Clozapine use in patients with severe mental illness was associated with a significantly increased risk of death compared with that for the general population. Causation could not be established. Adverse effects and death are common causes of clozapine discontinuation.

The herbal remedy St John's wort is widely used as an antidepressant but its efficacy has not been systematically investigated. Meta-analyses and systematic reviews of published trials strongly suggest St John's wort is more effective than placebo although comparative efficacy to standard antidepressants is less clearly established. We updated and expanded previous meta-analyses of St John's wort, scrutinised the validity of published reports and examined possible mechanisms of action. Twenty-two randomised controlled trials were identified. Meta-analysis showed St John's wort to be significantly more effective than placebo (relative risk (RR) 1.98 (95% CI 1.49-2.62)) but not significantly different in efficacy from active antidepressants (RR 1.0 (0.90-1.11)). A sub-analysis of six placebo-controlled trials and four active comparator trials satisfying stricter methodological criteria also suggested that St John's wort was more effective than placebo (RR 1.77 (1.16-2.70)) and of similar effectiveness to standard antidepressants (RR 1.04 (0.94-1.15)). There was no evidence of publication bias. Adverse effects occurred more frequently with standard antidepressants than with St John's wort. The mechanism of action of St John's wort remains unknown. Future research should include large scale, appropriately powered comparisons of St John's wort and standard antidepressants.

In this selected population, the initial neutropenia was unlikely to be related to clozapine in a substantial proportion of cases. This group was successfully rechallenged following careful consideration of the risks and benefits, and lithium and G-CSF contributed to allowing continued clozapine therapy. In addition to black patients, other ethnic groups can have persistently low ANC unrelated to clozapine.

Despite its unique effectiveness in treating refractory schizophrenia, substantial evidence indicates gross underuse of clozapine. 1,2 Aligned with the underuse is a demonstrable international variation in use of the drug. 3 Widespread geographical variation in usage has been reported in the United States, 4 Canada, 5 Middle East, 6 Europe 7 and the United Kingdom. 8 The factors responsible for the underuse of clozapine are numerous, varied and often interconnected; these can be separated into four key domains relating to the drug itself, the prescribers, the patients and associated infrastructure and regulatory processes. Clozapine causes neutropenia in about (3%) 9 of patients and the more severe agranulocytosis in (0.4%) 10 in treated patients. Haematological monitoring is therefore

Clozapine is the only available treatment for refractory schizophrenia but its use involves frequent physical contact with healthcare workers for the purpose of mandatory blood monitoring. During the COVID-19 pandemic, patients taking clozapine will be self-isolating to reduce the risk of infection, not least because these patients are at high risk of serious illness and fatality because of high rates of diabetes, obesity and pulmonary disease and an increased risk of pneumonia. Problems may also arise because both clozapine-induced myocarditis and neutropenic sepsis share signs and symptoms with COVID-19 (fever, chest pain, dyspnoea, etc.). We recommend decreasing the frequency of physical contacts by extending the blood monitoring interval to 12 weeks in those patients taking clozapine for more than 1 year. To distinguish COVID-19 from clozapine-related physical adverse effects, we suggest an urgent antigen test alongside a full blood count. In those taking clozapine who develop COVID-19, we suggest continuing with clozapine whenever possible (even during ventilation), reducing the dose if necessary in line with blood assay results. Blood monitoring should continue but clozapine should only cease if there is a significant fall in neutrophils (COVID-19 is linked to lymphopenia but not neutropenia). To protect against the likelihood and severity of respiratory infection, we recommend the use of vitamin D in all clozapine patients. Initiation of clozapine is likely to remain problematic while the risk of infection remains, given the degree of physical contact required to assure safety.