Background Treatment resistance (TR) in schizophrenia may be defined by the persistence of positive and/or negative symptoms despite adequate treatment. Whilst previous investigations have focused on positive symptoms, negative symptoms are highly prevalent, impactful, and difficult to treat. In the current study we aimed to develop easily employable prediction models to predict TR in positive and negative symptom domains from first episode psychosis (FEP). Methods Longitudinal cohort data from 1027 individuals with FEP was utilised. Using a robust definition of TR, n = 51 (4.97 %) participants were treatment resistant in the positive domain and n = 56 (5.46 %) treatment resistant in the negative domain 12 months after first presentation. 20 predictor variables, selected by existing evidence and availability in clinical practice, were entered into two LASSO regression models. We estimated the models using repeated nested cross-validation (NCV) and assessed performance using discrimination and calibration measures. Results The prediction model for TR in the positive domain showed good discrimination (AUC = 0.72). Twelve predictor variables (male gender, cannabis use, age, positive symptom severity, depression and academic and social functioning) were retained by each outer fold of the NCV procedure, indicating importance in prediction of the outcome. However, our negative domain model failed to discriminate those with and without TR, with results only just over chance (AUC = 0.56). Conclusions Treatment resistance of positive symptoms can be accurately predicted from FEP using routinely collected baseline data, however prediction of negative domain-TR remains a challenge. Detailed negative symptom domains, clinical data, and biomarkers should be considered in future longitudinal studies.

Abstract Background: Chimeric antigen receptor (CAR) T cell therapy is effective in treating B-cell malignancies, but factors influencing the persistence of functional CAR+ T cells, such as product composition, patients’ lymphodepletion, and immune reconstitution, are not well understood. To shed light on this issue, we conducted single-cell multi-omics analysis of transcriptional, clonal, and phenotypic profiles from pre- to 1-month post-infusion of CAR+ and CAR− T cells from patients who received a donor-derived 4-1BB CAR product targeting CD19. Methods: Longitudinal blood samples and infusion products were obtained from 10 individuals with large B cell lymphoma or B-cell acute lymphoblastic leukemia (CARTELL cohort in Sydney Australia1). CD45+ cells and enriched CAR+ T cells were single cell sorted for simultaneous scRNA-seq, 41 barcoded proteins (N=41) and T cell receptors, n= 115,000 cells across 21 samples. Machine learning methods were used to identify subsets of immune cells associated with clinically relevant parameters. Results: Following infusion, CAR+ and CAR− T cells showed similar differentiation profiles with clonally expanded populations across heterogeneous phenotypes, demonstrating clonal lineages and phenotypic plasticity. These findings were validated by performing the same analysis on two publicly available scRNA-seq data sets from two cohorts 2, 3 of paediatric (N=18) and adult (N=32) individual with large B cell lymphoma who received CAR19 T cells. Analysis of mass-cytometry data from our cohort and from 28 patients with B cell lymphoma treated with commercial CAR19 T cells (axi-cel)4, identified an association of CAR− and also CAR+ T cells, both expressing an 2B4− CD11b+ CD8+ phenotype, with complete remission or progressive disease at 3 and 6 months post-infusion. Finally, we report additional analysis on the immunogenomics of circulating CAR T cells in two patients who developed CAR T cell induced lymphoma and compared it with ascites and CAR-Lymphoma cells. Discussion: These results suggest that CAR+ and CAR− CD8+ T cells share a differentiation trajectory terminating in an NK-like phenotype that is associated with clinical outcome, and that non-CAR-derived signals may influence patients’ immune recovery and outcomes.References 1.Bishop, D.C. et al. Development of CAR T-cell lymphoma in 2 of 10 patients effectively treated with piggyBac-modified CD19 CAR T cells. Blood 138, 1504-1509 (2021).2.Haradhvala, N.J. et al. Distinct cellular dynamics associated with response to CAR-T therapy for refractory B cell lymphoma. Nat Med 28, 1848-1859 (2022).3.Wilson, T.L. et al. Common Trajectories of Highly Effective CD19-Specific CAR T Cells Identified by Endogenous T-cell Receptor Lineages. Cancer Discov 12, 2098-2119 (2022).4.Good, Z. et al. Post-infusion CAR T(Reg) cells identify patients resistant to CD19-CAR therapy. Nat Med 28, 1860-1871 (2022). Citation Format: Raymond Y. Louie, Jerome Samir, Curtis Cai, Helen McGuire, Tim Amos, James Fergsuson, Ira Deveson, Thiruni Adikari, Martina Bonomi, David Bishop, Christopher E. Mason, Robert Balderas, Marco Ruella, Mandeep Singh, David Gottlieb, Emily Blyth, Ken Micklethwaite, Fabio Luciani. Harnessing single cell multi-omics data to identify predictors of clinical outcome in CD19 CAR T cell therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 882.

