There is a considerable overlap in clinical features and genetics between schizophrenia (SZ) and bipolar disorder (BD). Previous neuroimaging research has demonstrated common and distinct brain damage patterns between relatives (RELs) of SZ and BD patients, suggesting shared and differential genetic influences on the brain. Despite an increasing recognition that disorders localize better to distributed brain networks than individual brain regions, studies investigating network localization of genetic risk for SZ and BD are still lacking.

To address this gap, we initially identified brain functional and structural damage locations in SZ- and BD-RELs from 103 published studies with 2364 SZ-RELs, 864 BD-RELs, and 4114 healthy controls. By applying novel functional connectivity network mapping to large-scale discovery and validation resting-state functional MRI datasets, we mapped these affected brain locations to four disorder-susceptibility networks.

SZ-susceptibility functional damage network primarily involved the executive control and salience networks, while its BD-counterpart principally implicated the default mode and basal ganglia networks. SZ-susceptibility structural damage network predominantly involved the auditory and default mode networks, yet its BD-counterpart mainly implicated the language and executive control networks. Although these networks showed cross-disorder inconsistencies when focusing on either imaging modality alone, the combined SZ- and BD-susceptibility brain damage networks had a substantially increased spatial similarity.

These findings may support the concept that SZ and BD represent distinct diagnostic categories from a neurobiological perspective, helping to clarify the common network substrates via which the shared genetic mechanisms underlying both disorders give rise to their overlapping clinical phenotypes.

Schizophrenia is associated with a reduced average lifespan due to accelerated ageing. Early studies have predominantly focused on the global brain age gap, limiting our understanding of region-specific ageing. Moreover, the relationship between accelerated ageing and schizophrenia disease progression has not been directly examined.

Our aim was to investigate the cortical spatiotemporal patterns in ageing and disease progression in schizophrenia.

Using multi-site, resting-state functional magnetic resonance imaging data, we analysed intrinsic activity fluctuations in 2353 healthy controls and 546 subjects with schizophrenia. We assessed normative models of ageing trajectories in brain activities in healthy controls, and examined the developmental trajectory of deviations from normative reference ranges with disease progression in schizophrenia.

The ageing trajectories of both groups demonstrated spatiotemporal variability unfolding along the sensorimotor–association cortical axis, characterised by a rapid decline in transmodal association cortices at younger ages and followed by an accelerated decline in primary cortices at older ages. However, schizophrenia exhibited a more rapid rate of decline across the entire cerebral cortex, particularly during the short-duration stage. Further analysis revealed that the spatial variability of disease-induced ageing deviations persisted along the sensorimotor–association cortical axis throughout disease progression. The premature involvement of neurotransmitter systems, including dopamine and serotonin, may underlie accelerated ageing.

Our work uncovers regional ageing trajectories organised along the sensorimotor–association cortical axis, and provides new insights into the mechanisms of atypical ageing and disease progression in schizophrenia.

Schizophrenia spectrum disorders confer an increased and earlier dementia diagnosis risk, but the relative timing and course of cognitive decline compared to individuals with affective disorders is unclear.

This retrospective study used de-identified electronic patient records to compare cognitive trajectories from the first recorded MMSE, representing the earliest cognitive concerns in relation to a possible dementia syndrome, and subsequent dementia risk between patients with a schizophrenia spectrum and primary affective disorder diagnosis. Patients had at least two MMSE scores recorded at least 6 months apart. We examined annual MMSE change from the first recorded MMSE, dementia risk, dementia subtypes, and rates of dementia assessment and treatment.

Compared to affective disorders (n = 2,264; 71.1 years), schizophrenia spectrum disorders (n = 1,217; 65.0 years) showed earlier initial MMSE scores (by 6.1 years, 95% CI = 5.2–7.0), earlier dementia diagnoses (by 2.3 years, 95% CI = 0.9–3.7) but lower dementia risk (adjusted HR = 0.81; 95% CI = 0.69–0.95). Cognitive decline rates and dementia subtype diagnoses did not differ between affective and schizophrenia spectrum disorders, but it took longer for schizophrenia spectrum disorder patients to receive a dementia diagnosis (5.6 vs. 4.4 years). Anti-dementia medication was less likely to be prescribed in patients with schizophrenia versus depression.

Cognitive concerns in older individuals with schizophrenia spectrum disorders arise from around 63 years and are associated with earlier dementia risk versus older individuals with affective disorders. Findings emphasize the importance of targeted dementia prevention and treatment strategies in these individuals and the need to reduce the existing inequity of access to dementia services.

Amisulpride, a substituted benzamide derivative, has a unique pharmacological profile characterised by a high affinity for dopaminergic D2/D3 receptors, as well as an affinity for 5-HT7 receptors. Its effectiveness and safety surpass those of traditional antipsychotic drugs and multi-receptor antipsychotic medications in improving global symptoms, including both positive and negative symptoms. This makes it a compelling subject for study. However, the molecular mechanisms that contribute to its clinical efficacy in treating schizophrenia remain largely unexplored.

