Rationale Tardive dyskinesia (TD) is a neurological syndrome of involuntary repetitive movements which results from treatment with antipsychotic medication. The pathoetiology of TD is not well understood but a possible mechanism involves dopaminergic overactivity in the nigrostriatal pathway. If this theory is correct, then levels of neuromelanin (a long-term marker of dopaminergic activity) should be higher in people with TD than those without TD. Objectives The aim of the study was to test the hypothesis that neuromelanin levels are higher in patients with TD relative to those without TD. Methods Data from 27 participants (TD: n = 13; non-TD n = 14) with a diagnosis of schizophrenia, all taking antipsychotic drugs, was used. Neuromelanin was measured in the midbrain via Magnetic Resonance Imaging (MRI) and compared between the groups. Movement symptoms were measured using the Abnormal Involuntary Movement Scale (AIMS), and antipsychotic dose recorded. Results MRI-measured neuromelanin levels were significantly higher in patients with TD, as compared to those without (mean = 0.223; t(17.27) = 3.817, p = 0.001; g = 1.386, 95% CI=[0.559, 2.213]). This remained significant after controlling for age, sex, substantia nigra/ventral tegmental area volume and antipsychotic dose (ANCOVA: F(1,20) = 12.08, p = 0.0024; adjusted β = 0.0301, 95% CI [0.0120, 0.0481]). The most pronounced difference was seen in the ventral substantia nigra. Conclusions The finding of higher midbrain neuromelanin in patients with TD aligns with the dopamine overactivity hypothesis of TD aetiology. It also supports a neurobiological basis for treatment of TD with drugs that target presynaptic dopamine activity, such as VMAT2 inhibitors. Additionally, it identifies the ventral substantia nigra as a key locus. Future longitudinal studies are needed to delineate if dopamine overactivity develops in response to antipsychotic treatment or is a trait vulnerability marker for risk of TD.

Background: Antibiotics and antidepressants are commonly co-prescribed, yet it remains unclear whether antibiotic exposure around the initiation of antidepressant treatment is associated with later development of difficult-to-treat depression. In this study, we used routine care electronic health records to test whether antibiotic prescriptions in proximity to starting a first-line antidepressant are associated with subsequent treatment escalation to difficult-to-treat options. Methods: We ran a propensity score–matched retrospective cohort study using de-identified electronic health records from the TriNetX US Collaborative Network. We included adults aged 18–65 years with a coded diagnosis of depression (ICD-10 F32–F34) who received their first antidepressant prescription (index date). We excluded individuals with lifetime bipolar disorder or psychotic disorders and those with any of the outcomes of interest on or before the index date. Antibiotic exposure was defined as at least one antibiotic prescription in a window from 1 year before to 3 months after the index antidepressant prescription; follow-up started at the end of this window and continued for up to 5 years. The primary outcome was difficult-to-treat depression, defined as first recorded use of ketamine or esketamine, tricyclic antidepressants, monoamine oxidase inhibitors, lithium augmentation, or electroconvulsive therapy. Propensity scores were estimated using logistic regression, and exposed and unexposed patients were matched 1:1 using a greedy nearest-neighbour algorithm. We used Kaplan–Meier methods with log-rank tests and estimated 5-year restricted mean time lost (RMTL) ratios, with prespecified sensitivity analyses. Negative control outcomes were used to assess residual confounding. Outcomes: In the matched cohort (n=783,406; 391,703 antibiotic-exposed and 391,703 unexposed), antibiotic exposure was associated with higher risk of difficult-to-treat depression (RMTL ratio 1.09, 95% CI 1.07-1.11; p<0.0001) over 5 years. Associations were strongest for ketamine/esketamine (1.17, 1.13-1.20; p<0.0001) and tricyclic antidepressants (1.05, 1.02-1.08; p=0.0006). Negative control outcomes showed no association. When exposure was restricted to topical-only antibiotics, the association was null (RMTL ratio 1.06, 95% CI 0.93–1.20, p=0.389), suggesting that the signal is specific to systemically absorbed antibiotics. Findings were robust in all other prespecified sensitivity analyses, including exclusion of antibiotic prescriptions within ±7 days of index. Interpretation: Our findings suggest that recent antibiotic exposure at the time of antidepressant initiation may help identify patients at higher subsequent risk of treatment escalation to difficult-to-treat depression. Given that both antibiotics and antidepressants are commonly prescribed, findings could have important implications at the population level.

