Subtle behavioral and cognitive symptoms precede schizophrenia (SCZ) and appear in individuals with elevated risk based on polygenic risk scores (SCZ-PRS) and family history of psychosis (SCZ-FH). However, most SCZ-PRS studies focus on European ancestry youth, limiting generalizability. Furthermore, it remains unclear whether SCZ-FH reflects common-variant polygenic risk or broader SCZ liability.

Using baseline data from the Adolescent Brain Cognitive Development (ABCD) study, we investigated associations of SCZ-FH and SCZ-PRS with cognitive, behavioral, and emotional measures from NIH-Toolbox, Child Behavior Checklist (CBCL), and Kiddie Schedule for Affective Disorders and Schizophrenia (KSADS) for 9,636 children (mean age = 9.92 yrs, 47.4% female), specifically, 5,636 European, 2,093 African, and 1,477 Admixed American ancestry individuals.

SCZ-FH was associated with SCZ-PRS (b = 0.05, FDR-p = 0.02) and subthreshold psychotic symptoms (b = 0.46, FDR-p = 0.01) in European youth, higher CBCL scores (b range = 0.36–0.6, FDR-p < 0.001), and higher odds of multiple internalizing and externalizing disorders (OR = 1.10–1.22, FDR-p < 0.001) across ancestries. SCZ-PRS was associated with lower cognition across ancestries (b = −0.43, FDR-p = 0.02), higher CBCL total problems, anxious/depressed, rule-breaking and aggressive behaviors in European youth (b range = 0.16–0.33, FDR-p < 0.04), and depressive disorders in Admixed American youth (OR = 1.37, FDR-p = 0.02). Results remained consistent when SCZ-PRS and SCZ-FH were jointly modeled. Some SCZ-FH associations weakened when income-to-needs was accounted for, suggesting that SCZ-FH may capture both genetic and environmental influences.

SCZ-FH showed associations with broad psychopathology, while SCZ-PRS was associated with cognition and specific symptoms in European youth. Findings highlight their complementary role in SCZ risk assessment and the need to improve PRS utility across ancestries.

Antipsychotics are first-line treatments for schizophrenia, yet many patients show inadequate response. Clozapine, the gold standard for treatment-resistant schizophrenia, remains underutilised due to safety and monitoring concerns.

To evaluate the adverse effects of clozapine in schizophrenia through a meta-analysis of randomised controlled trials (RCTs).

We systematically searched MEDLINE, CENTRAL, Embase, PsycINFO, ClinicalTrials.gov and WHO ICTRP up to 10 October 2024 for RCTs comparing clozapine (as either monotherapy or combination therapy) with other antipsychotics. We assessed 37 distinct adverse outcomes. Risk ratios were calculated for dichotomous outcomes and standardised mean differences for continuous outcomes, with confidence intervals.

A total of 116 RCTs (n = 8431) were included. In 69 monotherapy RCTs (n = 6281), clozapine showed no difference in either mortality (risk ratio 1.01, 95% CI: 0.50, 2.01, prevalence 0.1%) or discontinuation due to adverse effects (risk ratio 1.18, 95% CI: 0.91, 1.53, prevalence 7.2%). Agranulocytosis risk was nearly tripled (risk ratio 2.81, 95% CI: 0.97, 8.12, prevalence 0.7%), although with wide confidence intervals. Clozapine increased the risk of seizures (risk ratio 3.61, 95% CI: 1.80, 7.95, prevalence 3.1%) and orthostatic hypotension/bradycardia/syncope (risk ratio 1.66, 95% CI: 1.00, 2.77, prevalence 11%). No difference was found for myocarditis/cardiomyopathy (risk ratio 0.33, 95% CI: 0.01, 8.13). Clozapine increased the risk of leukopenia, hypersalivation, sedation, tachycardia, hypertension, constipation, nausea/vomiting, fever, flu-like syndrome and headache. In 47 combination RCTs (n = 2150), clozapine combinations were not associated with increased risk of severe adverse effects; no cases of agranulocytosis (21 RCTs, n = 894) or seizures (8 RCTs, n = 313) were reported in trials that explicitly assessed these outcomes.

Life-threatening adverse events remain rare with clozapine. With appropriate monitoring, its safety profile supports broader and potentially earlier use. Future studies should refine monitoring protocols and explore additional indications.

Schizophrenia is a severe psychiatric disorder characterised by positive symptoms, such as hallucinations and delusions, which are linked to dysregulated striatal connectivity. Although traditional models highlight the limbic striatum’s role in salience processing, emerging evidence suggests that the associative striatum, critical for cognitive control and habit formation, also plays a significant role. However, the structural connectivity underlying striatal subregions and its relationship to symptom severity and treatment response remains poorly understood.

