Psychiatric disorders in adult patients with early-treated phenylketonuria.

OBJECTIVE: To determine psychiatric disorders in patients with phenylketonuria (PKU) and to test whether biochemical control, intellectual functioning, white matter abnormalities visible on magnetic resonance imaging (MRI), and/or style of parenting influence psychopathology. DESIGN AND SUBJECTS: This cross-sectional study consisted of 35 PKU patients 17 to 33 years of age (mean: 22.2). From a total of 67 patients, 3 patients were selected because of other causes of possible brain damage. Then 35 patients were randomly drawn with comparison with a control sample (n = 181) from an epidemiologic study. METHODS: We used a standardized, highly structured, face-to-face interview; intelligence quotient (IQ) test; cranial MRI (n = 26); and monitoring of plasma phenylalanine. RESULTS: The overall rate of psychiatric disorders was 25.7% in PKU patients and 16.1% in controls. This difference was not statistically significant. The pattern of psychiatric disturbances was different for PKU patients and controls (Fisher's exact test): in PKU patients, externalizing disorders were reduced (PKU: not present, controls: 7.8%), whereas internalizing disorders (PKU: 25.7%, controls: 8.3%) were increased. International Classification of Diseases, version 10, diagnoses were predominantly those of the depressive category and more frequent in women (8 of 18 females and 1 of 17 males). A correlation between IQ and both biochemical control up to 12 years of age and school education of parents was confirmed. No correlation was found between the severity or pattern of psychiatric disturbances and school education of parents, biochemical control, IQ, or the extension of MRI-visible, white matter abnormalities. It was found that a restrictive controlling style of parenting is a risk factor for the development of psychiatric symptoms. CONCLUSIONS: Our results support a psychological perspective for the development of psychiatric symptoms in PKU. Thus, optimizing medical treatment necessary to prevent brain damage should be accompanied by psychiatric monitoring and psychological support for the families.

Excess mortality among elderly psychiatric in-patients with organic mental disorder.

BACKGROUND: Many studies have shown hospitalised mentally ill patients to have a higher mortality risk than the general population. METHOD: Data of patients with organic mental disorders of ICD-9 categories 290, 293, 294 and 310 from seven psychiatric hospitals with defined catchment areas were analysed. During an observation period of 2.5 years 1821 treatment periods in these diagnostic categories were recorded. RESULTS: During hospitalisation 137 patients died from natural causes. The age- and sex-adjusted mortality rates show an increased mortality risk of 7.5 times, compared to the general population. The odds ratio of a logistic regression demonstrate the overwhelming influence of the medical diagnosis. CONCLUSION: Medical factors, including pneumonias, contribute most to the excess mortality.

Mortality among patients in psychiatric hospitals in Germany.

Data from 7 psychiatric hospitals with defined catchment areas were analyzed; 14,195 episodes of treatment in acute psychiatry wards were recorded within 30 months. During their stay in hospital 196 patients died, 174 from natural causes and 22 by suicide, compared to the expected 32 deaths. Standardized mortality ratios (SMRs) were calculated for the different diagnostic and age groups, mortality risk being highest in organic mental disorder (SMR 7.55), followed by functional psychoses (SMR 4.55) and the "other disorders" (alcoholism, neurotic and related disorders, SMR 3.25). Roughly one half of the 196 deaths were due to cardiovascular disorders and pneumonia. In patients with nonorganic psychiatric syndromes, suicide was the most frequent cause of death (21 of 58 fatalities). With regard to the elevated mortality risk of patients with acute mental illness, a reduction of fatality rates from natural and unnatural causes should remain a major objective of hospital care in psychiatry.

New perspectives in the epidemiology of schizophrenia.

It was with great pleasure that I accepted the invitation to contribute to the present symposium in honour of my friend Jules Angst. It gives me the opportunity to pay tribute to his outstanding scientific work. The topic of my presentation has been inspired by the genius loci. In his foreword to a proceedings volume entitled 'Die Entstehung der Schizophrenie' (The Origin of Schizophrenia), which he edited on the occasion of the 100th anniversary of the Psychiatric University Hospital Zurich in 1970, Jules Angst pointed out that two former heads of the 'Burgholzli', Eugen and Manfred Bleuler, who had held that office longest, had dedicated their life's work to schizophrenia, which had received its name from Eugen Bleuler. Jules Angst's most successful research field has been psychiatric epidemiology. I therefore thought it appropriate to talk about new perspectives in the epidemiology of schizophrenia.

