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To minimise infection during COVID-19, the clozapine haematological monitoring interval was extended from 4-weekly to 12-weekly intervals in South London and Maudsley NHS Foundation Trust.
To investigate the impact of this temporary policy change on clinical and safety outcomes.
All patients who received clozapine treatment with extended (12-weekly) monitoring in a large London National Health Service trust were included in a 1-year mirror-image study. A comparison group was selected with standard monitoring. The proportion of participants with mild to severe neutropenia and the proportion of participants attending the emergency department for clozapine-induced severe neutropenia treatment during the follow-up period were compared. Psychiatric hospital admission rates, clozapine dose and concomitant psychotropic medication in the 1 year before and the 1 year after extended monitoring were compared. All-cause clozapine discontinuation at 1-year follow-up was examined.
Of 569 participants, 459 received clozapine with extended monitoring and 110 controls continued as normal. The total person-years were 458 in the intervention group and 109 in the control group, with a median follow-up time of 1 year in both groups. During follow-up, two participants (0.4%) recorded mild to moderate neutropenia in the intervention group and one (0.9%) in the control group. There was no difference in the incidence of haematological events between the two groups (IRR = 0.48, 95% CI 0.02–28.15, P = 0.29). All neutropenia cases in the intervention group were mild, co-occurring during COVID-19 infection. The median number of admissions per patient during the pre-mirror period remained unchanged (0, IQR = 0) during the post-mirror period. There was one death in the control group, secondary to COVID-19 infection.
There was no evidence that the incidence of severe neutropenia was increased in those receiving extended monitoring.
Antipsychotic treatment resistance affects up to a third of individuals with schizophrenia. Of those affected, 70–84% are reported to be treatment resistant from the outset. This raises the possibility that the neurobiological mechanisms of treatment resistance emerge before the onset of psychosis and have a neurodevelopmental origin. Neuropsychological investigations can offer important insights into the nature, origin and pathophysiology of treatment-resistant schizophrenia (TRS), but methodological limitations in a still emergent field of research have obscured the neuropsychological discriminability of TRS. We report on the first systematic review and meta-analysis to investigate neuropsychological differences between TRS patients and treatment-responsive controls across 17 published studies (1864 participants). Five meta-analyses were performed in relation to (1) executive function, (2) general cognitive function, (3) attention, working memory and processing speed, (4) verbal memory and learning, and (5) visual−spatial memory and learning. Small-to-moderate effect sizes emerged for all domains. Similarly to previous comparisons between unselected, drug-naïve and first-episode schizophrenia samples v. healthy controls in the literature, the largest effect size was observed in verbal memory and learning [dl = −0.53; 95% confidence interval (CI) −0.29 to −0.76; z = 4.42; p < 0.001]. A sub-analysis of language-related functions, extracted from across the primary domains, yielded a comparable effect size (dl = −0.53, 95% CI −0.82 to −0.23; z = 3.45; p < 0.001). Manipulating our sampling strategy to include or exclude samples selected for clozapine response did not affect the pattern of findings. Our findings are discussed in relation to possible aetiological contributions to TRS.
Clozapine is associated with increased risk of myocarditis. However, many common side-effects of clozapine overlap with the clinical manifestations of myocarditis. As a result, there is uncertainty about which signs, symptoms and investigations are important in distinguishing myocarditis from benign adverse effects of clozapine. Clarity on this issue is important, since missing a diagnosis of myocarditis or discontinuing clozapine unnecessarily may both have devastating consequences.
To examine the clinical characteristics of clozapine-induced myocarditis and to identify which signs and symptoms distinguish true myocarditis from other clozapine adverse effects.
A retrospective analysis of the record database for 247 621 patients was performed. A natural language processing algorithm identified the instances of patients in which myocarditis was suspected. The anonymised case notes for the patients of each suspected instance were then manually examined, and those whose instances were ambiguous were referred for an independent assessment by up to three cardiologists. Patients with suspected instances were classified as having confirmed myocarditis, myocarditis ruled out or undetermined.
