Abstract
I welcome the recent contributions published in this journal to the debate surrounding the appropriate monitoring of clozapine [1,2]. Although I believe that liberalization of the monitoring of clozapine use is justified, I also believe that liberalization may ironically diminish clozapine's efficacy in the real world. This is because some of clozapine's efficacy could be explained by the very uniqueness of the existing monitoring process, which represents a systemic inequity that needs to be redressed.
The close monitoring apparently required by clozapine's potential haematological and cardiovascular toxicities means that patients on clozapine are likely to receive better follow up and support than patients on other medications. In the past year I have worked as a psychiatry resident at a clozapine clinic. At a minimum, patients at this clinic had their full blood count and basic cardiometabolic parameters recorded, and were asked about side effects such as hypersalivation and sedation. Given that such scrutiny at follow up does not exist for any other psychotropic medication, patients on other medications lose out on similarly assiduous monitoring of side effects and toxicities. Of equal importance was the fact that the clinic appointment was also an opportunity to explore relapsing psychopathology and its possible psychosocial and biological precipitants, and to develop interventions against relapse. Therefore, patients on clozapine may be better monitored for relapsing psychopathology than patients on other medications.
The special follow up arrangements for clozapine discriminate against patients on other antipsychotic medications whose potential side effects are not necessarily less concerning. It is not clear from the available evidence that the many side effects (or “non-target effects”) clozapine shares with other antipsychotic agents are sufficiently more severe or frequent to justify the significantly more careful monitoring they incidentally receive as a result of its more idiosyncratic and potentially acutely lethal toxicities, such as agranulocytosis and cardiomyopathy. With regards to cardiometabolic toxicities, despite expert consensus that all patients on second generation antipsychotics should receive comparable monitoring [3], such consensus does not yet appear to have greatly influenced the clinical reality [4] and the existence of specialized centres outside the mainstream of adult psychiatry dedicated to the monitoring of the cardiometabolic health of patients on antipsychotic drugs [5] proves the rule that the monitoring arrangements available for clozapine, though not necessarily ideal, remain special.
The fact that more pharmacoepidemiological data exist for clozapine than for any other drug [6] could be a reflection of this uniquely assiduous monitoring, which may have generated a positive feedback loop whereby assiduity has increased as a result of the existence of more data and therefore more adverse phenomena for which to monitor. To illustrate this point, the protocol that we as residents were meant to adhere to at the clozapine clinic demanded that at each appointment we ask every patient about manifestations of hyperprolactinaemia and movement disorders, both of which are rare associations with clozapine therapy [6,7]. This means that patients on clozapine are potentially better monitored for side effects that they may never suffer from, than patients on other drugs with which such side effects are common. What is practised at clozapine clinics appears to confuse the pharmacological concepts of tolerability and safety, two dimensions that may be significantly dissociated in the case of any given drug or drug class.
The more careful follow up provided for patients on clozapine provides more frequent opportunities for biological as well as psychosocial interventions than is the case for patients on other less carefully monitored medications. Although these differences appear to have been effectively controlled for in the seminal studies that enshrined clozapine's effectiveness [8], the effect of this difference on the outcomes of a population treated with clozapine in a ‘real world’ setting has not been studied but is surely not trivial.
The need for long-term follow up for patients on clozapine in order to monitor for toxicity is not disputed. However, the inequity between the follow up provided for patients on clozapine and those on other medications needs to be redressed. Furthermore, this inequity may have inflated both the perception and reality of clozapine's unique effectiveness and efficacy. Treatment with clozapine may well lead to superior outcomes, but such outcomes may be, in part, an artefact of the monitoring and not the chemical.