Systematic Schizophrenias Research Articles

Empirical validity of Leonhard's psychoses: A long-term follow-up study of first-episode psychosis patients

The validation of nosological diagnoses in psychiatry remains a conundrum. Leonhard's (1979) nosology seems to be one of the few acceptable alternative categorical models to current DSM/ICD systems.We aimed to empirically validate Leonhard's four classes of psychoses: systematic schizophrenia (SSch), unsystematic (USch), cycloid psychosis (Cyclo), and manic-depressive illness (MDI) using a comprehensive set of explanatory validators.243 patients with first-episode psychosis were followed between 10 and 31 years. A wide-ranging assessment was carried out by collecting data on antecedent, illness-related, concurrent, response to treatment, neuromotor abnormalities, and cognitive impairment variables.Compared with USch, Cyclo, and MDI, SSch displayed a pattern of impairments significantly larger across the seven blocks of explanatory variables. There were no significant differences between Cyclo and MDI in explanatory variables. Except for the majority of illness-onset features, USch displayed more substantial abnormalities in the explanatory variables than Cyclo and MDI. SSch and MDI showed higher percentages of correctly classified patients than USch and Cyclo in linear discriminant analyses.Partial validation of Leonhard's classification was found. SSch showed differences in explanatory variables with respect to Cyclo and MDI. USch showed also significant differences in explanatory variables regarding Cyclo and MDI, although with a lower strength than SSch. There was strong empirical evidence of the separation between both Leonhard's schizophrenia subtypes; however, the distinction between the Cyclo and MDI groups was not empirically supported. A mild to moderate discriminative ability between Leonhard's subtypes on the basis of explanatory blocks of variables was observed.

A neuropsychological study on Leonhard's nosological system.

Phenotype validation of endogenous psychosis is a problem that remains to be solved. This study investigated the neuropsychological performance of endogenous psychosis subtypes according to Wernicke-Kleist-Leonhard's classification system (WKL). The participants included consecutive admissions of patients with schizophrenia spectrum disorder or mood disorder with psychotic symptoms (N = 98) and healthy comparison subjects (N = 50). The patients were assessed by means of semi-structured interviews and diagnosed through the WKL system into three groups: a manic-depressive illness and cycloid psychosis group (MDC), unsystematic schizophrenia (USch) and systematic schizophrenia (SSch). All the participants completed a comprehensive neuropsychological battery. The three Leonhard's psychosis subtypes showed a common neuropsychological profile with differences in the severity of impairment relative to healthy controls. MDC patients showed better performance on premorbid intelligence, verbal memory and global cognitive index than USch and SSch patients, and they showed better performance on processing speed, and working memory than SSch patients. USch patients outperformed SSch patients in verbal memory, working memory and global cognitive index. Neuropsychological performance showed a modest accuracy for classification into the WKL nosology. Our results suggest the existence of a common profile of cognitive impairment cutting across WKL subtypes of endogenous psychosis but with significant differences on a severity continuum. In addition, classification accuracy in the three WKL subtypes by means of neuropsychological performance was modest, ranging between 40 and 64% of correctly classified patients.

Familiality of Psychotic Disorders: A Polynosologic Study in Multiplex Families.

