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Glutamate and increased inflammation have been separately implicated in the pathophysiology of schizophrenia and the extent of clinical response to antipsychotic treatment. Despite the mechanistic links between pro-inflammatory and glutamatergic pathways, the relationships between peripheral inflammatory markers and brain glutamate in schizophrenia have not yet been investigated. In this study, we tested the hypothesis that peripheral levels of pro-inflammatory cytokines would be positively associated with brain glutamate levels in schizophrenia. Secondary analyses determined whether this relationship differed according to antipsychotic treatment response. The sample consisted of 79 patients with schizophrenia, of whom 40 were rated as antipsychotic responders and 39 as antipsychotic non-responders. Brain glutamate levels were assessed in the anterior cingulate cortex (ACC) and caudate using proton magnetic resonance spectroscopy ( 1H-MRS) and blood samples were collected for cytokine assay on the same study visit (IL-6, IL-8, IL-10, TNF- α and IFN-γ). Across the whole patient sample, there was a positive relationship between interferon-gamma (IFN-γ) and caudate glutamate levels (r = 0.31, p = 0.02). In the antipsychotic non-responsive group only, there was a positive relationship between interleukin-8 (IL-8) and caudate glutamate (r = 0.46, p = 0.01). These findings provide evidence to link specific peripheral inflammatory markers and caudate glutamate in schizophrenia and may suggest that this relationship is most marked in patients who show a poor response to antipsychotic treatment.

The Goldacre review, published in April, 2022, 1 is a landmark evaluation of the use, availability, and safety of National Health Service (NHS) data across all four nations of the UK. The review underscores the necessary role of data in driving health-care improvement and innovation, and the potential risks inherent in using data routinely contributed by health service users. The review recommends a radical overhaul in NHS data curation, access, and analysis, and, crucially, argues that substantial new resources must be marshalled to make this aspiration a reality.

Background: Clozapine is uniquely effective in treatment-resistant psychosis. In the UK, patients must discontinue clozapine indefinitely if they are placed on the Central Non-Rechallenge Database (CNRD) after their haematological parameters fall below particular thresholds. Under exceptional circumstances, patients can be rechallenged on clozapine under an off-licence agreement. In the USA in 2015, restrictive practice was discontinued to allow greater flexibility for clozapine maintenance. The absolute neutrophil count leading to treatment interruption was lowered from less than 1·5 × 109/L to less than 1·0 × 109/L and platelet and white cell count monitoring were ceased. We aimed to investigate the implications of a similar policy change on clozapine use in the UK. Methods: This was a modelling study of all patients registered on the UK CNRD. First, we determined the proportion of patients placed on the database in the UK who would have had to discontinue clozapine treatment under the US Food and Drug Administration (FDA) criteria. Second, we compared the haematological characteristics of patients who did or did not meet FDA criteria for discontinuing clozapine, including the time to registration from clozapine initiation and the proportion of cases of severe neutropenia at registration. Third, we investigated the success rates of clozapine re-challenge for patients that had been placed on the CNRD. Successful rechallenge was defined as no recurrence of CNRD registration. Findings: Between May 2, 2002 and March 1, 2021, 3731 patients were placed on the CNRD, with a mean age of 47 years (SD 15), including 1420 (38%) women and 2311 (62%) men, of whom 3089 (83%) were White, 360 (10%) were Black, 190 (5%) were Asian, and 92 (2%) were classified as other. 566 (15%) of 3731 patients met the equivalent criteria for clozapine discontinuation under the FDA guidelines. The median time to CNRD registration from clozapine initiation was 1·6 years (IQR 0·2–4·9). Data for 519 rechallenged patients were examined; 419 (81%) were successful. Clozapine rechallenge success rates were broadly similar between individuals who did not meet the US CNRD registration criteria (36 [78%] of 46) and those who did meet the criteria (383 [81%] of 473). Interpretation: Implementing the revised FDA monitoring criteria in the UK would substantially reduce clozapine discontinuation for haematological reasons, which would greatly improve the mental health outcomes of these patients without having a major effect on their physical health. Funding: None.

Clozapine, an antipsychotic, is associated with increased susceptibility to infection with COVID-19, compared to other antipsychotics. Here, we investigate associations between clozapine treatment and increased risk of adverse outcomes of COVID-19, namely COVID-related hospitalisation, intensive care treatment, and death, among patients taking antipsychotics with schizophrenia-spectrum disorders. Using the clinical records of South London and Maudsley NHS Foundation Trust, we identified 157 individuals who had an ICD-10 diagnosis of schizophrenia-spectrum disorders, were taking antipsychotics (clozapine or other antipsychotics) at the time of COVID-19 pandemic in the UK and had a laboratory-confirmed COVID-19 infection. The following health outcomes were measured: COVID-related hospitalisation, COVID-related intensive care treatment and death. We tested associations between clozapine treatment and each outcome using logistic regression models, adjusting for gender, age, ethnicity, neighbourhood deprivation, obesity, smoking status, diabetes, asthma, bronchitis and hypertension using propensity scores. Of the 157 individuals who developed COVID-19 while on antipsychotics (clozapine or other antipsychotics), there were 28% COVID-related hospitalisations, 8% COVID-related intensive care treatments and 8% deaths of any cause during the 28 days follow-up period. Among those taking clozapine, there were 25% COVID-related hospitalisations, 7% COVID-related intensive care treatments and 7% deaths. In both unadjusted and adjusted analyses, we found no significant association between clozapine and any of the outcomes. Thus, we found no evidence that patients with clozapine treatment at time of COVID-19 infection had increased risk of hospitalisation, intensive care treatment or death, compared to non-clozapine antipsychotic-treated patients. However, further research should be considered in larger samples to confirm this.•schizophrenia•clozapine•Antipsychotic agents•COVID-19•SARS-CoV-2

Background: A proportion of people with treatment-resistant schizophrenia fail to show improvement on clozapine treatment. Knowledge of the sociodemographic and clinical factors predicting clozapine response may be useful in developing personalised approaches to treatment. Methods: This retrospective cohort study used data from the electronic health records of the South London and Maudsley (SLaM) hospital between 2007 and 2011. Using the Least Absolute Shrinkage and Selection Operator (LASSO) regression statistical learning approach, we examined 35 sociodemographic and clinical factors’ predictive ability of response to clozapine at 3 months of treatment. Response was assessed by the level of change in the severity of the symptoms using the Clinical Global Impression (CGI) scale. Results: We identified 242 service-users with a treatment-resistant psychotic disorder who had their first trial of clozapine and continued the treatment for at least 3 months. The LASSO regression identified three predictors of response to clozapine: higher severity of illness at baseline, female gender and having a comorbid mood disorder. These factors are estimated to explain 18% of the variance in clozapine response. The model’s optimism-corrected calibration slope was 1.37, suggesting that the model will underfit when applied to new data. Conclusions: These findings suggest that women, people with a comorbid mood disorder and those who are most ill at baseline respond better to clozapine. However, the accuracy of the internally validated and recalibrated model was low. Therefore, future research should indicate whether a prediction model developed by including routinely collected data, in combination with biological information, presents adequate predictive ability to be applied in clinical settings.