Purpose Psychosis disproportionally affects ethnic minority groups in high-income countries, yet evidence of disparities in outcomes following intensive early intervention service (EIS) for First Episode Psychosis (FEP) is less conclusive. We investigated 5-year clinical and social outcomes of young people with FEP from different racial groups following EIS care. Method Data were analysed from the UK-wide NIHR SUPEREDEN study. The sample at baseline ( n = 978) included White ( n = 750), Black ( n = 71), and Asian ( n = 157) individuals, assessed during the 3 years of EIS, and up to 2 years post-discharge ( n = 296; Black [ n = 23]; Asian [ n = 52] and White [ n = 221]). Outcome trajectories were modelled for psychosis symptoms (positive, negative, and general), functioning, and depression, using linear mixed effect models (with random intercept and slopes), whilst controlling for social deprivation. Discharge service was also explored across racial groups, 2 years following EIS. Results Variation in linear growth over time was accounted for by racial group status for psychosis symptoms—positive (95% CI [0.679, 1.235]), negative (95% CI [0.315, 0.783]), and general (95% CI [1.961, 3.428])—as well as for functioning (95% CI [11.212, 17.677]) and depressive symptoms (95% CI [0.261, 0.648]). Social deprivation contributed to this variance. Black individuals experienced greater levels of deprivation ( p < 0.001, 95% CI [0.187, 0.624]). Finally, there was a greater likelihood for Asian (OR = 3.04; 95% CI [2.050, 4.498]) and Black individuals (OR = 2.47; 95% CI [1.354, 4.520]) to remain in secondary care by follow-up. Conclusion Findings suggest variations in long-term clinical and social outcomes following EIS across racial groups; social deprivation contributed to this variance. Black and Asian individuals appear to make less improvement in long-term recovery and are less likely to be discharged from mental health services. Replication is needed in large, complete data, to fully understand disparities and blind spots to care.

The extant literature is inconsistent over whether manic symptoms in first‐episode psychosis (FEP) impact on its development and trajectory. This study addressed the following: (1) Does Duration of Untreated Illness (DUI) and Duration of Untreated Psychosis (DUP) differ between FEP patients with and without manic symptoms? (2) Do manic symptoms in FEP have an impact on time to remission over 1 year?

Early psychosis is characterised by heterogeneity in illness trajectories, where outcomes remain poor for many. Understanding psychosis symptoms and their relation to illness outcomes, from a novel network perspective, may help to delineate psychopathology within early psychosis and identify pivotal targets for intervention. Using network modelling in first episode psychosis (FEP), this study aimed to identify: (a) key central and bridge symptoms most influential in symptom networks, and (b) examine the structure and stability of the networks at baseline and 12-month follow-up. Data on 1027 participants with FEP were taken from the National EDEN longitudinal study and used to create regularised partial correlation networks using the 'EBICglasso' algorithm for positive, negative, and depressive symptoms at baseline and at 12-months. Centrality and bridge estimations were computed using a permutation-based network comparison test. Depression featured as a central symptom in both the baseline and 12-month networks. Conceptual disorganisation, stereotyped thinking, along with hallucinations and suspiciousness featured as key bridge symptoms across the networks. The network comparison test revealed that the strength and bridge centralities did not differ significantly between the two networks (C = 0.096153; p = 0.22297). However, the network structure and connectedness differed significantly from baseline to follow-up (M = 0.16405, p = <0.0001; S = 0.74536, p = 0.02), with several associations between psychosis and depressive items differing significantly by 12 months. Depressive symptoms, in addition to symptoms of thought disturbance (e.g. conceptual disorganisation and stereotyped thinking), may be examples of important, under-recognized treatment targets in early psychosis, which may have the potential to lead to global symptom improvements and better recovery.

