Clozapine rechallenge or continuation despite neutropenia or agranulocytosis using colony-stimulating factor: A systematic review.

OBJECTIVES: Rechallenge/continuation of clozapine in association with colony-stimulating factors (CSFs) following neutropenia/agranulocytosis has been reported, but many questions remain unanswered about efficacy and safety. This systematic review aims to assess the efficacy and safety of rechallenging/continuing clozapine in patients following neutropenia/agranulocytosis using CSFs. METHODS: MEDLINE, Embase, PsycInfo, and Web of Science databases were searched from inception date to July 31, 2022. Articles screening and data extraction were realized independently by two reviewers, according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 systematic review guidance. Included articles had to report on at least one case where clozapine was rechallenged/continued using CSFs despite previous neutropenia/agranulocytosis. RESULTS: Eight hundred forty articles were retrieved; 34 articles met the inclusion criteria, totaling 59 individual cases. Clozapine was successfully rechallenged/continued in 76% of patients for an average follow-up period of 1.9 years. There was a trend toward better efficacy reported in case reports/series, compared with consecutive case series (overall success rates of 84% and 60%, respectively, p-value = 0.065). Two administration strategies were identified, "as-needed" and prophylactic, both yielding similar success rates (81% and 80%, respectively). Only mild and transient adverse events were documented. CONCLUSIONS: Although limited by the relatively small number of published cases, factors such as time of onset to first neutropenia and severity of the episode did not seem to impact the outcome of a subsequent clozapine rechallenge using CSFs. While the efficacy of this strategy remains to be further adequately evaluated in more rigorous study designs, its long-term innocuity warrants considering its use more proactively in the management of clozapine hematological adverse events as to maintain this treatment for as many individuals as possible.

Management of Rhabdomyolysis in a Patient Treated with Clozapine: A Case Report and Clinical Recommendations.

Clozapine has a unique efficacy in treatment-resistant schizophrenia. Its use is, however, associated with potential adverse events. Among those, clozapine induced rhabdomyolysis can compromise clozapine treatment. Recommendations surrounding the management of this rare adverse event are limited. We present a case of clozapine-induced rhabdomyolysis. A 20-year-old Caucasian male diagnosed with resistant schizophrenia developed, after a 5-month total exposition and a significant response to treatment, a marked creatine kinase (CK) elevation and important myalgia in the weeks following an increment from 175 to 200 mg of the daily dose of clozapine. This event also coincided with weight training as reported by the patient. The patient was hospitalized, and the clozapine was stopped following the diagnosis of rhabdomyolysis (CK 45,564 U/L). The cause of rhabdomyolysis was thoroughly investigated, and clozapine was held accountable for most. Clozapine cessation led to a severe psychotic relapse. Clozapine rechallenge while strictly monitoring CK was then performed allowing a significant clinical response. Clozapine was pursued despite two other episodes of mild CK elevations observed following weight training. Rhabdomyolysis comes as a rare adverse event of clozapine and its mechanism is poorly understood. Evidence on clozapine rechallenge following this adverse event is lacking and the innocuity of such practice is unknown. The unique aspect of our case report is that a shared decision with the medical team, patient and family led to a proactive clozapine rechallenge. More research is needed to provide robust guidelines and evidenced based approaches for clinicians in such a clinical dilemma.

Clozapine rechallenge following neutropenia using granulocyte colony-stimulating factor: A Quebec case series.

BACKGROUND: Clozapine has a unique efficacy profile among individuals suffering from treatment-resistant schizophrenia, but is associated with hematological side effects. The use of granulocyte colony-stimulating factors (G-CSF) to allow clozapine continuation or rechallenge has emerged as a promising option, but evidence is still scarce. AIM: To describe the largest case series so far published regarding this practice. METHOD: A national clozapine hematological monitoring database was consulted to identify all patients who had had neutrophil count <1.5 × 109/L since 2004 in Quebec and was cross-referenced with hospital pharmacy software to identify patients who had received at least one dose of G-CSF, such as filgrastim, while being exposed to clozapine. All data were collected retrospectively, using patients' medical files, from January to July 2019. RESULTS: Using G-CSF, three out of eight patients could maintain clozapine despite neutropenia episodes that otherwise would have required treatment discontinuation. The only side effect reported was mild short-lived back pain, over a mean 3-year follow-up period. In all but one case, filgrastim was used on an "as-needed" basis at doses of 300 mcg administered subcutaneously. CONCLUSION: These results suggest that the "as-needed" use of G-CSF is well-tolerated and may allow clozapine rechallenge in some well-selected patients, adding to the paucity of data regarding long-term safety and efficacy of this strategy. More research may help to better define potential candidates and optimal regimen of such practice.