Antipsychotic treatment resistance affects up to a third of individuals with schizophrenia. Of those affected, 70–84% are reported to be treatment resistant from the outset. This raises the possibility that the neurobiological mechanisms of treatment resistance emerge before the onset of psychosis and have a neurodevelopmental origin. Neuropsychological investigations can offer important insights into the nature, origin and pathophysiology of treatment-resistant schizophrenia (TRS), but methodological limitations in a still emergent field of research have obscured the neuropsychological discriminability of TRS. We report on the first systematic review and meta-analysis to investigate neuropsychological differences between TRS patients and treatment-responsive controls across 17 published studies (1864 participants). Five meta-analyses were performed in relation to (1) executive function, (2) general cognitive function, (3) attention, working memory and processing speed, (4) verbal memory and learning, and (5) visual−spatial memory and learning. Small-to-moderate effect sizes emerged for all domains. Similarly to previous comparisons between unselected, drug-naïve and first-episode schizophrenia samples v. healthy controls in the literature, the largest effect size was observed in verbal memory and learning [dl = −0.53; 95% confidence interval (CI) −0.29 to −0.76; z = 4.42; p < 0.001]. A sub-analysis of language-related functions, extracted from across the primary domains, yielded a comparable effect size (dl = −0.53, 95% CI −0.82 to −0.23; z = 3.45; p < 0.001). Manipulating our sampling strategy to include or exclude samples selected for clozapine response did not affect the pattern of findings. Our findings are discussed in relation to possible aetiological contributions to TRS.

Objective To investigate whether patients with clozapine treatment are at an increased risk of a more severe COVID-19 infection as compared with patients on other antipsychotic drugs. Methods In this register-based cohort study, all residents (age 18 or older) in the Stockholm Region with a psychotic disorder diagnosis and antipsychotic treatment were included (N = 8 233) and followed from March 1, 2020 to January 14, 2021. The exposure was defined as clozapine treatment and the outcome measures (indicating a more severe COVID-19 infection) were: inpatient care, care within intensive care unit or death due to COVID-19 infection. Differences in outcome rates between exposed (n = 966) and unexposed (other antipsychotics; n = 7 267) were examined using Cox proportional hazards models and expressed as hazard ratios (HR) with 95% confidence intervals (CI). Results No statistically significant differences in outcome rates were found between the two groups of patients after adjusting for age, sex, and residence in retirement homes. The adjusted HR for the exposed compared to the unexposed was 0.96 (95% CI: 0.54, 1.70) for inpatient care; 1.69 (0.48, 5.93) for care in intensive care unit (ICU); and 0.86 (0.26, 2.80) for death. Regarding inpatient care, additional adjusting for country of birth, living in socioeconomically vulnerable areas, number of care visits during the previous year, and comorbid medical illnesses did not alter the results. Conclusions Our results may add support to the present guidelines, recommending sustained clozapine treatment during the current COVID-19 pandemic with careful monitoring and readiness to alter drug doses as needed.

Objective: Although frequently reported in psychosis, obsessive-compulsive symptoms (OCS) are often not recognized and thus undertreated. We aimed to estimate the prevalence of OCS and obsessive-compulsive disorder (OCD) in patients with schizophrenia, schizoaffective disorder, or bipolar disorder in clinical records and identify clinical associations of OCS co-occurrence. Methods: Data were retrieved from the South London and Maudsley NHS Foundation Trust Biomedical Research Centre case register. The study population was restricted to individuals diagnosed with schizophrenia (ICD F20.x), schizoaffective disorder (ICD F25.x), or bipolar disorder (ICD F31.x) between 2007 and 2015. OCS and OCD were ascertained from structural fields and via Natural Language Processing software applied to free-text records. Clinical characteristics were obtained from Health of the Nation Outcome Scales for the analyses on associations between clinical characteristics and OCS/OCD status using logistic regressions with confounders considered. Results: 22,551 cases of schizophrenia, schizoaffective disorder, or bipolar disorder were identified in the observation window. Among these, 5,179 (24.0%) were identified as having OCS (including an OCD diagnosis) and 2,574 (11.9%) specifically with comorbid OCD. OCS/OCD was associated with an increased likelihood of recorded aggressive behavior (OR = 1.18; 95% CI, 1.10-1.26), cognitive problems (OR = 1.21; 95% CI, 1.13-1.30), hallucinations and delusions (OR = 1.11; 95% CI, 1.04-1.20), and physical problems (OR = 1.17; 95% CI, 1.09-1.26). Conclusions: OCS and OCD are frequently recorded for patients with schizophrenia, schizoaffective disorder, and bipolar disorder and are associated with more severe psychiatric clinical characteristics. Automated information extraction tools hold potential to improve recognition and treatment of co-occurring OCS/OCD for psychosis.

Background: There is evidence of heterogeneity within treatment-resistant schizophrenia (TRS), with some people not responding to antipsychotic treatment from illness onset and others becoming treatment-resistant after an initial response period. These groups may have different aetiologies. Aim: This study investigates sociodemographic and clinical correlates of early onset of TRS. Method: Employing a retrospective cohort design, we do a secondary analysis of data from a cohort of people with TRS attending the South London and Maudsley. Regression analyses were conducted to identify the correlates of the length of treatment to TRS. Predictors included the following: gender, age, ethnicity, problems with positive symptoms, problems with activities of daily living, psychiatric comorbidities, involuntary hospitalisation and treatment with long-acting injectable antipsychotics. Results: In a cohort of 164 people with TRS (60% were men), the median length of treatment to TRS was 3 years and 8 months. We observed no cut-off on the length of treatment until TRS presentation differentiating between early and late TRS (i.e. no bimodal distribution). Having mild to very severe problems with hallucinations and delusions at the treatment start was associated with earlier TRS (~19 months earlier). In sensitivity analyses, including only complete cases (subject to selection bias), treatment with a long-acting injectable antipsychotic was additionally associated with later TRS (~15 months later). Conclusion: Our findings do not support a clear separation between early and late TRS but rather a continuum of the length of treatment before TRS onset. Having mild to very severe problems with positive symptoms at treatment start predicts earlier onset of TRS.

