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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., (© 2024. The Author(s).)

Background: Clozapine is an antipsychotic drug with unique efficacy, and it is the only recommended treatment for treatment-resistant schizophrenia (TRS: failure to respond to at least two different antipsychotics). However, clozapine is also associated with a range of adverse effects which restrict its use, including blood dyscrasias, for which haematological monitoring is required. As treatment resistance is recognised earlier in the illness, the question of whether clozapine should be prescribed in children and young people is increasingly important. However, most research to date has been in older, chronic patients, and evidence regarding the efficacy and safety of clozapine in people under age 25 is lacking. The CLEAR (CLozapine in EARly psychosis) trial will assess whether clozapine is more effective than treatment as usual (TAU), at the level of clinical symptoms, patient rated outcomes, quality of life and cost-effectiveness in people below 25 years of age. Additionally, a nested biomarker study will investigate the mechanisms of action of clozapine compared to TAU., Methods and Design: This is the protocol of a multi-centre, open label, blind-rated, randomised controlled effectiveness trial of clozapine vs TAU (any other oral antipsychotic monotherapy licenced in the British National Formulary) for 12 weeks in 260 children and young people with TRS (12-24 years old)., Aim and Objectives: The primary outcome is the change in blind-rated Positive and Negative Syndrome Scale scores at 12 weeks from baseline. Secondary outcomes include blind-rated Clinical Global Impression, patient-rated outcomes, quality of life, adverse effects, and treatment adherence. Patients will be followed up for 12 months and will be invited to give consent for longer term follow-up using clinical records and potential re-contact for further research. For mechanism of action, change in brain magnetic resonance imaging (MRI) biomarkers and peripheral inflammatory markers will be measured over 12 weeks., Discussion: The CLEAR trial will contribute knowledge on clozapine effectiveness, safety and cost-effectiveness compared to standard antipsychotics in young people with TRS, and the results may guide future clinical treatment recommendation for early psychosis., Trial Registration: ISRCTN Number: 37176025, IRAS Number: 1004947., Trial Status: In set-up. Protocol version 4.0 01/08/23. Current up to date protocol available here: https://fundingawards.nihr.ac.uk/award/NIHR131175# /., (© 2024. The Author(s).)

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., (© 2023. The Author(s).)

Background: Little is known about patients with a first episode of psychosis (FEP) who had first presented to prodromal services with an "at risk mental state" (ARMS) before making the transition to psychosis. We set out to identify the proportion of patients with a FEP who had first presented to prodromal services in the ARMS state, and to compare these FEP patients with FEP patients who did not have prior contact with prodromal services., Methods: In this study information on 338 patients aged ≤37 years who presented to mental health services between 2010 and 2012 with a FEP was examined. The data on pathways to care, clinical and socio-demographic characteristics were extracted from the Biomedical Research Council Case Register for the South London and Maudsley NHS Trust., Results: Over 2 years, 14 (4.1% of n = 338) young adults presented with FEP and had been seen previously by the prodromal services. These ARMS patients were more likely to enter their pathway to psychiatric care via referral from General Practice, be born in the UK and to have had an insidious mode of illness onset than FEP patients without prior contact with the prodromal services., Conclusions: In the current pathways to care configuration, prodromal services are likely to prevent only a few at-risk individuals from transitioning to psychosis even if effective preventative treatments become available.

Background: Schizophrenia is a highly heterogeneous disorder, and around a third of patients are treatment-resistant. The only evidence-based treatment for these patients is clozapine, an atypical antipsychotic with relatively weak dopamine antagonism. It is plausible that varying degrees of response to antipsychotics reflect categorically distinct illness subtypes, which would have significant implications for research and clinical practice. If these subtypes could be distinguished at illness onset, this could represent a first step towards personalised medicine in psychiatry. This systematic review investigates whether current evidence supports conceptualising treatment-resistant and treatment-responsive schizophrenoa as categorically distinct subtypes., Method: A systematic literature search was conducted, using PubMed, EMBASE, PsycInfo, CINAHL and OpenGrey databases, to identify all studies which compared treatment-resistant schizophrenia (defined as either a lack of response to two antipsychotic trials or clozapine prescription) to treatment-responsive schizophrenia (defined as known response to non-clozapine antipsychotics)., Results: Nineteen studies of moderate quality met inclusion criteria. The most robust findings indicate that treatment-resistant patients show glutamatergic abnormalities, a lack of dopaminergic abnormalities, and significant decreases in grey matter compared to treatment-responsive patients. Treatment-resistant patients were also reported to have higher familial loading; however, no individual gene-association study reported their findings surviving correction for multiple comparisons., Conclusions: Tentative evidence supports conceptualising treatment-resistant schizophrenia as a categorically different illness subtype to treatment-responsive schizophrenia. However, research is limited and confirmation will require replication and rigorously controlled studies with large sample sizes and prospective study designs.