BACKGROUND:Treatment resistance causes significant burden in psychosis. Clozapine is the only evidence-based pharmacologic intervention available for people with treatment-resistant schizophrenia; current guidelines recommend commencement after two unsuccessful trials of standard antipsychotics.AIMS:This paper aims to explore the prevalence of treatment resistance and pathways to commencement of clozapine in UK early intervention in psychosis (EIP) services.METHOD:Data were taken from the National Evaluation of the Development and Impact of Early Intervention Services study (N = 1027) and included demographics, medication history and psychosis symptoms measured by the Positive and Negative Syndrome Scale (PANSS) at baseline, 6 months and 12 months. Prescribing patterns and pathways to clozapine were examined. We adopted a strict criterion for treatment resistance, defined as persistent elevated positive symptoms (a PANSS positive score ≥16, equating to at least two items of at least moderate severity), across three time points.RESULTS:A total of 143 (18.1%) participants met the definition of treatment resistance of having continuous positive symptoms over 12 months, despite treatment in EIP services. Sixty-one (7.7%) participants were treatment resistant and eligible for clozapine, having had two trials of standard antipsychotics; however, only 25 (2.4%) were prescribed clozapine over the 12-month study period. Treatment-resistant participants were more likely to be prescribed additional antipsychotic medication and polypharmacy, instead of clozapine.CONCLUSIONS:Prevalent treatment resistance was observed in UK EIP services, but prescription of polypharmacy was much more common than clozapine. Significant delays in the commencement of clozapine may reflect a missed opportunity to promote recovery in this critical period.

Background Delayed treatment for first episodes of psychosis predicts worse outcomes. We hypothesised that delaying treatment makes all symptoms more refractory, with harm worsening first quickly, then more slowly. We also hypothesised that although delay impairs treatment response, worse symptoms hasten treatment, which at presentation mitigates the detrimental effect of treatment delay on symptoms. Methods In this longitudinal analysis and modelling study, we included two longitudinal cohorts of patients with first-episode psychosis presenting to English early intervention services from defined catchments: NEDEN (recruiting 1003 patients aged 14-35 years from 14 services between Aug 1, 2005, and April 1, 2009) and Outlook (recruiting 399 patients aged 16-35 years from 11 services between April 1, 2006, and Feb 28, 2009). Patients were assessed at baseline, 6 months, and 12 months with the Positive and Negative Symptom Scale (PANSS), Calgary Depression Scale for Schizophrenia, Mania Rating Scale, Insight Scale, and Social and Occupational Functioning Assessment Scale. Regression was used to compare different models of the relationship between duration of untreated psychosis (DUP) and total symptoms at 6 months. Growth curve models of symptom subscales tested predictions arising from our hypotheses. Findings We included 948 patients from the NEDEN study and 332 patients from the Outlook study who completed baseline assessments and were prescribed dopamine antagonist antipsychotics. For both cohorts, the best-fitting models were logarithmic, describing a curvilinear relationship of DUP to symptom severity: longer DUP predicted reduced treatment response, but response worsened more slowly as DUP lengthened. Increasing DUP by ten times predicted reduced improvement in total symptoms (ie, PANSS total) by 7.339 (95% CI 5.762 to 8.916; p<0.0001) in NEDEN data and 3.846 (1.689 to 6.003; p=0.0005) in Outlook data. This was true of treatment response for all symptom types. Nevertheless, longer DUP was not associated with worse presentation for any symptoms except depression in NEDEN (coefficients 0.099 [95% CI 0.033 to 0.164]; p=0.0028 in NEDEN and 0.007 [-0.081 to 0.095]; p=0.88 in Outlook). Interpretation Long DUP was associated with reduced treatment response across subscales, consistent with a harmful process upstream of individual symptoms' mechanisms; response appeared to worsen quickly at first, then more slowly. These associations underscore the importance of rapid access to a comprehensive range of treatments, especially in the first weeks after psychosis onset.

