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The 100-year epidemiology of schizophrenia
SCHIZOPHRENIA RESEARCH ELSEVIER
SchizophreniaResearch 28 (1997) 111-125
The 100-year epidemiology of schizophrenia Assen Jablensky * Department of Psychiatry and Behavioural Science, University of Western Australia, 50 Murray Street, Perth, WA 6000, Australia Received 13 March 1997; accepted 15 July 1997
Abstract
Since Kraepelin delineated dementia praecox as a disease entity construct, epidemiological studies conducted since the beginning of the century have produced remarkably consistent estimates of its prevalence, incidence and lifetime risk across various populations and geographic areas. A similar pattern emerged from the WHO ten-country study on first-contact incidence of schizophrenia. The diagnostic concept of dementia praecox originally used by Kraepelin and that of schizophrenia employed in the WHO studies were found to overlap extensively, indicating continuity over time. However, the findings of a similar incidence of schizophrenia in diverse populations and across time periods are unusual for a multifactorial disease and are compatible with at least two alternative interpretations that have different implications for the search for genetic and environmental causes of the disorder. © 1997 Elsevier Science B.V. Keywords: Schizophrenia; Dementia praecox; Epidemiology; Nosology; Phenotype definition
A future historian is likely to describe the 100 years since Kraepelin's inception of the disease entity dementia praecox as a fascinating and extraordinary chapter in the history of medicine. It would be difficult to find many medical conditions that have been investigated with similar vigor and persistence over a century and have proved to be as intractable to understanding as schizophrenia. The history of schizophrenia research is a chronology of recurrent themes, many promising clues that have subsequently been abandoned, and a plethora of explanatory models of which none has yet been either categorically rejected or unequivocally proven. It is remarkable that many of the current research ideas are, in fact, rediscoveries * Tel: +61 9 224 0290; Fax: +61 9 224 0285; e-mail: [email protected] 0920-9964/97/$17.00© 1997ElsevierScienceB.V. All rights reserved. PH S0920-9964 (97) 00108-4
of early observations and hypotheses, many of them datable to the first decades following the adoption of the Kraepelinian diagnostic scheme (Table 1). There is another sense in which the history of schizophrenia is at odds with the rest of medicine: the fundamental conceptual framework within which schizophrenia research has been conducted, i.e. the Kraepelinian dichotomy of the major psychoses, has hardly been modified since its inception. Despite many attempts at alternative formulations of the diagnostic classification of the psychoses, and continual doubts by researchers and clinicians (including Kraepelin himself) about the validity of the disease concept of dementia praecox, the categorical nosology constructed by Kraepelin has not been seriously challenged. Its essential features are present in ICD-I0 ( W H O ,
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Table 1 Early findingsin schizophrenia Abnormal eye movements Cortical atrophy Recurrence risks in biologicalrelatives;anticipation Attention deficit Ventricleenlargement(air encephalography) Possible role of influenza Birth seasonality Negative associationwith rheumatoidarthritis
1993) and DSM-IV (APA, 1994). Prominent researchers and teachers who describe themselves as 'neo-Kraepelinians' (Compton and Guze, 1995) indicate an allegiance to a particular school of thought in psychiatry, in a way similar to philosophers' adherence to 'neo-Kantian', 'neoHegelian', or even 'neo-Platonist' ideas. It is generally accepted that there is no single test or procedural rule to establish the validity of a disease concept or of a diagnostic classification in psychiatry (Kendell, 1975). The acceptance of a particular diagnostic concept or a classification scheme is usually based on the interpretation of converging evidence from multiple sources, including descriptive psychopathology, neuropathology, pathophysiology, genetics, and epidemiology. This process bears a similarity to the way that 'paradigms' evolve in science (Kuhn, 1962). The discussion below aims to review the contribution of one of those sources--psychiatric epidemiology--to the continuing debate on the validity of the Kraepelinian disease model of dementia praecox.
1. Early epidemiological research in schizophrenia Psychiatric epidemiology originated in 19th-century censuses of the insane, which were carried out primarily for administrative purposes. However, by the end of the century, scientific questions proper began to be addressed, and by 1915, Joseph Goldberger provided the first, and probably the most successful example to date, of the application of analytic epidemiology to a medical and public health problem with a significant psychiatric component: the etiology of pellagra (Goldberger, 1915). Probably, the first application of the epide-
Diefendorfand Dodge(1908) Southard (1915) R~din (1916) Kraepelin (1919) Jacobi and Winkler(1927) Menninger(1928) Tramer (1929) Nissen and Spencer(1936)
miological method in a modern sense to the investigation of psychoses was the work of a female physician, Jenny Koller, who in 1895 conducted a case-control study of the aggregation of psychiatric disorders in the families of 284 probands and 370 healthy control subjects in Zurich (Koller, 1895). In many ways, her conclusions anticipated presentday knowledge about the genetic epidemiology of the psychoses in that she found that 'the hereditary loading of the healthy subjects is much higher than generally assumed'; that 'the strongest loading is that of psychoses and accentuated characters'; and that 'the loading in distant relatives is quite low, unless a person at risk is exposed to multiple factors'. Kraepelin himself--whose greatest historic contribution was perhaps first the vision and then the practical organization of the first truly multidisciplinary program of psychiatric research--saw quite clearly the potential of the epidemiological method to 'throw light on the causes of mental disorder' and proposed comparative population studies of the psychoses and the underlying personality-related factors across different cultures (Kraepelin, 1904). In the first half of the 20th century, epidemiological research into the psychoses took two relatively distinct paths. While the focus of German, Swiss, and Scandinavian investigators was primarily on the genetic factors, North American research took a more active interest in the social ecology of mental illness, as represented, for example, by the 'Chicago school' (Faris and Dunham, 1939). On both sides of the Atlantic, however, epidemiological research was pursued vigorously, and the general contours of the epidemiological map of schizophrenia were, by and large, complete before World War II. Most of the
A. Jablensky / Schizophrenia Research 28 ( 1997) 111-125
methodological tools of psychiatric epidemiology were developed and applied with considerable success during the four decades between 1910 and 1950 (Table 2). It is of interest to note how these early epidemiological studies were actually conducted 'in the field'. The majority were carried out single-handedly by dedicated researchers who typically spent months and sometimes years in a community, collecting information and interviewing, literally, door-to-door. Personal knowledge of the respondents, access to multigenerational records from the local parish registers, and generous cooperation by the community as a whole resulted in detailed and accurate data of a descriptive quality that would be difficult to match today. For example, Graemiger (1931), a Swiss general practitioner working in a rural community, published 66 extended genealogies segregating psychotic illnesses and claimed to have known personally 1357 of their members across four generations. EssenM611er et al. (1956) interviewed personally each one of the 2550 inhabitants of the Lundby community in Sweden. The same respondents, as well as their offspring, were followed up and periodically reinterviewed by Hagnell (1966,) and Hagnell and C)jesj6 (1975) over 25 years, which resulted in what is probably the most accurate data set on the age- and sex-specific incidence rates of the major categories of psychiatric disorders. Many of the results of those early studies retain their benchmark value today. As a matter of fact, none of the more recent contributions from epidemiological research has substantially altered the conclusions of the earlier studies as regards the population incidence and prevalence of schizophrenia, the age at onset curve, the age- and sexspecific morbid risk, the morbidity risks for specified biological relatives of a schizophrenic proband, the outcomes of dual matings of individuals with psychoses, and the data on reduced fertility of persons with schizophrenia (Gottesman et al., 1987).
