ABC Schizophrenia study: an overview of results since 1996.

PURPOSE: The ABC Schizophrenia study, led by a single research team, investigated a schizophrenia sample systematically over quarter of a century. This paper summarises results from 1996 onwards. The initial goals were to explain the considerably higher age at first admission in women, and to obtain precise information on the onset and early course of schizophrenia as a prerequisite for early intervention. METHOD: The study was hypothesis-driven. People with schizophrenia were compared in the prodrome and at first admission to those with unipolar depression and to healthy controls. We analysed the medium-term (5-year) and the long-term (12-year) course of schizophrenia, its symptom dimensions, social parameters and predictors. SAMPLES: (1) 276 population-based first admissions (232 first episodes) of schizophrenia (age range 12-59 years); (2) a subsample of 130 first admissions for schizophrenia; (3) 130 first admissions for unipolar depression; (4) 130 healthy population controls and (5) 1,109 consecutive first admissions for schizophrenia spectrum disorder without an age limit. RESULTS: The prodromal stages of schizophrenia and depression were very similar until positive symptoms appeared. The most frequent symptom in schizophrenia was depressed mood. The course of psychosis from prodrome to 12 years following first admission was very variable. From 5 to 12 years after first admission the course was characterised by irregular exacerbations of the main symptom dimensions, with no overall deterioration or improvement. CONCLUSIONS: Schizophrenic psychosis and severe affective disorder, rather than representing discrete illnesses, probably mark different stages in the manifestation of psychopathology produced by various degrees of brain dysfunction.

[Schizophrenia - a disorder in its own right?: results from 25 years of the ABC study]. / Schizophrenie - eine einheitliche Krankheit?: Ergebnisse aus 25 Jahren ABC-Studie.

BACKGROUND: The ABC schizophrenia study conducted by the same team over 25 years initially aimed at illuminating the onset, prodromal stage and sex differences in age at first hospitalization in schizophrenia. New hypotheses were systematically generated from the results achieved. METHODS: A population-based sample of 276 first admission cases (232 first episodes, age 12-59 years), including a subsample of 130 first admissions (115 first episodes), were assessed to study prodromal stage, first illness episode, medium and long-term course and symptom dimensions in schizophrenia. The samples were compared with age and sex-matched healthy controls and with patients first admitted for unipolar depression. A total of 1,109 consecutive first admissions for schizophrenia spectrum disorders independent from the other study samples were assessed to study changes in symptomatology across the age range. RESULTS: Before the onset of psychotic symptoms the prodromal stages of schizophrenia and severe and moderately severe depression are difficult to distinguish. The most frequent symptom in the course of schizophrenia, depressed mood, also represents the most frequent initial symptom in both disorders. Prodromal depression is a predictor of more depressive and positive symptoms in the first episode but not in the further course of the illness. Psychosis incidence for men, diagnosed according to ICD 9 (295, 297, 298.3/4), shows a pronounced peak at age 15-24 years, for women a lower peak at age 15-29 years and a second, still lower peak at the menopausal age of 45-49 years. The explanation, confirmed in animal experiments, lies in a protective effect of estrogen due to reduced D2 receptor sensitivity. The effect is antagonized by an elevated genetic risk. Functional and social impairment emerge even at the prodromal stage and the severity depends on sex and social status. Young men with schizophrenia show a less favorable social course because of the earlier age of onset and socially adverse illness behavior. Late onset is associated with a milder, primarily paranoid symptomatology and less severe social impairment. Schizophrenia is a disorder of all ages showing roughly equal life time incidence rates for men and women but considerable difference in certain periods of age. The symptom dimensions show a plateau-like course 2-5 years after the first episode. Hidden behind this picture are irregular symptom exacerbations which vary in duration. Schizophrenia conveys the picture of recurrent vulnerability to crisis and not of a stable residual state of disordered brain development or of a progressive neurodegenerative process.

Main risk factors for schizophrenia: increased familial loading and pre- and peri-natal complications antagonize the protective effect of oestrogen in women.

