In The epidemiology of schizophrenia (eds. R.M. Murray, P. Jones, E. Susser, J. van Os, and M. Cannon), pp. 275–87. Cambridge University Press, Cambridge.Find this resource:

                                      62. Lawrence, D.M., Holman, C.D.J., Jablensky, A.V., et al. (2003). Death rate from ischaemic heart disease in Western Australian psychiatric patients 1980–1998. The British Journal of Psychiatry, 182, 32–6.Find this resource:

                                      63. Goff, D.C., Sullivan, L.M., McEvoy, J.P., et al. (2005). A comparison of ten-year cardiac risk estimates in schizophrenia patients from the CATIE study and matched controls. Schizophrenia Research, 80, 45–53.Find this resource:

                                      64. Saari, K.M., Lindeman, S.M., Viilo, K.M., et al. (2005). A 4-fold risk of metabolic syndrome in patients with schizophrenia: the Northern Finland 1966 birth cohort study. The Journal of Clinical Psychiatry, 66, 559–63.Find this resource:

                                      65. Hyde, T.M., Ziegler, J.C., and Weinberger, D. (1992). Psychiatric disturbances in metachromatic leucodystrophy. Archives of Neurology, 49, 401–6.Find this resource:

                                      66. Murphy, K.C. and Owen, M.J. (1996). Minor physical anomalies and their relationship to the aetiology of schizophrenia. The British Journal of Psychiatry, 168, 139–42.Find this resource:

                                      67. Eaton, W.M., Hayward, C., and Ram, R. (1992). Schizophrenia and rheumatoid arthritis: a review. Schizophrenia Research, 6, 181–92.Find this resource:

                                      68. Murray, R.M., Grech, A., Phillips, P., et al. (2003). What is the relationship between substance abuse and schizophrenia? In The epidemiology of schizophrenia (eds. R.M. Murray, P. Jones, E. Susser, J. van Os, and M. Cannon), pp. 317–42. Cambridge University Press, Cambridge.Find this resource:

                                        69. Koethe, D., Llenos, I.C., Dulay, J.R., et al. (2007). Expression of CB1 cannabinoid receptor in the anterior cingulate cortex in schizophrenia, bipolar disorder, and major depression. Journal of Neural Transmission, 114, 1055–63.Find this resource:

                                        70. Myers, C.S., Robles, O., Kakoyannis, N., et al. (2004). Nicotine improves delayed recognition in schizophrenic patients. Psychopharmacology, 174, 334–40.Find this resource:

                                        71. Henquet, C., Murray, R., Linszen, D., et al. (2005). The environment and schizophrenia: the role of cannabis use. Schizophrenia Bulletin, 31, 608–12.Find this resource:

                                        72. Semple, D.M., McIntosh, A.M., and Lawrie, S.M. (2005). Cannabis as a risk factor for psychosis: systematic review. Journal of Psychopharmacology, 19, 187–94.Find this resource:

                                        73. Curran, C., Byrappa, N., and McBride, A. (2004). Stimulant psychosis: systematic review. The British Journal of Psychiatry, 185, 196–204.Find this resource:

                                        74. De Leon, J. and Diza, F.J. (2005). A meta-analysis of worldwide studies demonstrates an association between schizophrenia and tobacco smoking behaviors. Schizophrenia Research, 76, 135–57.Find this resource:

                                        75. Zammitt, S., Allebeck, P., Dalman, C., et al. (2003). Investigating the association between cigarette smoking and schizophrenia in a cohort study. The American Journal of Psychiatry, 160, 2216–21.Find this resource:

                                        76. Boydell, J. and Murray, R. (2003). Urbanization, migration and risk of schizophrenia. In The epidemiology of schizophrenia (eds. R.M. Murray, P. Jones, E. Susser, J. van Os, and M. Cannon), pp. 49–67. Cambridge University Press, Cambridge.Find this resource:

                                          77. Murray, C.J.L. and Lopez, A.D. (eds.) (1996). The global burden of disease. A comprehensive assessment of mortality and disability from diseases, injuries, and risk factors in 1990 and projected to 2020. Harvard School of Public Health, Cambridge, MA.Find this resource:

                                            78. Jablensky, A. (2000). Epidemiology of schizophrenia: the global burden of disease and disability. European Archives of Psychiatry and Clinical Neuroscience, 250, 274–85.Find this resource:

                                            79. Gottesman, I.I. (1991). Schizophrenia genesis: the origins of madness. W.H. Freeman, New York.Find this resource:

                                              80. Lichtenstein, P., Björk, C., Hultman, C.M., et al. (2006). Recurrence risks for schizophrenia in a Swedish National Cohort. Psychological Medicine, 36, 1417–25.Find this resource:

                                              81. Kendler, K.S. and Eaves, L.J. (1986). Models for the joint effect of genotype and environment on liability to psychiatric illness. The American Journal of Psychiatry, 143, 279–89.Find this resource:

