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Context: Smaller brain volumes have consistently been found in patients with schizophrenia, particularly in gray matter and medial temporal lobe structures. Although several studies have investigated brain volumes in nonpsychotic relatives of patients with schizophrenia, results have been inconsistent. Objective: To determine the magnitude and extent of brain volume differences in first-degree relatives of schizophrenic patients. Data Sources: A systematic search was conducted to identify relevant studies. Computer searches of the MEDLINE database were performed for English-language articles published before July 2005. Relevant abstracts published in 2005 were also selected. Study Selection: Magnetic resonance imaging studies that examined differences in brain volumes between first-degree relatives of patients with schizophrenia and healthy control subjects were obtained through computerized databases, including MEDLINE. Studies had to report sufficient data for computation of effect sizes. Data Extraction: For each study, the Cohen d was calculated. Data extraction and calculation of the effect size were performed by 2 authors ( H. B. M. B. and A. A.) who reached a consensus in cases of uncertainty and discrepancies. All analyses were performed using the random-effects model. Data Synthesis: Twenty-five studies were identified as suitable for analysis and included 1065 independent first-degree relatives of patients, 679 patients with schizophrenia, and 1100 healthy control subjects. The largest difference between relatives and healthy control subjects was found in hippocampal volume, with relatives having smaller volumes than controls (d=0.31; 95% confidence interval [CI], 0.13-0.49; 9 effect sizes). Gray matter was smaller (d=0.18; 95% CI, 0.02-0.33; 7 effect sizes) and third-ventricle volume was larger (d=0.21; 95% CI, 0.03-0.40; 7 effect sizes) in relatives compared with healthy control subjects. Conclusion: Brain abnormalities are present in nonpsychotic first-degree relatives of patients with schizophrenia and are most pronounced in the hippocampus.

Objective: The primary aim of this study was to investigate whether depressive symptoms were significantly associated with functional outcome measures in a clinically stable group of outpatients with schizophrenia. We also analyzed whether depressive and negative symptoms presented different patterns of predictors. Method: Seventy-eight consecutive outpatients meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria for schizophrenia in the stable period were enrolled in this cross-sectional study. Assessment were performed using the Calgary Depression Scale for Schizophrenia, Positive and Negative Syndromes Scale (PANSS), Clinical Global Impression Scale-severity, Social and Occupational Functioning Assessment Scale, Sheehan Disability Scale, and Quality of Life Scale. A neuropsychologic battery including the vocabulary and block design subtests of the Wechsler Adult Intelligence Scale-Revised, Wechsler Memory Scale, Wisconsin Card Sorting Test, and Continuous Performance Test was also administered to the patients. Two multiple regressions were performed testing demographic and clinical factors, rating scales, and cognitive measures as independent variables and Calgary Depression Scale for Schizophrenia and PANSS-negative subscale scores as dependent variables. Results: Four variables were predictors of depressive symptoms in our sample of schizophrenic patients: 2 outcome measures (Sheehan Disability Scale and Quality of Life Scale), gender, and Continuous Performance Test reaction time. Predictors of negative symptoms were the measures of severity of psychopathology (Clinical Global Impression Scale-severity and PANSS-general psychopathology subscale) and the cognitive tests Wechsler Adult Intelligence Scale-Revised block design and Wechsler Memory Scale. Conclusion: We found that depressive symptoms in schizophrenia are mainly a function of the level of social adjustment and quality of life, whereas negative symptoms constitute an indicator of severity of schizophrenia. The 2 symptom dimensions showed also distinct cognitive correlates.

During a first episode of psychosis, treatment with antipsychotic drugs can improve both positive and negative symptoms. If sufficient amelioration does not occur, adding psychotropic comedication may result in a favorable outcome. To establish sex differences in psychotropic comedication use, we conducted an exploratory retrospective study among first-break patients diagnosed with schizophrenia or schizophreniform disorder. Concerning patient characteristics, no difference in age or antipsychotic drug use was established. At admission, men significantly more often had comorbid substance abuse. Analysis showed that significantly more women than men received benzodiazepines after the onset of psychosis (OR 1.92, 95% CI 1.13-1.27). No sex difference was found in antidepressant comedication (OR 1.22, 95% CI 0.48-3.11). We established a definite sex difference in concomitant benzodiazepine use in first-break patients with schizophrenia. Since women have a better prognosis, we suggest farther research to evaluate the efficacy and safety of early benzodiazepine use in the course of schizophrenia. Furthermore, we recommend investigating the possible correlation between benzodiazepine use and substance abuse as a way of treating premorbid symptoms of schizophrenia. © 2005 Elsevier Ireland Ltd. All rights reserved.

