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Objective: To explore the effect of group psychological crisis intervention on the defense mechanism and anxiety of the first-degree relatives of patients with the first-episode schizophrenia Methods: Totally 245 first-degree relatives of patients with first episode schizophrenia who met the diagnostic criteria of ICD-10 were enrolled and randomly divided into the intervention group ( 127 cases) and the non-intervention group ( 118 cases) . The informed consent for all participants were obtained. The intervention group received group psychological crisis intervention for 4 weeks. The Defense Style Questionnaire (DSQ) and Hamilton Anxiety Scale (RAMA) were used to evaluate the type and the degree of defense mechanism as well as anxiety level in the two groups before and after the intervention, respectively. Results: There was no significant difference in both DSQ and HAMA scores within the two groups at baseline (Ps > 0.05) . After 4 weeks, the scores of mature defense mechanism in DSQ in the intervention group increased [ ( 38. 0 ± 15.7) vs. ( 32.3 ± 11.9)], and both immature defense mechanism scores [ (94.5 ± 24.0) vs. ( 108.4 ± 32.5)] and intermediate defense mechanism scores [ ( 160.4 ± 48.8) vs. ( 177.5 ± 55.4) ] decreased compared with the baseline ( Ps < 0.05). The DSQ scores of the non-intervention group showed no significant difference between The scores of each defense mechanism and 1hose in the baseline ( Ps > 0. 05) . RAMA score difference [ ( 6.1 ± L 3) vs. ( 4.0 ± 0.9)] and response rate( 66. 1 % vs. 45. 8 % ) were both higher in intervention group than in non-intervention group ( P < 0. 001). Conclusion: It suggests that group psychological crisis intervention could improve the defense mechanism of the first -degree relatives of patients with first episode schizophrenia, through increasing the application of mature defense mechanism, and significantly improve anxiety. [ABSTRACT FROM AUTHOR]

Introduction: Electrophysiological (EEG) abnormalities in subjects with schizophrenia have been largely reported. In the last decades, research has shifted to the identification of electrophysiological alterations in the prodromal and early phases of the disorder, focusing on the prediction of clinical and functional outcome. The identification of neuronal aberrations in subjects with a first episode of psychosis (FEP) and in those at ultra high-risk (UHR) or clinical high-risk (CHR) to develop a psychosis is crucial to implement adequate interventions, reduce the rate of transition to psychosis, as well as the risk of irreversible functioning impairment. The aim of the review is to provide an up-to-date synthesis of the electrophysiological findings in the at-risk mental state and early stages of schizophrenia. Methods: A systematic review of English articles using Pubmed, Scopus, and PsychINFO was undertaken in July 2020. Additional studies were identified by hand-search. Electrophysiological studies that included at least one group of FEP or subjects at risk to develop psychosis, compared to healthy controls (HCs), were considered. The heterogeneity of the studies prevented a quantitative synthesis. Results: Out of 319 records screened, 133 studies were included in a final qualitative synthesis. Included studies were mainly carried out using frequency analysis, microstates and event-related potentials. The most common findings included an increase in delta and gamma power, an impairment in sensory gating assessed through P50 and N100 and a reduction of Mismatch Negativity and P300 amplitude in at-risk mental state and early stages of schizophrenia. Progressive changes in some of these electrophysiological measures were associated with transition to psychosis and disease course. Heterogeneous data have been reported for indices evaluating synchrony, connectivity, and evoked-responses in different frequency bands. Conclusions: Multiple EEG-indices were altered during at-risk mental state and early stages of schizophrenia, supporting the hypothesis that cerebral network dysfunctions appear already before the onset of the disorder. Some of these alterations demonstrated association with transition to psychosis or poor functional outcome. However, heterogeneity in subjects' inclusion criteria, clinical measures and electrophysiological methods prevents drawing solid conclusions. Large prospective studies are needed to consolidate findings concerning electrophysiological markers of clinical and functional outcome. [ABSTRACT FROM AUTHOR]

Negative symptoms (NS) represent a detrimental symptomatic domain in schizophrenia affecting social and occupational outcomes. We aimed to identify factors from the baseline visit (V1) — with a mean illness duration of 0.47 years (SD = 0.45) — that predict the magnitude of NS at the follow-up visit (V3), occurring 4.4 years later (mean +/− 0.45). Using longitudinal data from 77 first-episode schizophrenia spectrum patients, we analysed eight predictors of NS severity at V3: (1) the age at disease onset, (2) age at V1, (3) sex, (4) diagnosis, (5) NS severity at V1, (6) the dose of antipsychotic medication at V3, (7) hospitalisation days before V1 and; (8) the duration of untreated psychosis /DUP/). Secondly, using a multiple linear regression model, we studied the longitudinal relationship between such identified predictors and NS severity at V3 using a multiple linear regression model. DUP (Pearson's r = 0.37, p = 0.001) and NS severity at V1 (Pearson's r = 0.49, p < 0.001) survived correction for multiple comparisons. The logarithmic-like relationship between DUP and NS was responsible for the initial stunning incremental contribution of DUP to the severity of NS. For DUP < 6 months, with the sharpest DUP/NS correlation, prolonging DUP by five days resulted in a measurable one-point increase in the 6-item negative symptoms PANSS domain assessed 4.9 (+/− 0.6) years after the illness onset. Prolongation of DUP to 14.7 days doubled this NS gain, whereas 39 days longer DUP tripled NS increase. The results suggest the petrification of NS during the early stages of the schizophrenia spectrum and a crucial dependence of this symptom domain on DUP. These findings are clinically significant and highlight the need for primary preventive actions. • Study focuses on link between DUP and negative symptoms ∼5 years after schizophrenia onset. • Findings reveal a logarithmic DUP-negative symptom link, with extended DUP heightening symptoms after five years. • Early treatment's critical role is highlighted; small treatment delays worsen future symptoms. [ABSTRACT FROM AUTHOR]

It is clear that people with schizophrenia typically have cognitive problems in multiple domains as part of their illness. The cognitive deficits are among the main contributors to limitations in their everyday functioning, including their work recovery. Cognitive remediation has been applied successfully to help people with long-term, persistent schizophrenia to improve their cognitive functioning, but it is only beginning to be applied with individuals who have recently had a first episode of psychosis. Several different approaches to cognitive training have been developed. Some approaches emphasize extensive systematic practice with lower-level cognitive processes and building toward higher-level processes ("bottom-up"), while others emphasize greater focus on high-level cognitive processes that normally integrate and organize lower-level processes ("top-down"). Each approach has advantages and disadvantages for a disorder like schizophrenia, with its multiple levels of cognitive dysfunction. In addition, approaches to cognitive remediation differ in the extent to which they systematically facilitate transfer of learning to everyday functioning. We describe in this article the cognitive training approach that was developed for a UCLA study of people with a recent first episode of schizophrenia, a group that may benefit greatly from early intervention that focuses on cognition and recovery of work functioning. This approach integrated bottom-up and top-down computerized cognitive training and incorporated an additional weekly group session to bridge between computerized training and application to everyday work and school functioning.

Beata Galińska-Skok,1 Agata Szulc,2 Aleksandra Małus,1 Beata Konarzewska,1 Urszula Cwalina,3 Eugeniusz Tarasów,4 Napoleon Waszkiewicz1 1Department of Psychiatry, Medical University of Białystok, Choroszcz, Poland; 2Department of Psychiatry, Faculty of Health Sciences, Medical University of Warsaw, Pruszków, Poland; 3Department of Statistics and Medical Informatics, Medical University of Białystok, Białystok, Poland; 4Department of Radiology, Medical University of Białystok, Białystok, Poland Purpose: Investigation of the longitudinal effect of schizophrenia on changes in various brain-metabolite levels and their relationships with cognitive deficits that have not been fully explained yet.Methods: Five years subsequent to their first examination for their first episode of schizophrenia, eleven patients from an original group of 30 were reexamined. Their cognitive functions were assessed with the Wisconsin Card Sorting Test. Magnetic resonance imaging and proton magnetic resonance spectroscopy were performed on a 1.5 T scanner. Voxels of 8 cm3 were positioned in the left frontal lobe, left temporal lobe, and the left thalamus. The study had a naturalistic design, and patients were treated with various antipsychotics.Results: No significant statistical differences between the baseline and follow-up in N-acetylaspartate (NAA:creatine plus phosphocreatine [Cr] and NAA/H2O) levels were observed in any region of interest. We found a significant statistical correlation between 5-year difference in frontal NAA/Cr levels and duration of the last antipsychotic treatment in this period (R=0.908, P=0.012). We found a trend (P=0.068) toward lower choline-containing compounds (Cho/Cr ratio) in the temporal lobe over 5 years and a trend (P=0.079) in higher glutamate–glutamine–GABA (Glx/H2O) levels in the left thalamus. The patients showed social and clinical improvement at follow-up examination, and there were no changes in Wisconsin Card Sorting Test results.Conclusion: The observed tendency toward decline in choline ratio might have been due to decreased temporal cell density or impaired neuron-membrane or myelin functions. A tendency for higher Glx levels suggest the involvement of thalamus dysfunction in the chronic schizophrenia process. The lack of NAA decrease might have been due to effective antipsychotic treatment. Further longitudinal studies on large patient groups are required to confirm these metabolic changes in schizophrenia. Keywords: first-episode schizophrenia, proton magnetic resonance spectroscopy, longitudinal study, cognitive functioning, N-acetylaspartate, choline

