Flexibilization in controlling the use of clozapine: A great opportunity

Dear Editor,

The Spanish Association for Medicines and Healthcare Products (AEMPS) recently published an informative note¹ explaining that healthcare professionals are now free of the obligation to send reports containing the analytical results of patients to treatment with clozapine. Nevertheless, the said analytical monitoring must continue, and the same conditions for prescribing and dispensing these medicines must remain.

This change is due to the request by a group of clinical psychiatrists who are experts in the use of clozapine. They met in September 2016 to unify their criteria and exchange experiences in the use of the said drug. The same meeting produced a document containing a range of considerations about 3 main questions: the patient profile of those who could be treated using clozapine, the use of clozapine as a monotherapy or in combined therapy, and the use of clozapine as a second-line antipsychotic drug.²

Respecting the first point, it seems to be unanimously accepted that patients who are refractory to conventional treatment are the first candidates for treatment using clozapine. In any case, and correctly, it is said that patients have usually received a large number of treatments and that treatment using clozapine has been delayed for too long. This leads to an increase in refractory responses, and patients are also denied a possible previous improvement. Given the benefits of clozapine, this improvement does not only consist of improved positive psychotic symptoms as negative symptoms also improve. There are benefits in terms of cognitive functioning and a practically zero incidence of extra-pyramidal symptoms (EPS).³ There is therefore a demand that the term “refractory response” be used correctly. I.e., when there is a lack of suitable response after 2 previous attempts to use antipsychotic treatments in monotherapy, at a suitable dose and during a sufficiently long waiting time. Apart from these patients, other groups are proposed such as those at major risk of suicide, patients with aggressive behaviour (without overemphasising the diagnosis), patients with comorbid substance abuse, and some patients with neurological diseases (Parkinson's disease and cases of dementia with severe behavioural alterations).

The importance of the “setting” is also mentioned, and it is recommended that specialised clozapine units be created. In this point we consider that it should be pointed out that no all healthcare areas would be able to do so: an alternative in small healthcare areas could be to have a clinic familiarised with clozapine use to take charge of the patients in question. It would also thereby be possible to indicate the treatment during team meetings.

The preference is to use clozapine as a monotherapy, and this seems to be objectively recommendable, even though there are some circumstances when combined strategies would be justified. Such cases would be those with an insufficient or less than optimum response to clozapine, or those in which doubts exist about therapeutic adherence. With the aim of optimising these questions, it is important to monitor clozapine levels, given that as a recent paper by Iglesias García et al.⁴ correctly points out, this makes it possible to prevent variations in the dose and minimise potentially undesirable clinical situations. It is of interest in this respect to underline the recent research by Geers et al.⁵ into Dried Blood Spot (DBS) analysis as a reliable and new way of carrying out such monitoring. In the same way the said levels could be used as treatment response markers, given the lack of specific biomarkers in psychiatric pathologies, as Meana and Mollinedo-Gajate correctly state in their editorial “Biomarkers in psychiatry: between myth and clinical reality”.⁶

If it is necessary to add a second antipsychotic drug, it should have a different receptor profile. Amisulpride, risperidone and aripiprazole have all given good results when used in this way.⁷

The combination of clozapine with electroconvulsive therapy (ECT) is also mentioned, and it is said that this may be even more recommendable than antipsychotic polytherapy. Although it is true that this combination has been shown to be more effective than medication alone,⁸ it is also true that a certain number of clinics are hardly familiar with its use, so that for them it may be a rather complicated combination to use, given the reluctance that already exists to use clozapine by itself.

Respecting the use of clozapine as a second-line antipsychotic drug, this is the reason why the said collective requests flexibilization of the pharmacovigilance plan, so that in this way clozapine could play the role that corresponds to it in treating schizophrenia.

To conclude, we therefore consider that eliminating the obligation to send the reports would be a step forwards in eliminating barriers and increasing the use of clozapine. Given the recent nature of this change, it is still too early to evaluate the effects of this increase in monitoring flexibility. Nevertheless, it is a hopeful first step and a great opportunity to consolidate clozapine as the effective therapeutic tool it has proven itself to be.