Quality of melatonin use in children and adolescents: findings from a UK clinical audit.

BACKGROUND: Melatonin is commonly used to treat sleep disturbance in children and adolescents, although uncertainties about its optimal use remain. OBJECTIVE: To determine to what extent prescribing of melatonin complies with evidence-based clinical practice standards. METHODS: As part of a quality improvement programme, the Prescribing Observatory for Mental Health conducted a retrospective clinical audit in UK services for children and adolescents. FINDINGS: Data were submitted for 4151 children and adolescents up to 18 years of age, treated with melatonin: 3053 (74%) had a diagnosis of neurodevelopmental disorder. In 2655 (73%) of the 3651 patients prescribed melatonin to be taken regularly, the main reason was to reduce sleep latency (time taken to fall asleep). In 409 patients recently starting melatonin, a non-pharmacological intervention had already been tried in 279 (68%). The therapeutic response of patients early in treatment (n=899) and on long-term treatment (n=2353) had been assessed and quantified in 36% and 31%, respectively, while for review of side effects, the respective proportions were 46% and 43%. Planned treatment breaks were documented in 317 (13%) of those on long-term treatment. CONCLUSIONS: Melatonin was predominantly prescribed for evidence-based clinical indications, but the clinical review and monitoring of this treatment fell short of best practice. CLINICAL IMPLICATIONS: With limited methodical review of melatonin use in their patients, clinicians will fail to garner reliable information on its risks and benefits for individual patients. The lack of such practice-based evidence may increase the risk of melatonin being inappropriately targeted or continued despite being ineffective or no longer indicated.

Efficacy and tolerability of antipsychotic polypharmacy for schizophrenia spectrum disorders. A systematic review and meta-analysis of individual patient data.

BACKGROUND: Antipsychotic polypharmacy (APP) is frequently prescribed for schizophrenia-spectrum disorders. Despite the inconsistent findings on efficacy, APP may be beneficial for subgroups of psychotic patients. This meta-analysis of individual patient data investigated moderators of efficacy and tolerability of APP in adult patients with schizophrenia-spectrum disorders. DESIGN: We searched PubMed, EMBASE, and the Cochrane Central Register of Randomized Trials until September 1, 2022, for randomized controlled trials comparing APP with antipsychotic monotherapy. We estimated the effects with a one-stage approach for patient-level moderators and a two-stage approach for study-level moderators, using (generalized) linear mixed-effects models. Primary outcome was treatment response, defined as a reduction of 25 % or more in the Positive and Negative Syndrome Scale (PANSS) score. Secondary outcomes were study discontinuation, and changes from baseline on the PANSS total score, its positive and negative symptom subscale scores, the Clinical Global Impressions Scale (CGI), and adverse effects. RESULTS: We obtained individual patient data from 10 studies (602 patients; 31 % of all possible patients) and included 599 patients in our analysis. A higher baseline PANSS total score increased the chance of a response to APP (OR = 1.41, 95 % CI 1.02; 1.94, p = 0.037 per 10-point increase in baseline PANSS total), mainly driven by baseline positive symptoms. The same applied to changes on the PANSS positive symptom subscale and the CGI severity scale. Extrapyramidal side effects increased significantly where first and second-generation antipsychotics were co-prescribed. Study discontinuation was comparable between both treatment arms. CONCLUSIONS: APP was effective in severely psychotic patients with high baseline PANSS total scores and predominantly positive symptoms. This effect must be weighed against potential adverse effects.

Antipsychotic dose reduction and discontinuation versus maintenance treatment in people with schizophrenia and other recurrent psychotic disorders in England (the RADAR trial): an open, parallel-group, randomised controlled trial.

