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Elevated brain glutamate has been implicated in non-response to antipsychotic medication in schizophrenia. Biomarkers that can accurately predict antipsychotic non-response from the first episode of psychosis (FEP) could allow stratification of patients; for example, patients predicted not to respond to standard antipsychotics could be fast-tracked to clozapine. Using proton magnetic resonance spectroscopy (1H-MRS), we examined the ability of glutamate and Glx (glutamate plus glutamine) in the anterior cingulate cortex (ACC) and caudate to predict response to antipsychotic treatment. A total of 89 minimally medicated patients with FEP not meeting symptomatic criteria for remission were recruited across two study sites. 1H-MRS and clinical data were acquired at baseline, 2 and 6 weeks. Response was defined as >20% reduction in Positive and Negative Syndrome Scale (PANSS) Total score from baseline to 6 weeks. In the ACC, baseline glutamate and Glx were higher in Non-Responders and significantly predicted response (P n = 42). Overall accuracy was greatest for ACC Glx (69%) and increased to 75% when symptom severity at baseline was included in the model. Glutamate metabolites in the caudate were not associated with response, and there was no significant change in glutamate metabolites over time in either region. These results add to the evidence linking elevations in ACC glutamate metabolites to a poor antipsychotic response. They indicate that glutamate may have utility in predicting response during early treatment of first episode psychosis. Improvements in accuracy may be made by combining glutamate measures with other response biomarkers.

Clozapine is the most effective medication for treatment-resistant psychosis, but evidence points to substantial underuse, especially within early intervention psychosis (EIP) services. We explored clinicians’ views on perceived barriers and facilitators to offering patients clozapine within EIP services. A cross-sectional survey was distributed electronically to clinicians practising in EIP services across England. A mixed methods approach was used to assess barriers to clozapine, and attitudes and opinions concerning clozapine underutilisation. Based on the barriers identified in the literature, clinicians were asked to rate each one (scale:1-7) based on importance, with a higher score indicating higher importance. Clinicians were also asked open-ended questions on barriers to clozapine and how access can be improved in EIP services. Quantitative data were analysed using descriptive and inferential statistics, and qualitative responses were analysed thematically. One hundred and nineteen EIP clinicians from 35 services in England completed the survey. In total, 37% (n = 45) of clinicians perceived that clozapine was under-prescribed in their EIP service. The most important barrier to utilising clozapine were patient concerns with side effects, followed by monitoring requirements and clinician concerns with side effects. Thematic analysis identified 17 perceived barriers, which were grouped into three major themes: administrative (5 subthemes), clinician-related (6 subthemes), and patient-related (6 subthemes). Perceived facilitators to improving clozapine use were greater training, improved resources, and optimised monitoring. The main barriers to clozapine in EIP services, as identified by clinicians, are patient concerns regarding side effects and monitoring requirements. Identified facilitators for improved clozapine use include clinician training, improved resources, guidelines, and point-of-care testing.

The Viewpoint describes variations in stringency of clozapine hematologic monitoring among countries and suggests hematologic monitoring approaches.

Clozapine has proven efficacy in treatment-resistant schizophrenia, though there have been reports of untoward reactions to its use, including cases of rare side effects. The authors here describe a case of an unusual constellation of symptoms, predominantly diarrhoea, that consistently occurred over 3 attempts to treat a patient with clozapine. We conclude with a recommendation that clinicians need to be aware that new-onset diarrhoea may be an adverse reaction to clozapine.

Aims Clozapine is licensed for treatment-resistant psychosis and remains underutilised. This may berelated to the stringent haematological monitoring requirements that are mandatory in most countries. We aimed to compare guidelines internationally and develop a novel Stringency Index. We hypothesised that the most stringent countries would have increased healthcare costs and reduced prescription rates. Method We conducted a literature review and survey of guidelines internationally. Guideline identification involved a literature review and consultation with clinical academics. We focused on the haematological monitoring parameters, frequency and thresholds for discontinuation and rechallenge after suspected clozapine-induced neutropenia. In addition, indicators reflecting monitoring guideline stringency were scored and visualised using a choropleth map. We developed a Stringency Index with an international panel of clozapine experts, through a modified-Delphi-survey. The Stringency Index was compared to health expenditure per-capita and clozapine prescription per 100 000 persons. Results One hundred twocountries were included, from Europe (n = 35), Asia (n = 24), Africa (n = 20), South America (n = 11), North America (n = 7) and Oceania and Australia (n = 5). Guidelines differed in frequency of haematological monitoring and discontinuation thresholds. Overall, 5% of included countries had explicit guidelines for clozapine-rechallenge and 40% explicitly prohibited clozapine-rechallenge. Furthermore, 7% of included countries had modified discontinuation thresholds for benign ethnic neutropenia. None of the guidelines specified how long haematological monitoring should continue. The most stringent guidelines were in Europe, and the least stringent were in Africa and South America. There was a positive association (r = 0.43, p < 0.001) between a country's Stringency Index and healthcare expenditure per capita. Conclusions Recommendations on how haematological function should be monitored in patients treated with clozapine vary considerably between countries. It would be useful to standardise guidelines on haematological monitoring worldwide.