Treatment resistance causes significant burden in psychosis. Clozapine is the only evidence-based pharmacologic intervention available for people with treatment-resistant schizophrenia; current guidelines recommend commencement after two unsuccessful trials of standard antipsychotics. Aims This paper aims to explore the prevalence of treatment resist- ance and pathways to commencement of clozapine in UK early intervention in psychosis (EIP) services. Method Data were taken from the National Evaluation of the Development and Impact of Early Intervention Services study ( N = 1027) and included demographics, medication history and psychosis symptoms measured by the Positive and Negative Syndrome Scale (PANSS) at baseline, 6 months and 12 months. Prescribing patterns and pathways to clozapine were examined. We adopted a strict criterion for treatment resistance, defined as persistent elevated positive symptoms (a PANSS positive score ≥ 16, equating to at least two items of at least moderate severity), across three time points. A total of 143 (18.1%) participants met the definition of treatment resistance of having continuous positive symptoms over 12 months, despite treatment in EIP services. Sixty-one (7.7%) participants were treatment resistant and eligible for clozapine, having had two trials of standard antipsychotics; however, only 25 (2.4%) were prescribed clozapine over the 12-month study period. Treatment-resistant participants were more likely to be prescribed additional antipsychotic medication and polypharmacy, instead of clozapine. Prevalent was observed in UK EIP services, but prescription of polypharmacy was much more common than clozapine. Significant delays in the commencement of clozapine may reflect a missed opportunity to promote recovery in this critical period.

Aim Duration of untreated psychosis (DUP) is considered as a key prognostic variable in psychosis. Yet, it is unclear whether a longer DUP causes worse outcomes or whether reported associations have alternative explanations. Methods Data from 2 cohorts of patients with first episode psychosis were used ( n = 2134). Measures of DUP were assessed at baseline and outcomes at 12 months. Regression models were used to investigate the associations between DUP and outcomes. We also investigated whether any associations were replicated using instrumental variables (IV) analysis to reduce the effect of residual confounding and measurement bias. Results There were associations between DUP per 1‐year increase and positive psychotic symptoms (7.0% in symptom score increase 95% confidence interval (CI) 4.0%, 10.0%, P < .001), worse recovery (risk difference [RD] 0.78, 95%, CI 0.68, 0.83, P < .001) and worse global functioning (0.62 decrease in functioning score 95% CI −1.19, −0.04, P = .035). There was no evidence of an association with negative psychotic symptoms (1.0%, 95%, CI −2.0%, 5.0%, P = .455). The IV analysis showed weaker evidence of associations in the same direction between DUP per 1‐year increase and positive psychotic symptoms, recovery and global functioning. However, there was evidence of an inverse association with negative psychotic symptoms (decrease of 15.0% in symptom score 95% CI −26.0%, −3.0%, P = .016). Conclusions We have confirmed previous findings of a positive association between positive psychotic symptoms, global functioning and recovery and DUP using regression analysis. IV analysis shows some support for these findings. Future investigation using IV analysis should be repeated in large data sets.

