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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., Competing Interests: Conflict of interest The Authors have declared that there are no conflicts of interest in relation to the subject of this study., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Cognitive impairment is a key feature in patients with psychotic disorders. The Montreal Cognitive Assessment (MoCA) is a brief tool that has been shown to be effective in identifying mild cognitive impairment and early dementia. This study explores the usefulness of this instrument to detect cognitive impairment in long-term psychotic disorders. One hundred-forty stabilized patients were re-evaluated more than 15 years after a First Episode of Psychosis (FEP). Patients were psychopathologically assessed, and the MoCA test and MATRICS Consensus Cognitive Battery (MCCB) were administered. Two cut-off scores for cognitive impairment using the MCCB were applied (T score <40 and < 30). Concurrent validation was found between the total scores of the MoCA and MCCB. We also found significant associations between 5 out of 7 MoCA subtests (visuospatial-executive, attention, language, abstraction and delayed recall) and MCCB subtests but not for the naming and orientation MoCA subtests. Receiver operating characteristic (ROC) analysis suggested a <25 cut-off for cognitive impairment instead of the original <26. Our results suggest that the MoCA test is a useful screening instrument for assessing cognitive impairment in psychotic patients and has some advantages over other available instruments, such as its ease-of-use and short administration time., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: This study examines the familial aggregation (familiality) of different phenotypic definitions of catatonia in a sample of multiplex families with psychotic and mood disorders., Methods: Participants were probands with a lifetime diagnosis of a DSM-IV functional psychotic disorder, their parents and at least one first-degree relative with a psychotic disorder. The study sample included 441 families comprising 2703 subjects, of whom 1094 were affected and 1609 unaffected. Familiality (h 2 ) was estimated by linear mixed models using family membership as a random effect, with h 2 indicating the portion of phenotypic variance accounted for by family membership., Results: Familiality estimates highly varied for individual catatonia signs (h 2 =0.17-0.65), principal component analysis-derived factors (h 2 =0.29-0.49), number of catatonia signs present (h 2 =0.03-0.43) and severity of the catatonia syndrome (h 2 =0.25-0.59). Phenotypes maximizing familiality estimates included individual signs (mutism and rigidity, both h 2 =0.65), presence of ≥5 catatonia signs (h 2 =0.43), a classical catatonia factor (h 2 =0.49), a DSM-IV catatonia syndrome at a severity level of moderate or higher (h 2 =0.59) and the diagnostic construct of psychosis with prominent catatonia features (h 2 =0.56). Familiality estimates of a DSM-IV catatonia syndrome did not significantly differ across the diagnostic categories of psychotic and mood disorders (h 2 =0.40-0.47)., Conclusions: The way in which catatonia is defined has a strong impact on familiality estimates with some catatonia phenotypes exhibiting substantial familial aggregation, which may inform about the most adequate phenotypes for molecular studies. From a familial-genetic perspective, the catatonia phenotype in psychotic and mood disorders has a transdiagnostic character., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Schizotypal traits are phenotypic risk factors for schizophrenia, associated with biological changes across a putative schizophrenia spectrum. In this study, we tested the hypothesis that brain structural changes in key brain areas relevant to this spectrum (esp. medial and lateral prefrontal cortex) would vary across different degrees of schizotypal trait expression and/or phenotypic markers of psychosis proneness in healthy non-clinical volunteers. We analysed high-resolution 3Tesla magnetic resonance images (MRI) of 59 healthy volunteers using voxel-based morphometry (VBM), correlating grey matter values to the positive and negative symptom factors of the schizotypal personality questionnaire (SPQ, German version) and a measure of psychosis proneness (community assessment of psychic experiences, CAPE). We found positive correlations between positive SPQ dimension and bilateral inferior and right superior frontal cortices, and positive CAPE dimension and left inferior frontal cortex, as well as CAPE negative dimension and right supplementary motor area (SMA) and left inferior parietal cortex. However, only the positive correlation of the right precuneus with negative schizotypy scores was significant after FWE correction for multiple comparisons. Our findings confirm an effect of schizotypal traits and psychosis proneness on brain structure in healthy subjects, providing