[Bernhard von Gudden on the occasion of the 125th anniversary of his death]. / Bernhard von Gudden zum 125. Todestag.

Bernhard von Gudden died 125 years ago together with King Ludwig II of Bavaria, his royal patient. The prominence of the "Fairy Tale King", the circumstances surrounding the deprivation of his power and his psychiatric internment as well as the establishment of Luitpold's reign and above all the catastrophic ending of the Bavarian royal drama still outshine Gudden's importance for the scientific development of the new subject of Nervenheilkunde (psychiatry and neurology), particularly Bernhard von Gudden's importance and integrity as a physician. Not only was he a much sought-after academic teacher, but he was also a patient-focused advocate of the principle of no restraint. As director of mental institutions, Gudden gave vital impulses for the improvement of mental health treatment. For 14 years he treated Prince Otto, the mentally ill brother of Ludwig II. Gudden rendered an expert opinion together with three other Bavarian psychiatrists resulting in Ludwig's legal incapacitation. Concerning the justification for the King's ousting there have been very different and controversial arguments from the constitutional and psychiatric point of view even in recent times. There is, however, a growing conviction that Ludwig II was incapable of reigning, the deprivation of his power followed the path prescribed by the constitution, and Gudden and his colleagues carried out a reviewing procedure considered valid by today's standards and appropriate under the circumstances. The royal disaster ending with the patient's and reviewer's death, however, has to be attributed to a misjudgement by Gudden that is based on the role diffusion between reviewer and treating physician.

Prescribing practices in German and Swiss psychiatric university and in non-university hospitals: national differences.

OBJECTIVE: There are great variations between hospitals in the way drugs are prescribed, and these variations may be due to multiple factors such as local prescribing traditions, pharmacoeconomic considerations, drug availability, regional differences of population, disease prevalence etc. Available studies on prescribing habits, apart from studies performed in a unique center, have until now been mainly restricted to single countries or regions and the comparisons across countries or regions have often been limited by the use of diverse methodologies and definitions. The aim of the present study was to compare drug prescriptions between German and Swiss psychiatric services with regard to their preference of newer psychotropics. MATERIAL AND METHODS: Five psychiatric hospitals, associated to the AMSP project, were chosen to represent Swiss and German clinics, university and non-university settings. Data were available from one index day on 572 patients and 1,745 prescriptions. The comparisons were adjusted for age and gender. RESULTS: There was a significant difference (p < 0.001) with regard to the prescription of newer antidepressants (NAD), Swiss clinicians giving proportionally more (65.2%) than the German psychiatrists (48.3%). No significant difference was, on the other hand, found as to the proportion of atypical antipsychotics, the lack of difference being due to the higher proportion of clozapine among the atypical antipsychotics in Germany. CONCLUSION: There seems, therefore, to be a higher propensity for Swiss hospital psychiatrists to prescribe newer antidepressants. This seems to be due to national or regional prescribing traditions. Further studies are needed to investigate the economical influences on antidepressant prescribing in Swiss and German clinics.

The AMSP drug safety program: methods and global results.

The AMSP (Arzneimittelsicherheit in der Psychiatry) study is a drug safety program that ensures the continuous assessment of severe adverse drug reactions (ADR) in psychiatric inpatients under the natural conditions of routine clinical treatment. It developed out of the preceding drug surveillance study AMUP (Arzneimittelüberwachung in der Psychiatrie). Currently 35 hospitals participate in the study. This paper describes the methods of the AMSP, gives detailed definitions of ADRs assessed to be "severe," and discusses the implications of these definitions and the methodological approach for evaluating the AMSP data. In addition, some overall data compiled on ADR rates from 1993 to 2000 are given.

Research methods in drug surveillance.

Adverse drug reactions must be monitored, beginning with the development of a new drug, and continuing throughout its complete life cycle. During these various stages, different methods are necessary. This paper describes the advantages and disadvantages of common methods of collecting data on adverse drug reactions after a drug has been approved. We then concentrate on two drug surveillance projects, the Prescription Event Monitoring (PEM) of the Drug Surveillance Research Unit and the AMSP Project ("Arzneimittelsicherheit in der Psychiatrie", Drug Safety in Psychiatry). AMSP is compared to cohort studies and spontaneous reporting systems on the one hand, and the specialised PEM project, on the other. The possible influence of various sources of bias is critically analysed.

The AMUP study for drug surveillance in psychiatry - a summary of inpatient data.