2. Diagnostic comparabifity over time However, the question of comparability of diagnoses of dementia praecox, or schizophrenia, made
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by researchers earlier in this century with more recent diagnostic practice--especially since the introduction of explicit diagnostic criteria--needs to be addressed in this context. Careful reading of the early publications and archival documents suggests that it would be an oversimplification to assert that imprecise, variable, and often broad diagnostic concepts dominated the field prior to the Research Diagnostic Criteria (RDC) and DSM-III. Similarly unsupported by fact is the belief (Keefe et al., 1991) in the existence of two variants of the diagnostic concept of schizophrenia: one 'Kraepelinian' (narrow) and the other 'Bleulerian' (broad). The evidence indicates that, at least in Europe, the diagnosis of schizophrenia was usually made along fairly restrictive lines, and the concept of schizophrenia remained consistent over time (Jablensky, 1986). Direct evidence for this was provided by a study (Jablensky et al., 1993) in which Kraepelin's original research case summaries (Z~ihlblgtter) on all patients with diagnoses of dementia praecox and manic-depressive illness admitted to the Munich University Clinic in 1908 (total number, 187) were rated and scored in terms of the Present State Examination syndrome checklist (Wing et al., 1974) and processed with the CATEGO algorithm to generate 'presentday' ICD-9 diagnoses. The clinical features of these 'archival' cases from 1908 were then compared with 'modern' cases assessed in the WHO International Pilot Study of Schizophrenia, IPSS (WHO, 1979). The overall concordance between Kraepelin's original diagnoses and the computerassigned ICD-9 diagnosis was 88.6%. The comparison between the most frequent symptoms of Kraepelin's dementia praecox cases and the IPSS schizophrenia cases (Table 3) indicates a substantial overlap. There should therefore be no doubt that the diagnoses of dementia praecox in 1908 and of ICD-9 schizophrenia in the 1970s refer to the same clinical syndrome. The diagnostic drift that eventually separated European and American concepts of schizophrenia originated primarily in the United States with the expansion of the boundaries of the disorder under the influence of psychodynamic theory. This was well documented by the landmark US-UK Diagnostic Study (Cooper et al., 1972),
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A. Jablensky / Schizophrenia Research 28 (1997) 111-125
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Table 3 Most frequent symptoms and syndromes in a sample of Kraepelin's dementia praecox cases and in the WHO International Pilot Study of Schizophrenia Kraepelin's first-admission dementia
WHO International Pilot Study of Schizophrenia cases assessed in 1968-1969 (N=811)
praecox cases in 1908 (N= 53) PSE-9 syndrome
Frequency (%)
PSE-8 unit of analysis
Frequency (%)
Non-specific psychosis Delusions of persecution Catatonia
54.7 54.7 47.2
Lack of insight Suspiciousness Unwilling to cooperate
82.7 60.0 57.3
Fantastic and sexual delusions Auditory hallucinations Flat affect Simple depression Delusions of reference Grandiose and religiousdelusions Generalized anxiety Visual hallucinations Slowness Incoherent speech Overactivity Nuclear syndrome Irritability Loss of interests
39.6 35.8 32.1 30.2 30.2 24.5 24.5 24.5 24.5 22.6 22.6 20.8 20.8 15.1
Ideas of reference Flat affect Delusions of reference Poor rapport Delusions of persecution Delusional mood Auditory hallucinations Verbal auditory hallucinations Voices speaking to patient Gloomy thoughts Thought alienation Autism Apathy Restricted speech
55.1 51.0 50.3 49.5 48.1 47.5 43.8 37.9 36.3 35.7 33.5 30.7 30.4 17.5
which, along with an early version of 'operational' diagnostic criteria (Feighner et al., 1972), prepared the ground for the development of the DSMIII system.
3. The epidemiological map of schizophrenia prior to DSM-III The general picture emerging from epidemiological research in schizophrenia prior to the 1970s is one of a disorder of a relatively low population incidence (range, 0.17-0.57 per 1000), a relatively high point prevalence (range, 2.4-6.7 per 1000), and a lifetime morbid risk in the range of 0.38-1.87% (Table 4). Part of the variation within those ranges can be explained by sampling and design differences between individual studies, but on the whole, data from census surveys, birth cohort investigations, and case registers of treated morbidity tend to converge. Exceptions to the ranges quoted above are studies of 'outlier' populations. The existence of such unusual populations has been documented
for a long time. These include, for example, the well-known area in North Sweden, where an unusually high prevalence (17 per 1000) and a familial clustering of cases had first been decribed by B66k (1953) and B66k et al. (1978); several Swedish island populations (Sj6gren, 1948; Larsson and Sj6gren, 1954); and two areas on the Istrian peninsula in Croatia (Crocetti et al., 1971). Although the high concentration of cases in the North Sweden area is attributable to a founder effect in an isolated population, the genetic studies of pedigrees from this region have so far failed to demonstrate any linkage to possible susceptibility genes. Populations of extremely low incidence and prevalence of schizophrenia have been more difficult to find, and the evidence is only slightly better than anecdotal. The findings of a virtual absence of schizophrenic psychoses among the Hutterites in North America (Eaton and Weil, 1955) have not been replicated by subsequent research in those communities (Murphy, 1980). The very low prevalence rates reported by Torrey et al. (1974) in Papua New Guinea are likely to reflect a low detection rate.
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Table 4 Results from selected epidemiological studies of schizophrenia, 1930s through 1970s Author
Country
Brugger ( 1931)
Germany
2.4
Klemperer (1933) Odegaard (1946) Str0mgren (1938) Fremming (1947) Sj6gren (1948) B66k (1953) Essen-M611er et al. (1956) Norris (1959) Helgason (1986)
Germany Norway Denmark Denmark Sweden Sweden Sweden UK Iceland
10.0
Walsh (1969)
Ireland
Crocetti et al. (1971)
Croatia
Lieberman (1974)
Former USSR
Nielsen (1976)
Denmark: island of Samso Iceland USA (Rochester, NY)
Helgason (1986) Babigian (1980)
Prevalence per 1000
Incidence per 1000
0.24 4.6 9.5b 6.7c
Lifetime risk per 100
Remarks
0.38
Door-to-door survey, population age 10+ Birth cohort First admissions, age 10+ Door-to-door, all ages Birth cohort Door-to-door, all ages Genetic isolate
1.40a 1.87 0.58 0.90 1.60 2.66
0.17 0.69 (men) 1.02 (women) 0.57 (men) 0.46 (women)
First admissions
5.9
Area known for high rate of psychosis Admission cohort
0.20 (men) 0.19 (women) 0.20 0.27 0.69
First admissions Birth cohort, up to age 61
First admissions 0.90
Birth cohort, up to age 75 Case register study
"Estimate corrected for cohort attrition. b17.0 in 1978. c3.9 psychotic on census date.
4. Effects of the operational diagnostic criteria on epidemiological research The introduction o f standardized, operational diagnostic criteria in D S M - I I I and its subsequent versions, and in ICD-10, has raised expectations o f a new impetus to epidemiological research t h r o u g h improved reliability o f assessment and greater homogeneity o f clinical and population samples. Both sets o f criteria have been shown to be relatively reliable. For example, the multicenter trial o f the I C D - 1 0 criteria resulted in a k a p p a o f 0.84 for all schizophrenic disorders; a similar result (0.83) was obtained for the diagnosis o f bipolar affective disorder (Sartorius et al., 1993). However, in any patient population that is sampled on a 'checklist' basis with either I C D - 1 0 or D S M - I I I R / D S M - I V criteria, at least two kinds o f exclusion are likely to occur: (1) less severe, transient or atypical cases, (2) a residual o f cases with missing
data. In addition, the two checklists, i.e. D S M - I I I R / I V and ICD-10, differ and result in overlapping but not identical patient populations. The two systems are likely to produce substantial agreement on the severe, 'core' cases o f schizophrenia but m a y result in discordant classifications o f the less severe or incipient cases. Whereas the D S M I V / I C D - 1 0 differences would be o f m i n o r importance in clinical or biological research, their implications for epidemiological and genetic studies m a y be serious. The use o f D S M - I V criteria for case ascertainment in a field survey m a y result in the exclusion o f atypical, recent-onset, or subclinical presentations o f the schizophrenic syndrome, unless a provision is m a d e to identify separately cases not meeting the full set o f criteria. Furthermore, since epidemiological data are a m o n g the validating criteria for the clinical concept o f schizophrenia, collecting epidemiological data via the diagnostic criteria that are themselves
A. Jablensky / Schizophrenia Research 28 (1997) 111-125
to be validated introduces a diffficult-to-avoid circularity. It would be desirable, therefore, to develop less restrictive screening DSM-IV and ICD-10 criteria for epidemiological research. Epidemiological and clinical instruments developed in the past 10years are linked to the new diagnostic criteria. The NIMH Diagnostic Interview Schedule, DIS (Robins et al., 1981), and the related WHO-ADAMHA Composite International Diagnostic Interview, CIDI (Robins et al., 1988), are fully structured interviews written to match the DSM-III-R/DSM-IV and ICD-10 criteria and designed for use by lay interviewers. Clinical interviews such as the Schedules for Clinical Assessment in Neuropsychiatry, SCAN (Wing et al., 1990), cover a broader range of psychopathology and require clinical judgment to elicit data that can be processed by ICD-10 and DSM-III-R diagnostic algorithms. However, there is still a clear need for a relatively simple and psychometrically sound screening instrument for case finding of schizophrenia in field surveys. When applied in epidemiological field studies, the operational diagnostic criteria predictably identify lower rates of schizophrenia, as compared with studies employing a less structured ICD-9 diagnostic assessment. This is particularly evident in the Camberwell study (Castle et al., 1991), in which DSM-III research diagnoses were made in addition to the ICD-9 diagnoses recorded in the case register. The data on schizophrenia or 'non-affective psychosis' from large-scale surveys designed to estimate the total psychiatric morbidity in the general population, such as the Epidemiological Catchment Area Study (Keith et al., 1991) and the National Comorbidity Survey (Kendler et al., 1996) in the United States, are difficult to interpret because of the relatively small numbers of subjects with psychotic disorders in the samples studied and possible misclassification problems associated with the use of fully structured diagnostic instruments by lay interviewers. Overall, there is no evidence that the current operationalized diagnostic systems identify more homogeneous samples of individuals with schizophrenia in epidemiological studies. However, the potential benefits of the rulebased, structured approach to diagnosis in epidemiological research are yet to materialize, provided
117
that further methodological work is undertaken for the appropriate adaptation of the criteria to field studies.