AIM:Exploring how negative symptoms are experienced and understood by individuals with lived experience of psychosis has the potential to offer insights into the complex psychosocial processes underlying negative symptom presentations. The aim of the current study was to investigate lived experiences of negative symptoms through secondary analysis of interviews conducted with individuals recovering from first-episode psychosis. METHOD:Transcripts of in-depth interviews with participants (n = 24) recruited from Early Intervention in Psychosis services were analysed thematically with a focus on participants' experiences and personal understandings of features corresponding to the negative symptoms construct. RESULTS:Descriptions of reductions in expression, motivation and sociability were common features of participants' accounts. Several participants described the experience of having difficulty interacting as like being a "zombie". Some participants experienced diminished capacity for emotion, thought or drive as underlying these experiences. However, participants typically attributed reductions in expression, motivation and sociability to medication side-effects, lack of confidence or active avoidance intended to protect them from rejection or ridicule, sometimes linked to internalized stigma. CONCLUSIONS:Personal accounts of experiences of reduced expression, motivation and sociability during first-episode psychosis highlight the personal meaningfulness and role of agency in these features, challenging the framing of negative symptoms as passive manifestations of diminished capacity.

Background: A second antipsychotic is commonly added to clozapine to treat refractory schizophrenia, notwithstanding the limited evidence to support such practice. Methods: The efficacy and adverse effects of this pharmacological strategy were examined in a double-blind, placebo-controlled, 12-week randomized trial of clozapine augmentation with amisulpride, involving 68 adults with treatment-resistant schizophrenia and persistent symptoms despite a predefined trial of clozapine. Results: There were no statistically significant differences between the amisulpride and placebo groups on the primary outcome measure (clinical response defined as a 20% reduction in total Positive and Negative Syndrome Scale score) or other mental state measures. However, the trial under recruited and was therefore underpowered to detect differences in the primary outcome, meaning that acceptance of the null hypothesis carries an increased risk of type II error. The findings suggested that amisulpride-treated participants were more likely to fulfil the clinical response criterion, odds ratio 1.17 (95% confidence interval 0.40–3.42) and have a greater reduction in negative symptoms, but these numerical differences were not statistically significant and only evident at 12 weeks. A significantly higher proportion of participants in the amisulpride group had at least one adverse event compared with the control group ( p = 0.014), and these were more likely to be cardiac symptoms. Conclusions: Treatment for more than 6 weeks may be required for an adequate trial of clozapine augmentation with amisulpride. The greater side-effect burden associated with this treatment strategy highlights the need for safety and tolerability monitoring, including vigilance for indicators of cardiac abnormalities, when it is used in either a clinical or research setting.

BACKGROUND:Previous evidence suggests that delusional disorder has a later onset and better functional outcomes compared to schizophrenia. However, studies have not examined longitudinal outcomes in a first episode population, where confounding factors may be adjusted for. METHODS:A nested case control study was designed within the National EDEN study; a cohort of 1027 first episode psychosis patients. Patients with a baseline diagnosis of delusional disorder (n = 48) were compared with schizophrenia (n = 262) at 6 and 12 months with respect to symptomatic and functional outcomes. Regression analysis was used to adjust for possible confounders. RESULTS:Delusional disorder patients had a shorter duration of untreated psychosis compared to schizophrenia but were similar in other baseline characteristics. At baseline, delusional disorder patients had lower symptom scores but higher function scores compared to those with schizophrenia. At 12 months the differences persisted for symptoms scores but not overall function scores. After adjusting for baseline score, age and duration of untreated psychosis, differences between the groups remained significant only for Positive and Negative Syndrome Scale (PANNS) negative, general and total scores and recovery rates. There were no differences in changes in outcomes scores. CONCLUSIONS:Delusional disorder in a first episode psychosis population presents with less severe symptoms, higher recovery rates and better functioning than schizophrenia, but at 12 months differences are ameliorated when adjusting for baseline differences.