further support to a biological continuum model., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Histone deacetylases (HDACs) are key enzymes of histone acetylation, and abnormalities in histone modifications and in the level of HDAC proteins have been reported in schizophrenia. The objective of the present study was to systematically test the HDAC genes for its association with schizophrenia., Methods: A family-based genetic association study (951 Caucasian subjects in 313 nuclear families) using 601 tag-single nucleotide polymorphisms in HDAC genes was conducted followed by a replication study of top-ranked markers in a sample of 1427 Caucasian subjects from 241 multiplex families and 176 trios. Epistasis interaction was tested by using the pedigree-based generalized multifactor dimensionality reduction (GMDR). Furthermore, we analyzed exome sequencing data of 1134 subjects for detection of rare mutations in HDAC genomic regions., Results: In the exploratory study, ten markers were in significant association with schizophrenia (P<0.01). One maker rs14251 (HDAC3) was replicated (P=0.04) and remained significant in the whole sample (P=0.004). GMDR identified that a significant three-locus interaction model was detected involving rs17265596 (HDAC9), rs7290710 (HDAC10) and rs7634112 (HDAC11) with a good testing accuracy (0.58). No rare mutations were found associated with schizophrenia., Conclusion: This first exploratory systematic study of the HDAC genes provides consistent support for the involvement of the HDAC3 gene in the etiology of schizophrenia. A statistical epistatic interaction between HDAC9, HDAC10, and HDAC11 was detected and seems biologically plausible., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Executive dysfunction represents a core deficit that is associated with schizophrenia spectrum disorders (SSDs). However, the longitudinal course of executive deficits in SSDs is still controversial. The aim of this study was to examine the executive performance of 34 SSD patients in relation to 34 of their unaffected siblings over a period of 10 years. Both groups completed psychopathological and executive assessments. Thirteen healthy controls were assessed using the same instruments. At baseline, the SSD patients differed significantly from siblings and controls in their performance on the Trail Making Test-B (TMT-B) and the number of categories in which they succeeded in the Wisconsin Card Sorting Test (WCST). They also differed significantly from the controls in the total number of errors in the WCST. The siblings did not differ in executive functioning from the controls over the follow-up. Longitudinally, the patients demonstrated significant improvement only for the TMT-B. However, only 14.71% of the patients showed reliable and clinically significant improvements for the TMT-B, and 8.82% made more errors on the WCST at the follow-up evaluation. Less than 3% of the patients showed either improved or worse results on the remaining measures of the WCST. A stabilisation pattern for the WCST was observed in the three groups. The patients performed worse than their siblings and controls on both executive tests. Some patients exhibited significant improvements in the TMT-B over time, but this improvement was reliable and clinically significant for less than 15% of the sample. Thus, we conclude that the patients exhibited stable impairments over time in the executive functions assessed., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Large individual variation in the clinical presentation of schizophrenia-spectrum disorders raises key questions regarding their aetiological underpinnings. In this respect, age at onset of the disorder is a particularly interesting marker of liability, as it has been reported to be associated with other signs of developmental compromise, such as male gender, increased presence of familial history of psychosis and poor premorbid adjustment, as well as a more severe clinical outcome in terms of cognition and symptomatology. The association between these variables has encouraged a neurodevelopmental perspective of the aetiological mechanisms involved in the pathophysiology of schizophrenia. However, the complex relationships within neurobiological liability markers, and between these markers and clinical outcome, remain to be understood. In the present study, we used a path-analytic approach to explore: i) the fit of the model to observed data; and both ii) direct and iii) indirect associations between the variables. In a sample of 106 patients with schizophrenia-spectrum disorders, we found a good fit of the model to the observed data, providing further evidence that supports a neurodevelopmental pathway to the disease in a subgroup of patients. However, the most parsimonious model showed complex relationships, where age at onset and premorbid functioning acted as mediators between gender, familial history of psychosis and clinical outcome. These findings refine