BACKGROUND: Maintenance antipsychotic medication is recommended for people with schizophrenia or recurrent psychosis, but the adverse effects are burdensome, and evidence on long-term outcomes is sparse. We aimed to assess the benefits and harms of a gradual process of antipsychotic reduction compared with maintenance treatment. Our hypothesis was that antipsychotic reduction would improve social functioning with a short-term increase in relapse. METHODS: RADAR was an open, parallel-group, randomised trial done in 19 National Health Service Trusts in England. Participants were aged 18 years and older, had a diagnosis of recurrent, non-affective psychotic disorder, and were prescribed an antipsychotic. Exclusion criteria included people who had a mental health crisis or hospital admission in the past month, were considered to pose a serious risk to themselves or others by a treating clinician, or were mandated to take antipsychotic medication under the Mental Health Act. Through an independent, internet-based system, participants were randomly assigned (1:1) to gradual, flexible antipsychotic reduction, overseen by treating clinicians, or to maintenance. Participants and clinicians were aware of treatment allocations, but assessors were masked to them. Follow-up was for 2 years. Social functioning, assessed by the Social Functioning Scale, was the primary outcome. The principal secondary outcome was severe relapse, defined as requiring admission to hospital. Analysis was done blind to group identity using intention-to-treat data. The trial is completed and has been registered with ISRCTN registry (ISRCTN90298520) and with ClinicalTrials.gov (NCT03559426). FINDINGS: 4157 people were screened, of whom 253 were randomly allocated, including 168 (66%) men, 82 (32%) women, and 3 (1%) transgender people, with a mean age of 46 years (SD 12, range 22-79). 171 (67%) participants were White, 52 (21%) were Black, 16 (6%) were Asian, and 12 (5%) were of other ethnicity. The median dose reduction at any point during the trial was 67% in the reduction group and zero in the maintenance group; at 24 months it was 33% versus zero. At the 24-month follow-up, we assessed 90 of 126 people assigned to the antipsychotic dose reduction group and 94 of 127 assigned to the maintenance group, finding no difference in the Social Functioning Scale (ß 0·19, 95% CI -1·94 to 2·33; p=0·86). There were 93 serious adverse events in the reduction group affecting 49 individuals, mainly comprising admission for a mental health relapse, and 64 in the maintenance group, relating to 29 individuals. INTERPRETATION: At 2-year follow-up, a gradual, supported process of antipsychotic dose reduction had no effect on social functioning. Our data can help to inform decisions about the use of long-term antipsychotic medication. FUNDING: National Institute for Health Research.

Antidepressants for the prevention of depression following first-episode psychosis (ADEPP): study protocol for a multi-centre, double-blind, randomised controlled trial.

BACKGROUND: Depressive episodes are common after first-episode psychosis (FEP), affecting more than 40% of people, adding to individual burden, poor outcomes, and healthcare costs. If the risks of developing depression were lower, this could have a beneficial effect on morbidity and mortality, as well as improving outcomes. Sertraline is a selective serotonin reuptake inhibitor and a common first-line medication for the treatment of depression in adults. It has been shown to be safe when co-prescribed with antipsychotic medication, and there is evidence that it is an effective treatment for depression in established schizophrenia. We present a protocol for a multi-centre, double-blind, randomised, placebo-controlled clinical trial called ADEPP that aims to investigate the efficacy and cost-effectiveness of sertraline in preventing depression after FEP. METHODS: The recruitment target is 452 participants between the ages of 18 and 65 years who are within 12 months of treatment initiation for FEP. Having provided informed consent, participants will be randomised to receive either 50 mg of sertraline daily or matched placebo for 6 months, in addition to treatment as usual. The primary outcome measure will be a comparison of the number of new cases of depression between the treatment and placebo arms over the 6-month intervention phase. Secondary outcomes include suicidal behaviour, anxiety, rates of relapse, functional outcome, quality of life, and resource use. DISCUSSION: The ADEPP trial will test whether the addition of sertraline following FEP is a clinically useful, acceptable, and cost-effective way of improving outcomes following FEP. TRIAL REGISTRATION: ISRCTN12682719 registration date 24/11/2020.

Network analysis of inflammation and symptoms in recent onset schizophrenia and the influence of minocycline during a clinical trial.