We assessed cell viability following amisulpride treatment using the MTT and a real-time cell viability assay. Subsequently, we conducted RNA-seq and LC-MS/MS analyses to identify differentially expressed genes and proteins in SH-SY5Y neuroblastoma cells treated with amisulpride.

In the present study, we used RNA-seq analysis to identify downregulated expression of a transcriptional factor, FOSB, in amisulpride-treated SH-SY5Y neuroblastoma cells, while using LC-MS/MS analysis to identify multiple differentially expressed proteins in these cells. Among these differentially expressed proteins, we confirmed four proteins (ACTG1, ANP32E, CLTC, IPO8) that are differentially expressed under the administration of amisulpride.

Our data reveal novel insights into the role of amisulpride in modulating the differential expression of genes and proteins. These findings, which involve genes/proteins related to AP-1 transcription factor family gene regulation, cytoskeleton, histone binding activity, the intracellular trafficking of receptors and endocytosis of a variety of macromolecules, and nuclear localisation signal, are particularly significant as they shed light on the molecular underpinnings of the clinical efficacy of amisulpride and the pathogenesis of schizophrenia.

People with severe mental disorders (SMDs) have about 15 years shorter life expectancy than the general population. Cardiovascular disease (CVD) is among the leading causes of premature mortality and shares genetic underpinnings with SMDs. We investigated the link between clinical traits in SMDs and time to the first CVD diagnosis.

The study included 1,627 well-characterized participants with schizophrenia spectrum (SCZ, N = 998) and bipolar spectrum disorders (BDs, N = 629), and a reference group of 1,201 healthy controls. CVD diagnoses were obtained from two Norwegian national registries (covering both primary and specialist health care) for the period of 2006–2020. Applying Cox proportional hazard models, we investigated associations between SMD clinical traits and time to first CVD diagnosis in SMD participants, adjusting for age, sex, diagnosis, and tobacco use.

Among individuals with SMD, recurring self-harming behavior (SHB) was associated with a shorter time to first CVD diagnosis (p = .029) relative to those without SHB. In the subgroup with SHB and a history of attempted suicide(s), more suicide attempts were associated with shorter time to first CVD diagnosis (p = .041). Significant associations of time to first CVD diagnosis with age at SMD onset and comorbid substance use disorder were not demonstrated.

SHB and a history of suicide attempts in individuals with SMD seem to be associated with earlier CVD onset, and may improve the prediction of CVD, in addition to standard cardiovascular risk factors.

Immunomodulatory effects of psychotropic agents used to treat severe mental disorders (SMDs) have been suggested. We investigated associations between immune marker levels and antipsychotic- (AP), antidepressant- (AD), and mood stabilizing agents (MS) use in SMDs.

We included 1215 participants with SMDs (777 with schizophrenia spectrum disorders and 438 with bipolar disorders). Circulating levels of 45 immune markers were determined by enzyme-immunoassay or immunoturbidimetry and analyzed for associations with use, doses, and serum concentrations of AP, AD, and MS. Extensive adjustments for potential confounders were performed. Immune marker levels of 1008 healthy controls served as a reference.

AP use was significantly associated with higher plasma levels of beta defensin 2 (BD-2) (β = 0.094, p = 0.8E-4), AD use with higher serum levels of CRP (β = 0.072, p = 0.8E-3), and MS use with higher plasma levels of soluble interleukin 2 receptor (sIL-2R) (β = 0.063, p = 0.9E-4). These findings were paralleled by positive associations with psychotropic agent dose and serum concentrations: AP dose was associated with BD-2 levels (β = 0.045, p = 2.3E-4), AD dose with CRP levels (β = 0.039, p = 0.001), MS dose with sIL-2R levels (β = 0.048, p = 0.001), and serum concentration of AD was nominally positively associated with CRP (β = 0.072, p = 0.002).

The findings suggest that AP and MS use affect pathways involved in immune homeostasis and inflammatory regulation in individuals with SMDs, while AD use augments low-grade systemic inflammation reflected by CRP.

Some psychotic experiences in the general population show associations with higher schizophrenia and other mental health-related polygenic risk scores (PRSs), but studies have not usually included interviewer-rated positive, negative and disorganised dimensions, which show distinct associations in clinical samples.

To investigate associations of these psychotic experience dimensions primarily with schizophrenia PRS and, secondarily, with other relevant PRSs.

Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort participants were assessed for positive, negative and disorganised psychotic experience dimensions from interviews, and for self-rated negative symptoms, at 24 years of age. Regression models were used to investigate associations between psychotic experience dimensions and schizophrenia and other PRSs (2500+ participants for each analysis).

Against expectation, none of the positive, negative or disorganised dimensions was associated with schizophrenia PRS. In secondary analysis, self-rated negative symptoms were associated with higher depression (β = 0.10 [95% CI 0.06–0.15]), anxiety (β = 0.09 [95% CI 0.04–0.13]), neuroticism (β = 0.11 [95% CI 0.06–0.15]) and autism (β = 0.09 [95% CI 0.05–0.13]) PRSs (all P < 0.001); and first-rank delusions were nominally associated with higher schizophrenia PRS (odds ratio 7.35 [95% CI 2.10–25.77], P = 0.002), although these experiences/symptoms were rare.

