A Position Paper published in The Lancet Psychiatry in 2020 suggested an agenda for research about the effects of the COVID-19 pandemic on mental health, following which an interdisciplinary Lancet Psychiatry standing commission was established in 2022 to examine the emerging evidence and refine recommendations for more research. In this first Series paper from the standing commission, we focus on changes in the delivery of clinical mental health care during the COVID-19 pandemic. The second paper in the Series focuses on public mental health and policy perspectives, and the third will address neuropsychiatric consequences of infection by SARS-CoV-2. Evidence from high-quality longitudinal studies with pre-pandemic baseline data, controlled intervention trials, or systematic reviews took time to accrue. During the early months of the COVID-19 pandemic, symptoms of anxiety and depression became more prevalent, and many mental health services were compromised by pandemic-related factors; however, whether the COVID-19 pandemic accelerated pre-existing long-term trends of increasing incidence of mental health disorders, especially in children and adolescents, is unclear. Little research has been done in low-income and middle-income countries, or regarding post-COVID-19 condition (also known as long COVID), which emerged as a multisystem condition with mental health implications. Vulnerable populations, including socioeconomically disadvantaged and minoritised groups, faced disproportionate mental health impacts and limited access to care during the COVID-19 pandemic, reflecting systemic, pre-pandemic inequalities. Bold implementation of existing evidence-based mental health support for vulnerable communities, ambitious trials of novel interventions, and systematic pooling of rapidly accumulating evidence about best healh care should be priorities in future pandemics.

The COVID-19 pandemic revealed essential weaknesses in mental health systems and intensified existing inequities, highlighting the need for a comprehensive assessment of policy responses and strategies for future resilience. Guided by four questions relating to system adaptations, approaches to inequities, financing strategies, and evidence gaps, we synthesised evidence from a structured literature search (2020-24), expert consultation, and lived experience. We found that public health systems embedded infodemic management, expanded digital services, and mobilised community workforces, but responses varied in equity and effectiveness. Although gender, age, socioeconomic, and racial disparities worsened during the COVID-19 pandemic, social protection, gender-sensitive policies, school-based services, and culturally adapted interventions showed promise. High-income countries buffered shocks with welfare measures while low-income and middle-income countries faced sharp fiscal constraints. Few studies evaluated cost-effectiveness or equity impacts of psychosocial interventions. Building resilient, equitable mental health systems requires integrated policies spanning communication, digital and community care, gender-responsive and youth-responsive strategies, and sustainable financing, alongside investment in longitudinal and cross-national research.

Importance:Interleukin 6 (IL-6), a keystone inflammatory cytokine, is a credible mechanistic candidate for causing depression. However, randomized clinical trials testing its treatment potential remain scarce. Objective:To identify likely treatment-sensitive outcomes and effect size for systemic IL-6 inhibition in patients with difficult-to-treat depression. Design, Setting, and Participants:This 4-week, proof-of-concept, double-blind, parallel-arm, placebo-controlled randomized clinical trial recruited adults with moderate-to-severe International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) depression, poor antidepressant response, low-grade systemic inflammation (high-sensitivity C-reactive protein [hs-CRP] level ≥0.3 mg/dL on 2 tests), and depression somatic symptoms (Beck Depression Inventory II somatic symptoms score ≥7) from primary and secondary care and self-referral from 2018 to 2022. Participants were randomized into minimization balanced groups on depression severity and sex. Assessments were conducted at baseline and 7, 14, and 28 days after infusion. Data were analyzed from 2023 to 2025. Intervention:Single intravenous infusion of IL-6R antagonist tocilizumab (8 mg/kg, maximum 800 mg/patient) or normal saline. Main Outcomes and Measures:The primary outcome was depression somatic symptoms at 14 days after infusion. The secondary outcome was total depression severity. Exploratory outcomes included fatigue, anxiety, anhedonia, quality of life, and cognition. Outcomes were assessed using validated scales and interpreted against clinically meaningful thresholds. Results:A total of 30 participants (mean [SD] age, 41.1 [12.3] years; 24 [80.0%] female) were randomized, including 14 in the tocilizumab group and 16 in the placebo group. Of these, 29 participants received the assigned infusion and completed follow-up. As expected for a small proof-of-concept study, no results reached statistical significance, including little improvement in depression somatic symptoms at day 14 (adjusted mean difference: -0.12; 95% CI, -2.51 to 2.28). However, a pattern of greater stepwise improvement over time was observed with tocilizumab in somatic symptoms, depression severity, fatigue, psychological symptoms, state anxiety, and quality of life, with the largest effects observed at the final follow-up (day 28). Tocilizumab may also improve more individual depressive symptoms. Treatment effects were within ranges considered clinically meaningful for depression severity, fatigue, anxiety, and quality of life. At the final follow-up, remission (7 participants [53.9%] vs 5 participants [31.3%]; number needed to treat [NNT] = 5) and response (6 participants [46.2%] vs 3 participants [18.8%]; NNT = 4) rates favored tocilizumab compared with placebo. Baseline hs-CRP level, but not IL-6 level, tracked depression improvement, suggesting hs-CRP may better predict immunotherapy response in depression than drug-specific biomarkers. Tocilizumab was well tolerated, with no serious adverse events or withdrawals. Conclusions and Relevance:These findings highlight treatment-sensitive outcomes, effect sizes, and patient selection methods for testing systemic IL-6 inhibition in patients with difficult-to-treat depression, and call for a large-scale efficacy trial of anti-IL-6 treatment in depression. Trial Registration:isrctn.org Identifier: ISRCTN16942542.