5. Recent findings necessitating further research Two themes have recently gained prominence in the literature on the epidemiology of schizophrenia: a very high treated incidence rate in AfroCaribbeans born in the United Kingdom and statistical data suggesting that over recent decades the incidence of schizophrenia may have been declining in Western populations. Again, none of these findings is truly novel: the unusual level of morbidity among Afro-Caribbeans was described in 1967 (Hemsi, 1967), and data suggesting a declining incidence of schizophrenia were published in 1978 (Weeke and Str6mgren, 1978). As regards the excess of schizophrenia among second-generation Afro-Caribbeans, it now seems that the phenomenon cannot be fully attributed to diagnostic bias and misclassification (Wessely et al., 1991), or to a lower admission threshold. A recent study that reported a significantly increased risk of schizophrenia for siblings of second-generation Afro-Caribbean probands but not for their parents (Hutchinson et al., 1996) suggests that an unknown environmental factor may be involved. Although the epidemiological evidence presented to date is weakened by the lack of reliable data on the size and age structure of the Afro-Caribbean population in the United Kingdom (Harrison et al., 1989), the reported risk elevation is of a magnitude that is unlikely to be substantially discounted. If further confirmed, these data, as well as somewhat similar findings on immigrants from Surinam and the Dutch Antilles in the Netherlands (Selten and Sijben, 1994), may provide unique clues to risk factors in schizophrenia. In contrast to the Afro-Car~bean phenomenon, the case for a true decline in the population incidence rate of schizophrenia is less well supported, and the actual data from national statistics or case registers: are inconsistent (Jablensky, 1995a). Indeed, some independent epidemiologicat evidence that real decreases may have occurred is provided by the two census surveys on the island
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of Bornholm in 1935 and 1983 (Bojholm and StrOmgren, 1989), which documented a prevalence decline from 4.2 to 2.7 per 1000 in females but not in males. However, no study to date has taken into account all the possible confounding factors, such as a variation in the definitions of first admission or first contact; changes in diagnostic practice (e.g. a tendency to defer a diagnosis of schizophrenia on first admission); changes in treatment modality (an increasing number of patients being managed on an outpatient basis without admission to hospital); or changes in the age structure of the population, which may affect the rates if no standardization for age is carried out. As a corollary, a compensatory increase could be expected in diagnoses other than schizophrenia. Such increases have actually been reported for borderline states (Munk-Jorgensen, 1986) and for affective psychosis (Geddes et al., 1993).
6. Overview of established and putative risk factors
The search for risk factors is a major aim of analytical epidemiology, and the results are usually expressed as relative risk ratios or odds ratios. Of the many putative risk factors and disease markers that have been implicated over the period, only a limited number have been successfully replicated. The data are summarized in Table 5 (Jablensky and Eaton, 1995), which lists estimated odds ratios across a number of studies. It should be noted that these odds ratios are not based on a proper meta-analysis (which would be hardly feasible) but reflect the judgment of two investigators who have examined the studies concerned and reached a consensus that inevitably contains an element of subjective judgment. The term 'potential risk factors' is used in Table 5 because not all factors have been identified either as causes or even as clearly antecedent in time. The column labeled 'P or I' aids in this distinction, with 'P' indicating that the association presented originates from prevalence data and 'I' indicating the association is from prospective or incidence data. Potential risk factors were selected only if the preponderance of evidence suggested that the asso-
ciation presented was credible. At least two methodologically rigorous studies were required for selection in Table 5. If there were many studies, more than three-quarters of their results were required to be in the direction presented in the table for a 'preponderance of evidence' to be accepted. Some potential risk factors are entered in the table that have not been included in prior reviews. For example, the literature in the area of pre- and perinatal factors shows that positive evidence has been developing rapidly in this area, which led to its inclusion. Neuropsychological and neurocognitive factors have been added because developments in measurement methods have shown that epidemiological studies can be conducted with these constructs. With all the reservations about the exact values of the odds ratios, it is likely that at least the order-of-magnitude differences between the odds ratios for the different categories of risk factors are not far off the mark and reveal important aspects of the disorder. The difference between the top category (familial factors) and the rest is obvious, and it is difficult to escape the conclusion that familial, presumably genetic, findings are at present the only class of variables that would satisfy the epidemiological criteria for a major risk factor. This conclusion, based on genetic-epidemiological evidence, tends to be reinforced by promising recent developments in genetic linkage and candidate gene research (reviewed by Asherson et al., 1995; Ross and Pearlson, 1996). The general, and probably nonspecific, sociodemographic descriptors, such as country of birth or ancestry, single marital status, and low socioeconomic status, seem to fare much better than factors such as winter birth, maternal influenza, or obstetric complications. The data on candidate markers, including ventricular-brain ratio (VBR), eye tracking abnormalities, or attention deficit, would probably fail the threshold of epidemiological interest in the study of a disorder other than schizophrenia. This is not to say that such borderline or inconsistent findings are without intrinsic significance. It is quite possible that the present system of conceptualizing and classifying schizophrenia tends to lump together subgroups of cases in which some of these risk factors and markers might be expressed much more sharply.
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Table 5 Estimated odd ratios for risk factors in schizophrenia (Jablensky and Eaton, 1995) Potential risk factors
Authors' estimate N studies
Odds ratio
Relevant references P or I a
Familial (biological relative with schizophrenia) Biological parent Two parents Monozygotic twin Dizygotic twin Non-twin sibling Second-degree relative
12 5 5 5 5 3
Gottesman et al. (1987); Kendler (1988); Kendler and Diehl (1993); Moldin (1994) 7 37 45 14 9 1.1
I P P P P P
Social
Eaton (1974); Eaton et al. (1994); Freeman (1994); L6ffler and H/finer (1994)
Low socioeconomic status Single status Stressful life events
17 8 3
3 4 1.5
I I I
Sociodemographic Country of birth or ancestry Urban birth or upbringing
3 2
5 2
I I
Harrison et al. (1988); Eagles (1991); Wessely et al. (1991)
Pregnancy and birth related
Winter birth Obstetric complications Maternal influenza
H~ifner et al. (1987); Eaton (1991); McNeil (1995); Mednick et al. (1988); Mednick et al. (1994); Kendell and Kemp (1989); Wright and Murray (1993); Takei et al. (1994) 30 10 9
1,1 2 1,1
I I P
Neuropsychological Oculomotor dysfunction Attentional dysfunction
Mirsky and Duncan (1986); Levy et al. (1993); Kremen et al. (1994) 20 15
1.5 1.5
P P Shelton and Weinberger (1986); Raz and Raz (1990); Nasrallah (1993)
Neuropathologieal/neuroimaging Increased ventricle-brain ratio
6
1.5
I
a p = prevalence data; I = incidence data.
7. Comparative epidemiology of schizophrenia I n 1904, K r a e p e l i n suggested t h a t ' c o m p a r a t i v e p s y c h i a t r y ' , i.e. the s t u d y o f disease incidence in p o p u l a t i o n s o f c o n t r a s t i n g cultures, d e m o g r a p h i c features, a n d physical e n v i r o n m e n t s , c o u l d p r o v i d e clues to the e t i o l o g y o f p s y c h o s e s ( K r a e p e l i n , 1904). Differences in the incidence, o r c o n t r a s t i n g p a t t e r n s o f course a n d o u t c o m e , s h o u l d t h e r e f o r e be s y s t e m a t i c a l l y e x a m i n e d for c o r r e l a t i o n s with v a r i a t i o n s in gene p o o l s o r e n v i r o n m e n t a l factors.
