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Dysfunction of glutamate neurotransmission has been implicated in the pathophysiology of schizophrenia and may be particularly relevant in severe, treatment-resistant symptoms. The underlying mechanism may involve hypofunction of the NMDA receptor. We investigated whether schizophrenia-related pathway polygenic scores, composed of genetic variants within NMDA receptor encoding genes, are associated with cortical glutamate in schizophrenia. Anterior cingulate cortex (ACC) glutamate was measured in 70 participants across 4 research sites using Proton Magnetic Resonance Spectroscopy ( 1 H-MRS). Two NMDA receptor gene sets were sourced from the Molecular Signatories Database and NMDA receptor pathway polygenic scores were constructed using PRSet. The NMDA receptor pathway polygenic scores were weighted by single nucleotide polymorphism (SNP) associations with treatment-resistant schizophrenia, and associations with ACC glutamate were tested. We then tested whether NMDA receptor pathway polygenic scores with SNPs weighted by associations with non-treatment-resistant schizophrenia were associated with ACC glutamate. A higher NMDA receptor complex pathway polygenic score was significantly associated with lower ACC glutamate (β = -0.25, 95 % CI = -0.49, -0.02, competitive p = 0.03). When SNPs were weighted by associations with non-treatment-resistant schizophrenia, there was no association between the NMDA receptor complex pathway polygenic score and ACC glutamate (β = 0.05, 95 % CI = -0.18, 0.27, competitive p = 0.79). These results provide initial evidence of an association between common genetic variation implicated in NMDA receptor function and ACC glutamate levels in schizophrenia. This association was specific to when the NMDA receptor complex pathway polygenic score was weighted by SNP associations with treatment-resistant schizophrenia., Competing Interests: Declaration of competing interest JTW is an investigator on a grant from Takeda Pharmaceuticals Ltd. to Cardiff University, for a project unrelated to the work presented here. SES is employed on this grant. GJB receives honoraria for teaching from GE Healthcare. All other authors have no conflicts of interest to disclose., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Antipsychotic treatment resistance affects up to a third of individuals with schizophrenia, with recent research finding systematic biological differences between antipsychotic resistant and responsive patients. Our aim was to determine whether cognitive impairment at first episode significantly differs between future antipsychotic responders and resistant cases., Methods: Analysis of data from seven international cohorts of first-episode psychosis (FEP) with cognitive data at baseline (N = 683) and follow-up data on antipsychotic treatment response: 605 treatment responsive and 78 treatment resistant cases. Cognitive measures were grouped into seven cognitive domains based on the pre-existing literature. We ran multiple imputation for missing data and used logistic regression to test for associations between cognitive performance at FEP and treatment resistant status at follow-up., Results: On average patients who were future classified as treatment resistant reported poorer performance across most cognitive domains at baseline. Univariate logistic regressions showed that antipsychotic treatment resistance cases had significantly poorer IQ/general cognitive functioning at FEP (OR = 0.70, p = .003). These findings remained significant after adjusting for additional variables in multivariable analyses (OR = 0.76, p = .049)., Conclusions: Although replication in larger studies is required, it appears that deficits in IQ/general cognitive functioning at first episode are associated with future treatment resistance. Cognitive variables may be able to provide further insight into neurodevelopmental factors associated with treatment resistance or act as early predictors of treatment resistance, which could allow prompt identification of refractory illness and timely interventions., Competing Interests: Declaration of competing interest J.T.R.W. is an investigator on a grant from Takeda Pharmaceuticals Ltd. to Cardiff University, for a project unrelated to the work presented here. S.E.S. is employed on this grant. M.D.F. has received a fee for educational seminars from Lundbeck and Janssen. O.A.A. is a consultant to HealthLytix and has received speakers honorarium from Lundbeck and Sunovion. T.R.E.B. has been a member of an advisory board for Gedeon Richter. B.C.F. has received honoraria for participation as a consultant and/or as a speaker at educational events from ADAMED, Mylan, Angelini, Janssen Johnson & Johnson, Lundbeck, and Otsuka Pharmaceuticals. R.M.M. has received payments for non-promotional lectures from Janssen, Otsuka, Sunovian, and Lundbeck. J.H.M. has received research funding from H Lundbeck., (Copyright © 2023. Published by Elsevier B.V.)