Women fall ill with schizophrenia 3 to 4 years later than men. The neurobiological mechanism, explaining the delay of onset in women until menopause, is presumably due to a sensitivity reducing effect of oestrogen on central d(2) receptors, as we have previously shown in animal experiments and in a controlled clinical study. The gender difference in age at onset seems to disappear in familial cases with schizophrenia, but it increases to highly significant values of 5 years or more in isolated cases according to a recent study by Albus and Maier (Schizophrenia Research 18:51-57, 1995). We tried to replicate these findings and to test the hypothesis of a functional antagonism between genetic predisposition to illness and the protective effect of oestrogen in a population-based sample of 232 first illness episodes of schizophrenia. In women with at least one first-degree relative suffering from schizophrenia, age at onset defined by first psychotic symptom was significantly reduced by several years and the difference with men disappeared. In sporadic female cases (no mental disorder in first-degree relatives) the age at onset was slightly increased compared with the total sample, which was in accordance with our hypothesis. In men with familial schizophrenia, but without a protective agent like oestrogen, the age at onset was only slightly and non-significantly reduced compared with the total group and with sporadic cases. This was in line with Albus and Maier and with our hypothesis that only the protective effect of oestrogen could be antagonized by a strong genetic disposition. The second main risk factor for schizophrenia is pre- and peri-natal complications. We compared men and women from our sample of first illness episodes with a history of pre- and peri-natal complications with those without a history of obstetric complications. In women the age at first psychotic symptom was markedly reduced, but due to small case numbers not significantly, compared with women without the risk factor and with the total group. Again, schizophrenic men with a history of pre- and peri-natal complications showed only a small, non-significant reduction of age at onset compared with the total and the group without the risk factor. Therefore, we concluded that the degree of genetically determined vulnerability and, presumably to a slightly lesser extent, the degree of pre- and peri-natal brain injury antagonizes the onset delaying effect of oestrogen in schizophrenia.

The contribution of European case registers to research on schizophrenia.

Psychiatric case registers have become important instruments for epidemiological research and for the evaluation of care provided for persons suffering from schizophrenia. Under the condition of a sufficient provision of care, case registers permit relatively reliable estimates of "treated" incidence and prevalence, and enable the investigation of associations between morbidity risks, disease courses, and variables such as ecological, social, and occupational factors. The linkage with twin, adoption, and birth registers provides new opportunities for the investigation of the impact of genetic versus environmental factors on the probability of becoming ill with schizophrenia. On the basis of long-term utilization figures, case registers enable a valid measure for controlling utilization, effectiveness, quality, and costs of care. Because case registers take demographic and regional factors into account, they enable better planning of mental health services--a task that grows more important with the shift from hospital-based to community-based treatment, especially for the chronic patients.

Evaluating effectiveness and cost of community care for schizophrenic patients.

The two main types of mental health services research are (1) the evaluation of the mental health sector within comprehensive systems of health care and (2) the evaluation of individual mental health facilities or types of care. Depending on the information systems available, the difficulties of evaluating complex systems of care can be partially obviated by using descriptive approaches. Structural quality can be assessed by structural indices, the functioning of a system by monitoring utilization, and the overall effectiveness of a national mental health care system roughly by health indicators. Causal analyses of effectiveness are practical when they are based on individual facilities or types of care, which can be studied as isolated systems on the basis of intervention and outcome variables. Reliable and reproducible results can be achieved only if a standardized intervention is used or if the intervention and its objectives are described clearly, the output indicators are defined in terms of identifiable and repeatable operations. The assets and liabilities of quasi-experimental designs and three types of naturalistic approaches will be discussed. When the cost of a new type of care is compared with the cost of traditional mental health care, the section of the population actually served out of the total of patients with comparable needs for care should be considered. Results from the authors' studies will show how the neglect of this epidemiological aspect can lead to false statements.

Causes and consequences of the gender difference in age at onset of schizophrenia.

