Treatment-resistant schizophrenia constitutes a significant challenge for clinicians, patients, and their families. It is associated with major impairment in social, occupational, and vocational spheres.1 The challenge is even higher in present times, after the evolution of medical act from paternalistic approach to the concept of shared decision, patient–physician therapeutic alliance, and informed consent.2,3 Although the definition of treatment-resistant schizophrenia varies, the main features are psychotic symptoms that failed to respond to 2–3 conventional antipsychotics, preferably from 2 different classes, at appropriate doses that are equivalent or higher to chlorpromazine 600 mg daily and used for a minimum of 4–6 weeks.4 Response is typically defined as at least 20% symptom reduction as measured by rating scales such as Brief Psychiatric Rating Scale (BPRS) or Positive and Negative Syndrome Scale (PANSS).5–7 It is important to note that to meet the criteria for treatment resistance, adequate adherence is implied. Given the absence of precise definition, the prevalence of treatment-resistant schizophrenia is difficult to estimate. However, different sources cite prevalence as being between 5% and 60%.8,9
Clozapine is a second-generation antipsychotic that carries a unique indication for treatment-refractory schizophrenia. Its efficacy and superiority to first-generation antipsychotics was first studied and demonstrated in the late 1980s10 and has been reproduced by others in later studies.11 In addition, clozapine has been shown to reduce suicidality in patients with schizophrenia12 and, up until this year, has been the only drug with an effect on tardive dyskinesia.13 However, patients and clinicians alike are hesitant to initiate the drug secondary to the perceived burden of frequent blood monitoring and fears of potential serious, and even life-threatening, adverse effects, such as agranulocytosis and severe neutropenia, myocarditis and cardiomyopathy, gastrointestinal hypomotility leading to bowel infarction, pancreatitis, and renal insufficiency. As a result of reluctance to start the drug, by the time many patients started taking clozapine, they have failed in numerous other drugs and combination of drugs.
Clinically, complex situations arise when patients survive major adverse effects of clozapine to clozapine during treatment with clozapine but have severe psychotic symptoms that do not respond to any other pharmacological intervention. Therefore, it is important to know if and when it is safe to proceed to a clozapine rechallenge, but these issues have never been assessed in randomized controlled trials, controlled studies without randomization, quasi-experimental studies, in comparative, correlational, and case–control studies, or expert committee reports, that is, acceptable levels of evidence for developing clinical guidelines.14 All we have are individual case reports, which contain clinical narratives that cannot be generalized, may be prone to publication bias through selection of positive experiences by authors and journal editors, and may reflect the memory recall inherent in retrospective and unplanned work.15 Nonetheless, we believe that by systematically searching and assembling issue-specific case reports, clinicians may derive knowledge helpful for informing decisions when sources with higher levels of evidence are not available.
In 2012, we evaluated the 138 case reports of clozapine rechallenge after life-threatening adverse effects16 and concluded that the intervention was reasonable in patients who had returned to baseline after neutropenia (ie, absolute neutrophil count 500/cubic millimeter or greater) and neuroleptic malignant syndrome (NMS) but was not recommended for agranulocytosis (ie, absolute neutrophil count less than 500/cubic millimeter) and myocarditis. For this updated evaluation of the safety of clozapine rechallenge, we expanded the database with the case reports published in the past 5 years.
We used PubMed site to search the published literature for all reports of cases and studies of patients who were rechallenged after developing adverse reactions to clozapine from January 1972 through June 2017. The search was performed using the search terms “clozapine,” “rechallenge,” and “retrial.” Successful rechallenge was defined as a case when a patient did not redevelop the complication of interest or any other serious adverse effect during an interval time of follow-up as determined by the authors of the report. We calculated confidence intervals (CIs) for adverse effects that had at least 5 reported patients. The outcome of rechallenge after a particular adverse effect was considered favorable if the proportion of patients able to continue clozapine treatment after rechallenge had a lower bound of the continuity-corrected 95% CI of greater than 50%.
Our search identified a total of 259 published case reports of clozapine rechallenge after major adverse effects, of which 138 had been published by July 2011 and analyzed in a previous publication16 and 121 published from August 2011 through June 2017. Of the 259 cases, 222 reported rechallenge after hematological adverse effects, 21 after cardiac events, 7 after NMS, and 6 after gastrointestinal tract disorders (Table 1). The 95% CI was calculated for the 4 adverse effects with at least 5 case reports, that is, neutropenia, agranulocytosis, myocarditis, and NMS.
