Schizophrenia Bulletin最新文献

Background and hypothesis: Schizophrenia is a devastating psychiatric disorder characterized by positive (eg, hallucinations) and negative (eg, reduced motivation) symptoms, and cognitive deficits. Chronic gastrointestinal tract issues exist as comorbid symptoms of schizophrenia. Recent findings indicate the involvement of the microorganisms that inhabit the gut, the microbiota (and the broader microbiome which also includes microbial genomes, etc.) in schizophrenia pathogenesis. In the present study, we hypothesized that chronic administration with prebiotics fructooligosaccharide and galactooligosaccharide (FOS and GOS; a combination used clinically for other disorders) would restore gut microbiome composition of the metabotropic glutamate receptor 5 (mGlu5) knockout (KO) mouse model of schizophrenia, which we previously demonstrated to exhibit gut dysbiosis.

Study design: We assessed the impact of prebiotics on gut microbiome composition and function, as well as the gastrointestinal function and schizophrenia-like phenotype of mGlu5 KO mice and wild-type littermates. We administered a combination of the prebiotics FOS and GOS, vs vehicle control administration, in both the mouse model of schizophrenia and wild-type littermates.

Study results: The present study firstly corroborated the altered gut microbiome composition in the mGlu5 KO mouse model of schizophrenia. Importantly, we have revealed an altered microbial metabolic profile. We have also shown that the prebiotics we administered were not only able to rescue these gut microbiome changes but also had additional beneficial effects including cognitive enhancement and improved gastrointestinal function.

Conclusion: These preclinical findings indicate that prebiotics, such as the combination of FOS and GOS used in the present study, may have therapeutic potential in schizophrenia as an add-on intervention with an exceptional safety profile.

Background and hypothesis: Self-dehumanization is the experience of feeling less or other than human, and is known to be experienced by people with psychosis. Existing measures of self-dehumanization are limited in their applicability to psychosis, and have not been developed with people with lived experience. The aim of this study was to develop and validate a measure of self-dehumanization in psychosis in partnership with key stakeholder groups.

Study design: Firstly, domains were specified based on review of existing theories of self-dehumanization and qualitative research on self-dehumanization in psychosis. Secondly, items were generated from a systematic literature review of existing measures of self-dehumanization, transcripts from qualitative research on self-dehumanization in psychosis, and lived experience consultations. Third, items were reduced and revised in a Delphi study (n = 49). Fourth, cognitive interviews (n = 9) were conducted to improve comprehensibility and further revise items. Finally, in psychometric validation, the DiPS underwent exploratory and confirmatory factor analysis, item reduction, and reliability and validity assessment (n = 456).

Study results: The 13-item DiPS was developed. Both two- and four-factor solutions were tested; the four-factor solution, comprising Humanity, Identity, Personhood, and Agency, demonstrated optimal fit. The DiPS showed strong construct validity, correlating positively with internalized stigma, paranoid thoughts, and voice-hearing, and negatively with self-compassion. Test-retest reliability and internal consistency were excellent.

Conclusions: The DiPS is a reliable and valid measure of self-dehumanization in psychosis. This novel measure can be used in research and clinical practice to better understand distress in psychosis.

Background: Early intervention in first-episode psychosis (FEP) is critical for long-term outcomes with antipsychotic medicines among the primary treatment options. However, existing clinical practice guidelines (CPGs) do not provide sex-specific recommendations, despite females experiencing distinct vulnerabilities to antipsychotic side-effects. In particular, hyperprolactinemia and cardiometabolic side-effects are associated with substantial subjective distress and potential long-term physical health risks for females across the reproductive lifespan. We aimed therefore to develop a CPG on the preferred antipsychotic medicines for females experiencing FEP.

Study design: An international multidisciplinary panel, including experts-by-experience, used the GRADE-ADOLOPMENT process and AGREE II framework to adapt existing FEP guidelines for adults and adolescents. Key health questions were developed through stakeholder consultation and literature review. Critically important patient outcomes were prioritized, and evidence was synthesized on side-effect profiles, with recommendations agreed by consensus. The guideline algorithm was field-tested and externally reviewed by experts.

Study results: Prolactin-elevation and cardiometabolic side-effects were prioritized in antipsychotic medicine selection for females. Medicines with higher risks-first-generation antipsychotics, olanzapine, quetiapine, risperidone, paliperidone, and amisulpride-are not recommended first-line. Aripiprazole is recommended as the preferred first-choice due to its consistently favorable prolactin and cardiometabolic profile. Alternative options with low or low-to-medium risk profiles are recommended for adults and adolescents, supported by shared decision-making tools.

