Moving forward with clozapine

Acta Psychiatrica Scandinavica, vol. 142, pp. 75–77

Abstract

In the famous network meta-analysis of 32 oral antipsychotics for the acute treatment of adults with multi-episode non-refractory schizophrenia, clozapine showed the highest effect size of all 32 antipsychotics for the treatment of overall and secondary negative symptoms in the acute phase, the second best result for depressive symptoms, the lowest incidence of akathisia and the lowest use of anti-cholinergic medication (1). For treatment-refractory schizophrenia, clozapine is the only approved drug and is associated with fewer hospitalizations in these patients (2). Furthermore, clozapine is recommended (off-label) when treating patients with schizophrenia and comorbid alcohol/drug use disorder, persistent violence and hostility, and antipsychotic-induced tardive dyskinesia. Furthermore, the indications listed for clozapine in the United States include the management of recurrent suicidality in individuals with schizophrenia or schizoaffective disorder. Due to a very low but potentially life-threatening risk of severe neutropenia (formerly known as agranulocytosis), prescribers in most countries are obliged to monitor neutrophil counts weekly and later monthly throughout clozapine treatment and for at least four weeks after its discontinuation. In the event of low absolute neutrophil counts (ANC), clozapine must be discontinued and/or the frequency of blood tests increased. Since an FDA revision in 2015, there have been two striking differences between the rules for clozapine in the United States and in Europe: in the EU, an individual with an ANC < 1500/mm3 must not be re-exposed to clozapine and there are no exceptions to ANC cut-offs, whereas in the United States a rechallenge is permitted as soon as the ANC increases above 1000/mm3 and for individuals with benign ethnic neutropenia lower cut-offs have been determined. The peak incidence of severe neutropenia occurs at one month of clozapine exposure with an exponential decline thereafter (3). After the first twelve months, the incidence of severe neutropenia shows little variation and is almost negligible. We have calculated that if neutrophil checks are stopped after the first six months of clozapine treatment, the risk of death due to severe neutropenia is about the same as the mortality associated with other medications, such as mianserin or phenylbutazone, and with life in general (traffic or occupational accident) (4). Since the prospect of endless mandatory blood tests may contribute to patient non-compliance and premature cessation of clozapine treatment, the Dutch Clozapine Collaboration Group (DCCG) has stated in its clozapine guideline that off-label clozapine treatment without ANC monitoring may be permitted after the first six months of treatment if this is what a mentally competent and adequately informed patient explicitly wants (5). However, the ANC must still be checked immediately if there is any clinical suspicion of severe neutropenia. Even if the routine ANC checks are stopped, low-frequency tests, for example four times a year, are still advisable, because they may detect slow progressive drops in ANC. Some patients who refuse cubital venipuncture do consent to a finger prick to collect one drop of blood (6). A point-of-care device can determine the total white blood cell and differential counts and even a clozapine serum level can be measured from a single drop of blood. We strongly advocate revision of clozapine regulations to alleviate the restrictive rules requiring mandatory ANC monitoring and categorically prohibiting rechallenge after granulopenia. Because of the current rules, many patients and doctors decide not to continue clozapine treatment or to conduct a rechallenge, even though inadequately treated refractory schizophrenia has its own hazards and is associated with increased mortality (7). A second notorious risk is the development of myocarditis and cardiomyopathy, which has very low rates except in Australia (8). A nationwide register-based study in Denmark among over 3000 outpatients found one case of myocarditis and six of cardiomyopathy within two years after initiation of clozapine (9). Rates were similar for other antipsychotics. In this issue of Acta Psychiatrica Scandinavica, Rohde et al. published another study based on the same Danish health registers (10). Their question was whether exposure to antipsychotic medication was associated with increased risk of pneumonia and whether patients receiving clozapine were more likely to develop pneumonia than patients receiving other antipsychotic medications. They chose a very elegant mirror-image design, using each patient as their own control to reduce unmeasured confounders. Only the initiation of risperidone was associated with a significant increase in pneumonia rates. Nevertheless, the biggest increase in pneumonia – though not significant, probably due to low numbers – was seen for clozapine: 1.8% of clozapine users developed pneumonia in the year after initiation of the drug in comparison with 1.2% in the year before. In a subsequent letter, the authors clarified that approximately one-third of the population attributable risk of pneumonia is due to clozapine and two-thirds to treatment-resistant schizophrenia. In view of these figures, clinicians should bear in mind that not only benign fever, severe neutropenia and myocarditis can lead to fever in a clozapine user, but that pneumonia is also a possibility. This is particularly important because pneumonia may have more fatal outcomes with clozapine than with other second-generation antipsychotics, possibly due to clozapine intoxication as a result of the associated inflammation (11). Unfortunately, as regards risk monitoring in clozapine treatment, most attention is devoted to severe neutropenia and myocarditis. Gastro-intestinal hypomotility (GIH), which in many patients presents as constipation, is often wrongly regarded as uncomfortable but not dangerous, whereas in fact our estimates show that three to ten times more clozapine users die from GIH than from agranulocytosis or myocarditis (8). We therefore advocate frequent, targeted questioning by mental healthcare providers regarding the patients' defecation pattern, to ensure timely detection and treatment of treatment-emergent GIH throughout clozapine treatment. We want to stress that many clozapine users do not spontaneously complain of constipation or abdominal pain. A frequent and clinically important side-effect of clozapine is sedation, which can induce secondary negative depressive and cognitive symptoms (1). For most patients we recommend cautious titration, beginning with 6.25 mg and then daily dose increments of 12.5 mg to a level, which is well tolerated. In many patients, subnormal clozapine plasma levels are therapeutic. There are some more common but mostly innocuous side-effects such as sialorrhea and orthostatic hypotension, and other rare but potentially dangerous complications such as seizures or diabetes, but they are manageable in most cases and should generally not lead to discontinuation of clozapine therapy (12). Despite all these reported risks, a 20-year follow-up study of physical morbidity and mortality in relationship to antipsychotic treatment in a nationwide cohort of 62 250 patients with schizophrenia found the most beneficial mortality outcome was associated with the use of clozapine in terms of all-cause, cardiovascular and suicide mortality (7). In spite of clozapine's unique efficacy in refractory schizophrenia and its excellent mortality records, worldwide underprescription is the rule rather than the exception (13). We estimate that a clozapine prescription rate of 20% of patients with schizophrenia is a conservative quality standard, but unfortunately in most reports this is not met. Since there is no plausible rational explanation for this phenomenon, we have coined the term 'prescribers' fear' to refer to the resistance to and fear of prescribing clozapine (14). The Dutch Clozapine Collaboration Group (DCCG) has been promoting and facilitating the evidence-based prescription of clozapine for over fifteen years. A clinical guideline for the use of clozapine published in Dutch and English covers a wide range of topics such as on-label and off-label indications, clozapine titration schedules, criteria for an adequate clozapine trial, detection and treatment of both common and rare side-effects, prevention of complications, rechallenge after granulopenia, termination of mandatory ANC checks, compulsory treatment and what to do if clozapine is not efficacious (5). A separate structured protocol with many decision trees can guide less experienced healthcare providers such as advanced nurse practitioners. The Glasgow antipsychotic side-effect scale was modified and validated to screen clozapine users for side-effects. We have published a patient-focused brochure in Dutch and English that provides information on clozapine treatment. Recently, we have produced a short information video clip for patients. All documents and tools are accessible online and available free of charge (https://www.clozapinepluswerkgroep.nl). Annual workshops at the national psychiatry congress, frequent symposia throughout the country, the integration of a clozapine learning module into the national curriculum for psychiatry residents and clozapine master classes for advanced nurse practitioners have considerably raised the standard of knowledge about clozapine. The website offers a frequently used online facility which enables professionals seeking advice in complex clinical situations to receive feedback from board members of the DCCG. In recent years, patients and their family members have also discovered the question facility. Since the foundation of the DCCG, the number of Dutch outpatients on clozapine has increased from 7764 in 2004 to 14 628 in 2019, an increase of 88%, which compares favourably with the 36% increase in the number of patients on other antipsychotics during the same period (15). In the Netherlands in 2016, the mean prescription rate of clozapine in 20 flexible assertive community (FACT) teams treating 2,286 schizophrenia-spectrum patients was 23.0% (16). Nevertheless, 6.9% of the schizophrenia-spectrum patients who were eligible for clozapine treatment were not receiving it (range 1.7–15.6 %). The identification of these patients who were eligible for clozapine failed to lead to improved prescription rates, even when an advanced nurse practitioner was available to conduct physical examinations for clozapine treatment, provide psychoeducation for patients and their relatives and monitor side-effects (17). A systematic review of prescriber and institutional barriers to and facilitators of clozapine use has shown that the most successful interventions for increasing clozapine prescription are financial incentives and institutional pressure, such as a continuous audit and feedback process or requiring centres with low levels of clozapine use to present detailed action plans (18). The DCCG is working with the Dutch Centre for Certification of ACT and FACT to ensure that clozapine use is included as a quality criterion in their audits. However, on an international and institutional level more needs to be done: mental health organizations should integrate clozapine prescription rates into their quality management of schizophrenia treatment. Drug regulatory agencies should review the unnecessarily restrictive blood testing regime for clozapine prescription, as advocated above. Moreover, health insurers should pay care providers for the additional time needed to start clozapine treatment and help patients stick with it, thereby reducing the suffering and mortality resulting from undertreated schizophrenia. Let's move forward together with clozapine! None.