This study aimed to investigate the structural connectivity of striatal subregions in first-episode schizophrenia (FE-SCZ) patients and to evaluate its association with positive symptoms and changes following antipsychotic treatment.

We recruited 80 FE-SCZ patients and 80 healthy controls who underwent diffusion tensor imaging probabilistic tractography to assess white matter tract strength between the striatum and ten cortical targets. Longitudinal analysis was conducted in patients at baseline (within 2 weeks of initial antipsychotic exposure) and after ongoing treatment to evaluate changes in connectivity and their relationship to symptom improvement.

FE-SCZ patients exhibited reduced connectivity between the dorsolateral prefrontal cortex (dlPFC) and associative striatum and increased connectivity between the anterior cingulate cortex (ACC) and associative striatum compared to controls. Longitudinal analysis revealed that antipsychotic treatment increased dlPFC–associative striatum connectivity and decreased ACC–associative striatum connectivity, which correlated with reductions in positive symptom severity.

These findings highlight the critical role of striatal subregions in the pathophysiology of schizophrenia, emphasising the associative striatum’s involvement in cognitive control and salience attribution. Changes in striatal connectivity after continued antipsychotic therapy may serve as a biomarker for symptom improvement, advancing our understanding of schizophrenia and guiding future therapeutic strategies.

The treatment response for the negative symptoms of schizophrenia is not ideal, and the efficacy of antidepressant treatment remains a matter of considerable controversy. This systematic review and meta-analysis aimed to assess the efficacy of adjunctive antidepressant treatment for negative symptoms of schizophrenia under strict inclusion criteria.

A systematic literature search (PubMed/Web of Science) was conducted to identify randomized, double-blind, effect-focused trials comparing adjuvant antidepressants with placebo for the treatment of negative symptoms of schizophrenia from database establishment to April 16, 2025. Negative symptoms were examined as the primary outcome. Data were extracted from published research reports, and the overall effect size was calculated using standardized mean differences (SMD).

A total of 15 articles, involving 655 patients, were included in this review. Mirtazapine (N = 2, n = 48, SMD −1.73, CI −2.60, −0.87) and duloxetine (N = 1, n = 64, SMD −1.19, CI −2.17, −0.21) showed significantly better efficacy for negative symptoms compared to placebo. In direct comparisons between antidepressants, mirtazapine showed significant differences compared to reboxetine, escitalopram, and bupropion, but there were no significant differences between other antidepressants or between antidepressants and placebo. No publication bias for the prevalence of this condition was observed.

These findings suggest that adjunctive use of mirtazapine and duloxetine can effectively improve the negative symptoms of schizophrenia in patients who are stably receiving antipsychotic treatment. Therefore, incorporating antidepressants into future treatment plans for negative symptoms of schizophrenia is a promising strategy that warrants further exploration.

Significant changes in Taiwan’s psychiatric services over recent decades include expansion of community-based clinics and implementation of the Schizophrenia Pay-for-Performance programme.

This study aimed to assess the trend of the quality of healthcare for individuals with schizophrenia, using various indicators of the treatment process and outcomes between 2010 and 2019.

Individuals with schizophrenia were identified using Taiwan’s National Health Insurance claims database. The quality of healthcare for individuals with schizophrenia was assessed using treatment process and outcome indicators, including antipsychotic types, medication adherence, daily dose for antipsychotics and concurrent use of other psychotropic agents. Outcome indicators included all-cause mortality, suicide deaths, psychiatric hospitalisation, emergency department visits and employment status.

Antipsychotic medication usage has shifted towards second-generation antipsychotics (SGAs) and long-acting injectable antipsychotics (LAIs), with declines in first-generation antipsychotics. The percentage of medication adherence declined, while that of individuals with an adequate daily dose increased. Concurrently, anticholinergic and benzodiazepine use decreased while antidepressant and mood stabiliser use increased. Outcome indicators showed no significant change in all-cause mortality or suicide rates over time, but there were reductions in psychiatric hospitalisations and emergency department visits. Employment rates increased overall, particularly in urban areas.

The quality of healthcare for individuals with schizophrenia, as measured by treatment process and outcome indicators, improved alongside changes in Taiwan’s psychiatric services; however, causality cannot be inferred from our findings. Future research should evaluate the effectiveness of psychiatric service policies and continuously monitor healthcare quality to further enhance the lives of individuals with schizophrenia.

Schizophrenia progresses through high-risk, first-episode, and chronic stages, each associated with altered spontaneous brain activity. Resting state functional MRI studies highlight these changes, but inconsistencies persist, and the genetic basis remains unclear.