BACKGROUND:Poverty is associated with the severity of common mental health disorders and increased physical comorbidities. However, its effects on severe mental illness (SMI), beyond increasing their incidence, are less understood, especially in low- and middle-income countries. We here examined the relationship between baseline household income and subsequent mental and physical health outcomes in a large cohort of individuals diagnosed with schizophrenia or bipolar disorder in Colombia. METHODS:Retrospective cohort and case-control study using electronic health records from over 5 million Colombians. We identified individuals diagnosed with schizophrenia or bipolar disorder and their baseline household income. Mental health outcomes included third-line antipsychotic treatments (clozapine or antipsychotic polypharmacy) and psychiatric hospitalizations. Physical outcomes included diagnoses of hypertension, type 2 diabetes, and HbA1c levels, compared with rates in individuals without SMI. RESULTS:We included 12,216 (6,485 women) participants newly diagnosed with bipolar disorder or schizophrenia between 2019 and 2023. Compared to middle-income participants (between $700-1,750USD/month), patients on a low income (less than $700USD/month) were more likely to require third-line antipsychotic treatment (OR 1.84 [1.64, 2.08]) and psychiatric hospitalization (incidence rate ratio 1.30 [1.21, 1.41]). Low-income participants with SMI had hypertension and diabetes rates like middle-income participants without SMI who were 20 years older. However, the combined effect of SMI and low income together posed a less-than-additive risk. Lower income was associated with higher HbA1c levels in diabetes, while a diagnosis of SMI was associated with lower levels. CONCLUSIONS:Low income at SMI onset is associated with worse mental and physical health outcomes.

Psychomotor retardation, defined as generalized slowing of movement and speech, is a feature of several neurological and psychiatric disorders. In this review, we discuss the hypothesis that reduced striatal dopaminergic transmission is a transdiagnostic substrate for psychomotor retardation underlying the motor features of conditions such as Parkinson's disease, drug-induced parkinsonism, neuroleptic malignant syndrome, catatonia and depression. We examine the evidence across clinical, epidemiological, neuroimaging, laboratory and therapeutic studies. Parkinsonian disorders share slowed movement and a reduction in verbal output with catatonia and depression. Bradyphrenia, slowed cognitive processing, also occurs in Parkinson's disease and depression. In addition, there are close epidemiological relationships between depression and Parkinson's disease, and between catatonia and neuroleptic malignant syndrome. Neuroimaging studies also generally support the association of psychomotor retardation with reduced dopaminergic transmission, particularly in the dorsal striatum. CSF measurement of homovanillic acid (a dopamine catabolite) yields inconsistent results and is non-specific. Parkinson's disease and catatonia generally respond well to dopaminergic medication. In contrast, dopamine antagonists can induce both parkinsonism and catatonia. Our review is limited by the variability in measurement of psychomotor retardation and difficulty distinguishing between cognitive and motor slowing. It is also likely that other neurotransmitters, such as GABA and serotonin, play an important role in psychomotor speed. It is possible that dopaminergic deficits in psychiatric disorders represent functional disruptions, in contrast to the structural damage to the substantia nigra in Parkinson's disease. We propose further research be conducted into the effects of levodopa and dopamine agonists in depression with psychomotor retardation. Alternative neuroimaging methods such as PET sequences with shorter imaging protocols and neuromelanin-MRI should also be explored.

