On the Possible Mechanisms and Predictability of Clozapine†-Induced Agranulocytosis

Abstract

Studies were conducted on serum removed from 15 patients before, during, and after, clozapine-induced agranulocytosis. Cytotoxic studies were compared with samples taken from patients during treatment with clozapine who did not develop agranulocytosis or treatment controls (TC); additional controls consisted of allogeneic (NC) and autogeneic serum from apparently normal people. The effect of serum on measurable functions of polymorphonuclear neutrophils (PMNs) taken from normal people was tested. Procedures under study included suppression of postphagocytosis-induced 14C02-indicated respiratory burst, as well as ejection of try pan blue by test PMNs. PMNs exposed to active agranulocytosis serum plus complement displayed diminished 14C02 emission during phagocytosis or failed to eject trypan blue. PMNs exposed to serum of TC and NC continued to function normally as regards 14C02 emission and trypan blue ejection. Five patients studied before the development of agranulocytosis showed suppressed PMN function, which increased to peak value during agranulocytosis and then disappeared within 40 days of recovery. Similar suppression of colony forming units of granulocytes and macrophages (CFU-GM) was found whenever agranulocytosis serum was included in the marrow culture. The cytotoxic material required complement for its full expression, was not dialysable, was neutralised by anti-IgM serum, and was absorbed by test PMNs. Furthermore, solutions of clozapine or 5 of its metabolites offered no similar suppression of PMN function in vitro after incubation in an aqueous medium or with normal serum. These observations favour development of an immunogenic clone in sensitive people during active treatment with clozapine, which eventually leads to precipitous depletion of PMNs and their precursors. The early appearance of this suppressive substance may offer an early warning for development of agranulocytosis.

Human Leukocyte Antigen System in Clozapine-lnduced Agranulocytosis

“…Thus the mecha nism of clozapine-induced agranulocytosis has not been identified yet. although a factor cytotoxic to granulocytes has been isolated in the sera of patients with acute cloza pine-induced agranulocytosis [23], It has also been suggest ed that a particular clozapine metabolite, N-desmethylclozapine, may be responsible for this adverse reaction [24], In our study, agranulocytosis was observed in 3 out of 43 clozapine-treated patients (7%). The percentage is much higher than those quoted overall in the past 0.8% but lower than that reported by Lieberman et al [14] in Jewish patients (20%).…”

“…As has been reported, drug-induced unwanted effects of the haematopoietic system are possibly due to immunolog ical reactions, drug toxicity including direct toxic effect of a drug or one of its metabolites, congenital metabolic defects as well as idiosyncratic reactions [20][21][22]. Thus the mecha nism of clozapine-induced agranulocytosis has not been identified yet.…”

Clozapine-induced agranulocytosis and thrombopenia in a patient with dopaminergic psychosis

“…The mechanisms of bone marrow toxicity from clozapine are still under debate. Toxic damage from clozapine or its metabolites (Veys et al, 1992) and immunological reactions (Pisciotta et al, 1992) are discussed. Recent studies demonstrate that clozapine probably impairs two stages of hematopoesis: damage to myeloblasts results in persisting agranulocytosis, toxic effects to late stages of granulocyte maturation result in granulocytopenia (Veys et al, 1992).…”

Hematotoxicity: In Vitro and Ex Vivo Compound Profiling

“…Clozapine and olanzapine bioactivation is thought to occur through a nitrenium ion [20]; however clozapine but not olanzapine induce toxicity to neutrophils. This can lead to an immune-mediated depletion of neutrophils and their precursors (CFU-GM) [21]. Also, nonsteroidal antiinflammatory drugs (NSAIDs) have pro-oxidant radicals that when metabolized could cause oxidative stress [22].…”