Early Schizophrenia Research Articles

Comparison of Negative Symptom Network Structures Between Patients With Early and Chronic Schizophrenia: A Network and Exploratory Graph Analysis.

Despite the clinical relevance of negative symptoms in schizophrenia, our understanding of negative symptoms remains limited. Although various courses and stages of schizophrenia have been identified, variations in the negative symptom networks between distinct stages of schizophrenia remain unexplored. We examined 405 patients with early schizophrenia (ES) and 330 patients with chronic schizophrenia (CS) using the Scale for the Assessment of Negative Symptoms. Network analysis and exploratory graph analysis were used to identify and compare the network structures and community memberships of negative symptoms between the two groups. Further, associations between communities and social functioning were evaluated. The potential influences of other symptom domains and confounding factors were also examined. Multidimensional differences were found in the networks of negative symptoms between ES and CS. The global connectivity strength was higher in the network of ES than in the network of CS. In ES, central symptoms were mainly related to expressive deficits, whereas in CS they were distributed across negative symptom domains. A three-community structure was suggested across stages but with different memberships and associations with social functioning. Potential confounding factors and symptom domains, including mood, positive, disorganization, and excitement symptoms, did not affect the network structures. Our findings revealed the presence of stage-specific network structures of negative symptoms in schizophrenia, with negative symptom communities having differential significance for social functioning. These findings provide implications for the future development of tailored interventions to alleviate negative symptoms and improve functionality across stages.

The psychiatrist as a ragpicker. Introduction to Walter Benjamin for psychiatrists (II): the dialectics between the fragment and the whole

In this paper, taking a cue from the image provided by Walter Benjamin, I argue that the work of the psychiatrist can be compared to that of the ragpicker who collects what others consider to be ‘waste’, rescuing it from oblivion and transforming it into a key resource for treatment. I review two ‘logics of discovery’- phenomenologically inspired structural psychopathology and that of narrative psychopathology - whose purpose is to complement mainstream diagnostic approach based on ‘ticking boxes’. I try to identify the shortcomings of these two methodologies, in particular the confirmation bias that can cause selective inattention to anything that does not fit into the expected structure or narrative. I highlight the heuristic importance of these ‘fragments’ that are in danger of remaining on the fringes of the clinician’s attention who is too focused on ‘making ends meet,’ showing how in certain psychopathological conditions - e.g. early schizophrenia and borderline personality disorder, marked by fragmentation - inattention to fragments can impede understanding and treatment. I argue for the importance in psychiatry of an ‘emergentist’ logic of discovery, of a kind of psychopathological knowledge ‘co-produced’ with patients, and of fragment-oriented listening in order not to lose the richness of patients’ own accounts.

Investigating the interpretability of schizophrenia EEG mechanism through a 3DCNN-based hidden layer features aggregation framework

Background and objectiveElectroencephalogram (EEG) signals record brain activity, with growing interest in quantifying neural activity through complexity analysis as a potential biological marker for schizophrenia. Presently, EEG complexity analysis primarily relies on manual feature extraction, which is subjective and yields varied findings in studies involving schizophrenia and healthy controls. MethodsThis study aims to leverage deep learning methods for enhanced EEG complexity exploration, aiding early schizophrenia screening and diagnosis. Our proposed approach utilizes a three-dimensional Convolutional Neural Network (3DCNN) to extract enhanced data features for early schizophrenia identification and subsequent complexity analysis. Leveraging the spatiotemporal capabilities of 3DCNN, we extract advanced latent features and employ knowledge distillation to reintegrate these features into the original channels, creating feature-enhanced data. ResultsWe employ a 10-fold cross-validation strategy, achieving the average accuracies of 99.46% and 98.06% in subject-dependent experiments on Dataset 1(14SZ and 14HC) and Dataset 2 (45SZ and 39HC). The average accuracy for subject-independent is 96.04% and 92.67% on both datasets. Feature extraction and classification are conducted on both the re-aggregated data and the original data. Our results demonstrate that re-aggregated data exhibit superior classification performance and a more stable training process after feature extraction. In the complexity analysis of re-aggregated data, we observe lower entropy features in schizophrenic patients compared to healthy controls, with more pronounced differences in the temporal and frontal lobes. Analyzing Katz's Fractal Dimension (KFD) across three sub-bands of lobe channels reveals the lowest α band KFD value in schizophrenia patients. ConclusionsThis emphasizes the ability of our method to enhance the discrimination and interpretability in schizophrenia detection and analysis. Our approach enhances the potential for EEG-based schizophrenia diagnosis by leveraging deep learning, offering superior discrimination capabilities and richer interpretive insights.