Phenotype definition of psychotic disorders has a strong impact on the degree of familial aggregation. Nevertheless, the extent to which distinct classification systems affect familial aggregation (ie, familiality) remains an open question. This study was aimed at examining the familiality associated with 4 nosologic systems of psychotic disorders (DSM-IV, ICD-10, Leonhard's classification and a data-driven approach) and their constituting diagnoses in a sample of multiplex families with psychotic disorders. Participants were probands with a psychotic disorder, their parents and at least one first-degree relative with a psychotic disorder. The sample was made of 441 families comprising 2703 individuals, of whom 1094 were affected and 1709 unaffected. The Leonhard classification system had the highest familiality (h (2) = 0.64), followed by the empirical (h (2) = 0.55), DSM-IV (h (2) = 0.50), and ICD-10 (h (2) = 0.48). Familiality estimates for individual diagnoses varied considerably (h (2) = 0.25-0.79). Regarding schizophrenia diagnoses, Leonhard's systematic schizophrenia (h (2) = 0.78) had the highest familiality, followed by latent class core schizophrenia (h (2) = 0.74), DSM-IV schizophrenia (h (2) = 0.48), and ICD-10 schizophrenia (h (2) = 0.41). Psychotic mood disorders showed substantial familiality across nosologic systems (h (2) = 0.60-0.77). Domains of psychopathology other than reality-distortion symptoms showed moderate familiality irrespective of diagnosis (h (2) = 0.22-0.52) with the deficit syndrome of schizophrenia showing the highest familiality (h (2) = 0.66). While affective psychoses showed relatively high familiality estimates across classification schemes, those of nonaffective psychoses varied markedly as a function of the diagnostic scheme with a narrow schizophrenia phenotype maximizing its familial aggregation. Leonhard's classification of psychotic disorders may be better suited for molecular genetic studies than the official diagnostic systems.

GABRB2 Association with Schizophrenia: Commonalities and Differences Between Ethnic Groups and Clinical Subtypes

Single nucleotide polymorphisms (SNPs) and haplotypes in intron 8 of type A gamma-aminobutyric acid (GABA(A)) receptor beta2 subunit gene (GABRB2) were initially found to be associated with schizophrenia in Chinese. This finding was subjected to cross-validation in this study with Japanese (JP) and German Caucasian (GE) subjects. Single nucleotide polymorphisms discovery and genotyping were carried out through resequencing of a 1839 base pair (bp) region in GABRB2. Tagging SNPs (tSNPs) were selected based on linkage disequilibrium (LD), combinations of which were analyzed with Bonferroni correction and permutation for disease association. Random resampling was applied to generate size- and gender-balanced cases and control subjects. Out of the 17 SNPs (9.2/kilobase [kb]) revealed, 6 were population-specific. Population variations in LD were observable, and at least two low LD points were identified in both populations. Although disease association at single SNP level was only shown in GE, strong association was demonstrated in both JP (p = .0002 - .0191) and GE (p = .0033 - .0410) subjects, centering on haplotypes containing rs1816072 and rs1816071. Among different clinical subtypes, the most significant association was exhibited by systematic schizophrenia. Cross-population validation of GABRB2 association with schizophrenia has been obtained with JP and GE subjects, with the genotype-disease correlations being strongest in systematic schizophrenia, the most severe subtype of the disease.

Association of SNPs and haplotypes in GABRB2 with schizophrenia in Japanese and German‐Caucasians

SNPs and haplotypes in Intron 7 of GABAA receptor β2 gene (GABRB2) were previously found to be associated with schizophrenia in Han Chinese. In the present study, cross-validation of this finding was performed with two ethnically-divergent groups: Japanese (JP) and German Caucasian (GE). SNP genotyping was achieved through resequencing of 1,839-bp, harboring the positively-associated SNPs. For disease association, all possible combinations of selected tagging-SNPs were analyzed with Bonferroni-correction and permutation. Random re-sampling was applied to generate size- and gender-balanced samples. Seventeen SNPs, including six newly-discovered, were revealed (0.93% density). Linkage disequilibrium (LD) maps illustrated at least two low LD points, common to the two populations. Strong disease associations of SNP combinations were demonstrated in JP (P = 0.0002 – 0.0191) and GE (P = 0.0033 – 0.0410). They were found largely convergent to SNP combinations with rs1816072 and rs1816071 in both populations. Among the clinical subtypes, the more significant association was observed with systematic schizophrenia. The present study thus provides a multi-population validation of disease association with GABRB2 and places emphasis on the potential role of this gene in schizophrenia etiology. This study was supported by the University Grants Council and the Innovations and Technology Fund of Hong Kong.