Polygenic risk prediction remains an important aim of genetic association studies. Currently, the predictive power of schizophrenia polygenic risk scores (PRSs) is not large enough to allow highly accurate discrimination between cases and controls and thus is not adequate for clinical integration. Since PRSs are rarely used to reveal biological functions or to validate candidate pathways, to fill this gap, we investigated whether their predictive ability could be improved by building genome-wide (GW-PRSs) and pathway-specific PRSs, using distance- or expression quantitative trait loci (eQTLs)- based mapping between genetic variants and genes. We focused on five pathways (glutamate, oxidative stress, GABA/interneurons, neuroimmune/neuroinflammation and myelin) which belong to a critical hub of schizophrenia pathophysiology, centred on redox dysregulation/oxidative stress. Analyses were first performed in the Lausanne Treatment and Early Intervention in Psychosis Program (TIPP) study (n = 340, cases/controls: 208/132), a sample of first-episode of psychosis patients and matched controls, and then validated in an independent study, the epidemiological and longitudinal intervention program of First-Episode Psychosis in Cantabria (PAFIP) (n = 352, 224/128). Our results highlighted two main findings. First, GW-PRSs for schizophrenia were significantly associated with early psychosis status. Second, oxidative stress was the only significantly associated pathway that showed an enrichment in both the TIPP (p = 0.03) and PAFIP samples (p = 0.002), and exclusively when gene-variant linking was done using eQTLs. The results suggest that the predictive accuracy of polygenic risk scores could be improved with the inclusion of information from functional annotations, and through a focus on specific pathways, emphasizing the need to build and study functionally informed risk scores., National Center of Competence in Research (NCCR) “SYNAPSY-The Synaptic Bases of Mental Diseases” from the Swiss National Science Foundation (n°51AU40_125759 to KQD & PC), and Alamaya Foundation. SP was supported by European Union’s Horizon 2020 Research and Innovation Program (Psych-STRATA). The PAFIP cohort was funded by the following grants (to BC-F): Instituto de Salud Carlos III (FIS00/3095, PI020499, PI050427, PI060507), Plan Nacional de Drogas Research (2005-Orden sco/3246/2004), SENY Fundatio Research (2005-0308007), Fundacion Marques de Valdecilla (A/02/07, API07/011) and MINECO/FEDER (SAF2016-76046-R, SAF2013-46292-R). JV-B was supported by Instituto de Investigación Sanitaria Valdecilla (INT/A21/10, INT/A20/04). Open access funding provided by University of Lausanne.

Impaired cognition is associated with lower quality of life and poor outcomes in schizophrenia. Brain glutamate may contribute to both clinical outcomes and cognition, but these relationships are not well-understood. We studied a multicentre cohort of 85 participants with non-affective psychosis using proton magnetic resonance spectroscopy. Glutamate neurometabolites were measured in the anterior cingulate cortex (ACC). Cognition was assessed using the Brief Assessment for Cognition in Schizophrenia (BACS). Patients were categorised as antipsychotic responders or non-responders based on treatment history and current symptom severity. Inverted U-shaped associations between glutamate or Glx (glutamate + glutamine) with BACS subscale and total scores were examined with regression analyses. We then tested for an interaction effect of the antipsychotic response group on the relationship between glutamate and cognition. ACC glutamate and Glx had a positive linear association with verbal memory after adjusting for age, sex and chlorpromazine equivalent dose (glutamate, β = 3.73, 95% CI = 1.26–6.20, P = 0.004; Glx, β = 3.38, 95% CI = 0.84–5.91, P = 0.01). This association did not differ between good and poor antipsychotic response groups. ACC glutamate was also positively associated with total BACS score (β = 3.12, 95% CI = 0.01–6.23, P = 0.046), but this was not significant after controlling for antipsychotic dose. Lower glutamatergic metabolites in the ACC were associated with worse verbal memory, and this relationship was independent of antipsychotic response. Further research on relationships between glutamate and cognition in antipsychotic responsive and non-responsive illness could aid the stratification of patient groups for targeted treatment interventions.

BackgroundClozapine is associated with increased risk of myocarditis. However, many common side-effects of clozapine overlap with the clinical manifestations of myocarditis. As a result, there is uncertainty about which signs, symptoms and investigations are important in distinguishing myocarditis from benign adverse effects of clozapine. Clarity on this issue is important, since missing a diagnosis of myocarditis or discontinuing clozapine unnecessarily may both have devastating consequences.AimsTo examine the clinical characteristics of clozapine-induced myocarditis and to identify which signs and symptoms distinguish true myocarditis from other clozapine adverse effects.MethodA retrospective analysis of the record database for 247 621 patients was performed. A natural language processing algorithm identified the instances of patients in which myocarditis was suspected. The anonymised case notes for the patients of each suspected instance were then manually examined, and those whose instances were ambiguous were referred for an independent assessment by up to three cardiologists. Patients with suspected instances were classified as having confirmed myocarditis, myocarditis ruled out or undetermined.ResultsOf 254 instances in 228 patients with suspected myocarditis, 11.4% (n = 29 instances) were confirmed as probable myocarditis. Troponin and C-reactive protein (CRP) had excellent diagnostic value (area under the curve 0.975 and 0.896, respectively), whereas tachycardia was of little diagnostic value. All confirmed instances occurred within 42 days of clozapine initiation.ConclusionsSuspicion of myocarditis can lead to unnecessary discontinuation of clozapine. The ‘critical period’ for myocarditis emergence is the first 6 weeks, and clinical signs including tachycardia are of low specificity. Elevated CRP and troponin are the best markers for the need for further evaluation.

Background: The use of clozapine demands regular monitoring of clozapine plasma concentrations and of white blood cell parameters. The delay between sending blood samples for analysis and receiving the results hinders clinical care. Point-of-care testing (POCT) can provide drug assay results within a few minutes. Aim: This study aimed to investigate the utility of a novel point-of-care device that can measure clozapine concentrations using capillary blood samples collected via a finger stick. Method: During a five-week period starting in June 2019 eligible patients were asked to provide a finger-stick capillary sample in addition to their usual venous blood sample. Samples were analysed by the novel point-of-care device and by the standard laboratory method. Capillary blood samples were tested by the MyCare™ Insite POCT analyser, and a quantitative measurement of clozapine concentration was provided within six minutes. Results: A total of 309 patients agreed to measurements by the two methods. Analysis revealed clozapine concentrations in venous blood as determined by the laboratory method ranged from 20 to 1310 ng/mL and by POCT from 7 to 1425 ng/mL. There was a strong positive correlation ( R = 0.89) between the results from the venous and the capillary sample methods. The slope of the association between standard assay and MyCare™ Insite was 1.0 with an intercept of –21 ng/mL, indicating minimal bias. Conclusion: Clozapine concentrations can be accurately measured at the point of care using capillary blood samples collected via a finger stick. This approach may be more acceptable than venous sampling to patients and, with almost instant results available, more useful to clinicians.