Shenglin She,1,* Bei Zhang,1,* Lin Mi,1 Haijing Li,1 Qijie Kuang,1 Taiyong Bi,2 Yingjun Zheng1 1Department of Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), National Clinical Research Center on Mental Disorders (Changsha), Guangzhou 510370, China; 2School of Management, Zunyi Medical University, Guizhou 563000, China *These authors contributed equally to this work Purpose: Working memory (WM) deficits have been observed in people with schizophrenia (SZ) and are considered a core cognitive dysfunction in these patients. However, little is known about how stimuli and memory load influence visual WM deficits. Patients and methods: In the present study, we adopted a match-to-sample task to examine the visual WM in 18 first-episode patients with SZ and 18 healthy controls (HCs). Faces and houses were used as the stimuli, and there were two levels of memory load – one item and two items; the average accuracy (ACC) and reaction time were calculated for each condition. The Positive and Negative Syndrome Scale and the Personal and Social Performance scale were used to assess the psychiatric symptoms and social function, respectively. Results: The results showed equivalent levels of WM deficit when using face and house stimuli. Moreover, the WM deficits were not related to the duration of illness, medication, or SZ symptoms. Conclusion: These results demonstrate that stimuli may have little impact on ACC in WM tasks in people with SZ. In addition, the memory load may have little impact on WM ACC when the load is relatively low. Keywords: visual working memory, first-episode schizophrenia, face perception, match-to-sample, memory load, working memory deficit

Persistent negative symptoms are associated with worse outcome in both first-episode and chronic subjects with schizophrenia. The identification of these symptoms in recent-onset subjects is still controversial as retrospective data are often unavailable. The prospective assessment of persistence of negative symptoms might represent a valid alternative but the length of the persistence is still to be established. The present study investigated the prevalence of negative symptoms of moderate severity, unconfounded by depression and extrapyramidal symptoms at baseline in a large cohort of patients in the early stage of a schizophrenia-spectrum disorder, recruited to the OPTiMiSE trial. Persistent unconfounded negative symptoms were assessed at 4, 10 and 22 weeks of treatment. Symptomatic remission, attrition rate and psychosocial functioning was evaluated in subjects with short-term (4 weeks) persistent negative symptoms (PNS) and in those with negative symptoms that did not persist at follow-up and/or were confounded at baseline (N-PNS). Negative symptoms of moderate severity were observed in 59% of subjects at baseline and were associated to worse global functioning. PNS were observed in 7.9% of the cohort, unconfounded at both baseline and end of 4-week treatment. PNS subjects showed lower remission and higher attrition rates at the end of all treatment phases. Fifty-six percent of subjects completing phase 3 (clozapine treatment) had PNS, and 60% of them were non-remitters at the end of this phase. The presence of short-term PNS during the first phases of psychosis was associated with poor clinical outcome and resistance to antipsychotic treatment, including clozapine.

Impairments in self-representation are relevant to the expression of psychosis. To date, the characteristics and neural mechanisms of self-impairment in schizophrenia remain unclear. To this end, we used event-related potentials (ERPs) to measure brain activity in 56 first-episode patients with schizophrenia and 56 healthy controls. Participants judged personal trait adjectives regarding themselves, their mothers, or a public person, followed by an unexpected old/new recognition test. The recognition score for mother-reference adjectives was lower than that for self-reference adjectives in patients, while the control group showed comparatively high recognition scores for both self- and mother-referential adjectives. In addition, control subjects recognized more negative words, while patients remembered more positive words. ERP data revealed that controls exhibited typical task effects (self-reference = mother-reference > other-reference) during both automatic attention and effortful encoding periods [indexed by P2 and the late positive potential (LPP), respectively]. In contrast, patients only exhibited the task effect in the P2 amplitude. Moreover, controls exhibited larger P2 amplitudes during encoding negative than positive words, whereas patients had enhanced LPP amplitudes during memory retrieval of positive compared to negative words. These findings demonstrated self-representation dysfunction in first-episode schizophrenic patients in mother (the intimate other) referential processing and the absence of a negative memory bias.

Impairments in self-representation are relevant to the expression of psychosis. To date, the characteristics and neural mechanisms of self-impairment in schizophrenia remain unclear. To this end, we used event-related potentials (ERPs) to measure brain activity in 56 first-episode patients with schizophrenia and 56 healthy controls. Participants judged personal trait adjectives regarding themselves, their mothers, or a public person, followed by an unexpected old/new recognition test. The recognition score for mother-reference adjectives was lower than that for self-reference adjectives in patients, while the control group showed comparatively high recognition scores for both self- and mother-referential adjectives. In addition, control subjects recognized more negative words, while patients remembered more positive words. ERP data revealed that controls exhibited typical task effects (self-reference = mother-reference > other-reference) during both automatic attention and effortful encoding periods [indexed by P2 and the late positive potential (LPP), respectively]. In contrast, patients only exhibited the task effect in the P2 amplitude. Moreover, controls exhibited larger P2 amplitudes during encoding negative than positive words, whereas patients had enhanced LPP amplitudes during memory retrieval of positive compared to negative words. These findings demonstrated self-representation dysfunction in first-episode schizophrenic patients in mother (the intimate other) referential processing and the absence of a negative memory bias. [ABSTRACT FROM AUTHOR]

This study aimed to shed light on the linguistic style affecting the communication discourse in first-episode schizophrenia (FES) by investigating the analytic thinking index in relation to clinical scores of conceptual and thought disorganization (Positive and Negative Syndrome Scale, PANSS-P2 and Thought and Language Index, TLI). Using robust Bayesian modeling, we report three major findings: (1) FES subjects showed reduced analytic thinking, exhibiting a less categorical linguistic style than healthy control (HC) subjects (Bayes factor, BF10 > 1000), despite using the same proportion of function and content words as HCs; (2) the lower the analytic thinking score, the higher the symptoms scores of conceptual disorganization (PANSS-P2, BF = 22.66) and global disorganization of thinking (TLI, BF10 = 112.73); (3) the linguistic style is a better predictor of conceptual disorganization than the cognitive measure of processing speed in schizophrenia (SZ). These findings provide an objectively detectable linguistic style with a focus on Natural Language Processing Analytics of transcribed speech samples of patients with SZ that require no clinical judgment. These findings also offer a crucial insight into the primacy of linguistic structural disruption in clinically ascertained disorganized thinking in SZ. Our work contributes to an emerging body of literature on the psychopathology of SZ using a first-order lexeme-level analysis and a hypothesis-driven approach. At a utilitarian level, this has implications for improving educational and social outcomes in patients with SZ. [ABSTRACT FROM AUTHOR]

Background: Pitch and duration mismatch negativity (pMMN/dMMN) are related to left Heschl's gyrus gray matter volumes in first-episode schizophrenia (FESz). Previous methods were unable to delineate functional subregions within and outside Heschl's gyrus. The Human Connectome Project multimodal parcellation (HCP-MMP) atlas overcomes this limitation by parcellating these functional subregions. Further, MMN has generators in inferior frontal cortex, and therefore, may be associated with inferior frontal cortex pathology. With the novel use of the HCP-MMP to precisely parcellate auditory and inferior frontal cortex, we investigated relationships between gray matter and pMMN and dMMN in FESz. Methods: pMMN and dMMN were measured at Fz from 27 FESz and 27 matched healthy controls. T1-weighted MRI scans were acquired. The HCP-MMP atlas was applied to individuals, and gray matter volumes were calculated for bilateral auditory and inferior frontal cortex parcels and correlated with MMN. FDR correction was used for multiple comparisons. Results: In FESz only, pMMN was negatively correlated with left medial belt in auditory cortex and area 47L in inferior frontal cortex. Duration MMN negatively correlated with the following auditory parcels: left medial belt, lateral belt, parabelt, TA2, and right A5. Further, dMMN was associated with left area 47L, right area 44, and right area 47L in inferior frontal cortex. Conclusions: The novel approach revealed overlapping and distinct gray matter associations for pMMN and dMMN in auditory and inferior frontal cortex in FESz. Thus, pMMN and dMMN may serve as biomarkers of underlying pathological deficits in both similar and slightly different cortical areas. [ABSTRACT FROM AUTHOR]

