Systemic inflammation is increasingly recognised as a key modulator of brain function, yet its impact on large-scale brain network topology remains incompletely understood. In particular, it is unclear whether inflammation alters the balance between functional segregation and integration, as captured by small-world organisation, and whether such effects are better detected using dynamic rather than static connectivity analyses. In this study, we conducted a secondary analysis of a previously collected dataset to examine the effects of experimentally induced inflammation on static and dynamic small-world topology using resting-state fMRI and graph-theoretical methods. Eighteen healthy male participants completed a double-blind, placebo-controlled, randomised crossover trial involving typhoid vaccination, a well-established model of low-grade systemic inflammation. Small-worldness was quantified across a fixed density range for both static and dynamic functional connectivity. No significant differences were observed in static small-worldness between conditions. In contrast, dynamic analyses revealed a significant reduction in mean small-worldness following vaccination. This effect was primarily driven by reduced clustering coefficient, with no change in characteristic path length, indicating a selective alteration in local segregation while preserving global integration. Dynamic state analysis identified two recurring connectivity states with distinct topological profiles. Although differences in fractional occupancy and dwell time were not statistically significant, participants showed a consistent tendency to spend less time in the high small-worldness state following inflammation. These preliminary findings indicate that inflammation modulates the temporal organisation of brain networks in ways not detectable using static approaches and are consistent with a metabolically efficient reconfiguration of network topology under inflammatory challenge.

Treatment-resistant schizophrenia (TRS) poses significant challenges. Clozapine, the most effective antipsychotic for TRS, is underused due to its side effect profile and intensive monitoring requirements during initiation. This article describes a collaborative virtual ward model in Peterborough, UK, for community-based clozapine initiation. Integrating wearable technology for real-time health tracking with video consultations, the service provides hospital-equivalent care at home. A partnership between Cambridgeshire and Peterborough NHS Foundation Trust and North West Anglia NHS Foundation Trust merges mental health expertise with acute care infrastructure. Early experiences suggest higher patient engagement, increased clinician confidence and reduced inpatient burden. This initiative has the potential to transform clozapine access, bridge physical and mental health services and offer a blueprint for patient-centred TRS care.

Background: People with psychosis have a reduced life expectancy by 15 years, mainly due to preventable physical illnesses for which obesity is a precursor. Obesity is three times more common in psychosis and antipsychotics are an important cause. Prediction could individualise obesity treatment but current models are not fully actionable for individuals. Aims: We test whether antipsychotic-induced weight increase at 1 year is causally mediated by weight change in the first 12 weeks of treatment, rather than the following 40 weeks. We then develop and internally validate a causal actionable prediction pathway to prevent antipsychotic-induced obesity. Methods: We use parallel causal mediation analysis to determine the natural direct and indirect, and total effects of antipsychotic choice on weight in a trial of olanzapine versus haloperidol in 97 participants. We develop a baseline causal actionable prediction model to predict weight gain at 12 weeks in 172 participants, and a 12-week model to predict obesity at 1 year in 97 of the participants, and then demonstrate counterfactual prediction. Results: Antipsychotic-induced weight gain at 1 year appears to be causally mediated by weight change during the first 12 weeks treatment – indirect effect 5.70 (95% CI 2.83 to 8.66). At internal validation, the discrimination c-statistic for the baseline causal actionable prediction model was 0.732 and the calibration slope was 0.768. For the 12-week model, the c-statistic was 0.914 and the calibration slope was 0.601. We use the models to predict the counterfactual outcomes of antipsychotic choice and 12-week weight change. Conclusions: Our study shows it may be early, rather than later weight change, which causally mediates antipsychotic-induced weight gain at 1 year. We also demonstrate the potential for causal prediction of counterfactuals targeting obesity for true precision medicine. Further research in larger samples is necessary before causal prediction models could be applied clinically.

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).