Making informed clinical decisions based on individualised outcome predictions is the cornerstone of precision psychiatry. Prediction models currently employed in psychiatry rely on algorithms that map a statistical relationship between clinical features (predictors/risk factors) and subsequent clinical outcomes. They rely on associations that overlook the underlying causal structures within the data, including the presence of latent variables, and the evolution of predictors and outcomes over time. As a result, predictions from sparse associative models from routinely collected data are rarely actionable at an individual level. To be actionable, prediction models should address these shortcomings. We provide a brief overview of a general framework for the rationale for implementing causal and actionable predictions using counterfactual explanations to advance predictive modelling studies, which has translational implications. We have included an extensive glossary of terminology used in this paper and the literature (Supplementary Box 1) and provide a concrete example to demonstrate this conceptually, and a reading list for those interested in this field (Supplementary Box 2).

BACKGROUND:Young people with psychosis spectrum disorders are at a high risk of cardiometabolic morbidity and subsequent premature mortality, but there are no accurate clinic-ready prediction models for this group. We aimed to collaboratively refine, extend, and validate the Psychosis Metabolic Risk Calculator (PsyMetRiC) prediction models for accuracy, clinical usefulness, and acceptability, and to translate the models into a regulated, clinically available medical device. METHODS:In this retrospective, multicohort clinical prediction model study, we used primary care (Clinical Practice Research Datalink and QResearch) and secondary care (South London and Maudsley NHS Foundation Trust) datasets. Individuals from primary care sources were aged 16-35 years when they received a first recorded diagnosis of a psychosis-spectrum disorder between Jan 1, 2005, and Dec 31, 2015, with follow-up to Dec 31, 2020. Individuals from the secondary care source were enrolled in the psychosis early intervention service between Jan 1, 2012, and Dec 31, 2024. We developed models for a binary outcome of metabolic syndrome within 1-6 years using logistic regression; a time-to-event outcome of type 2 diabetes within 10 years using Weibull regression; and a binary outcome of clinically significant weight gain within 1 year using logistic regression. We revised existing predictors (hereafter referred to as the PsyMetRiC1 models) for finer detail and added new predictors: a family history of cardiometabolic disorder, antidepressant prescription, systolic blood pressure, and HbA1C (hereafter PsyMetRiC2 models). Refinement and external validation were performed for metabolic syndrome models (PsyMetRiC1-MetS and PsyMetRiC2-MetS), and development and external validation were performed for the type 2 diabetes model (PsyMetRiC2-T2D). Development and internal validation were performed for the clinically significant weight gain model (PsyMetRiC2-WG), but external validation was not possible due to data availability. Partial versions without biochemical results were also developed for weight gain and metabolic syndrome models. We involved stakeholders including people with lived experience; and implemented the models in a web application compliant with regulatory standards in Great Britain. FINDINGS:In total, we included 25 850 individuals (male, n=13 614 [52·7%]; female, n=12 236 [47·3%]; White European, 16 445 [63·6%]; Black African or Caribbean, south Asian, mixed, and east Asian or other n=9405 [36·3%]; and mean age 26·7 years [SD=5·4]). For primary care, we included 3989 individuals for development and 4347 individuals for external validation of metabolic syndrome outcomes; and 9181 individuals for development and 7487 individuals for external validation of type 2 diabetes outcomes. For secondary care, we included 846 individuals for development and internal validation of weight gain outcomes. For metabolic syndrome, the performance of PsyMetRiC2-MetS at external validation was C=0·81 (95% CI 0·77-0·84) for the full model (with biochemical predictors) and C=0·79 (0·76-0·83) for the partial model (without biochemical predictors). For type 2 diabetes, discriminative performance at internal validation of PsyMetRiC2-T2D was C=0·86 (0·76-0·95) for the full model, and at external validation it was C=0·81 (0·71-0·88). For weight gain, discriminative performance at internal validation of PsyMetRiC2-WG was C=0·78 (0·73-0·82) for the full model and C=0·77 (0·72-0·80) for the partial model. Calibration plots were acceptable for all models. All models displayed evidence of clinical usefulness at all plausible thresholds. The PsyMetRiC web application is available at https://psymetric.app. INTERPRETATION:We developed prediction models for incident cardiometabolic disorders in young people with psychosis. The PsyMetRiC models are among the first in psychiatry to be available for routine clinical use. PsyMetRiC can support a shift toward collaborative, preventive physical health care for young people with psychosis. FUNDING:National Institute for Health and Care Research.

People with semantic dementia (SD) or semantic variant primary progressive aphasia typically present with marked atrophy of the anterior temporal lobe, and thereafter progress more slowly than other forms of frontotemporal dementia. This suggests a prolonged prodromal phase with accumulation of neuropathology and minimal symptoms, about which little is known. To study early and presymptomatic SD, we first examine a well-characterized cohort of people with SD recruited from the Cambridge Centre for Frontotemporal Dementia. Five people with early SD had coincidental MRI prior to the onset of symptoms or were healthy volunteers in research with anterior temporal lobe atrophy as an incidental finding. We model longitudinal imaging changes in left- and right-lateralized SD to predict atrophy at symptom onset. We then assess 61 203 participants with structural brain MRI in the UK Biobank to find individuals with imaging changes in keeping with SD but with no neurodegenerative diagnosis. To identify these individuals in the UK Biobank, we design an ensemble-based classifier, differentiating baseline structural MRI in SD from healthy controls and patients with other neurodegenerative diseases, including other causes of frontotemporal lobar degeneration. We train the classifier on a Cambridge-based cohort (SD n = 47, other neurodegenerative diseases n = 498, healthy controls n = 88) and test it on a combined cohort from the Neuroimaging in Frontotemporal Dementia study and the Alzheimer's Disease Neuroimaging Initiative (SD n = 42, other neurodegenerative disease n = 449, healthy controls n = 127). From our case series, we find people with marked atrophy 3 to 5 years before recognition of symptom onset in left- or right-predominant SD. We present right-lateralized cases with subtle multimodal semantic impairment, found concurrently with only mild behavioural disturbance. We show that imaging measures can reliably and accurately differentiate clinical SD from other neurodegenerative diseases (recall: 0.88, precision: 0.95, F1 score: 0.91). We find individuals with no neurodegenerative diagnosis in the UK Biobank with striking left-lateralized (prevalence ages 45-85, 4.8/100 000) or right-lateralized (5.9/100 000) anterior temporal lobe atrophy, with deficits on cognitive testing suggestive of semantic impairment. These individuals show progressive involvement of other cognitive domains in longitudinal follow-up. Together, our findings suggest that (i) there is a burden of incipient early anterior temporal lobe atrophy in older populations, with comparable prevalence of left- and right-sided cases from this prospective unbiased approach to identification; (ii) substantial atrophy is required for manifest symptoms, particularly in right-lateralized cases; and (iii) semantic deficits across multiple domains can be detected in the early symptomatic phase.