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., Competing Interests: Declaration of competing interest The Authors declare no Competing Non-Financial Interests but the following Competing Financial Interests: J.T.R.W. is an investigator on a grant from Takeda Pharmaceuticals Ltd. to Cardiff University, for a project unrelated to the work presented here. S.E.S. is employed on this grant. M.D.F. has received a fee for educational seminars from Lundbeck and Janssen. O.A.A. is a consultant to HealthLytix and has received speakers honorarium from Lundbeck and Sunovion. T.R.E.B. has been a member of an advisory board for Gedeon Richter. C.B.E. received honoraria for conferences from Forum pour la formation médicale, Janssen-Cilag, Lundbeck, Otsuka, Sandoz, Servier, Sunovion, Sysmex Suisse AG, Takeda, Vifor-Pharma, and Zeller in the past 3 years. B.C.F. has received honoraria for participation as a consultant and/or as a speaker at educational events from ADAMED, Mylan, Angelini, Janssen Johnson & Johnson, Lundbeck, and Otsuka Pharmaceuticals. R.M.M. has received payments for non-promotional lectures from Janssen, Otsuka, Sunovian, and Lundbeck. J.H.M. has received research funding from H Lundbeck., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Little is known about predictors of clinical response to clozapine treatment in treatment-resistant psychosis. Most published cohorts are small, providing inconsistent results. We aimed to identify baseline clinical predictors of future clinical response in patients who initiate clozapine treatment, mainly focusing on the effect of age, duration of illness, baseline clinical symptoms and homelessness., Methodology: Retrospective cohort of patients with treatment-resistant schizophrenia, aged between 15 and 60 years, that initiated clozapine between 2014 and 2017. Sociodemographic characteristics, years from illness diagnosis, and clinical presentation before the initiation of clozapine were collected and analyzed. All-cause discontinuation at two years follow-up was used as the primary measure of clozapine response., Results: 261 patients were included with a median age at illness diagnosis of 23 years old (IQR 19-29) and a median age at clozapine initiation of 25 (IQR: 21-33). 72.33% (183/253) continued clozapine after two years follow-up. Being homeless was associated to higher clozapine non-adherence, with an OR of 2.78 (95%CI 1.051-7.38) (p = 0.039, controlled by gender). Older age at clozapine initiation and longer delay from first schizophrenia diagnosis to clozapine initiation were also associated with higher clozapine non-adherence, with each year increasing the odds of discontinuation by 1.043 (95%CI 1.02-1.07; p = 0.001) and OR 1.092 (95%CI 1.01-1.18;p = 0.032) respectively., Conclusion: Starting clozapine in younger patients or shortly after schizophrenia diagnosis were associated with better adherence., (Copyright © 2021. Published by Elsevier B.V.)

Background: Gender disparities in treatment are apparent across many areas of healthcare. There has been little research into whether clozapine prescription, the first-line treatment for treatment-resistant schizophrenia (TRS), is affected by patient gender., Methods: This retrospective cohort study identified 2244 patients with TRS within the South London and Maudsley NHS Trust, by using a bespoke method validated against a gold-standard, manually coded, dataset of TRS cases. The outcome and exposures were identified from the free-text using natural language processing applications (including machine learning and rules-based approaches) and from information entered in structured fields. Multivariable logistic regression was carried out to calculate the odds ratios for clozapine prescription according to patients' gender, and adjusting for numerous potential confounders including sociodemographic, clinical (e.g., psychiatric comorbidities and substance use), neutropenia, functional factors (e.g., problems with occupation), and clinical monitoring., Results: Clozapine was prescribed to 77% of the women and 85% of the men with TRS. Women had reduced odds of being prescribed clozapine as compared to men after adjusting for all factors included in the present study (adjusted OR: 0.66; 95% CI 0.44-0.97; p = 0.037)., Conclusion: Women with TRS are less likely to be prescribed clozapine than men with TRS, even when considering the effects of multiple clinical and functional factors. This finding suggests there could be gender bias in clozapine prescription, which carries ramifications for the relatively poorer care of women with TRS regarding many outcomes such as increased hospitalisation, mortality, and poorer quality of life., Competing Interests: Declaration of competing interest RDH and HS have received research funding from Roche, Pfizer, Janssen and H. Lundbeck A/S. GKS and DFdF have received research funding from Janssen and H. Lundbeck A/S. JHM has received research funding from H. Lundbeck A/S. RP has received research funds from Janssen and consultancy fees from Induction Healthcare and Holmusk. AS and EWW have no conflicts of interest to report., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Peripheral immune markers have previously been linked to a poor response to antipsychotic medication and more severe negative symptoms at the onset of psychosis. The present study investigated the association of blood cytokines and complement markers with the presence of antipsychotic non-response and symptom severity in patients with psychosis., Methods: This cross-sectional study recruited 94 patients with schizophrenia and other psychoses, of whom 47 were defined as antipsychotic responders and 47 as antipsychotic non-responders. In all subjects we measured plasma levels of cytokines (IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, TNF-α, and IFN-γ), complement markers (C1-inhibitor, C3, C4, C3a, C3b, Bb, factor D, C5a, terminal complement complex) and high sensitivity C-reactive protein (hsCRP). Symptom severity was recorded using the Positive and Negative Syndrome scale for Schizophrenia (PANSS). Binary logistic regression tested each immune marker as predictor of response status while covarying for relevant socio-demographic variables. Correlation analyses tested the association between immune markers and the severity of symptoms., Results: Interleukin (IL)-8 significantly predicted antipsychotic non-response (OR=24.70, 95% CI, 1.35-453.23, p = 0.03). Other immune markers were not associated with antipsychotic response. IL-6, IL-8, IL-10 and TNF-α significantly positively correlated with negative psychotic symptoms., Conclusions: Higher levels of IL-8 are associated with a poor response to antipsychotic treatment. Increased cytokines levels are specifically associated with more severe negative symptoms in patients with schizophrenia and other psychoses., Competing Interests: Declaration of competing interest VM has received research funding from Johnson & Johnson as part of a research program on depression and inflammation. BD has share options in P1vital and has received consultancy fees from Autifony.com. BPM has provided advice on complement to Roche and is a consultant to GlaxoSmithKline; all fees were paid to Cardiff University. JW reported receiving a grant from Takeda Pharmaceuticals outside of the submitted work. In the past three years, SML has received funding for research from Janssen, and personal fees for participating in educational meetings from Janssen and Sunovion. The remaining authors report no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Large-scale pharmacoepidemiological research on treatment resistance relies on accurate identification of people with treatment-resistant schizophrenia (TRS) based on data that are retrievable from administrative registers. This is usually approached by operationalising clinical treatment guidelines by using prescription and hospital admission information. We examined the accuracy of an algorithm-based definition of TRS based on clozapine prescription and/or meeting algorithm-based eligibility criteria for clozapine against a gold standard definition using case notes. We additionally validated a definition entirely based on clozapine prescription. 139 schizophrenia patients aged 18-65years were followed for a mean of 5years after first presentation to psychiatric services in South-London, UK. The diagnostic accuracy of the algorithm-based measure against the gold standard was measured with sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). A total of 45 (32.4%) schizophrenia patients met the criteria for the gold standard definition of TRS; applying the algorithm-based definition to the same cohort led to 44 (31.7%) patients fulfilling criteria for TRS with sensitivity, specificity, PPV and NPV of 62.2%, 83.0%, 63.6% and 82.1%, respectively. The definition based on lifetime clozapine prescription had sensitivity, specificity, PPV and NPV of 40.0%, 94.7%, 78.3% and 76.7%, respectively. Although a perfect definition of TRS cannot be derived from available prescription and hospital registers, these results indicate that researchers can confidently use registries to identify individuals with TRS for research and clinical practices., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: The use of clozapine is limited due to the occurrence of neutropenia, and the rare but life threatening adverse event of agranulocytosis. There is little epidemiological research into clinical factors that may impact on this risk. We conducted a case control study examining the clinical risk factors for neutropenia patients treated with clozapine., Method: A case-control study was conducted within a database of anonymised electronic clinical records. All patients who discontinued clozapine due to a neutropenic event were included as cases. Matched controls were selected from patients with a documented clozapine exposure at the time of the clozapine neutropenic event of the case patient, matched by duration of clozapine treatment., Results: 136 cases and 136 controls were included. In multivariable analysis, the concurrent use of sodium valproate was associated with neutropenia (Odds Raito (OR) 2.28, 95%CI: 1.27-4.11, p=0.006). There was a dose-response effect, with greater associations for higher doses. Patients who discontinued clozapine due to neutropenia were more likely to be of black ethnicity (OR 2.99, p<0.001), were younger (t=5.86, df=267, p<0.001), and received lower doses of clozapine (t=-2.587, p=0.01) than those who did not develop neutropenia., Conclusion: We identified an association between the concurrent use of sodium valproate and an increased risk of clozapine associated neutropenia. These results, taken in combination with the results from previous case series, suggest that the risk of clozapine associated neutropenia could be reduced by avoiding concurrent valproate treatment., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Clozapine is uniquely effective in the management of treatment-resistant schizophrenia (TRS). However, a