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Synaptic dysfunction is increasingly recognized as a core feature of psychiatric disorders, yet fluid biomarkers that reflect such changes in vivo are lacking. Here, we applied targeted mass spectrometry to quantify low-abundant synaptic proteins in cerebrospinal fluid from 672 individuals with anorexia nervosa, attention-deficit/hyperactivity disorder (ADHD), bipolar disorder (BD), schizophrenia spectrum disorders (SCZ + ), and healthy controls. Synaptic protein levels were markedly reduced in SCZ + , with intermediate reductions in BD and ADHD. Using a data-driven approach to model transdiagnostic contrasts-psychotic experience, cognitive and functional impairment-a shared two-biomarker signature emerged: elevated LAMP1, a phagolysosomal marker, and reduced NPTX2, a synaptic activity marker which inhibits complement-dependent synapse elimination. Combining this ratio with polygenic scores improved diagnostic classification. Key findings were extended to an independent cohort at first-episode psychosis. These results support synaptic pathology as a measurable and transdiagnostic feature across several psychiatric disorders and highlight the potential of integrating fluid and genetic biomarkers.

The complement genes C4A and C4B share high sequence similarity yet differ in biological function and disease relevance. C4A, in contrast to C4B, is implicated in synaptic pruning and increased risk for schizophrenia, however beyond this their distinct roles within the human brain remain poorly understood. We analyzed cerebrospinal fluid (CSF) levels of C4A, C4B, C1Q, along with 48 inflammation-related proteins, measured in both CSF and plasma, in 90 healthy controls and 113 patients with first-episode psychosis (FEP). In controls, C4A and C4B were positively associated with C1Q (z = 0.41, p < 0.001, and z = 0.48, p < 0.001, respectively), whereas in FEP, the CSF C1Q-C4A association was abolished (z = 0.09, p = 0.40). Across inflammatory markers, C4A levels in controls showed predominantly negative correlations in CSF, while C4B and C1Q exhibited mostly positive correlations. Using permutation tests on directional mean differences, we observed a robust positive directional shift for C4A in FEP (z = 3.81, p < 0.0001), while C4B showed a non-significant negative shift (z = -2.64, p > 0.9). The overall C4A directional shift was largely preserved in plasma, though the structure of complement-protein interactions differed markedly between the biological compartments, CSF and plasma. Together, these findings identify distinct and compartment-specific patterns of immune network interactions for C4A and C4B and suggest that C4A-inflammatory protein relationships are selectively altered in FEP.

BACKGROUND: Cognitive deficits are core findings in schizophrenia, but whether the severity of impairments is related to the age of onset remains unclear. We hypothesized that early onset schizophrenia (EOS; onset before age 19) is associated with lower IQ compared to adult-onset schizophrenia (AOS; onset from age 19).

METHODS: We included 99 adult patients with EOS (age of onset: 15.3 ± 2.8 years), 282 adult patients with AOS (age of onset: 26.5 ± 7.4 years), and 863 adult healthy controls (HC). We assessed current IQ with Wechsler Abbreviated Scale of Intelligence (WASI) and estimated premorbid IQ with National Adult Reading Test (NART).

RESULTS: Both patient groups had lower current IQ than HC (p < 0.001). Full-scale (p = 0.004), performance (p = 0.003) and verbal (p = 0.011) current IQ were significantly lower in EOS than in AOS, with 5 IQ units difference for all three measures. EOS and AOS did not differ in premorbid IQ, but EOS showed a steeper IQ decline from premorbid levels than AOS (11.4 vs. 8 IQ units, respectively, p = 0.013).

CONCLUSION: EOS had lower current IQ than AOS, but did not differ in premorbid IQ, suggesting a larger decline from premorbid IQ levels. This could imply different neurodevelopmental processes underlying cognitive dysfunction related to age of onset in schizophrenia, underscoring the necessity for further inquiry into the mechanisms driving this decline and strategies for its prevention.

