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Abstract Background Clozapine is the only recommended antipsychotic medication for individuals diagnosed with treatment-resistant schizophrenia. Unfortunately, its wider use is hindered by several possible adverse effects, some of which are rare but potentially life threatening. As such, there is a growing interest in studying clozapine use and safety in routinely collected healthcare data. However, previous attempts to characterise clozapine treatment have had low accuracy. Aim To develop a methodology for identifying clozapine treatment dates by combining several data sources and implement this on a large clinical database. Methods Non-identifiable electronic health records from a large mental health provider in London and a linked database from a national clozapine blood monitoring service were used to obtain information regarding patients' clozapine treatment status, blood tests and pharmacy dispensing records. A rule-based algorithm was developed to determine the dates of starting and stopping treatment based on these data, and more than 10% of the outcomes were validated by manual review of de-identified case note text. Results A total of 3,212 possible clozapine treatment periods were identified, of which 425 (13.2%) were excluded due to insufficient data to verify clozapine administration. Of the 2,787 treatments remaining, 1,902 (68.2%) had an identified start-date. On evaluation, the algorithm identified treatments with 96.4% accuracy; start dates were 96.2% accurate within 15 days, and end dates were 85.1% accurate within 30 days. Conclusions The algorithm produced a reliable database of clozapine treatment periods. Beyond underpinning future observational clozapine studies, we envisage it will facilitate similar implementations on additional large clinical databases worldwide.

Abstract Background Clozapine is the treatment of choice in refractory psychosis. In most countries, clozapine must be stopped indefinitely if white blood cells fall below a defined threshold during routine monitoring. Despite evidence of severe adverse consequences of clozapine discontinuation, published accounts on the lived experiences and perspectives of patients and carers are scarce. Method We completed semi-structured interviews with patients (n = 4) and family carers (n = 4) on experiences of clozapine cessation following suspected drug-induced neutropenia. Interviews were audio-recorded, transcribed and analysed thematically. Results The two overarching themes comprised:(i) stress of clozapine below threshold neutrophil results and (ii) patient and carer priorities. Conclusions There is a suggested need for evidence-based pharmacological and psychological approaches to support patients and carers after clozapine cessation. Such approaches will minimise the potentially negative physical and emotional sequela in the aftermath of a below threshold neutrophil result and reduce the likelihood of experiencing additional health and social inequalities after clozapine discontinuation.

Abstract Objective The objective of the study is to explore the long-term effectiveness and tolerability of metoclopramide in the treatment of CIH. Method This study is a retrospective, observational cohort study of patients prescribed metoclopramide for CIH at the South London & Maudsley (SLaM) NHS Foundation Trust. Results Of the 96 patients identified, 14 patients were eligible for inclusion in our study. Five patients continued treatment with a mean duration of 27 months (SD = 17.8), and one patient continued until transfer with a duration of 3 months. Eight patients discontinued treatment after a mean duration of 8 months. Conclusion Metoclopramide may be an effective and tolerated drug in CIH, but more data is required to establish its place in the pharmacotherapy of this condition.

Background: Clozapine is the only medication licenced for patients with psychosis that is resistant to conventional antipsychotic treatment. However, despite its effectiveness, it remains widely underutilised. One contributory factor for this may be clinicians’ lack of confidence around the management of clozapine. Objective: We conducted a survey of clinicians working in Early Intervention in Psychosis (EIP) services to determine their training needs for clozapine management in EIP services. Methods: An electronic survey was made available to all clinicians working in EIP services in England. The survey assessed confidence and training needs regarding managing clozapine in patients with treatment-resistant psychosis. Quantitative data were analysed using total mean scores and the Mann–Whitney U test. Results: In all, 192 (27%) of approximately 700 clinicians from 35 EIP services completed the survey. Approximately half (54%) had not received training on treatment with clozapine. Experience of training was higher in prescribers than non-prescribers, and among medical than non-medical clinicians. Previous training was associated with significantly higher confidence in offering clozapine and managing treatment-resistant psychosis ( p

