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The little-known writing by Frederik Lange translated in this Classic Text belongs to what can be called the prolegomenal history of the construction of the concept of schizophrenia. It describes one effort to capture the convergence of certain words of diverse coinage (dementia praecox, acquired idiocy, hebephrenia, heboidophrenia, etc.) with some newly accepted concepts (e.g. the temporalization of madness and the view that adolescence was an independent period of life), and with some old behaviours (which for centuries had been called madness, the portmanteau soon to be rebaptized as psychosis). This convergence culminated in the work of Kraepelin, who was to call it ‘dementia praecox’. Lange’s transitional efforts and pangs can be sensed as he struggles to describe a new form of madness that affects young people.

Pre-Kraepelinian observations converged in Kahlbaum’s and Hecker’s description of Hebephrenia. For Kraepelin, Hebephrenia was an ‘idiopathic incurable dementia whose onset is in adolescence’. It became the core of ‘Dementia Praecox’, and then Bleulerian ‘Schizophrenia’. In recent decades, the resurgence of the ‘late neurodevelopment’ hypothesis of schizophrenia has brought into focus Hecker’s clinical reports of adolescents who, as a result of a putative loss of psychic energy, showed a rapidly progressive cognitive impairment leading to functional and behavioural disorganization. This paper summarizes the nineteenth-century conceptualization of Hebephrenia as a developmental illness.

Given the emerging evidence in support of parietal brain stimulation to treat speech disorder in psychosis, we investigated structural and functional parietal dysconnectivity in schizophrenia (n = 34) and bipolar disorder with psychotic symptoms (n = 16). We found that both patient groups demonstrated reduced left parietal structural connectivity compared to healthy controls (n = 32). The three groups also differed significantly on the variability of left and right parietal dynamic functional connectivity. In patients with schizophrenia, parietal dysconnectivity predicted the severity of disorganisation symptoms. These findings suggest that dysconnectivity between the parietal lobe and the rest of the brain plays a key role in disorganisation symptoms of schizophrenia.

The nature and severity of semantic memory (SM) impairments in schizophrenia has been related to symptoms, mainly formal thought disorder (FTD), and other clinical factors like length of illness. Symptom-related studies in schizophrenia are often confounded by clinical factors, for example medication and hospitalisations. We completed a schizotypy analogue study to examine the relationship between SM processing and FTD using an analogue schizotypy score referred to as cognitive disorganisation. Sixty individuals without a history of mental illness (M=22.92, SD=2.70) completed a schizotypy questionnaire and three semantic tasks – naming pictures, category fluency and semantic priming. Only decreasing fluency was associated with increasing cognitive disorganisation scores (p=0.029). In line with the prevailing dyssemantic theories, the results highlight that cognitive disorganisation is associated with some difficulties in SM processes, though not all. The observed differential relationships of SM processes to disorganised schizotypy are discussed in relation to previous work, and in terms of potential developmental trajectories for SM impairment in schizophrenia.

Neurocognitive and social cognition deficits have been largely reported in Schizophrenia (SKZ) but their association with psychopathology remains uncertain. Our purpose was to explore the relationship between symptom dimensions and neuropsychological performances. We enrolled 35 stabilized schizophrenic outpatients of the Department of Psychiatry of Policlinico Hospital, University of Milan, who completed psychiatric Rating Scales, the Brief Assessment of Cognition in Schizophrenia (BACS) and the Executive and Social Cognition Battery (ESCB). Disorganized dimension seems to have the most significant impact on cognition, being associated with performance in several BACS subtests (verbal memory, working memory, motor speed, symbol coding, Tower of London) and ESCB tasks (MET and Hotel task number of tasks attempted, number of broken MET rules, sum of deviations in Hotel Task). Positive dimension correlated with performance in verbal fluency, negative dimension with IOWA Test results, cognitive dimension with MET number of inefficiencies and Eyes test score. Impulsive-aggressive and depressive dimensions weakly correlated only with Faux Pas test. Our study supports the existence of a specific disorganized dimension in SKZ, separated from cognitive dimension evaluated through clinical instruments (e.g. PANSS), but capable of influencing cognitive abilities. Furthermore, it strengthens the validity of ecological tasks in evaluating cognition in SKZ.

In developing his mature concept of hebephrenic dementia praecox (DP) in his 4th (1893) through 6th textbook editions (1899), Kraepelin worked from the hebephrenic syndrome first described by Hecker (1871) and then carefully studied by his student Daraszkiewicz (1892). Working under Kraepelin's supervision, Daraszkiewicz followed Hecker in emphasizing several key features of hebephrenia (distinctive deteriorative course, importance of silliness and minimal positive psychotic symptoms) but expanded the syndrome to include cases developing severe dementia, rejected the link to prodromal depressive and manic phases, and reduced the emphasis on thought disorder. Daraszkiewicz proposed a soft subtyping of hebephrenia based on level of deterioration, which Kraepelin adopted in his 4th edition with an additional emphasis on severe positive psychotic symptoms. In his 5th edition, Kraepelin created a third subform with even more pronounced and bizarre delusions and hallucinations. In his 6th edition, which contained his first articulation of DP, Kraepelin eliminated his hebephrenia subforms presenting a single syndrome, which, compared to Hecker, included more emphasis on positive psychotic and catatonic symptoms and severe dementia. Kraepelin's paths to hebephrenic and paranoid DP differed in important ways. Paranoid DP was a de novo syndrome created by differentiation from paranoia. Hebephrenia, by contrast, evolved from a disorder created in the Kahlbaum/Hecker paradigm of the iterative study of clinical features, course and outcome. Kraepelin further implemented this approach in substantially reworking, over several drafts, the hebephrenic syndrome to fit into his emerging construct of dementia praecox.

