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The cellular pathology of schizophrenia and the potential of antipsychotics to target underlying neuronal dysfunctions are still largely unknown. We employed glutamatergic neurons derived from induced pluripotent stem cells (iPSC) obtained from schizophrenia patients with known histories of response to clozapine and healthy controls to decipher the mechanisms of action of clozapine, spanning from molecular (transcriptomic profiling) and cellular (electrophysiology) levels to observed clinical effects in living patients. Glutamatergic neurons derived from schizophrenia patients exhibited deficits in intrinsic electrophysiological properties, synaptic function and network activity. Deficits in K+ and Na+ currents, network behavior, and glutamatergic synaptic signaling were restored by clozapine treatment, but only in neurons from clozapine-responsive patients. Moreover, neurons from clozapine-responsive patients exhibited a reciprocal dysregulation of gene expression, particularly related to glutamatergic and downstream signaling, which was reversed by c lozapine treatment. Only neurons from clozapine responders showed return to normal function and transcriptomic profile. Our results underscore the importance of K+ and Na+ channels and glutamatergic synaptic signaling in the pathogenesis of schizophrenia and demonstrate that clozapine might act by normalizing perturbances in this signaling pathway. To our knowledge this is the first study to demonstrate that schizophrenia iPSC-derived neurons exhibit a response phenotype correlated with clinical response to an antipsychotic. This opens a new avenue in the search for an effective treatment agent tailored to the needs of individual patients. [ABSTRACT FROM AUTHOR]

Objectives: Schizophrenia is accompanied by impaired cortical inhibition, as measured by several markers including the cortical silent period (CSP). It is thought that CSP measures gamma-aminobutyric acid receptors B (GABAB) mediated inhibitory activity. But the mutual roles of schizophrenia as a disease and the drugs used for the treatment of psychosis on GABA mediated neurotransmission are not clear.Methods: We recruited 13 drug-naive patients with first-episode schizophrenia. We used transcranial magnetic stimulation to assess CSP prior to initiating risperidone monotherapy and again four weeks later. At the same time, we rated the severity of psychopathology using the Positive and Negative Syndrome Scale (PANSS).Results: We obtained data from 12 patients who showed a significant increase in CSP, from 134.20±41.81 ms to 162.95±61.98 ms ( p=0.041; Cohen's d=0.544). After the treatment, the PANSS total score was significantly lower, as were the individual subscores ( p<0.05). However, no correlation was found between ΔCSP and ΔPANSS.Conclusion: Our study in patients with first-episode schizophrenia demonstrated an association between risperidone monotherapy and an increase in GABAB mediated inhibitory neurotransmission. [ABSTRACT FROM AUTHOR]

Abstract: Schizophrenia is a disabling psychiatric disorder that usually begins to affect individuals during their adolescence or early adulthood and most patients continue to suffer social, economic, and psychological difficulties from the very onset of the disorder. The neurobiology of the disorder comprises of changes in the brain that can be detected using MR imaging. Focus on the morphological changes in patients with first episode schizophrenia limits the confounding effect of factors such as long-term medication or progression. Therefore, the detected abnormalities are more likely to indicate the primary pathology and the existence of such changes provides the opportunity of applying them for subject recognition based on brain imaging. This paper presents a combination of methods pertaining to automated whole-brain morphometry of MR images and the methods of supervised learning. The designed recognition procedure is successfully used here for classification of 104 subjects into groups of patients and healthy volunteers with the use of k-NN and SVM classifiers. The same algorithm is further used for distinguishing between patients who responded well to treatment and those who did not show adequate symptomatic relief. [Copyright &y& Elsevier]

Deficits in the execution of a sequence of movements are common in schizophrenia. Previous studies reported reduced functional activity in the motor cortex and cerebellum in schizophrenic patients with deficits in movement sequencing. The corticospinal tract (CST) and superior cerebellar peduncle (SCP) are fiber tracts that are involved in movement sequencing. However, the integrity of these tracts has not been evaluated in schizophrenic patients with respect to the performance of movement sequencing yet. Diffusion tensor magnetic resonance images (DT-MRI) were acquired from 24 patients with schizophrenia and 23 matched control subjects. Tractography was applied to reconstruct the CST and SCP and DT-MRI-specific parameters such as fractional anisotropy (FA) and radial diffusivity (RD) were reported. The patient group was further subdivided based on the score of sequencing of complex motor acts subscale of the Neurological Evaluation Scale into those with deficits in sequencing motor acts, the SQ group ( n = 7), and those with normal performance, the SQ group ( n = 17). Schizophrenia patients of the SQ subgroup had significantly reduced FA and increased RD values in the right CST in comparison to the control group; the SQ subgroup did not differ from the controls. However, the SQ subgroup showed impaired integrity of the left SCP, whereas the SQ subgroup did not. Abnormalities in the right CST in the SQ and in the left SCP in SQ groups suggest that the patients with SQ represent subgroups with distinct deficits. Moreover, these results demonstrate the involvement of the SCP in the pathogenesis of movement sequencing in schizophrenia. [ABSTRACT FROM AUTHOR]

