Prescribers fear as a major side‐effect of clozapine

Recently, clinicians fear for clozapine non-compliance was found to play a role in clozapine underuse (1). Interestingly, the results of the largest US study of non-compliance (N = 2247) of antipsychotic treatment point into the opposite direction as they unequivocally favor clozapine (2). Compared with non-clozapine treatment, the number of treatment days for clozapine was twice as long in the White population and three times as long in the Latino and African-American population. The data indicate that clozapine is accompanied not by the worst but by the best (and longest) compliance. Safety issues, by some considered as obstacles to clozapine initiation, can be broken down into three treatment-emergent side-effects. The first is the risk and mortality of agranulocytosis that featured among the main three concerns in psychiatrists’ attitude toward clozapine (3). In clozapine-treated patients, the mortality rate of clozapine-induced agranulocytosis is very low, 0.1– 0.3&, probably as a result of obligatory white blood cell monitoring, which enables early detection and treatment (4). The prevalence of myocarditis, a second safety concern, has a strong regional component: for Australia, even the lowest incidence rate of 7.0& is 10–100 times higher than the rates reported in the rest of the world (4). Consequently, outside Australia or New Zealand, myocarditis and cardiomyopathy are too rare to be considered as a clinically relevant safety issue. The third topic is increased general mortality in clozapine treatment. Of the three studies so far, two studies found a lowered mortality in clozapine use, while a third study with unchanged mortality rates in clozapine treatment. The question clearly is in debate with for the moment no conclusive evidence available for increased clozapine-associated mortality. If safety issues are not prohibitive of clozapine prescription, what are the determining factors that prevent psychiatrists from prescribing clozapine? Phrased differently: Having examined the plausible rational explanations for the phenomenon of underutilization of clozapine, we are forced to look beyond the domain of rationality for an irrational explanation. A study on psychiatrist’ attitude toward clozapine concluded that psychiatrists seem to be reluctant to use clozapine (4). I propose to coin a new term that describes more than it explains and that is the term ‘prescribers’ fear, the resistance against and fear of prescription of clozapine. This fear runs counter to the available evidence and is therefore irrational. From a psychological perspective, this fear seems to originate in the death of eight Finnish patients in 1975 from agranulocytosis that still reverberates among the psychiatric community. These deaths that occurred at the introduction of clozapine seems to have traumatized the psychiatrist community, which, in spite of the safety measures taken and the evidence that has become available since, has been unable, to digest these pieces of information, to integrate and to incorporate them in our clinical practice, in short to overcome this trauma. This unscientific and irrational fear is a clinically relevant phenomenon as it causes psychiatrists to withhold their patients an effective, evidence-based treatment, thereby unnecessarily prolonging their patients’ suffering. What can be done to remedy this situation? I suggest a threefold approach. First is the establishment of national clozapine expertise centers, which will exercise three tasks. They will function as oracle – for free of charge – to mental health professionals on all questions that are somehow related to clozapine, such as treatment indications and initiation, prevention or treatment of side-effects, the role of comedication etc. Second, they will educate mental health professionals by lecturing to staff in mental health organizations, at congresses, and other scientific meetings and by providing educational materials, such as patient information, algorithms for frequently encountered situations (sialorrhea, constipation, fever), or potentially dangerous situation (leucopenia, hyperglycemia). Third, the modernization of the clozapine guideline to ensure it is in keeping with the latest findings and results. The monitoring protocol of white blood cell counts needs to be amended on benign ethnic neutropenia to prevent unnecessarily low treatment rates in patients of African origin. The frequency of white blood cell monitoring after the first year of treatment in well-informed patients can also be reduced, thereby considerably reducing the burden for the patients (5). Obligatory monitoring of fasting plasma glucose during the initial 3 months and monitoring of constipation throughout treatment can improve early detection of dangerous side-effects (4). As second part of the threefold approach, a pharmacy vigilance system needs to be developed and installed for signaling all cases that are being described a third antipsychotic drug other than clozapine. When this occurs, the prescribing psychiatrist has to be asked to provide a rationale in favor of and a convincing argument against prescribing clozapine. Local or national board and/or authorities will judge the validity of the arguments presented for withholding clozapine to patients with therapy-resistant schizophrenia. Third, local or regional boards have to be developed and to be given the authority to decide on the arguments to withhold clozapine to patients with therapy-resistant schizophrenia. Are these advice a chimaera or are they practicable? The Dutch situation can serve as an example: Between 2008 and 2012, the prescription for all antipsychotics rose 8.2% (http://www.gipdatabank.nl/databank. asp? tabel=01-basis&geg=gebr&item=N05) compared with 20% for clozapine (http://www.gipdatabank.nl/databank.asp). The difference can probably be attributed to the active and easily accessible Dutch Clozapine Collaboration Group, which promotes and facilitates evidence-based prescription of clozapine (www.clozapinepluswerkgroep.nl). Given the fact that the USA has by far the lowest clozapine prescription rate worldwide, we think that this issue is most urgent in the USA. It would give the USA a possibility to catch up on its arrears and to provide care to one of the its most vulnerable populations that is evidence-based and not only costeffective but also much cheaper than the currently prevailing costly and ineffective antipsychotic polypharmacy. On top of that, it could set an example to other countries that are