Schizophrenia Bulletin Open最新文献

Treatment-resistant schizophrenia (TRS) affects around 30% of patients with schizophrenia (SZ) resulting in poor functioning, relapses, and reduced quality of life. Convergent findings show that inflammation could contribute to resistance. We thus search for immune signatures of patients with TRS/ultra TRS (UTRS) in a sample of community-dwelling outpatients with SZ. In total, 195 stabilized SZ patients (mean age = 31.2 years, 73% male gender) were consecutively included in the network of the FondaMental Expert Centers for Schizophrenia in France and received a thorough clinical assessment. At inclusion, psychotic symptomatology was evaluated by the Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Circulating serum/plasma levels of a large panel of markers reflecting the main inflammatory pathways were evaluated. TRS was defined by current treatment by clozapine (CLZ) and UTRS by current CLZ treatment + PANSS total score ≥ 70. The frequency of TRS and UTRS patients was, respectively, 20% and 7.7% and was defined using multivariable analysis elevated by high levels of interleukin (IL)-12/IL-23p40, IL-17A, IL-10, and beta 2 microglobulin (B2M) and IL-12/IL-23p40, IL-17A, IL-6, IL-10, IFNγ, and B2M, respectively. These observations suggest that resistance and ultra resistance to CLZ treatment are underpinned by pro-inflammatory molecules mainly belonging to the T helper 17 pathway, a finding making sense given the interplay between inflammation and antipsychotic treatment responses. If confirmed, our findings may allow us to consider IL-23/IL-17 pathway as a therapeutic target for patients with resistance to antipsychotics.

Background: Determining the best latent structure of negative symptoms in schizophrenia could benefit assessment tools, neurobiological research, and targeted interventions. However, no review systematically evaluated studies that assessed and validated latent models of negative symptoms.

Objective: To identify and evaluate existing latent structure models in the literature of negative symptoms and to determine the best model.

Method: Systematic search of MEDLINE, EMBASE, and Scopus on July 19, 2020, for confirmatory factor analysis models of negative symptoms in patients with schizophrenia. The available evidence was assessed through 2 sets of criteria: (1) study design quality-based on negative symptoms assessment and modeling strategy and (2) psychometric quality and model fit-based on fit indices and factor definition quality.

Results: In total, 22 studies (n = 17 086) from 9 countries were included. Studies differed greatly regarding symptom scales, setting, and sample size (range = 86-6889). Dimensional models included 2-6 factors (median = 4). Twelve studies evaluated competing models and adopted appropriate instruments to assess the latent structure of negative symptoms. The 5-factor and hierarchical models outperformed unitary, 2-factor, and 3-factor models on all direct comparisons, and most of the analyses derived from the Brief Negative Symptom Scale. Considering the quality criteria proposed, 5-factor and hierarchical models achieved excellent fit in just one study.

Conclusions: Our review points out that the 5-factor and hierarchical models represent the best latent structure of negative symptoms, but the immaturity of the relevant current literature may affect the robustness of this conclusion. Future studies should address current limitations regarding psychometric properties and also address biological and clinical validity to refine available models.

It is unclear whether inequalities in mental healthcare and mortality following the onset of psychosis exist by migrant status and region-of-origin. We investigated whether (1) mortality (including by major causes of death); (2) first admission type (inpatient or outpatient); (3) in-patient length of stay (LOS) at first diagnosis for psychotic disorder presentation, and; (4) time-to-readmission for psychotic disorder differed for refugees, non-refugee migrants, and by region-of-origin. We established a cohort of 1 335 192 people born 1984-1997 and living in Sweden from January 1, 1998, followed from their 14th birthday or arrival to Sweden, until death, emigration, or December 31, 2016. People with ICD-10 psychotic disorder (F20-33; N = 9399) were 6.7 (95% confidence interval [95%CI]: 5.9-7.6) times more likely to die than the general population, but this did not vary by migrant status (P = .15) or region-of-origin (P = .31). This mortality gap was most pronounced for suicide (adjusted hazard ratio [aHR]: 12.2; 95% CI: 10.4-14.4), but persisted for deaths from other external (aHR: 5.1; 95%CI: 4.0-6.4) and natural causes (aHR: 2.3; 95%CI: 1.6-3.3). Non-refugee (adjusted odds ratio [aOR]: 1.4, 95%CI: 1.2-1.6) and refugee migrants (aOR: 1.4, 95%CI: 1.1-1.8) were more likely to receive inpatient care at first diagnosis. No differences in in-patient LOS at first diagnosis were observed by migrant status. Sub-Saharan African migrants with psychotic disorder were readmitted more quickly than their Swedish-born counterparts (adjusted sub-hazard ratio [sHR]: 1.2; 95%CI: 1.1-1.4). Our findings highlight the need to understand the drivers of disparities in psychosis treatment and the mortality gap experienced by all people with disorder, irrespective of migrant status or region-of-origin.

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.