Abstract: Recent techniques of image analysis brought the possibility to recognize subjects based on discriminative image features. We performed a magnetic resonance imaging (MRI)-based classification study to assess its usefulness for outcome prediction of first-episode schizophrenia patients (FES). We included 39 FES patients and 39 healthy controls (HC) and performed the maximum-uncertainty linear discrimination analysis (MLDA) of MRI brain intensity images. The classification accuracy index (CA) was correlated with the Positive and Negative Syndrome Scale (PANSS) and the Global Assessment of Functioning scale (GAF) at 1-year follow-up. The rate of correct classifications of patients with poor and good outcomes was analyzed using chi-square tests. MLDA classification was significantly better than classification by chance. Leave-one-out accuracy was 72%. CA correlated significantly with PANSS and GAF scores at the 1-year follow-up. Moreover, significantly more patients with poor outcome than those with good outcome were classified correctly. MLDA of brain MR intensity features is, therefore, able to correctly classify a significant number of FES patients, and the discriminative features are clinically relevant for clinical presentation 1 year after the first episode of schizophrenia. The accuracy of the current approach is, however, insufficient to be used in clinical practice immediately. Several methodological issues need to be addressed to increase the usefulness of this classification approach. [Copyright &y& Elsevier]

Abstract: Schizophrenia is a condition with a highly variable course that is hard to predict. The aim of the present study was to investigate if local gray matter volume (GMV) can differentiate poor (PF) and good (GF) functioning patients using voxel-wise analysis in a group of first-episode schizophrenia subjects (FES). Method: 32 FES male patients were assessed twice: at the time of the first episode of schizophrenia and one year later. 18 healthy controls matched for age, gender, and handedness were also included. Local gray matter volume was analyzed using voxel-wise full-factorial design with factors group (GF, PF) and time. Results: FES subjects had bilateral gray matter reduction in the lateral prefrontal cortex as compared with healthy controls. PF subjects had smaller GMV in the left orbitofrontal and frontopolar cortex. Conclusion: GMV in the left prefrontal cortex differentiates later poor and good functioning schizophrenia patients. Morphological analysis might be considered a candidate for a biological marker in outcome prediction. However, the small sample size, and the lack of female subjects limit generalization of results. Moreover, studies analyzing the predictive value of brain morphology on a single-subject level should be performed to assess its real usefulness in outcome prediction. [Copyright &y& Elsevier]

We investigated a combination of three classification algorithms, namely the modified maximum uncertainty linear discriminant analysis (mMLDA), the centroid method, and the average linkage, with three types of features extracted from three-dimensional T1-weighted magnetic resonance (MR) brain images, specifically MR intensities, grey matter densities, and local deformations for distinguishing 49 first episode schizophrenia male patients from 49 healthy male subjects. The feature sets were reduced using intersubject principal component analysis before classification. By combining the classifiers, we were able to obtain slightly improved results when compared with single classifiers. The best classification performance (81.6% accuracy, 75.5% sensitivity, and 87.8% specificity) was significantly better than classification by chance. We also showed that classifiers based on features calculated using more computation-intensive image preprocessing perform better; mMLDA with classification boundary calculated as weighted mean discriminative scores of the groups had improved sensitivity but similar accuracy compared to the original MLDA; reducing a number of eigenvectors during data reduction did not always lead to higher classification accuracy, since noise as well as the signal important for classification were removed. Our findings provide important information for schizophrenia research and may improve accuracy of computer-aided diagnostics of neuropsychiatric diseases. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: To examine the relationship between the severity of neurological soft signs at onset and at the 1-year follow-up of patients with schizophrenia, and to investigate temporal stability of neurological soft signs within 1year from the onset of the first episode schizophrenia. Methods: The study included 92 first-episode male schizophrenic patients. Neurological soft signs were assessed on the Neurological Evaluation Scale (NES) during index hospitalization and at a 1-year follow-up. The patients were divided into remitters and non-remitters according to their psychiatric status assessed at the 1-year follow-up, using the Positive and Negative Syndrome Scale (PANSS). Results: A trend for a lower score for the NES item “others” in late remitters versus non-remitters at baseline was found during index hospitalization. At the 1-year follow-up, the overall severity of the neurological soft signs was statistically significantly higher in non-remitters than in remitters. Within 1year after index hospitalization, a significant reduction of neurological soft signs, with the exception of sensory integration, occurred in remitters. Within 1year after index hospitalization, the non-remitters reported a significant reduction of the overall NES score. Conclusion: These findings in a population of patients with first episode schizophrenia are in accord with the findings of previous studies which found an association between neurological soft signs, treatment response and outcome. This association may characterize a subgroup of patients with a poor course of illness and outcome. Neurological soft signs might be regarded as one of the indicators of treatment outcome in patients suffering from their first episode of schizophrenia. [Copyright &y& Elsevier]