substantial proportion of patients discontinue treatment and this carries a poor prognosis., Methods: We investigated the risk factors, reasons and timing of clozapine discontinuation in a two-year retrospective cohort study of 316 patients with TRS receiving their first course of clozapine. Reasons for discontinuation of clozapine and duration of treatment were obtained from case notes and Cox regression was employed to test the association of baseline clinical factors with clozapine discontinuation., Results: A total of 142 (45%) patients discontinued clozapine within two years. By studying the reasons for discontinuations due to a patient decision, we found that adverse drug reactions (ADRs) accounted for over half of clozapine discontinuations. Sedation was the most common ADR cited as a reason for discontinuation and the risk of discontinuation due to ADRs was highest in the first few months of clozapine treatment. High levels of deprivation in the neighbourhood where the patient lived were associated with increased risk of clozapine discontinuation (HR=2.12, 95% CI 1.30-3.47)., Conclusions: Living in a deprived neighbourhood was strongly associated with clozapine discontinuation. Clinical management to reduce the burden of ADRs in the first few months of treatment may have a significant impact and help more patients experience the benefits of clozapine treatment., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Living in a larger city is associated with increased risk of schizophrenia; and world-wide, consistent evidence shows that the higher the degree of urbanicity the higher the risk of schizophrenia. However, the association between urbanicity and treatment-resistant schizophrenia (TRS) as a more severe form of schizophrenia or separate entity of schizophrenia has not been fully explored yet. We aimed to investigate the association between urbanicity and incidence of TRS., Methods: A large Danish population-based cohort of all individuals with a first schizophrenia diagnosis after 1996 was followed until 2013 applying survival analysis techniques. TRS was assessed using a treatment-based proxy, defined as the earliest observed instance of either clozapine initiation or hospital admission due to schizophrenia after having received two prior antipsychotic monotherapy trials of adequate duration., Results: Among the 13,349 schizophrenia patients, 17.3% experienced TRS during follow-up (median follow-up: 7years, inter-quartile range: 3-12years). The 5-year risk of TRS ranged from 10.5% in the capital area to 17.6% in the rural areas. Compared with individuals with schizophrenia residing in the capital area, hazard ratios were 1.44 (1.31-1.59) for provincial areas and 1.60 (1.43-1.79) for rural areas., Conclusion: Higher rates of TRS were found in less urbanized areas. The different direction of urban-rural differences regarding TRS and schizophrenia risk may indicate urban-rural systematic differences in treatment practices, or different urban-rural aetiologic types of schizophrenia., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Introduction: The predictors of long-term antipsychotic polypharmacy (APP) initiation are poorly understood. Existing research has been hampered by residual confounding, failure to exclude cross-titration, and difficulties in separating the timing of predictors and APP administration., Materials and Methods: Using data from the South London and Maudsley (SLaM) case register, we identified all adult patients with serious mental illness (SMI) who were receiving care between 1st July 2011 and 30th June 2012. Exposures measured between 1st July and 31st December 2011 included socio-demographic, socioeconomic, clinical and service use characteristics. We then determined if long-term APP (six or more months) had been initiated between 1st January and 30th June 2012. Multivariable logistic regression models, adjusted for socio-demographic and socioeconomic factors, were built to investigate the associations between the above factors and the initiation of long-term APP., Results: We identified 6857 adults with SMI receiving SLaM care, of whom 115 (1.7%) were newly prescribed long-term APP. In the adjusted models, predictors of long-term APP initiation included: symptoms (severity of hallucinations and/or delusions), previous treatments (clozapine and long-acting injectable antipsychotic agents), service use (more contact with outpatient services, community treatment order receipt), social factors (higher area-level deprivation, homelessness) and socio-demographic status (younger age, not in a relationship)., Conclusion: Our findings highlight that certain patient groups are at an increased risk for long-term APP initiation. Identifying these groups earlier in their treatment could encourage clinicians to employ a broader range of interventions in addition to pharmacotherapy to reduce the risk of APP prescribing., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