BACKGROUND:Provision of early intervention services has increased the rate of social recovery in patients with first-episode psychosis; however, many individuals have continuing severe and persistent problems with social functioning. We aimed to assess the efficacy of early intervention services augmented with social recovery therapy in patients with first-episode psychosis. The primary hypothesis was that social recovery therapy plus early intervention services would lead to improvements in social recovery. METHODS:We did this single-blind, phase 2, randomised controlled trial (SUPEREDEN3) at four specialist early intervention services in the UK. We included participants who were aged 16-35 years, had non-affective psychosis, had been clients of early intervention services for 12-30 months, and had persistent and severe social disability, defined as engagement in less than 30 h per week of structured activity. Participants were randomly assigned (1:1), via computer-generated randomisation with permuted blocks (sizes of four to six), to receive social recovery therapy plus early intervention services or early intervention services alone. Randomisation was stratified by sex and recruitment centre (Norfolk, Birmingham, Lancashire, and Sussex). By necessity, participants were not masked to group allocation, but allocation was concealed from outcome assessors. The primary outcome was time spent in structured activity at 9 months, as measured by the Time Use Survey. Analysis was by intention to treat. This trial is registered with ISRCTN, number ISRCTN61621571. FINDINGS:Between Oct 1, 2012, and June 20, 2014, we randomly assigned 155 participants to receive social recovery therapy plus early intervention services (n=76) or early intervention services alone (n=79); the intention-to-treat population comprised 154 patients. At 9 months, 143 (93%) participants had data for the primary outcome. Social recovery therapy plus early intervention services was associated with an increase in structured activity of 8·1 h (95% CI 2·5-13·6; p=0·0050) compared with early intervention services alone. No adverse events were deemed attributable to study therapy. INTERPRETATION:Our findings show a clinically important benefit of enhanced social recovery on structured activity in patients with first-episode psychosis who received social recovery therapy plus early intervention services. Social recovery therapy might be useful in improving functional outcomes in people with first-episode psychosis, particularly in individuals not motivated to engage in existing psychosocial interventions targeting functioning, or who have comorbid difficulties preventing them from doing so. FUNDING:National Institute for Health Research.

BackgroundWhen treatment-refractory schizophrenia shows an insufficient response to a trial of clozapine, clinicians commonly add a second antipsychotic, despite the lack of robust evidence to justify this practice.ObjectivesThe main objectives of the study were to establish the clinical effectiveness and cost-effectiveness of augmentation of clozapine medication with a second antipsychotic, amisulpride, for the management of treatment-resistant schizophrenia.DesignThe study was a multicentre, double-blind, individually randomised, placebo-controlled trial with follow-up at 12 weeks.SettingsThe study was set in NHS multidisciplinary teams in adult psychiatry.ParticipantsEligible participants were people aged 18–65 years with treatment-resistant schizophrenia unresponsive, at a criterion level of persistent symptom severity and impaired social function, to an adequate trial of clozapine monotherapy.InterventionsInterventions comprised clozapine augmentation over 12 weeks with amisulpride or placebo. Participants received 400 mg of amisulpride or two matching placebo capsules for the first 4 weeks, after which there was a clinical option to titrate the dosage of amisulpride up to 800 mg or four matching placebo capsules for the remaining 8 weeks.Main outcome measuresThe primary outcome measure was the proportion of ‘responders’, using a criterion response threshold of a 20% reduction in total score on the Positive and Negative Syndrome Scale.ResultsA total of 68 participants were randomised. Compared with the participants assigned to placebo, those receiving amisulpride had a greater chance of being a responder by the 12-week follow-up (odds ratio 1.17, 95% confidence interval 0.40 to 3.42) and a greater improvement in negative symptoms, although neither finding had been present at 6-week follow-up and neither was statistically significant. Amisulpride was associated with a greater side effect burden, including cardiac side effects. Economic analyses indicated that amisulpride augmentation has the potential to be cost-effective in the short term [net saving of between £329 and £2011; no difference in quality-adjusted life-years (QALYs)] and possibly in the longer term.LimitationsThe trial under-recruited and, therefore, the power of statistical analysis to detect significant differences between the active and placebo groups was limited. The economic analyses indicated high uncertainty because of the short duration and relatively small number of participants.ConclusionsThe risk–benefit of amisulpride augmentation of clozapine for schizophrenia that has shown an insufficient response to a trial of clozapine monotherapy is worthy of further investigation in larger studies. The size and extent of the side effect burden identified for the amisulpride–clozapine combination may partly reflect the comprehensive assessment of side effects in this study. The design of future trials of such a treatment strategy should take into account that a clinical response may be not be evident within the 4- to 6-week follow-up period usually considered adequate in studies of antipsychotic treatment of acute psychotic episodes. Economic evaluation indicated the need for larger, longer-term studies to address uncertainty about the extent of savings because of amisulpride and impact on QALYs. The extent and nature of the side effect burden identified for the amisulpride–clozapine combination has implications for the nature and frequency of safety and tolerability monitoring of clozapine augmentation with a second antipsychotic in both clinical and research settings.Trial registrationEudraCT number 2010-018963-40 and Current Controlled Trials ISRCTN68824876.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 21, No. 49. See the NIHR Journals Library website for further project information.