Introduction Progressive supranuclear palsy (PSP) is a devastating neurodegenerative disease characterised by cognitive, behavioural and motor problems. Motor symptoms are highly disabling, while cognitive and behavioural changes have a major impact on carer burden, quality of life and prognosis. Apathy and impulsivity are very common, often coexistent in PSP, and negatively predict survival. In preclinical models and other diseases, apathy and impulsivity are associated with noradrenergic deficits, which can be severe in PSP.Methods and analysis Noradrenaline for Progressive Supranuclear Palsy Syndromes trial is a randomised, double-blind, placebo-controlled, crossover design, Phase IIb clinical trial to evaluate the efficacy and safety of oral atomoxetine for the treatment of cognitive and behavioural changes in PSP. Participants receive atomoxetine 40 mg (10 mg/mL oral solution) once daily or a matched placebo solution, in random order, each for 8 weeks. An ‘informant’, who knows the patient with PSP well, is co-recruited to complete some of the trial outcome measures. Participants remain in the trial for 22 weeks after randomisation. The primary objectives are to assess (1) safety and tolerability and (2) efficacy versus placebo on challenging behaviours as reported in a subscale of the Cambridge Behavioural Inventory. Secondary and exploratory measures relate to cognition, the PSP Rating Scale, mood and potential baseline predictors of individual response to atomoxetine computed from imaging, genetic and cognitive measures at baseline.Ethics and dissemination The trial was approved by the South Central-Oxford B Research Ethics Committee (REC) and the Medicines and Healthcare products Regulatory Agency (REC reference: 20/SC/0416). Dissemination will include publication in peer-reviewed journals, presentations at academic and public conferences and engagement with patients, the public, policymakers and practitioners.Trial registration number ISRCTN99462035; DOI: https://doi.org/10.1186/ISRCTN99462035; EudraCT (European Union Drug Regulating Authorities Clinical Trials Database)/CTIS (Clinical Trial Information System) number: 2019-004472-19; IRAS (Integrated Research Application System) number: 272063; Secondary identifying numbers: CPMS (Central Portfolio Management System) 44441.

The link between regional tau load and clinical manifestation of Alzheimer's disease (AD) highlights the importance of characterizing spatial tau distribution across disease variants. In typical (memory-predominant) AD, the spatial progression of tau pathology mirrors the functional connections from temporal lobe epicentres. However, given the limited spatial heterogeneity of tau in typical AD, atypical (non-amnestic-predominant) AD variants with distinct tau patterns provide a key opportunity to investigate the universality of connectivity as a scaffold for tau progression. In this large-scale, multicentre study across 14 international sites, we included cross-sectional tau-PET data from 320 individuals with atypical AD (n = 139 posterior cortical atrophy/PCA-AD; n = 103 logopenic variant primary progressive aphasia/lvPPA-AD; n = 35 behavioural variant AD/bvAD; n = 43 corticobasal syndrome/CBS-AD), with a subset of individuals (n = 78) having longitudinal tau-PET data. Additionally, as an independent sample, we included regional post-mortem tau stainings from 93 atypical AD patients from two sites (n = 19 PCA-AD, n = 32 lvPPA-AD, n = 23 bvAD, n = 19 CBS-AD). Gaussian mixture modelling was used to harmonize different tau-PET tracers by transforming tau-PET standardized uptake value ratios to tau positivity probabilities (a uniform scale ranging from 0% to 100%). Using linear regression, we assessed whether brain regions with stronger resting-state functional MRI-based functional connectivity, derived from healthy elderly controls in the Alzheimer's Disease Neuroimaging Initiative (ADNI), showed greater covariance in cross-sectional and longitudinal tau-PET and post-mortem tau pathology. Furthermore, we examined whether functional connectivity of tau-PET epicentres (i.e. the top 5% of regions with the highest baseline tau load) and tau-PET accumulation epicentres (i.e. the top 5% of regions with the highest tau accumulation rates) was associated with cross-sectional and longitudinal tau patterns. Our findings show that tau-PET epicentres aligned with clinical variants, e.g. a visual network predominant pattern in PCA-AD ('visual AD') and left-hemispheric temporal predominance, particularly within the language network, in lvPPA-AD ('language AD'). Moreover, more strongly functionally connected regions showed correlated concurrent tau-PET levels (confirmed with post-mortem data) and tau-PET accumulation rates. The functional connectivity profile of tau-PET epicentres and accumulation epicentres corresponded to tau-PET progression patterns, with higher tau-PET levels and accumulation rates in functionally close regions, and lower tau-PET levels and accumulation rates in functionally distant regions. Our data are consistent with the hypothesis that tau propagation occurs along functional connections originating from local epicentres, across all AD clinical variants. Since tau proteinopathy is a major driver of neurodegeneration and cognitive decline, this finding may advance personalized medicine and participant-specific end points in clinical trials.

