Aims and method A series of eleven patients prescribed intramuscular clozapine at five UK sites is presented. Using routinely collected clinical data, we describe the use, efficacy and safety of this treatment modality. Results We administered 188 doses of intramuscular clozapine to eight patients. The remaining three patients accepted oral medication. With the exception of minor injection site pain and nodules, side-effects were as expected with oral clozapine, and there were no serious untoward events. Nine patients were successfully established on oral clozapine with significant improvement in their clinical presentations. Clinical implications Although a novel formulation in the UK, we have shown that intramuscular clozapine can be used safely and effectively when the oral route is initially refused.

Pan-microbial inactivation technologies that do not require high temperatures, reactive chemical compounds, or UV radiation could address gaps in current infection control strategies and provide efficient sterilization of biologics in the biotechnological industry. Here, we demonstrate that femtosecond (fs) laser irradiation of resonant gold nanoparticles (NPs) under conditions that allow for E-field mediated cavitation and shockwave generation achieve an efficient plasmon-enhanced photonic microbial pathogen inactivation. We demonstrate that this NP-enhanced, physical inactivation approach is effective against a diverse group of pathogens, including both enveloped and nonenveloped viruses, and a variety of bacteria and mycoplasma. Photonic inactivation is wavelengthdependent and in the absence of plasmonic enhancement from NPs, negligible levels of microbial inactivation are observed in the near-infrared (NIR) at 800 nm. This changes upon addition of resonant plasmonic NPs, which provide a strong enhancement of inactivation of viral and bacterial contaminants. Importantly, the plasmon-enhanced 800 nm femtosecond (fs)pulse induced inactivation was selective to pathogens and was obtained without specific targeting of the NPs to the pathogens. No measurable damage was observed for antibodies included as representative biologics under identical conditions.

Objective: Clozapine remains the most effective intervention for treatment resistant schizophrenia; however, its use is prohibited following neutropenias. We review neutrophil biology as applied to clozapine and describe the strategies to initiate clozapine following neutropenia used in a case series of 14 consecutive patients rechallenged in a United Kingdom (UK) high-secure psychiatric hospital. We examine outcomes including the use of seclusion and transfer. Methods: A case series of 14 male patients with treatment resistant schizophrenia treated with clozapine despite previous episodes of neutropenia between 2006 and 2015 is presented. Data were collected during 2015 and 2019. Using this routinely collected clinical data, we describe the patient characteristics, causes of neutropenia, the strategies used for rechallenging with clozapine and clinical outcomes. Results: Previous neutropenias were the result of benign ethnic neutropenia, clozapine, other medications and autoimmune-related. Our risk mitigation strategies included: granulocyte-colony stimulating factor (G-CSF), lithium and watch-and-wait. There were no serious adverse events; at follow up half of the patient’s had improved sufficiently to transfer them to conditions of lesser security. There were dramatic reductions in the use of seclusion. Conclusion: Even in this extreme group, clozapine can be safely and effectively re/initiated following neutropenias, resulting in marked benefits for patients. This requires careful planning based on an understanding of neutrophil biology and the aetiology of the specific episode of neutropenia.

The atypical antipsychotic clozapine is the only effective medication for treatment-resistant schizophrenia. However, it can also induce serious adverse drug reactions, including agranulocytosis and neutropenia. The mechanism by which it does so is largely unknown, but there is evidence for contributing genetic factors. Several studies identified HLA-DQB1 variants and especially a polymorphism located in HLA-DQB1 (6672G>C, rs113332494) as associated with clozapine-induced agranulocytosis and neutropenia. We analysed the risk allele distribution of SNP rs113332494 in a sample of 1396 controls and 178 neutropenia cases of which 60 developed agranulocytosis. Absolute neutrophil counts of 500/mm3 and 1500/mm3 were used for defining agranulocytosis and neutropenia cases, respectively. We also performed association analyses and analysed local ancestry patterns in individuals of European ancestry, seeking replication and extension of earlier findings. HLA-DQB1 (6672G>C, rs113332494) was associated with neutropenia (OR = 6.20, P = 2.20E−06) and agranulocytosis (OR = 10.49, P = 1.83E−06) in individuals of European ancestry. The association signal strengthened after including local ancestry estimates (neutropenia: OR = 10.38, P = 6.05E−08; agranulocytosis: OR = 16.31, P = 1.39E−06), with effect sizes being considerably larger for agranulocytosis. Using local ancestry estimates for prediction, the sensitivity of rs113332494 increased from 11.28 to 55.64% for neutropenia and from 16.67 to 53.70% for agranulocytosis. Our study further strengthens the evidence implicating HLA-DQB1 in agranulocytosis and neutropenia, suggesting components of the immune system as contributing to this serious adverse drug reaction. Using local ancestry estimates might help in identifying risk variants and improve prediction of haematological adverse effects.