INTRODUCTION:Positron Emission Tomography (PET) imaging is a close ally of Precision Medicine, and it has been proven to be indispensable in the field of Psychiatry. This imaging modality may also present an important role in understanding Neurodevelopmental disorders and their link to Psychiatric conditions, with new highly selective binders being used currently in research. PET imaging requires the administration of radiopharmaceuticals, where the radioisotope is in incorporated into a highly selective binder. Dosimetry and injected activity optimisation play a crucial role in the field of PET imaging as they allow to determine the radiation dose absorbed by target and non-target tissues, and determine the lowest amount required to deliver images with diagnostic quality and obtain reliable quantitative data, without overexposing patients. The aim of this research is to investigate the feasibility of reducing the injected activity of the [11C]-(+)-PHNO and [11C]UCB-J radiopharmaceuticals, for patients with neurodevelopmental disorders who undergo brain imaging in the PET-Magnetic Resonance (MR) scanner, without compromising quantitative accuracy of outcome measures. RESULTS:No statistically significant differences were found when comparing the 1/2 to 1/6 datasets with the full injected activity [11C]-(+)-PHNO dataset. Furthermore, the findings obtained from investigating the impact of low injected activity administrations of [11C]UCB-J revealed that it is possible to reduce the administered activity by 1/2, when the clinical outcome measure under evaluation is the binding potential relative to non-displaceable volume (BPND). When the outcome measure under investigation is the standard uptake volume ratio (SUVR), it is possible to decrease the injected activity to 1/3, for [11C]UCB-J. CONCLUSIONS:The simulation and analysis methodologies deployed in this project are suitable for investigating scans with low injected activity for tracers with cortical and striatal uptake, when the outcome measure assessed is the BPND or the SUVR. Whilst the data suggests that imaging with low injected activity is achievable, the efficacy of the investigation is highly dependent on the algorithm used to reconstruct the images, the outcome measure and the radiopharmaceutical used to acquire the PET-MR scans. For the [11C]UCB-J radiopharmaceutical, it is possible to decrease the injectable activity to 1/3 of the original administration without compromising the SUVR.

Correlation matrices are fundamental summaries of functional brain networks, yet standard analyses often treat entries independently, ignoring the curved geometry of correlation space. Existing geometric methods frequently lack closed-form operations or depend on arbitrary region ordering, limiting scalability. We introduce a scalable geometric framework with two components: (i) the Off-log metric, a smooth transformation mapping correlation matrices to symmetric zero-diagonal matrices. This enables closed-form expressions for distances, Fréchet means, and linear models, allowing standard statistical modeling without complex manifold optimization. (ii) Grassmannian subspace discrimination, which compares subjects via principal-angle distances between eigenvector subspaces, resolving inherent sign and basis ambiguities. Both components integrate into standard machine-learning workflows for inference, regression, and classification. Validated across two clinical cohorts (Parkinson's and psychosis) and three ageing fMRI datasets, the Off-log metric increased sensitivity in permutation tests and matched or exceeded Riemannian and Euclidean baselines in classification. Brain-age prediction performance was comparable, with Riemannian metrics excelling in two of three cohorts. The Grassmannian method consistently outperformed Euclidean baselines, highlighting disease-relevant networks. Overall, geometry-aware representations improve sensitivity and predictive performance while remaining straightforward to deploy at scale.

Background Overweight and obesity are highly prevalent in people with severe mental illness (SMI). Antipsychotic-induced weight gain (AIWG) is one of the most commonly reported and distressing side effects of treatment and people living with SMI place a high value on the avoidance of this side effect. Metformin is the most effective pharmacological intervention studied for the prevention of AIWG yet clear guidelines are lacking and evidence has not translated into practice. The aim of this research was to develop a guideline for the use of metformin for the prevention of AIWG.Study Design The appraisal of guidelines for research and evaluation II instrument (AGREE II) was followed for guideline development. Literature was reviewed to address key health questions. The certainty of evidence was evaluated using GRADE methodology and an evidence-to-decision framework informed the strength of the recommendations. A consensus meeting was held where the algorithm and strength of recommendations were agreed. An independent external review was conducted involving experts in the field, including patient and public partners.Study Results Metformin is the only pharmacological agent that has demonstrated efficacy for preventing AIWG. Co-commencement with antipsychotic medicines can reduce the extent of weight gain by 4.03 kg (95% CI -5.78 kg to -2.28 kg) compared to controls. A guideline for the use of metformin for the prevention of AIWG was developed with specific recommendations for co-commencement of metformin at initiation with an antipsychotic or commencement if certain criteria are present. Core recommendations were graded as strong by consensus agreement.Conclusions This is the first published evidence-based guideline using the AGREE II framework and GRADE methods for the use of metformin to prevent AIWG incorporating recommendations for co-commencement. Implementation and evaluation of the guideline will be supported by a shared decision-making package and assessment of barriers and facilitators to implementation.