The ABC (age, beginning, course) schizophrenia study was commenced in 1987 to generate and test hypotheses about pathogenic aspects of schizophrenia. One of the main branches of the study focused on how gender influences the age distribution of onset, symptomatology, illness behavior, and early course in schizophrenia. Proceeding from one of the rare, strikingly deviating, consistent findings--the gender difference in age at first admission--we launched a systematic search for explanations by generating and testing hypotheses in a series of substudies. We moved from the epidemiological to the neurobiological and finally to the clinical level. The present article is an attempt to provide a brief overview of the individual stages of the ABC study and the different levels of investigation involved in formulating and testing the estrogen hypothesis in animal experiments and in demonstrating its applicability to human schizophrenia. From these results, three hypotheses were formulated and tested on data from an ABC study sample of 232 first-episode cases of schizophrenia. The analyses described here represent the latest stages of the ABC study.

The epidemiology of early schizophrenia. Influence of age and gender on onset and early course.

For the investigation of the early course of schizophrenia starting from onset, the standardised Interview for the Retrospective Assessment of the Onset of Schizophrenia was developed and validated. In a representative sample of 267 first-admitted German schizophrenics of a broad diagnosis from a population of 1.5 million, the age at which different diagnostic and onset definitions were satisfied, the symptoms at the time of the interview, and the accumulation of positive and negative symptoms until first admission were assessed. Comparison between the two sexes and three age groups yielded hardly any differences in the accumulation of symptoms and their course until first admission, except for a slightly shorter period of negative symptoms in young males and a slightly longer one in older women--which contradicts prevailing opinion. At the time of the interview, no significant sex differences were found with respect to the core symptoms of schizophrenia (negative and first-rank symptoms), but clear and substantial differences emerged in disease behaviour. The significantly higher age at first onset in women is explained, on the basis of animal experiments and a clinical study, by the neuromodulatory effect of oestrogen on D2 receptors and by a higher vulnerability threshold in women.

[Sex differences in age of onset, symptomatology and evolution of schizophrenia]. / Différences selon le sexe dans l'âge d'apparition, la symptomatologie et l'évolution de la schizophrénie.

Gender differences in age at onset, symptomatology and course of schizophrenia are examined by analyzing case register data and by direct investigation of a representative sample of first-admitted patients. The main finding that males fall ill at an earlier age than females can be confirmed even after ruling out other interpretations due to sample bias, different time span between real onset and first hospital admission, gender differences in symptom development or other confounding factors. When looking for causes of these gender differences it seems that disturbances in early social development must be understood as a consequence of beginning schizophrenia rather than a prerequisite. The need for explanatory models is stressed that allow for the empirical testing of hypotheses concerning gender specific development of schizophrenia.

[Schizophrenia and depression]. / Schizophrenie und Depression.

BACKGROUND: Comparison of symptom-related and social role development between patients with schizophrenia, major depression and healthy controls provided insights into the untreated early course of the two disorders. SAMPLES AND METHODS: Symptoms, functional impairment and social disability were assessed and compared using the IRAOS and several other cross-sectional instruments in three samples. RESULTS: At the early illness stages there was considerable overlap in the symptom patterns and impairments presented by persons with schizophrenia and severe depression. The two disorders did not diverge until later in the early illness course with the onset of psychotic symptoms. Depressive symptoms showed a maximum in the first psychotic episode and relapse episodes and decreased with the remitting episode. Due to differences in cognitive appraisal depressed patients reported more functional impairment and social disability than patients with schizophrenia did. CONCLUSION: The early course of symptoms and social impairment in schizophrenia and depression seems to offer an opportunity to distinguish these disorders from variants of normal development fairly early. However, early diagnostic distinction and prediction of psychosis versus depression risk at the pre-psychotic prodromal stage do not seem promising due to the broad overlap in symptoms and impairment.

[Can outpatient measures prevent inpatient admission?]. / Können durch ausserstationäre Massnahmen stationäre Aufenthalte verhindert werden?