Background and AimsIn the United Kingdom, patients on clozapine whose hematological parameters fall below certain thresholds are placed on the Central Non-Rechallenge Database (CNRD), meaning that they cannot be prescribed clozapine again except under exceptional circumstances. This practice was discontinued in the United States in 2015 by expanding the hematological monitoring guidelines, allowing more patients to receive clozapine. Our objective was to investigate the implications this policy change would have on clozapine utilization in the United Kingdom.MethodsThis was an observational, retrospective analysis of patients registered on the CNRD in a large mental health trust. The first objective was to compare the number of patients placed on the CNRD under the United Kingdom and the US Food and Drug Administration (FDA) criteria. The second objective was to explore the hematological and clinical outcomes of CNRD patients. The third objective was to investigate the hematological outcomes of patients rechallenged on clozapine after nonrechallengeable status.ResultsOne hundred and fifteen patients were placed on CNRD from 2002 to 2019, of whom 7 (6%) met the equivalent criteria for clozapine discontinuation under the FDA guidelines. Clinical outcomes, as measured by the Clinical Global Impression-Severity scale, were worse 3 months after clozapine cessation than on clozapine (t = −7.4862; P < .001). Sixty-two (54%) patients placed on CNRD were rechallenged. Fifty-nine of those (95%) were successfully rechallenged; 3 patients were placed back on CNRD, only one of which would have had to stop clozapine again under FDA criteria.ConclusionImplementation of the updated FDA’s monitoring criteria in the United Kingdom would significantly reduce clozapine discontinuation due to hematological reasons. The evidence suggests an urgent need for revising the UK clozapine monitoring guidelines to improve outcomes in treatment-resistant schizophrenia.

BackgroundCommon mental disorders (CMD), such as depression and anxiety, are an important cause of morbidity, economic burden and public mental health need. The UK Improving Access to Psychological Therapies (IAPT) programme is a national effort to reduce the burden and impact of CMD, available since 2008.AimsTo examine ethnic and migration-related differences in use of IAPT-based psychological treatment using a novel epidemiological dataset with linkage to de-identified IAPT records.MethodData from a psychiatric morbidity survey of two South East London boroughs (2008–2010) were individually-linked to data on IAPT services serving those boroughs. We used Poisson regression to estimate association between ethnicity and migration status (including years of UK residence), with rate of subsequent use of psychological treatment.ResultsThe rate of psychological treatment use was 14.4 cases per thousand person years [cases/1000 pyrs, 95% confidence intervals (95% CI) 12.4, 16.7]. There was strong statistical evidence that compared to non-migrants, migrants residing in the UK for less than 10 years were less likely to use psychological treatment after adjustment for probable sociodemographic predictors of need, life adversity, and physical/psychiatric morbidity at baseline [rate ratio (RR) 0.4 (95% CI 0.20, 0.75]. This difference was not explained by migration for asylum/political reasons, or English language proficiency, and was evident for both self- and GP referrals.ConclusionsLower use of IAPT among recent migrants is unexplained by sociodemographics, adversity, and baseline morbidity. Further research should focus on other individual-level and societal barriers to psychological treatment use among recent migrants to the UK, including in categories of intersecting migration and ethnicity.

Introduction: The Prescribing Observatory for Mental Health initiated a quality improvement (QI) programme on clozapine use in UK mental health services. Methods: Clinical audits conducted in 2019 and 2021. Results: Sixty-three participating NHS Trusts/healthcare organisations in 2019, and 61 in 2021, submitted treatment data for 6948 and 8155 patients, respectively. In both audits, high-dose and/or combined antipsychotic medications had been prescribed immediately before initiating clozapine in over a quarter of patients recently started on clozapine. In patients who were tobacco smokers and recently discharged from a smoke-free ward, the impact of the potential change in smoking status had been considered in the care plans of just under one-third in 2019 and just over a half in 2021. For community patients, their Summary Care Records (SCRs) included their clozapine prescriptions in 58% of cases in 2019 and 72% in 2021. Conclusions: Three QI issues were identified. (1) Antipsychotic regimens with limited evidence for efficacy in treatment-resistant schizophrenia were prescribed for over a quarter of cases before starting clozapine. Use of such strategies may delay clozapine treatment, potentially reducing the likelihood of a therapeutic response. (2) While anticipation of the consequences of a change in smoking status on plasma clozapine concentration following discharge from hospital showed improvement over time, even in 2021 it was not evident for nearly a half of relevant cases. (3) While inclusion of clozapine in the SCR also improved over time, even in 2021 it was missing for more than a quarter of community patients.

BackgroundClozapine is the only licensed pharmacotherapy for patients with treatment-resistant schizophrenia (TRS), but its use is limited due to adverse effects. Clozapine treatment has been recently associated with reductions in immunoglobulin (Ig) levels cross-sectionally, however prospective studies are required to establish longitudinal effects. This study aimed to determine whether reductions in immunoglobulin levels occur over 6 months after initiating clozapine treatment. An exploratory aim was to investigate relationships between immunoglobulin levels and symptom severity over the course of clozapine treatment.MethodsIn 56 participants with TRS, Ig A, M and G levels were measured in serum using a sandwich immunoassay. Samples for analysis were acquired prior to starting clozapine and at 6, 12 and 24 weeks after initiating clozapine treatment. Clinical symptoms were measured using the positive and negative syndrome scale for schizophrenia (PANSS).ResultsAll three classes of Ig decreased during clozapine treatment. For IgA and IgG the reduction was significant at 24 weeks (IgA: B – 32.7, 95% CI = -61.19, -4.2, p = 0.04; IgG: B – 55.94, 95% CI = -111.03, -0.844, p = 0.05). For IgM the reduction was significant at 12 and 24 weeks (12 weeks: B = -21.73, 95% CI = -37.10, -6.35, p = 0.006; 24 weeks: B = -32.54, 95% CI = -48.89, 16.18, p = 0.0001). Changes in both IgA and IgG were correlated with the percentage change in PANSS total scores over 12 weeks, such that greater reductions in IgA and IgG during clozapine treatment were associated with greater reductions in symptom severity (n = 32, IgA r = 0.59, p = 0.005; IgG r = 0.50, p = 0.02)ConclusionsThe observed reductions in immunoglobulin levels over six months of clozapine treatment add further evidence linking clozapine to secondary antibody deficiency. The associations between Ig reduction and symptom improvement may however indicate that immune mechanisms contribute to both desirable and undesirable effects of clozapine.