AimEarly intervention services (EIS) for psychosis are being implemented, internationally. It is important to learn from established examples and define the components and intensity of services that provide good value for money. This study aims to assess the cost‐effectiveness of EIS according to how closely they adhered to the recommendations of the English Department of Health 2001 Policy Implementation Guide (PIG).MethodsEIS from the National Eden Study were assessed using a measure of fidelity to the PIG that rated the presence or absence of 64 recommended items relating to team structure and practice. EIS were then classified into three groups: those with fidelity of 75–80%, 81–90% and 91–95%. Patient‐level resource use and outcomes were measured 1 year following inception into the service; costs were calculated and combined with quality‐adjusted life years (QALYs) gained.ResultsAt a threshold of £20 000 per QALY, the 81–90% fidelity group had a 56.3% likelihood of being the most cost‐effective option followed by 75–80% fidelity at 35.8% and 91–95% fidelity group (7.9%).ConclusionsThe results from England suggest that striving to maximize fidelity may not be warranted, but that dropping below a certain level of fidelity may result in inefficient use of resources.

Background: In around a third of people with schizophrenia, the illness responds poorly to standard treatment with antipsychotic medication. Clozapine is the only antipsychotic medication with robust evidence for efficacy in strictly defined treatment-resistant schizophrenia, but even then, an adequate response is seen in only 30%–60% of patients. When a trial of clozapine proves to be insufficient, clinicians commonly add a second antipsychotic, although robust evidence to justify this practice, with regard to the potential benefits and risks, is lacking. Methods: The AMICUS study was a multicentre, double-blind, individually randomized, placebo-controlled trial with follow-up at 12 weeks. Eligible participants were people aged 18–65 years with treatment-resistant schizophrenia unresponsive, at a criterion level of persistent symptom severity and impaired social function, to an adequate trial of clozapine monotherapy. Interventions comprised clozapine augmentation over 12 weeks with amisulpride or placebo. Participants received 400 mg of amisulpride or one matching placebo capsule for the first 4 weeks, after which there was a clinical option to titrate the dosage of amisulpride up to 800 mg or 2 matching placebo capsules for the remaining 8 weeks. Results: A total of 68 participants were randomized. Compared with the participants assigned to placebo, those receiving amisulpride had a greater chance of being a responder (defined as a 20% or more reduction in total score on the Positive and Negative Syndrome Scale by the 12-week follow-up: OR: 1.17, 95% CI: 0.40–3.42) and a greater improvement in negative symptoms, although neither finding was statistically significant. Amisulpride was associated with a greater side effect burden, including cardiac side effects. The trial under-recruited and, therefore, the power of statistical analysis to detect significant differences between the active and placebo groups was limited. Conclusion: The risk-benefit of amisulpride augmentation of clozapine for schizophrenia that has shown an insufficient response to a trial of clozapine monotherapy is worthy of further investigation in larger studies. The design of future trials of such a treatment strategy should take into account that any modest benefit with the clozapine-amisulpride combination may be delayed beyond the 4–6 week follow-up considered adequate for acute psychotic episodes. The size and extent of the side effect burden identified for the amisulpride–clozapine combination may partly reflect the comprehensive assessment of side effects in this study. It has implications for the safety and tolerability monitoring of clozapine augmentation with a second antipsychotic in clinical and research settings.