There is a strong link between tau and progression of Alzheimer’s disease (AD), necessitating an understanding of tau spreading mechanisms. Prior research, predominantly in typical AD, suggested that tau propagates from epicenters (regions with earliest tau) to functionally connected regions. However, given the constrained spatial heterogeneity of tau in typical AD, validating this connectivity-based tau spreading model in AD variants with distinct tau deposition patterns is crucial. We included 269 amyloid-β-positive (PET/CSF) individuals with clinically diagnosed atypical AD (113 posterior cortical atrophy, PCA-AD; 83 logopenic variant primary progressive aphasia, lvPPA-AD; 33 behavioural variant AD, bvAD; 40 corticobasal syndrome, CBS-AD) and 68 with typical AD from 12 international cohorts, who underwent tau-PET (54% [ 18 F]AV1451/[ 18 F]flortaucipir/Tauvid, 27% [ 18 F]MK6240, 19% [ 18 F]PI2620). Using Gaussian mixture modeling including amyloid-β-negative controls, cross-sectional tau-PET standardized uptake value ratios within Schaefer-200 atlas regions were transformed to tau positivity probabilities. Tau epicenters were defined as the 5% regions with highest tau positivity probabilities. For each variant, the association between functional connectivity-based distance (using the 30% strongest positive region-to-region connections of a group-average connectivity matrix from ADNI elderly controls) and tau-PET covariance (group-average correlation per region pair) was assessed through linear regression, adjusting for age, sex, site, and Euclidean distance. Regions were categorized based on functional proximity to the epicenter (quartiles 1-4) and tau positivity probabilities were assessed accordingly. Tau positivity probabilities matched clinical variants, with a posterior pattern in PCA-AD, left-hemispheric dominant pattern in lvPPA-AD, widespread pattern in bvAD, sensorimotor cortex involvement in CBS-AD, and temporo-parietal predominance in typical AD (Figure 1). In line with this, tau epicenters were highly heterogeneous across variants (Figure 1). In all variants, greater tau-PET covariance was associated with shorter functional connectivity-based distance (Figure 2). We observed that regions in closer functional proximity to the epicenter exhibited higher tau positivity probabilities than regions functionally further away (p<0.05, Figure 3). This multi-center study shows that the brain’s functional architecture serves as a universal predictor of tau spreading in AD. Since tau is a key driver of neurodegeneration and cognitive decline in AD, this finding holds potential for personalized medicine and defining participant-specific endpoints in clinical trials.

Background:The prevalence of anxiety disorders among the adult population in Latin America (LATAM) and its association with development indicators is insufficiently characterised. We estimated pooled regional, country, and sex-specific prevalence rates of anxiety disorders in LATAM based on International Classification of Diseases (ICD) or Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria. Additionally, we examined the association between its prevalence and four country-level development indicators: Human Development Index (HDI), income inequality (Gini coefficient), Gender Inequality Index (GII), and Intentional Homicide Rate (IHR). Methods:We conducted a systematic review and meta-analysis of population-based studies on the prevalence of ICD/DSM anxiety disorders in LATAM from 1990 to 2024, irrespective of language. We searched PubMed, PsycINFO, Cochrane Library, SciELO, LILACS, and grey literature. Study quality was assessed using JBI's critical appraisal tools. Pooled estimates were generated using random-effects meta-analysis, and heterogeneity was evaluated using the I-squared (I 2) statistic. Meta-regression analyses were performed to examine the ecological association between anxiety disorders prevalence and four development indicators. The study was registered with PROSPERO (CRD42020190238). Findings:Using data from 36 studies in LATAM, we calculated the lifetime, 12-month, and current prevalence of ICD/DSM anxiety disorders at 14.55% (95% Confidence Interval 12.32%-17.11%; I 2 = 97.9%); 6.61% (5.20-8.37; I 2 = 98.1%), and 3.27% (2.34-4.56; I 2 = 97.5%), respectively. Heterogeneity was high across prevalence periods, sexes, and countries (all I 2 ≥ 91.4%), warranting caution in interpreting pooled estimates. Elevated 12-month and current prevalence rates of anxiety disorders were associated with higher Gini coefficients (p ≤ 0.0013). Additionally, higher current prevalence was associated with lower HDI (p = 0.0103) and higher GII (p = 0.0023), while elevated 12-month prevalence was associated with higher IHR (p = 0.011). Interpretation:This study shows that approximately one in seven people in LATAM experience anxiety disorders at some point in their lives. These findings highlight the need to strengthen mental health systems in the region, and evidence the association between prevalence of anxiety disorders and development indicators. Our results can serve as a baseline for tracking anxiety disorders and for informed decision-making at the national and regional levels. The substantial heterogeneity between studies and the underrepresentation of some countries underscore the imperative for enhancing regional mental health capacities. Funding:Pfizer Independent Medical Education Grant (69879319).

Neuroinflammation is a key pathological driver in neurodegenerative diseases, including Alzheimer’s disease (AD) and Progressive Supranuclear Palsy (PSP). Positron emission tomography (PET) with tracers targeting the translocator protein (TSPO) enables the in vivo quantification of microgliosis. TSPO tracers have shown similar disease-specific patterns across cohorts. However, direct quantitative comparisons between commonly used TSPO-PET tracers in tauopathies have not been performed. Here, we apply a TSPO-PET standardization pipeline across clinically matched AD cohorts and PSP cohorts, to quantify, compare and combine multi-centre TSPO-PET data. Patients with PSP were scanned with either [11C]PK11195 or [18F]GE-180 at one of two centres, while patients with AD and control participants were scanned with either [11C]PK11195, [18F]GE-180 or [11C]PBR28 at one of three centres. A standardised pre-processing pipeline was implemented and participant standardised uptake volume ratio (SUVR) values were z-scored using tracer-specific control participant values. In a data-driven approach, dissimilarity analyses were employed to assess differences between tracers across clinically matched cohorts. In PSP, dissimilarity analysis suggested that [11C]PK11195 and [18F]GE-180 binding patterns were comparable following standardisation. In AD, comparability across tracers was less robust, with [11C]PK11195 and [18F]GE-180 being most comparable, followed by [18F]GE-180 vs. [11C]PBR28, then by [11C]PK11195 vs. [11C]PBR28. The pipeline was effective at harmonising TSPO-PET tracers and standardising the regional quantification of neuroinflammation in clinically matched cohorts of PSP, while the standardisation pipeline results were less robust across AD cohorts.