Background Clozapine is the only effective medication for treatment-resistant schizophrenia; however, its mechanism of action remains unclear. The present study explored whether its effectiveness is related to changes in hematological measures after clozapine initiation. Methods Patients with treatment-resistant schizophrenia commenced on clozapine between January 2007 and December 2014 by the United Kingdom’s largest mental health trust were identified from electronic patient records. Hematological data from these patients were obtained from a monitoring registry. White blood cell, neutrophil, and platelet count were assessed at baseline and during the early phase of clozapine treatment. Clozapine response at 3 months was defined as “much,” or “very much” improved on the seven-point Clinical Global Impression—Improvement (CGI-I) subscale. Results In the total sample (n = 188), clozapine initiation was associated with a significant transient increase (peaking in weeks 3 to 4) in white blood cell, neutrophil, and platelet count (P < 0.001). There were 112 (59.6%) patients that responded to treatment; however, none of the hematological factors assessed at baseline, nor changes in these factors, were directly associated with treatment response. Implications Clozapine treatment is associated with transient hematological changes during the first month of treatment; however, there was no evidence that these were related to the therapeutic response.

Objective:We sought to assess the effectiveness of clozapine augmentation with Electroconvulsive therapy (ECT) (C+ECT) in patients with clozapine-resistant schizophrenia.Methods:We conducted a retrospective review of electronic health records to identify patients treated with C+ECT. We determined the response to C+ECT and the rate of rehospitalisation over the year following treatment with C+ECT.Results:Forty-two patients were treated with C+ECT over a 10-year period. The mean age of the patients at initiation of ECT was 46.3 (SD = 8.2) years (range 27–62 years). The mean number of ECTs given was 10.6 (SD = 5.3) (range 3–25) with the majority receiving twice weekly ECT. Seventy-six per cent of patients (n = 32) showed a Clinical Global Impression-Improvement (CGI-I) score of ≤3 (at least minimally improved) following C+ECT. The mean number of ECT treatments was 10.6 (SD = 5.3) (range 3–25) with the majority receiving twice weekly ECT. Sixty-four per cent of patients experienced no adverse events. Response to C+ECT was not associated with gender, age, duration of illness or duration of clozapine treatment. Seventy-five per cent of responders remained out of hospital over the course of 1-year follow-up, while 70% of those with no response to C+ECT were not admitted to hospital. Three patients received maintenance ECT, one of whom was rehospitalised.Conclusion:This study lends support to emerging evidence for the effectiveness of C+ECT in clozapine-resistant schizophrenia. These results are consistent with the results of a meta-analysis and the only randomised controlled trial (RCT) of this intervention. Further RCTs are required before this treatment can be confidently recommended.

Wider use of clozapine, one of the most effective antipshychotic drugs, is precluded by its propensity to cause agranulocytosis. Currently, clozapine is used for treatment-resistant schizophrenia, with mandatory blood count monitoring for the duration of treatment. Agranulocytosis occurs in up to 0.8% of patients and presents a significant medical challenge, despite decreasing mortality rates. In this paper, we review the epidemiology of clozapine-induced agranulocytosis (CLIA), advances in identifying genetic risk factors, and the preventive measures to reduce the risk of CLIA. We discuss the pathogenesis of CLIA, which, despite receiving considerable scientific attention, has not been fully elucidated. Finally, we address the clinical management and suggest the approach to clozapine re-challenge in patients with a previous episode of neutropenia. With a significant proportion of clozapine recipients in Western hemisphere being Black, we comment on the importance of recognizing benign ethnic neutropenia as a potential impediment to clozapine administration. This review aims to aid haematologists and psychiatrists to jointly manage neutropenia and agranulocytosis caused by clozapine.

BackgroundClozapine, an antipsychotic with unique efficacy in treatment-resistant psychosis, is associated with increased susceptibility to infection, including pneumonia.AimsTo investigate associations between clozapine treatment and increased risk of COVID-19 infection in patients with schizophrenia-spectrum disorders who are receiving antipsychotic medications in a geographically defined population in London, UK.MethodUsing information from South London and Maudsley NHS Foundation Trust (SLAM) clinical records, via the Clinical Record Interactive Search system, we identified 6309 individuals who had an ICD-10 diagnosis of schizophrenia-spectrum disorders and were taking antipsychotics at the time of the COVID-19 pandemic onset in the UK. People who were on clozapine treatment were compared with those on any other antipsychotic treatment for risk of contracting COVID-19 between 1 March and 18 May 2020. We tested associations between clozapine treatment and COVID-19 infection, adjusting for gender, age, ethnicity, body mass index (BMI), smoking status and SLAM service use.ResultsOf 6309 participants, 102 tested positive for COVID-19. Individuals who were on clozapine had increased risk of COVID-19 infection compared with those who were on other antipsychotic medication (unadjusted hazard ratio HR = 2.62, 95% CI 1.73–3.96), which was attenuated after adjusting for potential confounders, including clinical contact (adjusted HR = 1.76, 95% CI 1.14–2.72).ConclusionsThese findings provide support for the hypothesis that clozapine treatment is associated with an increased risk of COVID-19 infection. Further research will be needed in other samples to confirm this association. Potential clinical implications are discussed.

Objective Early treatment of schizophrenia improves outcomes. Clozapine appears to have unique benefit when other antipsychotic medication has failed. This systematic review and meta-analysis aims to assess clozapine's superiority over alternative antipsychotic medication and examine whether earlier use is associated with additional benefit. Method Systematic retrieval of blinded, randomized controlled trials comparing clozapine with alternative antipsychotics in adults with schizophrenia. The effect of mean age on relative clozapine response was examined using random effects meta-regression, and multiple linear regression on available patient data. Results A total of 276 studies were retrieved. Thirty-four studies were included in the meta-analysis. Clozapine was significantly more effective than alternative antipsychotics in reducing psychotic symptoms and increasing response. However, meta-regression failed to show a more significant effect in younger patients (age on effect size (total psychotic symptoms) 0.00, P = 0.79 CI -0.03 to 0.03). Individual patient data were available for two studies, the larger of which showed a significant interaction between younger age and superiority of clozapine. Conclusion The results support clozapine's superiority over other antipsychotics. A convincing effect of age on this effect was not demonstrated, although this was suggested in one study. In view of the age of many of the included studies, and changes in reporting practice over time, new clozapine RCTs, which include age of illness onset as well as age at trial time, would be welcome in order to provide meta-analysable data for future use.