earlier explanations of the neurobiological basis of schizophrenia, with potential applications in genetic studies based on more homogeneous forms of the disease. We further discuss the putative implications of our results in clinical practice and prevention policies., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Several studies have reported an increase of dermatoglyphic anomalies in schizophrenic patients compared to controls. However, the recognition of specific dermatoglyphic variables related to this disorder and their genetic and/or environmental component are still controversial., Method: We conducted a dermatoglyphic analysis in a new sample of 617 individuals: 205 patients with schizophrenia-spectrum disorders, 224 healthy first degree relatives and 188 healthy controls. The dermatoglyphic variables studied were: the total a-b ridge count (TABRC) and its fluctuating asymmetry (FAABRC), and the presence of ridge dissociations (RD) and abnormal palmar flexion creases (APFC)., Results: Patients, relatives and controls did not differ in TABRC. However, within the patients group those with a low birth weight or absence of psychiatric family history showed lower TABRC than the others. The frequency of ectodermic derivates abnormalities (RD and/or APFC) appeared to be higher in patients and relatives than in controls, while first degree relatives did not differ from patients. Males showed an increased rate of ectodermic derivates abnormalities compared to females in all groups and male patients also presented higher FAABRC than female patients., Conclusions: Our results suggest a different relative weight of genetic and environmental factors on each dermatoglyphic variable analyzed: i) TABRC may be a sensitive marker to environmental factors in schizophrenia, ii) ectodermal derivates abnormalities appear to be influenced by genetic risk factors, which could be involved both in the disrupted development of ectodermic derivates like dermatoglyphics and central nervous system and in the vulnerability for schizophrenia.

Unlabelled: Working memory (WM) has hardly been explored in non-psychotic relatives of schizophrenic patients despite its potential suitability as a neurocognitive endophenotype. Indeed, WM modalities, components and processes have rarely been compared in the same group of relatives. The present study examined neurocognitive performance in healthy siblings of schizophrenic patients, including both spatial and verbal WM modalities and tests tapping maintenance (Spatial Span Backwards and CPT-IP d') and manipulative (Letters and Numbers Sequencing) WM processes., Methods: 68 schizophrenia patients, 38 healthy siblings and 63 controls were assessed on IQ, attention, memory, WM, and executive functions. Cluster A symptoms were screened out in siblings and controls., Results: Siblings had an intermediate performance between that of schizophrenic patients and controls. They performed worse than controls on IQ, LNS, animal naming, backwards spatial span, phonemic fluency, numbers d', and forward spatial span., Discussion: Consistent with the WM literature in schizophrenia, both verbal and spatial WM differed significantly between siblings and controls, suggesting that WM deficits are modality independent. Our results failed to support the hypothesis that tests tapping WM manipulative processes heavily loading on DLFPC are quantitatively more impaired in relatives and, therefore, more sensitive to liability for schizophrenia. However, firm conclusions cannot be drawn until more studies assessing both maintenance and manipulative WM processes in relatives are available.

Background: Patients with schizophrenia show deviances in their dermatoglyphics, in particular reductions in palmar a-b ridge counts (ABRCs), which are evidence of an early developmental deviance. However, the severity or the origin of these ABRC changes has not been established., Method: (i) We examined the published literature on the ABRC in patients with schizophrenia against controls with a random effects meta-analysis. (ii) We used linear regression to study the ABRC in our sample of families including 125 patients with schizophrenia, 107 of their unaffected relatives and 98 controls. (iii) The effect of obstetric complications on the patient's ABRC was examined using the Lewis Murray scale., Results: The pooled standardised effect size of ABRC differences between patients and controls obtained by our meta-analysis was 0.39 (95% CI: 0.05-0.73; p=0.03). In our sample, there were no significant differences in ABRCs between those with schizophrenia, their relatives and controls. Only those patients with obstetric complications had significantly reduced ABRC compared to controls (p=0.01)., Conclusions: We confirmed the presence of significant yet mild ABRC reductions in schizophrenia. These represent a subtle deviance from the norm and could be present in certain subsets of patients, possibly those who suffered early developmental insults.

