The structure of schizotypal personality traits: a cross-national study.

BACKGROUND: Schizotypal traits are considered a phenotypic-indicator of schizotypy, a latent personality organization reflecting a putative liability for psychosis. To date, no previous study has examined the comparability of factorial structures across samples originating from different countries and cultures. The main goal was to evaluate the factorial structure and reliability of the Schizotypal Personality Questionnaire (SPQ) scores by amalgamating data from studies conducted in 12 countries and across 21 sites. METHOD: The overall sample consisted of 27 001 participants (37.5% males, n = 4251 drawn from the general population). The mean age was 22.12 years (s.d. = 6.28, range 16-55 years). The SPQ was used. Confirmatory factor analysis (CFA) and Multilevel CFA (ML-CFA) were used to evaluate the factor structure underlying the SPQ scores. RESULTS: At the SPQ item level, the nine factor and second-order factor models showed adequate goodness-of-fit. At the SPQ subscale level, three- and four-factor models displayed better goodness-of-fit indices than other CFA models. ML-CFA showed that the intraclass correlation coefficients values were lower than 0.106. The three-factor model showed adequate goodness of fit indices in multilevel analysis. The ordinal α coefficients were high, ranging from 0.73 to 0.94 across individual samples, and from 0.84 to 0.91 for the combined sample. CONCLUSIONS: The results are consistent with the conceptual notion that schizotypal personality is a multifaceted construct and support the validity and utility of SPQ in cross-cultural research. We discuss theoretical and clinical implications of our results for diagnostic systems, psychosis models and cross-national mental health strategies.

Associations between psychosis endophenotypes across brain functional, structural, and cognitive domains.

BACKGROUND: A range of endophenotypes characterise psychosis, however there has been limited work understanding if and how they are inter-related. METHODS: This multi-centre study includes 8754 participants: 2212 people with a psychotic disorder, 1487 unaffected relatives of probands, and 5055 healthy controls. We investigated cognition [digit span (N = 3127), block design (N = 5491), and the Rey Auditory Verbal Learning Test (N = 3543)], electrophysiology [P300 amplitude and latency (N = 1102)], and neuroanatomy [lateral ventricular volume (N = 1721)]. We used linear regression to assess the interrelationships between endophenotypes. RESULTS: The P300 amplitude and latency were not associated (regression coef. -0.06, 95% CI -0.12 to 0.01, p = 0.060), and P300 amplitude was positively associated with block design (coef. 0.19, 95% CI 0.10-0.28, p 0.38). All the cognitive endophenotypes were associated with each other in the expected directions (all p < 0.001). Lastly, the relationships between pairs of endophenotypes were consistent in all three participant groups, differing for some of the cognitive pairings only in the strengths of the relationships. CONCLUSIONS: The P300 amplitude and latency are independent endophenotypes; the former indexing spatial visualisation and working memory, and the latter is hypothesised to index basic processing speed. Individuals with psychotic illnesses, their unaffected relatives, and healthy controls all show similar patterns of associations between endophenotypes, endorsing the theory of a continuum of psychosis liability across the population.

Psychosis prevalence and physical, metabolic and cognitive co-morbidity: data from the second Australian national survey of psychosis.

BACKGROUND: There are insufficient data from nationwide surveys on the prevalence of specific psychotic disorders and associated co-morbidities. METHOD: The 2010 Australian national psychosis survey used a two-phase design to draw a representative sample of adults aged 18-64 years with psychotic disorders in contact with public treatment services from an estimated resident population of 1 464 923 adults. This paper is based on data from 1642 participants with an International Classification of Diseases (ICD)-10 psychotic disorder. Its aim is to present estimates of treated prevalence and lifetime morbid risk of psychosis, and to describe the cognitive, physical health and substance use profiles of participants. RESULTS: The 1-month treated prevalence of psychotic disorders was 3.10 cases per 1000 population aged 18-64 years, not accounting for people solely accessing primary care services; lifetime morbid risk was 3.45 per 1000. Mean premorbid intelligence quotient was approximately 0.5 s.d.s below the population mean; current cognitive ability (measured with a digit symbol coding task) was 1.6 s.d.s below the population mean. For both cognitive tests, higher scores were significantly associated with better independent functioning. The prevalence of the metabolic syndrome was high, affecting 60.8% of participants, and pervasive across diagnostic groups. Of the participants, two-thirds (65.9%) were current smokers, 47.4% were obese and 32.4% were sedentary. Of the participants, half (49.8%) had a lifetime history of alcohol abuse/dependence and 50.8% lifetime cannabis abuse/dependence. CONCLUSIONS: Our findings highlight the need for comprehensive, integrative models of recovery to maximize the potential for good health and quality of life for people with psychotic illness.

