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.

GPs' views on the implementation of combined lifestyle interventions in primary care in the Netherlands: a qualitative study.

OBJECTIVES: Prevention and lifestyle support are emerging topics in general practice. Healthcare insurance companies reimburse combined lifestyle interventions (CLIs) in the Netherlands since January 2019. CLIs support people with overweight (body mass index, BMI 25-30) or obesity (BMI >30) to reduce weight in peer groups. General practitioners (GPs) are key in the successful implementation of lifestyle interventions in primary care. This study explored GPs' experiences and views on the implementation of CLIs to identify barriers and facilitators to the successful implementation in primary care. DESIGN: Qualitative study using semistructured interviews. Content analysis consisted of thematic coding and mapping a first stage of predefined and second stage of iterative evolving set of themes. SETTING: GPs were interviewed in a variety of primary care practices between February and April 2019. PARTICIPANTS: Fifteen GPs were purposively recruited for semi-structured interviews through snowballing. RESULTS: Experiences with lifestyle support among GPs ranged from referring patients to other healthcare professionals to taking a proactive role in lifestyle support themselves. Whether or not GPs took an active role in lifestyle support was related to their belief in the effect of lifestyle interventions. Overall, GPs had little experience with CLI in every day practice. Perceived barriers were a lack of availability of CLIs in the region and the potential lack of added value of CLIs on top of existing lifestyle support. Perceived facilitators were coordination of care provision by GP cooperatives and monitoring of the CLI implementation and their results. Reimbursement of CLIs without any costs for participants enabled application. CONCLUSION: The importance of lifestyle interventions in primary care was acknowledged by all GPs, but they differed in their level of experience with providing lifestyle support and awareness of CLIs. Successful integration of CLIs with primary care requires a solid promotion, a well-coordinated implementation strategy and structural evaluation of long-term effectiveness.

The influence of tetraphenylborates (hydrophobic anions) on yeast cell electro-rotation.

The action of a series of tetraphenylborate ion (TPB) derivatives on yeast cells was studied by electro-rotation of the pre-treated cells. TPB derivatives in which all four phenyl groups were substituted with fluorine, chlorine or trifluoromethyl were much more toxic than the unsubstituted compound, the effect increasing dramatically with increasing size of substituents. These observations suggest that the toxicity of these hydrophobic ions is determined mainly by their size and possibly also by the chemical inductivity of their substituent groups. The order of the toxicities of these ions was in fair agreement with literature values for their translocation rates across artificial bilayers. Incubation times of 3 h were used as standard, longer incubations (up to 48 h) showed that the number of cells affected by low doses of TPB increased with the logarithm of time after the first hour of incubation. Although measurements of the percentage of cells showing co-field rotation showed that controls were not adversely affected by incubations as long as 9 h, rotation spectra showed that some cells suffer loss of internal conductivity during extended incubations. Decrease of the pH of the incubation medium, or inclusion of high concentrations of NaCl or KCl, potentiated the effects of these hydrophobic ions. The toxicity developed slowly, and the sensitivity of the assay was only very weakly dependent on the cell suspension density.

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.

IRAOS: an instrument for the assessment of onset and early course of schizophrenia.

Since Kraepelin's first description of dementia praecox in 1889 many data and theories have been published on the onset and course of schizophrenia. Until now studies on these topics had to rely on first admission data and on the subsequent course of the disease. However, first hospitalisation is preceded by a wide variety of patterns and duration of the early course. Items taken from the pre-admission phase of the disease are often incorrectly used as premorbid characteristics, understandably preceding the subsequent course and outcome of schizophrenia with high predictive power. In relation to our interest to study the beginning of schizophrenia, systematically, paying special attention to the age and gender distribution of true onset and the symptomatology and pattern of the early and later course, we developed an 'Interview for the Retrospective Assessment of the Onset of Schizophrenia (IRAOS)'. It allows an objective, reliable, and valid assessment of the symptoms, psychological impairments, demographic and social characteristics as well as the referring points in time of the early course of psychosis. The instrument is administered as a semi-structured interview with both the patient and a key informant. The obtained information is extended by a systematic examination of the clinician's case notes. Some results derived from an ongoing study on age and gender differences in onset and patterns of early course are added to demonstrate the use of the instrument.

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.

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.

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.

Segmentation of protein surfaces using fuzzy logic.

An algorithm has been developed that can be used to divide triangulated molecular surfaces into distinct domains on the basis of physical and topographical molecular properties. Domains are defined by a certain degree of homogeneity concerning one of these properties. The method is based on fuzzy logic strategies, thus taking into consideration the smooth changes of the properties considered along complex macromolecular surfaces. Scalar qualities assigned to every node point on a triangulated surface are translated into linguistic variables, which can then be processed using a special fuzzy dissimilarity operator. Possible applications are demonstrated using surface segmentation for properties like electrostatic potential, lipophilicity and shape for the analysis of serine proteinase substrate/inhibitor specificity.

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: 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.

The evaluation of mental health care systems.

While the demand for deinstitutionalization, strongly supported by the economic aspect of the issue, has resulted in a steep decline in the number of psychiatric beds in many Western countries, the evaluation of extramural psychiatric care has several difficulties, including that of proving effectiveness without experimental control of confounding influences. For a cohort of schizophrenic patients we investigated the impact of out-patient psychiatric treatment on length of stay in hospital and length of stay in the community. Out-patient care had a significant influence on readmission, but no effect on the length of in-patient treatment. While the average cost of community care was less than half that of traditional hospital care, in 6% of the patients this threshold value of continued in-patient care was exceeded. There also seems to be a non-monetary threshold, above which community care is no longer appropriate.

[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.

A new approach to analysis and display of local lipophilicity/hydrophilicity mapped on molecular surfaces.

A new method for display and analysis of lipophilic/hydrophilic properties on molecular surfaces is presented. The present approach is based on the concept of Crippen and coworkers that the overall hydrophobicity of a molecule (measured as the logarithm of the partition coefficient in an octanol/water system) can be obtained as a superposition of single atom contributions. It is also based on the concept of molecular lipophilicity potentials (MLP) first introduced by Audry and coworkers in order to establish a 3D lipophilicity potential profile in the molecular environment. Instead of using a l/r- or an exponential distance law between the atomic coordinates and a point on the molecular surface, a new distance dependency is introduced for the calculation of an MLP-value on the solvent-accessible surface of the molecule. In the present formalism the Crippen values (introduced for atoms in their characteristic structural environment) are 'projected' onto the van der Waals surface of the molecule by a special weighting procedure. This guarantees that only those atomic fragments contribute significantly to the surface values that are in the close neighbourhood of the surface point. This procedure not only works for small molecules but also allows the characterization of the surfaces of biological macromolecules by means of local lipophilicity. Lipophilic and hydrophilic domains can be recognized by visual inspection of computer-generated images or by computational procedures using fuzzy logic strategies. Local hydrophobicities on different molecular surfaces can be quantitatively compared on the basis of the present approach.