Objective Psychosocial trauma during childhood is associated with schizophrenia vulnerability. The pattern of grey matter decrease is similar to brain alterations seen in schizophrenia. Our objective was to explore the links between childhood trauma, brain morphology and schizophrenia symptoms. Method Twenty-one patients with schizophrenia stabilized with atypical antipsychotic monotherapy and 30 healthy control subjects completed the study. Anatomical MRI images were analysed using optimized voxel-based morphometry (VBM). Childhood trauma was assessed with the Childhood Trauma Questionnaire, and symptoms were rated on the Scale for the Assessment of Negative Symptoms (SANS) and Scale for the Assessment of Positive Symptoms (SAPS) (disorganization, positive and negative symptoms). In the schizophrenia group, we used structural equation modelling in a path analysis. Results Total grey matter volume was negatively associated with emotional neglect (EN) in patients with schizophrenia. Whole-brain VBM analyses of grey matter in the schizophrenia group revealed a specific inversed association between EN and the right dorsolateral prefrontal cortex (DLPFC). Path analyses identified a well-fitted model in which EN predicted grey matter density in DLPFC, which in turn predicted the disorganization score. Conclusion Our findings suggest that EN during childhood could have an impact on psychopathology in schizophrenia, which would be mediated by developmental effects on brain regions such as the DLPFC.

Owing to unresolved questions concerning the efficacy and safety of electroconvulsive therapy (ECT) in the treatment of schizophrenia, and widespread negative attitudes toward ECT, maintenance ECT (mECT) is generally considered only as a last resort. Nevertheless, in some clinical situations, the advantages of mECT may outweigh the risks and associated concerns. We report the case of a patient suffering from disorganized schizophrenia who had life-threatening hematological side effects to treatment with antipsychotic agents. Long-term mECT was administered and the patient achieved remission with no notable side effects. He was able to maintain a peaceful daily routine and improved functioning. Considering the lack of controlled trials in this area, this case and other similar cases reported in the literature add support to a possible benefit of mECT in disorganized schizophrenia, particularly when pharmacotherapy is insufficient or contraindicated.

Ewald Hecker was the first psychiatrist to describe the disease entity of hebephrenia in some detail, focusing mainly on disturbances of affect. Later Emil Kraepelin and Eugen Bleuler saw hebephrenia as a subtype of dementia praecox or schizophrenia. Willy Mayer-Gross and Karl Leonhard characterized hebephrenia with highly differentiated psychopathological descriptions, whereas this construct only played a minor role in the works of Klaus Conrad and Kurt Schneider. The International Classification of Diseases (ICD-10) lists hebephrenia as a subtype of schizophrenia but in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) no subtypes of schizophrenia are mentioned and the concept of hebephrenia is thus lost. Hebephrenia can be seen as an ideal type describing a psychopathological course pattern. This construct can be useful to conceptualize a group of disorders of affect which otherwise escape description, especially since these psychopathological alterations of affect are difficult to operationalize. To have a viable concept of these disorders is relevant for the prognosis and therapy planning. If the concept of hebephrenia is abolished, important psychopathological knowledge might be lost for future generations of psychiatrists.

In this article, based on literature review, we present an integrated description of heboidophrenia and pseudo-psychopathic schizophrenia. Both diagnostic constructs describe latent psychotic processes inextricably bound with psychopathic features. Although both have been described in different eras and research threads, they are that similar that we could not find divergences. We formulated operational criteria for clinical and research purpose. The recognition of this syndrome improves risk management, treatment, and legal decisions.

Bleuler in his book “Dementia Praecox, or the group of the schizophrenias” described basic forms of mental disorganization in schizophrenia related to “loosening of associations” (Bleuler, 1950). In this historical context disorganized symptoms are currently understood as important factors of cognitive disturbances in schizophrenia, especially in patients with first episode psychosis (Minor and Lysaker, 2014).

CASE Isela is an 11-year-old Mexican-American girl with mild intellectual disability. During a vacation with her family, she went swimming with dolphins. A few days later, Isela awoke at night with laughing spells; during the day, she was pacing, aggressive, and had a decline in self-care and communication skills. Her parents attributed the symptoms to the dolphins. She was evaluated by a pediatric neurologist. The sleep-deprived electroencephalogram, brain magnetic resonance imaging, lumbar puncture, and thyroid function tests were normal. A genomic microarray was sent. The neurologist initiated empirical therapy for seizures with lamotrigine, which caused a rash. It was discontinued. She was then treated with oxcarbazepine followed by topiramate for several months without any change in symptoms. Comparative genomic hybridization revealed a small deletion at 14q13.1, which includes the NPAS3 gene. Psychiatry was consulted after several months of persistent symptoms. Isela seemed to be laughing in response to internal stimuli. Owing to the decline in communication and her apparent preoccupation with visual and auditory internal stimuli, Isela could not be interviewed adequately to confirm that she was experiencing hallucinations, but her laughter seemed to be in response to hallucinations. Isela was diagnosed with disorganized schizophrenia with psychosis. Risperidone was prescribed. A psychology evaluation was completed a few months later. Parents noted significant improvement after starting risperidone with reduced inappropriate laughing spells, reduced pacing, as well as improved eating, sleeping, communication, and self-care. Cognitive assessment with the Wechsler Abbreviated Scale of Intelligence-II indicated the following: verbal estimated intelligence quotient (IQ) = 70, perceptual estimated IQ = 71, and full-scale estimated IQ = 68. There was no cognitive decline compared with testing at school 4 years previously. Although psychotic symptoms were significantly improved on antipsychotic medication and function appeared to have been restored to her previous level, her parents continued to perceive a significant decline of functioning, and they continued to attribute the psychosis to swimming with the dolphins.

Background: There is considerable variation in progressive brain volume changes in schizophrenia. Whether this is related to the clinical heterogeneity that characterizes the illness remains to be determined. This study examines the relationship between change in brain volume over time and individual variation in psychopathology, as measured by five continuous symptom dimensions (i.e. negative, positive, disorganization, mania and depression). Methods: Global brain volume measurements from 105 schizophrenia patients and 100 healthy comparison subjects, obtained at inclusion and 5-year follow-up, were used in this study. Symptom dimension scores were calculated by factor analysis of clinical symptoms. Using linear regression analyses and independent-samples t-tests, the relationship between symptom dimensions and progressive brain volume changes, corrected for age, gender and intracranial volume, was examined. Antipsychotic medication, outcome and IQ were investigated as potential confounders. Results: In patients, the disorganization dimension was associated with change in total brain (beta= -0.295, p=0.003) and cerebellar (beta= -0.349, p

St John's wort (Hypericum perforatum) is notorious for its ability to induce the enzymes of the P450 system. Especially, it induces CYP1A2 and CYP3A4, enzymes that are closely involved in the metabolism of clozapine. We present a patient with schizophrenia, who was stable on a fixed dose with stable plasma level of clozapine, and who deteriorated after she started self-medicating with St John's wort. The reduced plasma clozapine level and the psychiatric condition normalized after the withdrawal of St John's wort. It is possible that, beside the induction of P450-enzymes, the induction of P-glycoprotein by St John's wort aggravated psychiatric deterioration of the patient. Physicians should be alert to patients self-medicating with over-the-counter medicines, especially when these medicines can lower clozapine concentrations below the therapeutic range.