Add-on Sodium Benzoate and N-Acetylcysteine in Patients With Early Schizophrenia Spectrum Disorder: A Multicenter, Double-Blind, Randomized Placebo-Controlled Feasibility Trial.

Oxidative stress pathways may play a role in schizophrenia through direct neuropathic actions, microglial activation, inflammation, and by interfering with NMDA neurotransmission. N-acetylcysteine (NAC) has been shown to improve negative symptoms of schizophrenia, however, results from trials of other compounds targeting NMDA neurotransmission have been mixed. This may reflect poor target engagement but also that risk mechanisms act in parallel. Sodium Benzoate (NaB) could have an additive with NAC to act on several pathophysiological mechanisms implicated in schizophrenia. A multicenter, 12 weeks, 2 × 2 factorial design, randomized double-blind placebo-controlled feasibility trial of NaB and NAC added to standard treatment in 68 adults with early schizophrenia. Primary feasibility outcomes included recruitment, retention, and completion of assessments as well as acceptability of the study interventions. Psychosis symptoms, functioning, and cognitive assessments were also assessed. We recruited our desired sample (n = 68) and retained 78% (n = 53) at 12 weeks, supporting the feasibility of recruitment and retention. There were no difficulties in completing clinical outcome schedules. Medications were well tolerated with no dropouts due to side effects. This study was not powered to detect clinical effect and as expected no main effects were found on the majority of clinical outcomes. We demonstrated feasibility of conducting a clinical trial of NaB and NAC. Given the preliminary nature of this study, we cannot draw firm conclusions about the clinical efficacy of either agent, and a large-scale trial is needed to examine if significant differences between treatment groups emerge. ClinicalTrials.gov: NCT03510741.

Automatic Diagnosis of Schizophrenia in EEG Signals using CNN Models

This study uses convolutional neural networks (CNNs) to analyze electroencephalogram (EEG) signals to tackle the crucial problem of early schizophrenia diagnosis. In the study, two different CNN models with different architectural characteristics are compared and contrasted, with a focus on measures related to accuracy, loss, selectivity, and specificity. A meticulously selected dataset is obtained and preprocessed, containing EEG signals from people with and without schizophrenia. The chosen CNN architectures differ in terms of activation functions, filter sizes, and layer depth. The performance of the models is carefully assessed using metrics appropriate to the particulars of the problem, such as accuracy, loss, selectivity (true positive rate), and specificity (true negative rate), after they have undergone rigorous training on the preprocessed dataset. The goal of the comparison analysis is to offer a thorough grasp of how various architectural decisions affect the model’s capacity to correctly identify patterns linked to schizophrenia in EEG data. In addition to examining optimization and fine-tuning techniques to improve the model’s performance, the research also focuses on ethical issues to guarantee the responsible use of private health information. In the end, this work aims to further the development of deep learning-based EEG signal analysis diagnostic tools for schizophrenia, with a focus on the selection of assessment metrics that are important benchmarks for judging model performance. Keywords: schizophrenia, mental disorders, machine learning, biomedical signals, EEG signals, CNN

Predictive Coding in Early Schizophrenia and Clinical High Risk for Psychosis: Mechanistic Insights From Computational Modeling of the Mismatch Negativity Response

Predictive Coding in Early Schizophrenia and Clinical High Risk for Psychosis: Mechanistic Insights From Computational Modeling of the Mismatch Negativity Response

Adjunctive agents to antipsychotics in schizophrenia: a systematic umbrella review and recommendations for amino acids, hormonal therapies and anti-inflammatory drugs

QuestionThis umbrella review and guidelines aimed to provide evidence to support the rational choice of selected adjunctive therapies for schizophrenia.Study selection and analysisFollowing the Preferred Reporting Items for Systematic Reviews...