Objective: The purpose of the study was to assess the independent influences of gender and cannabis use on milestones of early course in schizophrenia.Method: in this population-based, first-contact incidence study conducted in The Hague, the Netherlands, patients (N=133) were interviewed with the Comprehensive Assessment of Symptoms and History, and key informants were interviewed with the Instrument for the Retrospective Assessment of the Onset of Schizophrenia. Milestones of early course were 1) first social and/or occupational dysfunction, 2) first psychotic episode, and 3) first negative Symptoms.Results: Male patients were significantly younger than female patients at first social and/or occupational dysfunction, first psychotic episode, and first negative symptoms. Cannabis-using patients were significantly younger at these milestones than were patients who did not use cannabis. Multivariate analyses showed that cannabis use, but not gender, made an independent contribution to the prediction of age at first psychotic episode: male cannabis users were a mean of 6.9 years younger at illness onset than male nonusers in contrast, age at first social and/or occupational dysfunction and the risk of developing negative symptoms before the first contact with a physician for treatment of possible psychotic disorder were predicted by gender, but not by cannabis use.Conclusions: The results indicate a strong association between use of cannabis and earlier age at first psychotic episode in male schizophrenia patients. Additional studies examining this possibly causal relationship are needed.

Objective: The purpose of the study was to assess the independent influences of gender and cannabis use on milestones of early course in schizophrenia. Method: in this population-based, first-contact incidence study conducted in The Hague, the Netherlands, patients (N=133) were interviewed with the Comprehensive Assessment of Symptoms and History, and key informants were interviewed with the Instrument for the Retrospective Assessment of the Onset of Schizophrenia. Milestones of early course were 1) first social and/or occupational dysfunction, 2) first psychotic episode, and 3) first negative Symptoms. Results: Male patients were significantly younger than female patients at first social and/or occupational dysfunction, first psychotic episode, and first negative symptoms. Cannabis-using patients were significantly younger at these milestones than were patients who did not use cannabis. Multivariate analyses showed that cannabis use, but not gender, made an independent contribution to the prediction of age at first psychotic episode: male cannabis users were a mean of 6.9 years younger at illness onset than male nonusers in contrast, age at first social and/or occupational dysfunction and the risk of developing negative symptoms before the first contact with a physician for treatment of possible psychotic disorder were predicted by gender, but not by cannabis use. Conclusions: The results indicate a strong association between use of cannabis and earlier age at first psychotic episode in male schizophrenia patients. Additional studies examining this possibly causal relationship are needed.

The full body of research on the nature of psychosis and its determinants indicates that a considerable number of factors are relevant to the development of hallucinations, delusions, and other positive symptoms, ranging from neurodevelopmental parameters and altered connectivity of brain regions to impaired cognitive functioning and social factors. We aimed to integrate these factors in a single mathematical model based on network theory. At the microscopic level this model explains positive symptoms of psychosis in terms of experiential equivalents of robust, high-frequency attractor states of neural networks. At the mesoscopic level it explains them in relation to global brain states, and at the macroscopic level in relation to social-network structures and dynamics. Due to the scale-free nature of biological networks, all three levels are governed by the same general laws, thereby allowing for an integrated model of biological, psychological, and social phenomena involved in the mediation of positive symptoms of psychosis. This integrated network model of psychotic symptoms (INMOPS) is described together with various possibilities for application in clinical practice. (C) 2015 The Authors. Published by Elsevier Ltd.

Despite evidence that clozapine may be neuroprotective, there are few longitudinal magnetic resonance imaging (MRI) studies that have specifically explored an association between commencement of clozapine treatment for schizophrenia and changes in regional brain volume or cortical thickness. A total of 33 patients with treatment-resistant schizophrenia and 31 healthy controls matched for age and gender underwent structural MRI brain scans at baseline and 6-9 months after commencing clozapine. MRI images were analyzed using SIENA (Structural Image Evaluation, using Normalization, of Atrophy) and FreeSurfer to investigate changes over time in brain volume and cortical thickness respectively. Significantly greater reductions in volume were detected in the right and left medial prefrontal cortex and in the periventricular area in the patient group regardless of treatment response. Widespread further cortical thinning was observed in patients compared with healthy controls. The majority of patients improved symptomatically and functionally over the study period, and patients who improved were more likely to have less cortical thinning of the left medial frontal cortex and the right middle temporal cortex. These findings demonstrate on-going reductions in brain volume and progressive cortical thinning in patients with schizophrenia who are switched to clozapine treatment. It is possible that this gray matter loss reflects a progressive disease process irrespective of medication use or that it is contributed to by switching to clozapine treatment. The clinical improvement of most patients indicates that antipsychotic-related gray matter volume loss may not necessarily be harmful or reflect neurotoxicity.