BACKGROUND:Major depressive episodes (MDEs) are highly recurrent in clinical samples. However, the course of MDEs and predictors of their endurance are unclear in the general youth population. METHODS:We investigated prospective factors associated with enduring MDE (the presence of 12-month DSM-IV MDE at baseline and 1 year using the Composite International Diagnostic Interview-Screening Scales) in 1,833 participants of a 1-year epidemiological youth cohort study in Hong Kong. Multivariable logistic regression models were used to examine the influences of a range of personal and environmental factors. RESULTS:At baseline, 13.7% participants had MDEs, among whom 21.1% presented enduring MDEs. More severe symptoms of post-traumatic stress disorder (adjusted odds ratio [aOR] = 5.54, confidence interval [CI] = 2.14-14.38), depression (aOR = 3.92, CI = 1.79-8.62), and generalized anxiety (aOR = 2.27, CI = 1.21-4.25) at baseline were among the strongest associated factors for enduring MDE, with trends of associations observed for psychotic-like experiences (aOR = 1.98, CI = 0.98-4.02) and eating disorder symptoms (aOR = 1.88, CI = 0.90-3.95). Among various types of stressors, only dependent stressors at follow-up showed a clear association with enduring MDE (aOR = 4.22, CI = 1.81-9.83). Those with enduring MDE showed poorer functioning and mental health-related quality of life at follow-up, with only 35.6% having sought any psychiatric/psychological help during the past year. CONCLUSIONS:Detecting comorbid symptoms in those with prior MDEs and reducing the impact of dependent stressors may help reduce their long-term implications. Enhancing the accessibility and acceptability of youth-targeted mental health services would also be crucial to improve help-seeking.