Reduced prefrontal response control in patients with schizophrenias: a subgroup analysis

We investigated the function of the anterior cingulate cortex (ACC) with the continuous performance test (CPT) in patients with chronic schizophrenias. We had previously shown that the NoGo anteriorisation (NGA), which consists of a more anterior center of gravity (centroid) of the event-related potentials during the inhibition of a prepared motor response, correlates with physiological activation of the ACC in healthy probands. However, in patients with schizophrenias, the event-related potentials are located more anteriorly in the Go condition and more posteriorly in the NoGo condition, which leads to a decreased NGA reflecting reduced activation of the ACC. We now extend our observations to a larger number of patients with different subgroups of chronic schizophrenias according to Leonhard's classification system. While the schizophrenic patients as a group showed only a trend towards a decreased NGA, there was a significant reduction of the NGA in patients with systematic schizophrenias but not in those with unsystematic schizophrenias. Our results show that a subclassification of "schizophrenic" patients is useful to detect differences between subgroups, which may reflect differences in pathophysiology.

Karl Kleist (1879-1960)- a pioneer of neuropsychiatry.

Karl Kleist (1879-1960) was instrumental in pioneering German neuropsychiatry and neuropsychology, including the description of frontal, constructional, limb-kinetic (innervatory) and psychomotor apraxias, frontal akinesia and aspontaneity, as well as object and form blindness. Besides isolating episodic twilight states, involutional paranoia and symptomatic (especially influenza) psychoses, he was particularly involved in applying Wernicke's syndromatic and Kraepelin's prognostic and aetiological principles to classify "neurogenous" psychoses by refuting the assumption of mixed entities whenever possible. Thus, has phasophrenias denoted manic-depressive illness, unipolar affective disorders and marginal, i.e., atypical psychoses. The rather benign cycloid psychoses form the most prominent examples of the latter. Schizophrenias, on the other hand, were limited to poor long-term catamnestic outcomes. Kleist conceptualized the core group of schizophrenic illness as psychic system diseases-hence the origin of the term "systematic schizophrenias" within the Wernicke-Kleist-Leonhard School. Kleist was mainly influenced by Wernicke and his psychic reflex arc, but Ernst Mach's empiriocriticism, Theodor Meynert's cerebral connectionism, and associationism also shaped his outlook. Kleist's localization of cerebral functions by lesion analyses was indeed the best available at the time and continues to reveal insights to the interested reader. From his Frankfurt School, which may have been the last of a completely unified neuropsychiatry, came sound representatives of psychiatry, neurology and neurosurgery. His technical mastery and achievements seem indisputable, but his balancing acts during the Third Reich may today be questioned. Despite joining the National Socialist German Workers' Party (NSDAP) and the local Court of Genealogical Health (Erbgesundheitsgericht), Kleist was, however, one of the few German physicians who continued to treat Jewish patients, to employ Jewish colleagues and to voice evident criticism of the policies of "eugenics" and "euthanasia". This paper attempts to illuminate Kleist's biography and life's work in the relevant historical context.

Exposure to prenatal infections, genetics and the risk of systematic and periodic catatonia.

The meaning of heterogeneity in schizophrenia and the impact of genetic and environmental factors on etiology are a matter of continuous debate in psychiatric research. Different clinical and birth history variables were investigated in a sample of 68 patients with chronic catatonic schizophrenia according to DSM III-R, classified into Leonhard's systematic schizophrenia (n = 32) and periodic catatonia (n = 36). Parental transmission of the disease was evident in 44% of the periodic catatonia cases compared to one case in systematic catatonia (3%; p = 0.0003). In systematic catatonia, 34% of the index cases were exposed to prenatal infections compared to 8% in periodic catatonia (p = 0.008). Using logistic regression analysis exposure to gestational maternal infections predicted diagnosis of systematic catatonia at p = 0.008, and parental psychosis predicted diagnosis of periodic catatonia in the index cases at p = 0.0001. The latter finding is substantiated by the recent mapping of a periodic catatonia-susceptibility locus on chromosome 15q15 with evidence for autosomal dominant transmission. These findings support the hypothesis that distinct schizophrenia phenotypes are based on different etiological mechanisms.