Modelling the prodrome to severe mental disorders (SMD), including unipolar mood disorders (UMD), bipolar mood disorders (BMD) and psychotic disorders (PSY), should consider both the evolution and interactions of symptoms and substance use (prodromal features) over time. Temporal network analysis can detect causal dependence between and within prodromal features by representing prodromal features as nodes, with their connections (edges) indicating the likelihood of one feature preceding the other. In SMD, node centrality could reveal insights into important prodromal features and potential intervention targets. Community analysis can identify commonly occurring feature groups to define SMD at-risk states. This retrospective (2-year) cohort study aimed to develop a global transdiagnostic SMD network of the temporal relationships between prodromal features and to examine within-group differences with sub-networks specific to UMD, BMD and PSY. Electronic health records (EHRs) from South London and Maudsley (SLaM) NHS Foundation Trust were included from 6462 individuals with SMD diagnoses (UMD:2066; BMD:740; PSY:3656). Validated natural language processing algorithms extracted the occurrence of 61 prodromal features every three months from two years to six months before SMD onset. Temporal networks of prodromal features were constructed using generalised vector autoregression panel analysis, adjusting for covariates. Edge weights (partial directed correlation coefficients, z) were reported in autocorrelative, unidirectional and bidirectional relationships. Centrality was calculated as the sum of (non-autoregressive) connections leaving (out-centrality, cout) or entering (in-centrality, cin) a node. The three sub-networks (UMD, BMD, PSY) were compared using permutation analysis, and community analysis was performed using Spinglass. The SMD network revealed strong autocorrelations (0.04 ≤ z ≤ 0.10), predominantly positive connections, and identified aggression (cout = 0.103) and tearfulness (cin = 0.134) as the most central features. Sub-networks for UMD, BMD, and PSY showed minimal differences, with 3.5% of edges differing between UMD and PSY, 0.8% between UMD and BMD, and 0.4% between BMD and PSY. Community analysis identified one positive psychotic community (delusional thinking-hallucinations-paranoia) and two behavioural communities (aggression-cannabis use-cocaine use-hostility, aggression-agitation-hostility) as the most common. This study represents the most extensive temporal network analysis conducted on the longitudinal interplay of SMD prodromal features. The findings provide further evidence to support transdiagnostic early detection services across SMD, refine assessments to detect individuals at risk and identify central features as potential intervention targets.

A great deal is known about the use, benefits, and side effects of clozapine in treatment-resistant schizophrenia (TRS). However, why clozapine is more effective than other antipsychotics in TRS remains unclear. In this article, we address this question. Patients with TRS show glutamate abnormalities, and clozapine has widespread effects on glutamate. However, these actions have not been proven to be different from those of other antipsychotics. Immune dysfunction is also reported in TRS, and clozapine has anti-inflammatory actions, but these have not been correlated with clinical improvement. Currently, there is a great deal of interest in muscarinic abnormalities in psychosis. Unlike most antipsychotics, clozapine has important effects on muscarinic receptors, particularly M1 and M4, and its major metabolite, N-desmethylclozapine, is a full agonist at M1. These effects are likely crucial to clozapine's effectiveness. In addition, clozapine's lower dopamine D2 receptor occupancy has been postulated to allow gradual resolution of dopamine receptor supersensitivity in the minority of patients with TRS who initially respond to antipsychotics but become resistant following long-term dopamine blockade. However, this hypothesis remains controversial. Clozapine's multireceptor profile enables it to have beneficial actions on the nonpsychotic symptoms common in TRS; its ability to bind to histamine H1, serotonin 5-HT1A, and GABAB (gamma-aminobutyric acid B) receptors offers an explanation for its anxiolytic actions, while effects on 5-HT1A, 5-HT2A, and 5-HT7 receptors likely underlie its antidepressant properties. Clozapine shares these properties with olanzapine and quetiapine, but its affinity for muscarinic receptors may be the mechanism by which it is more effective in TRS.