From 1979 to 1989 the AMUP study (AMUP = Arzneimittelüberwachung in der Psychiatrie) was conducted in two psychiatric hospitals in Germany with the aim to provide a systematic and standardized assessment of all adverse reactions to psychotropic drugs under conditions of routine practice. A total of 60.7 % of patients experienced at least one adverse drug reaction (ADR) with probable or definite causality during their stay in the hospital; 37.1 % of patients exhibited ADRs that had some therapeutic impact on further treatment. ADRs that led to drug discontinuation were observed in 8.6 %. This rate ranged from 9.5 to 5.1 % for haloperidol and perazine, the most common neuroleptics at that time; sedating antidepressants (AD) rated lower than non-sedating (amitriptyline 5.1 %, clomipramine 10.4 %). Lithium salts, antiparkinson drugs, and benzodiazepines were associated with considerably lower rates of ADRs than neuroleptics or antidepressants. Severe ADRs occurred in 1.4 % of exposed patients (e. g., toxic delirium, grand mal seizures, malignant neuroleptic syndrome, or agranulocytosis). The AMUP data suggest that administration of psychotropic drugs in psychiatric hospitals at that time was a safe, but also inconvenient treatment for many patients due to a wide range of bothersome side effects that compromised patient compliance. The data can serve as a reference base for comparisons with newer compounds introduced to the market over the last decade such as serotonin reuptake inhibitors (SSRIs) and other new AD, atypical neuroleptics, or other new generation psychotropic drugs.

Severe and uncommon involuntary movement disorders due to psychotropic drugs.

Disorders of involuntary movement due to psychotropic drugs pose a major problem when treating mentally ill patients. These adverse drug reactions (ADR) frequently undermine the patients' compliance and may have serious consequences as well. The drug safety program in psychiatry AMSP (Arzneimittelsicherheit in der Psychiatrie) surveyed a population of 122,562 patients between 1993 and 2000, and documented 129 especially severe or uncommon involuntary movement disorders (IMD): 9 episodes of severe acute dyskinesia, 32 of severe Parkinsonism, 5 of especially severe akathisia, 16 of 'atypical dyskinesia', 38 of Pisa syndrome, 6 of catatonic neuroleptic syndrome, 15 of neuroleptic malignant syndrome, and 8 of tardive dyskinesia. The epidemiological data for this population were systematically analyzed as regards the patient's history of medication, comedication, and clinical course. In those cases, in which a certain drug was imputed to cause an ADR alone and the causal relationship was rated as definite or probable, typical neuroleptics with mainly antipsychotic effects showed a relatively high incidence of 0.1047 %, those with hypnotic-sedative effect a lower incidence of 0.0198 %, and the atypical neuroleptics an incidence of 0.0567 %. This difference was highly significant in an chi (2)-analysis (chi (2) = 18.81, df = 2, p < 0.0001). Our data provide important information on the frequency, severity, and the consequences of ARD for the patients' compliance, and thus are of clinical interest.

Blood dyscrasias induced by psychotropic drugs.

Drugs can cause a variety of blood dyscrasias, e. g., by interfering with hematopoiesis in the bone marrow or damaging mature blood cells by antibodies. Although numerous reports on the risks of adverse hematological effects associated with psychotropic drugs have led to stringent monitoring requirements for some compounds, particularly neuroleptics, it is still difficult to estimate the true prevalence of such risks. Sixteen episodes of thrombocytopenia, 63 of neutropenia, 22 of agranulocytosis, 4 episodes of severe neutro- and thrombocytopenia, and 2 of pancytopenia were documented by the drug safety program in psychiatry AMSP (Arzneimittelsicherheit in der Psychiatrie) in a population of 122,562 patients between 1993 and 2000. All cases were related to the epidemiological data provided for this population and systematically analyzed as regards history of medication, co-medication, and the clinical course. Putative risk rates for the main groups of medications and a number of drugs could be estimated with this database. Most changes in the white blood cell counts, which were rated as probably or definitely drug-induced, were attributed to clozapine (0.18 % of patients exposed), carbamazepine (0.14 %) and perazine (0.09 %). In patients on newer atypical neuroleptics, we documented neutropenia assumed to be probably or definitely drug-related in five patients during treatment with olanzapine and in one case with risperidone. In all five olanzapine-related cases, the drugs were the sole cause of the adverse drug reactions. All surveyed patients who received clozapine showed no difference in age and gender distribution from those who developed hematological changes. Incidences of hematological changes for antidepressants were much lower (about 0.01 %). Although the methodological accuracy of these findings has to be critically discussed these data could be of considerable clinical relevance and should be helpful in making clinical treatment decisions.