At doses lower than those needed to stimulate prolactin release directly, TRH almost completely antagonizes the inhibitory effect of dopamine on prolactin release. We have previously reported that prolactin response to administration of 12.5 microg TRH i.v. correlates with prolactin response to 0.5 mg i.m. haloperidol and negatively with 24-h urinary excretion of HVA in normal subjects, suggesting that the response reflects dopamine activity. An association between central dopamine hyperactivity and SANS scores relating to poverty of content of speech and inattention has been suggested by studies utilizing methylphenidate administration in patients with first-episode schizophrenia. The hypothesis that small plasma prolactin responses to administration of 12.5 microg TRH i.v. (Delta prolactin) correlate with SANS scores for these symptoms was tested in 19 drug-naïve patients with first-episode schizophrenia. Significant negative correlations were found between the response and scores relating to poverty of content of speech (r = - 0.55, p = 0.014) and inattention (r = - 0.52, p = 0.022), supporting the hypothesis of increased dopamine activity in association with disorganization symptoms. A significant positive correlation between basal prolactin levels and prolactin response to stimulation by 12.5 microg TRH was also found (r = + 0.61, p = 0.0058). Our previous study in normal subjects found a similar positive correlation between basal prolactin levels and prolactin response to stimulation by 200 microg TRH i.v., but not by 12.5 microg TRH i.v. As far as we know, this is the first study to report an abnormality in TRH-induced prolactin release in acute schizophrenia.

Background/Aims: Cluster analysis has had limited success in establishing whether there are subtypes of schizophrenia. Grade of membership (GoM) analysis is a multivariate statistical technique which has advantages when, as in schizophrenia, individuals conforming to pure types are uncommon and mixed forms are frequent. Methods: GoM analysis was applied to 118 chronic schizophrenic patients. The patients were of all clinical subtypes, including 13 with simple schizophrenia. Both current and ‘lifetime’ symptoms were assessed, and two different rating systems were used. Results: Specifying 3 pure types resulted in robust findings across analyses. One pure type corresponded to paranoid schizophrenia, one to simple schizophrenia and the third combined elements of hebephrenic and catatonic schizophrenia. Specifying 4 pure types split the original 3 pure types in ways which were not clinically intuitive. Conclusion: GoM analysis divides schizophrenia into subtypes along conventional lines, with the proviso that hebephrenic and catatonic schizophrenic patients are not separable, at least in the chronic stage of the illness.

Introduction Visual orientation and attention are impaired in schizophrenia. Engagement and disengagement of attention and the ability to prompt responses to a stimulus in patients before and after six weeks of risperidone were compared to controls. Methods Ten unmedicated (nine naive) schizophrenic patients, and eleven controls performed 1) A visual orienting task, the Cued Target Detection task (CTD), with the detection of a visual stimulus in valid, invalid, no cue and double cue trials, two conditions for fixation offset for a modulation of visual fixation: Gap: 200 ms before target; No Gap: simultaneous with target, 2) Choice Reaction Time (CRT 0.5 and 2 s delays). Results At baseline, patients showed longer RT than controls in CRT, but not in CTD, with in CTD, no facilitation of RT with the gap procedure. The alertness index was almost null in CTD-Gap and comparable to controls in CTD-No Gap. Efficiency to detect attended stimuli (CTD-No Gap) and warning effect (CRT 0.5 s) were negatively correlated to disorganization. After treatment, readiness to act in CRT had decreased. In CTD-No Gap, change in PANSS disorganization was correlated to an increased validity index, change in negative sub-score was correlated to decreased attention cost. Conclusion Untreated patients displayed a deficit of Gap effect and a slowing in sustained attention. Disorganization interfered with warning and visual detection. After treatment, its improvement and negative symptoms improvement were associated with better visual detection. These alterations in visual orienting provide new evidence for an oculomotor dysregulation of attentional engagement in schizophrenia.

Because of the risk for development of psychopathology such as psychotic symptoms, it has been suggested that studying men with the XXY karyotype may help in the search for underlying cognitive, neural and genetic mechanisms. The aim of this study was to identify cognitive mechanisms that may contribute to disorganization of thought in XXY men.A group of 24 XXY men and two non-clinical control groups (N = 20, N 18) participated in the study. The level of disorganization of thought was measured using the Schizotypal Personality Questionnaire. We assessed IQ lateralization of verbal information processing and executive functions including inhibition and mental flexibility.XXY men with high levels of disorganization showed More severe impairments in mental flexibility and inhibition as compared to non-clinical controls and other XXY men. This subgroup also showed a stronger reduction in lateralization of verbal information processing. IQ measures did not differentiate XXY men with high versus low levels of disorganization.These findings indicate that executive impairments in the domains of inhibition and mental flexibility might play a role in the increased vulnerability for disorganized thought in the XXY group. Reduced lateralization of verbal information processing points to non-optimal cerebral specialization in the XXY group, especially in XXY men with high levels of disorganization. This fits with deficits in brain functions most vulnerable to such Maturational disruptions, i.e. executive dysfunctions. Our findings are in line with those reported for schizophrenia patients with thought disorder. We speculate that the underlying mechanisms of thought disorder probably are deficit specific rather than disorder specific. (C) 2009 Elsevier B.V. All rights reserved.