Major depressive disorder (MDD) is a leading cause of suicide and disability. Better understanding changes to serotonin2A receptors (5-HT2ARs) in MDD and suicide may help to improve treatments. We systematically reviewed and meta-analysed positron emission tomography (PET), single photon emission computed tomography (SPECT) and post-mortem radioligand binding studies of cortical 5-HT2ARs in MDD and suicide. Databases were searched from inception to August/September 2024. Binding data were extracted and pooled before random-effects meta-analyses of mean difference (Hedges’ g) and variance were undertaken. Simple linear regression was performed to investigate the relationship between receptor binding and depression severity at baseline in PET and SPECT studies. We also assessed study quality and tested for evidence of publication bias. Data on 556 MDD patients or suicide victims and 526 controls from 31 studies were included. Cortical 5-HT2AR binding was significantly lower in living MDD patients, who had not taken antidepressants for between one week and forever, than controls in frontal, prefrontal, cingulate, anterior cingulate and, upon sensitivity analysis, temporal cortex (Hedges’ g = –0.40 to –0.57). In frontal and cingulate regions, binding effect size correlated with depression severity at baseline. There was study-level evidence of lower regional binding in never-medicated MDD patients than controls which, upon exploratory meta-analysis, reached significance in anterior cingulate cortex. Most PET or SPECT studies were of good or fair quality. The results of most post-mortem analyses were negative and included studies were of variable quality. There was limited evidence of publication bias. In vivo 5-HT2AR binding is reduced in MDD in frontal, cingulate and temporal cortex. This finding is based mainly on studies that used antagonist or inverse agonist radiotracers.

Treatment resistance affects up to one in four individuals with psychosis in the first few years of illness. However, there is limited information about the brain changes associated with treatment resistance, restricting our ability to develop effective prognostic biomarkers or new treatments. Using resting-state functional MRI, we examined striatocortical connectivity in 87 patients who presented a non-affective first-episode of psychosis and 118 healthy controls, with follow-up imaging on more than half of the participants in the next 6 years, totaling 361 images. Crucially, we identified 30 patients who presented treatment-resistant psychosis in this follow-up period. Thus, we examined baseline (at first episode) and longitudinal striatocortical differences within psychosis subgroups (treatment-responsive and treatment-resistant psychosis), and between patients subgroups and healthy controls. Compared to healthy controls, participants with treatment-responsive psychosis presented baseline differences in functional connectivity of ventral striatal systems, without changes over time; whereas patients with treatment-resistant psychosis showed both baseline and longitudinal differences in ventral striatal systems, compared to healthy controls. Treatment-responsive and treatment-resistant psychosis groups differed in longitudinal changes in connectivity between ventral striatal and temporal cortical regions. This is one of the circuits which has been previously related to symptom improvements in patients with first-episode of psychosis. No baseline differences were observed between the two psychosis groups. Overall, treatment-resistant psychosis is characterized by longitudinal changes in striatal systems in early psychosis, which might be used as the basis of future prognostic biomarkers.

Importance:There is limited neurobiological or trial evidence guiding treatment of comorbid affective syndromes in psychotic disorders. Given the use of dopamine-blocking antipsychotics, understanding dopamine function across these mood states is warranted. Objective:To test for differences in dopamine synthesis capacity (Kicer) between affective syndromes across psychotic disorders and for association with psychotic symptom severity. Design, Setting, and Participants:In this cross-sectional study using fluorine F 18-labeled fluorodopa (18F-DOPA) positron emission tomography (PET), individuals with first-episode psychosis and comorbid affective syndromes, including a current major depressive episode (MDE) or mixed/mania syndromes, and matched controls were recruited from early intervention services in inner-city London, United Kingdom. Data were collected from March 2013 to February 2022 and analyzed from October 1, 2023, to January 1, 2025. Exposure:Striatal Kicer measured by 18F-DOPA PET. Main Outcomes and Measures:Striatal Kicer and scores on the Positive and Negative Syndrome Scale, Hamilton Depression Rating Scale, Montgomery-Åsberg Depression Rating Scale, and Young Mania Rating Scale were determined. Results:The study included a total of 76 individuals (38 with first-episode psychosis and comorbid affective syndromes [25 with MDE and 13 with mixed/mania syndromes] and 38 matched controls). The mean (SD) age was 27.2 (8.9) years overall, 30.7 (12.8) years among those with MDE, 23.7 (3.1) years among those with mixed/mania syndromes, and 26.0 (6.0) years among controls. Sex distribution did not differ (MDE, 13 [52%] male; mixed/mania syndromes, 8 [62%] male; controls, 25 [66%] male; P = .56). Kicer (controlling for age and sex) was significant across groups in whole striatum (F2,71 = 4.04; P = .02; R2 = 0.13). People with psychosis and MDE had lower Kicer compared with those with psychosis and mixed/mania syndromes (β [SE], 0.014 [0.001]; P = .02), with the largest difference observed in the limbic striatum (Cohen d = 1.57; P < .001). In the overall psychosis sample, higher striatal Kicer was associated with greater positive psychotic symptoms (R2 = 0.13; β [SE], 0.000066 [0.000030]; P = .03), notably in the associative striatum (R2 = 0.15; P = .02). No significant association was found in the limbic striatum. Conclusions and Relevance:Kicer was lower in psychosis and comorbid MDE than mixed/mania syndromes, and transdiagnostically, greater positive psychotic symptoms were associated with higher Kicer in the associative, but not limbic, striatum. This subregion dopamine dysregulation has relevance for dopamine-modulating therapeutic agents and drug discovery.