T h e evidence f r o m earlier e p i d e m i o l o g i c a l research has been extensively reviewed f r o m such a p o i n t o f view ( E a t o n , 1985; J a b l e n s k y , 1986, 1995b), b u t its i n t e r p r e t a t i o n c a n l e a d to diverging conclusions. It is e q u a l l y possible to give weight m a i n l y to the similarities across different p o p u l a t i o n s as it is to e m p h a s i z e the differences. F o r example, T o r r e y (1989) suggested t h a t even if the effects o f m e t h o d o l o g i c a l inconsistencies a m o n g prevalence studies c o u l d be s u b t r a c t e d , there w o u l d be at least 10-fold residual differences across p o p u l a t i o n s . I n
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this respect, the incidence data from the WHO 10-country study on determinants of outcome of severe mental disorders (Jablensky et al., 1992) are of particular interest. The WHO study, conducted in 13 geographical catchment areas in Europe, the Indian subcontinent, West Africa, North and South America, and Japan, was the first cross-cultural epidemiological investigation in which standardized instruments and closely comparable case-finding methods were applied simultaneously at all sites to ascertain the first-contact incidence of schizophrenia and schizophrenialike illnesses in populations that differed widely in terms of demography, economy, culture, and general health profiles. All of the 1379 cases were interviewed, diagnosed, and reinterviewed at a 2-year follow-up by psychiatrists using the Present State Examination (ninth edition). The results have triggered considerable debate. The age- and sex-specific incidence rates for 'broadly' ICD-9 diagnosed schizophrenia ranged from 0.16 per 1000 in Honolulu to 0.42 per 1000 in a rural area in India (p < 0.001 ), and the differences across sites were significant. However, the rates for a more narrowly, computer-defined 'core' syndrome characterized by first-rank 'Schneiderian' symptoms were in the range of 0.07 per 1000 (Aarhus, Denmark) to 0.14 per 1000 (Nottingham, UK), and the differences across sites were not significant. In all the areas, there was an excess of males in the age groups of 15-24, whereas females were overrepresented in the age groups of 35-54. Lifetime disease expectancy was almost equal for males and females. The conclusions of the WHO report emphasized the striking similarities of incidence and symptoms across populations--a finding that had not been anticipated by the investigators at the outset. The suggestion that these results might be affected by insufficient statistical power (Frangou and Murray, 1996) is not supported by the confidence intervals, which were calculated for each age- and sex-specific incidence rate (Table 6). The more difficult epidemiological question-that the similarity of the incidence rates might conceal differences in lifetime disease expectancy, since the age distributions in the different catchment areas differed markedly--was largely
answered by a reanalysis carried out by Chang (1990), who used life tables to apply survival models to the incidence rates found for each of the catchment areas under comparison. He found that the differences were no greater than 2:1, e.g. 10.82 in Moscow and 5.46 in Honolulu. The results of the WHO study, therefore, seem capable of withstanding critical scrutiny, and the question that remains to be answered is their meaning in the context of the epidemiology of schizophrenia. One possible interpretation is that the comparable liability to schizophrenia across very different populations points to a common, fundamental genetic basis for the disorder, possibly linked to other species characteristics, such as the evolution of cerebral asymmetry and the related issue of language (Crow, 1995). Another plausible hypothesis that remains to be explored is that the observed similarity of rates might be the effect of a syndroreal admixture (Gibbons et al., 1984), i.e. that a number of low-incidence syndromes of heterogeneous etiology but hardly distinguishable phenotypical expression combine together to produce a seemingly uniform rate of schizophrenia across different populations. This would be in conformity with the idea that schizophrenia is the common final pathway for a variety of etiologically different conditions.
8. Alternatives to the categorical nosology of psychoses The view of schizophrenia as a single disease entity, which continues to dominate current biological research (including genetic and neuropathological studies), is in conflict with the large body of data suggesting that the extent of phenotypic heterogeneity in schizophrenia is too large to support a simple nosological model of the disorder. There are at present powerful analytical tools that make it possible to address the difficult issue of heterogeneity in schizophrenia. One such technique, the Grade of Membership model (Woodbury and Manton, 1982), based on the 'fuzzy set' theory, was applied to the analysis of schizophrenia symptom profiles in the WHO International Pilot Study of Schizophrenia
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Table 6 Age- and sex-specificincidence rates per 10000 (and 95% confidenceintervals) for CATEGO S+ schizophrenia in six centers participating in the WHO study on determinants of outcome of severe mental disorders Males
Aarhus (Denmark) Chandigarh (India) Ibadan (Nigeria) Moscow (Russia) Nagasaki (Japan) Nottingham(U.K.)
Females
15-24 years
25 34 years
35-54 years
15-24 years
25-34 years
35-54 years
2.9 (1.3-4.5) 3.3 (1.6 5.0) 2.3 (1.5-3.0) 1.3 (0.0-2.5) 4.7 (2.4-7.1) 5.3(2.87 . 6 )
1.6 (0.5-2.7) 0.8 (0.1-1.6) 2.1 (1.3-2.8) 2.5 (0.8 4.2) 2.7 (1.0-4.4) 3.0(0.95 . 0 )
1.2 (0.4-2.1) 0.3 (0.3-0.8) 0.4 (0.0-0.8) 1.9 (0.7-3.0) 0.4 (0.1-0.9) 1.9(0.6-3.2)
1.8 (0.6-3.1) 2.6 (0.9-4.3) 2.1 (1.3-3.0) 1.5 (0.2 2.8) 3.7 (1.8-5.7) 2.8(1.0 4 . 7 )
1.1 (0.1-2.0) 1.2 (0.0-2.4) 2.3 (l.4-3.2) 3.3 (1.4-5.2) 1.4 (0.3-2.6) 1.8(0.2-3.3)
0.6 (0.0-1.2) 2.2 (0.3-4.1) 1.7 (0.6 2.9) 2.7 (1.4~J,.0) 0.5 (0.1-1.0) 2.3(0.9 3.8)
(Manton et al., 1994) and to Kraepelin's case summaries of the year 1908 (Jablensky and Woodbury, 1995); a more recent version of the model is currently in use with the data from the 10-country study. Both the IPSS results and the preliminary data from the application of the Grade of Membership model suggest that several independent dimensions underlie the observed symptomatology. These symptomatological 'pure types' have stronger associations with external validating criteria, such as age at onset, pattern of course, and familial occurrence of psychotic disorders, than the ICD subtype diagnoses. One way of resolving the conundrum of conceptual difficulties in which schizophrenia research appears to be today is by going back to the origins. It should be recalled that in 1896, Kraepelin conflated into a single hypothetical disease entity, on the basis of a presumed common outcome, three quite different disorders: hebephrenia, catatonia, and 'dementia paranoides'. However, two decades later, Kraepelin had doubts about the validity of his original formulation. Toward the end of his career, he conceded that 'our formulation of the problem may be incorrect'. In one of his last papers (Kraepelin, 1920), he proposed to step back and abandon the categorical disease notions of schizophrenia and manic-depressive disorder by replacing them with a dimensional-hierarchical model, according to which schizophrenic and affective syndromes 'do not represent the expression of particular pathological processes, but rather indicate the areas of our personality in which these processes unfold'. The role of 'hereditary factors' is to 'make certain areas more suscep-
tible and accessible to pathological stimuli'. According to Kraepelin, 'the various syndromes of illness may be compared with the different registers of an organ, any of which may be brought into play according to the severity or extent of the pathological changes involved. They impart a characteristic tone to the illness quite irrespective of the mechanism which has brought them into play'.
9. Conclusion There is no doubt that the introduction of a categorical nosology of psychiatric disorders at the end of the 19th century represented a major advance. By simplifying and ordering into a clear conceptual scheme, a previously chaotic array of descriptive labels, Kraepelin's nosology aligned psychiatry with the rest of medicine and made research into the nature and causes of mental disorders possible. Unfortunately, this nosological system became too easily 'reified' and institutionalized. Kraepelin's own creative reappraisal of the field of psychoses in 1920 came too late to change anything because by that time, the categorical nosology was already firmly entrenched. At present, some 75 years later, there are signs of a growing awareness of the disparity between the power of the new research techniques in psychiatry and the constraints of the nosological paradigm within which schizophrenia research is being conducted. This extent of heterogeneity should call into question the validity of the phenotype definition and lead to a reexamination of the possibility that the diagnostic category itself is an amalgama-
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tion of several independent dimensions. Therefore, it may be wise to restore to psychiatric research the syndromes and symptoms as the basic units of observation and to adopt a radically syndromological approach to the clinical and epidemiological study of psychiatric conditions. The resolution power of present-day research technologies makes it more likely that significant associations between dynamic cerebral processes and psychopathology will be eventually found at the level of symptoms and syndromes rather than at the level of disorders as defined in the current diagnostic systems. Similarly, the study of selected neurophysiological, cognitive, and neurochemical markers, assessed as dimensions across the conventional diagnostic groups and in the general population, may reveal patterns of association with clinically significant symptoms, behavior, or personality traits that might result in refined definitions of clinical entities and in better validated phenotypes for genetic research.
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SchizophreniaResearch 28 (1997) 111-125
The 100-year epidemiology of schizophrenia Assen Jablensky * Department of Psychiatry and Behavioural Science, University of Western Australia, 50 Murray Street, Perth, WA 6000, Australia Received 13 March 1997; accepted 15 July 1997
Abstract
Since Kraepelin delineated dementia praecox as a disease entity construct, epidemiological studies conducted since the beginning of the century have produced remarkably consistent estimates of its prevalence, incidence and lifetime risk across various populations and geographic areas. A similar pattern emerged from the WHO ten-country study on first-contact incidence of schizophrenia. The diagnostic concept of dementia praecox originally used by Kraepelin and that of schizophrenia employed in the WHO studies were found to overlap extensively, indicating continuity over time. However, the findings of a similar incidence of schizophrenia in diverse populations and across time periods are unusual for a multifactorial disease and are compatible with at least two alternative interpretations that have different implications for the search for genetic and environmental causes of the disorder. © 1997 Elsevier Science B.V. Keywords: Schizophrenia; Dementia praecox; Epidemiology; Nosology; Phenotype definition
A future historian is likely to describe the 100 years since Kraepelin's inception of the disease entity dementia praecox as a fascinating and extraordinary chapter in the history of medicine. It would be difficult to find many medical conditions that have been investigated with similar vigor and persistence over a century and have proved to be as intractable to understanding as schizophrenia. The history of schizophrenia research is a chronology of recurrent themes, many promising clues that have subsequently been abandoned, and a plethora of explanatory models of which none has yet been either categorically rejected or unequivocally proven. It is remarkable that many of the current research ideas are, in fact, rediscoveries * Tel: +61 9 224 0290; Fax: +61 9 224 0285; e-mail: [email protected] 0920-9964/97/$17.00© 1997ElsevierScienceB.V. All rights reserved. PH S0920-9964 (97) 00108-4
of early observations and hypotheses, many of them datable to the first decades following the adoption of the Kraepelinian diagnostic scheme (Table 1). There is another sense in which the history of schizophrenia is at odds with the rest of medicine: the fundamental conceptual framework within which schizophrenia research has been conducted, i.e. the Kraepelinian dichotomy of the major psychoses, has hardly been modified since its inception. Despite many attempts at alternative formulations of the diagnostic classification of the psychoses, and continual doubts by researchers and clinicians (including Kraepelin himself) about the validity of the disease concept of dementia praecox, the categorical nosology constructed by Kraepelin has not been seriously challenged. Its essential features are present in ICD-I0 ( W H O ,
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Table 1 Early findingsin schizophrenia Abnormal eye movements Cortical atrophy Recurrence risks in biologicalrelatives;anticipation Attention deficit Ventricleenlargement(air encephalography) Possible role of influenza Birth seasonality Negative associationwith rheumatoidarthritis
1993) and DSM-IV (APA, 1994). Prominent researchers and teachers who describe themselves as 'neo-Kraepelinians' (Compton and Guze, 1995) indicate an allegiance to a particular school of thought in psychiatry, in a way similar to philosophers' adherence to 'neo-Kantian', 'neoHegelian', or even 'neo-Platonist' ideas. It is generally accepted that there is no single test or procedural rule to establish the validity of a disease concept or of a diagnostic classification in psychiatry (Kendell, 1975). The acceptance of a particular diagnostic concept or a classification scheme is usually based on the interpretation of converging evidence from multiple sources, including descriptive psychopathology, neuropathology, pathophysiology, genetics, and epidemiology. This process bears a similarity to the way that 'paradigms' evolve in science (Kuhn, 1962). The discussion below aims to review the contribution of one of those sources--psychiatric epidemiology--to the continuing debate on the validity of the Kraepelinian disease model of dementia praecox.
1. Early epidemiological research in schizophrenia Psychiatric epidemiology originated in 19th-century censuses of the insane, which were carried out primarily for administrative purposes. However, by the end of the century, scientific questions proper began to be addressed, and by 1915, Joseph Goldberger provided the first, and probably the most successful example to date, of the application of analytic epidemiology to a medical and public health problem with a significant psychiatric component: the etiology of pellagra (Goldberger, 1915). Probably, the first application of the epide-
Diefendorfand Dodge(1908) Southard (1915) R~din (1916) Kraepelin (1919) Jacobi and Winkler(1927) Menninger(1928) Tramer (1929) Nissen and Spencer(1936)
miological method in a modern sense to the investigation of psychoses was the work of a female physician, Jenny Koller, who in 1895 conducted a case-control study of the aggregation of psychiatric disorders in the families of 284 probands and 370 healthy control subjects in Zurich (Koller, 1895). In many ways, her conclusions anticipated presentday knowledge about the genetic epidemiology of the psychoses in that she found that 'the hereditary loading of the healthy subjects is much higher than generally assumed'; that 'the strongest loading is that of psychoses and accentuated characters'; and that 'the loading in distant relatives is quite low, unless a person at risk is exposed to multiple factors'. Kraepelin himself--whose greatest historic contribution was perhaps first the vision and then the practical organization of the first truly multidisciplinary program of psychiatric research--saw quite clearly the potential of the epidemiological method to 'throw light on the causes of mental disorder' and proposed comparative population studies of the psychoses and the underlying personality-related factors across different cultures (Kraepelin, 1904). In the first half of the 20th century, epidemiological research into the psychoses took two relatively distinct paths. While the focus of German, Swiss, and Scandinavian investigators was primarily on the genetic factors, North American research took a more active interest in the social ecology of mental illness, as represented, for example, by the 'Chicago school' (Faris and Dunham, 1939). On both sides of the Atlantic, however, epidemiological research was pursued vigorously, and the general contours of the epidemiological map of schizophrenia were, by and large, complete before World War II. Most of the
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methodological tools of psychiatric epidemiology were developed and applied with considerable success during the four decades between 1910 and 1950 (Table 2). It is of interest to note how these early epidemiological studies were actually conducted 'in the field'. The majority were carried out single-handedly by dedicated researchers who typically spent months and sometimes years in a community, collecting information and interviewing, literally, door-to-door. Personal knowledge of the respondents, access to multigenerational records from the local parish registers, and generous cooperation by the community as a whole resulted in detailed and accurate data of a descriptive quality that would be difficult to match today. For example, Graemiger (1931), a Swiss general practitioner working in a rural community, published 66 extended genealogies segregating psychotic illnesses and claimed to have known personally 1357 of their members across four generations. EssenM611er et al. (1956) interviewed personally each one of the 2550 inhabitants of the Lundby community in Sweden. The same respondents, as well as their offspring, were followed up and periodically reinterviewed by Hagnell (1966,) and Hagnell and C)jesj6 (1975) over 25 years, which resulted in what is probably the most accurate data set on the age- and sex-specific incidence rates of the major categories of psychiatric disorders. Many of the results of those early studies retain their benchmark value today. As a matter of fact, none of the more recent contributions from epidemiological research has substantially altered the conclusions of the earlier studies as regards the population incidence and prevalence of schizophrenia, the age at onset curve, the age- and sexspecific morbid risk, the morbidity risks for specified biological relatives of a schizophrenic proband, the outcomes of dual matings of individuals with psychoses, and the data on reduced fertility of persons with schizophrenia (Gottesman et al., 1987).