Progressive reduction in glutamatergic transmission has been proposed as an important component of the illness trajectory of schizophrenia. Despite its popularity, to date, this notion has not been convincingly tested in patients in early stages of schizophrenia. In a longitudinal 7T magnetic resonance spectroscopy (1H-MRS), we quantified glutamate at the dorsal anterior cingulate cortex in 21 participants with a median lifetime antipsychotic exposure of less than 3 days and followed them up after 6 months of treatment. Ten healthy controls were also scanned at 2 time points. While patients had significantly lower overall glutamate levels than healthy controls (F(1,27) = 5.23, P = .03), we did not observe a progressive change of glutamate concentration in patients (F(1,18) = 0.47, P = .50), and the group by time interaction was not significant (F(1,27) = 0.86, P = .36). On average, patients with early psychosis receiving treatment showed a 0.02 mM/y increase, while healthy controls showed a 0.06 mM/y reduction of MRS glutamate levels. Bayesian analysis of our observations does not support early, post-onset gluta-mate loss in schizophrenia. Interestingly, it provides evidence in favor of a lack of progressive glutamate change in our schizophrenia sample--indicating that the glutamate level at the onset of illness was the best predictor of the levels 6 months after treatment. A more nuanced view of glutamatergic physiology, linked to early cortical maturation, may be required to understand glutamate-mediated dynamics in schizophrenia. [ABSTRACT FROM AUTHOR]

Objectives: This clinical trial primarily aimed to investigate the effects of blonanserin on social functioning in patients with first-episode schizophrenia., Methods: In this prospective, multi-centre, single-arm clinical trial study, blonanserin (flexible oral dose ranging from 8mg to 24mg per day) was given 26 weeks. Outcome measures included the Personal and Social Performance (PSP) scale for evaluating social functioning, the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB) for measuring neurocognitive performance, and the Positive and Negative Syndrome Scale (PANSS) for assessing symptom severity. The primary endpoint was social function improvement evaluated by PSP scale at the end of blonanserin treatment. And the secondary endpoint was to validate the efficacy and neurocognitive effects of blonanserin. Adverse drug reactions (ADRs) were also recorded and analysed., Results: A total of 96 patients with first-episode schizophrenia were recruited and proceeded to analysis. Fifty-one participants (53.1%) completed the PSP scale measurements at baseline and week 26. Following 26 weeks of blonanserin treatment, all outcome measurements demonstrated significant improvement during the follow-up period. Notably, PSP scores exhibited a continuous increase up to 68.1% ± 103.7% at the end of the treatment (46.6 ± 14.6 at baseline, 69.4 ± 17.4 at week 26, p<0.001), indicating positive effects on social functioning that were already noticeable by week 8., Conclusion: Blonanserin treatment exhibited favourable effects on social functioning in individuals with first-episode schizophrenia. The results suggest that blonanserin was effective treatment options for patients with schizophrenia encountering functional impairments., Competing Interests: HL was employed by Sumitomo Pharma (Suzhou) Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from Sumitomo Pharma (Suzhou) Co., Ltd. The funder had the following involvement in the study: conceptualization, methodology, analysis, and manuscript review & editing., (Copyright © 2024 Gao, Deng, Sheng, Wu, Liu, Yang, Wang, Hu, Wang, Li, Pu and Yu.)

More than one hundred studies have used the mainland Chinese version of the MATRICS Consensus Cognitive Battery (MCCB) to assess cognition in schizophrenia, but the results of these studies, the quality of the reports, and the strength of the evidence provided in the reports have not been systematically assessed. We identified 114 studies from English-language and Chinese-language databases that used the Chinese MCCB to assess cognition in combined samples of 7394 healthy controls (HC), 392 individuals with clinical high risk for psychosis (CHR-P), 4922 with first-episode schizophrenia (FES), 1549 with chronic schizophrenia (CS), and 2925 with schizophrenia of unspecified duration. The mean difference (MD) of the composite MCCB T-score (-13.72) and T-scores of each of the seven cognitive domains assessed by MCCB (-14.27 to -7.92) were significantly lower in individuals with schizophrenia than in controls. Meta-analysis identified significantly greater cognitive impairment in FES and CS than in CHR-P in six of the seven domains and significantly greater impairment in CS than FES in the reasoning and problem-solving domain (i.e., executive functioning). The only significant covariate of overall cognitive functioning in individuals with schizophrenia was a negative association with the severity of psychotic symptoms. These results confirm the construct validity of the mainland Chinese version of MCCB. However, there were significant limitations in the strength of the evidence provided about CHR-P (small pooled sample sizes) and the social cognition domain (inconsistency of results across studies), and the quality of many reports (particularly those published in Chinese) was rated 'poor' due to failure to report sample size calculations, matching procedures or methods of handling missing data. Moreover, almost all studies were cross-sectional studies limited to persons under 60 with at least nine years of education, so longitudinal studies of under-educated, older individuals with schizophrenia are needed., Competing Interests: All authors declare no conflict of interest., (© 2024 The Author(s).)

Investigations of brain structure in schizophrenia using magnetic resonance imaging (MRI) have identified variations in regional grey matter (GM) volume throughout the brain but the results are mixed. This study aims to investigate whether the inconsistent voxel-based morphometry (VBM) findings in schizophrenia are due to the use of different software packages. T1 MRI images were obtained from 86 first-episode schizophrenia (FESZ) patients and 86 age- and gender-matched Healthy controls (HCs). VBM analysis was carried out using FMRIB software library (FSL) 5.0 and statistical parametric mapping 8 (SPM8). All images were processed using the default parameter settings as provided by these software packages. FSL-VBM revealed widespread GM volume reductions in FESZ patients compared with HCs, however, for SPM-VBM, only increased and circumscribed GM volume changes were found, both software revealed increased GM volume within cerebellum. Significant correlations between Positive and Negative Syndrome Scale (PANSS) and GM volume were mainly found in frontal regions. Algorithms of GM tissue segmentation, image registration and statistical strategies might contribute to these disparate results. [ABSTRACT FROM AUTHOR]

Working memory dysfunction may be central to neurocognitive deficits in schizophrenia. Maintenance of visual information in working memory, or visual short-term memory (vSTM), is linked to general cognitive dysfunction and predicts functional outcome. Lateralized change-detection tasks afford investigation of the contralateral delay activity (CDA), a useful tool for investigating vSTM dysfunction. Previous work suggests "hyperfocusing" of attention in schizophrenia, such that CDA is increased when a single item is maintained in vSTM but reduced for multiple items. If observed early in the disease, vSTM dysfunction may be a key feature of schizophrenia or target for intervention. We investigated CDA during lateralized vSTM of one versus three items using sensor-level electroencephalography and source-level magnetoencephalography in 26 individuals at their first episode of schizophrenia-spectrum psychosis (FESz) and 26 matched healthy controls. FESz were unable to modulate CDA with increased memory load – high-load CDA was reduced and low-load CDA was increased compared to controls. Further, sources of CDA in posterior parietal cortex were reduced in FESz and indices of working memory were correlated with neurocognitive deficits and symptom severity. These results support working memory maintenance dysfunction as a central and early component to the disorder. Targeted intervention focusing on vSTM deficits may be warranted to alleviate downstream effects of this disability. [ABSTRACT FROM AUTHOR]

Introduction: Cognitive impairment is a core feature of schizophrenia. The effects of atypical antipsychotics on the cognitive functions of patients with first-episode schizophrenia have not been comprehensively investigated so far. This study aims to compare neurocognitive effects of risperidone, olanzapine, and aripiprazole for first-episode schizophrenia. Methods: The study was a multicenter, randomized, open-label clinical trial. 546 patients were randomly divided into three medication groups, and followed up for 1 year. Cognitive performance was evaluated with a neuropsychological test battery. The Clinical trials.gov ID of the study is NCT01057849. Results: At 6 months, treatment resulted in significant improvements in all three groups in most cognitive domains except verbal learning and memory. At 12 months, three treatment groups had further improvements in three cognitive domains, but visual learning and memory performance dropped back to baseline. Conclusion: All three atypical antipsychotics tested in the study can potentially improve cognitive performance in first-episode schizophrenia, but no significant difference in the degree of improvement was found between drugs. [ABSTRACT FROM AUTHOR]

Cognitive deficits in people with schizophrenia are among the hardest to treat and strongly predict functional outcome. The ability to maintain sensory precepts in memory over a short delay is impacted early in the progression of schizophrenia and has been linked to reliable neurophysiological markers. Yet, little is known about the mechanisms of these deficits. Here, we investigated possible neurophysiological mechanisms of impaired visual short-term memory (vSTM, aka working memory maintenance) in the first-episode schizophrenia spectrum (FESz) using magnetoencephalography (MEG). Twenty-eight FESz and 25 matched controls performed a lateralized change detection task where they were cued to selectively attend and remember colors of circles presented in either the left or right peripheral visual field over a 1 s delay. Contralateral alpha suppression (CAS) during the delay period was used to assess selective attention to cued visual hemifields held in vSTM. Delay-period CAS was compared between FESz and controls and between trials presenting one vs three items per visual hemifield. CAS in dorsal visual cortex was reduced in FESz compared to controls in high-load trials, but not low-load trials. Group differences in CAS were found beginning 100 ms after the disappearance of the memory set, suggesting deficits were not due to the initial deployment of attention to the cued visual hemifield prior to stimulus presentation. CAS was not greater for high-load vs low-load trials in FESz subjects, although this effect was prominent in controls. Further, lateralized gamma (34–40 Hz) power emerged in dorsal visual cortex prior to the onset of CAS in controls but not FESz. Gamma power in this cluster differed between groups at both high and low load. CAS deficits observed in FESz were correlated with change detection accuracy, working memory function, estimated IQ, and negative symptoms. Our results implicate deficits in CAS in trials requiring broad, but not narrow, focus of attention to spatially distributed objects maintained in vSTM in FESz, possibly due to reduced ability to broadly distribute visuospatial attention (alpha) or disruption of object-location binding (gamma) during encoding/consolidation. This early pathophysiology may shed light upon mechanisms of emerging working memory deficits that are intrinsic to schizophrenia.