Case management for schizophrenic patients at risk for rehospitalization: a case control study.

In many countries deinstitutionalization of psychiatric patients is accompanied by fragmentation of care, giving responsibility to an array of different services and providers. One of the possible side effects of this is an increased rehospitalization rate and length of stay. The need to coordinate the services involved for the benefit of individuals has led to the conceptual development of case management. However, despite an apparent belief in the effectiveness of case management, there is only limited scientific evidence to support this assumption. In the case control study presented we compared a group of 97 schizophrenic patients in the aftercare of case management services with a group of patients who received no outpatient care by case management services after discharge from hospital. Each patient in the case-managed group was exactly matched with a control patient with regard to diagnosis and known risk factors for rehospitalization. Additionally, we considered influencing factors that result from general health system conditions such as regional differences and different types of hospital care. Our analyses demonstrate that, during an observation period of 2.5 years, case management had neither a significant effect on the risk of rehospitalization nor on the length of time in hospital in the event of rehospitalization.

Symptom assessment in casenotes and the clinical diagnosis of schizophrenia.

It is well known from several international studies that the incidence rates for schizophrenia, based on first-admission samples, are low in Denmark, especially in females, compared with other countries. This might be due to special diagnostic traditions in Denmark. To analyze how Danish psychiatrists reach a diagnosis of schizophrenia, a stratified subsample of 122 cases out of all 1,259 patients, aged between 12 and 64 years, with a first hospital admission in 1976 under the diagnosis of schizophrenia, paranoid psychosis, acute reactive paranoid psychosis, or casus limitaris was selected. For this subsample, psychopathological symptoms, as documented in the clinical casenotes, were rated by PSE-9 symptom lists for subsequent CATEGO analysis. The core syndrome of schizophrenia, as defined by the CATEGO class S+, showed no association with the clinical schizophrenia diagnosis compared with the other diagnoses mentioned. Also, positive symptoms of schizophrenia did not determine the diagnosis, but for typical negative symptoms such associations were indicated. Some negative symptoms also seemed to be linked to a depressive state. Furthermore, the present work indicates that using first-admission data leads to a higher age at schizophrenia onset and a lower first-admission rate in Denmark compared with Germany.

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.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Higher morbidity risk for schizophrenia in males: fact or fiction?

Male to female ratios in published annual incidence rates for schizophrenia range from 0.70 to 3.47. These variations between studies are attributed to differences in sampling, diagnostic criteria, design characteristics, and methods of calculation, which limit the quality of the studies. In an effort to overcome these shortcomings, we collected a comprehensive sample of 392 consecutive first admissions with a diagnosis of schizophrenia or a similar disorder out of a population of 1.5 million in a central region of western Germany. In this large representative sample, no significant gender differences in the incidence of schizophrenia could be detected regardless of different diagnostic definitions.

[A chapter in systematic schizophrenia research--the search for causal explanations for sex differences in age of onset]. / Ein Kapitel systematischer Schizophrenieforschung-Die Suche nach kausalen Erklärungen für den Geschlechtsunterschied im Ersterkrankungsalter.

With the aim of detecting causal processes contributing to the onset of schizophrenic symptoms a systematic search strategy was worked out. One of the few epidemiological findings on schizophrenia consistently diverging from expected values, the sex difference in age at first admission, was taken as a basis and replicated on data from the Danish and the Mannheim case registers by controlling for selection and diagnostic artefacts. Danish psychiatrists turned out to have underdiagnosed schizophrenia to a considerable extent at least in 1976, the year from which the analysed case-register data dated. After the exclusion of alternative explanations, the time when symptoms appeared for the first time and the first acute episode occurred was determined for a representative sample of 267 first-admitted cases with a diagnosis of non-affective functional disorder by using the IRAOS interview designed for this purpose. At any of the definitions of first onset applied the mean age of females was significantly higher than that of males, the difference ranging from 3.2 to 4.1 years. The distribution of onsets across the female life cycle showed a clearly delayed increase at young age and a second, lower peak of onsets at the age of 45-54, whereas the cumulative incidence up to the age of 60 years was equal for males and females. On assessing the plausibility of psychosocial versus biological explanations it was hypothesized that due to the effect of estrogens the vulnerability threshold for schizophrenia is raised in females until the menopause. Animal experiments and postmortem analysis showed that chronic estrogen applications significantly shortened dopamine-induced behaviour and reduced D2 receptor sensitivity in the brain. The applicability of this pathophysiological mechanism on human schizophrenia was tested on acutely schizophrenic females with normal menstrual cycles. A significant negative correlation was found between measures of symptomatology and plasma estrogen levels. Apparently, the manifestation of schizophrenic symptoms is influenced by a sufficiently sensitive D2 receptor system in the brain, blocked by neuroleptics and modulated by estrogens.

