Hematological Monitoring with the Use of Clozapine: Historical Facts, Evidence, Current Status, and Future Directions

Clozapine is the gold standard medication for the management of treatment-resistant schizophrenia (TRS). There is ample evidence to show that clozapine is more effective than other antipsychotics for the management of TRS.[1] Data from different meta-analyses and studies suggest that clozapine reduces the risk of suicide,[2] mortality,[3] number of hospitalizations, duration of hospitalizations,[4] relapse rates in the long run,[5] and increases the chances of abstinence in schizophrenia patients with comorbid substance use disorder.[6] Available data also suggest that clozapine leads to improvement in tardive syndromes associated with the use of other antipsychotics.[7] Data also show that medication adherence with clozapine is not inferior to other antipsychotics,[8] and clozapine is associated with lower all-cause discontinuation rates when compared to other antipsychotics.[9] Clozapine has also been shown to reduce the risk of violence, aggression, and prevent incarceration.[10,11] Clozapine also leads to long-term reductions in healthcare costs.[12] Besides improving symptoms, clozapine also leads to improvements in quality of life[13] and increased employment rates.[14] Despite all these advantages, clozapine is often underused. A study from the United Kingdom reported a wide variation in clozapine prescription rates across different regions of England, with only about a third of eligible patients actually receiving the medication.[15] Available data also suggest that even when used, it is often started late, and this delay leads to poorer outcomes.[16] One of the primary reasons for the underutilization of clozapine has been the requirement for hematological monitoring.[17] Hence, it is essential to understand the emergence, benefits, and demerits of hematological monitoring with clozapine. When one looks at the history of clozapine, it emerged in 1958 as a unique molecule that had structural similarity with tricyclic antidepressants and had an antipsychotic effect without the extrapyramidal side effects. The initial effectiveness data for the molecule were mixed. However, the use of molecules continued to increase until 1975.[18] The major setback to clozapine came in 1975, when, within 4 months of its marketing in Finland, 18 patients were found to have one or more severe blood dyscrasias, nine of whom died.[19] This led to the withdrawal of the molecule from European countries and the United States, as well as the cessation of ongoing trials. However, some of the patients who had benefited from the molecule kept on receiving it as part of the “compassionate need” program. During the late 1970s and early 1980s, although some researchers showed that the incidence of neutropenia with clozapine was not significantly higher compared to other antipsychotics, it did not lead to the re-emergence of the molecule on the market. However, in the 1980s, when deinstitutionalization was occurring in different developing countries, it became evident that there were many patients with treatment-refractory schizophrenia who were not responding to available medications and, as a result, could not be sent to the community.[18] This provided an opportunity to the pharmaceutical company marketing the drug to reapply for conducting a trial in this subgroup of patients. When the company applied to the Food and Drug Administration (FDA) in the United States, the FDA participated in designing the trial and allowed evaluation of clozapine in treatment-refractory schizophrenia patients. This led to the development of the concept of TRS.[20] The trial by Kane et al.[20] established the superiority of clozapine over chlorpromazine. Based on the findings of this trial and a previous incomplete trial (Claghorn trial), the FDA approved the use of clozapine in the management of TRS. However, this approval of clozapine came with a recommendation for strict hematological monitoring.[18] This gave rise to the Clozaril Patient Management System (CPMS), requiring frequent blood tests to prevent agranulocytosis.[18] The initial CPMS was conceptualized to provide a 100% fail-safe system to monitor white blood cell counts (WBCs) in patients being treated with clozapine and to develop a database on the incidence of agranulocytosis. The CPMS program had a case administrator and a registered pharmacist. The case administrator was expected to track outpatient phlebotomy appointments, follow up on missed appointments, ensure that WBCs are obtained and analyzed weekly by the national laboratory, follow-up on the results, liaise with the pharmacy, maintain a database of patients receiving clozapine, and update clinicians about the results.[21] Over the years, a substantial amount of data has emerged, and the rules for monitoring WBCs during clozapine therapy have evolved. By 2015, a lower frequency of monitoring was recommended, which led to the establishment of the Risk Evaluation and Mitigation Strategy (REMS) program in the United States. In line with the United States, rules for WBC monitoring were formulated in many developed countries, and different professional organizations came up with recommendations for the frequency of WBC monitoring.[22] The systems were built in such a way that the pharmacy could not dispense clozapine without a WBC count, and this led to the mandate of “NO BLOODS, NO CLOZAPINE.” Accordingly, over the years, the need for regular WBC monitoring of the hemogram emerged as a significant limitation for offering clozapine. It led to lower acceptance of clozapine by patients and lower offering/recommendation by clinicians. Over the years, many clinicians and researchers have questioned the need for regular monitoring of WBCs with clozapine, and a lot of data have emerged to prove the low rate of neutropenia. A meta-analysis of 108 studies involving data of 4.5 lakhs subjects reported the incidence of neutropenia (i.e., absolute neutrophil count [ANC] <1500) with clozapine to be 3.8% (95% CI: 2.7%–5.2%) and that of severe neutropenia (i.e., ANC <500) to be 0.9% (95% CI: 0.7%–1.1%). The incidence of mortality associated with clozapine-related to neutropenia was reported to be 0.013% (95% CI: 0.01%–0.017%) and a case fatality rate of 2.1% (95% CI: 1.6%–2.8%) for severe neutropenia. In terms of the peak incidence of severe neutropenia, it was noted to occur 1 month after starting clozapine and to reduce to negligible levels after 1 year of treatment.