Identifying updated, evidence-based risk and protective factors for psychotic disorders is essential to advancing scientific and clinical knowledge of their etiology. Since the most recent umbrella review published in this journal, the evidence base has expanded substantially. Following a pre-registered protocol, we searched the Web of Science for systematic reviews with meta-analyses of observational studies published between the search date of the last umbrella review (February 1, 2017) and March 31, 2025, examining associations of sociodemographic, parental, perinatal, and later factors or antecedents with ICD/DSM (any version) diagnoses of non-organic psychotic disorders. We graded associations between each putative factor and psychotic disorders using standardized international classification criteria: convincing (class I), highly suggestive (class II), suggestive (class III), and weak (class IV). We also conducted sensitivity analyses: a) lowering the classification criterion requiring more than 1,000 cases to 500 cases, b) restricted to prospective studies (class I-II factors), and c) testing more robust estimates of uncertainty (Hartung-Knapp-Sidik-Jonkman method). Then, we estimated the population attributable fraction (PAF) for potentially modifiable class I-III factors. Study quality was assessed with A MeaSurement Tool to Assess systematic Reviews (AMSTAR). A total of 69 systematic reviews and meta-analyses were included, reporting on 970 individual studies and 221 risk or protective factors for psychotic disorders. Six risk factors showed convincing (class I) evidence of association: Black-African ethnicity in England (odds ratio, OR=4.89, 95% CI: 4.04-5.92), South Asian ethnicity in England (OR=2.15, 95% CI: 1.69-2.73), paternal age <20 years (OR=1.34, 95% CI: 1.20-1.50), birthweight under 2,000 g (OR=1.77, 95% CI: 1.48-2.13), birthweight under 2,500 g (OR=1.50, 95% CI: 1.38-1.64), and maternal history of three or more previous pregnancies (OR=1.32, 95% CI: 1.20-1.45). Eighteen additional factors were highly suggestive (class II): maternal psychosis, Black-Caribbean ethnicity in England, any maternal mental health disorder, ethnic minority status in a low ethnic density area, first-generation immigrant status, cannabis use 5 to 7 days per week, Toxoplasma gondii IgG positivity, history of attention-deficit/hyperactivity disorder (ADHD), trait anhedonia, olfactory identification ability, premorbid IQ, and seven factors pertaining to minor physical anomalies. Two additional factors were upgraded from class IV to class II in our sensitivity analyses: clinical high-risk for psychosis (CHR-P) state, and soft neurological signs. Twenty-six factors (including four protective factors) were suggestive (class III), 75 were weak (class IV), and 96 were non-significant. Sensitivity analyses restricted to prospective studies downgraded some of the above factors, but only total minor physical anomalies became non-significant. The largest PAFs (>10%) were found for childhood adversities (40.69%), Toxoplasma gondii IgG positivity (20.47%), cannabis use 5-7 days per week (12.75%), and CHR-P state (12.68%). The sensitivity analyses employing robust uncertainty estimates confirmed that, among class I factors, Black-African ethnicity in England, birthweight under 2,000 g, and birthweight under 2,500 g retained their level of evidence. The mean AMSTAR score was 7.73 (SD=2.09). These findings provide an evidence-based, updated atlas of risk and protective factors for psychosis, advancing epidemiological knowledge, refining precision psychiatry, identifying targets for preventive intervention, and guiding global public health research.

Using Swedish register data, we estimated the proportion of individuals with first-episode psychosis (FEP) who would be eligible to participate in a typical neurobiological study and found that only 39% met criteria. Eligible and ineligible individuals differed on sociodemographic variables and two-year outcome measures (inpatient admission, work disability). Our findings suggest that neurobiological studies may yield samples that are not fully representative of the wider FEP population, potentially limiting generalisability.

Background: Negative symptoms are experienced by up to 60% of the individuals with schizophrenia and represent a stronger indicator of current and future functioning than positive symptoms. These symptoms respond poorly to pharmacological and existing psychosocial interventions, highlighting the need for targeted treatments. Previous research suggests that defeatist performance beliefs, combined with metacognitive deficits, may contribute to negative symptoms. A recent pilot study, adapting the cognitive intervention metacognitive training (MCT) to address negative symptoms, found symptom reduction, primarily due to improved reflective functioning and reduced perceived stigma. The current study aims to further assess the efficacy of this intervention and to explore potential mechanisms of change in negative symptoms.

Methods: Ninety participants aged 18 and older with a psychotic disorder will be recruited from psychiatric care settings in Sweden. Participants will be randomly assigned to either the intervention group (MCT-Minus) or a control group receiving supportive counselling (SC). Data will be collected at baseline, post-intervention, and at 12-week and 12-month follow-ups. Magnetic resonance imaging (MRI) will be performed at baseline and post-intervention. Exit interviews will be held after completing the intervention. The primary outcome is change in negative symptom, measured by the Clinical Assessment Interview for Negative Symptoms (CAINS), across all time points. Repeated measures ANCOVA will be used to evaluate primary outcomes. Additional analyses will address changes in positive symptoms and potential mechanisms of change, including metacognition and internalized stigma. Qualitative data from exit interviews will be analyzed using reflexive thematic analysis.

Discussion: This study is designed to evaluate the efficacy of MCT-Minus compared to supportive counselling. Given the limited treatment options for negative symptoms in schizophrenia, the findings may have important clinical implications.