Background: Gray and white matter brain changes have been found in schizophrenia but the anatomical organizing process underlying these changes remains unknown. We aimed to identify gray and white matter volumetric changes in a group of patients with schizophrenia and to quantify the distribution of white matter tract changes using a novel approach which applied three complementary analyses to diffusion imaging data. Methods: 21 patients with schizophrenia and 21 matched control subjects underwent brain magnetic resonance imaging. Gray and white matter volume differences were investigated using Voxel-based Morphometry (VBM). White matter diffusion changes were located using Tract Based Spatial Statistics (TBSS) and quantified within a standard atlas. Tracts where significant regional differences were located were examined using fiber tractography. Results: No significant differences in gray or white matter volumetry were found between the two groups. Using TBSS the schizophrenia group showed significantly lower fractional anisotropy (FA) compared to the controls in regions (false discovery rate < 0.05) including the genu, body and splenium of the corpus callosum and the left anterior limb of the internal capsule (ALIC). Using fiber tractography, FA was significantly lower in schizophrenia in the corpus callosum genu (p = 0.003). Conclusions: In schizophrenia, white matter diffusion deficits are prominent in medial frontal regions. These changes are consistent with the results of previous studies which have detected white matter changes in these areas. The pathology of schizophrenia may preferentially affect the prefrontal-thalamic white matter circuits traversing these regions.

Objective: To review evidence-based literature regarding the necessary duration of antipsychotic relapse prevention in schizophrenia and related psychoses. Method: A computerized search was performed on Medline, Embase Psychiatry and PsycLIT which covered the period 1974-99. We also used cross-references. Results: Although schizophrenia refers mainly to an intrinsic biological vulnerability, only maintenance studies with a follow-up of 2 years at most are available. Relapses appear unpredictable and occur even after long-term successful remission during antipsychotic treatment. Conclusion: Since rehabilitation efforts have effects only after long-term endeavours, antipsychotic relapse prevention should be maintained for long periods. It is reasonable to treat patients suffering from schizophrenia and related psychoses for longer periods than indicated by the current guidelines.

Background. This paper focuses on the long-term course of social disability in schizophrenia assessed at first onset, and after 1, 2 and 15 years in incidence cohorts in six European centres in Bulgaria, Germany, Ireland, The Netherlands, the Czech Republic and the United Kingdom. The study population comprises 349 patients comprising 75% of the original cohorts.Methods. Social disability was assessed in a standardized way with the WHO Disability Assessment Schedule.Results. Social disability in schizophrenia appears to be a persistent phenomenon. Its severity decreased overall in the period of follow-up, but this was not so in a small group traced to hospital or sheltered accommodation. Only 17% of subjects had no disability and 24% still suffered from severe disability. The great majority lived with their family, a partner, or alone. A deteriorating course was more frequent than late improvement. Gender, age, onset, duration of untreated psychosis or type of remission during the first 2 years did not predict the long-term outcome of disability. Severity of disability at the first three assessments of the illness contributed significantly to the explanation of its variance at 15 years.Conclusion. Disability generally ameliorates, but less than expected or hoped. It needs continuing attention and care in this era of de-institutionalization.

Diffusion MRI investigations in schizophrenia provide evidence of abnormal white matter (WM) microstructural organization as indicated by reduced fractional anisotropy (FA) primarily in interhemispheric, left frontal and temporal WM. Using tract-based spatial statistics (TBSS), we examined diffusion parameters in a sample of patients with severe chronic schizophrenia. Diffusion MRI data were acquired on 19 patients with chronic severe schizophrenia and 19 age- and gender-matched healthy controls using a 64 gradient direction sequence, (b = 1300 s/mm(2)) collected on a Siemens 1.5T MRI scanner. Diagnosis of schizophrenia was determined by Diagnostic and Statistical Manual for Mental Disorders 4th Edition (DSM-IV) Structured Clinical Interview for DSM disorder (SCID). Patients were treatment resistance, having failed to respond to at least two antipsychotic medications, and had prolonged periods of moderate to severe positive or negative symptoms. Analysis of diffusion parameters was carried out using TBSS. Individuals with chronic severe schizophrenia had significantly reduced FA with corresponding increased radial diffusivity in the genu, body, and splenium of the corpus callosum, the right posterior limb of the internal capsule, right external capsule, and the right temporal inferior longitudinal fasciculus. There were no voxels of significantly increased FA in patients compared with controls. A decrease in splenium FA was shown to be related to a longer illness duration. We detected widespread abnormal diffusivity properties in the callosal and temporal lobe WM regions in individuals with severe chronic schizophrenia who have not previously been exposed to clozapine. These deficits can be driven by a number of factors that are indistinguishable using in vivo diffusion-weighted imaging, but may be related to reduced axonal number or packing density, abnormal glial cell arrangement or function, and reduced myelin.

