Safer use of clozapine

Clozapine remains something of an enigma, more than 60 years after it was first synthesised and considered for clinical use. It is one of the very few drugs in psychiatry, which has therapeutic effects readily visible to the naked eye. When reintroduced around the world in the 1990s, many longstanding and severely ill patients were seen to make miraculous recoveries. Clinicians experienced in its use would unanimously attest to its unique and profound efficacy in people whose condition is left unchanged by other antipsychotics. Yet clozapine remains widely underused1 and academics continue to argue about the robustness of the evidence for the effectiveness of clozapine compared with other antipsychotics.2 It does not help, of course, that clozapine has a dizzying range of adverse effects, many of them potentially fatal, and in most countries, can only be prescribed within an arduous regimen of blood testing. Clozapine is most famously associated with neutropenia and agranulocytosis, although recent evidence suggests that it does not cause neutropenia and that life-threatening agranulocytosis occurs more rarely than previously thought.3 Safety monitoring is concentrated on detecting blood toxicity, but other adverse effects such as constipation4 may be a greater threat to life. In this issue, Mark Vickers and colleagues5 examine the risk factors for myocarditis and cardiomyopathy – two well-established adverse effects of clozapine. They note that both conditions have a relatively higher incidence in their home country of Australia but attribute this to probable surveillance bias (although over-diagnosis may also play a part6). In their analysis of six previously published studies, the only clear influence on the risk of myocarditis was the co-prescription of valproate, which increased the odds of myocarditis by a factor of 3.58. There is no obvious mechanism for this apparent interaction, but some kind of pharmacokinetic or metabolic competition is probable. Because valproate also increases the risk of clozapine-associated blood dyscrasia,7 this new evidence should provoke the abandoning of valproate as a mood-stabiliser or anti-seizure drug in clozapine patients, at least at the start of treatment when the risk of myocarditis and agranulocytosis is highest. No risk associations were found for cardiomyopathy, but this is a much rarer and more nebulous effect of clozapine (which, incidentally, occurs in a different timeframe, in a lower frequency and with a different pathology from clozapine-associated myocarditis). Another systematic review in this issue8 examines the whole range of adverse effects linked to clozapine, their treatment and the question of rechallenge after serious adverse effects. Gurrera and co-workers reiterate the observation that side effects such as myocarditis, clozapine-induced gastrointestinal hypomotility and diabetes are of greater concern that clozapine-associated agranulocytosis. This is, perhaps, the most comprehensive review of clozapine-related side effects ever published, especially when taking into account the huge volume of online supplementary data provided. It is an erudite synthesis of a huge volume of data containing many evidenced-based observations and recommendations. Perhaps inevitably, nonetheless, there are some omissions, or at least areas that are underemphasised or where interpretations of the data may differ. For example, there is no discussion of the underuse of laxatives in people prescribed clozapine9; little attention given to GLP-1 receptor agonists and their protective effects against clozapine-induced weight gain and diabetes,10 and there is nothing on clozapine's recently established association with increased risk of infection.11 The authors also rely on rather old data (from a time when clozapine plasma concentrations were not monitored and antiseizure medication not used) to describe the dose-related risk of seizures12 and implicitly link agranulocytosis and neutropenia as related, and indeed clozapine-related, phenomena when current thinking is leaning towards the conclusion that neutropenia is an incidental finding in people taking clozapine.13 Lastly, Guerra and colleagues suggest that therapeutic drug monitoring is only worthwhile as means of managing adverse effects in patients taking more than 600mg a day, when, in fact, doses of this magnitude would give rise to severe toxicity in some groups of patients, such as women non-smokers.14 The authors do, however, provide very sound advice on when clozapine rechallenge might be safely attempted, citing only myocarditis, cardiomyopathy and agranulocytosis as adverse effects, which make rechallenge 'inadvisable'. This does not rule out completely the possibility of rechallenge. Clozapine has been safely re-prescribed to many patients with a history of myocarditis15 and successful rechallenge following moderate or severe neutropenia (but not agranulocytosis) is more likely than not.16 Clozapine deserves to be more widely used, and more people with schizophrenia deserve the opportunity to be treated with clozapine. A better understanding of the possible adverse consequences of clozapine prescribing is likely to allow or even promote wider and safer use of this unique and remarkable medicine. The peer review history for this article is available at https://publons.com/publon/10.1111/acps.13427. The peer review history for this article is available at https://publons.com/publon/10.1111/acps.13427.