Genome-wide supported variant MIR137 and severe negative symptoms predict membership of an impaired cognitive subtype of schizophrenia.

Progress in determining the aetiology of schizophrenia (Sz) has arguably been limited by a poorly defined phenotype. We sought to delineate empirically derived cognitive subtypes of Sz to investigate the association of a genetic variant identified in a recent genome-wide association study with specific phenotypic characteristics of Sz. We applied Grade of Membership (GoM) analyses to 617 patients meeting ICD-10 criteria for Sz (n=526) or schizoaffective disorder (n=91), using cognitive performance indicators collected within the Australian Schizophrenia Research Bank. Cognitive variables included subscales from the Repeatable Battery for the Assessment of Neuropsychological Status, the Controlled Oral Word Association Test and the Letter Number Sequencing Test, and standardised estimates of premorbid and current intelligence quotient. The most parsimonious GoM solution yielded two subtypes of clinical cases reflecting those with cognitive deficits (CDs; N=294), comprising 47.6% of the sample who were impaired across all cognitive measures, and a cognitively spared group (CS; N=323) made up of the remaining 52.4% who performed relatively well on all cognitive tests. The CD subgroup were more likely to be unemployed, had an earlier illness onset, and greater severity of functional disability and negative symptoms than the CS group. Risk alleles on the MIR137 single-nucleotide polymorphism (SNP) predicted membership of CD subtype only in combination with higher severity of negative symptoms. These findings provide the first evidence for association of the MIR137 SNP with a specific Sz phenotype characterised by severe CDs and negative symptoms, consistent with the emerging role of microRNAs in the regulation of proteins responsible for neural development and function.

A whole-of-population study of the prevalence and patterns of criminal offending in people with schizophrenia and other mental illness.

BACKGROUND: Large epidemiological studies are needed to better understand the prevalence and profile of offending by people with mental illness. This study used a whole-of-population design to examine the prevalence, type and pattern of offending across all psychiatric diagnoses, including schizophrenia, compared to the general population. Method We used whole-of-population longitudinal record-linked data for a cohort of all Western Australians born 1955-1969 to determine arrest history over the period 1985-1996 and to ascertain recorded history of psychiatric illness. Of the cohort, 116 656 had been arrested and 40 478 were on the psychiatric case register. RESULTS: The period prevalence of arrest for people with any psychiatric illness was 32.1%. The highest arrest prevalence, by diagnostic category, was for substance use disorders (59.4%); the prevalence for schizophrenia was 38.7%. Co-morbid substance use disorders significantly increased risk of arrest in people with schizophrenia. The prevalence of mental illness among offenders was 11.1%: 6.5% of offenders had substance use disorders and 1.7% had schizophrenia. For the majority of offenders with a psychiatric illness, first arrest preceded first contact with mental health services; for schizophrenia only, this proportion was increasing over time. The mean percentage annual change in the number of arrests during 1985-1996 rose significantly for offenders with a psychiatric illness other than schizophrenia and dropped significantly for those with no mental illness. Compared to non-psychiatric offenders, offenders with schizophrenia were more likely to offend alone, to offend in open places and to target strangers. CONCLUSIONS: Our findings open the way to an informed approach to the management of offenders with mental illness.

Promoter polymorphisms in two overlapping 6p25 genes implicate mitochondrial proteins in cognitive deficit in schizophrenia.