Introduction: Studies on the neurocognitive correlates of schizotypy dimensions have found inconsistent results. This might stem from the fact that correlational methods, in contrast to cluster analysis, do not account for the possibility that a subject presents high scores on more than one dimension simultaneously. We aimed to establish clusters of normal adolescents based on schizotypy dimensions and compare them on neurocognitive, behavioural, and neurodevelopmental markers., Methods: Two hundred seventy normal adolescents from the general population (mean age 13.4, SD=0.72) attending obligatory education were evaluated., Results: A K-means iterative cluster analysis was performed with the Perceptual Aberration, Revised Social Anhedonia and Physical Anhedonia Scales. A forced four-cluster model yielded the following clusters: 'negative schizotypy', 'high or mixed schizotypy', 'positive schizotypy', and 'normal scorers'. Comparisons with ANOVAs showed that 'high schizotypes' performed poorly on neurocognition (Wechsler Intelligence Scales for Children-Revised (WISC-R) and Verbal Fluency (FAS)) and obtained the highest teacher ratings (TRF) of behavioural problems. 'Negative schizotypes' had the worst WCST results and more dermatoglyphic abnormalities. Both clusters had more neurological soft signs than 'normal scorers' and 'positive schizotypes'., Conclusions: Our results with community adolescents found the same cluster structure than the previous cluster analytic studies conducted in adult college subjects. Furthermore, we showed differences among them on neurocognitive and malneurodevelopment markers consistent with the adult literature on schizotypy.

Introduction: It has been suggested that evidence of developmental disturbance of cognition and lateralisation in schizophrenia can be best understood from the perspective of developmental stability (DS), an indicator of the extent to which an individual develops according to a specified ontogenic programme in the presence of environmental noise. Higher levels of fluctuating asymmetry (FA; the difference between right and left side of a quantitative morphological trait such as dermatoglyphics) are thought to reflect less DS. We examined this issue for dimensions of schizotypy., Methods: Associations between FA, measures of laterality and cognitive function on the one hand, and negative and positive dimensions of schizotypy on the other, were examined in a sample of 260 healthy adolescents aged 11.9-15.6years. FA was measured as a-b ridge count right-left differences. Neuropsychological measures yielded a general cognitive ability score and a frontal function score. Laterality was assessed with the Annett scale., Results: Measures of psychosis proneness were normally distributed. Negative schizotypy was associated with more FA and lower general cognitive ability in a dose-response fashion. The association with FA was more apparent in boys. No associations existed with laterality or frontal function., Conclusion: The negative dimension of schizotypy may be associated with early developmental instability, resembling the pattern seen in the negative symptom dimension of schizophrenia. Measures of fluctuating asymmetry may be more sensitive with regard to the schizotypy phenotype than measures of laterality.

Background: It has been reported that relatives of probands with severe, psychotic forms of bipolar illness have increased rates of schizophrenia but not the relatives of individuals with milder, non-psychotic forms of disorder. In this study, we examined the prevalence of psychiatric disorders in the first degree relatives of a sample of 103 inpatients with bipolar disorder and in a matched control sample of 84 healthy individuals., Method: Relatives of cases and controls were interviewed using the FH-RDC to determine familial morbid risk for schizophrenia and bipolar disorder. Age- and sex-adjusted morbidity risks were calculated in both samples according to the method of Strömgren., Results: The morbid risks for both bipolar disorder (4.9%) and schizophrenia (2.8%) were higher in relatives of patients than in relatives of controls (0.3% and 0.6% respectively). The relative risks were 14.2 [95% confidence interval (CI)=3.1-64.2] for bipolar disorder and 4.9 (95% CI=1.3-18.8) for schizophrenia. Relatives of women with early onset of bipolar illness had the highest morbid risks for both bipolar illness and schizophrenia. The presence of more than one patient with bipolar disorder in a family increased the risk for schizophrenia nearly fourfold (RR=3.5, 95% CI=1.2-10.2). There was no additional effect of presence of psychotic features., Conclusion: Our results suggest that the transmission of psychosis is not disorder-specific. Bipolar illness characterised by a high familial loading is associated with increased risk of schizophrenia in the relatives.