2. Diagnostic comparabifity over time However, the question of comparability of diagnoses of dementia praecox, or schizophrenia, made
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by researchers earlier in this century with more recent diagnostic practice--especially since the introduction of explicit diagnostic criteria--needs to be addressed in this context. Careful reading of the early publications and archival documents suggests that it would be an oversimplification to assert that imprecise, variable, and often broad diagnostic concepts dominated the field prior to the Research Diagnostic Criteria (RDC) and DSM-III. Similarly unsupported by fact is the belief (Keefe et al., 1991) in the existence of two variants of the diagnostic concept of schizophrenia: one 'Kraepelinian' (narrow) and the other 'Bleulerian' (broad). The evidence indicates that, at least in Europe, the diagnosis of schizophrenia was usually made along fairly restrictive lines, and the concept of schizophrenia remained consistent over time (Jablensky, 1986). Direct evidence for this was provided by a study (Jablensky et al., 1993) in which Kraepelin's original research case summaries (Z~ihlblgtter) on all patients with diagnoses of dementia praecox and manic-depressive illness admitted to the Munich University Clinic in 1908 (total number, 187) were rated and scored in terms of the Present State Examination syndrome checklist (Wing et al., 1974) and processed with the CATEGO algorithm to generate 'presentday' ICD-9 diagnoses. The clinical features of these 'archival' cases from 1908 were then compared with 'modern' cases assessed in the WHO International Pilot Study of Schizophrenia, IPSS (WHO, 1979). The overall concordance between Kraepelin's original diagnoses and the computerassigned ICD-9 diagnosis was 88.6%. The comparison between the most frequent symptoms of Kraepelin's dementia praecox cases and the IPSS schizophrenia cases (Table 3) indicates a substantial overlap. There should therefore be no doubt that the diagnoses of dementia praecox in 1908 and of ICD-9 schizophrenia in the 1970s refer to the same clinical syndrome. The diagnostic drift that eventually separated European and American concepts of schizophrenia originated primarily in the United States with the expansion of the boundaries of the disorder under the influence of psychodynamic theory. This was well documented by the landmark US-UK Diagnostic Study (Cooper et al., 1972),
A. Jablensky / Schizophrenia Research 28 (1997) 111-125
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A. Jablensky / Schizophrenia Research 28 (1997) 111-125
115
Table 3 Most frequent symptoms and syndromes in a sample of Kraepelin's dementia praecox cases and in the WHO International Pilot Study of Schizophrenia Kraepelin's first-admission dementia
WHO International Pilot Study of Schizophrenia cases assessed in 1968-1969 (N=811)
praecox cases in 1908 (N= 53) PSE-9 syndrome
Frequency (%)
PSE-8 unit of analysis
Frequency (%)
Non-specific psychosis Delusions of persecution Catatonia
54.7 54.7 47.2
Lack of insight Suspiciousness Unwilling to cooperate
82.7 60.0 57.3
Fantastic and sexual delusions Auditory hallucinations Flat affect Simple depression Delusions of reference Grandiose and religiousdelusions Generalized anxiety Visual hallucinations Slowness Incoherent speech Overactivity Nuclear syndrome Irritability Loss of interests
39.6 35.8 32.1 30.2 30.2 24.5 24.5 24.5 24.5 22.6 22.6 20.8 20.8 15.1
Ideas of reference Flat affect Delusions of reference Poor rapport Delusions of persecution Delusional mood Auditory hallucinations Verbal auditory hallucinations Voices speaking to patient Gloomy thoughts Thought alienation Autism Apathy Restricted speech
55.1 51.0 50.3 49.5 48.1 47.5 43.8 37.9 36.3 35.7 33.5 30.7 30.4 17.5
which, along with an early version of 'operational' diagnostic criteria (Feighner et al., 1972), prepared the ground for the development of the DSMIII system.
3. The epidemiological map of schizophrenia prior to DSM-III The general picture emerging from epidemiological research in schizophrenia prior to the 1970s is one of a disorder of a relatively low population incidence (range, 0.17-0.57 per 1000), a relatively high point prevalence (range, 2.4-6.7 per 1000), and a lifetime morbid risk in the range of 0.38-1.87% (Table 4). Part of the variation within those ranges can be explained by sampling and design differences between individual studies, but on the whole, data from census surveys, birth cohort investigations, and case registers of treated morbidity tend to converge. Exceptions to the ranges quoted above are studies of 'outlier' populations. The existence of such unusual populations has been documented
for a long time. These include, for example, the well-known area in North Sweden, where an unusually high prevalence (17 per 1000) and a familial clustering of cases had first been decribed by B66k (1953) and B66k et al. (1978); several Swedish island populations (Sj6gren, 1948; Larsson and Sj6gren, 1954); and two areas on the Istrian peninsula in Croatia (Crocetti et al., 1971). Although the high concentration of cases in the North Sweden area is attributable to a founder effect in an isolated population, the genetic studies of pedigrees from this region have so far failed to demonstrate any linkage to possible susceptibility genes. Populations of extremely low incidence and prevalence of schizophrenia have been more difficult to find, and the evidence is only slightly better than anecdotal. The findings of a virtual absence of schizophrenic psychoses among the Hutterites in North America (Eaton and Weil, 1955) have not been replicated by subsequent research in those communities (Murphy, 1980). The very low prevalence rates reported by Torrey et al. (1974) in Papua New Guinea are likely to reflect a low detection rate.
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Table 4 Results from selected epidemiological studies of schizophrenia, 1930s through 1970s Author
Country
Brugger ( 1931)
Germany
2.4
Klemperer (1933) Odegaard (1946) Str0mgren (1938) Fremming (1947) Sj6gren (1948) B66k (1953) Essen-M611er et al. (1956) Norris (1959) Helgason (1986)
Germany Norway Denmark Denmark Sweden Sweden Sweden UK Iceland
10.0
Walsh (1969)
Ireland
Crocetti et al. (1971)
Croatia
Lieberman (1974)
Former USSR
Nielsen (1976)
Denmark: island of Samso Iceland USA (Rochester, NY)
Helgason (1986) Babigian (1980)
Prevalence per 1000
Incidence per 1000
0.24 4.6 9.5b 6.7c
Lifetime risk per 100
Remarks
0.38
Door-to-door survey, population age 10+ Birth cohort First admissions, age 10+ Door-to-door, all ages Birth cohort Door-to-door, all ages Genetic isolate
1.40a 1.87 0.58 0.90 1.60 2.66
0.17 0.69 (men) 1.02 (women) 0.57 (men) 0.46 (women)
First admissions
5.9
Area known for high rate of psychosis Admission cohort
0.20 (men) 0.19 (women) 0.20 0.27 0.69
First admissions Birth cohort, up to age 61
First admissions 0.90
Birth cohort, up to age 75 Case register study
"Estimate corrected for cohort attrition. b17.0 in 1978. c3.9 psychotic on census date.
4. Effects of the operational diagnostic criteria on epidemiological research The introduction o f standardized, operational diagnostic criteria in D S M - I I I and its subsequent versions, and in ICD-10, has raised expectations o f a new impetus to epidemiological research t h r o u g h improved reliability o f assessment and greater homogeneity o f clinical and population samples. Both sets o f criteria have been shown to be relatively reliable. For example, the multicenter trial o f the I C D - 1 0 criteria resulted in a k a p p a o f 0.84 for all schizophrenic disorders; a similar result (0.83) was obtained for the diagnosis o f bipolar affective disorder (Sartorius et al., 1993). However, in any patient population that is sampled on a 'checklist' basis with either I C D - 1 0 or D S M - I I I R / D S M - I V criteria, at least two kinds o f exclusion are likely to occur: (1) less severe, transient or atypical cases, (2) a residual o f cases with missing
data. In addition, the two checklists, i.e. D S M - I I I R / I V and ICD-10, differ and result in overlapping but not identical patient populations. The two systems are likely to produce substantial agreement on the severe, 'core' cases o f schizophrenia but m a y result in discordant classifications o f the less severe or incipient cases. Whereas the D S M I V / I C D - 1 0 differences would be o f m i n o r importance in clinical or biological research, their implications for epidemiological and genetic studies m a y be serious. The use o f D S M - I V criteria for case ascertainment in a field survey m a y result in the exclusion o f atypical, recent-onset, or subclinical presentations o f the schizophrenic syndrome, unless a provision is m a d e to identify separately cases not meeting the full set o f criteria. Furthermore, since epidemiological data are a m o n g the validating criteria for the clinical concept o f schizophrenia, collecting epidemiological data via the diagnostic criteria that are themselves
A. Jablensky / Schizophrenia Research 28 (1997) 111-125
to be validated introduces a diffficult-to-avoid circularity. It would be desirable, therefore, to develop less restrictive screening DSM-IV and ICD-10 criteria for epidemiological research. Epidemiological and clinical instruments developed in the past 10years are linked to the new diagnostic criteria. The NIMH Diagnostic Interview Schedule, DIS (Robins et al., 1981), and the related WHO-ADAMHA Composite International Diagnostic Interview, CIDI (Robins et al., 1988), are fully structured interviews written to match the DSM-III-R/DSM-IV and ICD-10 criteria and designed for use by lay interviewers. Clinical interviews such as the Schedules for Clinical Assessment in Neuropsychiatry, SCAN (Wing et al., 1990), cover a broader range of psychopathology and require clinical judgment to elicit data that can be processed by ICD-10 and DSM-III-R diagnostic algorithms. However, there is still a clear need for a relatively simple and psychometrically sound screening instrument for case finding of schizophrenia in field surveys. When applied in epidemiological field studies, the operational diagnostic criteria predictably identify lower rates of schizophrenia, as compared with studies employing a less structured ICD-9 diagnostic assessment. This is particularly evident in the Camberwell study (Castle et al., 1991), in which DSM-III research diagnoses were made in addition to the ICD-9 diagnoses recorded in the case register. The data on schizophrenia or 'non-affective psychosis' from large-scale surveys designed to estimate the total psychiatric morbidity in the general population, such as the Epidemiological Catchment Area Study (Keith et al., 1991) and the National Comorbidity Survey (Kendler et al., 1996) in the United States, are difficult to interpret because of the relatively small numbers of subjects with psychotic disorders in the samples studied and possible misclassification problems associated with the use of fully structured diagnostic instruments by lay interviewers. Overall, there is no evidence that the current operationalized diagnostic systems identify more homogeneous samples of individuals with schizophrenia in epidemiological studies. However, the potential benefits of the rulebased, structured approach to diagnosis in epidemiological research are yet to materialize, provided
117
that further methodological work is undertaken for the appropriate adaptation of the criteria to field studies.