                                              82. Essen-Möller, E. (1935). Untersuchungen über die Fruchtbarkeit gewisser Gruppen von Geisteskranken. Acta Psychiatrica et Neurologica, 8, 1–314.Find this resource:

                                                83. Huxley, J., Mayr, E., Osmond, H., et al. (1964). Schizophrenia as a genetic morphism. Nature, 204, 220–1.Find this resource:

                                                84. Sipos, A., Rasmussen F., Harrison, G., et al. (2004). Paternal age and schizophrenia: a population based cohort study. British Medical Journal, 330, 147–8.Find this resource:

                                                85. Tramer, M. (1929). Über die biologische Bedeutung des Geburtsmonates, insbesondere für die Psychoseerkrankung. Schweizerischer Archiv für Neurologie und Psychiatrie, 24, 17–24.Find this resource:

                                                  86. Mortensen, P.B., Pedersen, C.B., Westergaard, T., et al. (1999). Effects of family history and place and season of birth on the risk of schizophrenia. The New England Journal of Medicine, 340, 603–8.Find this resource:

                                                  87. Torrey, E.F., Miller, J., Rawlings, R., et al. (1997). Seasonality of births in schizophrenia and bipolar disorder: a review of the literature. Schizophrenia Research, 28, 1–38.Find this resource:

                                                  88. Mednick, S.A., Machon, R.A., Huttunen, M.O., et al. (1988). Adult schizophrenia following prenatal exposure to an influenza epidemic. Archives of General Psychiatry, 45, 189–92.Find this resource:

                                                  89. Morgan, V., Castle, D., Page, A., et al. (1997). Influenza epidemics and incidence of schizophrenia, affective disorders and mental retardation in Western Australia: no evidence of a major effect. Schizophrenia Research, 26, 25–39.Find this resource:

                                                  90. Grech, A., Takei, N., and Murray, R.M. (1997). Maternal exposure to influenza and paranoid schizophrenia. Schizophrenia Research, 26, 121–5.Find this resource:

                                                  91. Cannon, M., Cotter, D., Coffey, V.P., et al. (1996). Prenatal exposure to the 1957 influenza epidemic and adult schizophrenia: a follow-up study. The British Journal of Psychiatry, 168, 368–71.Find this resource:

                                                  92. Brown, A.S., Cohen, P., Harkavy-Friedman, J., et al. (2001). Prenatal rubella, premorbid abnormalities, and adult schizophrenia. Biological Psychiatry, 49, 473–86.Find this resource:

                                                  93. Brown, A.S., Schaefer, C.A., Quesenberry, C.P., et al. (2005). Maternal exposure to toxoplasmosis and risk of schizophrenia in the offspring. The American Journal of Psychiatry, 162, 767–73.Find this resource:

                                                  94. Cannon, T.D. (1997). On the nature and mechanisms of obstetric influence in schizophrenia: a review and synthesis of epidemiological studies. International Review of Psychiatry, 9, 387–97.Find this resource:

                                                  95. Done, D.J., Johnstone, E.C., Frith, C.D., et al. (1991). Complications of pregnancy and delivery in relation to psychosis in adult life: data from the British perinatal mortality survey sample. British Medical Journal, 202, 1576–80.Find this resource:

                                                  96. Buka, S.L., Tsuang, M.T., and Lipsitt, L.P. (1993). Pregnancy/delivery complications and psychiatric diagnosis: a prospective study. Archives of General Psychiatry, 50, 151–6.Find this resource:

                                                  97. Cannon, M., Jones, P.B., and Murray, R.M. (2002). Obstetric complications and schizophrenia: historical and meta-analytic review. The American Journal of Psychiatry, 159, 1080–92.Find this resource:

                                                  98. Zornberg, G.L., Buka, S.L., and Tsuang, M.T. (2000). Hypoxic-ischemia-related fetal/neonatal complications and risk of schizophrenia and other nonaffective psychoses: a 19-year longitudinal study. The American Journal of Psychiatry, 157, 196–202.Find this resource:

                                                  99. Cannon, T.D., Rosso, I.M., Hollister, J.M., et al. (2000). A prospective cohort study of genetic and perinatal influences in the etiology of schizophrenia. Schizophrenia Bulletin, 26, 351–66.Find this resource:

                                                  100. Bennedsen, B.E., Mortensen, P.B., Olesen, A.V., et al. (2001). Obstetric complications in women with schizophrenia. Schizophrenia Research, 47, 167–75.Find this resource:

                                                  101. Jablensky, A.V., Morgan, V., Zubrick, S.R., et al. (2005). Pregnancy, delivery, and neonatal complications in a population cohort of women with schizophrenia and major affective disorders. The American Journal of Psychiatry, 162, 79–91.Find this resource:

                                                  102. Cannon, T.D., Mednick, S.A., Parnas, J., et al. (1993). Developmental brain abnormalities in the offspring of schizophrenic mothers. Archives of General Psychiatry, 50, 551–64.Find this resource:

                                                  103. Keshavan, M.S., Diwadkar, V.A., Spencer, S.M., et al. (2002). A preliminary functional magnetic resonance imaging study in offspring of schizophrenic patients. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 26, 1143–49.Find this resource:

                                                  104. Leask, S.J., Done, D.J., and Crow, T.J. (2002). Adult psychosis, common childhood infections and neurological soft signs in a national birth cohort. The British Journal of Psychiatry, 181, 387–92.Find this resource:

                                                  105. Thaden, E., Rhinewine, J.P., Lencz, T., et al. (2006). Early-onset schizophrenia is associated with impaired adolescent development of attentional capacity using the identical pairs continuous performance test. Schizophrenia Research, 81, 157–66.Find this resource:

                                                  106. Winterer, G., Egan, M.F., Raedler, T., et al. (2003). P300 and genetic risk for schizophrenia. Archives of General Psychiatry, 60, 1158–67.Find this resource:

                                                  107. Calkins, M.E., Curtis, C.E., Iacono, W.G., et al. (2004). Antisaccade performance is impaired in medically and psychiatrically healthy biological relatives of schizophrenia patients. Schizophrenia Research, 71, 167–78.Find this resource:

                                                  108. Zammitt, S., Allebeck, P., David, A.S., et al. (2004). A longitudinal study of premorbid IQ score and risk of developing schizophrenia, bipolar disorder, severe depression, and other nonaffective psychoses. Archives of General Psychiatry, 61, 354–60.Find this resource:

                                                  109. Reichenberg, A., Weiser, M., Rabinowitz, J., et al. (2002). A population-based cohort study of premorbid intellectual, language, and behavioral functioning in patients with schizophrenia, schizoaffective disorder, and nonpsychotic bipolar disorder. The American Journal of Psychiatry, 159, 2027–35.Find this resource:

                                                  110. Cannon, T.D., Mednick, S.A., and Parnas, J. (1990). Antecedents of predominantly negative- and predominantly positive-symptom schizophrenia in a high-risk population. Archives of General Psychiatry, 47, 622–32.Find this resource:

                                                  111. Wahlberg, K.E., Wynne, L.C., Oja, H., et al. (1997). Gene-environment interaction in vulnerability to schizophrenia: findings from the Finnish adoptive family study of schizophrenia. The American Journal of Psychiatry, 154, 355–62.Find this resource:

                                                  112. van Os, J., Hanssen, M., Bak, M., et al. (2003). Do urbanicity and familial liability coparticipate in causing psychosis? The American Journal of Psychiatry, 160, 477–82.Find this resource:

                                                  113. Mischler, E.G. and Scotch, N.A. (1983). Sociocultural factors in the epidemiology of schizophrenia; a review. Psychiatry, 26, 315–51.Find this resource:

                                                    114. Goldberg, E.M. and Morrison, S.L. (1963). Schizophrenia and social class. The British Journal of Psychiatry, 109, 785–802.Find this resource:

                                                    115. Bhugra, D., Leff, J., Mallett, R., et al. (1997). Incidence and outcomes of schizophrenia in Whites, African-Caribbeans, and Asians in London. Psychological Medicine, 27, 791–8.Find this resource:

                                                    116. Harrison, G., Glazebrook, C., Brewin, J., et al. (1997). Increased incidence of psychotic disorders in migrants from the Caribbean to the United Kingdom. Psychological Medicine, 27, 799–806.Find this resource:

                                                    117. Selten, J.P., Slaets, J.P.I., and Kahn, R.S. (1997). Schizophrenia in the Surinamese and Dutch Antilean immigrants to the Netherlands: evidence of an increased incidence. Psychological Medicine, 27, 807–11.Find this resource:

                                                    118. Selten, J.P., Slaets, J., and Kahn, R. (1998). Prenatal exposure to influenza and schizophrenia in Surinamese and Dutch Antillean immigrants to the Netherlands. Schizophrenia Research, 30, 101–3.Find this resource:

                                                    119. Hutchinson, G., Takei, N., Fahy, T.A., et al. (1996). Morbid risk of schizophrenia in first-degree relatives of White and African-Caribbean patients with psychosis. The British Journal of Psychiatry, 169, 776–80.Find this resource:

                                                    120. Jablensky, A. (2006). Subtyping schizophrenia: implications for genetic research. Molecular Psychiatry, 11, 815–36.Find this resource:

                                                    121. Spitzer, R.L., Endicott, J., and Robins, E. (1978). Research diagnostic criteria. Rationale and reliability. Archives of General Psychiatry, 35, 773–82.Find this resource:

                                                    122. Hutchinson, G., Takei, N., Bhugra, D., et al. (1997). Increased rate of psychosis among African-Caribbeans in Britain is not due to an excess of pregnancy and birth complications. The British Journal of Psychiatry, 171, 145–7.Find this resource: