H. Häfner

Depression, negative symptoms, social stagnation and social decline in the early course of schizophrenia.

Häfner H, Löffler W, Maurer K, Hambrecht M, an der Heiden W. Depression, negative symptoms, social stagnation and social decline in the early course of schizophrenia.

Generating and testing a causal explanation of the gender difference in age at first onset of schizophrenia

Motivated by the lack of knowledge of the pathophysiological processes underlying the manifestation of symptoms in schizophrenia, we have worked out a systematic search strategy. Since epidemiological distribution patterns consistently deviating from expected values provide valuable indications of causal relationships, we chose the higher age of females at first admission for schizophrenia, first reported by Kraepelin and since then confirmed in over 50 studies, as the basis for our study. This unexplained epidemiological finding was replicated on Danish and Mannheim case-register data by systematically controlling for selection and diagnostic artefacts and by testing alternative explanations at the individual stage of the study. To check whether the difference in age at first admission was determined by a difference in age at onset, a representative sample of 267 first-admitted patients with non-affective functional psychosis was examined by using an interview for the retrospective assessment of the onset of schizophrenia (IRAOS) designed for this purpose. Any of the definitions of first-ever onset applied--first sign of mental disorder, first psychotic symptom, first acute episode--led to a significant age difference of 3.2 to 4.1 years between the sexes. The distribution of onsets across the life cycle showed a later increase and a second, lower peak between the ages of 45 and 54 years among females compared with males. The lifetime risk for schizophrenia was equal for males and females. After testing the plausibility of psychosocial versus biological explanations we hypothesized that due to the effect of oestrogens the vulnerability threshold for schizophrenia is elevated in females until the menopause. Animal experiments and post mortem analyses showed that chronic oestrogen applications significantly shortened dopamine-induced behaviour and reduced D2 receptor sensitivity in the brain. The applicability of this pathophysiological mechanism to human schizophrenia was tested on acutely schizophrenic females with normal menstrual cycles. A significant negative correlation was found between measures of symptomatology and plasma oestrogen levels. The manifestation of symptoms in schizophrenia appears to be influenced by a sufficiently sensitive D2 receptor system in the brain, blocked by neuroleptics and modulated by oestrogens.

The ABC schizophrenia study: a preliminary overview of the results

Abstract The ABC Schizophrenia Study, a large-scale epidemiological and neurobiological research project commenced in 1987, initially pursued two aims: (1) to elucidate the possible causes of the sex difference in age at first admission for schizophrenia and (2) to analyse the early course of the disorder from onset until first contact and its implications for further course and outcome. First, transnational case-register data (for Denmark and Germany) were compared, second, a population-based sample of first-episode cases of schizophrenia (nu2009=u2009232) were selected and third, the results obtained were compared with data from the WHO Determinants of Outcome Study by using a systematic methodology. A consistent result was a 3–4 years higher age of onset for women by any definition of onset, which was not explainable by social variables, such as differences in the male-female societal roles. A sensitivity-reducing effect of oestrogen on central D2 receptors was identified as the underlying neurobiological mechanism in animal experiments. Applicability to humans with schizophrenia was established in a controlled clinical study. A comparison of familial and sporadic cases showed that in cases with a high genetic load, the sex difference in age of onset disappeared due to a clearly reduced age of onset in women, whereas in sporadic cases it increased. To analyse early course retrospectively, a semistructured interview, IRAOS, was developed. The early stages of the disorder were reconstructed in comparison with age- and sex-matched controls from the same population of origin. The initial signs consisted mainly of negative and affective symptoms, which accumulated exponentially until the first episode, as did the later emerging positive symptoms. Social disability appeared 2–4 years before first admission on average. In early-onset cases, social course and outcome, studied prospectively over 5 years, was determined by the level of social development at onset through social stagnation. In late-onset cases, decline from initially high social statuses occurred. Socially negative illness behaviour contributed to the poor social outcome of young men. Symptomatology and other proxy variables of the disorder showed stable courses and no sex differences. Further aspects tested were the sequence of onset and the influence of substance abuse on the course of schizophrenia, primary and secondary negative symptoms, structural models and symptom clusters from onset until 5 years after first admission.

How does gender influence age at first hospitalization for schizophrenia? A transnational case register study

Numerous studies have reported a lower mean age at first hospitalization for schizophrenia in males than in females. For this finding not only a gender difference in age at first onset of schizophrenia, but also other factors can be responsible. With the aim of providing a comprehensive analysis of gender differences in onset, symptomatology and course of schizophrenia, we started by testing the hypothesis postulating a gender difference in mean age at first hospitalization. By using the Danish and the Mannheim psychiatric case registers we analysed all hospital admissions for schizophrenia and related diagnoses and all previous admissions for other diagnoses of the Danish population in 1976 and those of the inhabitants of the German city of Mannheim in the period of 1978-80. Artefacts were controlled for systematically. The impact of intervening variables such as selection factors as well as the influence of gender on the ascription of a diagnosis of schizophrenia for the first time were assessed. We found a mean difference of 5 to 6 years in age at first hospitalization between males and females in both countries when a broad definition of the diagnosis was used and of 4 to 5 years when a restrictive definition was applied. The higher mean age at first hospitalization among females is not attributable to artefacts, diagnostic procedures or to any essential extent to gender differences in help-seeking behaviour or occupational status. When a distinction was made between single and married, the significant difference in age at first hospitalization between the sexes disappeared in singles. With case register data and without knowing the chronological order of marriage and onset of the disease, it remains an open question whether this finding can be explained by purely correlative associations between sex, marital status and age of onset or by causal effects.

Gender aspects in schizophrenia: bridging the border between social and biological psychiatry.

Objective:u2002This paper tries to show that gender differences in mental diseases are a valuable paradigm for research into the interplay between biological and psychosocial factors — not only regarding pathogenetic mechanisms, but also concerning therapeutic approaches.

The epidemiology of onset and course of schizophrenia.

Abstract 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, other 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.

Is schizophrenia a disorder of all ages? A comparison of first episodes and early course across the life-cycle

BACKGROUNDnThe heterogeneity of schizophrenic and delusional syndromes by age of onset has frequently been discussed.nnnMETHODSnThe age distribution of symptoms and 5 year course was studied in a population-based first-episode sample admitted to 10 psychiatric hospitals before the age of 60 (N = 232) and in a clinical sample without age limit of consecutive first admissions to a single hospital (N = 1109), both samples with broadly diagnosed schizophrenia.nnnRESULTSnEarly-onset patients, particularly men, presented more non-specific symptoms and higher PSE-CATEGO total scores than late-onset patients. In men, symptom severity decreased with increasing age of onset. In women, it remained stable except for an increase of negative symptoms with late-onset. Only a few symptoms changed markedly with age: disorganization decreased, while paranoid and systematic delusions increased steeply across the whole age of onset range. Pronounced age- and sex-differences emerged in illness behaviour, socially negative behaviour and substance abuse. Within the group of late-onset psychoses there were continuous transitions in symptom profiles and no discrimination between schizophrenia and paranoid psychosis or late paraphrenia. The main determinant of social course was onset level of social development. Early-onset patients did not improve in social status, while late-onset patients, prior to retirement, suffered considerable decline in social status.nnnCONCLUSIONSnGender differences in age at onset and in age trends in symptom severity support the hypothesis of a mild protective effect of oestrogen. Social course results from an interplay between biological factors (age at onset and functional impairment) and development factors (level of social development at onset and illness behaviour).

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

Abstract 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.

Validation of Danish case register diagnosis for schizophrenia

The ABC schizophrenia study aims at investigating sex differences in age of onset, symptoms and course of schizophrenic and paranoid disorders. For this purpose, we used case register data from Denmark and Mannheim and a directly examined sample of first admissions (ABC sample). The Danish case register sample included less clinical diagnoses of schizophrenia and more schizophrenia‐related disorders (acute paranoid reaction, paranoid states and borderline schizophrenia) than the Mannheim data (case register and ABC sample). The problem therefore was whether the two datasets are comparable and the results are valid. For this reason a randomized, stratified sample of 116 patients was drawn from the Danish case register sample. The case notes of these 116 patients were requested from the hospitals where the patients had been treated and analyzed by means of a scoring sheet based on the Interview for the Retrospective Assessment of the Onset of Schizophrenia (IRAOS). The use of operationalized diagnoses of the CATEGO program, based on PSE items, which are integrated in IRAOS, demonstrated that the samples of the Danish and the Mannheim case registers and the directly investigated ABC sample have comparable diagnostic distributions. Possible explanations for the differences between the clinical and the CATEGO diagnoses in the Danish case register may be the frequent use of diagnoses of borderline schizophrenia and reactive psychoses (previously called psychogenic psychoses), and above all a more narrow concept of schizophrenia; in Denmark, schizophrenia is diagnosed relatively late, i.e., after the presence of enduring negative symptoms, and thus mostly after the appearance of residual state. These diagnostic preferences may help to explain the fall in first admission rates for schizophrenia – above all in women – in Denmark and the low incidence rates of schizophrenia by first contact within the WHO determinants of outcome study. The earlier hospitalization of men could be replicated as well as the course of treatment (readmissions and discharges) of schizophrenic men and women over 10 years after first admission.

Transnational stability of gender differences in schizophrenia? An analysis based on the WHO study on determinants of outcome of severe mental disorders.

SummaryGender-specific analyses of the multinational WHO-Determinants of Outcome-Study (including 1,292 cases from 10 countries) demonstrate the transnational stability of major findings on gender differences in schizophrenia: Male patients have an earlier mean age at onset in all countries. In female patients, the distribution of the age at onset shows a second peak after age 40 years. No gender differences on nuclear symptoms of schizophrenia can be detected, but on uncharacteristic symptoms, particularly some aspects of the illness behaviour, differences appear. This investigation supports the transcultural validity of gender differences found in the German ABC-Schizophrenia-Study and in the Danish-German Psychiatric Case Register studies.