Clozapine is a pharmacological treatment with strong evidence for treatment-resistant schizophrenia (TRS), yet it continues to be under-prescribed, initiated late, and offered to a minority of eligible patients. This treatment gap is felt most acutely in early intervention in psychosis (EIP) services. The accompanying study by Conaty et al. examines the clinico-demographic correlates of community versus hospital clozapine initiation in a first-episode psychosis (FEP) population. Over half of clozapine treated patients were initiated in the community, and this was associated with substantially lower discontinuation rates. This commentary situates those findings within the wider barriers literature in first episode psychosis, considers the emerging role of virtual wards and remote monitoring in facilitating community-based initiation, and outlines implications for service design and future research.

BACKGROUND:Electroconvulsive therapy (ECT) is often used to treat severe mental disorders in individuals with impaired capacity to consent to the treatment. Little is known about how different types of electrode placement are used in consensual and nonconsensual ECT. AIMS:To investigate whether there was an association between ECT consent status and electrode placement, given that ECT electrode placement affects efficacy and cognitive outcomes. METHOD:Using a statewide database across 3 years in Victoria, Australia, we performed chi-squared tests to determine whether consent status (consensual versus nonconsensual) was associated with particular electrode placements. A three-way log-linear analysis was then conducted to examine whether age, gender, level of education and psychiatric diagnosis influenced the relationship between consent status and electrode placement. Given the comparable cognitive outcomes of right unilateral and bifrontal ECT, these electrode placements were combined in the analysis. RESULTS:In total, 3882 participants received ECT in the Victorian public health service during the study period. In the nonconsensual ECT group, 722 of 1576 individuals (45.81%) received bitemporal ECT, compared with 555 of 2306 (24.06%) in the consensual group (χ2 = 200.53; P < 0.0001; odds ratio: 2.6673, 95% CI: 2.3244-3.0608). This association remained significant after adjustment for gender, age, level of education and diagnosis. CONCLUSION:Significantly more participants in the nonconsensual ECT group received bitemporal ECT rather than right unilateral or bifrontal ECT compared with those in the consensual group. As bitemporal ECT is associated with more cognitive impairment, this choice of electrode placement in vulnerable patients who lack capacity to consent raises ethical considerations in the practice of ECT.

Deficits in the hippocampus are a consistent finding in schizophrenia and have also been demonstrated in early-stage psychosis. Moreover, alterations in hippocampal anatomy and connectivity have been implicated in aberrant functional interactions in subcortical and cortical networks. However, the nature and extent of these alterations and their association with frontal and subcortical regions remain unclear. To address these questions, we analysed resting state fMRI functional connectivity and graph properties in n = 93 individuals at clinical high-risk for psychosis (CHR-P), n = 26 patients with first-episode psychosis (FEP), n = 31 individuals with affective disorders and substance abuse as well as n = 58 healthy controls. We used novel denoising techniques and individually optimised functional connectivity matrices, which were compared across clinical groups. Finally, the centrality of the hippocampus as well as network segregation and integration were assessed using graph-based analysis. Both the FEP and CHR-P groups were characterised by reduced functional connectivity between the hippocampus and inferior frontal cortex albeit the differences in CHR-P individuals did not survive corrections for multiple comparisons. Compared to CHR-P, FEP show lower centrality of the hippocampus but increased network segregation. Our findings show lower connectivity between the hippocampus and frontal cortex in early-stage psychosis, with FEP patients showing stronger decreases in connectivity compared to CHR-Ps. Furthermore, network-based analyses highlight reduced centrality in FEPs compared to CHR-Ps, indicating reduced influence on the wider network. Thus, altered connectivity along the hippocampal-frontal axis could be a potential marker of illness stage in early-stage psychosis.

This article examines ethnic bias in predictive algorithms and decision-making systems within precision psychiatry. While these models aim to provide individualised outcomes and improve healthcare, they often perpetuate historical biases present in training datasets. Factors such as historical disparities, poor access to care, and ethnic under-representation in data collection exacerbate these biases, leading to inequitable healthcare predictions and decisions that affect outcomes for ethnic minority groups. The article emphasizes the necessity of understanding the causal relationships underlying data patterns to mitigate some of these biases and enhance the effectiveness and fairness of machine learning applications in mental health care.