A dolgozat témája egyfelől két pszichopatológiai tünet elemzése egy hosszú távú utánkövetéses vizsgálat – „Budapest 2000” – keretében elsősorban szkizofréniában szenvedő nőbetegek körében; másfelől a genetikai prediszpozícióhoz közelinek tartott kognitív endofenotipikus vonás – az asszociatív tanulás és tanult ekvivalencia – vizsgálata szkizofrén betegek és hozzájuk illesztett egészséges kontrollok csoportjaiban. Célkitűzés: I. Megvizsgálni 1. a téveszme és a hallucináció súlyosságát, annak időbeli változását, előfordulásának valószínűségét az egyes klinikai csoportokban; 2. a klinikai csoportokra jellemző kórlefolyást a két tünet alapján. II. Tanulmányozni az asszociációs tanulás és a tanult ekvivalencia jelenségét abban az összefüggésben, hogy ezek a képességek elkülönítik-e a szkizofrén betegeket az egészséges kontrollcsoporttól, illetve a szkizofrénián belül elkülönülnek-e a deficit- és nem deficitszkizofrénia-alcsoportok. Módszerek: Az első, klinikai tüneteket elemző vizsgálatban 221 nőbeteg vett részt, a tüneteket a Rockland–Pollin-féle becslésskála, valamint a Sajátos tünetek listája segítségével értékeltük a betegség heveny szakában (indexidőpont), valamint 5 évvel és 21–33 évvel az indexidőpontot követően. Diagnosztikus besorolásuk eredetileg Leonhard rendszere szerint történt, de elvégeztük a DSM-IV szerinti diagnosztizálásukat is. A második vizsgálat keretében 49 szkizofrén férfi és nőbeteget, valamint 20 illesztett egészséges kontrollt vizsgáltunk meg a Rutgers-féle tanultekvivalencia-teszt, valamint három, döntően frontális neuropszichológiai teszt segítségével. Az utóbbi vizsgálat keretében a klinikai tüneteket a Positive and negative symptom scale-lel mértük. Eredmények: A pozitív dimenzió tüneteinek változásában a hosszú távú lefolyás során különbség mutatkozik: hallucináció súlyosságában az 5 éves vizsgálat utáni időszakban szignifikáns romlás van, míg a téveszme mérséklődik, de ez a javulás nem szignifikáns. A két tünet, valamint a szociális funkcionálás tekintetében elkülönül egymástól az affektív, cikloid és szkizofrén betegek csoportja az utánkövetés időszaka alatt, és a két tünet jellemzői szerint a paranoid, hebefrén és katatón alcsoportok is. A mediális temporalis lebeny működésével kapcsolatos tanultekvivalencia-vizsgálatban a szkizofrén betegek rosszabbul teljesítettek, mint az egészséges kontrollcsoport. Az agytörzsi magvak mediálta asszociatív tanulásban nyújtott teljesítményük elkülönítette a deficit- vs. nem deficitszkizofrén alcsoportot. Következtetések: 1. A kognitív dimenzió elkülöníti a szkizofrénia deficit- és nem deficitalcsoportjait. 2. A pozitív dimenzió tünetei alapján a szkizofrénia klasszikus típusai válnak szét.

A wealth of studies has demonstrated that patients with schizophrenia are impaired in "theory of mind" (ToM). Here, we used a novel five-factor model of the Positive and Negative Syndrome Scale (PANSS) to test the hypothesis that selectivity of ToM deficits in schizophrenia depends on the predominating symptoms. We predicted that ToM impairments would be non-selective in patients with pronounced negative (NF) or disorganized symptoms (DF), whereas selective ToM impairment would occur in patients with predominant positive symptoms (PF). We recruited 50 patients diagnosed with schizophrenia or schizoaffective disorder and examined premorbid intelligence, executive functioning, ToM and psychopathology in comparison to a group of 29 healthy controls. Compared with healthy controls, patients performed more poorly on tasks involving executive functioning and ToM abilities. Using a novel PANSS five-factor model, we found a significant association of ToM deficits with the "disorganization" factor. Moreover, several individual PANSS items that were included within the disorganization factor correlated with impaired ToM, albeit the majority of correlations disappeared when controlled for executive functioning, and, to a lesser degree, when controlled for IQ. In addition, in the patient group we found interactions of poor ToM with symptoms belonging to the "emotional distress" factor of the PANSS. Contrary to expectations, associations of impaired ToM with positive symptoms were absent, and poor with regards to negative symptoms. This study lends further support to the assumption of differential associations of ToM deficits with individual symptoms and symptom clusters in schizophrenia.

BackgroundRelationships between performance on various tests of executive functions and positive symptoms, especially delusions and hallucinations, have not been found consistently. This may be related to method of rating symptoms, to possible interactions between them, as well as to the low specificity of the cognitive test measures used. In this study, we have investigated the relationships between different aspects of positive symptomatology and several executive subprocesses.MethodStable schizophrenia patients (n=96) were assessed for disorganization, delusion and hallucination symptoms rated from the Scale for Assessment of Positive Symptoms and the Scale for Assessment of Negative Symptoms. Interference sensitivity, inhibition and flexibility were assessed using the Wickens paradigm. The relationships between symptom dimensions as well as with cognitive and other potentially confounding variables were assessed using Pearson correlations and (simple and partial) stepwise regressions.ResultsGenerally consistent with the cognitive constructs used to account for positive symptoms, the results indicated relationships between delusions, disorganization and inhibition, and between hallucinations and interference sensitivity. However, these relationships appeared more complex than expected, with some being dependent on interactions between symptoms.ConclusionsThese results suggest: (i) that the global measures usually employed may not be appropriate for demonstrating specific relationships between symptoms and executive functions and (ii) that it is necessary to take into account the interactions between positive symptoms as well as with other factors to reveal these relationships.

Aims: It clarifies a difference between early acute phase and late acute phase in medication. Methods: The present report describes three patients with schizophrenia who presented with restlessness and excitement requiring hospitalization. Results: Treatment with risperidone solution orally or parenteral haloperidol until the day after admission, followed by olanzapine, successfully improved the clinical condition of the patients. In the early stage of hospitalization, selection of fast-acting drugs that can be administered to uncooperative patients is considered preferable, focusing on rapid control of symptoms and behavioral disorders, whereas after this early stage, olanzapine is preferable for improving patient compliance in addition to stabilizing symptoms. Conclusions: Because the target symptoms differ between the early and late acute phases, the term ‘acute phase’ used in the broad sense should be divided into two units, each requiring a different therapeutic strategy, and independent clinical approaches should be considered in order to provide more suitable treatment.