Conclusions: This is the first CPG addressing antipsychotic choice for females with FEP. By prioritizing critically important patient outcomes and lived experience, the guideline supports safer, sex-sensitive prescribing for females that may improve treatment acceptability, adherence, and equity in psychosis care.

Background and hypothesis: The amygdala, crucial for mood, anxiety, fear, and reward regulation, shows neuroanatomical and molecular divergence in psychiatric disorders like schizophrenia, bipolar disorder and major depression. This region is also emerging as an important regulator of metabolic and immune pathways. The goal of this study is to address the paucity of molecular studies in the human amygdala. We hypothesize that diagnosis-specific gene expression alterations contribute to the unique pathophysiological profiles of these disorders.

Study design: We used a cohort of subjects diagnosed with SCZ, BPD or MDD, and nonpsychiatrically ill control subjects (n = 15/group), together with our bioinformatic 3-pod analysis consisting of full transcriptome pathway analysis, targeted pathway analysis, leading-edge gene analysis and iLINCS perturbagen analysis.

Study results: We identified altered expression of metabolic pathways in each disorder. Subjects with SCZ displayed downregulation of mitochondrial respiration and nucleotide metabolism pathways. In comparison, we observed upregulation of mitochondrial respiration pathways in subjects with MDD, while subjects with BPD displayed enrichment of pathways involved in carbohydrate metabolism. Several pathways associated with brain metabolism including immune system processes and calcium ion transport were also differentially altered between diagnosis groups.

Conclusion: Our findings suggest metabolic pathways, including downregulation of energy metabolism pathways in SCZ and upregulation of energy metabolism pathways in MDD, are uniquely altered in the amygdala in these disorders, which may impact approaches for therapeutic strategies.

Background and hypothesis: Negative symptoms of schizophrenia (SCZ), particularly amotivation, are prominent across both SCZ and bipolar disorder (BD). While orbitofrontal cortex (OFC) alterations have been implicated in the development of negative symptoms, their contributions across disorders remain to be established. Here, we examined how OFC thickness and network associations relate to amotivation compared to diminished expression across the BD-SCZ spectrum.

Study design: We included 50 individuals with SCZ, 49 with BD, and 122 controls. We assessed amotivation and diminished expression and estimated thickness in the medial and lateral OFC as regions of interest as well as 64 other cortical regions.

Study results: Across BD and SCZ, reduced right lateral and bilateral medial OFC thickness were specifically associated with amotivation, but not diminished expression or other clinical factors. We then generated intra-individual OFC structural covariance networks to evaluate how the system-level embedding of the OFC would link to brain-wide cortical maps of negative symptoms. We found that medial OFC covariance networks spatially correlated with the brain-wide cortical alterations of both negative symptom dimensions. Further analyses in independent SCZ data from the ENIGMA consortium (n = 4474) revealed associations with lateral OFC covariance networks. Finally, the brain-wide cortical alterations of amotivation were significantly correlated with normative functional and structural white-matter connectivity profiles of the right medial and left lateral OFC as well as adjacent prefrontal and limbic regions.

Conclusions: Our work identifies OFC alterations as a possible transdiagnostic signature of amotivation and provides insights into network associations underlying the system-wide cortical alterations of negative symptoms across SCZ and BD.

Background and hypothesis: The social defeat hypothesis posits that exclusion and discrimination experienced by socially marginalized populations predict psychotic experiences (PEs), particularly when perceived as defeatist. However, its emphasis on individual-level factors may obscure the role of structural and systemic influences. This is significant for the US context, given US histories of pronounced structural racism and economic inequality. This study extends the social defeat hypothesis by examining established indicators of social defeat, along with US-specific factors that capture structural influences on individuals' perceptions of discrimination and exclusion as defeatist.

Design: Data from the National Survey of Poly-victimization and Mental Health (N = 1 584) were analyzed to investigate cross-sectional associations between individual-level and structural indicators of marginalization and social defeat and self-reported PEs among young adults.

Study results: BIPOC participants had 60% higher odds of reporting PEs in the past year (OR = 1.60; 95% CI, 1.27-2.03; P = .003). Furthermore, participants with at least 1 experience of police violence in the past year have 52% higher odds of reporting PEs (OR = 1.52; 95% CI, 1.16-2.00; P = .003). Several additional indicators were associated with increased odds of PE, including race (non-White compared to White), high-frequency substance use, everyday discrimination, exposure to childhood abuse or bullying.

Conclusions: Findings align with European social defeat literature, confirming the relevance of the hypothesis in the US context. However, prominence of structural factors (racism, police violence) suggests that the social defeat hypothesis should incorporate systemic influences, emphasizing the need for interventions addressing societal contributors to psychosis risk.