Aims To support evidence gathering for Esteem's RCPsych Early Intervention in Psychosis (EIP) network accreditation efforts, an audit was conducted to investigate compliance with EIPN's quality standards (QS) no. 33 and no. 36. EIPN QS 33 = patients with first episode psychosis (FEP) are offered antipsychotic medication. EIPN QS 36 = If the patient's illness does not respond to an adequate trial of two different antipsychotic medicines given sequentially, they are offered clozapine. EIPN QS 36 is also specifically included in RCPsych's National Clinical Audit of Psychosis (NCAP) (listed as standard 4), but a more pragmatic definition is used, to factor in the issue of antipsychotic intolerance. NCAP Standard 4 = People with FEP who have not responded adequately to or tolerated treatment with at least two antipsychotic drugs should be offered clozapine (NICE QS80). This broader standard definition was used for this audit, to allow for results comparison with national data. Methods For EIPN QS 33, all patients on North East Esteem caseload (any primary diagnoses) for at least 6 months on 01/04/2023 were included. For EIPN QS 36/NCAP Standard 4, the same inclusion criteria were used but refined to FEP cases only. The electronic clinical records (EMIS) of such cases were reviewed manually by an ST5 and CT3 psychiatrist. Data on prescription history was collected then analysed in Microsoft Excel. Results EIPN QS 33: 58 patients with any primary diagnosis were initially identified as being on NE Esteem caseload > 6 months as of 01/04/23. 58 (100%) patients were offered antipsychotic medication ⋅ 1 (2%) patient was prescribed an antipsychotic but never took it ⋅ 21 (36%) patients were only ever prescribed one antipsychotic ⋅ 17 (29%) patients were prescribed two antipsychotics sequentially trialled ⋅ 11 (19%) patients were prescribed three antipsychotics sequentially trialled ⋅ The remainder, 8 (14%) patients, had four or more antipsychotics sequentially prescribed (with the maximum number of trials being eight). EIPN QS 36 / NCAP Standard 4: 55 patients with FEP diagnosis were initially identified as being on NE Esteem caseload > 6 months as of 01/04/23. 16 (29%) of these patients had at least three or more trials of antipsychotic medication, i.e. patients eligible for clozapine. However, only 5 (31%) of these 16 patients had either been prescribed clozapine (3 patients, 19%) or offered/trialled clozapine (2 patients, 13%). This 31% figure compares with 85% in Wales, 52% in England, and 50% in Ireland (NCAP 2021–22). Conclusion EIPN QS 33: The standard that patients with first episode psychosis are offered antipsychotic medication was fully met. About a third of patients required only one antipsychotic trial. Less than a third required two antipsychotic trials. One in five required three antipsychotic trials, and approximately one in seven patients required more than three antipsychotic trials. EIPN QS 36/NCAP Standard 4: The number of eligible patients being offered or prescribed clozapine for first episode psychosis under care of NE Esteem falls well below NCAP averages for Wales, England and Ireland.

SUMMARY Recent years have seen a rise in media coverage as well as demand for specialist attention-deficit hyperactivity disorder (ADHD) assessments in adults and children. This article explores the challenges in the diagnostic process for adult ADHD, amidst much misinformation and controversy. In doing so, we look at the social model of ADHD; a glossary of terms to better understand lived experience; underdiagnosis and misdiagnosis; and the fallacy of the ‘high functioning’ label. We propose the use of co-production to bridge the gap between the medical and social models. We conclude with suggestions for future research. The article includes anonymous contributions from doctors with ADHD.