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.

[Prevalence and follow-up of psychiatric disorders in childhood and adolescence. Results of a prospective epidemiologic longitudinal study from ages 8-18 years]. / Prävalenz und Verlauf psychischer Störungen im Kindes- und Jugendalter. Ergebnisse einer prospektiven epidemiologischen Längsschnittstudie von 8-18 Jahren.

In a prospective longitudinal epidemiological study with assessments at age 8, 13 and 18 the prevalence rate for psychiatric disorders remained constant at about 16%. The sex ratio for severe disorders was male dominated even in adolescence, which was a consequence of the high rate of unsocialized disturbances of conduct in boys. Persistence of psychiatric disorders between age 13 and 18 was about 50%, as had previously been the case between age 8 and 13. One child in four suffered from a psychiatric disorder for at least 10 years. In childhood, conduct disorders had a very poor prognosis and emotional disorders a very good one. In adolescence, the course of disorders depended on an interaction between diagnosis and gender. Boys with unsocialized disturbances and girls with emotional problems had a poor prognosis.

Does case management reduce the rehospitalization rate?

It was expected from deinstitutionalization that outpatient care could replace hospital care. But many empirical studies proved that the number of admissions to psychiatric hospitals rose when community-based care developed. This might be due to the lack of coordination and cooperation of extramural services. The concept of case management therefore originated in the last few years. In this study the effect of case management on the rehospitalization rate is examined by analyzing the data of 4 social-psychiatric services responsible for defined catchment areas. During the evaluation period of 2.5 years, 162 patients dismissed from psychiatric hospitals were referred to those services. For each of these index patients a matched control patient was identified, each identical in diagnosis, sex, age, living conditions and number of previous inpatient episodes. The results of a survival analysis show that there are no significant effects of case management on the rate of rehospitalization nor on the length of time in hospital in case of a rehospitalization.

Is age of onset in schizophrenia influenced by marital status? Some remarks on the difficulties and pitfalls in the systematic testing of a "simple" question.

Schizophrenia is a disease characterized by a distinctly higher age at onset and at first admission in females than in males. In a systematic study on gender differences in schizophrenia we have confirmed this finding using different sets of data, in particular through the examination of a large and representative sample of first-admitted patients. The question addressed in this paper is whether marital status influences this sex-specific age difference. Assuming that marriage or a stable relationship is a protective factor in schizophrenia, delaying the onset of the disease or first hospitalization, the hypothesis was formulated that the later age of onset in women is at least partly explained by their generally earlier age of marriage. Testing this hypothesis illustrates some of the methodological problems that often occur when a causal analysis of social data is attempted. The problems emerge especially when both the dependent variable (age of onset/first admission) and the independent variable (marital status) are essentially related to age. First results appearing to indicate an influence of marital status on age at first admission did not bear a critical interpretation.

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.

First onset and early symptomatology of schizophrenia. A chapter of epidemiological and neurobiological research into age and sex differences.

In the frame of the ABC (Age, Beginning and Course) Schizophrenia Project we studied the influence of age and sex on first-ever onset, symptom manifestation and early course up to first admission in schizophrenia by using a large, representative sample of first-admitted schizophrenic patients. The results showed that the two variables had surprisingly little bearing upon the core symptoms, particularly on negative and other most frequent symptoms and on first-rank symptoms. In 70% of the cases schizophrenia started solely with negative symptoms, in 20% with negative and positive and in 10% with positive symptoms only. In most of the cases symptoms accumulated exponentially up to the first acute episode with positive symptoms appearing considerably later. The age differences observed concerned secondary phenomena associated with developmental factors. Such phenomena, i.e. anxiety, depression and the cognitive formation of delusions, can be interpreted as responses to the psychosis. Also the sex differences, which culminated in far more frequent socially negative disease behaviour in males, were limited to secondary phenomena. This positive and negative core symptomatology of schizophrenia seems to be astonishingly uniform and fairly independent of age and sex at this early stage of the disease. The only remarkable difference was a three to four years higher mean age of onset in females. We were able to show in animal experiments and to confirm in a clinical study that this finding is attributable to a neuromodulatory effect of estrogens on the sensitivity of D2 receptors in the brain. Apparently, estrogens raise the vulnerability threshold until menopause and have a slight neuroleptic-like effect on the symptomatology in acute schizophrenic episodes.