OBJECTIVE: Studies have linked cognitive functioning to everyday social functioning in psychotic disorders, but the nature of the relationships between cognition, social cognition, symptoms, and social functioning remains unestablished. Modelling the contributions of non-social and social cognitive ability in the prediction of social functioning may help in more clearly defining therapeutic targets to improve functioning. METHOD: In a sample of 745 patients with a non-affective psychotic disorder, the associations between cognition and social cognition at baseline on the one hand, and self-reported social functioning three years later on the other, were analysed. First, case-control comparisons were conducted; associations were subsequently further explored in patients, investigating the potential mediating role of symptoms. Analyses were repeated in a subsample of 233 patients with recent-onset psychosis. RESULTS: Information processing speed and immediate verbal memory were stronger associated with social functioning in patients than in healthy controls. Most cognition variables significantly predicted social functioning at follow-up, whereas social cognition was not associated with social functioning. Symptoms were robustly associated with follow-up social functioning, with negative symptoms fully mediating most associations between cognition and follow-up social functioning. Illness duration did not moderate the strength of the association between cognitive functioning and follow-up social functioning. No associations were found between (social) cognition and follow-up social functioning in patients with recent-onset psychosis. CONCLUSIONS: Although cognitive functioning is associated with later social functioning in psychotic disorder, its role in explaining social functioning outcome above negative symptoms appears only modest. In recent-onset psychosis, cognition may have a negligible role in predicting later social functioning. Moreover, social cognition tasks may not predict self-reported social functioning. ispartof: Plos One vol:11 issue:4 ispartof: location:United States status: published

Pharmacogenetic studies have demonstrated significant associations between several candidate genes (DRD2, DRD3, 5HTR2A and 5HTR2C, COMT and MTHFR) and antipsychotic drug response. The present study investigates the effect of nine polymorphisms in these genes for an association with antipsychotic treatment response. 329 Caucasian patients with a non-affective psychotic disorder using antipsychotics were included. All patients participated in the longitudinal GROUP-study in The Netherlands. We genotyped 9 SNPs in 6 candidate genes (DRD2: Taql_A, -141C; DRD3: Ser9Gly; HTR2A: 102-T/C, His452Tyr; HTR2C: Cys23Ser; COMT: Val158Met; MTHFR: 677-C/T) using standard protocols. Polymorphisms were based on previous studies showing associations with positive symptoms treatment response. The Clinical Global Impression Improvement (CGI-I) scale was used to assess improvement in positive psychotic symptoms since the start of current antipsychotic treatment. Ordinal regression was used for association analyses. Ninety percent of the patients used second generation antipsychotics, with olanzapine (28%) and risperidone (29%) being the most prescribed drugs. Ser9Gly of the dopamine D3 receptor gene (P value 0.034) and 677-C/T of MTHFR (P value 0.019) were tested statistically significant. Gly-carriers and T-carriers, respectively, showed more clinical improvement on the CGI-I. The other polymorphisms did not show a statistically significant association (P values>0.10). In conclusion, we replicated two out of nine of the previously reported associations between polymorphisms and treatment response. The direction and magnitude of the associations presented here in DRD3 (Ser9Gly) and MTHFR (677-C/T) are in line with previous association studies in Caucasian patients. These polymorphisms may be of value for predicting clinical response. (C) 2012 Elsevier B.V. and ECNP. All rights reserved.

Lack of insight (unawareness of illness) is a common and clinically relevant feature of schizophrenia. Reduced levels of self-referential processing have been proposed as a mechanism underlying poor insight. The default mode network (DMN) has been implicated as a key node in the circuit for self-referential processing. We hypothesized that during resting state the DMN network would show decreased connectivity in schizophrenia patients with poor insight compared to patients with good insight. Patients with schizophrenia were recruited from mental health care centers in the north of the Netherlands and categorized in groups having good insight (n = 25) or poor insight (n = 19). All subjects underwent a resting state fMRI scan. A healthy control group (n = 30) was used as a reference. Functional connectivity of the anterior and posterior part of the DMN, identified using Independent Component Analysis, was compared between groups. Patients with poor insight showed lower connectivity of the ACC within the anterior DMN component and precuneus within the posterior DMN component compared to patients with good insight. Connectivity between the anterior and posterior part of the DMN was lower in patients than controls, and qualitatively different between the good and poor insight patient groups. As predicted, subjects with poor insight in psychosis showed decreased connectivity in DMN regions implicated in self-referential processing, although this concerned only part of the network. This finding is compatible with theories implying a role of reduced self-referential processing as a mechanism contributing to poor insight.

This article reviews the treatment of hallucinations in schizophrenia. The first treatment option for hallucinations in schizophrenia is antipsychotic medication, which can induce a rapid decrease in severity. Only 8% of first-episode patients still experience mild to moderate hallucinations after continuing medication for 1 year. Olanzapine, amisulpride, ziprasidone, and quetiapine are equally effective against hallucinations, but haloperidol may be slightly inferior. If the drug of first choice provides inadequate improvement, it is probably best to switch medication after 2-4 weeks of treatment. Clozapine is the drug of choice for patients who are resistant to 2 antipsychotic agents. Blood levels should be above 350-450 mu g/ml for maximal effect. For relapse prevention, medication should be continued in the same dose. Depot medication should be considered for all patients because nonadherence is high. Cognitive-behavioral therapy (CBT) can be applied as an augmentation to antipsychotic medication. The success of CBT depends on the reduction of catastrophic appraisals, thereby reducing the concurrent anxiety and distress. CBT aims at reducing the emotional distress associated with auditory hallucinations and develops new coping strategies. Transcranial magnetic stimulation (TMS) is capable of reducing the frequency and severity of auditory hallucinations. Several meta-analyses found significantly better symptom reduction for low-frequency repetitive TMS as compared with placebo. Consequently, TMS currently has the status of a potentially useful treatment method for auditory hallucinations, but only in combination with state of the art antipsychotic treatment. Electroconvulsive therapy (ECT) is considered a last resort for treatment-resistant psychosis. Although several studies showed clinical improvement, a specific reduction in hallucination severity has never been demonstrated.