Background: Data on the haematological outcomes of patients who continue clozapine treatment following neutropenia are very rare as even mild neutropenia results in mandatory discontinuation of clozapine in most countries. However, in Iceland where clozapine monitoring is less stringent allows an observational study to be done on the risk of agranulocytosis and neutropenia during treatment with clozapine compared with other antipsychotics among patients with schizophrenia., Methods: The present study is a part of a wider ongoing longitudinal study of schizophrenia in Iceland. We identified 201 patients with schizophrenia treated with clozapine and 410 patients with schizophrenia who had never been on clozapine by searching the electronic health records of Landspitali, the National University Hospital. Neutrophil counts were searched in electronic databases to identify patients who developed neutropenia/agranulocytosis and the frequency of neutrophil measurements was examined as well., Results: The median number of days between neutrophil measurements during the first 18 weeks of clozapine treatment was 25 days but after the first 18 weeks on the drug the median became 124 days. Thirty four cases of neutropenia were identified during clozapine treatment with an average follow up time of 9.2 years. The majority, 24 individuals developed mild neutropenia (1500-1900 neutrophils/mm 3 ). None of these progressed to agranulocytosis. The remaining 10 patients developed neutropenia in the range 500-1400 /mm 3 of whom one developed agranulocytosis, three stopped clozapine use and 6 patients continued on clozapine for at least a year without developing agranulocytosis. Unexpectedly, schizophrenia patients on other antipsychotics had an equal risk of developing neutropenia as those on clozapine., Conclusions: Neutropenia is common both in patients with schizophrenia on clozapine treatment and in those never on clozapine. Therefore a large part of neutropenia during clozapine treatment is probably not caused by clozapine. These findings have implications in assessing the balance between the risk of progression from neutropenia to agranulocytosis against the morbidity resulting from the premature discontinuation of clozapine under the current monitoring regulations in the US and in most of Europe.

Background: Antipsychotic prescription information is commonly derived from structured fields in clinical health records. However, utilising diverse and comprehensive sources of information is especially important when investigating less frequent patterns of medication prescribing such as antipsychotic polypharmacy (APP). This study describes and evaluates a novel method of extracting APP data from both structured and free-text fields in electronic health records (EHRs), and its use for research purposes., Methods: Using anonymised EHRs, we identified a cohort of patients with serious mental illness (SMI) who were treated in South London and Maudsley NHS Foundation Trust mental health care services between 1 January and 30 June 2012. Information about antipsychotic co-prescribing was extracted using a combination of natural language processing and a bespoke algorithm. The validity of the data derived through this process was assessed against a manually coded gold standard to establish precision and recall. Lastly, we estimated the prevalence and patterns of antipsychotic polypharmacy., Results: Individual instances of antipsychotic prescribing were detected with high precision (0.94 to 0.97) and moderate recall (0.57-0.77). We detected baseline APP (two or more antipsychotics prescribed in any 6-week window) with 0.92 precision and 0.74 recall and long-term APP (antipsychotic co-prescribing for 6 months) with 0.94 precision and 0.60 recall. Of the 7,201 SMI patients receiving active care during the observation period, 338 (4.7 %; 95 % CI 4.2-5.2) were identified as receiving long-term APP. Two second generation antipsychotics (64.8 %); and first -second generation antipsychotics were most commonly co-prescribed (32.5 %)., Conclusions: These results suggest that this is a potentially practical tool for identifying polypharmacy from mental health EHRs on a large scale. Furthermore, extracted data can be used to allow researchers to characterize patterns of polypharmacy over time including different drug combinations, trends in polypharmacy prescribing, predictors of polypharmacy prescribing and the impact of polypharmacy on patient outcomes.

Background: Accumulating evidence suggests that several adult mental disorders, particularly psychoses, are preceded by impairments in cognitive function, reflected in scholastic underachievement. This study investigates the association between scholastic underachievement and general mental health problems in adolescence, using delay in school progression as a marker of poor scholastic performance., Method: Cross-sectional secondary school survey comprising 10,803 adolescents. Participants completed the Strengths and Difficulties Questionnaire (SDQ) to assess mental health problems. The association of delayed school progression with the SDQ was investigated using logistic regression with SDQ as outcome and delayed school progression as primary exposure of interest while adjusting for socio-demographic characteristics, adverse life events, school-related factors, risk taking behaviour, healthy lifestyle and physical health., Results: Unadjusted analysis showed an association between delayed school progression and total mental health problems (OR 1.83, 95% CI 1.27-2.63) in adolescents. After adjusting for other risk factors (socio-demographic factors and life events) in a logistic regression model the association between delayed school progression en mental health problems was attenuated (OR 1.33, 95% CI 0.86-2.05)., Conclusion: Delayed school progression is associated with general mental health problems in adolescence, but this relationship is heavily confounded by other factors. A causal relationship between impaired cognitive function such as poor scholastic performance and general mental health at adolescence is less likely and delayed school progression may merely be considered an indicator of risk for mental health problems.