BACKGROUND:Targeting the glutamatergic system is posited as a potentially novel therapeutic strategy for psychotic disorders. While studies in subjects indicate that antipsychotic medication reduces brain glutamatergic measures, they were unable to disambiguate clinical changes from drug effects. AIMS:To address this, we investigated the effects of a dopamine D2 receptor partial agonist (aripiprazole) and a dopamine D2 receptor antagonist (amisulpride) on glutamatergic metabolites in the anterior cingulate cortex (ACC), striatum and thalamus in healthy controls. METHOD:A double-blind, within-subject, cross-over, placebo-controlled study design with two arms (n = 25 per arm) was conducted. Healthy volunteers received either aripiprazole (up to 10 mg/day) for 7 days or amisulpride (up to 400 mg/day) and a corresponding period of placebo treatment in a pseudo-randomised order. Magnetic resonance spectroscopy (1H-MRS) was used to measure glutamatergic metabolite levels and was carried out at three different time points: baseline, after 1 week of drug and after 1 week of placebo. Values were analysed as a combined measure across the ACC, striatum and thalamus. RESULTS:Aripiprazole significantly increased glutamate + glutamine (Glx) levels compared with placebo (β = 0.55, 95% CI [0.15, 0.95], P = 0.007). At baseline, the mean Glx level was 8.14 institutional units (s.d. = 2.15); following aripiprazole treatment, the mean Glx level was 8.16 institutional units (s.d. = 2.40) compared with 7.61 institutional units (s.d. = 2.36) for placebo. This effect remained significant after adjusting for plasma parent and active metabolite drug levels. There was an observed increase with amisulpride that did not reach statistical significance. CONCLUSIONS:One week of aripiprazole administration in healthy participants altered brain Glx levels as compared with placebo administration. These findings provide novel insights into the relationship between antipsychotic treatment and brain metabolites in a healthy participant cohort.