Of 254 instances in 228 patients with suspected myocarditis, 11.4% (n = 29 instances) were confirmed as probable myocarditis. Troponin and C-reactive protein (CRP) had excellent diagnostic value (area under the curve 0.975 and 0.896, respectively), whereas tachycardia was of little diagnostic value. All confirmed instances occurred within 42 days of clozapine initiation.
Suspicion of myocarditis can lead to unnecessary discontinuation of clozapine. The ‘critical period’ for myocarditis emergence is the first 6 weeks, and clinical signs including tachycardia are of low specificity. Elevated CRP and troponin are the best markers for the need for further evaluation.
Treatment-resistant schizophrenia (TRS) is associated with high levels of functional impairment, healthcare usage and societal costs. Cross-sectional studies may overestimate TRS rates because of selection bias.
We aimed to quantify TRS rates by using first-episode cohorts to improve resource allocation and clozapine access.
We undertook a systematic review of TRS rates among people with first-episode psychosis and schizophrenia, with a minimum follow-up of 8 weeks. We searched PubMed, PsycINFO, EMBASE, CINAHL and the Cochrane Database of Systematic Reviews, and meta-analysed TRS rates from included studies.
Twelve studies were included, totalling 11 958 participants; six studies were of high quality. The rate of TRS was 22.8% (95% CI 19.1–27.0%, P < 0.001) among all first-episode cohorts and 24.4% (95% CI 19.5–30.0%, P < 0.001) among first-episode schizophrenia cohorts. Subgroup sensitivity analyses by location of recruitment, TRS definition, study quality, time of data collection and retrospective versus prospective data collection did not lead to statistically significant differences in heterogeneity. In a meta-regression, duration of follow-up and percentage drop-out did not significantly affect the overall TRS rate. Men were 1.57 times more likely to develop TRS than women (95% CI 1.11–2.21, P = 0.010).
Almost a quarter of people with first-episode psychosis or schizophrenia will develop TRS in the early stages of treatment. When including people with schizophrenia who relapse despite initial response and continuous treatment, rates of TRS may be as high as a third. These high rates of TRS highlight the need for improved access to clozapine and psychosocial supports.
Clozapine is the only licensed pharmacotherapy for treatment-resistant schizophrenia. However, response to clozapine is variable. Understanding the demographic and clinical features associated with response to clozapine may be useful for patient stratification for clinical trials or for identifying patients for earlier initiation of clozapine. We systematically reviewed the literature to investigate clinical and demographic factors associated with variation in clozapine response in treatment-resistant patients with schizophrenia spectrum disorders. Subsequently, we performed a random-effects meta-analysis to evaluate differences in duration of illness, age at clozapine initiation, age of illness onset, body weight and years of education between clozapine responders and non-responders. Thirty-one articles were eligible for qualitative review and 17 of these were quantitatively reviewed. Shorter duration of illness, later illness onset, younger age at clozapine initiation, fewer hospitalisations and fewer antipsychotic trials prior to clozapine initiation showed a trend to be significantly associated with a better response to clozapine. Meta-analysis of seven studies, totalling 313 subjects, found that clozapine responders had a significantly shorter duration of illness compared to clozapine non-responders [g = 0.31; 95% confidence interval (CI) 0.06–0.56; p = 0.01]. The results imply that a delay in clozapine treatment may result in a poorer response and that a focus on prompt treatment with clozapine is warranted.
Sleep disruption is a common precursor to deterioration and relapse in people living with psychotic disorders. Understanding the temporal relationship between sleep and psychopathology is important for identifying and developing interventions which target key variables that contribute to relapse.
We used a purpose-built digital platform to sample self-reported sleep and psychopathology variables over 1 year, in 36 individuals with schizophrenia. Once-daily measures of sleep duration and sleep quality, and fluctuations in psychopathology (positive and negative affect, cognition and psychotic symptoms) were captured. We examined the temporal relationship between these variables using the Differential Time-Varying Effect (DTVEM) hybrid exploratory-confirmatory model.