In this study, we investigated and quantified the amygdalar and hippocampal morphometry abnormalities exerted by first-episode schizophrenia using a total of 92 patients and 106 healthy control participants. Magnetic resonance imaging (MRI) based automated segmentation was conducted to obtain the amygdalar and hippocampal segmentations. Disease-versus-control volume differences of the bilateral amygdalas and hippocampi were quantified. In addition, deformation-based statistical shape analysis was employed to quantify the region-specific shape abnormalities of each structure of interest. To better identify the key relevant areas in the pathology of first-episode schizophrenia, each structure was divided into four subregions; CA1, CA2, CA3 combined with dentate gyrus for the hippocampus in each hemisphere and basolateral, basomedial, centromedial, and lateral nucleus for the amygdala in each hemisphere. We observed significant global volume reduction and localized shape atrophy in each of the four structures of interest. The amygdalar shape abnormalities mainly occurred at the basolateral and centromedial subregions, whereas the hippocampal shape abnormalities mainly concentrated on the CA1 and CA2 subregions. For the same structure, the one on the right hemisphere was affected more by the disease pathology than that on the left hemisphere. To conclude, we have successfully quantified the global and local morphometric abnormalities of the bilateral amygdalas and hippocampi using a sophisticated statistical analysis pipeline and high-field subregion segmentations, with MRI data of a considerable sample size. This study is one of the very first of such kind in first-episode schizophrenia analyses.

Membrane phospholipid deficits have been well-documented in schizophrenia (SZ) patients. Free fatty acids (FFAs) partially come from the hydrolysis of membrane phospholipids and serve as the circulating pool of body fatty acids. These FFAs are involved in many important biochemical reactions such as membrane regeneration, oxidation, and prostaglandin production which may have important implications in SZ pathology. Thus, we compared plasma FFA levels and profiles among healthy controls (HCs), affective psychosis (AP) patients, and first-episode antipsychotic-naïve schizophrenia (FEANS) patients. A significant reduction of total FFAs levels was observed in SZ patients. Specifically, significant reductions of 16:0, 18:2n6c, and 20:4n6 levels were detected in FEANS patients but not in APs when compared with levels in HCs. Also, disrupted metabolism of fatty acids especially in saturated and n-6 fatty acid families were observed by comparing correlations between precursor and product fatty acid levels within each fatty acid family. These findings may suggest an increased demand of membrane regeneration, a homeostatic imbalance of fatty acid biosynthesis pathway and a potential indication of increased beta oxidation. Collectively, these findings could help us better understand the lipid metabolism with regard to SZ pathophysiology.

Background: Reward processing abnormalities may underlie characteristic pleasure and motivational impairments in schizophrenia. Some neural measures of reward processing show age-related modulation, highlighting the importance of considering age effects on reward sensitivity. We compared event-related potentials (ERPs) reflecting reward anticipation (stimulus-preceding negativity, SPN) and evaluation (reward positivity, RewP; late positive potential, LPP) across individuals with schizophrenia (SZ) and healthy controls (HC), with an emphasis on examining the effects of chronological age, brain age (i.e., predicted age based on neurobiological measures), and illness phase. Methods: Subjects underwent EEG while completing a slot-machine task for which rewards were not dependent on performance accuracy, speed, or response preparation. Slot-machine task EEG responses were compared between 54 SZ and 54 HC individuals, ages 19 to 65. Reward-related ERPs were analyzed with respect to chronological age, categorically-defined illness phase (early; ESZ versus chronic schizophrenia; CSZ), and were used to model brain age relative to chronological age. Results: Illness phase-focused analyses indicated there were no group differences in average SPN or RewP amplitudes. However, a group × reward outcome interaction revealed that ESZ differed from HC in later outcome processing, reflected by greater LPP responses following loss versus reward (a reversal of the HC pattern). While brain age estimates did not differ among groups, depressive symptoms in SZ were associated with older brain age estimates while controlling for negative symptoms. Conclusions: ESZ and CSZ did not differ from HC in reward anticipation or early outcome processing during a cognitively undemanding reward task, highlighting areas of preserved functioning. However, ESZ showed altered later reward outcome evaluation, pointing to selective reward deficits during the early illness phase of schizophrenia. Further, an association between ERP-derived brain age and depressive symptoms in SZ extends prior findings linking depression with reward-related ERP blunting. Taken together, both illness phase and age may impact reward processing among SZ, and brain aging may offer a promising, novel marker of reward dysfunction that warrants further study.

Altered resting-state functional connectivity (rsFC) of the amygdala has been demonstrated to be implicated in schizophrenia neuronal pathophysiology. However, whether rsFC of amygdala subregions is differentially affected in schizophrenia remains unclear. This study compared the functional networks of each amygdala subdivision between healthy controls (HC) and patients with first-episode schizophrenia (FES). In total, 47 HC and 78 patients with FES underwent resting-state functional magnetic resonance imaging. The amygdala was divided into the following three subregions using the Juelich histological atlas: basolateral amygdala (BLA), centromedial amygdala (CMA), and superficial amygdala (SFA). The rsFC of the three amygdala subdivisions was computed and compared between the two groups. Significantly increased rsFC of the right CMA with the right postcentral gyrus and decreased rsFC of the right BLA with the left precentral gyrus were observed in the FES group compared with the HC group. Notably, the right BLA-left precentral gyrus connectivity was negatively correlated with positive symptoms and conceptual disorganization in patients with FES. In conclusion, this study found that patients with FES had abnormal functional connectivity in the amygdala subregions, and the altered rsFC was associated with positive symptoms. The present findings demonstrate the disruptive rsFC patterns of amygdala subregional-sensorimotor networks in FES and may provide new insights into the neuronal pathophysiology of FES.

Abstract Background Schizophrenia is a recurrent, debilitating disease that is rarely curable. Rapid intervention after the first episode of schizophrenia has been shown to positively affect the prognosis. Unfortunately, basic data is scarce on first-episode schizophrenia in Korean patients making it difficult to create a comprehensive list of risk factors for relapse. This study aims to investigate the demographic characteristics and institutional factors of patients with first-episode schizophrenia in order to identify risk factors for relapse. Methods Data from the Health Insurance Review & Assessment Service (HIRA) was used for this study to represent the Korean patient population. To identify factors affecting relapse, we explored gender, age, geographic location, medical benefits, type of medical institution, type of medication used, medication adherence, and the severity of symptoms. Data analysis was performed using the Cox proportional hazard model. Results The number of patients diagnosed with first-episode schizophrenia in Korea over a 2-year period was 4567 of which 1265 (27.7%) patients experienced a relapse during the observational period. Factors affecting relapse included age, type of medical institution, type of medication used, medication adherence, and type of treatment (inpatient or outpatient) after the initial diagnosis, which varied depending upon the severity of symptoms. Conclusions It was found that environmental and institutional factors as well as the type of medical treatment were crucial in determining whether patients with first-episode schizophrenia subsequently relapsed. The results of this study can be utilized as source material for directing therapeutic interventions and improving mental health policies in the future.

The glutamatergic system has previously been shown to be involved in the pathophysiology of schizophrenia and the mechanisms of action of antipsychotic treatment. The present study aimed to investigate the relationship between the levels of glutamate (Glu) or Glu/total creatine (Glu/Cr+PCr) in the anterior cingulate cortex (ACC) and psychiatric symptoms as well as the response to antipsychotic treatment. We performed proton magnetic resonance spectroscopy (1H–MRS) to measure Glu and Glu/Cr+PCr in the ACC of 35 drug-naïve first-episode schizophrenia (FES) patients and 40 well-matched healthy controls (HCs). After scanning, we treated the patients with risperidone for eight weeks. Remission status was based on the Positive and Negative Syndrome Scale (PANSS) scores at week 8. At baseline, there were no significant differences in the levels of Glu or Glu/Cr+PCr in the ACC between drug-naïve FES patients and HCs. Lower baseline levels of Glu/Cr+PCr but not Glu in the ACC were associated with more severe negative symptoms of schizophrenia. Compared to the remission group (RM), the non-remission group (NRM) had lower baseline ACC Glu levels (P < 0.05). Our results suggest that ACC Glu levels may be related to the severity of symptoms in the early stages of schizophrenia and therefore may be a marker with which to evaluate the treatment effect of antipsychotics in schizophrenia patients. [ABSTRACT FROM AUTHOR]