Background: Up to one third of patients with schizophrenia do not benefit from standard antipsychotic treatment, termed treatment resistant schizophrenia (TRS). Clozapine is the only licensed treatment in TRS and is associated with better outcomes. However, it is underused, as its initiation is often limited by the need for inpatient admission, which is costly and unattractive to patients. Community clozapine titration services may address this. Aims: To describe a targeted outpatient clinic (TUNE-UP) for TRS management and assess its impact on clozapine initiation rates. Method: We reviewed clozapine titrations for patients under four community mental health teams in the United Kingdom from September 2021 to January 2025, noting whether titration occurred in inpatient or outpatient settings. The TUNE-UP clozapine clinic operated for 12 months (September 2023 to September 2024). Initiation rates during the TUNE-UP period were compared with rates when the service was unavailable using Poisson regression. Clinical outcomes were assessed using scales such as the Positive and Negative Syndrome Scale (PANSS) for symptom severity and the Social and Occupational Functioning Assessment Scale (SOFAS) for functioning. Results: 61 individuals were commenced on clozapine. During the TUNE-UP clinic period of operation, community initiation rates increased to 11.0 per year (up from 1.33 per year when the service was unavailable), while inpatient initiations were similar (11.0 per year vs. 11.67 per year). Increases in total initiations (p = 0.048) and community initiations (p = 0.0003) were statistically significant. Patients seen by TUNE-UP had improvements in PANSS (mean baseline 63.3 (SD 18.3); mean improvement 20.5 (SD 12.2; p = 0.009)), and SOFAS (mean baseline 48.3 (SD 7.5); mean improvement 8.8 (SD 7.1, p = 0.028)). Conclusion: A specialist community service was associated with a significant increase in clozapine initiations alongside improved clinical outcomes. This approach offers a clinically and cost effective strategy to enhance treatment for TRS. ### Competing Interest Statement RAM has received speaker/consultancy fees from Boehringer Ingelheim, Janssen, Karuna, Lundbeck, Newron, Otsuka, and Viatris, and co-directs a company that designs digital resources to support treatment of mental ill health. TP has received speaker/consultancy fees from Boehringer Ingelheim, Recordati, Lundbeck, Otsuka, Janssen, CNX Therapeutics, Sunovion, ROVI Biotech, Schwabe Pharma, and Lecturing Minds Stockholm AB; he receives book royalties from Wiley Blackwell; he co-directs a company that designs digital resources to support treatment of mental illness. Other authors have no conflicts of interest to declare. ### Funding Statement RAMs work is funded by a Wellcome Trust Clinical Research Career Development Fellowship (224625/Z/21/Z). This work and the TUNE UP clinic have been developed as part of a collaborative working partnership between Oxford Health NHS Trust and Boehringer Ingelheim Ltd. VM is supported by the Swiss National Science Foundation (P500PM_217669). TP is supported by the UK National Institute for Health Research (NIHR), Maudsley Charity, the Brain and Behaviour Research Foundation, the UK Academy of Medical Sciences, and the UKRI Hub for Metabolic Psychiatry (grant reference MR/Z503563/1, platform grant code MR/Z000548/1). JBF is supported by an NIHR Academic Clinical Fellowship (ACF-2023-13-016). ### 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: This project was approved by the Oxford Health NHS Foundation Trust Audit Management and Tracking service with further ethical approvals not required. 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 available from authors on request.

Importance:People with obesity and diabetes have poorer psychiatric and cognitive outcomes and lower quality of life (QOL) compared with those without. Glucagon-like peptide 1 receptor agonists (GLP1-RAs) are treatments for diabetes and obesity that may also influence psychiatric outcomes. Objective:To conduct a meta-analysis of randomized placebo-controlled trials to evaluate psychiatric, cognitive, and QOL outcomes with GLP1-RA treatment. Data Sources:MEDLINE, Embase, PsycINFO, and CENTRAL databases were searched from inception through June 24, 2024. Study Selection:Double-blind placebo-controlled trials comparing GLP1-RA to placebo in adults with overweight/obesity and/or diabetes, reporting on psychiatric, cognition, or QOL outcomes, were included. Data Extraction and Synthesis:Data extraction was performed in parallel by 2 reviewers. Random-effects meta-analysis was performed. Effect size measures were log risk ratios (log[RR]) and standardized mean differences (Hedges g). The quality of studies was appraised using the Cochrane risk-of-bias tool (RoB2). Certainty of evidence was assessed via GRADEpro. Main Outcomes and Measures:Main outcomes were risk of psychiatric adverse events (serious and nonserious) and change in mental health symptom severity, health-related quality of life, and cognition. Results:Eighty randomized clinical trials involving 107 860 patients were included in the meta-analysis. The mean (SD) age of participants across studies in the meta-analysis was 60.1 (7.1) years; 43 251 were female (40.1%) and 64 608 male (59.9%). GLP1-RA treatment was not associated with a significant difference in risk of serious psychiatric adverse events (log[RR] = -0.02; 95% CI, -0.20 to 0.17; P = .87) and nonserious psychiatric adverse events (log[RR] = -0.03; 95% CI, -0.21 to 0.16], P = .76), or depressive symptom change (g = 0.02; 95% CI, -0.51 to 0.55; P = .94), compared with placebo. GLP1-RA treatment was associated with improvements in restrained eating (g = 0.35; 95% CI, 0.13 to 0.57; P = .002) and emotional eating behavior (g = 0.32; 95% CI, 0.11 to 0.54; P = .003) and in mental health-related QOL (g = 0.15; 95% CI, 0.07 to 0.22; P < .001), physical health-related QOL (g = 0.20; 95% CI, 0.14 to 0.26; P < .001), diabetes-related QOL (g = 0.23; 95% CI, 0.15 to 0.32; P < .001), and weight-related QOL (g = 0.27; 95% CI, 0.18 to 0.35; P < .001) compared with placebo. Conclusions and Relevance:In patients with overweight/obesity and/or diabetes , GLP1-RA treatment is not associated with increased risk of psychiatric adverse events or worsening depressive symptoms relative to placebo and is associated with improvements in QOL, restrained eating, and emotional eating behavior. These findings provide reassurance regarding the psychiatric safety profile of GLP1-RAs and suggest that GLP1-RA treatment contributes to both physical and emotional well-being.