In a previous study, we detected a 6p25-p24 region linked to schizophrenia in families with high composite cognitive deficit (CD) scores, a quantitative trait integrating multiple cognitive measures. Association mapping of a 10 Mb interval identified a 260 kb region with a cluster of single-nucleotide polymorphisms (SNPs) significantly associated with CD scores and memory performance. The region contains two colocalising genes, LYRM4 and FARS2, both encoding mitochondrial proteins. The two tagging SNPs with strongest evidence of association were located around the overlapping putative promoters, with rs2224391 predicted to alter a transcription factor binding site (TFBS). Sequencing the promoter region identified 22 SNPs, many predicted to affect TFBSs, in a tight linkage disequilibrium block. Luciferase reporter assays confirmed promoter activity in the predicted promoter region, and demonstrated marked downregulation of expression in the LYRM4 direction under the haplotype comprising the minor alleles of promoter SNPs, which however is not driven by rs2224391. Experimental evidence from LYRM4 expression in lymphoblasts, gel-shift assays and modelling of DNA breathing dynamics pointed to two adjacent promoter SNPs, rs7752203-rs4141761, as the functional variants affecting expression. Their C-G alleles were associated with higher transcriptional activity and preferential binding of nuclear proteins, whereas the G-A combination had opposite effects and was associated with poor memory and high CD scores. LYRM4 is a eukaryote-specific component of the mitochondrial biogenesis of Fe-S clusters, essential cofactors in multiple processes, including oxidative phosphorylation. LYRM4 downregulation may be one of the mechanisms involved in inefficient oxidative phosphorylation and oxidative stress, increasingly recognised as contributors to schizophrenia pathogenesis.

Neuregulin 3 (NRG3) as a susceptibility gene in a schizophrenia subtype with florid delusions and relatively spared cognition.

Linkage of 10q22-q23 to schizophrenia and the recently reported association of Neuregulin 3 (NRG3) polymorphisms with high 'delusion factor' scores led us to attempt replication and further refinement of these findings in a sample of 411 schizophrenic patients and 223 nonpsychiatric control subjects. Using quantitative cognitive traits, patients were grouped into a cluster with pervasive cognitive deficit (CD) and a cluster with relatively spared cognition (CS). We found a significant association between rs6584400 and schizophrenia, with a trend for rs10883866. Post hoc analysis revealed that this result was mainly due to the CS cluster, characterized by elevated scores on Schneiderian first-rank symptoms, salience of complex delusions and positive thought disorder--thus closely related to the 'delusion factor'. In addition, both rs6584400 and rs10883866 were associated with the degraded-stimulus continuous performance task in which 'risk' alleles were associated with better than average performance in patients and worse performance in controls. This suggests that NRG3 may be modulating early attentional processes for perceptual sensitivity and vigilance, with opposite effects in affected individuals and healthy controls. The two single-nucleotide polymorphisms are in close proximity to the alternative first exons of the NRG3-a, -b and -d isoforms, of which the human brain-specific NRG-b appears to be the most interesting candidate.

Kraepelin's concept of psychiatric illness.

Emil Kraepelin fundamentally shaped our current psychiatric nosology. Although much has been written about his diagnostic formulations, less is known about his views on the fundamental nature of psychiatric illness and the goals of psychiatric nosology. We focus on his writings from 1896 to 1903 but also review his inaugural lecture in Dorpat in 1887 and his last two papers, published in 1919­1920. Kraepelin hoped for a ' natural ' classification of psychiatric illness but realized that the level of etiologic knowledge required to undergird this effort was not feasible in his own lifetime. This did not stop him, however, from developing a pragmatic approach based on his clinical method of careful description with detailed follow-up, coupled with the available fallible tools of pathological anatomy and, by 1919, genetics and biochemistry. Kraepelin saw psychiatric disorders as multifactorial, arising from the difficult to untangle action and interaction of internal and external causes. He was aware of the problem of defining the boundaries of illness and health but knew this was not unique to psychiatry. Contrary to his stereotype, he was sensitive to the importance of personality factors in psychiatric illness and advocated for their investigation. He also recognized the limitations of his ' clinical method' and was especially critical of classifications based on single prominent symptoms. Ultimately, Kraepelin was a skeptical realist when it came to psychiatric nosology. His goal of developing a consistent ' natural ' classification of the major mental disorders has yet to be attained, but his ' research agenda' remains central to psychiatry to the present day.

'Social dysmetria' in first-episode psychosis patients.