Clozapine remains the only drug treatment likely to benefit patients with treatment resistant schizophrenia. Its use is complicated by an increased risk of neutropenia and so there are stringent monitoring requirements and restrictions in those with previous neutropenia from any cause or from clozapine in particular. Despite these difficulties clozapine may yet be used following neutropenia, albeit with caution. Having had involvement with 14 cases of clozapine use in these circumstances we set out our approach to the assessment of risks and benefits, risk mitigation and monitoring with a practical guide.

Purpose -High-secure hospital patients often have complex presentations that are marked by co-morbidity, violence, histories of poor concordance with oral medication, and treatment resistance. The ability to give a long-acting medication with a low propensity for extra pyramidal side effects is of potential value to clinicians treating these patients. Risperidone Long-acting Injection (RLAI) is the first long-acting atypical antipsychotic medication and may be potentially useful in this population. This paper aims to investigate this issue.Design/methodology/approach -This was a retrospective, naturalistic study to investigate the use and effectiveness, using hard outcome measures, of RLAI in the four UK high-secure psychiatric hospitals. Hospital pharmacy databases at Ashworth, Broadmoor, Carstairs and Rampton hospitals were used to identify all patients who had been prescribed RLAI. Anonymised data were then obtained from the pharmacy databases and case notes which were then pooled.Findings -A total of 159 patients were prescribed RLAI, most of whom had schizophrenia. The mean length of treatment with RLAI was 65 weeks (range two to 260 weeks) and the mean maximum dose was 43.2 mg every two weeks (range 25-75 mg every two weeks). No serious adverse effects were reported. In total, 42 per cent (67) patients responded to RLAI in as much as that they either remained on it in the long-term or were discharged to conditions of lower security whilst taking it. As there was no control group, it is not possible to determine if RLAI was a significant factor in such discharges to conditions of lower security. Of those patients who failed to respond to RLAI, 44 per cent were subsequently treated with clozapine.Originality/value -This pragmatic multi-centre study of a small but complex patient group demonstrated that RLAI was effective in 42 per cent of patients and was well-tolerated.

Five of the most extremely ill patients with treatment-resistant schizophrenia were established and/or maintained on clozapine, resulting in improvements to their mental state; incidents were reduced, segregation was terminated and progression to less restrictive environments was achieved.Clinical implicationsDespite being underutilised and rarely enforced, in extreme circumstances, an assertive approach to clozapine can be justified. Nasogastric clozapine can be safely delivered and the approach itself, rather than actual nasogastric administration, may be enough to help establish and maintain patients with treatment-resistant schizophrenia on the most effective treatment.Declaration of interestE.S. has received speaker fees from Jansen Pharmaceuticals and Novartis.

SummaryMany ethical dilemmas in medicine are associated with highly unusual clinical situations and are an almost daily challenge for mental health teams. We describe the ethical issues that arose in relation to a significant difference of opinion between team members about using nasogastric clozapine in the treatment of a severely ill patient. We discuss how conflicting emotions and perspectives within teams acquire ethical significance and how negotiation and reflection are essential for good-quality ethical reasoning to take place.Learning Objectives• Understand the different effects and importance of reasoning and emotions in moral decision-making• Use a clinical scenario involving a difficult and controversial procedure to explore the impact of social persuasion in moral decision-making• Consider the effects of heuristics against rational thinking