Frontotemporal dementia (FTD) shows autosomal dominant transmission in up to a third of families, enabling the study of presymptomatic and prodromal phases. Despite self-reported well-being and normal daily cognitive functioning, brain structural changes are evident a decade or more before the expected onset of disease. This divergence between cognitive function and brain structure contrasts with the coupling of structural and functional decline after symptom onset. In healthy ageing, it has been shown that functional connectivity is a better predictor of cognitive function than volumetric structural imaging. We previously proposed that in the presymptomatic phase of genetic FTD, the maintenance of brain functional network integrity enables mutation carriers to sustain cognitive performance. However, prior work has focused on a small number of, often predefined, networks. This provides a limited and potentially biased characterisation of the substrates and moderators of brain network integration. Here, we test the hypothesis that brain-wide functional integration in FTD determines resilience to progressive pathology before symptom onset. We assess functional connectome integration in 289 presymptomatic FTD-mutation carriers using functional magnetic resonance imaging in relation to cognition and contrast with 271 family members without mutations. Because structural atrophy, functional integration and cognitive profiles are multivariate, we used canonical correlation models, supplemented by multiple linear regression models for each imaging modality. We confirmed progressive atrophy and normal cognitive function in presymptomatic carriers compared to non-carriers. Notably, functional integration was preserved in presymptomatic carriers across age, while it declined in familial non-carriers. The strongest effects were observed in cognitive control networks. The changes in functional integration in presymptomatic carriers were behaviourally relevant and independent of the severity of atrophy, suggesting a resilience mechanism in those at risk of dementia. To generate hypotheses about the genetic and neurometabolic basis of resilience, we assessed the spatial overlap between behaviourally-relevant functional integration maps and gene transcription profiles. These spatial correlations suggested resilience signatures to glial cell composition (astrocytes, microglia, oligodendrocytes), revealing cellular mechanisms inaccessible to standard neuroimaging. Our findings suggest that resilience to atrophy arises from enhanced functional integration, protecting against clinical conversion for many years in individuals at risk of dementia. This result has implications for the design of presymptomatic disease-modifying therapy trials and gives hope for therapeutic strategies aimed at enhancing resilience and ability to maintain function despite the presence of genetically determined neuropathology. ### Competing Interest Statement All authors have no conflicts of interest. Untreated to this there are several disclosures. JBR is a non-remunerated trustee of the Guarantors of Brain, Darwin College, and the PSP Association; he provides consultancy to Alzheimer Research UK, Asceneuron, Alector, Biogen, CuraSen, CumulusNeuro, UCB, SV Health, and Wave, and has research grants from AZ-Medimmune, Janssen, Lilly as industry partners in the Dementias Platform UK. Prof. Lebouvier receives consultancy fees from Roche, Lilly, Biogen, and Eisai, which are directed entirely to his institution. M.M. has acted as a consultant for Astex Pharmaceuticals. ### Funding Statement K.A.T. was supported by Fellowship awards from the Guarantors of Brain (G101149) and the Alzheimer's Society, UK (Grant number 602). J.B.R was supported by the NIHR Cambridge Biomedical Research Centre (NIHR203312: BRC-1215-20014), NIHR funding to the NIHR BioResource (RG94028 & RG85445), Wellcome Trust (220258), Medical Research Council (SUAG/051G101400; SUAG/010 RG91365; MC\_UU\_00030/14 and MR/T033371/1), the Holt Fellowship and by the Addenbrookes Charitable Trust. We thank NIHR BioResource volunteers for their participation, and gratefully acknowledge NIHR BioResource centres, NHS Trusts and staff for their contribution. The views expressed are those of the author(s) and not necessarily those of the NHS or the NIHR. J.C.V.S., L.C.J. and H.S. are supported by the Dioraphte Foundation grant 09-02-03-00, Association for Frontotemporal Dementias Research Grant 2009, Netherlands Organization for Scientific Research grant HCMI 056-13-018, ZonMw Memorabel (Deltaplan Dementie, project number 733 051 042), ZonMw Onderzoeksprogramma Dementie (YOD-INCLUDED, project number10510032120002), EU Joint Programme-Neurodegenerative Disease Research-GENFI-PROX, Alzheimer Nederland and the Bluefield Project. C.G. received funding from EU Joint Programme-Neurodegenerative Disease Research-Prefrontals Vetenskapsrådet Dnr 529-2014-7504, EU Joint Programme-Neurodegenerative Disease Research-GENFI-PROX, Vetenskapsrådet 2019-0224, Vetenskapsrådet 2015-02926, Vetenskapsrådet 2018-02754, the Swedish FTD Inititative-Schörling Foundation, Alzheimer Foundation, Brain Foundation, Dementia Foundation and Region Stockholm ALF-project. C.G. is supported by the Swedish Frontotemporal Dementia Initiative Schörling Foundation; Vetenskapsrådet (Swedish Research Council) JPND Prefrontals, 2015-02926, 2018-02754, and JPND-GENFI-PROX 2019 02248; Swedish Alzheimer Foundation, ALF-project Region Stockholm, Karolinska Institutet Doctoral Funding, KI Strat-Neuro, Swedish Dementia Foundation, and Swedish Brain Foundation. D.G. received support from the EU Joint Programme Neurodegenerative Disease Research and the Italian Ministry of Health (PreFrontALS) grant 733051042. R.V. has received funding from the Mady Browaeys Fund for Research into Frontotemporal Dementia (Mady Browaeys Fonds voor Onderzoek naar Frontotemporale Degeneratie). J.L. received funding for this work by the Deutsche Forschungsgemeinschaft German Research Foundation under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy ID 390857198). E.F. has received funding from a Canadian Institute of Health Research grant #327387. MM was, in part, funded by the UK Medical Research Council, the Italian Ministry of Health and the Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant, and also Canadian Institutes of Health Research operating grants (Grant #s: MOP-371851 and PJT-175242) and funding from the Weston Brain Institute to Mario Masellis. FM is supported by the Tau Consortium and has received funding from the Carlos III Health Institute (PI19/01637). Several authors of this publication (J.C.V.S., M.S., R.V., A.d.M., M.O., R.V., J.D.R.) are members of the European Reference Network for Rare Neurological Diseases (ERN-RND) – Project ID No 739510. This work was also supported by the EU Joint Programme-Neurodegenerative Disease Research GENFI-PROX grant [2019 02248; to J.D.R., M.O., B.B., C.G., J.C.V.S. and M.S. RS-V was funded at the Hospital Clinic de Barcelona by Instituto de Salud Carlos III, Spain (grant code PI20/00448 to RSV) and Fundaci ó Marat ó TV3, Spain (grant code 20143810 to RSV). RL is supported by the Canadian Institutes of Health Research and the Chaire de Recherche sur les Aphasies Primaires Progressives Fondation Famille Lemaire. This work was funded by Mady Browaeys Fonds voor Onderzoek naar Frontotemporale Degeneratie. SD receives salary funding from the Fonds de Recherche du Québec-Santé. This research was undertaken thanks in part to funding from the Canada First Research Excellence Fund, awarded to McGill University for the Healthy Brains, Healthy Lives initiative. This work was supported by ANR-PRTS PREV-DemAls, PHRC PREDICT-PGRN and several authors of this publication are members of the European Reference Network for Rare Neurological Diseases - Project ID No 739510. This work was supported by the JPND grant ′GENFI-prox′ (by DLR/BMBF to M.S, joint with J.R. , JvS, M.O., B.B. and C.G.). FM is supported by the Tau Consortium and has received funding from the Carlos III Health Institute (PI19/01637). BB is supported by JPND grant ′GENFI-prox′ (2019 02248). JDR is supported by the Miriam Marks Brain Research UK Senior Fellowship and has received funding from an MRC Clinician Scientist Fellowship (MR/M008525/1) and the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). This work was also supported by the MRC UK GENFI grant (MR/M023664/1), the Bluefield Project and the JPND GENFI PROX grant (2019 02248). For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was given a favorable opinion by the Cambridge 2 Research Ethics Committee REC 17/EE/0032 IRAS ID 204052. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data were acquired from GENFI data freeze 5. Anonymized data not published within this article will be made available by request from any qualified investigator and can be requested via the GENFI website (https://www.genfi.org/contact-us-2) or via Dementias Platform UK (https://portal.dementiasplatform.uk/Apply).

The negative symptoms of schizophrenia can determine functional outcome in patients. Despite its clinical significance, no treatment exists to date, as numerous pharmacological and non-pharmacological clinical trials have failed to demonstrate efficacy. Many of these trials evaluated negative symptoms as a single clinical construct. However, consistent evidence in the past two decades has found that negative symptoms constitute at least two independent clinical dimensions, namely deficits in motivation and pleasure (MAP) and in emotional expression (EXP). These dimensions are best evaluated using new assessment tools, such as the Brief Negative Symptom Scale (BNSS). However, older assessment tools, and particularly the Positive and Negative Syndrome Scale (PANSS), remain widely used in past and current research. Here, we sought to predict BNSS MAP and EXP dimensions from the PANSS. Using complementary modelling approaches across three heterogeneous, multi- centre, multi-culture patient samples (n = 1241 patients, 1846 observations), we show that MAP can be estimated (43-60 % variance explained) predominantly using N2 and N4. Moreover, EXP can be estimated predominantly using the two PANSS items N1 and N6 (55-81 % variance explained across models and samples). Additionally, PANSS-derived MAP shows associations with functioning similar to those measured by the BNSS MAP dimension. Together, our results suggest that while EXP can be reliably estimated from PANSS, MAP cannot be consistently estimated from PANSS across samples and cultures. This warrants caution when using the PANSS to estimate MAP and emphasises the need for using the newer assessment tools for negative symptoms.