The disruption of salience network (SN) has been consistently found in patients with schizophrenia and thought to give rise to specific symptoms. However, the functional dysconnectivity pattern of SN remains unclear in first-episode schizophrenia (FES). Sixty-five patients with FES and sixty-six health controls (HC) were enrolled in this study and underwent resting-state functional magnetic resonance imaging (rs-fMRI). The eleven regions of interest (ROIs) within SN were derived from the peaks of the group independent component analysis (gICA). Seed-based whole-brain functional connectivity (FC) analyses were performed with all SN ROIs as the seeds. Both hyper- and hypo-connectivity of SN were found in the FES. Specifically, the increased FC mainly existed between the SN and cortico-cerebellar sub-circuit and prefrontal cortex, while the reduced FC mainly existed within cortico-striatal-thalamic-cortical (CSTC) sub-circuit. Our findings suggest that FES is associated with pronounced dysregulation of SN, characterized prominently by hyperconnectivity of SN-prefrontal cortex and cerebellum, as well as hypoconnectivity of CSTC sub-circuit of the SN. [ABSTRACT FROM AUTHOR]

Aim: The present study aimed to compare the social cognition (SC) deficits in patients with first-episode psychosis (FEP) and healthy controls and evaluate the association of SC deficits with socio-occupational functioning, insight, quality of life, and stigma. Methods: This study included 30 patients with FEP in remission phase and 26 healthy controls matched for age, gender, education, and intelligent quotient. SC was assessed on the domains of theory of mind (ToM), social perception, and attributional bias. Results: Compared to healthy controls, patients with FEP had significantly higher deficits in the domains of second-order ToM (unpaired t = 4.447, P < 0.001) and Faux Pas Composite Index (unpaired t = 2.824, P = 0.007). In the correlation analysis, higher age of patients with FEP was significantly associated with more externalizing bias (Pearson's correlation coefficient = 0.38, P = 0.039) and those with lower level of education had more social cognitive deficits in the domains of Faux Pas Composite Index (Pearson's correlation coefficient = 0.43, P = 0.018), Social Perception Index (Pearson's correlation coefficient = 0.38, P = 0.04), and Nonsocial Perception Index (Pearson's correlation coefficient = 0.5, P = 0.005). Duration of untreated psychosis was associated with higher deficits in the first-order ToM (Pearson's correlation coefficient = -0.38, P = 0.04) and Externalizing Bias Index (Pearson's correlation coefficient = -0.49, P = 0.006). Longer duration of treatment was associated with higher impairment in first-order ToM index (Pearson's correlation coefficient = -0.42, P = 0.02). General psychopathology and total Positive and Negative Syndrome Scale total score correlated significantly with externalizing bias, with a higher level of psychopathology associated with more severe deficits in this domain. There was no correlation of SC with the quality of life, cognitive insight, and stigma (except for occasional correlation of stereotype endorsement and externalizing bias). Conclusion: The present study suggests that compared to healthy controls, patients with FEP have impairment in the domains of second-order ToM and Faux Pas Composite Index. However, social cognitive deficits have only a few correlations with various psychosocial outcomes of FEP. [ABSTRACT FROM AUTHOR]

To evaluate the course of neuropsychological impairment, patients with first-episode schizophrenia and healthy controls were assessed with a comprehensive test battery at the time of index treatment and after a 5- and 15-year follow-up period. Summary scores for verbal intelligence (VBI), spatial organization, verbal fluency, verbal learning, semantic memory, visual memory, delay/retention rate, short-term memory, visual–motor processing and attention (VSM) and abstraction/flexibility were constructed. Our results show that neurocognitive functioning is impaired already at the onset of schizophrenia and remains stable over the 15-year follow-up period with an improvement in VBI. With regard to the presence of a deficit syndrome, it became apparent that the group with a deficit syndrome showed a deterioration of neurocognitive functions during the follow-up period, most pronounced in VSM. On the other hand, the group without a deficit syndrome showed an improvement in neurocognitive functions at the 15-year follow-up, which exceeded the learning effects of healthy control subjects. Neurocognitive performance at index assessment strongly predicted the performance at the 15-year follow-up. Most likely due to the small sample size, there were only weak associations between treatment with different types of neuroleptics and neurocognitive performance. [ABSTRACT FROM AUTHOR]

Cognitive deficits in people with schizophrenia are among the hardest to treat and strongly predict functional outcome. The ability to maintain sensory precepts in memory over a short delay is impacted early in the progression of schizophrenia and has been linked to reliable neurophysiological markers. Yet, little is known about the mechanisms of these deficits. Here, we investigated possible neurophysiological mechanisms of impaired visual short-term memory (vSTM, aka working memory maintenance) in the first-episode schizophrenia spectrum (FESz) using magnetoencephalography (MEG). Twenty-eight FESz and 25 matched controls performed a lateralized change detection task where they were cued to selectively attend and remember colors of circles presented in either the left or right peripheral visual field over a 1 s delay. Contralateral alpha suppression (CAS) during the delay period was used to assess selective attention to cued visual hemifields held in vSTM. Delay-period CAS was compared between FESz and controls and between trials presenting one vs three items per visual hemifield. CAS in dorsal visual cortex was reduced in FESz compared to controls in high-load trials, but not low-load trials. Group differences in CAS were found beginning 100 ms after the disappearance of the memory set, suggesting deficits were not due to the initial deployment of attention to the cued visual hemifield prior to stimulus presentation. CAS was not greater for high-load vs low-load trials in FESz subjects, although this effect was prominent in controls. Further, lateralized gamma (34–40 Hz) power emerged in dorsal visual cortex prior to the onset of CAS in controls but not FESz. Gamma power in this cluster differed between groups at both high and low load. CAS deficits observed in FESz were correlated with change detection accuracy, working memory function, estimated IQ, and negative symptoms. Our results implicate deficits in CAS in trials requiring broad, but not narrow, focus of attention to spatially distributed objects maintained in vSTM in FESz, possibly due to reduced ability to broadly distribute visuospatial attention (alpha) or disruption of object-location binding (gamma) during encoding/consolidation. This early pathophysiology may shed light upon mechanisms of emerging working memory deficits that are intrinsic to schizophrenia. [ABSTRACT FROM AUTHOR]

Membrane phospholipid deficits have been well-documented in schizophrenia (SZ) patients. Free fatty acids (FFAs) partially come from the hydrolysis of membrane phospholipids and serve as the circulating pool of body fatty acids. These FFAs are involved in many important biochemical reactions such as membrane regeneration, oxidation, and prostaglandin production which may have important implications in SZ pathology. Thus, we compared plasma FFA levels and profiles among healthy controls (HCs), affective psychosis (AP) patients, and first-episode antipsychotic-naïve schizophrenia (FEANS) patients. A significant reduction of total FFAs levels was observed in SZ patients. Specifically, significant reductions of 16:0, 18:2n6c, and 20:4n6 levels were detected in FEANS patients but not in APs when compared with levels in HCs. Also, disrupted metabolism of fatty acids especially in saturated and n-6 fatty acid families were observed by comparing correlations between precursor and product fatty acid levels within each fatty acid family. These findings may suggest an increased demand of membrane regeneration, a homeostatic imbalance of fatty acid biosynthesis pathway and a potential indication of increased beta oxidation. Collectively, these findings could help us better understand the lipid metabolism with regard to SZ pathophysiology. [ABSTRACT FROM AUTHOR]

In this study, we investigated and quantified the amygdalar and hippocampal morphometry abnormalities exerted by first-episode schizophrenia using a total of 92 patients and 106 healthy control participants. Magnetic resonance imaging (MRI) based automated segmentation was conducted to obtain the amygdalar and hippocampal segmentations. Disease-versus-control volume differences of the bilateral amygdalas and hippocampi were quantified. In addition, deformation-based statistical shape analysis was employed to quantify the region-specific shape abnormalities of each structure of interest. To better identify the key relevant areas in the pathology of first-episode schizophrenia, each structure was divided into four subregions; CA1, CA2, CA3 combined with dentate gyrus for the hippocampus in each hemisphere and basolateral, basomedial, centromedial, and lateral nucleus for the amygdala in each hemisphere. We observed significant global volume reduction and localized shape atrophy in each of the four structures of interest. The amygdalar shape abnormalities mainly occurred at the basolateral and centromedial subregions, whereas the hippocampal shape abnormalities mainly concentrated on the CA1 and CA2 subregions. For the same structure, the one on the right hemisphere was affected more by the disease pathology than that on the left hemisphere. To conclude, we have successfully quantified the global and local morphometric abnormalities of the bilateral amygdalas and hippocampi using a sophisticated statistical analysis pipeline and high-field subregion segmentations, with MRI data of a considerable sample size. This study is one of the very first of such kind in first-episode schizophrenia analyses. [ABSTRACT FROM AUTHOR]