Treatment-resistant schizophrenia (TRS) has been suggested to involve glutamatergic dysfunction. Glutathione (GSH), a dominant antioxidant, is known to be involved in glutamatergic neurotransmission. To date, no study has examined GSH levels in patients with TRS. The aim of this study was to examine GSH levels in the dorsal anterior cingulate cortex (dACC) of patients with TRS. Patients with schizophrenia were categorized into 3 groups with respect to their antipsychotic response: (1) clozapine (CLZ) nonresponders, (2) CLZ responders, and (3) first-line responders (FLR). GSH and glutamine + glutamate (Glx) levels were measured using 3T proton magnetic resonance spectroscopy. Firstly, dACC GSH levels were compared among the patient groups and healthy controls (HCs). Further, relationships between GSH and Glx levels were compared between the groups and GSH levels were explored stratifying the patient groups based on the glutamate-cysteine ligase catalytic (GCLC) subunit polymorphism. There was no difference in GSH levels between the groups. FLR showed a more negative relationship between GSH and Glx levels in the dACC compared to HCs. There were no effects of GCLC genotype on the GSH levels. However, CLZ responders had a higher ratio of high-risk GCLC genotype compared to CLZ nonresponders. This study demonstrated different relationships between GSH and Glx in the dACC between groups. In addition, the results suggest a potential link between CLZ response and GCLC genotype. However, it still remains unclear how these differences are related to the underlying pathophysiology of schizophrenia subtypes or the mechanisms of action of CLZ.

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.

Schizophrenia is a severe neuropsychiatric disorder associated with a wide array of transcriptomic and neurobiochemical changes. Genome-wide transcriptomic profiling conducted in postmortem brain have provided novel insights into the pathophysiology of this disorder, and identified biological processes including immune/inflammatory-related responses, metabolic, endocrine, and synaptic function. However, few studies have investigated whether similar changes are present in peripheral tissue. Here, we used RNA-sequencing to characterize transcriptomic profiles of lymphocytes in 18 nonpsychotic controls and 19 individuals with schizophrenia. We identified 2819 differentially expressed transcripts (P _nominal < .05) in the schizophrenia group when compared to controls. Bioinformatic analyses conducted on a subset of 293 genes (P _nominal < .01 and |log₂ FC| > 0.5) highlighted immune/inflammatory responses as key biological processes in our dataset. Differentially expressed genes in lymphocytes were highly enriched in gene expression profiles associated with cortex layer 5a and immune cells. Thus, we investigated whether the changes in transcripts levels observed in lymphocytes could also be detected in the prefrontal cortex (PFC, BA10) in a second replication cohort of schizophrenia subjects. Remarkably, mRNA levels detected in the PFC and lymphocytes were in strong agreement, and measurements obtained using RNA-sequencing positively correlated with data obtained by reverse transcriptase-quantitative polymerase chain reaction analysis. Collectively, our work supports a role for immune dysfunction in the pathogenesis of schizophrenia and suggests that peripheral markers can be used as accessible surrogates to investigate putative central nervous system disruptions.

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 glutamate 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.

Background: Converging evidence indicates impaired brain energy metabolism in schizophrenia and other psychotic disorders. Creatine kinase (CK) is pivotal in providing adenosine triphosphate in the cell and maintaining its levels when energy demand is increased. However, the activity of CK has not been investigated in patients with first-episode schizophrenia spectrum disorders.

Methods: Using in vivo phosphorus magnetization transfer spectroscopy, we measured CK first-order forward rate constant (k _f ) in the frontal lobe, in patients with first-episode psychosis (FEP; n = 16) and healthy controls (n = 34), at rest.

Results: CK k _f was significantly reduced in FEP compared to healthy controls. There were no differences in other energy metabolism-related measures, including phosphocreatine (PCr) or ATP, between groups. We also found increase in glycerol-3-phosphorylcholine, a putative membrane breakdown product, in patients.

Conclusions: The results of this study indicate that brain bioenergetic abnormalities are already present early in the course of schizophrenia spectrum disorders. Future research is needed to identify the relationship of reduced CK k _f with psychotic symptoms and to test treatment alternatives targeting this pathway. Increased glycerol-3-phosphorylcholine is consistent with earlier studies in medication-naïve patients and later studies in first-episode schizophrenia, and suggest enhanced synaptic pruning.

Objective: To estimate prevalence of major cardiovascular events among people with schizophrenia who had experience of sleep disturbance, sedentary behavior or muscular weakness, and assess evidence for raised prevalence in these individuals compared to people with schizophrenia without these characteristics.

Methods: UK Biobank data on individuals diagnosed with schizophrenia (n = 1544) were used to examine the prevalence of major cardiovascular events, specifically myocardial infarction, stroke, heart failure and cardiovascular death, among participants with candidate risk factors. Generalized linear models were fitted to estimate prevalence ratios (PRs) for major cardiovascular events among participants with self-reported sleep disturbance, self-reported sedentary behavior, and muscular weakness measured using a handgrip dynamometer. These ratios were adjusted for QRISK3 score-a validated cardiovascular risk prediction algorithm for the UK population.

Results: Prevalence of major cardiovascular events was significantly higher among participants with daytime sleepiness, independent of QRISK3 score, and snoring, a proxy for sleep-disordered breathing (adjusted PR 1.26; 95% CI 1.03, 1.55, P = .03). Prevalence was also independently higher among participants with low muscular strength (adjusted PR1.36; 95% CI 1.05, 1.75, P = .02). The adjusted prevalence ratios among participants with short or prolonged sleep duration, insomnia, or sedentary behavior did not indicate independently raised prevalence among these groups.

Conclusion: Prevalence of major cardiovascular events among people with schizophrenia was higher in participants with muscular weakness and sleep disturbance evidenced by daytime sleepiness. Further research is required to determine how these factors can be routinely identified and addressed in the clinical management of cardiovascular risk among patients with schizophrenia.