BACKGROUND:Negative symptoms in schizophrenia, particularly motivational deficits, pose significant challenges to treatment and recovery. Despite their profound impact on functional outcomes, these symptoms remain poorly understood and inadequately addressed by current interventions. AIMS:The CHANSS (Characterising Negative Symptoms in Schizophrenia) study aims to dissect the cognitive mechanisms underlying motivational impairments by focusing on three interconnected domains: executive cognition, motivational cognition and meta-cognition. METHOD:This large, international, cross-sectional study recruits a heterogeneous sample of patients across illness stages - from first-episode psychosis to treatment-resistant schizophrenia - and uses a comprehensive cognitive battery, clinical scales, self-report measures and computerised cognitive tasks. Four novel tasks assess key processes in motivated behaviour: option generation, reward-based decision-making, risk sensitivity and performance self-evaluation. By incorporating control for secondary influences like depression, psychosis, sedation and illness chronicity, the study seeks to identify distinct cognitive and behavioural subtypes within motivational dysfunction. RESULTS:CHANSS tests the hypothesis that specific patient profiles exhibit predominant impairments in one or more cognitive domains, which may differentially affect goal-directed behaviour. The study's design allows exploration of hierarchical relationships between cognitive processes, such as how neurocognitive deficits may cascade to impair motivation and self-evaluation. CONCLUSIONS:Ultimately, CHANSS aims to advance mechanistic understanding of motivational deficits in schizophrenia and pave the way for personalised, targeted interventions. Its findings may inform future clinical trials and contribute to a shift away from one-size-fits-all approaches towards more effective, stratified treatment strategies in schizophrenia.

Background Healthcare workers experience disproportionately high rates of depression, anxiety, and posttraumatic stress compared with the general population. Within the NHS, work related stress and mental health related sickness absence has increased over the past decade, a trend intensified by COVID-19. The mental health support offers are patchy across the UK, and the evidence base around the interventions is scarce. Staff Mental Health Service (SMHS), provides rapid, confidential support for NHS staff across Cambridgeshire and Peterborough. In this study, we aimed an economic evaluation of this dedicated service. Aims To assess costs and patient outcomes associated with SMHS treatment, compared with local NHS Talking Therapies (TT) support. Method A model based cost consequence analysis comparing two treatment pathways: SMHS or TT, versus TT only. Routinely collected service data and survey responses informed a decision tree model estimating costs (2022/23 GBP), clinical outcomes (PHQ9 and GAD7 scores), and quality adjusted life years (QALYs). Additional analyses examined service waiting times and productivity losses. Results Costs per patient were slightly higher for SMHS or TT (614 GBP vs 553 GBP), resulting in an incremental cost effectiveness ratio of 7,126 GBP/QALY. SMHS option yielded greater improvements in mental health outcomes than TT alone, with mean score reductions of 4.2 versus 2.8 (PHQ-9), and 4.6 versus 2.7 (GAD-7). Median waiting times were substantially shorter at SMHS versus TT from referral to assessment (14 vs 17 days), referral to treatment (22 vs 51 days), and assessment to first treatment (7 vs 30 days; all p<0.001). Productivity losses during waiting periods were lower for SMHS, with an estimated value of 2,018 GBP per patient. Conclusions The SMHS offers a clinically effective and cost-effective model of support for NHS staff, delivering greater improvements in mental health symptoms, substantially shorter waiting times, and reduced productivity losses at only modest additional cost compared with TT. These findings provide early evidence that specialist services for healthcare workers represent good value for money and support continued investment in staff mental health provision within the NHS. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by The Evelyn Trust (charity #232891). RC and APW (both UEA) are supported by the National Institute for Health and Care Research (NIHR) Applied Research Collaboration East of England (NIHR ARC EoE) at Cambridgeshire and Peterborough NHS Foundation Trust. MK is the Mental Health Specialty Lead in East of England at the NIHR Research Development Network. The views expressed are those of the authors and do not necessarily reflect those of the NIHR or the Department of Health and Social Care. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the NHS Health Research Authority (REC reference: 22/PR/0433, IRAS study ID: 301147) on 11th June 2022. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The authors confirm that the data supporting the findings of this study are included within the article. Source data are not publicly available due to the sensitive nature of participant information. Additional details can be requested from the corresponding author.

Progressive supranuclear palsy (PSP) is a primary tauopathy characterized by atrophy and neuroinflammation of the brainstem, the basal ganglia and, to a lesser degree, the cortex. This study investigates the association of regional atrophy (structural MRI), neuroinflammation ([11C]-PK11195 PET), peripheral markers of neurodegeneration [plasma neurofilament light chain (NfL)] and clinical severity [PSP rating scale (PSPRS)] with survival in people with PSP. Fifty-nine people with PSP underwent longitudinal structural MRI, surviving on average 3.2 years from the first scan (MRI cohort). Sixteen participants (PET cohort) within this cohort underwent cross-sectional [11C]-PK11195 PET and blood sampling for plasma NfL. We applied modality-specific principal component analyses on imaging data and ran partial correlations, multivariate regressions and Bayesian models to evaluate the association between survival and imaging patterns, clinical severity and plasma NfL. In the PET cohort, higher levels of localized inflammation in subcortical regions [rho = -0.49, P = 0.02, Bayes factor (BF) = 8.07] and plasma NfL (rho = -0.57, P = 0.01, BF = 4.63) were associated with shorter survival, while PSPRS scores were not significant predictors of survival. Subcortical atrophy was associated with shorter survival in the larger cohort (r = -0.38, P = 0.001; β = -0.66, P = 0.001). Spearman's correlations, multivariate regressions and Bayesian models converged to the same results. Regional subcortical atrophy is a robust biomarker associated with survival in people with PSP that can be utilized in large-scale clinical trials. Translocator protein (TSPO) PET and plasma NfL offer promising complementary markers for smaller-scale trials, where they may prove more sensitive than clinical scores or structural MRI alone. By linking neuroinflammation to survival, our results also highlight immunotherapy as a promising avenue for disease-modifying treatment in PSP.