Abstract Background Benign ethnic neutropenia (BEN) is the most common cause of chronic neutropenia seen in individuals of African, Middle Eastern and West Indian descent. This phenotype is broadly defined by an absolute neutrophil counts (ANC) below 1.8 × 109 cells/L in the absence of other causes, without an increased risk of infection. BEN has been implicated as a potential source of disparity in patients treated with clozapine, the antipsychotic of choice in treatment-resistant schizophrenia. Our main objective was to examine the current level of BEN recognition in a cohort of patients treated with clozapine and the potential impact of unidentified BEN on the initiation and maintenance of clozapine treatment. Methods This was an observational, retrospective analysis of patients registered with clozapine haematological monitoring systems in two large mental health trusts, chosen because they serve an ethnically diverse population. The first objective was to establish certified BEN prevalence in current users of clozapine. The second objective was to explore the stage of treatment at which BEN was identified. The third objective was to evaluate the extent of unrecognised BEN in patients registered on the Central Non-Rechallenge Database (CNRD), a database for patients whose haematological parameters fall below set thresholds when receiving clozapine treatment, meaning they cannot ordinarily be prescribed clozapine again. Results The study population comprised of 2020 patients on the clozapine register. 111 patients were monitored under BEN criteria. BEN was mostly identified after a below threshold haematological result or clozapine rechallenge (68%) compared to at clozapine initiation (32%). Eight of the 18 (42%) black patients registered on the CNRD were classified as BEN after assessment by a haematologist. Of these 8 patients, none would have met CNRD criteria again if monitored with BEN criteria at clozapine initiation. Conclusions Current evidence suggests that BEN remains an uncommonly recognised haematological phenotype. Improved timely identification of BEN will reduce unnecessary interruption or discontinuation of clozapine treatment. Our results suggest consideration should also be given to determining BEN status prior to initiating clozapine. Moreover, adoption of current FDA BEN monitoring criteria in the UK may further reduce clozapine discontinuation due to perceived neutropenia as drug toxicity, particularly in treatment-refractory schizophrenia patients.

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

Background: The evidence for safe and effective interventions to treat the negative and cognitive symptoms of schizophrenia is lacking. Objectives: Vortioxetine is a novel antidepressant that has been used as adjunctive therapy for the treatment of psychosis; however, its effectiveness in clinical practice is relatively unknown. In this study, we aimed to determine the potential clinical effectiveness and safety and tolerability of vortioxetine in psychosis. Design: This is a non-interventional, retrospective study on the add-on use of vortioxetine in a group of people with schizophrenia-spectrum disorders in a large UK NHS mental health trust. Methods: Clinical effectiveness of vortioxetine was retrospectively assessed through the Clinical Global Impression – Severity (CGI-S) scale at 3 months. Safety and tolerability were evaluated through treatment discontinuation rates at 3, 6, and 12 months, and clinical reasons were evaluated at the primary endpoint of 3 months. Results: Data were available for 40 subjects with a diagnosis of schizophrenia or schizoaffective disorder–prescribed vortioxetine treatment; 30 (75%) remained on treatment at 3 months. At CGI-S assessment, 15 of the 35 evaluated subjects reported at least a 1-point improvement, from 5 at baseline to 4 after 3 months of treatment. Twenty-six (65%) remained on treatment at 1-year follow-up. The main reasons for those discontinuing treatment were inadequate response (10%) and manic switch (7.5%), while one subject refused treatment. Tolerability to treatment was good, and 36 subjects (90%) reported no adverse events specific to vortioxetine treatment. Conclusion: Schizophrenia is a complex illness, and there is insufficient treatment response in many individuals. A significant proportion of whom may require adjunctive treatments depending on the nature of the residual symptoms. Vortioxetine could be a potentially safe and effective option in such people, but further controlled studies are required.