BackgroundClozapine, the only evidence-based drug for treatment-resistant schizophrenia is associated with agranulocytosis. For this reason, all clozapine patients are required to undergo mandatory regular blood monitoring throughout their clozapine treatment. The blood test results are reported using a traffic light system. The clozapine treatment is stopped immediately after a confirmed red result, which is the indication for risk of agranulocytosis. The need for blood tests places a burden on patients and acts as a barrier to clozapine treatment. There is growing evidence that the risk of agranulocytosis falls steeply after the first few months of treatment, raising the possibility that clozapine monitoring could be discontinued after a certain period of treatment.AimTo investigate the frequency density of the confirmed red results from clozapine monitoring across clozapine treatment.MethodBy merging electronic health records (EHR) data with clozapine blood monitoring data, we identified the clozapine treatment dates. The EHR data was from South London and Maudsley NHS Foundation Trust (SLAM). The clozapine blood monitoring data was from Zaponex Treatment Access System (ZTAS). ZTAS is one of the mandatory blood monitoring service providers in the United Kingdom. From these data, Kaplan-Meier survival curve was fitted to determine the time to get confirmed red results. At fixed points in the treatment, the future risk of obtaining a red result were calculated.ResultsBy merging over 301,000 data points that came from the blood monitoring results and EHR data of 1,362 patients, we identified 1,891 clozapine treatment periods. Of these, 75 treatments were stopped due to confirmed red results. The Kaplan-Meier survival curve and the incidence rates data showed that 56 (74.7%) confirmed red results occur within the first 6 months of clozapine treatment.ConclusionWe found a contrast between the relatively high density of the confirmed red results at the beginning of clozapine treatment which significantly reduces after 6 months of treatment which remained low thereafter.

BackgroundTreatment-resistant schizophrenia (TRS) is associated with high levels of functional impairment, healthcare usage and societal costs. Cross-sectional studies may overestimate TRS rates because of selection bias.AimsWe aimed to quantify TRS rates by using first-episode cohorts to improve resource allocation and clozapine access.MethodWe undertook a systematic review of TRS rates among people with first-episode psychosis and schizophrenia, with a minimum follow-up of 8 weeks. We searched PubMed, PsycINFO, EMBASE, CINAHL and the Cochrane Database of Systematic Reviews, and meta-analysed TRS rates from included studies.ResultsTwelve studies were included, totalling 11 958 participants; six studies were of high quality. The rate of TRS was 22.8% (95% CI 19.1–27.0%, P < 0.001) among all first-episode cohorts and 24.4% (95% CI 19.5–30.0%, P < 0.001) among first-episode schizophrenia cohorts. Subgroup sensitivity analyses by location of recruitment, TRS definition, study quality, time of data collection and retrospective versus prospective data collection did not lead to statistically significant differences in heterogeneity. In a meta-regression, duration of follow-up and percentage drop-out did not significantly affect the overall TRS rate. Men were 1.57 times more likely to develop TRS than women (95% CI 1.11–2.21, P = 0.010).ConclusionsAlmost a quarter of people with first-episode psychosis or schizophrenia will develop TRS in the early stages of treatment. When including people with schizophrenia who relapse despite initial response and continuous treatment, rates of TRS may be as high as a third. These high rates of TRS highlight the need for improved access to clozapine and psychosocial supports.

Introduction Our aim was to, firstly, identify characteristics at first-episode of psychosis that are associated with later antipsychotic treatment resistance (TR) and, secondly, to develop a parsimonious prediction model for TR. Methods We combined data from ten prospective, first-episode psychosis cohorts from across Europe and categorised patients as TR or non-treatment resistant (NTR) after a mean follow up of 4.18 years (s.d. = 3.20) for secondary data analysis. We identified a list of potential predictors from clinical and demographic data recorded at first-episode. These potential predictors were entered in two models: a multivariable logistic regression to identify which were independently associated with TR and a penalised logistic regression, which performed variable selection, to produce a parsimonious prediction model. This model was internally validated using a 5-fold, 50-repeat cross-validation optimism-correction. Results Our sample consisted of N = 2216 participants of which 385 (17 %) developed TR. Younger age of psychosis onset and fewer years in education were independently associated with increased odds of developing TR. The prediction model selected 7 out of 17 variables that, when combined, could quantify the risk of being TR better than chance. These included age of onset, years in education, gender, BMI, relationship status, alcohol use, and positive symptoms. The optimism-corrected area under the curve was 0.59 (accuracy = 64 %, sensitivity = 48 %, and specificity = 76 %). Implications Our findings show that treatment resistance can be predicted, at first-episode of psychosis. Pending a model update and external validation, we demonstrate the potential value of prediction models for TR. Funding: This work was supported by a Stratified Medicine Programme grant to JHM from the Medical Research Council (grant number MR/L011794/1 which funded the research and supported S.E.S., D.A., A.F.P, L.K., R.M.M., D.S., J.T.R.W, & J.H.M.); funding from the National Institute for Health Research Biomedical Research Centre at South London and Maudsley National Health Service Foundation Trust and King's College London to D.A. and D.S; and funding from the Collaboration for Leadership in Applied Health Research and Care (CLAHRC) South London at King's College Hospital National Health Service Foundation Trust to S.E.S. The views expressed are those of the author(s) and not necessarily those of the Medical Research Council, National Health Service, the National Institute for Health Research, or the Department of Health. The AESOP (London, UK) cohort was funded by the UK Medical Research Council (Ref: G0500817). The Belfast (UK) cohort was funded by the Research and Development Office of Northern Ireland. The Bologna (Italy) cohort was funded by the European Community's Seventh Framework Program under grant agreement (agreement No.HEALTH-F2-2010–241909, Project EU-GEI). The GAP (London, UK) cohort was funded by the UK National Institute of Health Research(NIHR) Specialist Biomedical Research Centre for Mental Health, South London and Maudsley NHS Mental Health Foundation Trust (SLaM) and the Institute of Psychiatry, Psychology, and Neuroscience at King's College London; Psychiatry Research Trust; Maudsley Charity Research Fund; and the European Community's Seventh Framework Program grant (agreement No. HEALTH-F2-2009-241909, Project EU-GEI). The Lausanne (Switzerland) cohort was funded by the Swiss National Science Foundation (no. 320030_135736/1 to P.C. and K.Q.D., no 320030-120686, 324730-144064 and 320030-173211 to C.B.E and P.C., and no 171804 to LA); National Center of Competence in Research (NCCR) “SYNAPSY - The Synaptic Bases of Mental Diseases” from the Swiss National Science Foundation (no 51AU40_125759 to PC and KQD); and Fondation Alamaya (to KQD). The Oslo (Norway) cohort was funded by the Research Council of Norway (#223273/F50, under the Centers of Excellence funding scheme, #300309, #283798) and the South-Eastern Norway Regional Health Authority (#2006233, #2006258, #2011085, #2014102, #2015088 to IM, #2017-112). The Paris (France) cohort was funded by European Community's Seventh Framework Program grant (agreement No. HEALTH-F2-2010–241909, Project EU-GEI). The Prague (Czech Republic) cohort was funded by the Ministry of Health of the Czech Republic (Grant Number: NU20-04-00393). The Santander (Spain) cohort was funded by the following grants (to B.C.F): Instituto de Salud Carlos III, FIS 00/3095, PI020499, PI050427, PI060507, Plan Nacional de Drogas Research Grant 2005-Orden sco/3246/2004, and SENY Fundatio Research Grant CI 2005-0308007, Fundacion Marques de Valdecilla A/02/07 and API07/011. SAF2016-76046-R and SAF2013-46292-R (MINECO and FEDER). The West London (UK) cohort was funded The Wellcome Trust (Grant Number: 042025; 052247; 064607).