The outcome of rechallenge was favorable in 128/203 patients after neutropenia (63.0%, 95% CI, 56.0%–69.6%), 3/17 after agranulocytosis (17.7%, 95% CI, 4.7%–44.2%), 11/17 after myocarditis (64.7%, 95% CI, 38.6%–84.7%), and 7/7 after NMS (100%, 95% CI, 56.1%–100%). No fatal outcomes were reported in any of the cases.
Based on the 259 case reports of clozapine rechallenge after adverse effects with life-threatening potential, our analysis suggests that starting clozapine after return to baseline is a reasonable clinical option for patients who had developed neutropenia or NMS, but not after agranulocytosis or myocarditis. The addition of the 121 cases published in the past 5 years did not change the conclusion reached by us16 after looking at the 138 cases reported from 1972 through 2011. The new data set indicates that most reports continue to describe cases of neutropenia and that there is increased interest in reporting rechallenge after myocarditis. There may be a selection bias among the authors of case reports as to which rechallenge outcomes get written up and published. Furthermore, there have been only 2 new rechallenge cases after agranulocytosis potentially signifying that clinicians do not anticipate a successful rechallenge based on previously reported data. On the contrary, there has been an increase in the number of rechallenge cases reported after the development of myocarditis.
The study identified agranulocytosis, myocarditis, pancreatitis, renal failure, and clozapine-induced lupus erythematosus as nonrechallengeable adverse effects. Only 3 reported patients have been successfully rechallenged after agranulocytosis, making up only 18% of patients. Historically, agranulocytosis has been the most feared adverse effect of clozapine. It led to the drug's withdrawal from the market after reports of fatalities among patients who developed agranulocytosis. Currently, prescribers are required to monitor patients' blood work including complete blood cell count once weekly for the first 6 months after the initiation of the drug, then every 2 weeks for the next 6 months, and every 4 weeks thereafter.77 If the patient's absolute neutrophil count drops below 500, clozapine has to be discontinued. According to the Clozapine Remote Electronic Monitoring System guide for health care providers,77 clozapine should not be restarted unless “prescriber determines benefits outweigh risks.” Based on our findings, the likelihood of successful rechallenge is very low. It may benefit the patient to consider other treatments, including nonpharmacological interventions such as electroconvulsive therapy.78 By contrast, neutropenia is a rechallengeable condition, as 63% of the reported cases were able to resume clozapine treatment. This difference is likely related to a higher incidence of neutropenia as an adverse effect and clinicians' acceptance of rechallenge as an appropriate strategy. The risks are minimized by the increased frequency of blood monitoring and the availability of filgrastim or another granulocyte colony-stimulating factor preparations.79,80 These drugs stimulate the proliferation and differentiation of myeloid precursor cells in the bone marrow and enhance mature neutrophil function.80 They can be used to shorten the recovery time after agranulocytosis and neutropenia. However, currently, there are no guidelines that would formally describe indications and treatment with granulocyte colony-stimulating factor preparations in patients undergoing clozapine rechallenge. In addition, lithium has been used during clozapine rechallenge. It enhances the release of reserve granulocytes from bone marrow, upregulates granulopoiesis-stimulating factors, and redistributes marginated neutrophils.80 Finally, clinicians should be aware of benign ethnic neutropenia. It is most commonly observed in patients of African descent but does occur in other races as well.81 These patients have lower baseline neutrophil counts and, hence, have different thresholds for neutropenia.82
Since 2011, we have seen an increase in the number of reported cases of clozapine rechallenge after myocarditis. It was successfully challenged in 11 of 17 patients or 64.7%. The proportion is similar to that calculated for rechallenge after neutropenia but failed to meet the lower bound of 95% CI set at 50%. Assuming that the current success rate remains stable, we will need at least 50 cases before recommending rechallenge for clozapine-induced myocarditis. Almost all these cases have occurred in Australia or New Zealand,47,51,53,55 a geographical difference that is possibly explained by the clinicians' lower threshold for diagnosing the condition and monitoring, and by the widespread use of laboratory monitoring of troponin and C-reactive protein during clozapine titration.83,84 Patients with absent or mild left ventricular dysfunction at the time of diagnosis seem to have a better chance of avoiding a new deterioration during rechallenge.53
The outcome after NMS continues to be excellent. All 7 patients or 100% were successfully rechallenged. However, NMS can be controversial during treatment with clozapine, as it can mimic other conditions, such as clozapine-induced benign fever. Slower titration of clozapine is the only strategy that has been used.65,66
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