Poorer sleep quality and shorter sleep duration maximally predicted deterioration in psychosis symptoms over the subsequent 1–8 and 1–12 days, respectively. These relationships were also mediated by negative affect and cognitive symptoms. Psychopathology variables also predicted sleep quality, but not sleep duration, and the effect sizes were smaller and of shorter lag duration.
Reduced sleep duration and poorer sleep quality anticipate the exacerbation of psychotic symptoms by approximately 1–2 weeks, and negative affect and cognitive symptoms mediate this relationship. We also observed a reciprocal relationship that was of shorter duration and smaller magnitude. Sleep disturbance may play a causal role in symptom exacerbation and relapse, and represents an important and tractable target for intervention. It warrants greater attention as an early warning sign of deterioration, and low-burden, user-friendly digital tools may play a role in its early detection.
Discrepancies between the National Institute for Health and Care Excellence (NICE) schizophrenia guideline recommendations and current clinical practice in the UK have been reported.
We aim to assess whether it is cost-effective to improve adherence to the NICE schizophrenia guideline recommendations, compared with current practice.
A previously developed whole-disease model for schizophrenia, using the discrete event simulation method, was adapted to assess the cost and health impacts of adherence to the NICE recommendations. Three scenarios to improve adherence to the clinical guidelines were modelled: universal provision of cognitive–behavioural therapy for patients at clinical high risk of psychosis, universal provision of family intervention for patients with first-episode psychosis and prompt provision of clozapine for patients with treatment-resistant schizophrenia. The primary outcomes were lifetime costs and quality-adjusted life-years gained.
The results suggest full adherence to the guideline recommendations would decrease cost and improve quality-adjusted life-years. Based on the NICE willingness-to-pay threshold of £20 000–£30 000 per quality-adjusted life-year gained, prompt provision of clozapine for patients with treatment-resistant schizophrenia results in the greatest net monetary benefit, followed by universal provision of cognitive–behavioural therapy for patients at clinical high risk of psychosis, and universal provision of family intervention for patients with first-episode psychosis.
Our results suggest that adherence to guideline recommendations would decrease cost and improve quality-adjusted life-years. Greater investment is needed to improve guideline adherence and therefore improve patient quality of life and realise potential cost savings.
We sought to assess the effectiveness of clozapine augmentation with Electroconvulsive therapy (ECT) (C+ECT) in patients with clozapine-resistant schizophrenia.
We conducted a retrospective review of electronic health records to identify patients treated with C+ECT. We determined the response to C+ECT and the rate of rehospitalisation over the year following treatment with C+ECT.
Forty-two patients were treated with C+ECT over a 10-year period. The mean age of the patients at initiation of ECT was 46.3 (SD = 8.2) years (range 27–62 years). The mean number of ECTs given was 10.6 (SD = 5.3) (range 3–25) with the majority receiving twice weekly ECT. Seventy-six per cent of patients (n = 32) showed a Clinical Global Impression-Improvement (CGI-I) score of ≤3 (at least minimally improved) following C+ECT. The mean number of ECT treatments was 10.6 (SD = 5.3) (range 3–25) with the majority receiving twice weekly ECT. Sixty-four per cent of patients experienced no adverse events. Response to C+ECT was not associated with gender, age, duration of illness or duration of clozapine treatment. Seventy-five per cent of responders remained out of hospital over the course of 1-year follow-up, while 70% of those with no response to C+ECT were not admitted to hospital. Three patients received maintenance ECT, one of whom was rehospitalised.
This study lends support to emerging evidence for the effectiveness of C+ECT in clozapine-resistant schizophrenia. These results are consistent with the results of a meta-analysis and the only randomised controlled trial (RCT) of this intervention. Further RCTs are required before this treatment can be confidently recommended.
Clozapine, an antipsychotic with unique efficacy in treatment-resistant psychosis, is associated with increased susceptibility to infection, including pneumonia.