A multicentre study on grey matter morphometric biomarkers for classifying early schizophrenia and parkinson’s disease psychosis

Psychotic symptoms occur in a majority of schizophrenia patients and in ~50% of all Parkinson’s disease (PD) patients. Altered grey matter (GM) structure within several brain areas and networks may contribute to their pathogenesis. Little is known, however, about transdiagnostic similarities when psychotic symptoms occur in different disorders, such as in schizophrenia and PD. The present study investigated a large, multicenter sample containing 722 participants: 146 patients with first episode psychosis, FEP; 106 individuals in at-risk mental state for developing psychosis, ARMS; 145 healthy controls matching FEP and ARMS, Con-Psy; 92 PD patients with psychotic symptoms, PDP; 145 PD patients without psychotic symptoms, PDN; 88 healthy controls matching PDN and PDP, Con-PD. We applied source-based morphometry in association with receiver operating curves (ROC) analyses to identify common GM structural covariance networks (SCN) and investigated their accuracy in identifying the different patient groups. We assessed group-specific homogeneity and variability across the different networks and potential associations with clinical symptoms. SCN-extracted GM values differed significantly between FEP and Con-Psy, PDP and Con-PD, PDN and Con-PD, as well as PDN and PDP, indicating significant overall grey matter reductions in PD and early schizophrenia. ROC analyses showed that SCN-based classification algorithms allow good classification (AUC ~0.80) of FEP and Con-Psy, and fair performance (AUC ~0.72) when differentiating PDP from Con-PD. Importantly, the best performance was found in partly the same networks, including the thalamus. Alterations within selected SCNs may be related to the presence of psychotic symptoms in both early schizophrenia and PD psychosis, indicating some commonality of underlying mechanisms. Furthermore, results provide evidence that GM volume within specific SCNs may serve as a biomarker for identifying FEP and PDP.

Cortical and subcortical brain morphometry abnormalities in youth at clinical high-risk for psychosis and individuals with early illness schizophrenia

Neuroimaging studies have documented morphometric brain abnormalities in schizophrenia, but less is known about them in individuals at clinical high-risk for psychosis (CHR-P), including how they compare with those observed in early schizophrenia (ESZ). Accordingly, we implemented multivariate profile analysis of regional morphometric profiles in CHR-P (n = 89), ESZ (n = 93) and healthy controls (HC; n = 122). ESZ profiles differed from HC and CHR-P profiles, including 1) cortical thickness: significant level reduction and regional non-parallelism reflecting widespread thinning, except for entorhinal and pericalcarine cortex, 2) basal ganglia volume: significant level increase and regional non-parallelism reflecting larger caudate and pallidum, and 3) ventricular volume: significant level increase with parallel regional profiles. CHR-P and ESZ cerebellar profiles showed significant non-parallelism with HC profiles. Regional profiles did not significantly differ between groups for cortical surface area or subcortical volume. Compared to CHR-P followed for ≥18 months without psychosis conversion (n = 31), CHR-P converters (n = 17) showed significant non-parallel ventricular volume expansion reflecting specific enlargement of lateral and inferolateral regions. Antipsychotic dosage in ESZ was significantly correlated with frontal cortical thinning. Results suggest that morphometric abnormalities in ESZ are not present in CHR-P, except for ventricular enlargement, which was evident in CHR-P who developed psychosis.

Oxidative stress impairs cognitive function by affecting hippocampal fimbria volume in drug-naïve, first-episode schizophrenia.

The aim of the present study was to explore influencing factors of cognitive impairments and their interrelationships in drug-naïve, first-episode schizophrenia (SCZ). Patients with drug naïve, first episode SCZ and healthy controls (HCs) were enrolled. Cognitive function was assessed by the MATRICS Consensus Cognitive Battery (MCCB). Serum levels of oxidative stress indices, including folate, superoxide dismutase (SOD), uric acid (UA) and homocysteine (Hcy), were determined after an overnight fast. Hippocampal subfield volumes were measured using FreeSurfer. Mediation models were conducted using the SPSS PROCESS v3.4 macro. A false discovery rate (FDR) correction was applied for multiple comparisons. Sixty-seven patients with SCZ and 65 HCs were enrolled in our study. The patient group had significantly lower serum levels of folate and SOD and higher serum levels of HCY compared with the HCs (all p < 0.05). The patient group had a significantly smaller volume of the whole hippocampus than the HC group (p < 0.05). We also found significant volume differences between the two groups in the following subfields: CA1, molecular layer, GC-ML-DG and fimbria (all p < 0.05, uncorrected). The partial correlation analysis controlling for age and sex showed that the fimbria volume in the patient group was significantly positively associated with NAB scores (r = 0.382, pFDR = 0.024); serum levels of SOD in the patient group showed a significantly positive correlation with fimbria volume (r = 0.360, pFDR = 0.036). Mediation analyses controlling for age and sex showed that the serum levels of SOD in patients with SCZ had significant indirect effects on the NAB scores which were mediated by the fimbria volume [indirect effect = 0.0565, 95% CI from the bootstrap test excluding zero (0.0066 to 0.0891)]. Oxidative stress, a reduction in hippocampal subfield volumes and cognitive impairments occur in early SCZ. Oxidative stress impairs cognitive function by affecting hippocampal subfield volumes.