5. Recent findings necessitating further research Two themes have recently gained prominence in the literature on the epidemiology of schizophrenia: a very high treated incidence rate in AfroCaribbeans born in the United Kingdom and statistical data suggesting that over recent decades the incidence of schizophrenia may have been declining in Western populations. Again, none of these findings is truly novel: the unusual level of morbidity among Afro-Caribbeans was described in 1967 (Hemsi, 1967), and data suggesting a declining incidence of schizophrenia were published in 1978 (Weeke and Str6mgren, 1978). As regards the excess of schizophrenia among second-generation Afro-Caribbeans, it now seems that the phenomenon cannot be fully attributed to diagnostic bias and misclassification (Wessely et al., 1991), or to a lower admission threshold. A recent study that reported a significantly increased risk of schizophrenia for siblings of second-generation Afro-Caribbean probands but not for their parents (Hutchinson et al., 1996) suggests that an unknown environmental factor may be involved. Although the epidemiological evidence presented to date is weakened by the lack of reliable data on the size and age structure of the Afro-Caribbean population in the United Kingdom (Harrison et al., 1989), the reported risk elevation is of a magnitude that is unlikely to be substantially discounted. If further confirmed, these data, as well as somewhat similar findings on immigrants from Surinam and the Dutch Antilles in the Netherlands (Selten and Sijben, 1994), may provide unique clues to risk factors in schizophrenia. In contrast to the Afro-Car~bean phenomenon, the case for a true decline in the population incidence rate of schizophrenia is less well supported, and the actual data from national statistics or case registers: are inconsistent (Jablensky, 1995a). Indeed, some independent epidemiologicat evidence that real decreases may have occurred is provided by the two census surveys on the island
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of Bornholm in 1935 and 1983 (Bojholm and StrOmgren, 1989), which documented a prevalence decline from 4.2 to 2.7 per 1000 in females but not in males. However, no study to date has taken into account all the possible confounding factors, such as a variation in the definitions of first admission or first contact; changes in diagnostic practice (e.g. a tendency to defer a diagnosis of schizophrenia on first admission); changes in treatment modality (an increasing number of patients being managed on an outpatient basis without admission to hospital); or changes in the age structure of the population, which may affect the rates if no standardization for age is carried out. As a corollary, a compensatory increase could be expected in diagnoses other than schizophrenia. Such increases have actually been reported for borderline states (Munk-Jorgensen, 1986) and for affective psychosis (Geddes et al., 1993).
6. Overview of established and putative risk factors
The search for risk factors is a major aim of analytical epidemiology, and the results are usually expressed as relative risk ratios or odds ratios. Of the many putative risk factors and disease markers that have been implicated over the period, only a limited number have been successfully replicated. The data are summarized in Table 5 (Jablensky and Eaton, 1995), which lists estimated odds ratios across a number of studies. It should be noted that these odds ratios are not based on a proper meta-analysis (which would be hardly feasible) but reflect the judgment of two investigators who have examined the studies concerned and reached a consensus that inevitably contains an element of subjective judgment. The term 'potential risk factors' is used in Table 5 because not all factors have been identified either as causes or even as clearly antecedent in time. The column labeled 'P or I' aids in this distinction, with 'P' indicating that the association presented originates from prevalence data and 'I' indicating the association is from prospective or incidence data. Potential risk factors were selected only if the preponderance of evidence suggested that the asso-
ciation presented was credible. At least two methodologically rigorous studies were required for selection in Table 5. If there were many studies, more than three-quarters of their results were required to be in the direction presented in the table for a 'preponderance of evidence' to be accepted. Some potential risk factors are entered in the table that have not been included in prior reviews. For example, the literature in the area of pre- and perinatal factors shows that positive evidence has been developing rapidly in this area, which led to its inclusion. Neuropsychological and neurocognitive factors have been added because developments in measurement methods have shown that epidemiological studies can be conducted with these constructs. With all the reservations about the exact values of the odds ratios, it is likely that at least the order-of-magnitude differences between the odds ratios for the different categories of risk factors are not far off the mark and reveal important aspects of the disorder. The difference between the top category (familial factors) and the rest is obvious, and it is difficult to escape the conclusion that familial, presumably genetic, findings are at present the only class of variables that would satisfy the epidemiological criteria for a major risk factor. This conclusion, based on genetic-epidemiological evidence, tends to be reinforced by promising recent developments in genetic linkage and candidate gene research (reviewed by Asherson et al., 1995; Ross and Pearlson, 1996). The general, and probably nonspecific, sociodemographic descriptors, such as country of birth or ancestry, single marital status, and low socioeconomic status, seem to fare much better than factors such as winter birth, maternal influenza, or obstetric complications. The data on candidate markers, including ventricular-brain ratio (VBR), eye tracking abnormalities, or attention deficit, would probably fail the threshold of epidemiological interest in the study of a disorder other than schizophrenia. This is not to say that such borderline or inconsistent findings are without intrinsic significance. It is quite possible that the present system of conceptualizing and classifying schizophrenia tends to lump together subgroups of cases in which some of these risk factors and markers might be expressed much more sharply.
A. Jablensky / Schizophrenia Research 28 (1997) 111-125
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Table 5 Estimated odd ratios for risk factors in schizophrenia (Jablensky and Eaton, 1995) Potential risk factors
Authors' estimate N studies
Odds ratio
Relevant references P or I a
Familial (biological relative with schizophrenia) Biological parent Two parents Monozygotic twin Dizygotic twin Non-twin sibling Second-degree relative
12 5 5 5 5 3
Gottesman et al. (1987); Kendler (1988); Kendler and Diehl (1993); Moldin (1994) 7 37 45 14 9 1.1
I P P P P P
Social
Eaton (1974); Eaton et al. (1994); Freeman (1994); L6ffler and H/finer (1994)
Low socioeconomic status Single status Stressful life events
17 8 3
3 4 1.5
I I I
Sociodemographic Country of birth or ancestry Urban birth or upbringing
3 2
5 2
I I
Harrison et al. (1988); Eagles (1991); Wessely et al. (1991)
Pregnancy and birth related
Winter birth Obstetric complications Maternal influenza
H~ifner et al. (1987); Eaton (1991); McNeil (1995); Mednick et al. (1988); Mednick et al. (1994); Kendell and Kemp (1989); Wright and Murray (1993); Takei et al. (1994) 30 10 9
1,1 2 1,1
I I P
Neuropsychological Oculomotor dysfunction Attentional dysfunction
Mirsky and Duncan (1986); Levy et al. (1993); Kremen et al. (1994) 20 15
1.5 1.5
P P Shelton and Weinberger (1986); Raz and Raz (1990); Nasrallah (1993)
Neuropathologieal/neuroimaging Increased ventricle-brain ratio
6
1.5
I
a p = prevalence data; I = incidence data.
7. Comparative epidemiology of schizophrenia I n 1904, K r a e p e l i n suggested t h a t ' c o m p a r a t i v e p s y c h i a t r y ' , i.e. the s t u d y o f disease incidence in p o p u l a t i o n s o f c o n t r a s t i n g cultures, d e m o g r a p h i c features, a n d physical e n v i r o n m e n t s , c o u l d p r o v i d e clues to the e t i o l o g y o f p s y c h o s e s ( K r a e p e l i n , 1904). Differences in the incidence, o r c o n t r a s t i n g p a t t e r n s o f course a n d o u t c o m e , s h o u l d t h e r e f o r e be s y s t e m a t i c a l l y e x a m i n e d for c o r r e l a t i o n s with v a r i a t i o n s in gene p o o l s o r e n v i r o n m e n t a l factors.