To investigate associations between clozapine treatment and increased risk of COVID-19 infection in patients with schizophrenia-spectrum disorders who are receiving antipsychotic medications in a geographically defined population in London, UK.
Using information from South London and Maudsley NHS Foundation Trust (SLAM) clinical records, via the Clinical Record Interactive Search system, we identified 6309 individuals who had an ICD-10 diagnosis of schizophrenia-spectrum disorders and were taking antipsychotics at the time of the COVID-19 pandemic onset in the UK. People who were on clozapine treatment were compared with those on any other antipsychotic treatment for risk of contracting COVID-19 between 1 March and 18 May 2020. We tested associations between clozapine treatment and COVID-19 infection, adjusting for gender, age, ethnicity, body mass index (BMI), smoking status and SLAM service use.
Of 6309 participants, 102 tested positive for COVID-19. Individuals who were on clozapine had increased risk of COVID-19 infection compared with those who were on other antipsychotic medication (unadjusted hazard ratio HR = 2.62, 95% CI 1.73–3.96), which was attenuated after adjusting for potential confounders, including clinical contact (adjusted HR = 1.76, 95% CI 1.14–2.72).
These findings provide support for the hypothesis that clozapine treatment is associated with an increased risk of COVID-19 infection. Further research will be needed in other samples to confirm this association. Potential clinical implications are discussed.
Cognitive impairments in childhood are associated with increased risk of schizophrenia in later life, but the extent to which poor academic achievement is associated with the disorder is unclear.
Major databases were searched for articles published in English up to 31 December 2019. We conducted random-effects meta-analyses to: (1) compare general academic and mathematics achievement in youth who later developed schizophrenia and those who did not; (2) to examine the association between education level achieved and adult-onset schizophrenia; and, (3) compare general academic achievement in youth at-risk for schizophrenia and typically developing peers. Meta-regression models examined the effects of type of academic assessment, educational system, age at assessment, measurement of educational level attained, school leaving age, and study quality on academic achievement and education level among individuals with schizophrenia.
Meta-analyses, comprising data of over four million individuals, found that: (1) by age 16 years, those who later developed schizophrenia had poorer general academic (Cohen's d = −0.29, p ⩽ 0.0001) and mathematics achievement (d = −0.23, p = 0.01) than those who did not; (2) individuals with schizophrenia were less likely to enter higher education (odds ratio = 0.49, p ⩽ 0.0001); and, (3) youth reporting psychotic-like experiences and youth with a family history of schizophrenia had lower general academic achievement (d = −0.54, p ⩽ 0.0001; d = −0.39, p ⩽ 0.0001, respectively). Meta-regression analyses determined no effect modifiers.
Despite significant heterogeneity across studies, various routinely collected indices of academic achievement can identify premorbid cognitive dysfunction among individuals who are vulnerable for schizophrenia, potentially aiding the early identification of risk in the population.
How neighbourhood characteristics affect the physical safety of people with mental illness is unclear.
To examine neighbourhood effects on physical victimisation towards people using mental health services.
We developed and evaluated a machine-learning-derived free-text-based natural language processing (NLP) algorithm to ascertain clinical text referring to physical victimisation. This was applied to records on all patients attending National Health Service mental health services in Southeast London. Sociodemographic and clinical data, and diagnostic information on use of acute hospital care (from Hospital Episode Statistics, linked to Clinical Record Interactive Search), were collected in this group, defined as ‘cases’ and concurrently sampled controls. Multilevel logistic regression models estimated associations (odds ratios, ORs) between neighbourhood-level fragmentation, crime, income deprivation, and population density and physical victimisation.
Based on a human-rated gold standard, the NLP algorithm had a positive predictive value of 0.92 and sensitivity of 0.98 for (clinically recorded) physical victimisation. A 1 s.d. increase in neighbourhood crime was accompanied by a 7% increase in odds of physical victimisation in women and an 13% increase in men (adjusted OR (aOR) for women: 1.07, 95% CI 1.01–1.14, aOR for men: 1.13, 95% CI 1.06–1.21, P for gender interaction, 0.218). Although small, adjusted associations for neighbourhood fragmentation appeared greater in magnitude for women (aOR = 1.05, 95% CI 1.01–1.11) than men, where this association was not statistically significant (aOR = 1.00, 95% CI 0.95–1.04, P for gender interaction, 0.096). Neighbourhood income deprivation was associated with victimisation in men and women with similar magnitudes of association.