Background70%–84% of individuals with antipsychotic treatment resistance show non-response from the first episode. Emerging cross-sectional evidence comparing cognitive profiles in treatment resistant schizophrenia to treatment-responsive schizophrenia has indicated that verbal memory and language functions may be more impaired in treatment resistance. We sought to confirm this finding by comparing cognitive performance between antipsychotic non-responders (NR) and responders (R) using a brief cognitive battery for schizophrenia, with a primary focus on verbal tasks compared against other measures of cognition.DesignCross-sectional.SettingThis cross-sectional study recruited antipsychotic treatment R and antipsychotic NR across four UK sites. Cognitive performance was assessed using the Brief Assessment of Cognition in Schizophrenia (BACS).ParticipantsOne hundred and six participants aged 18–65 years with a diagnosis of schizophrenia or schizophreniform disorder were recruited according to their treatment response, with 52 NR and 54 R cases.OutcomesComposite and subscale scores of cognitive performance on the BACS. Group (R vs NR) differences in cognitive scores were investigated using univariable and multivariable linear regressions adjusted for age, gender and illness duration.ResultsUnivariable regression models observed no significant differences between R and NR groups on any measure of the BACS, including verbal memory (ß=−1.99, 95% CI −6.63 to 2.66, p=0.398) and verbal fluency (ß=1.23, 95% CI −2.46 to 4.91, p=0.510). This pattern of findings was consistent in multivariable models.ConclusionsThe lack of group difference in cognition in our sample is likely due to a lack of clinical distinction between our groups. Future investigations should aim to use machine learning methods using longitudinal first episode samples to identify responder subtypes within schizophrenia, and how cognitive factors may interact within this.Trail registration numberREC: 15/LO/0038.

Clozapine is the only antipsychotic that is effective in treatment-resistant schizophrenia. However, in certain clinical situations, such as the emergence of serious adverse effects, it is necessary to discontinue clozapine. Stopping clozapine treatment poses a particular challenge due to the risk of psychotic relapse, as well as the development of withdrawal symptoms. Despite these challenges for the clinician, there is currently no formal guidance on how to safely to discontinue clozapine. We assessed the feasibility of developing evidence-based recommendations for (1) minimizing the risk of withdrawal symptoms, (2) managing withdrawal phenomena, and (3) commencing alternatives treatment when clozapine is discontinued. We then evaluated the recommendations against the Appraisal of Guidelines for Research and Evaluation (AGREE) II criteria. We produced 19 recommendations. The majority of these recommendation were evidence-based, although the strength of some recommendations was limited by a reliance of studies of medium to low quality. We discuss next steps in the refinement and validation of an evidence-based guideline for stopping clozapine and identify key outstanding questions.

Background:Clozapine is the only medication licenced for treating patients with treatment-refractory schizophrenia. However, there are no evidence-based guidelines as to the optimal plasma level of clozapine to aim for, and their association with clinical and functional outcome.Objective:We assessed the relationship between clinical and functional outcome measures and blood concentrations of clozapine among patients with treatment-refractory psychosis.Methods:Data were reviewed in 82 patients with treatment-refractory psychosis admitted to a specialised tertiary-level service and treated with clozapine. Analysis focussed on the relationship between clozapine and norclozapine plasma concentrations and the patient’s clinical symptoms and functional status.Results:Clinical symptom improvement was positively correlated with norclozapine plasma concentrations and inversely correlated with clozapine to norclozapine plasma concentrations ratio. Clozapine concentrations showed a bimodal association with clinical improvement (peaks around 350 and 660 ng/ml). Clinical symptom improvement correlated with functional outcomes, although there was no significant correlation between the latter and clozapine or norclozapine plasma concentrations.Conclusion:Clozapine treatment was associated with optimal clinical improvement at two different peak plasma concentrations around 350 and 650 ng/ml. Clinical improvement was associated with functional outcome; however, functionality was not directly associated with clozapine concentrations. A subset of patients may require higher clozapine plasma concentrations to achieve clinical improvement.

The neurobiological effects of clozapine are under characterised. We examined the effects clozapine treatment on subcortical volume and cortical thickness and investigated whether macrostructural changes were linked to alterations in glutamate or N-acetylaspartate (NAA). Data were acquired in 24 patients with treatment-resistant schizophrenia before and 12 weeks after switching to clozapine. During clozapine treatment we observed reductions in caudate and putamen volume, lateral ventricle enlargement (P P = 0.002). None of the morphometric changes were associated with changes in glutamate levels. These results indicate that clozapine treatment is associated with subcortical volume loss and cortical thinning and that at least some of these effects are linked to changes in neuronal or metabolic integrity.

BackgroundCo-occurrence of common mental disorders (CMD) with psychotic experiences is well-known. There is little research on the public mental health relevance of concurrent psychotic experiences for service use, suicidality, and poor physical health. We aim to: (1) describe the distribution of psychotic experiences co-occurring with a range of non-psychotic psychiatric disorders [CMD, depressive episode, anxiety disorder, probable post-traumatic stress disorder (PTSD), and personality dysfunction], and (2) examine associations of concurrent psychotic experiences with secondary mental healthcare use, psychological treatment use for CMD, lifetime suicide attempts, and poor self-rated health.MethodsWe linked a prospective cross-sectional community health survey with a mental healthcare provider database. For each non-psychotic psychiatric disorder, patients with concurrent psychotic experiences were compared to those without psychotic experiences on use of secondary mental healthcare, psychological treatment for CMD, suicide attempt, physical functioning, and a composite multimorbidity score, using logistic regression and Cox regressions.ResultsIn all disorders except for anxiety disorder, concurrent psychotic experiences were accompanied by a greater odds of all outcomes (odds ratios) for a unit change in composite multimorbidity score ranged between 2.21 [95% confidence interval (CI) 1.49–3.27] and 3.46 (95% CI 1.52–7.85). Hazard ratios for secondary mental health service use for non-psychotic disorders with concurrent psychotic experiences, ranged from 0.53 (95% CI 0.15–1.86) for anxiety disorders with psychotic experiences to 4.99 (95% CI 1.22–20.44) among those with PTSD with psychotic experiences.ConclusionsCo-occurring psychotic experiences indicate greater public mental health burden, suggesting psychotic experiences could be a marker for future preventive strategies improving public mental health.