Decreased prefrontal activation (hypofrontality) in schizophrenia is thought to underlie negative symptoms and cognitive impairments, and may contribute to poor social outcome. Hypofrontality does not always improve during treatment with antipsychotics. We hypothesized that antipsychotics, which share antagonism at dopamine receptors, with a relatively low dopamine receptor affinity and high serotonin receptor affinity may have a sparing effect on prefrontal function compared to strong dopamine receptor antagonists. We systematically investigated the relation between serotonin and dopamine antagonism of antipsychotics and prefrontal functioning by reviewing neuroimaging studies. The weight of the evidence was consistent with our hypothesis that antipsychotics with low dopaminergic receptor affinity and moderate to high serotonergic affinity were associated with higher activation of the prefrontal cortex. However, clozapine, a weak dopamine and strong serotonin antagonist, was associated with decrease in prefrontal activation. Future studies should further elucidate the link between prefrontal activation and negative symptoms using prospective designs and advanced neuroimaging techniques, which may ultimately benefit the development of treatments for disabling negative symptoms. (C) 2011 Elsevier B.V. and ECNP. All rights reserved.

Objective: To investigate the multifactorial relationship between illness insight, cognitive and emotional processes, and illness characteristics in bipolar disorder patients. Methods: Data from 85 euthymic or mildly to moderately depressed bipolar disorder patients were evaluated. Insight was measured using the Mood Disorder Insight Scale (total score and subscale scores: awareness of illness, symptom attribution, and need for treatment). Cognitive and emotional functioning was measured in four domains (processing speed, memory, executive functioning, and emotional learning) in addition to premorbid IQ. Illness characteristics were assessed using the Mini-International Neuropsychiatric Interview, the Questionnaire for Bipolar Disorder, and the Inventory of Depressive Symptomatology-self rating scale. Regression analyses were performed for the whole sample. Post-hoc, interactions with lifetime psychotic features (LPF) were statistically tested and if significant, analyses were repeated for patients with (n = 36) and without (n = 49) LPF separately. Results: In the whole group, better insight was associated with lower processing speed, better memory performance, increased emotional learning, higher level of depressive symptoms, and longer duration of illness. Patients with LPF had worse awareness of illness, but better symptom attribution than patients without LPF. No group differences for need for treatment and overall insight were found. Finally, processing speed significantly predicted subscores for symptom attribution in patients with LPF only. Conclusions: Cognitive functioning as well as impairments in emotional learning and psychotic features independently contributes to impaired insight in bipolar disorder. Processing speed seems to be a key variable in the prediction of insight in patients with LPF and not in patients without LPF.

Decreased language lateralization is a well-replicated finding in psychotic patients. It is currently unclear, however, whether this abnormality is related to a particular symptom of psychosis or to psychosis in general. It has been argued that decreased language lateralization may be related to auditory verbal hallucinations. To elucidate this, these hallucinations should be studied in isolation. Thirty-five patients with a psychotic disorder, 35 non-psychotic subjects with relatively isolated auditory verbal hallucinations and 35 healthy control subjects participated in this study. All subjects were scanned on a 3T magnetic resonance imaging scanner, while covertly performing a paced verbal fluency task. In order to measure performance on the task, one additional task block was presented during which subjects had to generate words overtly. In addition to calculating language lateralization indices, group-wise brain activation during verbal fluency was compared between the three groups. Task performance was nearly maximal for all groups and did not differ significantly between the groups. Compared with the healthy control subjects and non-psychotic subjects with auditory verbal hallucinations, language lateralization was significantly reduced for the patient group. In addition, the patients displayed significantly greater activity in the right precentral gyrus and left insula when compared with the healthy control subjects and the non-psychotic subjects with auditory verbal hallucinations. Furthermore, the patients showed greater activity in the right superior parietal lobule when compared with the healthy control subjects. Lateralization indices did not differ significantly between the non-psychotic subjects with auditory verbal hallucinations and the healthy control subjects. Moreover, there were no significant differences in brain activation during verbal fluency between the two non-psychotic groups. As language lateralization was not significantly reduced in the non-psychotic individuals with auditory verbal hallucinations, a direct relationship between auditory verbal hallucinations and decreased language lateralization can not be established at present.