Neighbourhood factors influencing safety, as well as individual characteristics including gender, may be relevant to understanding pathways to physical victimisation towards people with mental illness.
Co-occurrence of common mental disorders (CMD) with psychotic experiences is well-known. There is little research on the public mental health relevance of concurrent psychotic experiences for service use, suicidality, and poor physical health. We aim to: (1) describe the distribution of psychotic experiences co-occurring with a range of non-psychotic psychiatric disorders [CMD, depressive episode, anxiety disorder, probable post-traumatic stress disorder (PTSD), and personality dysfunction], and (2) examine associations of concurrent psychotic experiences with secondary mental healthcare use, psychological treatment use for CMD, lifetime suicide attempts, and poor self-rated health.
We linked a prospective cross-sectional community health survey with a mental healthcare provider database. For each non-psychotic psychiatric disorder, patients with concurrent psychotic experiences were compared to those without psychotic experiences on use of secondary mental healthcare, psychological treatment for CMD, suicide attempt, physical functioning, and a composite multimorbidity score, using logistic regression and Cox regressions.
In all disorders except for anxiety disorder, concurrent psychotic experiences were accompanied by a greater odds of all outcomes (odds ratios) for a unit change in composite multimorbidity score ranged between 2.21 [95% confidence interval (CI) 1.49–3.27] and 3.46 (95% CI 1.52–7.85). Hazard ratios for secondary mental health service use for non-psychotic disorders with concurrent psychotic experiences, ranged from 0.53 (95% CI 0.15–1.86) for anxiety disorders with psychotic experiences to 4.99 (95% CI 1.22–20.44) among those with PTSD with psychotic experiences.
Co-occurring psychotic experiences indicate greater public mental health burden, suggesting psychotic experiences could be a marker for future preventive strategies improving public mental health.
Neuropsychological investigations can help untangle the aetiological and phenomenological heterogeneity of schizophrenia but have scarcely been employed in the context of treatment-resistant (TR) schizophrenia. No population-based study has examined neuropsychological function in the first-episode of TR psychosis.
We report baseline neuropsychological findings from a longitudinal, population-based study of first-episode psychosis, which followed up cases from index admission to 10 years. At the 10-year follow up patients were classified as treatment responsive or TR after reconstructing their entire case histories. Of 145 cases with neuropsychological data at baseline, 113 were classified as treatment responsive, and 32 as TR at the 10-year follow-up.
Compared with 257 community controls, both case groups showed baseline deficits in three composite neuropsychological scores, derived from principal component analysis: verbal intelligence and fluency, visuospatial ability and executive function, and verbal memory and learning (p values⩽0.001). Compared with treatment responders, TR cases showed deficits in verbal intelligence and fluency, both in the extended psychosis sample (t = −2.32; p = 0.022) and in the schizophrenia diagnostic subgroup (t = −2.49; p = 0.017). Similar relative deficits in the TR cases emerged in sub-/sensitivity analyses excluding patients with delayed-onset treatment resistance (p values<0.01–0.001) and those born outside the UK (p values<0.05).
Verbal intelligence and fluency are impaired in patients with TR psychosis compared with those who respond to treatment. This differential is already detectable – at a group level – at the first illness episode, supporting the conceptualisation of TR psychosis as a severe, pathogenically distinct variant, embedded in aberrant neurodevelopmental processes.
Although psychotic experiences in people without diagnosed mental health problems are associated with mental health service use, few studies have assessed this prospectively or measured service use by real-world clinical data.
To describe and investigate the association between psychotic experiences and later mental health service use, and to assess the role of symptoms of common mental health disorders in this association.