Aims: To investigate trajectories of negative symptoms during the first 12 months of treatment for first episode psychosis (FEP), their predictors and relationship to social recovery.Method: 1006 participants were followed up for 12 months following acceptance into Early Intervention in Psychosis services. Negative symptom trajectories were modelled using latent class growth analysis (LCGA) and predictors of trajectories examined using multinomial regression. Social recovery trajectories - also modelled using LCGA - of members of each negative symptom trajectory were ascertained and the relationship between negative symptom and social recovery trajectories examined.Results: Four negative symptom trajectories were identified: Minimal Decreasing (63.9%), Mild Stable (13.5%), High Decreasing (17.1%) and High Stable (5.4%). Male gender and family history of non-affective psychosis predicted stably high negative symptoms. Poor premorbid adolescent adjustment, family history of non-affective psychosis and baseline depression predicted initially high but decreasing negative symptoms. Members of the Mild Stable, High Stable and High Decreasing classes were more likely to experience stably low functioning than the Minimal Decreasing class.Conclusions: Distinct negative symptom trajectories are evident in FEP. Only a small subgroup present with persistently high levels of negative symptoms. A substantial proportion of FEP patients with elevated negative symptoms at baseline will achieve remission of these symptoms within 12 months. However, elevated negative symptoms at baseline, whether or not they remit, are associated with poor social recovery, suggesting targeted interventions for service users with elevated baseline negative symptoms may help improve functional outcomes. (C) 2016 Elsevier B.V. All rights reserved.

AIM:To explore carers' and service users' experiences of UK Early Intervention Services following referral for first-episode psychosis. METHODS:Thirty-two semi-structured interviews (16 interviews with service users and 16 corresponding interviews with their carers) were completed and analysed. RESULTS:Carers spoke retrospectively and prospectively by framing their accounts into the periods before and since their engagement with Early Intervention Services. Desperation was evident as emotive experiences were recalled prior to referral. Relief then emerged as carers described support and engagement with key workers. Hope and optimism for the service user's prognosis and life trajectory were also expressed.Service users described similar positive experiences of Early Intervention Services and the support and insight they had gained through their relationships with key workers. They were however less focused on accounts of desperation and relief and more immersed in their current understanding and attempts to normalize their experiences of first-episode psychosis. Prognosis and future trajectories were only discussed tentatively. CONCLUSION:Communication and 'partnerships' with service users and carers are essential for effective service engagement, delivery of care and the reduction in relapse following first-episode psychosis. This study highlights how key workers from Early Intervention Services are appropriately valued and situated to develop such relationships. Findings also reveal that service users' and carers' focus and expectations of recovery vary during the early stages of engagement with services. How key workers manage awareness and communication around such differing expectations is a crucial consideration for maintaining the 'partnerships' necessary for effective service provision.

OBJECTIVE:The use of cannabis during the early stage of psychosis has been linked with increased psychotic symptoms. This study aimed to examine the use of cannabis in the 12 months following a first-episode of psychosis (FEP) and the link with symptomatic course and outcome over 1 year post psychosis onset.DESIGN AND SETTING:One thousand twenty-seven FEP patients were recruited upon inception to specialized early intervention services (EIS) for psychosis in the United Kingdom. Participants completed assessments at baseline, 6 and 12 months.RESULTS:The results indicate that the use of cannabis was significantly associated with increased severity of psychotic symptoms, mania, depression and poorer psychosocial functioning. Continued use of cannabis following the FEP was associated with poorer outcome at 1 year for Positive and Negative Syndrome Scale total score, negative psychotic symptoms, depression and psychosocial functioning, an effect not explained by age, gender, duration of untreated psychosis, age of psychosis onset, ethnicity or other substance use.CONCLUSION:This is the largest cohort study of FEP patients receiving care within EIS. Cannabis use, particularly "continued use," was associated with poorer symptomatic and functional outcome during the FEP. The results highlight the need for effective and early intervention for cannabis use in FEP.