Cognitive functioning has been found to be a predictor of functional outcome of schizophrenia. It is unclear, however, whether clinical recovery can be predicted by scores on specific cognitive domains. The predictive value of specific neurocognitive domains and other clinical variables for symptomatic and functional outcome and clinical recovery after a 2-year follow-up is explored in a group of 51 patients with non-affective first-episode psychosis. A comprehensive neurocognitive battery was administered 18 and 41 weeks after inclusion. Other patient characteristics, which were expected to independently predict clinical recovery, were assessed at baseline. Several neurocognitive tests, especially tests measuring speed of processing, and among others, Duration of Untreated Psychosis (DUP), were significant predictors of clinical recovery. Poor neuropsychological performance accurately predicted non-recovery, but improved neuropsychological performance did not accurately predict recovery. This study confirms previous findings of an association between neurocognition and outcome, but the results also suggest that in order to accurately predict recovery, the role of other factors needs to be investigated.

Background: Several studies have reported the presence of dyskinesia and parkinsonism in antipsychotic-naive patients with schizophrenia as well as in their first-degree relatives. These movement disorders may therefore form an integral part of the illness and its (genetic) liability. Method: A systematic search was conducted in the Medline, EMBASE, and PsychINFO databases to identify studies reporting on dyskinesia and parkinsonism assessed in antipsychotic-naive patients with schizophrenia (n = 213) and controls (n = 242) and separately in nonill first-degree relatives (n = 395) and controls (n = 379). Effect sizes were pooled using random-effect models to calculate odds ratios (ORs) to compare the risk of these movement disorders among patients and healthy relatives each with matched controls. Results: Antipsychotic-naive schizophrenia was found to be strongly associated with dyskinesia (OR: 3.59, 95% confidence interval [CI]: 1.53-8.41) and parkinsonism (OR: 5.32, 95% CI: 1.75-16.23) compared with controls. Dyskinesia and parkinsonism were also significantly more prevalent in healthy first-degree relatives of patients with schizophrenia as compared with healthy controls (OR: 1.38, 95% CI: 1.06-1.81, and OR: 1.37, 95% CI: 1.05-1.79, respectively).Conclusion: The results suggest that movement disorders, and by inference abnormalities in the nigrostriatal pathway, are not only associated with schizophrenia itself but may also be related to the (genetic) risk of developing the disease.

The interhemispheric asymmetries that originate from connectivity-related structuring of the cortex are compromised in schizophrenia (SZ). Under the assumption that such abnormalities affect functional connectivity, we analyzed its correlate-EEG synchronization-in SZ patients and matched controls. We applied multivariate synchronization measures based on Laplacian EEG and tuned to various spatial scales. Compared to the controls who had rightward asymmetry at a local level (EEG power), rightward anterior and leftward posterior asymmetries at an intraregional level (1st and 2nd order S-estimator), and rightward global asymmetry (hemispheric S-estimator), SZ patients showed generally attenuated asymmetry, the effect being strongest for intraregional synchronization in the alpha and beta bands. The abnormalities of asymmetry increased with the duration of the disease and correlated with the negative symptoms. We discuss the tentative links between these findings and gross anatomical asymmetries, including the cerebral torque and gyrification pattern, in normal subjects and SZ patients.

Background The etiology of schizophrenia is thought to involve differential—likely genetically mediated—sensitivity to environmental exposures. However, examination of differential sensitivity in models of psychopathologic constructs is subject to bias because psychopathology itself may distort exposure assessment. The use of neuroimaging phenotypes, conversely, may provide unbiased evidence for differential sensitivity to environmental exposures. This study examined the impact of two environmental exposures associated with both schizophrenia and magnetic resonance imaging (MRI) cerebral alterations in models of cerebral cortical thickness. Methods T1-weighted MRI scans were acquired from 88 patients with schizophrenia, 98 healthy siblings at higher than average genetic risk for schizophrenia, and 87 control subjects. Freesurfer software was used to measure cortical thickness for 68 brain regions. Associations between 1) cortical thickness and 2) cannabis use and developmental trauma were examined. Results A significant group × developmental trauma interaction (χ 2 = 9.65, p = .01), as well as a significant group × cannabis interaction (χ 2 = 6.04, p = .05) was apparent, indicating differential sensitivity of the patient group, which displayed stronger reductions of cortical thickness for both exposures. A similar pattern was found in the sibling–control comparison for cannabis. For developmental trauma, siblings did not differ from control subjects, displaying an increase in cortical thickness with higher levels of trauma. Conclusions The findings suggest that schizophrenia and its genetic liability are associated with differential cerebral cortical sensitivity to developmental environmental exposures such as cannabis. Gene–environment interactions may underlie some of the brain alterations observed in patients with schizophrenia and their relatives.