Background: Schizophrenia is a serious long-term psychotic disorder marked by positive and negative symptoms, severe behavioral problems and cognitive function deficits. The cause of this disorder is not completely clear, but is suggested to be multifactorial, involving both inherited and environmental factors. Since human brain regulates all behaviour, studies have focused on identifying changes in neurobiology and biochemistry of brain in schizophrenia. Brain is the most lipid rich organ (approximately 50% of brain dry weight). Total brain lipids is constituted of more than 60% of phospholipids, in which docosahexaenoic acid (DHA, 22:6n-3) is the most abundant (more than 40%) polyunsaturated fatty acid (PUFA) in brain membrane phospholipids. Results from numerous studies have shown significant decreases of PUFAs, in particular, DHA in peripheral blood (plasma and erythrocyte membranes) as well as brain of schizophrenia patients at different developmental phases of the disorder. PUFA deficiency has been associated to psychotic symptoms and cognitive deficits in schizophrenia. These findings have led to a number of clinical trials examining whether dietary omega-3 fatty acid supplementation could improve the course of illness in patients with schizophrenia. Results are inconsistent. Some report beneficial whereas others show not effective. The discrepancy can be attributed to the heterogeneity of patient population. Methods: In this review, results from recent experimental and clinical studies, which focus on illustrating the role of PUFAs in the development of schizophrenia were examined. The rationale why omega-3 supplementation was beneficial on symptoms (presented by subscales of the positive and negative symptom scale (PANSS), and cognitive functions in certain patients but not others was reviewed. The potential mechanisms underlying the beneficial effects were discussed. Results: Omega-3 fatty acid supplementation reduced the conversion rate to psychosis and improved both positive and negative symptoms and global functions in adolescents at ultra-high risk for psychosis. Omega-3 fatty acid supplementation could also improve negative symptoms and global functions in the first-episode patients with schizophrenia, but improve mainly total or general PANSS subscales in chronic patients. Patients with low PUFA (particularly DHA) baseline in blood were more responsive to the omega-3 fatty acid intervention. Conclusion: Omega-3 supplementation is more effective in reducing psychotic symptom severity in young adults or adolescents in the prodromal phase of schizophrenia who have low omega-3 baseline. Omega-3 supplementation was more effective in patients with low PUFA baseline. It suggests that patients with predefined lipid levels might benefit from lipid treatments, but more controlled clinical trials are warranted. [ABSTRACT FROM AUTHOR]

Background: Prior resting state functional Magnetic Resonance Imaging studies (rs-fMRI) via the regional homogeneity (ReHo) method have demonstrated inconsistent and conflicting results because of several confounding factors, such as small sample size, medicinal influence, and illness duration. Relationships between ReHo measures and cognitive impairments in patients with drug-naive First-Episode Schizophrenia (dn-FES) are rarely reported. This study was conducted to explore the correlations between ReHo measures and cognitive deficits and clinical symptoms in patients with dn-FES. Methods: A total of 69 patients with dn-FES and 74 healthy controls were recruited. MATRICS Consensus Cognitive Battery (MCCB), Wechsler Adult Intelligence Scale (WAIS), and Positive And Negative Syndrome Scale (PANSS) were used to assess cognitive function, Intelligence Quotient (IQ), and clinical symptoms, respectively. The correlations between ReHo maps and cognitive deficits and the severity of symptoms were examined using strict correlation analysis. Results: ReHo values in right Middle Frontal Gyrus (MFG) and Superior Frontal Gyrus (SFG) increased in dn-FES group, whereas ReHo values in right cuneus decreased. Correlation analysis showed that the ReHo values in right MFG positively correlated with attention/vigilance impairments, social cognition deficits, and the severity of clinical manifestations. Conclusions: These findings suggested that abnormal spontaneous activities in right MFG reflect illness severity and cognitive deficits, which also serve as a basis for establishing objective diagnostic markers and might be a clinical intervention target for treating patients with schizophrenia. [ABSTRACT FROM AUTHOR]

Negative symptoms are associated with poor clinical and psychosocial outcome in schizophrenia. Their prevalence and identification in first-episode patients remains controversial. In a large cohort of patients in the early stage of schizophrenia, schizophreniform or schizoaffective disorder, we investigated, over the different phases of the OPTiMiSE trial (baseline, 4, 10 and 22 weeks of treatment), the prevalence of negative symptoms of moderate severity, unconfounded by depression and extrapyramidal symptoms at baseline. Moreover, we assessed symptomatic remission, attrition rate and psychosocial functioning in subjects with short-term (4 weeks) persistent unconfounded negative symptoms (PNS) and in those with negative symptoms that did not persist at follow-up and/or were confounded at baseline (N-PNS). Negative symptoms of moderate severity were observed in 59% of subjects at baseline. They were associated with worse psychosocial functioning and longer duration of psychosis at intake in the study. Eleven percent of subjects had PNS unconfounded at baseline and 7.9% had PNS unconfounded at both baseline and end of 4-week treatment. Psychosocial functioning was comparable in PNS and N-PNS subjects at baseline but it was significantly worse in the former group after 4-weeks. PNS subjects showed lower remission and higher attrition rates at the end of all treatment phases. Fifty-six percent of subjects completing phase 3 (clozapine treatment) had PNS, and 60% of them were non-remitters at the end of this phase. The presence of short-term PNS during the first phases of psychosis was associated with poor clinical outcome and resistance to antipsychotic treatment, including clozapine. [ABSTRACT FROM AUTHOR]

Schizophrenia has been conceptualized as a disorder arising from structurally pathological alterations to white‐matter fibers in the brain. However, few studies have focused on white‐matter functional changes in schizophrenia. Considering that converging evidence suggests that white‐matter resting state functional MRI (rsfMRI) signals can effectively depict neuronal activity and psychopathological status, this study examined white‐matter network‐level interactions in antipsychotic‐naive first‐episode schizophrenia (FES) to facilitate the interpretation of the psychiatric pathological mechanisms in schizophrenia. We recruited 42 FES patients (FESs) and 38 healthy controls (HCs), all of whom underwent rsfMRI. We identified 11 white‐matter functional networks, which could be further classified into deep, middle, and superficial layers of networks. We then examined network‐level interactions among these 11 white‐matter functional networks using coefficient Granger causality analysis. We employed group comparisons on the influences among 11 networks using network‐based statistic. Excitatory influences from the middle superior corona radiate network to the superficial orbitofrontal and deep networks were disrupted in FESs compared with HCs. Additionally, an extra failure of suppression within superficial networks (including the frontoparietal network, temporofrontal network, and the orbitofrontal network) was observed in FESs. We additionally recruited an independent cohort (13 FESs and 13 HCs) from another center to examine the replicability of our findings across centers. Similar replication results further verified the white‐matter functional network interaction model of schizophrenia. The novel findings of impaired interactions among white‐matter functional networks in schizophrenia indicate that the pathophysiology of schizophrenia may also lie in white‐matter functional abnormalities. [ABSTRACT FROM AUTHOR]

Abstract Background Cognitive deficits are a core feature of early schizophrenia. However, the pathological foundations underlying cognitive deficits are still unknown. The present study examined the association between gray matter density and cognitive deficits in first-episode schizophrenia. Method Structural magnetic resonance imaging of the brain was performed in 34 first-episode schizophrenia patients and 21 healthy controls. Patients were divided into two subgroups according to working memory task performance. The three groups were well matched for age, gender, and education, and the two patient groups were also further matched for diagnosis, duration of illness, and antipsychotic treatment. Voxel-based morphometric analysis was performed to estimate changes in gray matter density in first-episode schizophrenia patients with cognitive deficits. The relationships between gray matter density and clinical outcomes were explored. Results Patients with cognitive deficits were found to have reduced gray matter density in the vermis and tonsil of cerebellum compared with patients without cognitive deficits and healthy controls, decreased gray matter density in left supplementary motor area, bilateral precentral gyrus compared with patients without cognitive deficits. Classifier results showed GMD in cerebellar vermis tonsil cluster could differentiate SZ-CD from controls, left supplementary motor area cluster could differentiate SZ-CD from SZ-NCD. Gray matter density values of the cerebellar vermis cluster in patients groups were positively correlated with cognitive severity. Conclusions Decreased gray matter density in the vermis and tonsil of cerebellum may underlie early psychosis and serve as a candidate biomarker for schizophrenia with cognitive deficits.

Amotivation is a major determinant of functional outcome in schizophrenia but it is understudied in the early course of illness. There is a paucity of longitudinal research investigating predictors of amotivation. In this study, we aimed to examine baseline cognitive and clinical predictors of amotivation at 6 and 12 months of follow-up in patients aged 18–55 years presenting with first-episode DSM-IV schizophrenia-spectrum disorder (FES). Of 145 patients recruited at intake, 116 and 113 completed assessments at 6- and 12-month follow-up, respectively. Amotivation was measured by avolition-apathy and anhedonia-asociality subscale scores of the Scale of the Assessment of Negative Symptoms. Cognitive assessment was administered at baseline. As executive dysfunction has been more consistently found to be associated with negative symptoms and amotivation in prior literature, we adopted fractionated approach to subdivide executive function into distinct components encompassing switching and flexibility, response initiation, response inhibition, planning and strategy allocation, sustained attention and working memory. Our results showed that baseline amotivation (p = 0.01) and switching and flexibility (p = 0.01) were found to independently predict amotivation at 6 months follow-up. Baseline amotivation (p < 0.01) and switching and flexibility (albeit with trend-wise significance, p = 0.06) were also retained in final multivariate regression model for 12-month amotivation prediction. No other executive components or cognitive domains predicted amotivation at follow-up. Findings of our study thus indicate amotivation at initial presentation as a critical determinant of subsequent motivational deficits over 1 year of treatment for FES patients. Cognitive flexibility might be specifically related to the development of amotivation in the early stage of illness. [ABSTRACT FROM AUTHOR]