Positive, negative and disorganised psychotic experiences are probably not strongly associated with polygenic liability to schizophrenia in this general population cohort of young adults. Self-rated negative symptoms may indicate social withdrawal/low motivation due to higher polygenic liability to affective disorders or autism, and first-rank delusions may indicate higher polygenic liability to schizophrenia, but these findings require independent confirmation.

There are differences in IgA responses to tryptophan catabolites (TRYCATs) in major neurocognitive psychosis (MNP) versus simple neurocognitive psychosis (SNP) and normal controls. MNP and SNP are distinct schizophrenia classes which are differentiated by neurocognitive deficits, phenome features, and biomarker pathways. Nevertheless, there is no data on serum concentrations of those TRYCATs in MNP and SNP. The aim of the present study is to examine serum concentrations of tryptophan and TRYCATs in MNP versus SNP and controls.

This case-control study examines serum levels of tryptophan and TRYCATs in 52 MNP patients, 68 SNP patients and 60 controls in association with overall severity of schizophrenia (OSOS).

MNP patients show lower tryptophan, kynurenic acid (KA), 3-OH-anthranilic acid (3HAA), and higher anthranilic acid (AA) and quinolinic acid (QA) than SNP patients and controls. There were no differences between SNP and controls in these TRYCATs. Kynurenine (KYN) was lower in MNP+SNP than in controls. We found that 36.5% of the variance in OSOS was explained by the combined effects of lowered tryptophan, KA, and 3-HK, and increased QA and AA. The most important biomarkers of MNP and OSOS were the QA/KA ratio followed by the QA/3HAA ratio.

The alterations in serum TRYCAT levels further emphasize that MNP and SNP represent two biologically distinct subtypes of schizophrenia. The reductions in TRYCATs diminish the antioxidant and immunoregulatory functions of the TRYCAT pathway. Elevated QA levels may exacerbate the disruption of the blood-brain barrier and the immune-related and oxidative neurotoxicity in MNP.

Transition from a categorical to a dimensional approach has been proposed in the field of psychosis. However, whether key features of schizophrenia, such as cognitive deficits, really do lie along a linear continuum remains uncertain. To explore this, we compared for the first time verbal learning impairments in six entities of the psychosis spectrum using linear, nonlinear, and categorical models.

Studies involving verbal learning tests in familial high risk, clinical high risk, schizotypy/schizotypal, ultra-high risk, first episode of psychosis (FEP), and chronic schizophrenia populations were systematically searched in three databases in September 2024. Studies were included if they reported an immediate, delayed, or total recall measure in subclinical or clinical entities and healthy controls. The metafor package was used to compute effect sizes for the comparison between cases and control groups, categorized by psychosis entities. Model comparisons were also performed to compare linear, nonlinear, and categorical distributions of the effect sizes.

The meta-analysis aggregated a total of 262 studies in the psychosis spectrum. Effect sizes were moderate in at-risk populations (<0.50) and large in clinical populations (−1.00 for FEP and >1.00 for chronic schizophrenia). A nonlinear model best explained our data in immediate recall, while the results in delayed and total recall suggest the inferiority of linear models.

Our findings suggest a discontinuity in verbal learning between at-risk populations and clinical entities, challenging a purely linear dimensional model of cognitive impairment in the psychosis spectrum.

Schizophrenia patients with auditory hallucinations have distinct morphological abnormalities, but whether this population have a progressive gray matter atrophy pattern and specific transmission chain of causal effects remains unclear. This study was designed to construct a causal structural covariance network in schizophrenia patients with persistent auditory hallucinations.

T1-weighted MRI images were acquired from 90 schizophrenia patients with persistent auditory hallucinations (pAH group) and 83 healthy controls (HC group). Stage-specific independent t tests of gray matter volume (GMV) comparisons between the two groups were used to depict the GMV atrophic pattern and locate the atrophic origin. In the pAH group, the causal structural covariance network (CaSCN) was constructed to map causal effects between the atrophic origin and other regions as the auditory hallucination severity increased.

With the ascending of hallucinatory severity, GMV reductions began from the thalamus, bilateral medial frontal gyri, left Rolandic operculum, and left calcarine, and expanded to other frontal and temporal regions, hippocampal complex, insula, anterior cingulate gyri, fusiform, and cerebellum. Using the peak region (thalamus) as the causal origin in the network, transitional nodes including the right opercular part of the inferior frontal gyrus, bilateral postcentral gyri, left thalamus, and right middle frontal gyrus received the casual information and projected to target nodes from the frontal, temporal, parietal, and occipital cortices, limbic system, and cerebellum.

Our study revealed causal effects from the thalamus and a specific transmission pattern of causal information within the network, indicating a thalamic–cortical–cerebellar circuitry dysfunction related to auditory hallucinations.