The Genetic Heterogeneity of “Schizophrenia”

Summary: The main reason for the inconsistent findings in schizophrenia research is the lack of diagnostic conformity. This has not changed markedly following the introduction of modern operational diagnostic systems. Taking schizophrenia as a disease entity or assuming schizophrenic spectrum psychoses to represent a continuum of diseases without any clear dividing lines, the results of family and twin studies point to a multifactorial etiology based on a polygenic mode of transmission. Further, then it has to be assumed a familial continuum from schizophrenia to affective psychosis and other spectrum disorders. However, in family and twin studies based on Leonhard's classification, there is clearcut evidence that schizophrenic spectrum psychoses have to be divided into clinical and etiological subgroups with a completely different genetic background. for example, systematic catatonia is, for the most part, a sporadic disease, whereas periodic catatonia aggregates in families in a manner consistent with a major gene effect. Further, the results indicate that schizophrenic spectrum psychoses consist of three main valid categories: cycloid psychoses, unsystematic schizophrenias and systematic schizophrenias. In the case of cycloid psychosis and systematic schizophrenias, genetic loading seem to be very low, while “environmental” factors, for example, birth complications, may play an important etiological role. Unsystematic schizophrenias, however, are predominantly inherited and “environmental” factors are not very prominent.

362. Abnormal processing of ambiguity in paranoid schizophrenia: A visual scan path study

differing diagnosticcriteria. In a systematictwin study (47 same-sex pairs, 22 monozygotic-25 dizygoticpairs) with index-twinsbelonging to psychosesof the schizophrenicspectrum,we investigatedtwin concordancerates, family loadingwith psychosesand frequencyand severity of birth complicationsbased on Leonhard’snosology.The Leonhardclassification is a highlyoperationalizeddiagnosticsystem dealing with hierarchical symptom clusters. Interrater reliability among experiencedpsychiatrists is about Kappa 0.9. The results of the twin study point to the existence of three genetically different groups: cycloid psychoses,unsystematicand systematic schizophrenias. In cycloid psychosis genetic loading is subordinate (pairwise concordance:MZ2770,DZ 18Yo) but birth complicationsmayhave an important role in the etiology. Unsystematic schizophrenias are predominantlyinherited (pairwise concordance:MZ 82%, DZ 25%) and “environmental”factors are not very prominent. Interestingly, MZ twins with a diagnosisof systematic schizophreniahave not yet heen found, whereas 24% of DZ index-twins (p<.001) received a diagnosis of systematic schizophrenia.All of the latter were discordant and the ill twins had threefold more and severe birth complications than their healthy partners.

Different genetic background of schizophrenia spectrum psychoses: a twin study.

The authors report on a systematic twin study of index twins suffering from schizophrenia spectrum psychoses. Using different diagnostic systems, they examined twin concordance, family history, and the frequency and severity of the birth complications of 22 monozygotic and 23 dizygotic twin pairs. All twins in the region of Lower Franconia, Germany, born after 1930 and hospitalized for psychiatric disease were ascertained. The zygosity diagnoses were based on molecular genetic methodology and a zygosity questionnaire. Two psychiatrists, working independently, formulated diagnoses according to DSM-III-R criteria and Leonhard's nosology. There were substantially different concordance rates with regard to diagnostic subgroups, and monozygotic concordance was significantly higher than dizygotic concordance in only two of the following five subgroups (subgroups 1 and 3): 1) strict schizophrenia according to DSM-III-R: monozygotic, 85.7%, dizygotic, 25.0%; 2) schizophreniform, schizoaffective, and delusional (paranoid) disorders and psychotic disorder not otherwise specified according to DSM-III-R: monozygotic, 47.1%, dizygotic, 30.8%; 3) unsystematic schizophrenia according to Leonhard: monozygotic, 88.9%, dizygotic, 25.0%; 4) systematic schizophrenia according to Leonhard: monozygotic pairs lacking, dizygotic, 0%; 5) cycloid psychoses according to Leonhard: monozygotic, 38.5%, dizygotic, 36.4%. In the case of cycloid psychoses and conditions less prominent in DSM-III-R schizophreniform, schizoaffective, and delusional (paranoid) disorders and psychotic disorder not otherwise specified, the affected twins had suffered significantly more severe birth complications than their healthy partners. Not one of the 37 monozygotic twins was diagnosed as having systematic schizophrenia, whereas six of the 25 dizygotic index twins received this diagnosis. The results of the study suggest that schizophrenia spectrum psychoses may consist of clinically and etiologically heterogeneous subgroups with different genetic backgrounds.