Attempts to delineate an immune subtype of schizophrenia have not yet led to the clear identification of potential treatment targets. An unbiased informatic approach at the level of individual immune cytokines and symptoms may reveal organisational structures underlying heterogeneity in schizophrenia, and potential for future therapies. The aim was to determine the network and relative influence of pro- and anti-inflammatory cytokines on depressive, positive, and negative symptoms. We further aimed to determine the effect of exposure to minocycline or placebo for 6 months on cytokine-symptom network connectivity and structure. Network analysis was applied to baseline and 6-month data from the large multi-center BeneMin trial of minocycline (N = 207) in schizophrenia. Pro-inflammatory cytokines IL-6, TNF-α, and IFN-γ had the greatest influence in the inflammatory network and were associated with depressive symptoms and suspiciousness at baseline. At 6 months, the placebo group network connectivity was 57% stronger than the minocycline group, due to significantly greater influence of TNF-α, early wakening, and pathological guilt. IL-6 and its downstream impact on TNF-α, and IFN-γ, could offer novel targets for treatment if offered at the relevant phenotypic profile including those with depression. Future targeted experimental studies of immune-based therapies are now needed.

Inflammatory subgroups of schizophrenia and their association with brain structure: A semi-supervised machine learning examination of heterogeneity.

OBJECTIVE: Immune system dysfunction is hypothesised to contribute to structural brain changes through aberrant synaptic pruning in schizophrenia. However, evidence is mixed and there is a lack of evidence of inflammation and its effect on grey matter volume (GMV) in patients. We hypothesised that inflammatory subgroups can be identified and that the subgroups will show distinct neuroanatomical and neurocognitive profiles. METHODS: The total sample consisted of 1067 participants (chronic patients with schizophrenia n = 467 and healthy controls (HCs) n = 600) from the Australia Schizophrenia Research Bank (ASRB) dataset, together with 218 recent-onset patients with schizophrenia from the external Benefit of Minocycline on Negative Symptoms of Psychosis: Extent and Mechanism (BeneMin) dataset. HYDRA (HeterogeneitY through DiscRiminant Analysis) was used to separate schizophrenia from HC and define disease-related subgroups based on inflammatory markers. Voxel-based morphometry and inferential statistics were used to explore GMV alterations and neurocognitive deficits in these subgroups. RESULTS: An optimal clustering solution revealed five main schizophrenia groups separable from HC: Low Inflammation, Elevated CRP, Elevated IL-6/IL-8, Elevated IFN-γ, and Elevated IL-10 with an adjusted Rand index of 0.573. When compared with the healthy controls, the IL-6/IL-8 cluster showed the most widespread, including the anterior cingulate, GMV reduction. The IFN-γ inflammation cluster showed the least GMV reduction and impairment of cognitive performance. The CRP and the Low Inflammation clusters dominated in the younger external dataset. CONCLUSIONS: Inflammation in schizophrenia may not be merely a case of low vs high, but rather there are pluripotent, heterogeneous mechanisms at play which could be reliably identified based on accessible, peripheral measures. This could inform the successful development of targeted interventions.

Management of medically assisted withdrawal from alcohol in acute adult mental health and specialist addictions in-patient services: UK clinical audit findings.

BACKGROUND: Medically assisted alcohol withdrawal (MAAW) is increasingly undertaken on acute adult psychiatric wards. AIMS: Comparison of the quality of MAAW between acute adult wards and specialist addictions units in mental health services. METHOD: Clinical audit conducted by the Prescribing Observatory for Mental Health (POMH). Information on MAAW was collected from clinical records using a bespoke data collection tool. RESULTS: Forty-five National Health Service (NHS) mental health trusts/healthcare organisations submitted data relating to the treatment of 908 patients undergoing MAAW on an acute adult ward or psychiatric intensive care unit (PICU) and 347 admitted to a specialist NHS addictions unit. MAAW had been overseen by an addiction specialist in 33 (4%) of the patients on an acute adult ward/PICU. A comprehensive alcohol history, measurement of breath alcohol, full screening for Wernicke's encephalopathy, use of parenteral thiamine, prescription of medications for relapse prevention (such as acamprosate) and referral for specialist continuing care of alcohol-related problems following discharge were all more commonly documented when care was provided on a specialist unit or when there was specialist addictions management on an acute ward. CONCLUSIONS: The findings suggest that the quality of care provided for medically assisted withdrawal from alcohol, including the use of evidence-based interventions, is better when clinicians with specialist addictions training are involved. This has implications for future quality improvement in the provision of MAAW in acute adult mental health settings.