OBJECTIVE: The 'embodied cognition' hypothesis suggests a close relationship between internal self-representations and the outward expression of social behaviours and emotions. Given self-awareness disturbances in patients with first-rank symptoms (FRS), we hypothesized that these patients would show abnormal social behaviours. In this study, we examined the social interactive skills of patients with first-episode psychosis during an interview, together with changes in performance over time. METHOD: We analysed previously unreported data from 227 patients with first-episode psychosis (90 with, and 137 without, FRS) who took part in the WHO multicentre study on the Determinants of Outcome of Severe Mental Disorders. They were assessed on the Psychological Impairment Rating Schedule (PIRS) and examined again after 2 years. RESULTS: A principal component analysis on the Psychosocial Impairment Rating Schedule produced two factors (interactive skills; withdrawal from interactions). Patients with FRS showed greater impairments in the domain linked to 'interactive skills', which remained 2 years after the first experience of a psychotic illness. These findings were not explained by clinical characteristics, or presence of non-FRS delusions. CONCLUSION: Self-awareness deficits, as indexed by the FRS symptom cluster, are linked to deficits in social interactive behaviours. These abnormalities are indicative of 'social dysmetria' in this group, which involves difficulties conveying motor aspects of behaviours, volition and affect to facilitate mutual communication. These findings point to the utility of behavioural assessment scales in clinical and research settings.

Is cannabis a risk factor for suicide attempts in men and women with psychotic illness?

OBJECTIVE: To investigate whether recent cannabis use by men and women with psychotic disorders was associated with increased risk of suicide attempt, and to determine associated factors, stratified by sex. METHODS: Data from 1065 men and 725 women interviewed in the Australian national survey of psychosis were analysed to model separately, for each sex, the impact of daily, casual or no past-year cannabis use and other risk factors including age, on a past-year suicide attempt. RESULTS: In the past year, 168 (9.4%) participants attempted suicide. Unadjusted analyses showed daily cannabis users of both sexes had significantly increased odds of attempting suicide compared to non-users. After adjusting for confounding factors, this relationship was no longer significant. Depression had the strongest association with attempting suicide for both sexes. Sex differences in other risk factors were observed. In post hoc analysis, daily cannabis use was associated with higher odds of attempting suicide in older men compared to non-users; this was not found in younger men or women. CONCLUSIONS: Associations between past-year cannabis use and suicide attempts were confounded by other factors (depression, loneliness, homelessness and hallucinations). The possibility of greater risk of suicidal behaviour with regular cannabis use for older men should be considered.

[Multi-centre clinical assessment of the Russian language version of the Diagnostic Interview for Psychoses]. / Mnogotsentrovoe klinicheskoe issledovanie russkoiazychnoi versii diagnosticheskogo interv'iu dlia psikhozov.

OBJECTIVES: The Diagnostic Interview for Psychoses (DIP) was developed to enhance the quality of diagnostic assessment of psychotic disorders. The aim of the study was the adaptation of the Russian language version and evaluation of its validity and reliability. MATERIAL AND METHODS: Ninety-eight patients with psychotic disorders (89 video recordings) were assessed by 12 interviewers using the Russian version of DIP at 7 clinical sites (in 6 cities of the Russian Federation). DIP ratings on 32 cases of a randomized case sample were made by 9 interviewers and the inter-rater reliability was compared with the researchers' DIP ratings. Overall pairwise agreement and Cohen's kappa were calculated. Diagnostic validity was evaluated on the basis of comparing the researchers' ratings using the Russian version of DIP with the 'gold standard' ratings of the same 62 clinical cases from the Western Australia Family Study Schizophrenia (WAFSS). RESULTS: The mean duration of the interview was 47±21 minutes. The Kappa statistic demonstrated a significant or almost perfect level of agreement on the majority of DIP items (84.54%) and a significant agreement for the ICD-10 diagnoses generated by the DIP computer diagnostic algorithm (κ=0.68; 95% CI 0.53,0.93). The level of agreement on the researchers' diagnoses was considerably lower (κ=0.31; 95% CI 0.06,0.56). The agreement on affective and positive psychotic symptoms was significantly higher than agreement on negative symptoms (F(2,44)=20.72, p<0.001, η2=0.485). The diagnostic validity of the Russian language version of DIP was confirmed by 73% (45/62) of the Russian DIP diagnoses matching the original WAFSS diagnoses. Among the mismatched diagnoses were 80 cases with a diagnosis of F20 Schizophrenia in the medical documentation compared to the researchers' F20 diagnoses in only 68 patients and in 62 of the DIP computerized diagnostic outputs. The reported level of subjective difficulties experienced when using the DIP was low to moderate. CONCLUSION: The results of the study confirm the validity and reliability of the Russian version of the DIP for evaluating psychotic disorders. DIP can be recommended for use in education and training, clinical practice and research as an important diagnostic resource.