Disorganized speech, or thought disorder, in schizophrenia may reflect abnormal processing of meaningful concepts. To examine whether schizophrenia involves abnormalities in how a meaningful context influences processing of concepts strongly, weakly, or not related to it, we used the N400, an event-related brain potential (ERP) index of semantic relatedness. ERPs were recorded from schizophrenia patients (n = 18) and normal controls (n = 18) while they viewed category definitions (e.g., a type of fruit), each followed by a target word that was either a high-typicality category exemplar (apple), low-typicality exemplar (cherry), or non-exemplar (clamp). Participants' task was to indicate via button-press whether or not the target belonged to the category. In both patients and controls, N400 amplitude was largest (most negative) for non-exemplars, intermediate for low-typicality exemplars, and smallest (least negative) for high-typicality exemplars. Compared to controls, patients showed a trend toward reduced N400 amplitude differences between non-exemplars and low-typicality exemplars. Most importantly, within patients, reduced N400 amplitude differences between high- and low-typicality exemplars were correlated with psychotic symptoms. This association of an N400 index of semantic processing with psychotic symptoms suggests that psychosis in schizophrenia may be associated with greater similarity in how concepts strongly and weakly meaningfully related to their context are processed.

Genetic isolates are exceptional resources for the detection of susceptibility genes for complex diseases because of the potential reduction in genetic and clinical heterogeneity. However, the outcome of these mapping efforts is dependent upon the demographic history of a given isolated population, with the most significant factors being a constant population size, the number of generations since founding, and the pathogenic loci and their allele frequencies among founders. Here we employed a cross-isolate genome-wide multipoint linkage study design using uniform genetic and clinical methods in four Daghestan ethnically and demographically diverse isolates with an aggregation of schizophrenia. Our previous population-genetics study showed that Daghestan has an extremely high genetic diversity between ethnic populations and a low genetic diversity within them. The isolates selected for this study include some with more than 200 and some with fewer than 100 generations of demographical history since their founding. Updated clinical data using DSM-IV criteria showed between-isolate differences in aggregation of distinct types of schizophrenia: one of the isolates had a predominant aggregation of disorganized schizophrenia, while the other three had predominantly paranoid schizophrenia. The summarized cross-isolate results indicated prominent within and between-isolate differences in clinical and genetic heterogeneity: the most ancient isolates have roughly twofold fewer incidences of distinct clinical phenotypes and fewer linked genomic regions compared to the demographically younger isolates, which exhibit higher clinical and genetic heterogeneity. Affected individuals in the demographically ancient isolate of ethnic Dargins (No. 6022) who suffered from disorganized schizophrenia showed the highest linkage evidence at 17p11–p12 (LOD = 3.73), while isolates with a predominant aggregation of paranoid schizophrenia (Nos. 6005, 6011, and 6034) showed the highest linkage evidence at 22q11 (LOD = 3.0 and 4.4). The unified clinical, genomic, and statistical design we used enabled us to separate the linked and unlinked pedigrees in an unbiased fashion for each genomic location. Overall maximized heterogeneity lod scores for the combined pedigrees ranging from 3.5 to 8.7 were found at 2p24, 10q26, 11q23, 12q24, 17p11–p12, 22q11, and 22q13. The cross-isolate homogeneity in linkage patterns may be ascribed to an identical-by-descent “metahaplotype” block with pathogenic loci derived from the Daghestan ethnic groups’ common ancestral metapopulation, while the cross-isolate differences may reflect differences in gene drift and recombination events in the history of local isolates. The results obtained support the notion that mapping genes of any complex disease (e.g., schizophrenia) in demographically older genetic isolates may be more time and cost effective in comparison with demographically younger isolates, especially in genetically heterogeneous outbred populations, due to higher clinical and genetic homogeneity of the primary isolates. A study at higher genotyping density across the regions of interest and fluorescence in situ hybridization analyses are currently underway.

This study evaluated visual perceptual grouping in schizophrenia to test the hypothesis that the disorganization syndrome in schizophrenia is related to a deficit in cognitive coordination. Perceptual grouping was examined with three psychophysically well-controlled tasks in patients with disorganized schizophrenia (n=11), non-disorganized schizophrenia (n=24), psychotic disorders other than schizophrenia (n=31) and non-psychotic psychiatric disorders (n=35). These measures assessed processing of both concurrent and preceding stimulus context. Deficits in perceptual grouping were observed on all three tasks in disorganized schizophrenia patients. Dysfunctional perceptual grouping mechanisms produced both enhanced and impaired task performance suggesting that the pattern of performance observed was the result of a specific deficit in the grouping of stimulus elements. We interpret these data as further support for the hypothesis that the disorganization syndrome in schizophrenia reflects a widespread deficit in the cognitive coordination of contextually related stimuli, leading to dysfunctional grouping of stimulus features in vision, thought and language.

Within the ASPIS (Athens Study of Psychosis Proneness and Incidence of Schizophrenia) we sought out to examine in accordance with previous reports if a deviation from dextrality is associated with an augmented endorsement of self rated schizotypal personality traits in a large population of 1129 young male army recruits. Schizotypal traits were assessed using the Schizotypal Personality Questionnaire and hand preference membership was determined by applying stringent criteria derived from the Annett Handedness Questionnaire and the Porac-Coren questionnaire of lateral preferences. By adopting three different definitions of hand preference membership, we confirmed an association between mixed handedness and increased schizotypal personality traits, and in particular with Disorganization schizotypy that encompasses aspects of self perceived difficulties in verbal communication. Non-verbal cognitive ability, as indexed by measurement of non-verbal IQ, sustained attention and working memory was not associated with hand preference. We argue that a deviation from normal cerebral lateralization, as indexed by mixed handedness, is associated with mild sub clinical language dysfunction, rather than non-verbal cognitive ability, and this might be relevant to the expression of psychosis phenotype.