There is an urgent need for accessible interventions to facilitate early intervention for young people with borderline personality disorder (BPD) symptoms. Existing evidence-based interventions for adolescent BPD are highly resource-intensive, and few young people with BPD symptoms have access to timely treatment. We adapted a brief psychological treatment for adolescent BPD symptoms previously provided within secondary mental health services for delivery within schools and colleges. This study aimed to assess the feasibility of evaluating the effectiveness and cost-effectiveness of this intervention (BEST (brief education support treatment)) in a future randomised controlled trial (RCT). The feasibility RCT involved 12 schools and colleges. Eligible participants were aged 13–18 years and self-reported BPD symptoms above a clinical threshold and a history of repeated self-harm. Over 9 months, 32 participants were randomised to receive either the BEST intervention plus treatment as usual (TAU) or TAU alone. Participants were assessed at baseline and 12 and 24 weeks. A mixed-methods process evaluation was conducted. Recruitment was slower than anticipated, but participant retention was high (89.5

BACKGROUND:Involving the public in evidence synthesis research is challenging due to the highly analytic nature of the projects, so it is important that involvement processes are documented, reflected upon, and shared to devise best practices. There is a literature gap on the involvement of the public in individual participant data meta-analyses, particularly in public health projects. We aimed to document and reflect on our collective experiences of involving and being involved as public stakeholders at all stages of a systematic review and individual participant data meta-analysis project. METHODS:We formed a stakeholder group made of four members of the public at the beginning of our evidence synthesis project comprising a systematic review, an aggregate data meta-analysis, and an individual participant data meta-analysis of mindfulness-based programmes for mental health promotion in non-clinical adults. Following each group meeting, members and participating researchers completed written reflections; one group member collected and collated these. At the end of the project, a reflective writing workshop was held before all members completed their final reflections. Everyone completed an adapted, open-ended questionnaire which asked about what did and did not work well, the overall experience, what could be improved, and the felt impact the stakeholder group had on the research. RESULTS:Overall, the stakeholders and researchers reported a positive experience of working together. Positives from the stakeholders' point of view included learning new skills, experiencing research, and making new friends. For the researchers, stakeholders helped them focus on what matters to the public and were reinvigorating research partners. The challenges stakeholders experienced included having long gaps between meetings and feeling overwhelmed. The researchers found it challenging to strike the balance between asking stakeholders to be involved and for them to learn research-related skills without overburdening them and making sure that the learning was engaging. When looking back at their experience, stakeholders described seeing their impact on the project in hindsight but that this was not felt while the project was being carried out. CONCLUSION:Successfully involving the public in complex evidence synthesis projects is possible and valuable from the points of view of the researchers and the stakeholders. However, it requires a significant time, skill, and resource investment that needs to be factored in from project inception. Further guidance and stakeholder training materials would be helpful. Specific suggestions are provided.

Background: Amongst different subtypes of frontotemporal dementia (FTD), semantic dementia (SD, also known as the semantic variant of primary progressive aphasia, svPPA), is the least likely to have a genetic basis. Methods: Our study had two aims: (i) to describe two SD cases and detailed assessments of their unaffected monozygotic (MZ) twins, and (ii) to review cases with FTD-associated mutations or known family history classified as SD/svPPA either in the Genetic Frontotemporal dementia Initiative (GENFI) or in the published literature. Results: The two affected twins displayed characteristic features of SD, both in neuroimaging and cognition, whereas their MZ twins exhibited no abnormalities in either regard, even up to 15 years of follow-up for one affected twin. Only five cases out of more than 1300 people in GENFI were classified as svPPA, with a genetic mutation. The systematic review revealed 29 cases with sufficient clinical and language details regarding 'genetic' SD/svPPA. A comparison of these five GENFI and 29 literature cases to the patterns observed in a large number of sporadic cases revealed critical differences in presentation. Conclusions: Both parts of our study suggest that true SD/svPPA is unlikely to have an autosomal dominant genetic aetiology and that, while mutation carriers may resemble SD/svPPA in some respects, they may not meet current clinical diagnostic criteria for this condition. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work and the first author (SKH) were supported and funded by the Bill & Melinda Gates Foundation, Seattle, WA, and Gates Cambridge Trust (Grant Number: OPP1144). This study was supported by the Cambridge Centre for Parkinson-Plus; the Medical Research Council (MC\_UU\_00030/14; MR/P01271X/1; MR/T033371/1); the Wellcome Trust (220258); the National Institute for Health and Care Research Cambridge Clinical Research Facility and the National Institute for Health and Care Research Cambridge Biomedical Research Centre (BRC-1215-20014; NIHR203312); an MRC Programme grant to MALR (MR/R023883/1) and an intramural award (MC\_UU\_00005/18); and MRC Career Development Award (MR/V031481/1). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Twin data were acquired under the PrEPPAReD protocol, approved by the Cambridge 2 Research Ethics Committee (REC reference: 07/Q0102/3; Title: Prospective Evaluation of Parkinson Plus & Related Disorders, formerly entitled: Diagnosis and prognosis in Progressive Supranuclear Palsy (PSP), Corticobasal degeneration (CBD) and Dementia). The affected twins had provided consent to research before losing mental capacity and the decision to include them in research after the loss of mental capacity was affirmed by their personal consultee as set out in the Health and Social Care Framework law for England and Wales. All healthy participants provided written informed consent. For data acquisition of genetic participants, all GENFI sites had local ethical approval for the study from relevant institutional review board or research ethics committee and all participants provided written informed consent. Analyses of GENFI data were conducted under the Cambridge Genetic Frontotemporal Dementia Initiative protocol approved by the Cambridge 2 Research Ethics Committee (REC reference: 17/EE/0032; title: Cambridge Genetic Frontotemporal Dementia Initiative). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The authors confirm that the derived data supporting the findings of this study are available within the article and its supplementary material.