Mismatch Negativity and Theta Oscillations Evoked by Auditory Deviance in Early Schizophrenia

BackgroundAmplitude reduction of mismatch negativity (MMN), an event-related potential component indexing NMDA receptor–dependent auditory echoic memory and predictive coding, is widely replicated in schizophrenia. Time-frequency analyses of single-trial electroencephalography epochs suggest that theta oscillation abnormalities underlie MMN deficits in schizophrenia. However, this has received less attention in early schizophrenia (ESZ). MethodsPatients with ESZ (n = 89), within 5 years of illness onset, and healthy control subjects (n = 105) completed an electroencephalography MMN paradigm (duration-deviant, pitch-deviant, duration + pitch double-deviant). Repeated measures analyses of variance assessed group differences in MMN, theta intertrial phase coherence (ITC), and theta total power from frontocentral electrodes, after normal age adjustment. Group differences were retested after covarying MMN and theta measures. ResultsRelative to healthy control subjects, patients with ESZ showed auditory deviance deficits. Patients with ESZ had MMN deficits for duration-deviants (p = .041), pitch-deviants (ps = .007), and double-deviants (ps < .047). Patients with ESZ had reduced theta ITC for standards (ps < .040) and duration-deviants (ps < .030). Furthermore, patients with ESZ had reduced theta power across deviants at central electrodes (p = .013). MMN group deficits were not fully accounted for by theta ITC and power, and neither were theta ITC group deficits fully accounted for by MMN. Group differences in theta total power were no longer significant after covarying for MMN. ConclusionsPatients with ESZ showed reduced MMN and theta total power for all deviant types. Theta ITC showed a relatively specific reduction for duration-deviants. Although MMN and theta ITC were correlated in ESZ, covarying for one did not fully account for deficits in the other, raising the possibility of their sensitivity to dissociable pathophysiological processes.

Dysfunction of microstructure and metabolism in corpus callosum in juvenile schizophrenia

IntroductionThe corpus callosum (CC) is one of the important structures responsible for communication between the brain hemispheres. Its role is particularly important in cognitive tasks performance, information processing, concentration of attention, in mnestic processes. The corresponding dysfunctions are the major symptoms of schizophrenia, and hence, structural characteristics of CC in schizophrenics are in the focus of attention.ObjectivesThe aim of the study was to analyze the microstructural and metabolic features of the corpus callosum in recently onset schizophrenia.MethodsThe study was carried out in 13 men with juvenile endogenous paroxysmal psychosis (disease standing ≤ 5 years after first manifestation) aged 17-27 years (median 22.0±3.1 years). The studies were carried out during unfolding remission or in remission. Control group consisted of 15 mentally healthy young men (18-28 years). MRI and 1H-MRS studies were carried out on Achieva 3T MRI scanner device (Phillips). Diffuse tensor images were obtained in the axial plane using echo-planar pulse sequence. Diffuse gradients were applied in 32 noncolinear vectors. The spectra were recorded by single voxel 1H-MRS. The spectroscopic voxel (2×1×1 cm) was placed in the CC genu region. The PRESS sequence was used (TR/TE=1500/40 msec).ResultsStatistical analysis showed no abnormal diffusion values in the CC splenium in the patients. Significant changes in the parameters were found in the CC genu. The values of ADC and RD increased, while FA coefficient decreased in the CC genu of patients with the initial stage of schizophrenia; PD values were normal. The increase of RD in the presence of unchanged PD indicated a decrease of water diffusion velocity and anisotropy in the direction perpendicular to the axon orientation. A typical 1H-MRS of the CC genu was presented in Figure 1. The results of statistical analysis of metabolite signal intensities in the CC genu of patients and normal subjects were presented in Figure 2. NAA level was reduced significantly in the patients. No appreciable changes in Cho values in the CC genu were detected in the patients vs. normal subjects.Image:Image 2:ConclusionsThe increase of RD could be caused by several factors: impairment of myelin membranes, axon damage because of impairment of axon cytoskeleton, and changed organization of fibrils. Our results showed that RD increase in patients with early schizophrenia did not conform to active demyelination, which was proven by the normal level of Cho, while axon damage, shown by low level of NAA, did not lead to PD reduction.The decrease of NAA level detected in our study indicated axonal damage in the CC genu of patients in the early stage of schizophrenia. The increase of RD in the presence of normal Cho level seemed to indicate disorders in the axon cytoskeleton damage, but not active demyelination.Disclosure of InterestNone Declared