Despite its superior effectiveness for treatment-resistant schizophrenia, clozapine has a high burden of adverse drug reactions (ADRs), which require monitoring and treatment. This global Delphi study has established consensus guidelines for absolute neutrophil count (ANC) thresholds for consideration of clozapine cessation and provided monitoring protocols for ADR management. Recommendations include lowering ANC thresholds for consideration of clozapine cessation to 1·0 × 109 cells per L (0·5 × 109 cells per L for Duffy antigen receptor for chemokines-null individuals) and discontinuing routine ANC monitoring after 2 years. Comprehensive ADR monitoring, with ANC monitoring in the first 2 years, then every 3 months after discontinuing routine ANC monitoring, should address the metabolic syndrome, constipation, gastro-oesophageal reflux, sialorrhea, nocturnal enuresis, tachycardia, sleep apnoea, sedation, and other ADRs. Consumer representatives underscored the need for shared decision-making, streamlined monitoring, and accessible patient education. Although barriers persist, these findings support updating global policies to reduce burden on patients, enhance adherence, and optimise clinical outcomes. Incorporating evidence-based guidelines into practice could transform clozapine care, balancing safety with practicality to improve the lives of those with treatment-resistant schizophrenia.

Clozapine is the only licensed pharmacotherapy for treatment resistant schizophrenia (TRS), but in some cases is not a suitable treatment option. A review of the efficacy of non-clozapine interventions in TRS may help inform clinical decision making when clozapine treatment is not feasible. A systematic review and meta-analysis was performed investigating the efficacy of non-clozapine augmentation of antipsychotic treatment in TRS on positive, negative, and total symptoms. The review protocol is registered at PROSPERO (ID: CRD42023418053). PsycInfo, PubMed and EMBASE were searched up until July 2023. Cochrane Risk of Bias tool (v2) was used to assess study quality. Data were pooled using a random-effects model for each class of intervention to give an estimate of effect size (Hedges’ g). 78 studies were included, of which 68 were included in the meta-analysis, comprising 3241 patients. High-dose antipsychotics (7 studies, 467 participants) did not improve any symptom domain. Augmentation of antipsychotics with glycine modulatory site agonists (9 studies, 187 participants) improved positive (g = −0.56 [−0.81, −0.31], GRADE rating Low), negative (g = −1.18 [−1.49, −0.87], GRADE rating Low) and total (g = −1.17 [−1.75, −0.59], GRADE rating Very Low) symptoms. Non-invasive stimulation (26 studies, 893 participants) moderately benefited positive symptoms (g = −0.42 [−0.65, −0.18], GRADE rating Low). Psychotherapy (10 studies, 565 participants) moderately improved positive symptoms (g = −0.56 [−1.01, −0.10], GRADE rating Low). Augmentation with antidepressants (3 studies, 187 participants) improved negative (g = −0.74 [−1.46, −0.02], GRADE rating Very Low) and total (g = −0.69 [−1.00, −0.38], GRADE rating Low) symptoms. Sample sizes were small, and publication bias was apparent for non-invasive stimulation studies. Several augmentation strategies, including pharmacotherapy, non-invasive stimulation, and psychotherapy demonstrated benefit in small studies, however no intervention reached the threshold of evidence to be routinely recommended as a viable alternative to clozapine. High-quality trials are needed for definitive recommendations.