BACKGROUND:Impairments in language processing in schizophrenia (ScZ) are a central aspect of the disorder but the underlying pathophysiology mechanisms are unclear. In the current study, we tested the hypothesis that neural oscillations are impaired during speech tracking in early-stage ScZ and in participants at clinical high-risk for psychosis (CHR-P). METHOD:Magnetoencephalography (MEG) was used in combination with source reconstructed time-series to examine delta and theta-band entrainment during continuous speech. Participants were presented with a 5-minute audio recording during which they either attened to the story or word level. MEG-data were obtained from n = 22 CHR-P participants, n = 23 early-stage ScZ-patients, and n = 44 healthy controls (HC). Data were analysed with a Mutual Information (MI) approach to compute statistical dependence between the MEG and auditory signal, thus estimating individual speech-tracking ability. MEG-activity was reconstructed in a language network (bilateral inferior frontal cortex [F3T; Broca's], superior temporal areas [STS3, STS4; Wernicke's areas], and primary auditory cortex [bilateral HES; Heschl's gyrus]). MEG-data were correlated with clinical symptoms. RESULTS:Theta-band entrainment in left Heschl's gyrus, averaged across groups, was significantly lower in the STORY compared to WORD condition (p = 0.022), and averaged over conditions, significantly lower in CHR-Ps (p = 0.045), but intact in early ScZ patients (p = 0.303), compared to controls. Correlation analyses between MEG data and symptom indicated that lower theta-band tracking in CHR-Ps was linked to the severity of perceptual abnormalities (p = 0.018). CONCLUSION:Our results show that CHR-P participants involve impairments in theta-band entrainment during speech tracking in left primary auditory cortex while higher-order speech processing areas were intact. Moreover, the severity of aberrant perceptual experiences in CHR-P participants correlated with deficits in theta-band entrainment. Together, these findings highlight the possibility that neural oscillations during language processing could reveal fundamental abnormalities in speech processing which may constitute candidate biomarkers for early detection and diagnosis of ScZ.

BackgroundAltered neural haemodynamic activity during decision making and learning has been linked to the effects of inflammation on mood and motivated behaviours. So far, it has been reported that blunted mesolimbic dopamine reward signals are associated with inflammation-induced anhedonia and apathy. Nonetheless, it is still unclear whether inflammation impacts neural activity underpinning decision dynamics. The process of decision making involves integration of noisy evidence from the environment until a critical threshold of evidence is reached. There is growing empirical evidence that such process, which is usually referred to as bounded accumulation of decision evidence, is affected in the context of mental illness.MethodsIn a randomised, placebo-controlled, crossover study, 19 healthy male participants were allocated to placebo and typhoid vaccination. Three to four hours post-injection, participants performed a probabilistic reversal-learning task during functional magnetic resonance imaging. To capture the hidden neurocognitive operations underpinning decision-making, we devised a hybrid sequential sampling and reinforcement learning computational model. We conducted whole brain analyses informed by the modelling results to investigate the effects of inflammation on the efficiency of decision dynamics and reward learning.ResultsWe found that during the decision phase of the task, typhoid vaccination attenuated neural signatures of bounded evidence accumulation in the dorsomedial prefrontal cortex, only for decisions requiring short integration time. Consistent with prior work, we showed that, in the outcome phase, mild acute inflammation blunted the reward prediction error in the bilateral ventral striatum and amygdala.ConclusionsOur study extends current insights into the effects of inflammation on the neural mechanisms of decision making and shows that exogenous inflammation alters neural activity indexing efficiency of evidence integration, as a function of choice discriminability. Moreover, we replicate previous findings that inflammation blunts striatal reward prediction error signals.