Abstract: Objective : (a) To investigate the correlation between clinical symptoms and neurological soft signs in patients suffering from their first episode of schizophrenia and (b) to examine the relationship between soft signs and the reactivity of first episode treatment. Methods: The trial included 92 male patients undergoing a first episode of schizophrenia. The clinical symptoms of the patients were rated on the positive and negative syndrome scale (PANSS). The PANSS scale was used to provide a measure for three syndromes: psychomotor poverty, disorganisation, and reality distortion. Neurological soft signs were assessed with the help of the neurological evaluation scale. Results: The findings corroborated significant positive correlations between soft neurological signs on the one hand and negative symptoms and reduced treatment response on the other. Conclusion: Our study of the population of patients with first episode schizophrenia has corroborated the findings of those trials that found a correlation between neurological soft signs and the negative symptomatic dimension of schizophrenia. Another finding of the trial is that neurological soft signs were associated with poorer response to treatment of the first episode of schizophrenia. [Copyright &y& Elsevier]

Abstract: Introduction: High-frequency repetitive transcranial magnetic stimulation (rTMS) over the left dorsolateral prefrontal cortex (DLPFC) seemed to decrease tobacco consumption and craving in nicotine-dependent people without psychiatric disorder or otherwise healthy people. Even if the prevalence of cigarette smoking in schizophrenia patients is high and estimated to be between 45% and 88%, this technique has not been systematically studied in this indication in schizophrenia yet. The aim of the study: The aim of this study was to test the ability of high-frequency (10Hz) rTMS over the left DLPFC to decrease cigarette consumption in schizophrenia patients. Methods: The study included 35 male schizophrenia patients on stable antipsychotic medication. The patients were divided into two groups: the first (18 patients) were actively stimulated and the second (17 patients) underwent sham (placebo) stimulation. The sham rTMS was administered using a purpose-built sham coil that was identical in appearance to the real coil and made the same noise but did not deliver a substantial stimulus. The rTMS was administered at the stimulation parameters: location (left dorsolateral prefrontal cortex: DLPFC), intensity of magnetic stimulation in % of motor threshold (110%), stimulation frequency (10Hz), number of trains (20), single train duration (10s), inter-train interval (30s), and total number of stimulation sessions (21). In each stimulation session, 2000TMSpulses were given, with a total of 42,000pulses per treatment course. Patients noted the number of cigarettes smoked in the 7days before treatment, during the whole stimulation treatment (21days), and again for a 7-day period after treatment. Results: Cigarette consumption was statistically significantly lower in the actively stimulated patients than in the sham rTMS group as early as the first week of stimulation. No statistically relevant correlations were found in the changes of ongoing negative or depressive schizophrenia symptoms and the number of cigarettes smoked. Conclusion: High-frequency rTMS over the left DLPFC has the ability to decrease the number of cigarettes smoked in schizophrenia patients. [Copyright &y& Elsevier]

Abstract: The aim of the study was to assess the dynamics of neurological soft signs (NSS) over four years from the clinical onset of schizophrenia, depending on the clinical course of the disease, and to evaluate the relationship of NSS to symptomatic dimensions in patients with first-episode schizophrenia. Sixty-eight patients with first-episode schizophrenia were included in the trial. The clinical status was assessed using Positive and Negative Syndrome Scale (PANSS) at the same time as the neurological examination, at admission to the hospital for first-episode schizophrenia and at a check-up examination four years later. The assessment of NSS using the Neurological Evaluation Scale (NES) coincided with the assessment of the clinical condition of the patients. According to the Andreasen remission criterion of schizophrenia, after four years we found that 57% of patients'' were remitters and 43% were non-remitters. During the monitoring period, in remitters total NES score and sensory integration/sequencing of motor acts items of the NES decreased. In non-remitters, increase in the total NES score and the ‘others’ item of the NES was observed. A connection between the dynamics of NSS and the clinical course of schizophrenia, over the period of four years, and a relationship between NSS and negative schizophrenia symptoms was found. [Copyright &y& Elsevier]