On the interconnectedness and prognostic value of visual and auditory hallucinations in first-episode psychosis.

BACKGROUND: Visual hallucinations (VH) are common symptoms in schizophrenia and other psychoses. An understanding of their cross-sectional and longitudinal patterns of association with auditory hallucinations (AH) is essential for developing accurate models of hallucinatory phenomena. OBJECTIVE: This study presents the most comprehensive examination of the association between VH and AH, and its change over time, in 1303 individuals with first-episode psychosis (FEP) and 469 individuals with chronic schizophrenia. METHOD: The samples included data from the WHO multicentre study on the Determinants of Outcome of Severe Mental Disorders and the Western Australian Family Study of Schizophrenia (WAFSS). Standardized assessment of symptoms and functioning were used to examine the clinical profile and symptom co-occurrence of hallucinations over time. RESULTS: VH were approximately half as frequent as AH, almost always co-occurred with AH, and tended to be linked to a more severe psychopathological profile. AH and VH at baseline also predicted higher disability, risk of relapse and duration of psychosis after 1 and 2 years, especially when occurring in combination. CONCLUSIONS: The findings point to three hallucination 'subtypes' with different symptom profile. The VH+AH combination signals greater psychopathology and a less favourable prognosis, than hallucinations occurring in isolation, and no hallucinations. This conclusion points to one common mechanism for all hallucinations, which can separate into distinct pathways and modalities. For a more complete clinical picture, clinicians should carefully probe for both auditory and VHs in presenting patients.

The 100-year epidemiology of schizophrenia.

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.

The conflict of the nosologists: views on schizophrenia and manic-depressive illness in the early part of the 20th century.

The distinction between schizophrenia (dementia praecox) and bipolar disorder (manic-depressive insanity), proposed by Kraepelin in 1896, was the subject of vigorous debate in the first decades of this century. The debate addressed fundamental questions about the principles underlying the nosology of psychiatric disorders, and the issues raised remain as relevant today as at the time they were formulated. A meta-analysis of a sample of Kraepelin's primary data suggests that his original classification was consistent with the empirical evidence. However, heeding his critics, Kraepelin modified considerably his earlier views and proposed a conceptual model of the pathogenesis of schizophrenia and affective psychosis that is consonant with present-day ideas arising out of neuroscience and genetics. The lesson to be drawn is that nosological arguments should be put on hold until basic understanding is gained of the specific mechanisms of syndromogenesis across diagnostic boundaries.

Influenza epidemics and incidence of schizophrenia, affective disorders and mental retardation in Western Australia: no evidence of a major effect.

In-utero exposure to influenza has been implicated as a risk factor for developmental CNS damage. This study tests the hypothesis that in-utero exposure to influenza: (1) in the second gestational trimester is associated with an increased risk of schizophrenia and affective psychoses; and (2) in the first gestational trimester is associated with an increased risk of mental retardation. Analysis was confined to 1852 cases on the Western Australian psychiatric case register with ICD-9 diagnoses of schizophrenia, affective psychoses, or neurotic depression (comparison group), and 804 cases on the Intellectual Handicap Register with mental retardation that were related to 82,963 'exposed' and 32,462 'non-exposed' births between 1950 and 1960 in the total population of Western Australia. The data were examined for effects associated with six influenza epidemics in the period 1950-1960. Using relative risk ratios for individual epidemics as well as Poisson regression and a proportional hazards model to examine systematic effects for the whole period, no major effect could be identified for maternal influenza on the incidence of schizophrenia, affective psychoses and neurotic depression, despite sufficient statistical power to detect an effect. However, a possible effect was found for mental retardation in males exposed in the first and second gestational trimester.

European Collaborative Project on Affective Disorders: interactions between genetic and psychosocial vulnerability factors.