Psychopathology in dual-diagnosis and nonaddicted schizophrenics: are there differences?

Analysis of 447 schizophrenic inpatients found a lifetime prevalence for substance use of 42.9% (3-month prevalence 29%). While the overall differences were small between schizophrenics using (dual diagnosis) and those not using substances, dual-diagnosis patients in general reported more positive symptoms, especially more intense hallucinations. These differences were observed in patients with current (3-month) substance use on admission but not on discharge, possibly as a result of substance use. The most marked differences were in previous suicide attempts and delinquency, which were more prevalent in dual-diagnosis schizophrenics. These findings indicate that patients with dual diagnosis are more disturbed than other schizophrenics. We discuss the implications for the self-medication hypothesis for substance use in schizophrenia and future research in this area are discussed.

Stability of exploratory eye movements as a marker of schizophrenia--a WHO multi-center study. World Health Organization.

The exploratory eye movements of patients with schizophrenia reportedly differ from those of patients without schizophrenia and healthy controls. In an attempt to determine whether exploratory eye movements provide valid markers for schizophrenia, the present collaborative study was conducted in six countries to analyze the stability of and variation in the following parameters of exploratory eye movements: the number of eye fixations (NEFs) and mean eye scanning length (MESL) in a retention task; the cognitive search score (CSS) that indicates how frequently the eye focused on each important area of a figure in order to recognize it in a comparison task; and the responsive search score (RSS), which reflects the frequency of eye fixations on each section of a figure in response to questioning in a comparison task. In addition, we investigated the validity of the currently employed discriminant function to extract a common feature of schizophrenia by applying it to the findings of the present study. The exploratory eye movements of 145 patients with schizophrenia, 116 depressed patients and 124 healthy controls at seven WHO collaborative centers in six countries were measured using eye mark recorders during viewing of stationary S-shaped figures in two sequential tasks. The RSSs of patients with schizophrenia were found to be significantly lower than those of depressed patients or healthy controls irrespective of geographical location, with no significant difference existing between the RSSs for depressed patients and those for healthy controls. By inserting the RSS and NEF data for each subject into the formula used to calculate discriminant function, patients with schizophrenia could be discriminated from depressed patients and healthy controls with a sensitivity of 89.0% and a specificity of 86.7%. The RSS is an exploratory eye movement parameter that detected schizophrenia irrespective of culture, race and various other subject variables. Furthermore, it is indicative of the stable, significant difference that exists between subjects with and without schizophrenia. The results of discriminant analysis confirm the previously reported validity of discriminant function.

[Wilhelm Griesinger (1817-1868)--his knowledge of psychiatry from the historical and current perspective]. / Wilhelm Griesinger (1817-1868)--sein Psychiatrieverständnis aus historischer und aktueller Perspektive.

Thorough re-analysis of Wilhelm Griesinger's scientific work is very interesting not only from the historical point of view, but also with regard to the present-day debate about the role and self-image of psychiatry. In the literature, Griesinger's ideas are often reported in a rather undifferentiated and condensed manner. Therefore, it may be overlooked that he did not avoid getting involved with the principal epistemological issues of psychiatry (which were an unpopular topic in his time as well), but discussed them intensively and with a constant look at their relevance for clinical and research purposes.

Psychopathology in dual diagnosis and non-addicted schizophrenics--are there differences?

In a previous publication we reported lifetime and 3-month prevalence estimates for substance use in two large samples of schizophrenic inpatients (Soyka et al. 1993). A subsequent analysis of psychopathological findings assessed by means of the AMDP Manual (Guy and Ban 1982) in schizophrenic in-patients of the Haar Mental State Hospital (N=447), in whom a lifetime prevalence for substance use of 42.9% (3-month prevalence 29%) had been reported, was performed. While the overall differences between substance using (dual diagnosis) and nonusing schizophrenics were small, dual diagnosis patients in general reported more positive symptoms, especially more intense hallucinations. These differences could basically be demonstrated in patients with current (3-month) substance use on admission but not on discharge possibly as a result of substance use. Most marked and highly significant results were found with respect to previous suicide attempts and delinquency which were more prevalent in dual diagnosis schizophrenics. Results of this study indicate that dual diagnosis patients compared to other schizophrenics represent a more disturbed patient group. Implications for the self-medication hypothesis for substance use in schizophrenia and future research in this area are discussed.

Pisa syndrome (pleurothotonus): report of a multicenter drug safety surveillance project.