On interrater reliability for Leonhard's classification of endogenous psychoses.

Twenty-two patients with a diagnosis of schizophrenia according to DSM-III-R and ICD-10 criteria, for whom the long-term courses of illness were all well documented, were classified by 4 independent investigators using Leonhard's classification of endogenous psychoses. With regard to the large nosological groups of cycloid psychoses (including the subtypes of anxiety-happiness psychosis, confusional psychosis and motility psychosis), of unsystematic schizophrenias (including the subtypes of affect-laden paraphrenia, cataphasia and periodic catatonia), and of systematic schizophrenias (divided into systematic catatonias, systematic paraphrenias, and hebephrenias), is was possible to reach a high level of agreement in the diagnosis, representing a Cohen kappa coefficient of 0.82 and 0.89, respectively. In only 2 out of 22 patients were discrepancies observed in the assignment to the above-mentioned groups. This clearly shows the high reliability of Leonhard's classification, which allows a differentiated diagnostic and prognostic judgement of schizophrenic psychoses according to the DSM-III-R and ICD-10.

University—Industry—Government Relations

This paper addresses governments' efforts to link knowledge production and a knowledge-based production system. It suggests that the ‘Triple Helix’ image of university—industry—government relations neglects important aspects of players' activity, the systematic schizophrenia in much public policy and the critical variations over time and technologies in inter-relations between the knowledge-producing system and the structures and functioning of the surrounding political economy. The paper suggests that analysis of a nation's industrial ‘complexes' will provide valuable information and permit better adapted approaches.

Maternal infectious diseases during pregnancy and obstetric complications in the etiology of distinct subtypes of schizophrenia: further evidence from maternal hospital records

On the basis of 24 maternity hospital records, the current study investigated the validity of maternal recall and the relationship of maternal infections during pregnancy and obstetric complications (OCs) to different diagnostic subgroups of endogenous psychoses on which we reported previously in this journal. Maternal recall showed good agreement to maternity hospital records in the Lewis and Murray scale (vartheta = 0.74). With regard to infectious diseases during pregnancy maternal recall and records showed a weaker, but also good correlation (vartheta = 0.18). Psychoses with low genetic loading had more OCs than psychoses with high genetic loading. Maternal infectious diseases, especially during the fourth or fifth month of gestation, were significantly allocated to Leonhard's systematic schizophrenias. Data from maternity hospital records support our report that infectious diseases during midgestation and further perinatal complications seem to be important etiologic factors in systematic forms of schizophrenia without marked familial loading.

Schwangerschafts- und Geburtskomplikationen - ihr Stellenwert in der Entstehung schizophrener Psychosen

In a retrospective study of 80 chronic DSM III-R schizophrenics and 80 controls, the occurrence of obstetric complications (OCs) into the development of chronic schizophrenias was investigated using Leonhard's distinction in systematic schizophrenia (no obvious familial loading) and unsystematic schizophrenia (mainly genetically determined according to Leonhard). The Lewis & Murray and Fuchs scales were used for evaluation. In both scales, unsystematic schizophrenias did not differ from controls, but those with OCs were significantly (p < 0.01) earlier hospitalized (20.5 years) than those without OCs (25.6 years). Systematic schizophrenics had an increased frequency, severity and total score of OCs compared to controls in the Fuchs scale (p < 0.01). Likewise, in the Lewis & Murray scale systematic schizophrenia showed an increased presence of OCs compared to controls (p < 0.05) and to unsystematic schizophrenia (p < 0.1). Systematic schizophrenias were significantly allocated to maternal infectious diseases during mid-gestation. Patients with maternal infections showed more additional OCs than those without (p < 0.05; Lewis & Murray scale). In systematic schizophrenia, a history of OC was not associated with an early onset of the disease. In the genetic determined schizophrenias prenatal and perinatal disturbances lead to an early onset of the disease, however, in systematic schizophrenias they seem to be of causal importance for the development of the disease.