Background Descriptions of psychiatric autoimmunity beyond N -methyl-d-aspartate (NMDA) receptor encephalitis are sparse. Objective To report the autoimmune psychiatric spectrum currently recognized in Mayo Clinic practice. Methods Medical record review, testing of stored serum and cerebrospinal fluid for IgGs reactive with synaptic receptors and ion channels, neuronal nuclear and cytoplasmic antigens (including glutamic acid decarboxylase 65-kDa isoform) and case-control comparison were conducted. Patients were categorized into group 1, all adult psychiatric inpatients tested for neural autoantibodies (2002–2011; n = 213), and group 2, all Mayo NMDA receptor IgG–positive patients (2009–2013; n = 13); healthy control subjects were also included ( n = 173). Results In group 1, at least 1 serum autoantibody (but not NMDA receptor IgG) was detected in 36 of 213 psychiatric inpatients. In total, 12 patients were determined retrospectively to have high-likelihood autoimmune encephalitic diagnoses. The most commonly detected autoantibody specificities were voltage-gated potassium channel ([Kv1] VGKC) complex (6) and calcium channel (P/Q type or N type; 5). Symptoms seen were as follows: depressive (8), anxious (7), psychotic (7), disorganized (5), suicidal (3), manic (1) and catatonic (1). In group 2, among 13 NMDA receptor IgG–positive patients, 12 had encephalitis; their psychiatric symptoms were as follows: depressive (9), catatonic (9), disorganized (8), anxious (8), psychotic (7), manic (6), and suicidal (3). Catatonic symptoms were more common in the 12 NMDA receptor IgG–positive patients than in the 12 group 1 patients with high likelihood of encephalitis ( p = 0.002). Antibody positivities were usually low positive in value among healthy controls (12 of 16 vs 3 of 12 group 1 encephalitis cases, p = 0.025). NMDA receptor IgG was not detected in any healthy control subject. Conclusions A spectrum of psychiatric autoimmunity beyond NMDA-R IgG may be under-recognized. Diagnosis is facilitated by combining results of comprehensive psychiatric, laboratory, radiologic, and electrophysiologic evaluations.

Aggression is a major concern in psychiatric inpatient care. Variations in study designs, settings, populations and data collection methods render comparisons of the prevalence of aggressive behavior in high-risk settings difficult. We proposed to estimate the pooled prevalence of aggression among inpatients with schizophrenia in China.Reports on aggressive behaviour involving physical contact or risks of interpersonal violence, in schizophrenia in Chinese general psychiatric wards were retrieved by using computer-assisted searches and manual searches of the reference lists of the relevant literature. Statistical analyses were conducted using the Comprehensive Meta-Analysis V2 software. Potential sources of heterogeneity were analyzed with Cochrane's Q analysis.The search yielded 19 eligible studies involving a total of 3,941 schizophrenia patients. The prevalence of aggressive behavior in psychiatric wards ranged between 15.3% and 53.2%. The pooled prevalence of aggression was 35.4% (95% CI: 29.7%, 41.4%). The most commonly reported significant risk factors for aggression were positive psychotic symptoms: hostility or suspiciousness, 78.9% (15 studies); delusions, 63.2% (12 studies); disorganized behavior, 26.3% (5 studies); and auditory hallucinations, 10.5% (2 studies); together with: past history of aggression, 42.1% (8 studies); and involuntary admission, 10.5% (2 studies).Aggressive behaviour is common in Chinese inpatients with schizophrenia. The prevalence figures indicate the need to identify reliable clinical and illness predictors for aggression in inpatient psychiatric wards and to test investigations aimed at reducing aggressive episodes and their adverse outcomes.

The aim of this study was to examine sex differences in emotion processing in patients with schizophrenia and control subjects. To this end, 53 patients with schizophrenia (28 men and 25 women), and 42 controls (21 men and 21 women) were assessed with the use of a facial affect recognition morphing task. Accuracy and sensitivity scores were measured. Women performed better than men in labelling negative emotions. On the same task, patients performed worse than control subjects, irrespective of sex, although the largest degree of impairment was seen in male patients. In conclusion, emotion perception was disproportionally affected in men with schizophrenia relative to women. This may explain, in part, why women with schizophrenia are less impaired in social life than men suffering from this illness. (c) 2005 Elsevier BV All rights reserved.

The symptoms of major psychosis aggregate in factors. Models of one to eight dimensions have been reported. In the present study, we tested six competing factor models, based on the psychotic and affective items of the OPCRIT checklist, in a large sample (N = 1294) of patients diagnosed with DSM-IV schizophrenia (n = 460), bipolar disorder (n = 726) and delusional disorder (n = 108). Confirmatory factor analysis was used to test the following models: (1) unique psychotic dimension; (2) positive-manic items, negative-depressive items; (3) model 2 with the addition of a disorganized factor; (4A) positive, negative, depressive and manic dimensions; (4B) model 4A with loss of pleasure (Anhedonia) and loss of energy (Apathy) included among depressive instead of negative symptoms; and (5) same as model 4B except for the addition of a disorganized domain. The four- and five-factor models fit the data much better than simpler ones. Between the two four-factor models, M4B emerged as more appropriate than M4A. The five-factor solution (M5) displayed the best fit. In conclusion, our confirmatory factor analysis in a large sample of psychotic subjects indicated that the symptomatology of major psychoses is composed of the following five factors: mania, positive symptoms, disorganization, depression and negative symptoms.

Direct assistance with academic study was given to 16 subjects who had hebephrenic schizophrenia (HS) and problems with school attendance, with the aim of helping the subjects to reaching their desired level of academic achievement. The subjects exhibited nine behavior patterns when they reached an impasse in their study: (i) difficulty understanding the degree of importance; (ii) difficulty integrating multiple concepts; (iii) difficulty understanding abstract concepts; (iv) difficulty developing an overview; (v) difficulty with applied problems; (vi) attempting to achieve complete understanding; (vii) becoming labile prior to exams; (viii) excess cramming leading to breakdown; and (ix) extreme reactions. These patterns were compared with those of 10 healthy junior high school students (normal group). In the HS group, patterns (i-v) were seen in at least a moderate degree in all subjects, but were significantly stronger than in the normal group and, even with study advice, improvement was temporary. Wide individual variations were seen in patterns (vi-ix) in the HS group, but again they were significantly stronger than in the normal group. The behavior patterns were influenced by the prospects of academic success, and were more prominent in subjects with higher expectations. Cognitive dysfunction was the root cause of these behavior patterns, with the additional involvement of psychological factors.