Increased blood neutrophil extracellular traps (NETs) associated with early life stress: translational findings in recent-onset schizophrenia and rodent model

Higher levels of interleukin (IL)-6 and elevated neutrophil counts are consistently reported in the blood of patients with schizophrenia. Stressors during childhood and/or adolescence are major socioenvironmental risk factors for schizophrenia and may contribute to immune dysregulation. Previous studies using blood cytokines to stratify patients with schizophrenia suggest that only a subset presents a low-grade inflammatory state. However, these studies have not addressed whether environmental factors such as childhood maltreatment contributed to identifying inflammatory clusters. Moreover, a neutrophil-related mechanism (Neutrophil Extracellular Traps; NETs) central to both the initiation and chronicity of autoimmune and inflammatory diseases has never been investigated in psychiatry. Elevated NETs in schizophrenia may predispose patients to inflammatory and autoimmune diseases resulting in reduced life expectancy. We, therefore, investigated NETs as a novel mechanism and biological target in early schizophrenia and their role together with IL-6 and childhood maltreatment in identifying cluster subgroups. We found increased NETs in the plasma of patients with early schizophrenia (n = 78) compared to both their unaffected siblings (n = 25) and community controls (n = 78), irrespective of sex, body mass index, psychoactive drug use, or tobacco smoking. Increased NETs in patients were unrelated to antipsychotic treatment, which was further tested in vitro using fresh neutrophils. By applying unsupervised two-step clustering analysis, we integrated values of NETs, IL-6, and childhood maltreatment scores. We identified two main clusters; childhood maltreatment scores and NETs were the most important variables contributing to cluster separation (high-CL1 and low-CL2), while IL-6 was the least contributor. Patients allocated in the high-CL1 (61.5%) had significantly higher childhood maltreatment scores, NETs, and IL-6 levels than the remaining groups (patients low-CL2, siblings, and controls high-CL1 and low-CL2). We complemented these findings with a rat model based on stress exposure during adolescence that results in several schizophrenia-like changes in adulthood. We found that adolescent stressed rats had higher NETs and IL-6 levels in serum compared to non-stressed rats with a tendency to produce more NETs from the bone marrow. Altogether, this study brings a novel cellular-based mechanism in schizophrenia that, combined with early-stress, could be useful to identify subgroups for more personalised treatments.

Moderators of metacognitive strategy training for executive functioning in early schizophrenia and psychosis risk

Goal Management Training (GMT) improved self-reported executive functioning in a recent randomized, controlled trial in early intervention for psychosis participants. Little is known about the mechanism for this benefit, so this study investigates objectively measured executive function, the difference between subjective and objective executive function, independent living and employment status as potential moderators of efficacy of GMT.Baseline scores from 81 participants (GMT n = 39 vs Treatment-as-usual; TAU n = 42) were analyzed in a linear mixed model analysis for repeated measures as predictors of improvement on the self-reported Behavior Rating Inventory of Executive Function–Adult version (BRIEF-A) immediately and 30 weeks after GMT. Potential moderators were scores from objective measures of executive functioning, discrepancy between subjective and objective measures, independent living and employment status. Discrepancy was assessed by comparing four clusters of participants with differing patterns of scores.The effect of GMT remained significant regardless of initial objective executive functioning at baseline. Those with higher subjective complaints at baseline in two clusters with (i) both objective and subjective executive dysfunction, and (ii) mostly subjective executive dysfunction experienced greater change after treatment. Living arrangements or participation in education or work did not significantly moderate the effects of GMT.Poor performance on neuropsychological tasks is not an obstacle to making use of GMT, but further knowledge is needed about the benefits of strategy training for individuals with a combination of poor performance with few subjective complaints.