During the last decades the focus of psychiatric care has shifted from hospital to the "community". As the philosophy of deinstitutionalisation implies that community mental health care is preferable to hospital care and that treatment functions may be performed equally well or even better outside a hospital, one of the main objectives of community-based care consisted in preventing hospital readmission. Despite many objections readmission data and length of stay become most popular as outcome criteria in the evaluation of treatment measures. However, until today evaluative research has failed to demonstrate the overall effectiveness in preventing inpatient treatment. This is mainly due to the fact that the complexity of the research topic could not be adequately modelled and controlled in observational studies as the main source of information.

[Methodological problems of longitudinal studies on schizophrenia]. / Methodische Probleme der Verlaufsforschung an der Schizophrenie.

Longitudinal studies are a key to understanding schizophrenia. They are the more informative, the longer the periods covered. Hence, good studies into the course of schizophrenia almost exclusively involve a lot of effort and cost. In practice, however, time-consuming methods and design variables must be avoided. The pitfalls this constraint produces are instructive of the difficulties longitudinal studies are faced with in striving for valid results. For reasons of research economy, requirements must be adjusted to study objectives. Studies into the short term course are less time-consuming, but because of the rapid changes in the illness course study intervals should be defined clearly and observed strictly. In long-term studies, too, one source of error lies in the highly varying lengths of illness of the patients studied. Even some of the classic long-term studies are marred by this error. The beginning of the follow-up period should be comparable across the study cohort and as close to illness onset as possible. To obtain generally valid results the probands must be representative of all the illness cases in the general population not only at the outset, but also all the later stages of the study. Besides the efforts to avoid attrition in the study cohort, ways must be found for correcting and estimating data for an acceptable proportion of drop-outs. In the analysis of course and outcome the indicators chosen must be apt to the traditional subtypes as well as to a theoretical symptom patterns and empirical symptom structures. In the context of typical design variables of longitudinal studies the assets and weaknesses of two retrospective and one prospective design will be discussed. Concerning the social course, importance of disease-independent factors, such as age, sex and level of social development at illness onset, as well as of control groups will be demonstrated. Predictor models will be discussed with reference to the direct and indirect influences involved. Examples of such analyses will be given.

The epidemiology of onset and course of schizophrenia.

Traditionally the heterogeneity of schizophrenia was dealt with by subdividing the syndrome into different subtypes. However, due to lacking standards, the result was an immense variety of subtypes partly based on cross-sectional assessments, partly taken the whole course between onset, resp. first admission and outcome after many years into account. Some solutions were based on symptomatology only, others also relied on social characteristics as the ability to fulfil different roles in family and the world of employment. So it is not surprising that the number of subtypes ranges from two up to more than 70. As one possible solution Carpenter and Kirkpatrick (1988) suggest that attempts to subdivide the schizophrenic syndrome should concentrate on few significant parts of the course thought of to represent specific disease processes. Based on two epidemiological studies finding about the onset, middle course and late course of schizophrenia are presented. In three quarter of the cases the onset of the first psychotic episode in schizophrenia is preceded by a prodromal phase with a mean length of about five years. The earliest signs of the disorder are depressive and negative symptoms. Early depressive symptoms predict higher overall symptom scores in the first illness episode and lower scores for affective flattening in the medium-term course. There is no decrease in the number of patients with acute symptomatology over fifteen years after first hospital admission, rather there is a tendency of an increase. With respect to social abilities we found a significant increase of disability over time. But the change already takes place during the first five years. Approx. 60% of those falling ill with schizophrenia become chronic and approx. 25% will recover during the first five to six years.

The course of schizophrenia in the light of modern follow-up studies: the ABC and WHO studies.

In schizophrenia most of the social consequences emerge in the prodromal phase of the illness and before treatment is initiated. Further course is determined by the level of social development at illness onset and by age- and sex-related illness behavior. Despite the sex difference in age at onset the disease process seems to be the same in both sexes, since social course in men and women converges in the long run. Although great variation in outcome between the patients is to be observed at each cross-section, the medium and long-term symptom-related course of schizophrenia shows a high degree of stability at the individual level.

Effectiveness and cost of community care for schizophrenic patients.

Schizophrenic patients in Mannheim, West Germany, were studied to determine whether psychiatric treatment in the community reduces duration and frequency of rehospitalization, whether it has an impact on symptomatology and behavior, and whether it can be provided less expensively than hospital care. The findings showed a relationship between increased psychiatric outpatient treatment and lower levels of inpatient care as well as between psychiatric aftercare and reduced symptomatology and disease-related behavior. The cost of community care was found to be substantially lower than that of hospital care for less disabled patients, but it exceeded the cost of hospital care for the more severely disabled.

[Research in psychiatric care: a contribution to the evaluation of the extramural care of schizophrenic patients]. / Psychiatrische Versorgungsforschung: Ein Beitrag zur Evaluation extramuraler Versorgung bei Schizophrenen.

The conceptual approach and the structures of psychiatric service have changed, and hence the question of efficacy of measures and institutions for mental patients is of special significance. In the U.S.A. this realization has led to a regulation that compulsorily prescribes the evaluation of Government-sponsored programs (Dowell and Ciarlo, 1983). Whereas the investigation into the efficacy of individual therapeutic measures is part of standard psychiatric research (Garfield and Bergin, 1978, Clark and del Guidice, 1970), the evaluation of institutions or part systems of service has only just begun, to a major part due to the methodical difficulties arising from investigating such a claim. It is often impossible, for both ethical and practical reasons, to initiate an experimental study approach that definitely provides for random allocation of patients to various service care and monitoring parameters. Hence, we must look for alternative research strategies enabling analysis of cause and effect relationships on the basis of observation studies. In this study we attempted to improve the significance of statistical analyses by means of adequate data analysis technique, the object of analysis being a community psychiatric service; such a procedure would restrict the number of possible alternative possibilities of interpretation. We could prove for a group of schizophrenic patients that continual aftercare by aftercare clinics had a really significant effect on the rehospitalization of patients, which was considerably reduced without entailing any adverse effect on the patients in consideration of the pattern of signs and symptoms involved.

Epidemiology of schizophrenia.

OBJECTIVE: To characterize the epidemiology of schizophrenia. METHOD: Narrative literature review. RESULTS: Each year 1 in 10,000 adults (12 to 60 years of age) develops schizophrenia. Based on a restrictive and precise definition of the diagnosis and using standardized assessment methods and large, representative populations, the incidence rates appear stable across countries and cultures and over time, at least for the last 50 years. Schizophrenic patients are not born into ecological and social disadvantage. The uneven distribution of prevalence rates is a result of social selection: an early onset leads to social stagnation, a late onset to descent from a higher social status. The main age range of risk for schizophrenia is 20 to 35 years. It is still unclear whether schizophrenia-like late-onset psychoses (for example, late paraphrenia) after age 60 should be classified as schizophrenia either psychopathologically or etiologically. In 75% of cases, first admission is preceded by a prodromal phase with a mean length of 5 years and a psychotic prephase of one year's duration. On average, women fall ill 3 to 4 years later than men and show a second peak of onset around menopause. Consequently, late-onset schizophrenias are more frequent and more severe in women than in men. The sex difference in age of onset is smaller in cases with a high genetic load and greater in cases with a low genetic load. Type of onset and core symptoms do not differ between the sexes. The most pronounced sex difference is the socially negative illness behaviour of young men. CONCLUSIONS: Among the factors determining social course and outcome are level of social development at onset, the disorder itself (for example, genetic liability, severity of symptoms, and functional deficits), general biological factors (for example, estrogen), and sex- and age-specific illness behaviour.

The course of schizophrenia: some remarks on a yet unsolved problem of retrospective data collection.

The retrospective assessment of symptoms and syndromes is a basic measure in research of the longitudinal course of schizophrenia. In spite of its importance there have been few studies evaluating the standard of quality of instruments for retrospective data collection. Combining retrospectively and cross-sectionally collected data on schizophrenic symptomatology in a cohort study over a period of 5 years revealed a significant underestimation of symptoms when assessed in retrospect. The need for studies on the validity of instruments for the retrospective assessment of symptoms is stressed.