The purpose of this study was to explore the relationship between Theory of Mind (ToM) performance and schizophrenia subtype, symptom, and neuropsychological variables. One hundred twenty-eight stable outpatients with schizophrenia or schizoaffective disorder were assessed during the intake phase of a vocational and cognitive rehabilitation study. Results indicate that ToM performance differed significantly by schizophrenia diagnosis, with people diagnosed with disorganized schizophrenia performing the most poorly. Theory of Mind performance was also significantly correlated with measures of thought disorder and verbal memory. Regression analysis revealed that thought disorder and verbal memory measures explained 30% of the variance in ToM scores. Findings suggest that there is theory of mind variance in the schizophrenia population and theory of mind is strongly related to thought disorder, verbal memory, and cognitive disorganization. Contrary to previous reports, ToM was not related to measures of paranoia.

Previous studies have suggested that schizophrenic psychopathology segregates into three orthogonal dimensions, viz., psychosis, negative and disorganization. Most of these reports were based on studies on medicated patients with varying degrees of chronicity. The present study aimed at exploring the dimensionality of psychopathology rated on the Scale for the Assessment of Negative Symptoms (SANS) and the Scale for the Assessment of Positive Symptoms (SAPS) in a sample of 43 neuroleptic-naïve patients with recent-onset schizophrenia/schizophreniform disorder. Principal Components Analysis (PCA) of SANS and SAPS global ratings, excluding inattention but including inappropriate affect as a separate global rating, revealed that the symptoms segregated into three dimensions, viz., negative (affective flattening, alogia, avolition anhedonia and inappropriate affect), psychosis (delusions and hallucinations) and disorganization (positive formal thought disorder and bizarre behavior). Cumulatively these three dimensions explained 74.07% of the variance. The results suggest that the three dimensions of schizophrenic psychopathology are valid even in neuroleptic-naïve, recent-onset patients with schizophrenia/schizophreniform disorder. PCA of the SANS and SAPS individual items revealed similar findings, but psychotic symptoms loaded under two components, thus yielding a four-factor solution; however, this observation needs to be confirmed in a larger sample of neuroleptic-naïve schizophrenic patients.

There has been a long history of investigation in the fields of neuropsychology and cognitive psychology into the question of functional integration in the brain. Each of the several dominant themes in that history can be interpreted as representing an important feature of a unitary general mechanism that integrates distributed processes in the cerebral cortex. This mechanism must allow local areas to function within the large-scale anatomical structure of the cortex so as to satisfy competing requirements for stability and flexibility. Each specialized cortical area must perform a unique role by expressing its own form of information, yet must have its performance constrained by interactions with other areas to which it is connected. In order to generate adaptive behavior within changing and not fully predictable environments, the cortex as a whole must be able to rapidly coordinate the activities of variable assemblages of areas that can collectively express consensual information that is appropriate for the functional requirements engendered by each successive stage of behavioral performance. This paper proposes that the phase synchronization of neuronal population activity from different cortical areas may serve a role in large-scale coordination. Theoretical studies suggest that the cortex normally operates in a metastable dynamic regime in which groups of areas are able to coordinate rapidly and reversibly their activities through changes in their degree of phase synchronization. A disruption of phase synchronization, leading to an excess of local information expression by cortical areas, is proposed as a contributing factor to the disorganization syndrome in schizophrenia.

The aim of this study is to circumscribe the cognitive deficits according to schizophrenic syndromes in a population of sub-acute untreated patients. We have studied the cross-sectional correlation between cognitive deficits and schizophrenic symptoms, in a group of 24 untreated patients (including 17 neuroleptic-naive patients) with recent onset of the disease. A task of alertness, a working memory (WM) test (including two levels of difficulty) and an abbreviated version of the Wisconsin Card Sorting Test (WCST) were selected. WM deficits and poor performance on the WCST were highly correlated with disorganized symptoms, modestly with the positive syndrome and not with the negative syndrome. Thus, disorganized symptoms, more than any other, appear to be related to the impairment of executive function and WM in recent onset unmedicated patients with schizophrenia.

In the human brain, cortical GABAergic interneurons represent an important population of local circuit neurons responsible for the intrinsic modulation of neuronal information and have been supposed to be involved in the pathophysiology of schizophrenia. We conducted a quantitative study on the differentiated three-dimensional morphological structure of two types of parvalbumin-immunoreactive interneurons in the anterior cingulate cortex (ACC) of schizophrenic patients versus controls. While type A interneurons ('small bipolar cells') showed a significant reduction of their soma size in schizophrenics, type B interneurons ('small multipolar cells') of schizophrenic patients exhibited a marked decrease in the extent of their dendritic system. These results further support the assumption of a considerable significance of the ACC, an important limbic relay centre, for the etiopathogenesis of schizophrenic psychoses.

This study examined the relationship between nonverbal social perception and symptomatology in schizophrenia. Schizophrenic patients (n=28) and normal controls (n=28) were given the profile of nonverbal sensitivity test (PONS). Patients' symptoms were rated with the brief psychiatric rating scale (BPRS). Schizophrenic subjects performed significantly more poorly than normal subjects in their ability to decode nonverbal cues. In addition, normal subjects improved their accuracy significantly more than patients when provided with additional cues per scene to decode. The patients' total PONS score was not significantly correlated with the BPRS summary scores for positive or negative symptoms, but was significantly correlated with the individual positive symptom of conceptual disorganization. Subjects classified as having paranoid schizophrenia (n=11) on the basis of chart diagnoses performed significantly better on the PONS than did undifferentiated schizophrenic subjects (n=13). The discussion reviews how these results contribute to our understanding of social deficits in schizophrenia.

Pharmacological risk factors for neuroleptic malignant syndrome (NMS) are better defined than clinical risk factors. We examined the psychopathological status preceding the onset of NMS in 20 patients. We evaluated four key psychiatric symptoms (psychomotor agitation, catatonia, disorganization and confusion) and grouped them into definite clinical syndromes. Six patients presented with an acute and severe catatonic syndrome, with all the four key psychiatric symptoms. Twelve patients presented with an acute and severe disorganized psychotic episode, with two or three key psychiatric symptoms, but not catatonia. Our study suggests that a clinical syndrome of acute disorganization, in addition to acute catatonia, is a potential clinical risk factor for NMS. The two syndromes, which can occur in the context of different mental disorders, are related to each other as both implicate alteration in behavioural monitoring, and were, in our experience, unresponsive to neuroleptics. In conclusion, we hypothesize that the recognition of these two syndromes should reduce NMS occurrence. We recommend a judicious use of neuroleptics not only in patients with acute catatonia, but also in patients with acute disorganization.