T h e evidence f r o m earlier e p i d e m i o l o g i c a l research has been extensively reviewed f r o m such a p o i n t o f view ( E a t o n , 1985; J a b l e n s k y , 1986, 1995b), b u t its i n t e r p r e t a t i o n c a n l e a d to diverging conclusions. It is e q u a l l y possible to give weight m a i n l y to the similarities across different p o p u l a t i o n s as it is to e m p h a s i z e the differences. F o r example, T o r r e y (1989) suggested t h a t even if the effects o f m e t h o d o l o g i c a l inconsistencies a m o n g prevalence studies c o u l d be s u b t r a c t e d , there w o u l d be at least 10-fold residual differences across p o p u l a t i o n s . I n
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this respect, the incidence data from the WHO 10-country study on determinants of outcome of severe mental disorders (Jablensky et al., 1992) are of particular interest. The WHO study, conducted in 13 geographical catchment areas in Europe, the Indian subcontinent, West Africa, North and South America, and Japan, was the first cross-cultural epidemiological investigation in which standardized instruments and closely comparable case-finding methods were applied simultaneously at all sites to ascertain the first-contact incidence of schizophrenia and schizophrenialike illnesses in populations that differed widely in terms of demography, economy, culture, and general health profiles. All of the 1379 cases were interviewed, diagnosed, and reinterviewed at a 2-year follow-up by psychiatrists using the Present State Examination (ninth edition). The results have triggered considerable debate. The age- and sex-specific incidence rates for 'broadly' ICD-9 diagnosed schizophrenia ranged from 0.16 per 1000 in Honolulu to 0.42 per 1000 in a rural area in India (p < 0.001 ), and the differences across sites were significant. However, the rates for a more narrowly, computer-defined 'core' syndrome characterized by first-rank 'Schneiderian' symptoms were in the range of 0.07 per 1000 (Aarhus, Denmark) to 0.14 per 1000 (Nottingham, UK), and the differences across sites were not significant. In all the areas, there was an excess of males in the age groups of 15-24, whereas females were overrepresented in the age groups of 35-54. Lifetime disease expectancy was almost equal for males and females. The conclusions of the WHO report emphasized the striking similarities of incidence and symptoms across populations--a finding that had not been anticipated by the investigators at the outset. The suggestion that these results might be affected by insufficient statistical power (Frangou and Murray, 1996) is not supported by the confidence intervals, which were calculated for each age- and sex-specific incidence rate (Table 6). The more difficult epidemiological question-that the similarity of the incidence rates might conceal differences in lifetime disease expectancy, since the age distributions in the different catchment areas differed markedly--was largely
answered by a reanalysis carried out by Chang (1990), who used life tables to apply survival models to the incidence rates found for each of the catchment areas under comparison. He found that the differences were no greater than 2:1, e.g. 10.82 in Moscow and 5.46 in Honolulu. The results of the WHO study, therefore, seem capable of withstanding critical scrutiny, and the question that remains to be answered is their meaning in the context of the epidemiology of schizophrenia. One possible interpretation is that the comparable liability to schizophrenia across very different populations points to a common, fundamental genetic basis for the disorder, possibly linked to other species characteristics, such as the evolution of cerebral asymmetry and the related issue of language (Crow, 1995). Another plausible hypothesis that remains to be explored is that the observed similarity of rates might be the effect of a syndroreal admixture (Gibbons et al., 1984), i.e. that a number of low-incidence syndromes of heterogeneous etiology but hardly distinguishable phenotypical expression combine together to produce a seemingly uniform rate of schizophrenia across different populations. This would be in conformity with the idea that schizophrenia is the common final pathway for a variety of etiologically different conditions.
8. Alternatives to the categorical nosology of psychoses The view of schizophrenia as a single disease entity, which continues to dominate current biological research (including genetic and neuropathological studies), is in conflict with the large body of data suggesting that the extent of phenotypic heterogeneity in schizophrenia is too large to support a simple nosological model of the disorder. There are at present powerful analytical tools that make it possible to address the difficult issue of heterogeneity in schizophrenia. One such technique, the Grade of Membership model (Woodbury and Manton, 1982), based on the 'fuzzy set' theory, was applied to the analysis of schizophrenia symptom profiles in the WHO International Pilot Study of Schizophrenia
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Table 6 Age- and sex-specificincidence rates per 10000 (and 95% confidenceintervals) for CATEGO S+ schizophrenia in six centers participating in the WHO study on determinants of outcome of severe mental disorders Males
Aarhus (Denmark) Chandigarh (India) Ibadan (Nigeria) Moscow (Russia) Nagasaki (Japan) Nottingham(U.K.)
Females
15-24 years
25 34 years
35-54 years
15-24 years
25-34 years
35-54 years
2.9 (1.3-4.5) 3.3 (1.6 5.0) 2.3 (1.5-3.0) 1.3 (0.0-2.5) 4.7 (2.4-7.1) 5.3(2.87 . 6 )
1.6 (0.5-2.7) 0.8 (0.1-1.6) 2.1 (1.3-2.8) 2.5 (0.8 4.2) 2.7 (1.0-4.4) 3.0(0.95 . 0 )
1.2 (0.4-2.1) 0.3 (0.3-0.8) 0.4 (0.0-0.8) 1.9 (0.7-3.0) 0.4 (0.1-0.9) 1.9(0.6-3.2)
1.8 (0.6-3.1) 2.6 (0.9-4.3) 2.1 (1.3-3.0) 1.5 (0.2 2.8) 3.7 (1.8-5.7) 2.8(1.0 4 . 7 )
1.1 (0.1-2.0) 1.2 (0.0-2.4) 2.3 (l.4-3.2) 3.3 (1.4-5.2) 1.4 (0.3-2.6) 1.8(0.2-3.3)
0.6 (0.0-1.2) 2.2 (0.3-4.1) 1.7 (0.6 2.9) 2.7 (1.4~J,.0) 0.5 (0.1-1.0) 2.3(0.9 3.8)
(Manton et al., 1994) and to Kraepelin's case summaries of the year 1908 (Jablensky and Woodbury, 1995); a more recent version of the model is currently in use with the data from the 10-country study. Both the IPSS results and the preliminary data from the application of the Grade of Membership model suggest that several independent dimensions underlie the observed symptomatology. These symptomatological 'pure types' have stronger associations with external validating criteria, such as age at onset, pattern of course, and familial occurrence of psychotic disorders, than the ICD subtype diagnoses. One way of resolving the conundrum of conceptual difficulties in which schizophrenia research appears to be today is by going back to the origins. It should be recalled that in 1896, Kraepelin conflated into a single hypothetical disease entity, on the basis of a presumed common outcome, three quite different disorders: hebephrenia, catatonia, and 'dementia paranoides'. However, two decades later, Kraepelin had doubts about the validity of his original formulation. Toward the end of his career, he conceded that 'our formulation of the problem may be incorrect'. In one of his last papers (Kraepelin, 1920), he proposed to step back and abandon the categorical disease notions of schizophrenia and manic-depressive disorder by replacing them with a dimensional-hierarchical model, according to which schizophrenic and affective syndromes 'do not represent the expression of particular pathological processes, but rather indicate the areas of our personality in which these processes unfold'. The role of 'hereditary factors' is to 'make certain areas more suscep-
tible and accessible to pathological stimuli'. According to Kraepelin, 'the various syndromes of illness may be compared with the different registers of an organ, any of which may be brought into play according to the severity or extent of the pathological changes involved. They impart a characteristic tone to the illness quite irrespective of the mechanism which has brought them into play'.
9. Conclusion There is no doubt that the introduction of a categorical nosology of psychiatric disorders at the end of the 19th century represented a major advance. By simplifying and ordering into a clear conceptual scheme, a previously chaotic array of descriptive labels, Kraepelin's nosology aligned psychiatry with the rest of medicine and made research into the nature and causes of mental disorders possible. Unfortunately, this nosological system became too easily 'reified' and institutionalized. Kraepelin's own creative reappraisal of the field of psychoses in 1920 came too late to change anything because by that time, the categorical nosology was already firmly entrenched. At present, some 75 years later, there are signs of a growing awareness of the disparity between the power of the new research techniques in psychiatry and the constraints of the nosological paradigm within which schizophrenia research is being conducted. This extent of heterogeneity should call into question the validity of the phenotype definition and lead to a reexamination of the possibility that the diagnostic category itself is an amalgama-
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tion of several independent dimensions. Therefore, it may be wise to restore to psychiatric research the syndromes and symptoms as the basic units of observation and to adopt a radically syndromological approach to the clinical and epidemiological study of psychiatric conditions. The resolution power of present-day research technologies makes it more likely that significant associations between dynamic cerebral processes and psychopathology will be eventually found at the level of symptoms and syndromes rather than at the level of disorders as defined in the current diagnostic systems. Similarly, the study of selected neurophysiological, cognitive, and neurochemical markers, assessed as dimensions across the conventional diagnostic groups and in the general population, may reveal patterns of association with clinically significant symptoms, behavior, or personality traits that might result in refined definitions of clinical entities and in better validated phenotypes for genetic research.
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