Discovery of early schizophrenia through neuroimaging

In order to understand the pathophysiology of schizophrenia we carried out a number of brain imaging studies in both medicated and unmedicated patients. In addition, to help unravel the pathophysiological mechanisms without the confound of prior exposure to antipsychotic medication or chronicity, we enrolled a large group of antipsychotic medication-naïve first episode psychosis patients at first treatment contact, and performed longitudinal multimodal neuroimaging studies over several months.In unmedicated patients we found both functional and structural connectivity alterations. Similarly, in medication-naïve patients we replicated many of our prior findings, suggesting that functional and structural connectivity alterations are core pathological features of the illness. We found that a longer duration of untreated psychosis, i.e. the time between first symptom onset and initial treatment contact, was associated with greater structural and functional connectivity abnormalities, which in turn was associated with worse subsequent clinical response to treatment.These results underscore the critical importance of early identification and treatment in patients with psychosis spectrum disorders.

Cerebrospinal fluid concentration of complement component 4A is increased in first episode schizophrenia

Postsynaptic density is reduced in schizophrenia, and risk variants increasing complement component 4A (C4A) gene expression are linked to excessive synapse elimination. In two independent cohorts, we show that cerebrospinal fluid (CSF) C4A concentration is elevated in patients with first-episode psychosis (FEP) who develop schizophrenia (FEP-SCZ: median 0.41 fmol/ul [CI = 0.34–0.45], FEP-non-SCZ: median 0.29 fmol/ul [CI = 0.22–0.35], healthy controls: median 0.28 [CI = 0.24–0.33]). We show that the CSF elevation of C4A in FEP-SCZ exceeds what can be expected from genetic risk variance in the C4 locus, and in patient-derived cellular models we identify a mechanism dependent on the disease-associated cytokines interleukin (IL)−1beta and IL-6 to selectively increase neuronal C4A mRNA expression. In patient-derived CSF, we confirm that IL-1beta correlates with C4A controlled for genetically predicted C4A RNA expression (r = 0.39; CI: 0.01–0.68). These results suggest a role of C4A in early schizophrenia pathophysiology.

The psychotomimetic ketamine disrupts the transfer of late sensory information in the corticothalamic network.

In prodromal and early schizophrenia, disorders of attention and perception are associated with structural and chemical brain abnormalities and with dysfunctional corticothalamic networks exhibiting disturbed brain rhythms. The underlying mechanisms are elusive. The non-competitive NMDA receptor antagonist ketamine simulates the symptoms of prodromal and early schizophrenia, including disturbances in ongoing and task & sensory-related broadband beta-/gamma-frequency (17-29 Hz/30-80 Hz) oscillations in corticothalamic networks. In normal healthy subjects and rodents, complex integration processes, like sensory perception, induce transient, large-scale synchronised beta/gamma oscillations in a time window of a few hundred ms (200-700 ms) after the presentation of the object of attention (e.g., sensory stimulation). Our goal was to use an electrophysiological multisite network approach to investigate, in lightly anesthetised rats, the effects of a single psychotomimetic dose (2.5mg/kg, subcutaneous) of ketamine on sensory stimulus-induced oscillations. Ketamine transiently increased the power of baseline beta/gamma oscillations and decreased sensory-induced beta/gamma oscillations. In addition, it disrupted information transferability in both the somatosensory thalamus and the related cortex and decreased the sensory-induced thalamocortical connectivity in the broadband gamma range. The present findings support the hypothesis that NMDA receptor antagonism disrupts the transfer of perceptual information in the somatosensory cortico-thalamo-cortical system.

Cerebellar Functional Dysconnectivity in Drug-Naïve Patients With First-Episode Schizophrenia.