The concept of hebephrenia has undergone more changes than almost any other diagnostic category in clinical psychiatry. In the present article we want to outline these changes from Hecker's first description of hebephrenia to contemporary concepts mainly based on Bleuler's viewpoints. Due to rather heterogeneous and vaguely defined symptomatology, hebephrenia lost relevance as a diagnostic category in today's classification systems. As an alternative approach, Kleist and Leonhard see hebephrenias as forming distinct clinical entities with insidious beginning and a chronically progressive course leading to specific and stable residual syndromes, mainly featured by disturbed affectivity and, thus, initiative. As known up to now, hebephrenias within Leonhard's classification show poor prognosis, little response to treatment and low heredity. This concept of hebephrenia seems to be more appropriate to demarcate a homogeneous subtype which can be the subject of further promising research to clarify aetiology and nosology of schizophrenic spectrum psychoses.

Our study was based on the hypothesis that a non competitive antagonist of NMDA receptors can improve clinical effects of antipsychotic therapy in a subgroup of patients with schizophrenia with clinical signs of glutamatergic hyperfunction such as catatonic symptoms and disorganization. The study design was open and non-comparative. The duration of the study for each patient was 6 months, the target dosage of acatinol was 20 mg. Forty stable patients with schizophrenia with predominance of signs of disorganization and subcatatonic symptoms were included. The following instruments were used: PANSS, NSA, CGI, BACS, UKU. Adding of acatinol to the antipsychotic treatment improved clinical symptoms, cognitive functioning and social functioning and decreased the number of side effects. The drug was well-tolerated.

The contribution of evoked potential (EP) latency jitter, a measure of CNS temporal variability, on startle and EP gating defects in schizophrenic subjects has not been characterized. The amplitude of the N100/P200 EP complex (peak to trough) derived using a time-locked averaging procedure, N100 EP latency jitter derived from single trial analysis, acoustic startle response and clinical symptoms were measured in 51 schizophrenic subjects. N100 latency jitter was inversely correlated with N100/P200 EP amplitude in both cross-sectional and longitudinal analysis. Subjects with elevated EP gating ratios (>0.5) had similar latency jitter values for initial (S1) and test (S2) stimuli, while subjects with a low gating ratio (0-0.5) had a lower level of S1 latency jitter. Temporal variability thus plays a significant and complex role in previously reported sensory gating deficits in schizophrenic subjects.

Objective The aim of this study was to compare the differential response to amisulpride in patients with paranoid versus disorganized schizophrenia. Method We reanalyzed the original data from five different randomized drug trials comparing Brief Psychiatric Rating Scale (BPRS) scores in a database containing 427 paranoid and 296 disorganized patients with schizophrenia. Results Both the disorganized and the paranoid group showed a substantial improvement of the BPRS total score within the first 4 weeks. In the paranoid group, mean (±SD) BPRS reduction was 16.9 (±14.6) (t = 24.06, df = 426, P

Background. While some cognitive accounts of disorganized speech, or thought disorder, in schizophrenia have emphasized failures in working memory/discourse planning or selective attention, we have suggested that thought disorder resides in the semantic system. In this study we assessed the effect of neuroleptic medication on thought disorder and semantic processing.Methods. Seventeen patients with schizophrenia were assessed while receiving neuroleptic medications and in crossover fashion, placebo. A number of measures were obtained: clinically rated thought disorder (using the Thought, Language and Communication Scale); working memory (letter number span); lexical integrity (naming and receptive vocabulary); and, semantic priming of intracategorical word pairs.Results. Semantic priming measures improved with neuroleptic medication, as did clinically rated thought disorder. No other measure changed significantly. Priming selectively covaried with changes in thought disorder.Conclusion. Changes in spreading semantic activation, measured in a semantic priming paradigm and presumably brought about by neuroleptics' influence on dopaminergic neuromodulatory systems, might reflect changes in the biases of pre-existing associative networks that favour or increase the accessibility of representations related by shared features. This study also has implications for the architecture of normal language in that a dissociation between the lexical and semantic levels was observed, due to the selective compromise of tasks demanding semantic processing.

Knowledge of the relationship between specific cognitive abnormalities and the clinical symptoms of schizophrenia could give insight into the nature of their underlying pathophysiology. Composite scores were generated for negative, disorganized, and psychotic symptom ratings in 134 patients with schizophrenia (DSM-IV criteria). Partial correlations (each composite corrected for the others) were computed with neuropsychological measures. Negative symptoms were related to poor performance on tests of verbal learning and memory, verbal fluency, visual memory, and visual-motor sequencing. Disorganized symptoms were correlated with lower verbal IQ and poor concept attainment. Psychotic symptoms had no significant relationship with cognitive deficit.

To determine whether patients with catatonic schizophrenia have specific alterations in brain morphology, internal (ventricles) and external (frontal, temporal, parieto-occipital) components of the cerebrospinal fluid (CSF) spaces were examined morphometrically. Planimetric measurements of computed tomographic (CT) scans from 37 patients with catatonic schizophrenia, 28 patients with hebephrenic schizophrenia, and 39 patients with paranoid schizophrenia, all diagnosed according to DSM-III-R criteria, were compared with separate age- and sex-matched non-psychiatric control groups, respectively. The areas of the frontal sulci, the parieto-occipital sulci, the inter-hemispheric fissure, and the lateral and third ventricles were measured separately for the right and left hemispheres. Catatonic patients showed significant enlargements in almost all CSF spaces, especially in the left fronto-temporal area which, in addition, correlated significantly with illness duration. Hebephrenic patients showed selective enlargements in left temporal and left/right lower frontal cortical sulci, whereas paranoid schizophrenic patients showed no enlargements but significant correlations between left temporal cortical sulcal volume and illness duration. Alterations in temporal cortical areas were present in all three sub-types of schizophrenia. In addition to temporal alterations, hebephrenic schizophrenia was characterised by lower frontal (i.e. orbitofrontal) enlargement. Catatonic schizophrenia, the most severe sub-type with regard to clinical symptomatology and brain pathology, showed fronto-parietal cortical alterations.