Despite strong evidence provided by genetic epidemiology of genetic involvement in the aetiology of bipolar and unipolar affective disorders, the exact nature of the predisposing gene(s) is still being investigated through linkage and association studies. The interaction of susceptibility genes and environmental factors in these diseases is also of fundamental importance and requires proper investigation. Interesting theories have recently been proposed examining the possible role of various chromosomal regions, candidate genes and mutations in affective disorders. Reliable multicentre-based methodology is currently being employed to examine these theories, with attention given to statistical analysis and the statistical power of the sample. The present article describes the European Collaborative Project on Affective Disorders (ECPAD) 'Interactions between genetic and psychosocial vulnerability factors', involving 15 European centres. A description is given of the association and family samples collected for the project and also the methodology used to analyse interactions in the gene-psychosocial environment. This material provides a powerful tool in the search for susceptibility genes in affective disorders and takes into account non-genetic aetiological factors.

Do loudness cues contribute to duration mismatch negativity reduction in schizophrenia?

The present study explored duration mismatch negativity (MMN) reduction in schizophrenia. Duration MMN studies usually employ tones of very short duration (< 200 ms). For stimuli < 200 ms in duration, an increment in duration is accompanied by an increase in perceived loudness. It was previously proposed that the effectiveness of duration MMN in revealing MMN reduction in schizophrenia might be explained by patients being insensitive to loudness cues and duration increments. In this study we equated loudness cues in a typical duration MMN paradigm and explored the effect of this manipulation on MMN amplitude reduction in schizophrenia. The manipulation had little effect on a healthy comparison group but had a marked effect on the MMN generated in the patient group who produced a significantly smaller MMN response to the regular duration deviant than to that in the equated loudness condition. This result was interpreted as demonstrating that patients exhibit a very marked insensitivity to duration increments.

Epidemiological and clinical research as a guide in the search for risk factors and biological markers.

One of the major events in psychiatric research in the last decade has been the firm establishment of the concept of biological markers and risk factors as legitimate signposts in the search for causes and pathogenetic mechanisms in mental disorders. However, to date, no single variable and no group of variables have been unequivocally identified as markers or risk factors, as far as the functional psychoses, or personality and neurotic disorders are concerned. The reasons for this state of affairs lie in the multifactorial nature of "idiopathic" psychiatric disorders, in persisting differences between the diagnostic criteria employed by various "schools", in the low statistical power of most research designs in biological psychiatry and in the lack of a general theory of cerebral and mental functioning which can yield testable hypotheses. Epidemiological methods, which had produced spectacular results in the past, are now rarely applied to narrow down the field of investigation where disease markers are most likely to be found. There are obvious similarities between the epidemiological strategy of risk factor identification and the biological strategy of disease marker research. A combination of these two strategies is more likely to advance the field than continued use of each singly. Schizophrenia research is an example of an area presenting interesting opportunities in this respect. The following priorities are suggested: development of a research classification of schizophrenia proceeding from well-defined sub-divisions of the phenotype; studies of the schizophrenia spectrum of disorders; search for populations with extremely high or extremely low incidence; studies of large pedigrees; further attempts to clarify the phenomenon of seasonal distribution of births of schizophrenia patients; studies on the occurrence of schizophrenic syndromes in association with other, well-defined diseases; search for early developmental precursors of the disorder; and subtyping of schizophrenia according to therapeutic response.

Epidemiology of schizophrenia: a European perspective.

Since its inception, the concept of dementia praecox and, later, of schizophrenia has been one of the most disputed entities in modern medicine. Schizophrenia was, and still is, defined by its clinical symptoms and their characteristic evolution over time. No external validating criteria for the diagnosis have been established, in spite of a host of suggestive biological findings, among which the genetic data carry most weight. This absence of clear-cut substrate markers and indicators underscores the importance of the epidemiological perspective in the study of the disorder. The European contributions to the epidemiological description and understanding of schizophrenic morbidity are numerous. They range from community surveys and studies of pedigrees to case-control designs for assessment of risk factors and long-term followup investigations of course and outcome. This review focuses on epidemiological approaches to schizophrenia that have attempted to highlight the essential attributes of a disease: its incidence and prevalence, ecology, and associated features. It is difficult to generalize about European epidemiological research in schizophrenia, because of the coexistence of a variety of "schools," traditions, and approaches. It is nevertheless possible to discern several clear trends in European epidemiological investigations of schizophrenia that can, to some extent, be contrasted to North American developments.