BackgroundClozapine is the only drug licensed for treatment-resistant schizophrenia (TRS) but the real-world clinical and cost-effectiveness of community initiation of clozapine is unclear.AimsThe aim was to assess the feasibility and cost-effectiveness of community initiation of clozapine.MethodThis was a naturalistic study of community patients recommended for clozapine treatment.ResultsOf 158 patients recommended for clozapine treatment, 88 (56%) patients agreed to clozapine initiation and, of these, 58 (66%) were successfully established on clozapine. The success rate for community initiation was 65.4%; which was not significantly different from that for in-patient initiation (58.82%, χ2(1,88) = 0.47, P = 0.49). Following clozapine initiation, there was a significant reduction in median out-patient visits over 1 year (from 24.00 (interquartile range (IQR) = 14.00–41.00) to 13.00 visits (IQR = 5.00–24.00), P < 0.001), and 2 years (from 47.50 visits (IQR = 24.75–71.00) to 22.00 (IQR = 11.00–42.00), P < 0.001), and a 74.71% decrease in psychiatric hospital bed days (z = −2.50, P = 0.01). Service-use costs decreased (1 year: –£963/patient (P < 0.001); 2 years: –£1598.10/patient (P < 0.001). Subanalyses for community-only initiation also showed significant cost reductions (1 year: –£827.40/patient (P < 0.001); 2 year: –£1668.50/patient (P < 0.001) relative to costs prior to starting clozapine. Relative to before initiation, symptom severity was improved in patients taking clozapine at discharge (median Positive and Negative Syndrome Scale total score: initial visit: 80 (IQR = 71.00–104.00); discharge visit 50.5 (IQR = 44.75–75.00), P < 0.001) and at 2 year follow-up (Health of Nation Outcome Scales total score median initial visit: 13.00 (IQR = 9.00–15.00); 2 year follow-up: 8.00 (IQR = 3.00–13.00), P = 0.023).ConclusionsThese findings indicate that community initiation of clozapine is feasible and is associated with significant reductions in costs, service use and symptom severity.

ObjectivesThis prospective cohort study tested for associations between baseline cognitive performance in individuals early within their first episode and antipsychotic treatment of psychosis. We hypothesised that poorer cognitive functioning at the initial assessment would be associated with poorer antipsychotic response following the subsequent 6 weeks.DesignProspective cohort .SettingNational Health Service users with a first-episode schizophrenia diagnosis, recently starting antipsychotic medication, recruited from two UK sites (King’s College London, UK and University of Manchester, UK). Participants attended three study visits following screening.ParticipantsEighty-nine participants were recruited, with 46 included in the main analysis. Participants required to be within the first 2 years of illness onset, had received minimal antipsychotic treatment, have the capacity to provide consent, and be able to read and write in English. Participants were excluded if they met remission criteria or showed mild to no symptoms.Primary and secondary outcome measuresAntipsychotic response was determined at 6 weeks using the Positive and Negative Syndrome Scale (PANSS), with cognitive performance assessed at each visit using the Brief Assessment of Cognition in Schizophrenia (BACS). The groups identified (responders and non-responders) from trajectory analyses, as well as from >20% PANSS criteria, were compared on baseline BACS performance.ResultsTrajectory analyses identified 84.78% of the sample as treatment responsive, and the remaining 15.22% as treatment non-responsive. Unadjusted and adjusted logistic regressions observed no significant relationship between baseline BACS on subscale and total performance (BACS t-score: OR=0.98, p=0.620, Cohen’s d=0.218) and antipsychotic response at 6 weeks.ConclusionsThis investigation identified two clear trajectories of treatment response in the first 6 weeks of antipsychotic treatment. Responder and non-responder groups did not significantly differ on performance on the BACS, suggesting that larger samples may be required or that an association between cognitive performance and antipsychotic response is not observable in the first 2 years of illness onset.Trial registration numberREC: 17/NI/0209.