Schizophrenia and birth seasonality--contrary results in relation to genetic risk

In 1299 DSM III-R schizophrenics a slight excess of winter and spring births was evident when compared to the general population. However, when patients were allocated to different diagnostic subgroups according to the Leonhard classification this remained true only for those forms without obvious genetic loading (cycloid psychoses and systematic schizophrenias). On the contrary those forms with high genetic loading (unsystematic schizophrenias) showed a clearcut decrease of births in these months. This decrease, however, was significantly caused by periodic catatonics and cataphasics, but not by affect-laden paraphrenics. The findings corroborate the hypothesis that exogenous noxious agents, present in a crucial period of brain maturation, may be of etiological significance in schizophrenia with low genetic loading. Further, it was suggested that in some foetuses at high genetic risk for the disorder more abortions, stillbirths, postnatal deaths and early childhood deaths can occur, if additional exogenous noxious agents affect these individuals.

The evaluation of the severity of illness, affective blunting and neuroleptic treatment outcome in schizophrenic subgroups

SummaryIn 61 schizophrenic patients divided into subgroups according to DSM III-R, positive/negative symptoms and Leonhard's classification of systematic and non-systematic schizophrenia, the severity of illness (BPRS) and affective blunting (MARS and RSEB scales) were measured before and after neuroleptic therapy. The evaluation of affective blunting with the use of RSEB revealed more significant differences within schizophrenic subgroups than with the use of MARS. The severity of illness did not differentiate the subgroups studied. The affective blunting was more severe in patients with systematic than with non-systematic schizophrenia as well as in mixed and negative than in positive schizophrenia. The severity of illness correlated however with the severity of affective blunting. Clinical improvement after neuroleptic treatment was more favorable in patients with positive schizophrenia. The diminution of affective blunting after neuroleptic therapy varied among the subgroups.

Clinical Pharmacology and Leonhard’s Classification of Endogenous Psychoses

Introduction of therapeutically effective psychotropic drugs focused attention on the heterogeneity of psychiatric populations within the traditional diagnostic categories of psychiatric disorders. Recognition that valid diagnostic concepts are essential for progress in the biology and pharmacotherapy of psychiatric disorders resulted in a revival of interest in psychiatric nosology with a special emphasis on Leonhard's classification of 'endogenous psychoses'. Of particular importance for psychopharmacology in Leonhard's system is the recognition of two distinctive populations within the schizophrenic disorders, i.e., 'unsystematic schizophrenias' and 'systematic schizophrenias'; three distinctive populations within the bipolar disorders, i.e., 'manic-depressive illness,' 'cycloid psychoses' and 'unsystematic schizophrenias'; and two distinctive populations within depressive disorders, i.e., 'unipolar depression' and 'bipolar depression'. In this paper supporting data for Leonhard's classification of 'endogenous psychoses' are presented.

Leonhard and the Classification of Psychomotor Psychoses in Childhood and Adolescence

The classification 'psychomotor psychoses' goes back to Wernicke, Kleist and Leonhard. The incidence of psychomotor deficiencies is a typical trait. The motility psychoses (a form of the cycloid psychosis), the periodical catatonia (a form of unsystematic schizophrenias) and the catatonic forms of systematic schizophrenias belong to the group of 'psychomotor psychoses'. To some extent they correspond with the 'catatonic type' according to DSM-III (295.2). The number of children and adolescents with psychomotor psychoses, who were examined by Leonhard and Neumärker have shown beside different clinical-psychopathological features a significant difference as regards the age-related manifestation of each psychomotor psychosis.

A contribution to the validity of Leonhard's classification of endogenous psychoses.

The author made a clinical-genetical study of the schizophrenias and cycloid (schizoaffective) psychoses following the Leonhardian classification, using the traditional pedigree analysis and multiple threshold method. According to the latter method--on the basis of phenotypical correlations--the systematic schizophrenias could be clearly distinguished from the cycloid psychoses, while the non-systematic category presumably occupies a genetical position between the two former categories.