Given the similar efficacies across antipsychotic medications for schizophrenia, understanding their safety profiles, particularly concerning receptor-binding differences, is crucial for optimal drug selection, especially for patients with first episode schizophrenia. We aimed to compare the safety outcomes of second-generation antipsychotics. We conducted a retrospective cohort study with new user active comparator design using a nationwide claims database in South Korea. Participants were drug-naïve adult patients with first-episode schizophrenia. Three representative drugs with different pharmacologic profiles were compared: risperidone, olanzapine, and aripiprazole. Propensity scores were used to match the study groups, and the Cox proportional hazard model was used to calculate hazard ratios. Sensitivity analyses were performed in various epidemiological settings. Seventeen safety outcomes, including neuropsychiatric, cardiometabolic and gastrointestinal events, were assessed, with upper-respiratory-tract infection as a negative control outcome. A total of 1044, 2078, and 3634 participants were matched for olanzapine vs. risperidone, olanzapine vs. aripiprazole, and risperidone vs. aripiprazole comparisons, respectively. For parkinsonism, there was a significant difference in outcomes between the risperidone and aripiprazole groups (HR 1.80 [95% CI 1.13–2.91]), with consistent sensitivity analysis results. There were no significant differences in other neuropsychiatry outcomes or in the risk of cardiometabolic and gastrointestinal outcomes between any of the comparative group pairs. The risk of drug-induced parkinsonism was significantly higher with risperidone than with aripiprazole. Although olanzapine is known for its metabolic risk, there were no significant differences in risk between the other pairs. • We compared the safety outcomes between representatives of each second-generation antipsychotics (SGA) class in drug-naïve patients with first-episode schizophrenia. • The risk of drug-induced parkinsonism was significantly higher with risperidone than with aripiprazole, and the risks of cardiometabolic outcomes did not differ between groups. • These results highlight that the importance of considering the risk of drug-induced parkinsonism and metabolic issues for patients with first-episode schizophrenia. [ABSTRACT FROM AUTHOR]

Patients with schizophrenia may have diverse functional outcomes. However, the long-term functional trajectories of patients with first-episode schizophrenia (FES) are unclear. We extracted data from the Chinese First-Episode Schizophrenia Trial, a 10-year prospective study of antipsychotic-naïve patients with FES. We applied K means cluster modelling to longitudinal data on the social function of patients with FES and examined associations of the empirically derived trajectories with baseline clinical characteristics of the 10-year follow-up. Three distinct functional trajectories emerged: improving-favorable (39·3%), improving-poor (17·8%) and improving-stable (42·9%). All three trajectories demonstrated Personal and Social Performance (PSP) score improvement in the first six months. The improving-poor trajectory demonstrated PSP score decline during the second six months and thereafter, while PSP scores in the other two trajectories were mainly stable during the same period. Patients in the improving-favorable trajectory had higher baseline PSP scores than those in the improving-poor trajectory (OR=0·904 [0·852, 0·961], p < 0·05) and the improving-stable trajectory (OR=0·870 [0·825, 0·918], p < 0·001) and were more likely to be female than those in the improving-stable trajectory (OR=2·699 [1·030, 7·074], p < 0·05). Patients with FES demonstrated varied long-term functional recovery profiles. The first year, especially the second half of the first year, is a key period for social function interventions that improve long-term functional outcomes. Male patients and patients with poor baseline function may particularly benefit from such interventions. • Patients with first-episode schizophrenia have diverse long-term functional trajectories. • The first year, especially the second six months, is a key period for social function intervention. • Male patients and patients with poor baseline function should be targeted. [ABSTRACT FROM AUTHOR]

• This is the first study to explore the therapeutic effect of 1 Hz rTMS over right orbitofrontal cortex (OFC) in patients with first-episode schizophrenia. • 1Hz rTMS applied to the right orbitofrontal cortex can improve psychotic symptoms and cognitive deficits in patients with drug-naïve, first-episode schizophrenia. Repetitive transcranial magnetic stimulation (rTMS) has been used in the treatment of patients with schizophrenia. The conventional targets of rTMS treatment are the dorsolateral prefrontal cortex (DLPFC) and temporoparietal cortex (TPC). However, the efficacy of these two treatment strategies was quite heterogeneous. Structural and functional abnormalities of the orbitofrontal cortex (OFC) in schizophrenia are closely related to negative symptoms. We sought to determine whether 1 Hz rTMS over the right OFC is effective in treating patients with first-episode schizophrenia. In this study, eighty-nine patients with drug-naïve, first-episode schizophrenia were randomly divided into the rTMS (n = 47) or sham stimulation (n = 42) groups, with both groups receiving twenty sessions of 1 Hz rTMS treatment. The PANSS was assessed at baseline, day 10, and day 20, and MATRICS Consensus Cognitive Battery (MCCB) was implemented to assess the cognitive impairment at baseline and day 20. Results showed that patients in the active rTMS group had more improvement in clinical symptoms and cognitive deficits than patients in sham group at day 20. In conclusion, 1 Hz rTMS over OFC can improve psychotic symptoms and cognitive functions in schizophrenic patients. Our study provides a new alternative for the treatment of negative symptoms and cognitive deficits in schizophrenia. [ABSTRACT FROM AUTHOR]

Background: Due to its impairment in patients with schizophrenia, mismatch negativity (MMN) generation has been identified as a potential biomarker for identifying primary impairments in auditory sensory processing. This study aimed to investigate the dysfunctional differences in different MMN deviants and evoked theta power in patients with first-episode schizophrenia (FES) and chronic schizophrenia (CS).Methods: We measured frequency and duration MMN from 40 FES, 40 CS, and 40 healthy controls (HC). Evoked theta power was analyzed by event-related spectral perturbation (ERSP) approaches.Results: Deficits in duration MMN were observed in both FES (p = 0.048, Bonferroni-adjusted) and CS (p < 0.001, Bonferroni-adjusted). However, deficits in frequency MMN were restricted to the CS (p < 0.001, Bonferroni-adjusted). Evoked theta power deficits were observed in both patient groups when compared with the HC (p FES = 0.001, p CS < 0.001, Bonferroni-adjusted), yet no significant differences were found between FES and CS. Frequency MMN was correlated with the MATRICS consensus cognitive battery (MCCB) combined score (r = -0.327, p < 0.05) and MCCB verbal learning (r = -0.328, p < 0.05) in FES. Evoked theta power was correlated with MCCB working memory in both FES (r = 0.347, p < 0.05) and CS (r = 0.408, p < 0.01).Conclusion: These findings suggest that duration MMN and evoked theta power deficits may be more sensitive for detection of schizophrenia during its early stages. Moreover, frequency MMN and theta power could potentially linked to poor cognitive functioning in schizophrenic patients. The findings mentioned above indicated that the neural mechanisms of the three indexes may vary between people.

Patients with schizophrenia suffer from stigma and discrimination due to their illness. Yet it is not well examined how experiences of stigma and discrimination express at the early illness stage and how they develop subsequently. Therefore, clinical and psycho-social correlates of stigma experiences and perceived stigma are analyzed in patients with first-episode schizophrenia over the course of 1 year after their first in-patient treatment. Questionnaire data assessed within the multi-centre-RCT "First-Episode Study" of the German Research Network on Schizophrenia were analyzed. Patients with first-episode schizophrenia were assessed 8 weeks after their first in-patient treatment (post-acute assessment) and 1 year later. N = 48 (post-acute) and N = 24 (1-year follow-up) patients provided questionnaire data appropriate for analyses, with N = 12 dyads. These data included burden due to stigma experiences (B-STE), perceived stigma (PDDQ), clinical (PANSS, CDSS, CGI, GAF, SAS) and psycho-social factors (LQLP, FSNK-self-esteem, KK-Scale). Cross-lag-correlation models showed a causal relation between stigma experiences (post-acute) and reduced self-esteem after 1 year. Multiple regression models revealed different models for experienced and perceived stigma. Factors associated with higher stigma experiences were older age, worse clinical global impression, better social adjustment, lower self-esteem, and the belief that illness is not driven by chance or fate. The different associations between psycho-social factors and stigma experiences and perceived stigma demonstrate the complexity of this inter-relationship. The results have practical implications for psycho-educational and other therapeutic interventions addressing stigma coping. Since the sample was small and selective, replication studies are needed. [ABSTRACT FROM AUTHOR]