We linked a representative survey of south-east London (SELCoH-1, n=1698) with health records from the local mental healthcare provider. Cox regression estimated the association of PEs with rate of mental health service use.
After adjustments, psychotic experiences were associated with a 1.75-fold increase in the rate of subsequent mental health service use (hazard ratio (HR) 1.75, 95% CI 1.03–2.97) compared with those without PEs. Participants with PEs experienced longer care episodes compared with those without.
Psychotic experiences in the general population are important predictors of public mental health need, aside from their relevance for psychoses. We found psychotic experiences to be associated with later mental health service use, after accounting for sociodemographic confounders and concurrent psychopathology.
The traditional approach to selecting antipsychotic medication involves little more than trial and error. Recent advances in genetics and molecular science offer the hope of a ‘personalised medicine’ approach to antipsychotic development and prescribing in schizophrenia. Personalised medicine is the practice of tailoring medical treatment to the individual characteristics of each patient. In schizophrenia, this will involve the identification of more homogeneous subsets of patients through the application of genetics, epigenetics, proteomics and metabolomics, neuroimaging and other biomarkers, and the use of these findings to stratify patients according to their response to treatment. In this article, we focus on the emerging evidence in pharmacogenetics and biomarkers for assessing individual response and tolerability of antipsychotic medication in schizophrenia.
N-methyl-d-aspartate receptor (NMDA-R) autoantibodies have
been reported in people with acute psychosis. We hypothesised that their
presence may be implicated in the aetiology of treatment-refractory
psychosis. We sought to ascertain the point prevalence of NMDA-R antibody
positivity in patients referred to services for treatment-refractory
psychosis. We found that 3 (7.0%) of 43 individuals had low positive NMDA-R
antibody titres. This suggests that NMDA-R autoantibodies are unlikely to
account for a large proportion of treatment-refractory psychosis.
The question of whether or not mental disorder is the price humanity pays for exceptional creativity has been debated since classical times. Modern research methodologies have been adding increasingly robust empirical data to inform this debate. Studies of accomplished individuals have found that exceptionally creative writers report more affective illness. Population-based studies have found an excess of extremely high scholastic achievement amongst people with bipolar affective disorder, but not schizophrenia. These findings have been interpreted as evidence that people with affective disorders are a likely source of society's most exceptional ideas and work. Widespread stigmatization of mental health problems would be profoundly challenged by evidence that social progress relies on individuals with mental illness. However, such a romantic ideal often tempts researchers to over-interpret findings in this area. Research in this area faces many methodological difficulties, and despite decades of research, there is little that can be confidently claimed regarding putative mechanisms that could explain how mental disorder translates into creative processes, or vice versa. This chapter does not claim to put these ancient debates to rest, but it does provide an account of the current research that has explored these seemingly paradoxical associations between psychiatric disorders and creativity.
Society throughout the ages has been drawn towards the archetype of the mad genius. Major figures from history have exemplified putative associations between exceptional creativity and mental disorder (Andreasen,1987; Jamison, 1989, 1993; Jamison and Goodwin, 2007; MacCabe, 2010; MacCabe et al. 2009).
Anecdotal and biographical reports suggest that bipolar disorder may be
associated with high IQ or creativity, but evidence for any such
connection is weak.
To investigate possible associations between scholastic achievement and
later bipolar disorder, using prospective data, in a whole-population
Using individual school grades from all individuals finishing compulsory
schooling in Sweden between 1988 and 1997, we tested associations between
scholastic achievement at age 15–16 and hospital admission for psychosis
between ages 17 and 31, adjusting for potential confounders.
Individuals with excellent school performance had a nearly fourfold
increased risk of later bipolar disorder compared with those with average
grades (hazard ratio HR = 3.79, 95% CI 2.11–6.82). This association
appeared to be confined to males. Students with the poorest grades were
also at moderately increased risk of bipolar disorder (HR = 1.86, 95% CI
These findings provide support for the hypothesis that exceptional
intellectual ability is associated with bipolar disorder.