BACKGROUND: Within clinical services, there can be a delay of years before patients with psychosis, who do not respond to antipsychotic medication, receive a diagnosis of treatment resistant schizophrenia (TRS). There is a need to identify these patients earlier within the course of their illness and expedite their access to specialist treatment. The aim of this project was to use data, available when patients first present to clinical services, to predict TRS. METHODS: We used existing prospective first-episode psychosis studies from across Europe (STRATA-G Consortium; N=2274, TRS=370 (16.27%)) and tested two statistical models: the first to find associations with TRS and the second to identify predictors of TRS. After using existing literature to perform variable selection, we ran a logistic regression to identify variables associated with TRS within our sample. We included all variables within a ‘Least Absolute Shrinkage and regression Operator’ (LASSO) logistic regression, tuned by bootstrapping to identify predictors of TRS. We report the LASSO predictive model that corresponds to the penalty which returns the area under the curve (AUC) within one standard error (1SE) of the maximum AUC. Internal validation of the LASSO model performance was run via bootstrap optimism-correction. RESULTS: In our multivariable logistic regression model, younger age of onset and less years in education were significantly associated with the odds of being TRS. The predictive model selected younger age of onset, less years in education, basic education vs. higher education, presence of a lifetime relationship vs. absence of a lifetime relationship, smoking vs. not smoking, poorer functioning measured using the Global Assessment of Functioning (GAF), and mode of onset between one and six months vs. longer than six months, as predictors of TRS. For a risk threshold of 50%, the AUC was 0.776 and the model had an accuracy of 83.9% (95% confidence interval: 82.3%, 85.4%). The sensitivity (correct identification of TRS) was 2.70%, with a positive predictive value of 58.82%, and the specificity (correct identification of responders) was 99.63% with a negative predictive value 84.05%. DISCUSSION: Our logistic regression model replicated previously published work on factors associated with TRS. Our prediction model performed well, but, due to the small proportion of TRS cases in our sample, was more accurate at identifying responders than patients with TRS. The predictors selected by our model highlight new areas in which to investigate the aetiology of TRS. We have also emphasised the difference between statistical models designed to test associations and those designed to predict outcomes.

Schizophrenia is a severe mental illness affecting several domains of cognition and behaviour. The illness most frequently becomes manifest in early adulthood, and often follows a chronic course. It is associated with high morbidity and mortality, and is a leading contributor to disease burden, health and social care costs throughout the world. Antipsychotics are the mainstay of treatment but are limited by significant adverse effects, and therapeutic options for many patients remain inadequate. Schizophrenia is associated with a range of adverse physical health outcomes, which can be compounded by lifestyle factors including substance use, barriers in accessing healthcare and the adverse effects of treatment. Psychological and social interventions are a crucial element of patient care, particularly in alleviating negative symptoms. Current theories view schizophrenia as a disorder of early brain development, with interacting genetic and environmental risk factors.

BACKGROUND There is growing interest in the potential for wearable and mobile devices to deliver clinically relevant information in real-world contexts. However, there is limited information on their acceptability and barriers to long-term use in people living with psychosis. OBJECTIVE This study aimed to describe the development, implementation, feasibility, acceptability, and user experiences of the Sleepsight platform, which harnesses consumer wearable devices and smartphones for the passive and unobtrusive capture of sleep and rest-activity profiles in people with schizophrenia living in their homes. METHODS A total of 15 outpatients with a diagnosis of schizophrenia used a consumer wrist-worn device and smartphone to continuously and remotely gather rest-activity profiles over 2 months. Once-daily sleep and self-rated symptom diaries were also collected via a smartphone app. Adherence with the devices and smartphone app, end-of-study user experiences, and agreement between subjective and objective sleep measures were analyzed. Thresholds for acceptability were set at a wear time or diary response rate of 70% or greater. RESULTS Overall, 14 out of 15 participants completed the study. In individuals with a mild to moderate symptom severity at baseline (mean total Positive and Negative Syndrome Scale score 58.4 [SD 14.4]), we demonstrated high rates of engagement with the wearable device (all participants meeting acceptability criteria), sleep diary, and symptom diary (93% and 86% meeting criteria, respectively), with negative symptoms being associated with lower diary completion rate. The end-of-study usability and acceptability questionnaire and qualitative analysis identified facilitators and barriers to long-term use, and paranoia with study devices was not a significant barrier to engagement. Comparison between sleep diary and wearable estimated sleep times showed good correspondence (ρ=0.50, P CONCLUSIONS Extended use of wearable and mobile technologies are acceptable to people with schizophrenia living in a community setting. In the future, these technologies may allow predictive, objective markers of clinical status, including early markers of impending relapse.

Self-reported psychotic experiences (PEs) are associated with psychopathology of all kinds, not just psychoses. However, systematic reviews on the relevance of this for health services are unavailable. Furthermore, whether association with service use is confounded by other psychopathology is unknown, and is relevant to prevention and treatment.Literature examining associations between PEs and service use was systematically reviewed. Study quality and the direction and extent of any associations were assessed, and meta-analysis conducted.Systematic review and meta-analysis was carried out as per PRISMA guidelines. A search of electronic databases was performed based on free-text and structured terms. Included studies were evaluated by two raters using a structured tool and estimates extracted for reporting.Thirteen studies were returned. We found two prospective studies, and a minority of studies accounted for concurrent psychopathology, limiting our ability to test our main hypotheses. Five studies reported associations by different types of service use. Almost all studies assessed service use by self-report. Meta-analysis suggested that people who reported PEs were around twice as likely to report service use compared to those who did not (pooled OR for all included studies: 2.20,95% confidence intervals (95%CI): 1.66,2.91).There was consistent evidence of association between PEs and mental health service use at the general population level. However, evidence for causation was poor due to a limited number of studies. Whether increased service use in this group is solely attributable to PEs, and therefore whether interventions aimed at limiting/preventing PEs might be effective, requires studies focusing on the relationships between PEs, psychopathology and service use.