Background: Evidence suggests that patients with schizophrenia (SZ) experience an acceleration of the typical aging process. However, it is unclear whether this process reflects premature aging in early life or accelerated aging in later years. Nevertheless, although the timing of accelerated aging in SZ is unclear, there is a consensus that this process is characterized by dysfunctions in immune-oxidative pathway.

Methods: It is a critical need to understand the mechanisms and trajectory of aging underlying SZ so we can target interventions earlier to the right mechanisms. This paper aims to review the recent literature regarding brain energy metabolism in aging with SZ, mainly focusing on the dysfunctions in immuno-oxidative pathway, limitations of studying aging in SZ, and perspective strategies for future studies.

Results: Most studies reviewed in this paper point toward age-related metabolic and cognitive alterations in individuals with SZ. There are complex relationships between normative aging processes and those in SZ. However, the available data neither definitively reveal when this acceleration occurs within the life span nor attribute premature onset of aging-related changes solely to a diagnosis of SZ.

Conclusions: Immuno-oxidative pathway dysregulation represents convergent processes underlying the pathophysiology of both SZ and aging, contributing to synaptic dysfunction, neuronal damage, and cognitive impairment. Further research in this domain, using an innovative accelerated longitudinal design and novel, advanced neuroimaging techniques, might open new avenues for understanding common pathophysiological mechanisms and developing therapeutic interventions targeting these interconnected pathways.

Background and hypothesis: Excessive saturated or deficient unsaturated fatty acids and white matter microstructural abnormalities are observed before the psychosis onset. Whereas fatty acids variations are implicated in white matter pathology, conventional Diffusion Tensor Imaging has limitations in disentangling their biological relevance. Free-water imaging provides improved biological specificity to white matter microstructure, such as fractional volume of free-water (FW) and tissue-specific fractional anisotropy (FAt). This study aims to investigate the associations between altered proportion of saturated or unsaturated fatty acids and free-water imaging parameters in prodromal psychosis.

Study design: We applied free-water imaging and Tract-Based Spatial Statistics to compare FAt and FW between 78 individuals with at-risk mental state (ARMS) and 129 healthy controls. In a subsample with available blood samples (n = 53 and n = 42, respectively), relationships between fatty acid composition of erythrocyte membrane and FAt or FW were examined alongside clinical and cognitive variables.

Study results: Compared to the controls, individuals with ARMS exhibited higher relative concentrations of saturated fatty acids as well as lower FAt and higher FW in multiple association and projection fibers. In the ARMS group, elevated proportion of saturated fatty acids was associated with lower FAt and with positive symptoms and impaired verbal fluency.

Conclusions: The association of saturated fatty acids with FAt in ARMS suggests that fatty acids may influence disrupted white matter microstructure, such as impaired myelin maintenance prior to psychosis onset. Future studies should explore early interventions to mitigate white matter cellular deterioration by optimizing saturated fatty acid levels.

Background and hypothesis: During menopause, estrogen levels change dramatically, which may decrease clozapine blood concentrations in women via estrogen's inhibitory effect on CYP1A2 activity. This reduction could contribute to increased relapse rates seen in older women with psychotic disorders.

Study design: Clozapine blood concentration data were retrieved from the University Medical Center Groningen, the Netherlands. A total of 982 patients (720 men, 262 women), aged 40-60, with 17 104 measurements, were included for analyses. Latent class growth analysis (LCGA) assessed clozapine trajectories by sex, while linear mixed-effects models (LMEM) assessed sex differences between trajectory classes.

Study results: The optimal LCGA model (7-quantile splines) identified 3 clusters. Most women (n = 157, 60%) showed a decline in clozapine levels from 520 to 400 μg/L between the ages of 40-60. In contrast, most men (n = 392, 54%) had stable levels (mean 460 μg/L). Two other trajectories appeared in both sexes: a mild increase starting at age 45 (men: n = 272, 38%; women: n = 97, 37%) and a marked increase from 40 to 60 (men: n = 56, ~8%; women: n = 8, ~3%). LMEM showed significantly higher levels in women than men with stable trajectories (estimate = 177.03, t = 2.62, P < .01). A significant age-by-sex interaction (estimate = -0.067, t = -2.63, P < .01) suggested these differences varied over time.

Conclusions: Sex-specific longitudinal trajectories of clozapine concentrations showed declines in 60% of women aged 40-60, while most men remained stable. As decreasing blood levels could increase relapse vulnerability, monitoring clinical efficacy and side effects is warranted during menopause.