Authors 4

1. Peter F.J. Schulte corresponding

   GGZ Noord-Holland-Noord

   Affiliation as printed

   Dutch Clozapine Collaboration Group Alkmaar The Netherlands

   Mental Health Service Noord‐Holland‐Noord Heerhugowaard The Netherlands

   Dutch Clozapine Collaboration Group, Alkmaar, The Netherlands

   Mental Health Service Noord-Holland-Noord, Heerhugowaard, The Netherlands

2. Jan P.A.M. Bogers Aachen Mental Health Service Rivierduinen Leiden The Netherlands Mental Health Service Rivierduinen

   GGZ Rivierduinen

   Affiliation as printed

   Dutch Clozapine Collaboration Group Alkmaar The Netherlands

   Mental Health Service Rivierduinen Leiden The Netherlands

   Dutch Clozapine Collaboration Group, Alkmaar, The Netherlands

   Mental Health Service Rivierduinen, Leiden, The Netherlands

3. Selene R. T. Veerman

   GGZ Noord-Holland-Noord

   Affiliation as printed

   Dutch Clozapine Collaboration Group Alkmaar The Netherlands

   Mental Health Service Noord‐Holland‐Noord Heerhugowaard The Netherlands

   Dutch Clozapine Collaboration Group, Alkmaar, The Netherlands

   Mental Health Service Noord-Holland-Noord, Heerhugowaard, The Netherlands

4. Dan Cohen

   GGZ Noord-Holland-Noord

   Affiliation as printed

   Dutch Clozapine Collaboration Group Alkmaar The Netherlands

   Mental Health Service Noord‐Holland‐Noord Heerhugowaard The Netherlands

   Dutch Clozapine Collaboration Group, Alkmaar, The Netherlands

   Mental Health Service Noord-Holland-Noord, Heerhugowaard, The Netherlands