Toxoplasma gondii is a common intracellular protozoan infection of humans worldwide. Severe disease can occur in immunocompromised individuals and the in the fetuses of nonimmune pregnant women. Chronic infection is associated with vision and hearing problems, and functional mental alterations, including schizophrenia. The mood-stabilizing agent valproic acid has been shown to inhibit the development of T. gondii in vitro at dosages that are normally achieved in the serum and cerebral spinal fluid of human patients and to have positive effects on the behavior of rats chronically infected with T. gondii. The present study was done to examine the in vivo activity of valproic acid against acute toxoplasmosis in mice. Two studies were done with valproic acid given in the drinking water at concentrations of 1.5 mg/ml (Experiment 1) or 3.0 mg/ml (Experiment 2). In a third experiment (Experiment 3), valproic acid was injected intraperitoneally (i.p.) at doses of 200 or 300 mg/kg every 12 hr. Valproic acid was not effective in preventing acute toxoplasmosis. All mice treated with valproic acid died or were killed and did not (P > 0.05) live significantly longer than the controls. Tachyzoites were demonstrated in the tissues of infected valproic-acid-treated mice. A fourth study was done to determine if valproic acid has activity against T. gondii tissue cysts in chronically infected mice. Mice were chronically infected with the ME-49 strain of T. gondii for 8 wk and then treated orally with valproic acid at approximately 6.6 mg/ml (800 mg/kg/day) in the drinking water for 10 wk (amount was varied due to increasing mouse weights). No significant differences (P > 0.05) were present in tissue cyst numbers in valproic-acid-treated T. gondii chronically infected mice and in mice chronically infected with T. gondii but not given valproic acid. Our results indicate that valproic acid, although effective in vitro against T. gondii tachyzoites, is not effective as a preventative in mice inoculated with T. gondii tachyzoites. Additionally, no activity against tissue cysts was observed in chronically T. gondii-infected valproic-acid-treated mice.

Context Smaller brain volumes have consistently been found in patients with schizophrenia, particularly in gray matter and medial temporal lobe structures. Although several studies have investigated brain volumes in nonpsychotic relatives of patients with schizophrenia, results have been inconsistent. Objective To determine the magnitude and extent of brain volume differences in first-degree relatives of schizophrenic patients. Data Sources A systematic search was conducted to identify relevant studies. Computer searches of the MEDLINE database were performed for English-language articles published before July 2005. Relevant abstracts published in 2005 were also selected. Study Selection Magnetic resonance imaging studies that examined differences in brain volumes between first-degree relatives of patients with schizophrenia and healthy control subjects were obtained through computerized databases, including MEDLINE. Studies had to report sufficient data for computation of effect sizes. Data Extraction For each study, the Cohen d was calculated. Data extraction and calculation of the effect size were performed by 2 authors (H.B.M.B. and A.A.) who reached a consensus in cases of uncertainty and discrepancies. All analyses were performed using the random-effects model. Data Synthesis Twenty-five studies were identified as suitable for analysis and included 1065 independent first-degree relatives of patients, 679 patients with schizophrenia, and 1100 healthy control subjects. The largest difference between relatives and healthy control subjects was found in hippocampal volume, with relatives having smaller volumes than controls (d = 0.31; 95% confidence interval [CI], 0.13-0.49; 9 effect sizes). Gray matter was smaller (d = 0.18; 95% CI, 0.02-0.33; 7 effect sizes) and third-ventricle volume was larger (d = 0.21; 95% CI, 0.03-0.40; 7 effect sizes) in relatives compared with healthy control subjects. Conclusion Brain abnormalities are present in nonpsychotic first-degree relatives of patients with schizophrenia and are most pronounced in the hippocampus.

ObjectiveTreatment in the ultra-high risk stage for a psychotic episode is critical to the course of symptoms. Markers for the development of psychosis have been studied, to optimize the detection of people at risk of psychosis. One possible marker for the transition to psychosis is social cognition. To estimate effect sizes for social cognition based on a quantitative integration of the published evidence, we conducted a meta-analysis of social cognitive performance in people at ultra high risk (UHR).MethodsA literature search (1970-July 2015) was performed in PubMed, PsychINFO, Medline, Embase, and ISI Web of Science, using the search terms 'social cognition', 'theory of mind', 'emotion recognition', 'attributional style', 'social knowledge', 'social perception', 'empathy', 'at risk mental state', 'clinical high risk', 'psychosis prodrome', and 'ultra high risk'. The pooled effect size (Cohen's D) and the effect sizes for each domain of social cognition were calculated. A random effects model with 95% confidence intervals was used.ResultsSeventeen studies were included in the analysis. The overall significant effect was of medium magnitude (d = 0.52, 95% CI = 0.38-0.65). No moderator effects were found for age, gender and sample size. Sub-analyses demonstrated that individuals in the UHR phase show significant moderate deficits in affect recognition and affect discrimination in faces as well as in voices and in verbal Theory of Mind (TOM). Due to an insufficient amount of studies, we did not calculate an effect size for attributional bias and social perception/knowledge. A majority of studies did not find a correlation between social cognition deficits and transition to psychosis, which may suggest that social cognition in general is not a useful marker for the development of psychosis. However some studies suggest the possible predictive value of verbal TOM and the recognition of specific emotions in faces for the transition into psychosis. More research is needed on these subjects.ConclusionThe published literature indicates consistent general impairments in social cognition in people in the UHR phase, but only very specific impairments seem to predict transition to psychosis.