Cerebellar functional dysconnectivity has long been implicated in schizophrenia. However, the detailed dysconnectivity pattern and its underlying biological mechanisms have not been well-charted. This study aimed to conduct an in-depth characterization of cerebellar dysconnectivity maps in early schizophrenia. Resting-state fMRI data were processed from 196 drug-naïve patients with first-episode schizophrenia and 167 demographically matched healthy controls. The cerebellum was parcellated into nine functional systems based on a state-of-the-art atlas, and seed-based connectivity for each cerebellar system was examined. The observed connectivity alterations were further associated with schizophrenia risk gene expressions using data from the Allen Human Brain Atlas. Overall, we observed significantly increased cerebellar connectivity with the sensorimotor cortex, default-mode regions, ventral part of visual cortex, insula, and striatum. In contrast, decreased connectivity was shown chiefly within the cerebellum, and between the cerebellum and the lateral prefrontal cortex, temporal lobe, and dorsal visual areas. Such dysconnectivity pattern was statistically similar across seeds, with no significant group by seed interactions identified. Moreover, connectivity strengths of hypoconnected but not hyperconnected regions were significantly correlated with schizophrenia risk gene expressions, suggesting potential genetic underpinnings for the observed hypoconnectivity. These findings suggest a common bidirectional dysconnectivity pattern across different cerebellar subsystems, and imply that such bidirectional alterations may relate to different biological mechanisms.

Abnormal levels of mitochondrial Ca2+ channel proteins in plasma neuron-derived extracellular vesicles of early schizophrenia.

Structural alterations or quantitative abnormalities of some mitochondrial ion channels and exchangers are associated with altered neuronal functions and increased susceptibility to mental illness. Here we have assessed levels of functionally prominent mitochondrial calcium ion channel proteins in plasma neuron-derived extracellular vesicles (NDEVs) of living patients with first episodes of psychosis (FP) and matched controls (Cs). NDEVs were enriched with an established method of precipitation and immunoabsorption by anti-human CD171 neural adhesion protein (L1CAM) antibody and extracted proteins quantified with ELISAs. CD81 exosome marker-normalized NDEV levels of leucine zipper EF-hand containing transmembrane 1 protein (LETM1), transient receptor potential cation channel subfamily M, member 4 (TRPM4), and solute carrier family 8 member B1 (SLC24A6) or mitochondrial Na+ /Ca2+ exchanger (NCLX) were significantly lower for FP patients (n=10) than Cs (n=10), whereas NDEV levels of voltage-dependent L-type calcium channel subunit α-1C (CACNA-1C) were significantly higher for FP patients than Cs. Abnormal structures or mitochondrial levels of LETM1, NCLX, and CACNA-1C have been linked through analyses of individual proteins, genome-wide association studies, and whole exome protein-coding sequence studies to neurodevelopmental disorders, mental retardation, schizophrenia, and major depressive diseases. A greater understanding of the altered calcium homeostasis in schizophrenia, that is attributable to underlying mitochondrial calcium channel abnormalities, will lead to improved diagnosis and treatment.

Naturalistic study on the use of clozapine in the early phases of non-affective psychosis: A 10-year follow-up study in the PAFIP-10 cohort

Clozapine is seldom prescribed in treatment-resistant schizophrenia (TRS) patients during early phases of the illness. We aimed to examine the pathway and patterns and the impact of clozapine use in patients with TRS who were followed up for 10 years after the first outbreak of the illness. Data were obtained retrospectively from an epidemiological cohort of first episode schizophrenia patients (n = 218) who had been treated in a specialized intervention program (PAFIP). Out of 218, 35 (16%) individuals were on clozapine at 10-year assessment, while 183 (84%) were taking other antipsychotics. Among those 183 psychosis subjects who were not on clozapine, 13 (7.1%) met criteria for TRS. In the clozapine group, ten (28.6%) met criteria for early-TR and twenty-five (71.4%) met criteria for late-TR. Before clozapine treatment was initiated, the median number of days under other antipsychotic treatment was 1551 days (IQR = 1715) and the median time that subjects remained on clozapine was 6.3 years (IC95%: 5.49–7.20). At 10 years, we found that those individuals taking clozapine had higher CGI total scores (F = 12.0, p = 0.001) and SANS total scores (F = 9.27, p = 0.003) than subjects taking other antipsychotics after correcting for baseline values. Interestingly, when performing these analyses at 10 years between subjects taking clozapine (n = 35) and subjects who despite meeting TRS criteria were not taking clozapine (n = 13), we found that subjects taking clozapine had significantly lower total scores on all clinical scales compared with subjects who met TRS criteria and were not taking clozapine (p values < 0.05). TRS patients who took the longest time to start clozapine (third tertile) showed significantly higher CGI scores at 10-year follow-up compared to those who initiated clozapine earlier (first tertile) (t = 2.60; p = 0.043). Our findings reinforce the need of a timely assessment of treatment-resistant criteria in early schizophrenia patients and highlight the long-term benefits of an early introduction of clozapine on those patients meeting treatment-resistant criteria.