The human thalamus is an integrative hub for multiple cortical and subcortical circuits involved in sensory processing and higher cognitive functions. Thalamic volume differences have been reported across multiple psychiatric and neurological disorders, but previous studies have typically relied on small samples, focused on one or a limited number of disorders, or investigated the thalamus as a whole without considering its functional subdivisions. In this multi-site study, we compared thalamic nuclei volumes across mild cognitive impairment (MCI), dementia (DEM), major depressive disorder, schizophrenia spectrum disorder (SCZ), clinical high risk for schizophrenia, bipolar spectrum disorder, autism spectrum disorder, attention-deficit/hyperactivity disorder, Parkinson's disease, multiple sclerosis (MS), and healthy controls (N > 8000). Using structural MRI, we segmented 25 bilateral thalamic nuclei, corresponding to six anatomical groups. Linear models revealed that anterior, medial and lateral regions of the thalamus were significantly smaller in several conditions, with largest effects observed for MCI, DEM, SCZ and MS. In contrast, the ventral and intralaminar groups were relatively normal. This pattern of effects largely corresponds to the canonical functional subdivision of the thalamus into higher-order and sensory regions. At the level of individual nuclei, the clinical conditions were associated with distinct patterns of alterations, while left and right lateral geniculate nuclei were implicated in six of the disorders, suggesting a possible relation with circadian and sleep disturbances. Together, the results highlight a role for the higher-order thalamus in common brain disorders and a differential involvement at the nuclei level, refining our understanding of thalamic pathology across common brain disorders.

Background. Schizophrenia-spectrum disorders (SSD) are characterized by structural and functional brain abnormalities, including disrupted functional connectivity within networks such as the salience network. The anterior cingulate cortex (ACC), a core hub of this network, has shown alterations in the major neurotransmitter systems comprising glutamate (Glu) and gamma-aminobutyric acid (GABA). While dysfunctional glutamatergic signaling has been proposed as a key mechanism in SSDs, the relationship between anterior cingulate cortex (ACC) functional connectivity, glutamatergic neurotransmission, and clinical symptomatology remains poorly understood.

Methods. Here, we combined resting-state functional MRI to measure functional brain connectivity with proton magnetic resonance spectroscopy to measure Glu and GABA levels in the dorsal ACC of 26 patients with schizophrenia spectrum disorders and 38 healthy controls.

Results. Patients showed reduced connectivity within the salience network compared to controls. Across the whole sample, a dorsal ACC-seed showed glutamate-dependent connectivity to several clusters, including right insula, thalamus, and cerebellum. In patients, the averaged connectivity of these clusters was associated with positive symptom severity.

Conclusions. These findings suggest that disrupted glutamatergic modulation of large-scale brain networks may underlie core clinical features in schizophrenia spectrum disorders.

Patients with schizophrenia have a threefold higher mortality from cardiovascular disease than people in the general population. Atherosclerosis is linked to immune activation, a process tentatively entwined with the underlying pathophysiological mechanisms of schizophrenia. The aim of the present study was to investigate an extensive array of cardiovascular biomarkers in individuals experiencing their first episode of psychosis (FEP), either drug-na & iuml;ve or exposed to short-term antipsychotic treatment, alongside a group of healthy controls (HC). Using the OLINK Proximity Extension Assay, Cardiovascular II Panel, we analyzed plasma from 72 FEP patients, including 42 later diagnosed with schizophrenia and 54 HCs. Biomarker levels, that significantly differed between patients and controls, were correlated with symptom severity, cognitive performance and cardiovascular risk factors. Fifteen out of 92 cardiovascular biomarkers were higher in individuals with FEP compared to HC, and one biomarker was lower in FEP patients compared to HC. BMI, waist size, blood pressure, fp-glucose, HbA1c and serum lipid levels were similar between the groups. No correlations that held for multiple comparisons were seen between biomarker concentrations and symptom severity, cognitive performance or cardiovascular risk factors in FEP patients. Higher concentrations of several cardiovascular biomarkers were observed in individuals with FEP compared to in HC. This suggests that patients with FEP are at an increased risk of developing cardiovascular disease from the onset of psychosis, even before changes in traditional biomarkers are detectable. It underscores the need for innovative approaches to detect and monitor this risk early.

Aims

Cognitive dysfunction is a core feature of psychotic disorders. The degree of impairment varies greatly between individuals, which may reflect different levels of decline from pre-morbid functioning. Diverse trajectories of cognitive change prior to or during development of psychosis have been hypothesized to reflect distinct underlying pathological processes. Our primary aim was to model cognitive change over time in a sample of individuals with first-episode psychosis (FEP) and controls. The secondary aim was to explore associations between cognitive change, clinical outcomes and select biological markers.

Methods

Our sample consisted of 72 individuals with FEP and 53 controls. School grades from nationwide population registers were used as a proxy for pre-morbid cognitive ability. All participants underwent formal cognitive testing at psychosis onset, with a subset returning for testing at 1,5 year follow up. Cognitive change was modelled using linear mixed-effects models, and resulting change scores were correlated to polygenic risk scores, cerebrospinal fluid levels of complement protein C4A and clinical outcomes.

Results

Groups did not differ in school performance prior to psychosis. Psychosis onset was associated with marked cognitive decline in FEP individuals, who subsequently performed significantly worse than controls. However, cognitive change over time varied widely between FEP individuals. Degree of cognitive change was not associated with the selected biological variables but did predict worse clinical outcomes.

Conclusions

Individual cognitive trajectories may be a clinically relevant topic for further study, and larger studies are needed to further explore their potential role in stratified models of care.