[23] However, despite the evidence of very low risk of neutropenia, the FDA did not agree to reduce the frequency of monitoring for about 35 years after its initial approval of clozapine in 1989. The COVID-19 pandemic emerged as a blessing in disguise for clozapine. Due to COVID-19 restrictions, strict hematological monitoring could not be performed in different parts of the world, and many researchers proposed different recommendations for the frequency of WBC monitoring.[24] Studies have shown that extended or irregular hematological monitoring is not associated with agranulocytosis and increased mortality.[25–27] Based on the emerging data showing a lower incidence of neutropenia, many clinicians/researchers have recommended reducing the hematological monitoring for clozapine. Besides clinicians, many patient groups and family members also requested the FDA to reconsider the need for monitoring. Many patients and caregivers provided testimonies that “NO BLOOD, NO CLOZAPINE” and errors in paperwork, despite giving blood samples, resulting in a lack of clozapine dispensing, led to rapid deterioration, relapse of illness, self-harm, suicide, and violence.[28] The patient and family groups also represented to the FDA about the profound implications of barriers in clozapine treatment in the form of reluctance on the part of the prescribers, need to frequent visits for the blood testing and medications, laboratory mix-ups, fear of needles, denied blood draws for unpaid balances, data entry delays, REMS program confusion, nonparticipating pharmacies, and even mistaking clozapine for a controlled substance with addiction risks. They also highlighted the issues of cognitive impairment, poor insight, and uncooperative and paranoid behaviors of patients that led to a lack of cooperation with the REMS. They also argued that REMS could help to reduce the risk of agranulocytosis and associated death, but what about the deaths related to nonuse of clozapine?[28] It also became apparent to the FDA that approximately one-fourth to one-third of patients on clozapine were receiving it outside the purview of REMS.[29] However, with the emerging evidence, a panel formed by the FDA voted against continuing the REMS program with an overwhelming majority, with 14 votes in favor of discontinuing the program, against one vote to continue it.[29] As a result, on February 24, 2025, the US FDA notified that the REMS program for clozapine is discontinued, effective immediately, as the beneficial effects of clozapine outweigh the risk of neutropenia. The FDA news stated that the FDA no longer expects prescribers, pharmacies, and patients to participate in the REMS program or to report the results of ANC blood tests prior to pharmacies dispensing clozapine. However, the FDA notice mentioned that it still recommends that clinicians monitor ANC according to the monitoring frequencies described in the prescribing information.[30] However, the FDA did not provide any information about modifications to the ANC monitoring. Many groups have come up with alternative monitoring recommendations for the ANC for patients on clozapine. The European Clozapine Task Force, which comprises psychiatrists and pharmacologists from 18 countries under European Medicines Agency (EMA) regulation, proposed a reduction in the ANC values for starting, discontinuation, and increasing the monitoring to twice weekly; and also suggested a decrease in the frequency of ANC monitoring after 18 weeks [Table 1]. This proposal also provides lower thresholds for ANC for patients with Benign Ethnic Neutropenia.[31] The consensus guidelines from a global Delphi panel that was established based on a Delphi survey involving 64 psychiatrists and 12 pharmacists the first round and 84 psychiatrists/pharmacists in the second round proposed reduction in the ANC threshold for stopping clozapine to ANC <1000/µL and to carry out ANC monitoring once weekly for first 18 weeks of clozapine therapy, then four weekly up to 2 years of clozapine treatment and once a year after 2 years of clozapine initiation [Table 1]. The majority of participants also endorsed the shared care program between the psychiatrist and primary care physicians, and recommended that after 2 years of clozapine treatment, individuals on clozapine be monitored for side effects at the primary care level (general physician).[32] When comparing the European clozapine task force proposal and the consensus guidelines based on the Delphi panel, there are more similarities between the two than differences. Accordingly, it can be said that there is an emerging consensus that, after 18 weeks, hematological monitoring for clozapine should shift to once a month for up to 2 years and then once a year after 2 years.Table 1: Different proposals for hematological monitoring for clozapineWHAT CHANGES WILL THIS REDUCTION IN MONITORING BRING? This reduction in monitoring will likely reduce the stigma associated with clozapine. The reduced monitoring may help clinicians to offer clozapine more often to the needy TRS patients and reduce the delay in starting clozapine. It is suggested that a delay in beginning clozapine by more than 2.8 years is associated with a poor response to clozapine.[33] Accordingly, it can be said that timely starting of clozapine will possibly help in improving the outcome of patients with TRS and those on clozapine. Reduction in the ANC monitoring and better access to clozapine without the blood reports can also reduce the risk of relapse and worsening of mental state, which has been reported to be an outcome of a complicated REMS program. It is also hoped that the reduction in monitoring will alleviate the distress of patients and their family members.