Emergence and antibody evasion of BQ, BA.2.75 and SARS-CoV-2 recombinant sub-lineages in the face of maturing antibody breadth at the population level.

BACKGROUND: The Omicron era of the COVID-19 pandemic commenced at the beginning of 2022 and whilst it started with primarily BA.1, it was latter dominated by BA.2 and the related sub-lineage BA.5. Following resolution of the global BA.5 wave, a diverse grouping of Omicron sub-lineages emerged derived from BA.2, BA.5 and recombinants thereof. Whilst emerging from distinct lineages, all shared similar changes in the Spike glycoprotein affording them an outgrowth advantage through evasion of neutralising antibodies. METHODS: Over the course of 2022, we monitored the potency and breadth of antibody neutralization responses to many emerging variants in the Australian community at three levels: (i) we tracked over 420,000 U.S. plasma donors over time through various vaccine booster roll outs and Omicron waves using sequentially collected IgG pools; (ii) we mapped the antibody response in individuals using blood from stringently curated vaccine and convalescent cohorts. (iii) finally we determine the in vitro efficacy of clinically approved therapies Evusheld and Sotrovimab. FINDINGS: In pooled IgG samples, we observed the maturation of neutralization breadth to Omicron variants over time through continuing vaccine and infection waves. Importantly, in many cases, we observed increased antibody breadth to variants that were yet to be in circulation. Determination of viral neutralization at the cohort level supported equivalent coverage across prior and emerging variants with isolates BQ.1.1, XBB.1, BR.2.1 and XBF the most evasive. Further, these emerging variants were resistant to Evusheld, whilst increasing neutralization resistance to Sotrovimab was restricted to BQ.1.1 and XBF. We conclude at this current point in time that dominant variants can evade antibodies at levels equivalent to their most evasive lineage counterparts but sustain an entry phenotype that continues to promote an additional outgrowth advantage. In Australia, BR.2.1 and XBF share this phenotype and, in contrast to global variants, are uniquely dominant in this region in the later months of 2022. INTERPRETATION: Whilst the appearance of a diverse range of omicron lineages has led to primary or partial resistance to clinically approved monoclonal antibodies, the maturation of the antibody response across both cohorts and a large donor pools importantly observes increasing breadth in the antibody neutralisation responses over time with a trajectory that covers both current and known emerging variants. FUNDING: This work was primarily supported by Australian Medical Foundation research grants MRF2005760 (SGT, GM & WDR), Medical Research Future Fund Antiviral Development Call grant (WDR), the New South Wales Health COVID-19 Research Grants Round 2 (SGT & FB) and the NSW Vaccine Infection and Immunology Collaborative (VIIM) (ALC). Variant modeling was supported by funding from SciLifeLab's Pandemic Laboratory Preparedness program to B.M. (VC-2022-0028) and by the European Union's Horizon 2020 research and innovation programme under grant agreement no. 101003653 (CoroNAb) to B.M.

Clozapine Optimization: A Delphi Consensus Guideline From the Treatment Response and Resistance in Psychosis Working Group.