A neuroimaging meta-analysis was conducted to assess spontaneous brain activity alterations in each schizophrenia stage. The largest available genome-wide association study (GWAS) summary statistics for schizophrenia (N = 53,386 cases, 77,258 controls) were used, followed by Hi-C-coupled multimarker analysis of genomic annotation (H-MAGMA) to identify schizophrenia-associated genes. Transcriptome-neuroimaging association and gene prioritization analyses were performed to identify genes consistently linked to brain activity alterations. Biological relevance was explored by functional enrichment.

Fifty-two studies met the inclusion criteria, covering the high-risk (Nhigh-risk = 409, Ncontrol = 475), first-episode (Ncase = 1842, Ncontrol = 1735), and chronic (Ncase = 1242, Ncontrol = 1300) stages. High-risk stage showed reduced brain activity in the right median cingulate and paracingulate gyri. First-episode stage revealed increased activity in the right putamen and decreased activity in the left gyrus rectus and right postcentral gyrus. Chronic stage showed heightened activity in the right inferior frontal gyrus and reduced activity in the superior occipital gyrus and right postcentral gyrus. Across all stages, 199 genes were consistently linked to brain activity changes, involved in biological processes such as nervous system development, synaptic transmission, and synaptic plasticity.

Brain activity alterations across schizophrenia stages and genes consistently associated with these changes highlight their potential as universal biomarkers and therapeutic targets for schizophrenia.

Schizophrenia is a chronic severe mental illness affecting 24-million people globally, associated with a life expectancy 15 years shorter than the general population. Approximately 70% of people with schizophrenia experience auditory verbal hallucinations (AVHs), i.e. ‘hearing voices’. Current treatment approaches remain unsuccessful in up to 30% of cases.

This systematic review and meta-analysis evaluated randomised controlled trials (RCTs) of non-pharmacological treatments for AVHs in schizophrenia spectrum disorders, assessing emerging treatment effectiveness and identifying research gaps.

A literature search was performed between 2013-2024 across five databases: PubMed, Embase, PsycINFO, Medline, and Web of Science. The meta-analysis included 45 studies based on predefined criteria and bias assessment. Effect sizes (Hedge’s g) were calculated using a random effects model with 95% confidence intervals. The study followed PRISMA guidelines and was pre-registered (PROSPERO ID: CRD42024598615).

Our sample included 2,314 patients and fourteen interventions. The overall mean effect size was -0.298 (95% CI, [-0.470, -0.126]), representing a medium, statistically significant effect. Subgroup analyses revealed medium, statistically significant effects for both AVATAR therapy and cognitive behavioural therapy (CBT). Conversely, repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) showed small, non-significant effects.

AVATAR therapy has the strongest evidence for treating AVHs, highlighting the need for large-scale RCTs and integration into treatment guidelines. CBT requires methodological standardisation. Acceptance and commitment therapy shows promise but needs further high-quality RCTs. Non-invasive brain stimulation techniques require additional trials before clinical implementation.

Clozapine remains underused despite its unparalleled efficacy in treatment-refractory schizophrenia. One of the reasons for its underuse is the fear of severe neutropenia and its consequences.

To scrutinise the association between severe neutropenia and clozapine in a cohort of patients clinically diagnosed with clozapine-induced severe neutropenia.

We used data from the South London and Maudsley National Health Service Foundation Trust’s anonymised case register, known as the Clinical Record Interactive Search. We extracted details of cases where clozapine use was associated with two consecutive neutrophil counts below 1.5 × 109/L. A panel of clinicians independently assessed each case. Agreement was reached on which cases clozapine was the likely or definite cause of the severe neutropenia, the risk to life and whether or not rechallenge with clozapine could be attempted.

There were 96 cases where two consecutive neutrophil counts below 1.5 × 109/L were registered. The panel judged that 9 (9.4%) were definitely caused by clozapine and a further 11 (11.5%) were probably caused by clozapine. Overall, 18 (18.8%) patients should be precluded from ever receiving clozapine again according to the panel (all from the 20 cases where clozapine was the definite or probable cause). Of the remaining 76 cases of severe neutropenia the cause could not be determined in 60 cases, but in 11 cases the cause was benign ethnic neutropenia, in 2 others the cause was cancer chemotherapy, in 2 it was infections and in 1 it was laboratory error. In almost 80% of cases, clozapine was not the clear cause of the neutropenia observed.

The large majority of severe neutropenia episodes mandating cessation of clozapine may not be caused by clozapine. Threshold-based monitoring systems cause unnecessary stopping of clozapine because they lack the necessary specificity for clozapine-related blood disorders.

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.