Background: Cognitive deficits are already present in early stages of schizophrenia. P3a and P3b event-related potentials (ERPs) are believed to underlie the processes of attention and working memory (WM), yet limited research has been performed on the associations between these parameters. Therefore, we explored possible associations between P3a/b amplitudes and cognition in a large cohort of antipsychotic-naïve, first-episode schizophrenia (AN-FES) patients and healthy controls (HC). Methods: Seventy-three AN-FES patients and 93 age- and gender-matched HC were assessed for their P3a/b amplitude with an auditory oddball paradigm. In addition, subjects performed several subtests from the Cambridge Neuropsychological Test Automated Battery (CANTAB). Results: AN-FES patients had significantly reduced P3a/b amplitudes, as well as significantly lower scores on all cognitive tests compared with HC. Total group correlations revealed positive associations between P3b amplitude and WM and sustained attention and negative associations with all reaction time measures. These associations appeared mainly driven by AN-FES patients, where we found a similar pattern. No significant associations were found between P3b amplitude and cognitive measures in our HC. P3a amplitude did not correlate significantly with any cognitive measures in either group, nor when combined. Conclusions: Our results provide further evidence for P3a/b amplitude deficits and cognitive deficits in AN-FES patients, which are neither due to antipsychotics nor to disease progress. Furthermore, our data showed significant, yet weak associations between P3b and cognition. Therefore, our data do not supply evidence for deficient P3a/b amplitudes as direct underlying factors for cognitive deficits in schizophrenia. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to explore the effectiveness and tolerability of long-acting paliperidone palmitate antipsychotic in adolescent first-episode schizophrenia patients while comparing the results with the oral antipsychotic risperidone.Methods: This study is a retrospective, noninterventional study to assess the effectiveness and tolerability of long-acting injectable antipsychotic paliperidone palmitate in first-episode adolescent patients during the first 12 months of treatment compared with the oral antipsychotic risperidone. The data include general sociodemographic characteristics, number of hospitalizations, side effects, and the following clinical scales: Positive and Negative Syndrome Scale (PANSS), Personal and Social Performance Scale (PSP), Clinical Global Impression Improvement and Severity (CGI-I and CGI-S), and Treatment Satisfaction Questionnaire for Medication (TSQM).Results: During the 12-month study period significant improvement was registered in patients receiving both paliperidone palmitate and risperidone in the following scales: PANSS, PSP, CGI-I, and CGI-S. Patients receiving paliperidone palmitate had significantly greater improvement in PANSS, CGI-S, and PSP compared with the risperidone group. Patients receiving risperidone had significantly higher number of hospitalizations than the patients receiving paliperidone palmitate. The TSQM revealed that the patients who were receiving paliperidone palmitate achieved significantly higher scores on the convenience scale, global satisfaction, and on the overall result, whereas no difference was observed on the effectiveness scale. There were several side effects reported for paliperidone (5.5% hyperprolactinemia, 5.5% weight gain) and risperidone (5.5% hyperprolactinemia, 16.7% weight gain).Conclusions: In conclusion, paliperidone palmitate seems to be safe and effective in adolescent patients. Furthermore, it compared favorably with risperidone in the clinical response, side effects, and hospitalizations. [ABSTRACT FROM AUTHOR]

A few magnetic resonance imaging (MRI) studies reported reduced pineal gland volume in chronic schizophrenia (Sz), implicating the involvement of melatonin in the pathophysiology of the illness. However, it is not known whether this abnormality, if present, exists at the early illness stages and/or develops progressively over the course of the illness. This MRI study examined pineal gland volume in 64 patients with first-episode schizophrenia (FESz), 40 patients with chronic Sz, 22 individuals with at-risk mental state (ARMS), and 84 healthy controls. Longitudinal changes in pineal volume (mean inter-scan interval = 2.5 ± 0.7 years) were also examined in a subsample of 23 FESz, 16 chronic Sz, and 21 healthy subjects. In the cross-sectional comparison, the ARMS, FESz, and chronic Sz groups had significantly smaller pineal volume to the same degree as compared with healthy controls. A longitudinal comparison demonstrated that pineal volume did not change over time in any group. There was no association between pineal volume and clinical variables (e.g., symptom severity, medication) in the ARMS and Sz groups. The results suggest that a smaller pineal gland may be a static vulnerability marker of Sz, which probably reflects an early neurodevelopmental abnormality. [ABSTRACT FROM AUTHOR]

Objective: Accumulating evidence suggests alterations of the innate immune system are related to schizophrenia, although the precise mechanism remains to be elucidated. In this study, we aimed to detect the monocytic toll-like receptor 4 (TLR4) expression under basal and lipopolysaccharide (LPS)-stimulated conditions in first-episode (FE) Han Chinese patients with schizophrenia, as well as its association with cognitive function.Methods: Whole blood samples were taken in 42 FE schizophrenia patients and 36 healthy controls. Expressions of TLR4 on monocytes under basal and LPS-stimulated conditions were measured with flow cytometry. Psychopathological symptoms of schizophrenia were assessed by the Positive and Negative Syndrome Scale (PANSS) and the MATRICS Consensus Cognitive Battery (MCCB) was administered to all of the participants.Results: We found no differences in percentage and mean fluorescence intensity (MFI) of TLR4 expression on monocytes between patients and controls at basal status. However, LPS challenge resulted in a lower cell-surface level of TLR4 on monocytes in FE schizophrenia patients as compared to healthy controls (TLR4+%: F = 4.092, p = 0.047; TLR4 + MFI: F = 4.820, p = 0.031). In addition, correlation analysis together with multivariate linear regression analysis identified basal percentage of TLR4 in monocytes as the beneficial factor for visual learning and working memory in FE patients with schizophrenia.Conclusions: Our findings suggested that TLR4 may be involved in the pathophysiology of schizophrenia, corroborating the role of innate immunity-related functional deficits in increased risk of schizophrenia. [ABSTRACT FROM AUTHOR]

Background: Due to its impairment in patients with schizophrenia, mismatch negativity (MMN) generation has been identified as a potential biomarker for identifying primary impairments in auditory sensory processing. This study aimed to investigate the dysfunctional differences in different MMN deviants and evoked theta power in patients with first-episode schizophrenia (FES) and chronic schizophrenia (CS). Methods: We measured frequency and duration MMN from 40 FES, 40 CS, and 40 healthy controls (HC). Evoked theta power was analyzed by event-related spectral perturbation (ERSP) approaches. Results: Deficits in duration MMN were observed in both FES (p = 0.048, Bonferroni-adjusted) and CS (p < 0.001, Bonferroni-adjusted). However, deficits in frequency MMN were restricted to the CS (p < 0.001, Bonferroni-adjusted). Evoked theta power deficits were observed in both patient groups when compared with the HC (p FES = 0.001, p CS < 0.001, Bonferroni-adjusted), yet no significant differences were found between FES and CS. Frequency MMN was correlated with the MATRICS consensus cognitive battery (MCCB) combined score (r = -0.327, p < 0.05) and MCCB verbal learning (r = -0.328, p < 0.05) in FES. Evoked theta power was correlated with MCCB working memory in both FES (r = 0.347, p < 0.05) and CS (r = 0.408, p < 0.01). Conclusion: These findings suggest that duration MMN and evoked theta power deficits may be more sensitive for detection of schizophrenia during its early stages. Moreover, frequency MMN and theta power could potentially linked to poor cognitive functioning in schizophrenic patients. The findings mentioned above indicated that the neural mechanisms of the three indexes may vary between people. [ABSTRACT FROM AUTHOR]

Background Historically, research investigating neural correlates of mentalizing deficits in schizophrenia has focused on patients who have been ill for several years with lengthy exposure to medication. Little is known about the neural and behavioral presentations of theory-of-mind deficits in schizophrenia, shortly after the first episode of psychosis. Methods We investigated social cognition in 17 recently diagnosed first-episode schizophrenia (FES) patients with little or no exposure to antipsychotic medication and 1:1 matched healthy controls. We recorded behavioral and neural responses to the Animated Triangles Task (ATT), which is a nonverbal validated mentalizing task that measures the ascription of intentionality to the movements of objects. Results FES patients under-interpreted social cues and over-interpreted nonsocial cues. These effects were influenced by current intelligence (IQ). Control group and FES neural responses replicated earlier findings in healthy adults. However, a region of anterior medial prefrontal cortex (amPFC) of FES patients showed a different response pattern to that of controls. Unlike healthy controls, patients increased activity in this social cognition region while studying "random" movements of shapes, as compared to the study of movements normally interpreted as "intentional". Conclusions Mentalizing deficits in FES consists of hypo- and hypermentalizing. The neural pattern of FES patients is consistent with deficits in the ability to switch off mentalizing processes in potentially social contexts, instead increasing them when intentionality is not forthcoming. Overall, results demonstrate complexities of theory of mind deficits in schizophrenia that should be considered when offering social cognitive training programs. [ABSTRACT FROM AUTHOR]

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Potential effects of initiating acute antipsychotic treatment on white matter (WM) microstructure in schizophrenia patients remain poorly characterized. Thirty-five drug-naïve first-episode schizophrenia patients were scanned before and after six weeks of treatment with second-generation antipsychotic medications. Nineteen demographically matched healthy subjects were scanned twice over the same time interval. Tract-based spatial statistics was used to test for changes in WM microstructural integrity after treatment. Widespread fractional anisotropy (FA) decrease was found in patients after antipsychotic treatment in bilateral posterior corona radiata, anterior corona radiata, superior corona radiata and posterior thalamic radiation, left posterior limb of the internal capsule, and mid-body of the corpus callosum. These effects appeared to result primarily from decreased axial diffusivity. These findings suggest an effect on brain white matter from acute antipsychotic therapy in schizophrenia. [ABSTRACT FROM AUTHOR]