BACKGROUND AND HYPOTHESIS: There is limited evidence to guide the approaches to clozapine treatment. Accordingly, an international initiative was undertaken with the aim of developing consensus recommendations for the optimization of clozapine monotherapy. STUDY DESIGN: We conducted an online Delphi survey among members of the Treatment Response and Resistance in Psychosis (TRRIP) working group comprising experts from twenty-nine countries. The threshold criterion for a consensus recommendation was ≥ 75% agreement ("agree" and "strongly agree" responses) on a question. Agreement of ≥ 50% but < 75% in a second or third Delphi round was deemed to provide guidance. STUDY RESULTS: Forty-nine (first round), 32 (second round), and 48 (third round) of the 91 current TRRIP members participated. Expert recommendations at ≥ 75% comprised second-line treatment with clozapine in cases of persistent positive symptoms with co-occurring extrapyramidal symptoms, tardive dyskinesia, or suicidality/aggression. There was considerable disagreement on myocarditis screening parameters. The management of somatic and neuropsychiatric adverse drug reactions warrants further research for more evidence-based recommendations. Rechallenge with clozapine was recommended for eosinophilia, sinus tachycardia and fever and guidance (agreement ≥ 50%) was reached for pneumonia and thrombocytopenia. CONCLUSIONS: Given the limited evidence available, this consensus-based series of recommendations and guidance statements supports clinical decision-making to optimize clozapine monotherapy and provides guidance for future research in treatment-resistant schizophrenia.

Cognitive performance at first episode of psychosis and the relationship with future treatment resistance: Evidence from an international prospective cohort study.

BACKGROUND: Antipsychotic treatment resistance affects up to a third of individuals with schizophrenia, with recent research finding systematic biological differences between antipsychotic resistant and responsive patients. Our aim was to determine whether cognitive impairment at first episode significantly differs between future antipsychotic responders and resistant cases. METHODS: Analysis of data from seven international cohorts of first-episode psychosis (FEP) with cognitive data at baseline (N = 683) and follow-up data on antipsychotic treatment response: 605 treatment responsive and 78 treatment resistant cases. Cognitive measures were grouped into seven cognitive domains based on the pre-existing literature. We ran multiple imputation for missing data and used logistic regression to test for associations between cognitive performance at FEP and treatment resistant status at follow-up. RESULTS: On average patients who were future classified as treatment resistant reported poorer performance across most cognitive domains at baseline. Univariate logistic regressions showed that antipsychotic treatment resistance cases had significantly poorer IQ/general cognitive functioning at FEP (OR = 0.70, p = .003). These findings remained significant after adjusting for additional variables in multivariable analyses (OR = 0.76, p = .049). CONCLUSIONS: Although replication in larger studies is required, it appears that deficits in IQ/general cognitive functioning at first episode are associated with future treatment resistance. Cognitive variables may be able to provide further insight into neurodevelopmental factors associated with treatment resistance or act as early predictors of treatment resistance, which could allow prompt identification of refractory illness and timely interventions.

Photoactivation of titanium-oxo cluster [Ti6O6(OR)6(O2C t Bu)6]: mechanism, photoactivated structures, and onward reactivity with O2 to a peroxide complex.

The molecular titanium-oxo cluster [Ti6O6(OiPr)6(O2C t Bu)6] (1) can be photoactivated by UV light, resulting in a deeply coloured mixed valent (photoreduced) Ti (iii/iv) cluster, alongside alcohol and ketone (photooxidised) organic products. Mechanistic studies indicate that a two-electron (not free-radical) mechanism occurs in this process, which utilises the cluster structure to facilitate multielectron reactions. The photoreduced products [Ti6O6(OiPr)4(O2C t Bu)6(sol)2], sol = iPrOH (2) or pyridine (3), can be isolated in good yield and are structurally characterized, each with two, uniquely arranged, antiferromagnetically coupled d-electrons. 2 and 3 undergo onward oxidation under air, with 3 cleanly transforming into peroxide complex, [Ti6O6(OiPr)4(O2C t Bu)6(py)(O2)] (5). 5 reacts with isopropanol to regenerate the initial cluster (1) completing a closed cycle, and suggesting opportunities for the deployment of these easily made and tuneable clusters for sustainable photocatalytic processes using air and light. The redox reactivity described here is only possible in a cluster with multiple Ti sites, which can perform multi-electron processes and can adjust its shape to accommodate changes in electron density.