The primary aim of this systematic review and meta-analysis was to assess the proportion of patients with Treatment Resistant Schizophrenia (TRS) that respond to ECT augmentation of clozapine (C+ECT). We searched major electronic databases from 1980 to July 2015. We conducted a random effects meta-analysis reporting the proportion of responders to C+ECT in RCTs and open-label trials. Five clinical trials met our eligibility criteria, allowing us to pool data from 71 people with TRS who underwent C+ ECT across 4 open label trials (n=32) and 1 RCT (n=39). The overall pooled proportion of response to C+ECT was 54%, (95% CI: 21.8-83.6%) with some heterogeneity evident (I(2)=69%). With data from retrospective chart reviews, case series and case reports, 192 people treated with C+ECT were included. All studies together demonstrated an overall response to C+ECT of 66% (95% CI: 57.5-74.3%) (83 out of 126 patients responded to C+ECT). The mean number of ECT treatments used to augment clozapine was 11.3. 32% of cases (20 out of 62 patients) with follow up data (range of follow up: 3-468weeks) relapsed following cessation of ECT. Adverse events were reported in 14% of identified cases (24 out of 166 patients). There is a paucity of controlled studies in the literature, with only one single blinded randomised controlled study located, and the predominance of open label trials used in the meta-analysis is a limitation. The data suggests that ECT may be an effective and safe clozapine augmentation strategy in TRS. A higher number of ECT treatments may be required than is standard for other clinical indications. Further research is needed before ECT can be included in standard TRS treatment algorithms., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Both substance use and poor medication adherence are associated with poor outcome in psychosis. To clarify the contributions of substance use and poor medication adherence to poor outcome in the year following a first episode of psychosis, 205 patients were evaluated for use of tobacco, alcohol, cannabis and stimulants at their psychosis onset, and in a 1-year follow-up. Data on medication adherence and symptom remission were also collected. Patients had high rates of overall substance use before (37-65%) and after psychosis onset (45-66%). 44% showed poor medication adherence and 55% did not reach remission from psychosis. Nicotine dependence and cannabis use after psychosis onset significantly predicted both poor medication adherence and non-remission, and poor medication adherence mediated the effects of these substances on non-remission. In conclusion, medication adherence lies on the causal pathway between nicotine dependence and cannabis on the one hand and non-remission on the other., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: To prospectively assess the relationship between cannabis use and psychotic experiences over time., Method: In a longitudinal design, young adults aged 18-27years (N=705) gave online information on cannabis use and completed the Community Assessment of Psychic Experiences (CAPE). These measures were repeated after an interval ranging from six months to five years., Results: A decrease in cannabis use was associated with a decrease in total psychotic experiences (β=-0.096, p=0.01) after adjustment for a range of potential confounders. An increase in cannabis use was associated with increased positive symptoms at follow-up (β=0.07, p=0.02), but was not significantly associated with increases in Negative and Depression symptom scores, nor with the total number of psychotic experiences., Conclusion: In the first study to the association of change in cannabis use and psychotic experiences over time in the general population, we found an association between changes in cannabis use and changes in the frequency of psychotic experiences. While this does not prove a causal relationship between cannabis use and psychosis, our findings are consistent with studies suggesting that cessation of cannabis use may be beneficial in terms of reducing psychotic experiences., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Individuals with psychotic illnesses are known to have a reduced fertility. It is unclear whether this is due to biological or social factors. Most fertility studies have been conducted in chronic schizophrenia, where confounders like medication and hospitalisation make this difficult to elicit. A less severe reduction of fertility has been observed in some ethnic minorities, but results are inconsistent. We sought to investigate pre-morbid fertility in an ethnically diverse sample of individuals with first-onset psychosis. Data were derived from 515 people with a first psychotic episode (FEP) and 383 controls. We made case-control comparisons of differences in the proportion of those with children (fertility rates) and mean number of children (MNC). Analyses were then stratified by diagnosis, gender and ethnicity, and adjusted for potential confounders. We found that FEP showed a reduced fertility rate (age-adjusted OR of having children 0.47 [95% CI=0.39, 0.56]), irrespective of diagnosis, and there was little evidence of confounding by gender, ethnicity, religious background, education level, or history of past relationships (fully adjusted OR=0.55, 95% CI=0.37, 0.80). Women had a somewhat greater reduction in fertility rates than men (Men: age-adjusted OR 0.61 [95% CI 0.42, 0.89]; Women: age-adjusted OR 0.46 [95% CI 0.31, 0.69]) and we could not find any evidence of ethnic differences in the degree of fertility reduction. FEP who had previously experienced a stable relationship had an MNC that was comparable to that of the general population and had a later onset of illness. This is the largest case-control study to date to investigate fertility in first-onset psychosis. Our data suggests that fertility is affected, even prior to the onset of a psychotic illness, and there are likely to be biological and environmental factors involved, but the former seem to have a stronger influence., (Copyright © 2014 Elsevier B.V. All rights reserved.)