Treatment-resistant schizophrenia, affecting approximately 20–30% of patients with schizophrenia, has a high burden both for patients and healthcare services. There is a need to identify treatment resistance earlier in the course of the illness, in order that effective treatment, such as clozapine, can be offered promptly. We conducted a systemic literature review of prospective longitudinal studies with the aim of identifying predictors of treatment-resistant schizophrenia from the first episode. From the 545 results screened, we identified 12 published studies where data at the first episode was used to predict treatment resistance. Younger age of onset was the most consistent predictor of treatment resistance. We discuss the gaps in the literature and how future prediction models can identify predictors of treatment response more robustly.

Objective: Clozapine is the only effective medication for treatment-resistant schizophrenia, but its worldwide use is still limited because of its complex titration protocols. While the discovery of pharmacogenomic variants of clozapine metabolism may improve clinical management, no robust findings have yet been reported. This study is the first to adopt the framework of genome-wide association studies (GWASs) to discover genetic markers of clozapine plasma concentrations in a large sample of patients with treatment-resistant schizophrenia. Methods: The authors used mixed-model regression to combine data from multiple assays of clozapine metabolite plasma concentrations from a clozapine monitoring service and carried out a genome-wide analysis of clozapine, norclozapine, and their ratio on 10,353 assays from 2,989 individuals. These analyses were adjusted for demographic factors known to influence clozapine metabolism, although it was not possible to adjust for all potential mediators given the available data. GWAS results were used to pinpoint specific enzymes and metabolic pathways and compounds that might interact with clozapine pharmacokinetics. Results: The authors identified four distinct genome-wide significant loci that harbor common variants affecting the metabolism of clozapine or its metabolites. Detailed examination pointed to coding and regulatory variants at several CYP* and UGT* genes as well as corroborative evidence for interactions between the metabolism of clozapine, coffee, and tobacco. Individual effects of single single-nucleotide polymorphisms (SNPs) fine-mapped from these loci were large, such as the minor allele of rs2472297, which was associated with a reduction in clozapine concentrations roughly equivalent to a decrease of 50 mg/day in clozapine dosage. On their own, these single SNPs explained from 1.15% to 9.48% of the variance in the plasma concentration data. Conclusions: Common genetic variants with large effects on clozapine metabolism exist and can be found via genome-wide approaches. Their identification opens the way for clinical studies assessing the use of pharmacogenomics in the clinical management of patients with treatment-resistant schizophrenia.

BACKGROUND: Clozapine is the most effective medication for the positive symptoms of treatment-refractory schizophrenia. Although clozapine use is associated with fewer admissions, less is known about the impact of clozapine cessation on hospitalisation.AIMS: The aims of this study were to investigate whether clozapine-reduced psychiatric inpatient admissions and bed days, and investigate patient factors associated with these changes from a sample of 1906 people commenced on clozapine.METHODS: All people commencing clozapine during an acute hospitalisation over a 10-year period in Queensland, Australia, were included in this retrospective cohort study. A mirror image design was used to compare psychiatric bed days and hospitalisations 2 years before and after clozapine treatment, and the impact of clozapine continuation or early cessation. Changes in psychiatric bed days and hospitalisations were analysed using linear regression, adjusting for the duration on clozapine, sex, age, indigenous status, country of origin and time to clozapine commencement.RESULTS/OUTCOMES: There was a significant reduction in bed days (29.55 days vs 24.46 days, p CONCLUSION/INTERPRETATION: Longer clozapine therapy led to a greater reduction in psychiatric bed days and hospitalisations. Early cessation was associated with a return to pre-clozapine levels of bed days and admissions.

Background Health services have advocated a stratified medicine approach in mental health, but little is known about whether service users would accept this approach. Aims To explore service users’ views of the acceptability of stratified medicine for treatment-resistant schizophrenia compared to the traditional “trial-and-error” approach. Methods A mixed methods observational study that explored questionnaire responses on acceptability and whether these responses were affected by demographic or clinical variables. We also investigated whether treatment responsiveness or experience of invasive tests (brain scans and blood tests) affected participants’ responses. Questionnaire generated qualitative data were analyzed thematically. Participants (N108) were aged 18–65, had a diagnosis of schizophrenia, and were adherent to antipsychotic medication. Results Acceptability of a stratified approach was high, even after participants had experienced invasive tests. Most rated it as safer (62% vs 43%; P < .01 [CI: −1.69 to 2.08]), less risky (77% vs 44%; P < .01 [CI: −1.75 to 1.10]), and less painful (90% vs 73%; P < 0.01 [CI: −0.84 to 0.5]) and this was not affected by treatment responsiveness or test experience. Although not statistically significant, treatment nonresponders were more willing to undergo invasive tests. Qualitatively, all participants raised concerns about the risks, discomfort, and potential side effects associated with the invasive tests. Conclusions Service users were positive about a stratified approach for choosing treatments but were wary of devolving clinical decisions to purely data-driven algorithms. These results reinforce the value of service user perspectives in the development and evaluation of novel treatment approaches.

BackgroundClozapine, an antipsychotic, is associated with increased susceptibility to infection with COVID-19, compared to other antipsychotics.AimsTo investigate associations between clozapine treatment and increased risk of adverse outcomes of COVID-19, namely COVID-related hospitalisation and intensive care treatment, and death, among patients taking antipsychotics with schizophrenia-spectrum disorders.MethodUsing data from South London and Maudsley NHS Foundation Trust (SLAM) clinical records, via the Clinical Record Interactive Search system, we identified 157 individuals who had an ICD-10 diagnosis of schizophrenia-spectrum disorders, were taking antipsychotics at the time of the COVID-19 pandemic in the UK, and had a laboratory-confirmed COVID-19 infection. The following health outcomes were measured: COVID-related hospitalisation, COVID-related intensive care treatment death. We tested associations between clozapine treatment and each outcome using logistic regression models, adjusting for gender, age, ethnicity, neighbourhood deprivation, obesity, smoking status, diabetes, asthma, bronchitis and hypertension using propensity scores.ResultsIn the 157 individuals who developed COVID while on antipsychotics, there were 44 COVID-related hospitalisations, 13 COVID-related intensive care treatments and 13 deaths of any cause during the follow-up period. In the unadjusted analysis, there was no significant association between clozapine and any of the outcomes and there remained no associations following adjusting for the confounding variables.ConclusionsIn our sample of patients with COVID-19 and schizophrenia-spectrum disorders, we found no evidence that clozapine treatment puts patients at increased risk of hospitalisation, intensive care treatment or death, compared to any other antipsychotic treatment. However, further research should be considered in larger samples to confirm this.Conflict of interestRDH has received research funding from Roche, Pfizer, Janssen, and Lundbeck. DFF has received research funding from Janssen and Lundbeck. JHM has received research funding from Lundbeck. JTT has received research funding from Bristol-Meyers-Squibb. RS declares research support in the last 36 months from Janssen, GSK and Takeda.Ethics statementThe research was conducted under ethical approval reference 18/SC/0372 from Oxfordshire Research Ethics Committee C.