Cognitive function in early-phase schizophrenia-spectrum disorder: IQ subtypes, brain volume and immune markers.

BACKGROUND: Evidence suggests that cognitive subtypes exist in schizophrenia that may reflect different neurobiological trajectories. We aimed to identify whether IQ-derived cognitive subtypes are present in early-phase schizophrenia-spectrum disorder and examine their relationship with brain structure and markers of neuroinflammation. METHOD: 161 patients with recent-onset schizophrenia spectrum disorder (<5 years) were recruited. Estimated premorbid and current IQ were calculated using the Wechsler Test of Adult Reading and a 4-subtest WAIS-III. Cognitive subtypes were identified with k-means clustering. Freesurfer was used to analyse 3.0 T MRI. Blood samples were analysed for hs-CRP, IL-1RA, IL-6 and TNF-α. RESULTS: Three subtypes were identified indicating preserved (PIQ), deteriorated (DIQ) and compromised (CIQ) IQ. Absolute total brain volume was significantly smaller in CIQ compared to PIQ and DIQ, and intracranial volume was smaller in CIQ than PIQ (F(2, 124) = 6.407, p = 0.002) indicative of premorbid smaller brain size in the CIQ group. CIQ had higher levels of hs-CRP than PIQ (F(2, 131) = 5.01, p = 0.008). PIQ showed differentially impaired processing speed and verbal learning compared to IQ-matched healthy controls. CONCLUSIONS: The findings add validity of a neurodevelopmental subtype of schizophrenia identified by comparing estimated premorbid and current IQ and characterised by smaller premorbid brain volume and higher measures of low-grade inflammation (CRP).

Plus ça change? Switching lithium preparations.

AIMS AND METHOD: A supply disruption alert in 2020, now rescinded, notified UK prescribers of the planned discontinuation of Priadel® (lithium carbonate) tablets. This service evaluation explored lithium dose and plasma levels before and after the switching of lithium brands, in order to determine the interchangeability of different brands of lithium from a pharmacokinetic perspective. RESULTS: Data on the treatment of 37 patients switched from Priadel® tablets were analysed. Switching to Camcolit® controlled-release tablets at the same dose did not result in meaningful differences in plasma lithium levels. Dose adjustment and known or suspected poor medication adherence were associated with greater variability in plasma lithium levels on switching brands. CLINICAL IMPLICATIONS: For comparable pre- and post-switch doses in adherent patients, the most common brands of lithium carbonate appear to produce similar plasma lithium levels. British National Formulary guidance relating to switching lithium brands may be unnecessarily complex.

Synthesis of a nanoscale Cu(II)31-oxo-carboxylate cluster, and effect of Cu-oxo cluster size on visible-light absorption.

Cu16-Cu31 Cu(II)-oxo-carboxylate clusters are reported, including those with condensed 1.5 nm Cu-O cores supported exclusively by O-donor ligands. A size-colour correlation is observed due to a red-shift of the charge transfer absorption band on increasing size; hence these clusters sit between small molecules and (black) CuO nanostructures.

Clinical predictors of antipsychotic treatment resistance: Development and internal validation of a prognostic prediction model by the STRATA-G consortium.

INTRODUCTION: Our aim was to, firstly, identify characteristics at first-episode of psychosis that are associated with later antipsychotic treatment resistance (TR) and, secondly, to develop a parsimonious prediction model for TR. METHODS: We combined data from ten prospective, first-episode psychosis cohorts from across Europe and categorised patients as TR or non-treatment resistant (NTR) after a mean follow up of 4.18 years (s.d. = 3.20) for secondary data analysis. We identified a list of potential predictors from clinical and demographic data recorded at first-episode. These potential predictors were entered in two models: a multivariable logistic regression to identify which were independently associated with TR and a penalised logistic regression, which performed variable selection, to produce a parsimonious prediction model. This model was internally validated using a 5-fold, 50-repeat cross-validation optimism-correction. RESULTS: Our sample consisted of N = 2216 participants of which 385 (17 %) developed TR. Younger age of psychosis onset and fewer years in education were independently associated with increased odds of developing TR. The prediction model selected 7 out of 17 variables that, when combined, could quantify the risk of being TR better than chance. These included age of onset, years in education, gender, BMI, relationship status, alcohol use, and positive symptoms. The optimism-corrected area under the curve was 0.59 (accuracy = 64 %, sensitivity = 48 %, and specificity = 76 %). IMPLICATIONS: Our findings show that treatment resistance can be predicted, at first-episode of psychosis. Pending a model update and external validation, we demonstrate the potential value of prediction models for TR.