[Sex differences in schizophrenic diseases]. / Geschlechtsunterschiede bei schizophrenen Erkrankungen.

Sex differences in schizophrenic diseases have been known for a long time but have also been subject to long-term neglect by psychiatric epidemiological research, although a study of these sex differences could, in our opinion, yield valuable pointers to pathogenic factors involved in this group of diseases the aetiology of which still awaits clarification. For this reason we initiated large-scale investigations focussed on this topic. The paper presented here discusses a few initial results, basing on data of Mannheim and National Danish Case Records and on our own study on schizophrenia, the latter being a representative record of 392 patients hospitalised for the first time in the Rhine-Neckar region and the eastern part of the Palatinate. First of all, sex differences at the age at which the disease appeared for the first time, were studied while paying close attention to artifacts and other, usually neglected methodical error sources. The difference in the average age of the sexes at first hospitalisation was confirmed, and also--using an instrument specially developed for that purpose--at the onset of the disease. At the time the first signs of the disease are noticed and the first schizophrenic symptoms become apparent, men are about 3 to 4 years younger than women. On the other hand, the cumulative lifetime risk--calculated up to 60 years of age--seems to be the same for both sexes. It appears that there are no sex differences in the pattern of symptoms of the disease at the time of initial hospital admittance, in respect of both the most common and the characteristic signs and symptoms. There were significant although quantitatively not very great differences in respect of patient behaviour which displays socially positive aspects somewhat more often in women and socially negative ones distinctly more often in men. In respect of the course of the disease we could not find any marked sex differences over a period of 10 years after onset of the disease; however, this is presently based only on the Danish case record data and on criteria of the course of the disease, such as number and duration of inpatient treatments.

[Somatic diseases in inpatient treatment of psychiatric patients]. / Somatische Erkrankungen bei stationär behandelten psychiatrischen Patienten.

This is a report on the frequency of somatic diseases in patients treated in regional psychiatric units (14471 courses of treatment). In 33.2% of all episodes (n = 4803) the psychiatrist diagnosed a somatic illness which was classified according to ICD-9. Most frequently quoted were diseases of the heart and the circulatory system (8.43% of all episodes), the nervous system (5.30%) and metabolic and endocrine disorders (5.17%). Distinct correlations between the rate of somatic morbidity and the variables age, sex and psychiatric diagnosis were found. In 4.04% of all episodes (n = 583) patients had to be transferred in a nonpsychiatric unit. 190 deaths were recorded, 18 of them in patients below the age of 65 years. The findings of this study show that hospitalized psychiatric patients are in need not only of psychiatric but also of medical care. A corroboration of this conclusion by further data is desirable.

[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.

[Mortality of patients with organ-induced psychiatric disorders during inpatient psychiatric treatment]. / Mortalität von Patienten mit organisch bedingten psychischen Störungen während des Zeitraums stationärer psychiatrischer Behandlung.

In this paper data from seven psychiatric hospitals in Baden-Württemberg, which can be regarded as representative for this region, are analysed. All patients with organic mental disorders of the ICD-9 categories 290, 293, 294 and 310 were included, while patients with alcohol- or psychoactive drug-induced psychoses were excluded. During the period from 01.01.1984 to 30.06.1986, 1821 episodes of treatment were recorded. 41% of all patients were male, the mean age of the population was 72.4 +/- 15.1 years. During their stay in hospital 137 patients died from natural causes, which is to compare with an expected number of deaths of 18.3, calculated according to the age- and sex-adjusted mortality rates of the German population. With a ratio of 7.5 the mortality of the whole study population was significantly raised. In all diagnostic subgroups a correlation with raised mortality was found, the risk being highest in patients with acute organic psychosis. An inverse relationship between age and mortality could be established. The main causes of death were cardiovascular disorders and pneumonias. The data of this investigation indicate an unequivocally increased mortality risk of patients with organic mental disorder during their stay in acute psychiatric units. The causes for this phenomenon are discussed, as well as potential consequences for hospital care of patients with organic mental disorder.