Only about 50% of patients with treatment-resistant schizophrenia respond to clozapine, and many more patients continue to experience ongoing and prominent negative symptoms. These negative symptoms, for which there are limited pharmacological options, may represent the greatest barrier to functional recovery. Cariprazine is a novel antipsychotic drug that is a partial agonist at dopamine D 2 and D 3 receptors with preferential binding to the D 3 receptor, antagonism of 5HT 2B receptors, and partial agonism at 5HT 1A receptors. Cariprazine is currently licenced for the treatment of schizophrenia in Europe and the United States and has also been approved for bipolar disorder in the United States. There is a limited body of evidence to suggest clinical effectiveness as an augmentation strategy for negative symptoms in those treated with clozapine. In this case series, we present five cases of successful treatment of negative symptoms by clozapine combined with cariprazine in treatment-resistant psychosis.

Clozapine is an atypical antipsychotic used in treatment-resistant schizophrenia. Whilst clozapine is highly effective, there are some clinical scenarios, such as the emergence of severe side effects, that necessitate its discontinuation. There is an emerging literature suggesting that discontinuing antipsychotics, in particular clozapine, can cause an array of withdrawal symptoms. We review the evidence for the existence of clozapine-induced withdrawal symptoms, and in particular focus on withdrawal-associated psychosis, cholinergic rebound, catatonia and serotonergic discontinuation symptoms. To date, there has been surprisingly little clinical guidance on how to minimise the likeliness of withdrawal symptoms in patients who are stopped on clozapine abruptly or gradually. We discuss the key outstanding questions in this area and why there is a need for guidance on the management of withdrawal symptoms associated with clozapine discontinuation.

BackgroundTreatment-resistant schizophrenia is a major disabling illness which often proves challenging to manage in a secondary care setting. The National Psychosis Unit (NPU) is a specialised tertiary in-patient facility that provides evidence-based, personalised, multidisciplinary interventions for complex treatment-resistant psychosis, in order to reduce the risk of readmission and long-term care costs.AimsThis study aimed to assess the long-term effectiveness of treatment at the NPU by considering naturalistic outcome measures.MethodUsing a mirror image design, we compared the numbers of psychiatric and general hospital admissions, in-patient days, acuity of placement, number of psychotropic medications and dose of antipsychotic medication prescribed before and following NPU admission. Data were obtained from the Clinical Records Interactive Search system, an anonymised database sourced from the South London and Maudsley NHS Trust electronic records, and by means of anonymous linkage to the Hospital Episode Statistics system.ResultsCompared with the 2 years before NPU admission, patients had fewer mental health admissions (1.65 ± 1.44 v. 0.87 ± 0.99, z = 5.594, P < 0.0001) and less mental health bed usage (335.31 ± 272.67 v. 199.42 ± 261.96, z = 5.195 P < 0.0001) after NPU admission. Total in-patient days in physical health hospitals and total number of in-patient days were also significantly reduced (16.51 ± 85.77 v. 2.83 ± 17.38, z = 2.046, P = 0.0408; 351.82 ± 269.09 v. 202.25 ± 261.05, z = 5.621, P < 0.0001). The reduction in level of support required after treatment at the NPU was statistically significant (z = −8.099, P < 0.0001).ConclusionsThis study demonstrates the long-term effectiveness of a tertiary service specialising in treatment-resistant psychosis.

Clozapine remains the gold standard intervention for treatment-resistant schizophrenia; however, it remains underused, especially for some minority groups. A significant impediment is concern about propensity to neutropenia. The aim of this article is to provide an update on current knowledge relating to: the pattern and incidence of severe blood dyscrasias; the effectiveness of current monitoring regimes in reducing harm; the mechanisms of and the distinctions between clozapine-induced neutropenia and agranulocytosis; benign ethnic neutropenia; and changes to the monitoring thresholds in the USA and other international variations. These all have implications for the practical use of clozapine; specifically, how barriers to initiating, maintaining and restarting clozapine can be understood and in many cases overcome, especially for patients from minority groups, potentially with simpler approaches than the use of lithium or G-CSF.