SARS-CoV-2 Omicron BA.5: Evolving tropism and evasion of potent humoral responses and resistance to clinical immunotherapeutics relative to viral variants of concern.

BACKGROUND: Genetically distinct viral variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been recorded since January 2020. The introduction of global vaccine programs has contributed to lower COVID-19 hospitalisation and mortality rates, particularly in developed countries. In late 2021, Omicron BA.1 emerged, with substantially altered genetic differences and clinical effects from other variants of concern. Shortly after dominating global spread in early 2022, BA.1 was supplanted by the genetically distinct Omicron lineage BA.2. A sub-lineage of BA.2, designated BA.5, presently has an outgrowth advantage over BA.2 and other BA.2 sub-lineages. Here we study the neutralisation of Omicron BA.1, BA.2 and BA.5 and pre-Omicron variants using a range of vaccine and convalescent sera and therapeutic monoclonal antibodies using a live virus neutralisation assay. Using primary nasopharyngeal swabs, we also tested the relative fitness of BA.5 compared to pre-Omicron and Omicron viral lineages in their ability to use the ACE2-TMPRSS2 pathway. METHODS: Using low passage clinical isolates of Clade A.2.2, Beta, Delta, BA.1, BA.2 and BA.5, we determined humoral neutralisation in vitro in vaccinated and convalescent cohorts, using concentrated human IgG pooled from thousands of plasma donors, and licensed monoclonal antibody therapies. We then determined infectivity to particle ratios in primary nasopharyngeal samples and expanded low passage isolates in a genetically engineered ACE2/TMPRSS2 cell line in the presence and absence of the TMPRSS2 inhibitor Nafamostat. FINDINGS: Peak responses to 3 doses of BNT162b2 vaccine were associated with a 9-fold reduction in neutralisation for Omicron lineages BA.1, BA.2 and BA.5. Concentrated pooled human IgG from convalescent and vaccinated donors and BNT162b2 vaccination with BA.1 breakthrough infections were associated with greater breadth of neutralisation, although the potency was still reduced 7-fold across all Omicron lineages. Testing of clinical grade antibodies revealed a 14.3-fold reduction using Evusheld and 16.8-fold reduction using Sotrovimab for the BA.5. Whilst the infectivity of BA.1 and BA.2 was attenuated in ACE2/TMPRSS2 entry, BA.5 was observed to be equivalent to that of an early 2020 circulating clade and had greater sensitivity to the TMPRSS2 inhibitor Nafamostat. INTERPRETATION: Observations support all Omicron variants to significantly escape neutralising antibodies across a range of vaccination and/or convalescent responses. Potency of therapeutic monoclonal antibodies is also reduced and differs across Omicron lineages. The key difference of BA.5 from other Omicron sub-variants is the reversion in tropism back to using the well-known ACE2-TMPRSS2 pathway, utilised efficiently by pre-Omicron lineages. Monitoring if these changes influence transmission and/or disease severity will be key for ongoing tracking and management of Omicron waves globally. FUNDING: This work was primarily supported by Australian Medical Foundation research grants MRF2005760 (ST, GM & WDR), MRF2001684 (ADK and ST) and Medical Research Future Fund Antiviral Development Call grant (WDR), Medical Research Future Fund COVID-19 grant (MRFF2001684, ADK & SGT) and the New South Wales Health COVID-19 Research Grants Round 2 (SGT).