Although schizophrenia is characterized by impairments in intelligence and the loss of brain volume, the relationship between changes in IQ and brain measures is not clear.To investigate the association between IQ and brain measures in patients with schizophrenia across time.Case-control longitudinal study at the Department of Psychiatry at the University Medical Center Utrecht, Utrecht, the Netherlands, comparing patients with schizophrenia and healthy control participants between September 22, 2004, and April 17, 2008. Magnetic resonance imaging of the brain and IQ scores were obtained at baseline and the 3-year follow-up. Participants included 84 patients with schizophrenia (mean illness duration, 4.35 years) and 116 age-matched healthy control participants.Associations between changes in IQ and the total brain, cerebral gray matter, cerebral white matter, lateral ventricular, third ventricles, cortical, and subcortical volumes; cortical thickness; and cortical surface area.Cerebral gray matter volume (P = .006) and cortical volume (P = .03) and thickness (P = .02) decreased more in patients with schizophrenia across time compared with control participants. Patients showed additional loss in cortical volume and thickness of the right supramarginal, posterior superior temporal, left supramarginal, left postcentral, and occipital regions (P values were between.001 and .03 after clusterwise correction). Although IQ increased similarly in patients with schizophrenia and control participants, changes in IQ were negatively correlated with changes in lateral ventricular volume (P = .05) and positively correlated with changes in cortical volume (P = .007) and thickness (P = .004) only in patients with schizophrenia. Positive correlations between changes in IQ and cortical volume and thickness were found globally and in widespread regions across frontal, temporal, and parietal cortices (P values were between.001 and .03 after clusterwise correction). These findings were independent of symptom severity at follow-up, cannabis use, and the use of cumulative antipsychotic medications during the 3 years of follow-up.Progressive brain tissue loss in schizophrenia is related to relative cognitive decline during the early course of illness.

Background A number of studies investigated the relationships of age at onset with clinical presentation and cognitive performance of schizophrenic patients. The aim of the present study was to assess demographic and clinical characteristics; psychopathologic, social functioning, and quality-of-life ratings; and neuropsychological measures in a sample of patients with stabilized schizophrenia and to identify which factors independently contributed to a multiple regression model with age at onset as the dependent variable. Method Ninety-six consecutive outpatients with schizophrenia (DSM-IV-TR criteria) were included in the study. Assessment instruments were as follows: a semistructured interview, the Clinical Global Impressions scale, the Comprehensive Psychopathological Rating Scale, and the Positive and Negative Syndrome Scale (PANSS) for psycho-pathology of schizophrenia; the Calgary Depression Scale for Schizophrenia (CDSS) for depression; the Social and Occupational Functioning Assessment Scale and the Sheehan Disability Scale for social functioning; the Quality of Life Scale; and a neuro-psychological battery including the Wisconsin Card Sorting Test (WCST) and the Continuous Performance Test. Two models of multiple regression were tested: the first included clinical features and psychopathologic, social functioning, and quality-of-life scales; the second also considered neuro-psychological variables. Data were collected from October 2001 to November 2002. Results The first multiple regression showed that age at onset was significantly related to scores on the PANSS subscale for negative symptoms (p =.042) and the CDSS (p =.041); the second regression found a relation of age at onset with PANSS score for negative symptoms (p =.002) and 2 neuropsychological measures, number of preservative errors on the WCST and Continuous Performance Test reaction time (p =.0005 for both). Conclusion Our data indicate that, when results of neuropsychological tests are considered, early age at onset of schizophrenia is associated with severity of negative symptoms and compromised cognitive measures of executive functioning and sustained attention.

Background. This paper focuses on the long-term course of social disability in schizophrenia assessed at first onset, and after 1, 2 and 15 years in incidence cohorts in six European centres in Bulgaria, Germany, Ireland, The Netherlands, the Czech Republic and the United Kingdom. The study population comprises 349 patients comprising 75% of the original cohorts.Methods. Social disability was assessed in a standardized way with the WHO Disability Assessment Schedule.Results. Social disability in schizophrenia appears to be a persistent phenomenon. Its severity decreased overall in the period of follow-up, but this was not so in a small group traced to hospital or sheltered accommodation. Only 17% of subjects had no disability and 24% still suffered from severe disability. The great majority lived with their family, a partner, or alone. A deteriorating course was more frequent than late improvement. Gender, age, onset, duration of untreated psychosis or type of remission during the first 2 years did not predict the long-term outcome of disability. Severity of disability at the first three assessments of the illness contributed significantly to the explanation of its variance at 15 years.Conclusion. Disability generally ameliorates, but less than expected or hoped. It needs continuing attention and care in this era of de-institutionalization.