[Evaluation of community care of psychiatric patients. Results of 4 years' scientific association with the building phase of the Mannheim model]. / Evaluation gemeindenaher Versorgung psychisch Kranker. Ergebnisse von 4 Jahren wissenschaftlicher Begleitung der Aufbauphase des Mannheimer Modells.

The implementation of a community mental health service in Mannheim (FRG), a city with 315,000 inhabitants, is being evaluated by means of the data of the Cumulative Psychiatric Case Register at the Central Institute of Mental Health. Within a four-year period of extending services for crisis intervention and emergency care, aftercare (sheltered apartments, homes, workshops) and of providing psychiatric beds in the city, the total number of treatment episodes has increased by more than 100% from about 1.1 to about 2.2 per 1000 inhabitants aged over 14, mainly at the out-patient level of care. Admissions to hospital showed an increase of about 40% whereas bed occupancy remained stable at a rate of about 1.7/1000-respectively 1.3/1000 if beds provided by a psychogeriatric nursing home are deducted. This development can be attributed to various factors: (1) A true increase of morbidity may occur mainly in diagnostic groups I.C.D. No.300, 301, 305-308, especially an increase in attempted suicides and in alcohol- and drug-related diseases. (2) The increased provision of help, mainly on the sector of crisis intervention and emergency care and - in diagnostic categories - mainly in minor neurotic disorders, crises, and affective psychoses, has resulted in a large rise in utilization. (3) The continuous decrease of long-term hospital stays, above all in schizophrenic patients, has led to increased utilization of out- and in-patient services in the community when crises and relapses occurred. A comparison of two cohorts of "old" and "new" patients, the latter having accumulated under the conditions of a community mental health service, has shown that these patients are admitted for a long-term hospital stay considerably later and less frequently than formerly, mostly only after several attempts for rehabilitation. In the group of schizophrenic patients, only about 5% of all first admissions stayed in a psychiatric hospital for more than one year in 1979/80. About the year 1900, this group had still amounted to between 60% and 70%. A comparison with evaluations of comprehensive community care systems in other countries shows that there are largely identical trends, although the initial rate for psychiatric beds was comparably lower in Mannheim.

[Schizophrenia research using psychiatric case registries]. / Schizophrenieforschung mit Hilfe psychiatrischer Fallregister.

Almost 60 years after the establishment of the National Register of Psychoses in Norway psychiatric case registers have become an indispensable instrument of psychiatric research. By enabling a consecutive, person-related registration of contacts with the health care services of a geographically circumscribed region over long periods they have opened up new perspectives for epidemiological and followup studies and the evaluation of the care provided for schizophrenics. The severity of the illness and the fact that it frequently takes a long-term course are highly likely to lead to contacts with psychiatric services in areas with well-developed service structures. In this way case registers permit relatively reliable estimates of the treatment prevalence and first contacts, providing indicators of the true incidence. In the Federal Republic of Germany, however, as the only country in the world, cumulative psychiatric case registers have become illegal. An examination of long-term ecological, social and individual distribution processes among persons fallen ill with schizophrenia shows that the uneven distribution becomes effective even prior to the first onset. This is reflected in the marriage rates--the more so among males than females--, in the choice of occupation and the social chances of the schizophrenics to-be. In contrast, there is no reliable evidence for an increased risk of falling ill with schizophrenia after exposure to severe stress over a longer period of time. The age at first onset is some 10 years lower for males than females. Neither for this finding nor for the deviating birth season distribution, exhibited by approximately 10% of the schizophrenics, has any conclusive explanation been found. Even after the successful combat against tuberculosis falling ill with schizophrenia clearly reduces further life expectancy. The linkage of data from psychiatric case registers with twin, adoption and birth registers confirms the assumption that the probability of falling ill with schizophrenia is increased by genetic factors, thus refuting the alternative hypothesis of an environment-related transmission of the illness. Case registers are an indispensable means for the evaluation and cost analysis of the care provided for schizophrenics, above all in the establishment of new programmes of community-based complementary care for the chronically ill. Furthermore, they provide a solid basis for methodological studies on questions such as the stability of or transitions in the diagnosis over time.