BACKGROUND: Pisa syndrome is usually regarded as a rare adverse event of neuroleptic medication. However, its frequency and predisposing factors have yet to be defined. Here, we investigated risk factors of Pisa syndrome occurring in a large population of psychiatric patients surveyed during a multicenter drug safety project. METHOD: Twenty episodes of Pisa syndrome were documented in 17 patients within a population of 45,000 psychiatric patients monitored by a multicenter drug safety surveillance project (Projekt zur Uberwachung der Arzneimittelsicherheit in der Psychiatrie) between 1990 and 1997. All results were related to the epidemiologic data provided for this population and systematically analyzed regarding history of medication, current medication, comedication, and clinical course. RESULTS: A constellation of putative risk factors was found in the majority of patients: previous treatment with classical neuroleptics, combined pharmacologic treatment, female gender, old age, and the presence of an organic brain disorder. Given these risk factors, Pisa syndrome was also documented with atypical neuroleptic drugs such as clozapine, olanzapine, and sertindole. CONCLUSION: We conclude that Pisa syndrome is a very rare adverse event occurring with neuroleptic treatment. In patients exhibiting the reported constellation of risk factors, neuroleptic drugs should be administered with particular caution.

A historical perspective of clozapine.

Having challenged the established view that extrapyramidal symptoms are an intrinsic feature of antipsychotic activity, clozapine was developed as the first atypical antipsychotic with activity against both the positive and negative symptoms of schizophrenia. Following its partial withdrawal due to concerns over agranulocytosis, clozapine was reintroduced in response to pressure from psychiatrists and is now used worldwide in patients with treatment-resistant schizophrenia, having demonstrated its superiority over typical antipsychotic agents. This, combined with its low propensity to cause tardive dyskinesia, has transformed the management of patients with schizophrenia. This article outlines the history of clozapine's development, from its discovery in 1958 to its current position as the "gold standard" therapy for treatment-resistant schizophrenia.

Assessment of adverse drug reactions in psychiatric inpatients with the AMSP drug safety program: methods and first results for tricyclic antidepressants and SSRI.

The AMSP (Arzneimittelsicherheit in der Psychiatrie) study is a new program for continuous assessment of adverse drug reactions (ADR) in psychiatric inpatients under naturalistic conditions of routine clinical treatment. It is based on the preceding drug surveillance study AMUP (Arzneimittelüberwachung in der Psychiatrie). Currently, 29 hospitals are participating in the study. This paper reports on the methods of the AMSP study and the first findings on the comparative risks of tricyclic antidepressants (TCA) and selective serotonin reuptake inhibitors (SSRI) . Data assessment is restricted to "severe" ADR as defined in the study protocol. Drug use is estimated from reference day data. From 1993 to 1997, 896 cases of severe ADR were observed in 48,564 patients (1.84%). SSRI and the new substances mirtazapine and venlafaxine were increasingly used as antidepressants (AD), but TCA were still the most common AD in 1997 (52.1% of all AD patients). Similar rates of ADR were observed for SSRI and TCA (1.7% and 1.5%, respectively, for all cases, 0.9% and 1.0%, respectively, only for cases rated as probable). However, different types of ADR occurred with the two AD subgroups; whereas toxic delirium and increased liver enzymes were the most frequent ADR related toTCA, nondelirious psychic and neurologic ADR predominated with SSRI. The duration of inpatient treatment was considerably longer in patients who experienced an ADR due to TCA or SSRI than in those who did not. The AMSP study promises to contribute greatly to drug safety by providing the relative frequencies of severe ADR from a large-scale database and by improving our knowledge of ADR.

Dissociation between corpus callosum atrophy and white matter pathology in Alzheimer's disease.

OBJECTIVE: To determine whether the size of the corpus callosum is related to the extent of white matter pathology in patients with AD and age-matched healthy control subjects. METHODS: White matter hyperintensity load and corpus callosum size were compared between 20 clinically diagnosed AD patients and 21 age-matched healthy control subjects. We investigated the effect of age and disease severity on corpus callosum size and white matter hyperintensity, in addition to the relation between corpus callosum areas and white matter hyperintensity load. RESULTS: We found significant regional atrophy of the corpus callosum in AD when compared with control subjects, although the groups did not differ in their white matter hyperintensity load. We further showed a region-specific correlation between corpus callosum size and white matter hyperintensity in the control group but not in AD patients. In the AD group, corpus callosum size correlated with age and dementia severity, whereas white matter hyperintensity correlated only with age. CONCLUSION: Corpus callosum atrophy in AD can occur independent of white matter degeneration, likely reflecting specific AD pathology in projecting neurons.