Background The choroid plexus is an important structure within the ventricular system. Schizophrenia has been associated with morphological changes to the choroid plexus but the presence and extent of alterations at different illness stages is unclear. Methods We examined choroid plexus volumes in participants at clinical high-risk for psychosis (N = 110), participants with first-episode psychosis (N = 37), participants with schizophrenia (N = 28), clinical (N = 38) and non-clinical controls (N = 75). Automated segmentation (Gaussian mixture model) was used to estimate choroid plexus volumes from T1 magnetic resonance (MR) images. We then conducted a linear model and Bayes factor analysis to investigate group differences. In addition, the relationship between choroid plexus volumes and clinical characteristics was assessed. Results Schizophrenia patients were characterized by increased choroid plexus and ventricular volume while first-episode psychosis and clinical high-risk for psychosis participants showed no differences in choroid plexus volumes. However, choroid plexus volumes in schizophrenia patients did not significantly differ from controls when controlling for ventricular volume. Finally, choroid plexus volumes were not associated with clinical characteristics in the clinical high-risk group. Conclusion Our findings suggest that morphological alterations are not specific to the choroid plexus in schizophrenia and early-stage psychosis. Previously reported choroid plexus abnormalities in schizophrenia patients could be explained by changes in ventricular volume.

Cognitive behavioral therapy (CBT) is an effective intervention for depression. At present there is no clinically viable predictor of CBT response. Here we combined computational modelling and multivariate classification of neuroimaging data to develop mechanistically interpretable neurocomputational predictors of CBT response in depression.

Motivational (i.e., Pavlovian) values interfere with instrumental responding and can lead to suboptimal decision-making. In humans, task-based neuroimaging studies have only recently started illuminating the functional neuroanatomy of Pavlovian biasing of instrumental control. To provide a mechanistic understanding of the neural dynamics underlying the Pavlovian and instrumental valuation systems, analysis of neuroimaging data has been informed by computational modeling of conditioned behavior. Nonetheless, because of collinearities in Pavlovian and instrumental predictions, previous research failed to tease out hemodynamic activity that is parametrically and dynamically modulated by coexistent Pavlovian and instrumental value expectations. Moreover, neural correlates of Pavlovian to instrumental transfer effects have so far only been identified in extinction (i.e., in the absence of learning). In this study, we devised a modified version of the orthogonalized go/no-go paradigm, which introduced Pavlovian-only catch trials to better disambiguate trial-by-trial Pavlovian and instrumental predictions in both sexes. We found that hemodynamic activity in the ventromedial pFC covaried uniquely with the model-derived Pavlovian value expectations. Notably, modulation of neural activity encoding for instrumental predictions in the supplementary motor cortex was linked to successful action selection in conflict conditions. Furthermore, hemodynamic activity in regions pertaining to the limbic system and medial pFC was correlated with synergistic Pavlovian and instrumental predictions and improved conditioned behavior during congruent trials. Altogether, our results provide new insights into the functional neuroanatomy of decision-making and corroborate the validity of our variant of the orthogonalized go/no-go task as a behavioral assay of the Pavlovian and instrumental valuation systems.

AIM:This review aims to identify factors that may prolong or reduce the duration of untreated psychosis for people with psychosis in low- and middle-income countries. METHODS:Electronic searches of six databases were conducted, to find studies from low- and middle-income countries on people with psychotic disorders provided they statistically measured an association between factors that may prolong or reduce the duration of untreated psychosis. Studies were critically appraised and a narrative synthesis exploring differences between and within studies is presented. A socio-ecological model is used to convey the main findings. RESULTS:Thirty studies of 16 473 participants in total were included in this review. Taken together participants were 51.5% male and 48.5% female. Various factors potentially associated with longer duration of untreated psychosis for people with psychosis in low- and middle-income countries were found. Examples of these factors are an insidious mode of onset, greater family stigma and low social class. Other factors, such as marital status, educational level, diagnostic type, predominant symptoms and employment status, yielded inconsistent results. CONCLUSIONS:The methodological quality of the included studies limits the conclusions of this review. The results indicate an urgent need for further high-quality research in these countries. The socio-ecological model is a helpful framework for clinicians, scholars, and decision-makers to conceptualize factors that may affect the duration of untreated psychosis, highlight gaps in the literature as well as reflect on potential prevention strategies that may ultimately support early intervention services for people with psychosis in developing countries.