Who is prescribed valproate and how carefully is this treatment reviewed in UK mental health services? Data from a clinical audit.

Background: The licensed indications for valproate are narrow, yet this medication is commonly prescribed in mental health services. Objectives: To explore the target symptoms/behaviours for which valproate is prescribed and how well the efficacy and tolerability of this treatment are monitored in routine clinical practice. Design: An audit-based quality improvement (QI) programme in UK mental health services. Methods: Information on valproate prescribing was collected from clinical records using a bespoke data collection tool. Results: Sixty-four NHS mental health Trusts/healthcare organisations submitted data on valproate treatment for 5320 patients. Valproate was clearly prescribed for a licensed indication in 1995 (38%) patients, off-label in 1987 (37%) while the indication was uncertain/not available in 1338 (25%). Of the 919 patients started on valproate treatment within the past year, between a half and two-thirds had each of the relevant baseline physical health checks documented. In 539 (59%) of these patients, valproate was prescribed for an unlicensed indication; the prescription was recognised as off-label in 363 (67%), 20 (6%) of whom were documented as having had this explained to them. Of 631 patients prescribed valproate for between 3 months and a year, early on-treatment assessments of response and side effects were documented in 441 (70%) and 332 (53%), respectively. Of 4401 patients treated for more than a year, annual on-treatment reviews of clinical response and side effects were documented in 2771 (63%) and 2140 (49%), respectively. Conclusion: Our data suggest the majority of prescriptions for valproate in mental health services are not for a licensed indication. Furthermore, patients rarely receive an explanation that their valproate prescription is off-label, perhaps partly because the licensed indications are not widely understood by prescribers. Given the very limited evidence for efficacy for the off-label uses of valproate, failure to routinely conduct early on-treatment and annual reviews of the benefits and side effects of this medication may result in patients remaining on ineffective and poorly tolerated treatment by default.

Analysis of 52 240 source plasma donors of convalescent COVID-19 plasma: Sex, ethnicity, and age association with initial antibody levels and rate of dissipation.

BACKGROUND: COVID-19 convalescent plasma (CCP) was approved under emergency authorization to treat critically ill patients with COVID-19 in the United States in 2020. We explored the demographics of donors contributing plasma for a hyperimmune, plasma-derived therapy to evaluate factors that may be associated with anti-SARS-CoV-2 antibody response variability and, subsequently, antibody titers. STUDY DESIGN: An electronic search of CCP donors was performed across 282 US plasma donation centers. Donations were screened for nucleocapsid protein-binding-IgG using the Abbott SARS-CoV-2 IgG assay. RESULTS: Overall, 52 240 donors donated 418 046 units of CCP. Donors were of various ethnicities: 43% Caucasian, 34% Hispanic, 17% African American, 2% Native American, 1% Asian, and 3% other. Females had higher initial mean anti-SARS-CoV-2 antibody titers but an overall faster rate of decline (P < .0001). Initial antibody titers increased with age: individuals aged 55 to 66 years had elevated anti-SARS-CoV-2 titers for longer periods compared with other ages (P = .0004). African American donors had the lowest initial antibody titers but a slower rate of decline (P < .0001), while Caucasian (P = .0088) and Hispanic (P = .0193) groups had the fastest rates of decline. Most donor antibody levels decreased below the inclusion criteria (≥1.50) within 30 to 100 days of first donation, but donation frequency did not appear to be associated with rate of decline. CONCLUSION: Several factors may be associated with anti-SARS-CoV-2 antibody response including donor age and sex. Evaluating these factors during development of future hyperimmune globulin products may help generation of therapies with optimal efficacy.

Time to re-evaluate the risks and benefits of valproate and a call for action.

Valproate is widely used in psychiatry and neurology, including off-label use. Here we consider its potential benefits and risks, particularly for women of childbearing potential, and the evidence that clinical guidelines are adhered to. Finally, we consider the implications for clinical practice and research into its efficacy in off-label indications.