Abstract
The wider use of clozapine is limited by the risk of agranulocytosis and the associated requirement for monitoring of neutrophil counts. We searched local electronic patient records for cases of agranulocytosis occurring during clozapine treatment during the period 2007–2020. We found 23 episodes recorded as agranulocytosis in clozapine patients. Of these, nine met pre-defined criteria and were considered episodes of life-threatening agranulocytosis (LTA). These episodes of clozapine-induced LTA exhibited a distinct pattern of continuous and rapid neutrophil count decline to zero or near zero. Mean time for neutrophils to fall from ANC > 2 to ANC <0.5 × 109/L was 8.4 days (range 2–15 days). Each event was also characterised by a prolonged nadir and delayed recovery (range 4–16 days). Non-LTA episodes were, in contrast, brief and benign. We conclude that an important proportion of cases of agranulocytosis identified in people prescribed clozapine are not life-threatening and may not even be clozapine-related. Monitoring schemes should aim to identify true clozapine-induced LTA as opposed to threshold-defined nominal agranulocytosis. Genetics studies might benefit from examining associations with clozapine-induced LTA rather than with recorded cases of agranulocytosis or neutropenia.
Highlights
Clozapine was the first drug found to possess antipsychotic action without causing extrapyramidal effects[1]
We defined clozapine-associated life-threatening agranulocytosis (LTA) as that occurring in people stopping clozapine when two consecutive neutrophil counts were recorded as being below 0.5 × 109/L/1.0 × 109/L and where there was evidence of infection, or the prescribing of antibiotics or G-CSF
The nine cases we identified showed a consistent pattern: neurophil counts fell quickly from a normal level and remained substantially below 0.5 × 109/L for several days until natural recovery or until GCSF took effect
Summary
Clozapine was the first drug found to possess antipsychotic action without causing extrapyramidal effects[1]. It eventually gained product registration and was marketed in Europe the early 1970s. Clozapine’s association with agranulocytosis was first reported in 1975 when Finnish authorities described eight cases occurring in around 2000 patients prescribed clozapine[2] (an incidence of approximately 0.4%). Outside Finland, the risk of clozapineassociated agranulocytosis at that time was estimated to be 0.027%3. A later and more complete analysis of the cases occurring in Finland suggested that there were “17 cases of neutropenia or agranulocytosis amongst about 3000 patients treated”[4]. There had been ten cases of agranulocytosis (seven of which were fatal)—an incidence of agranulocytosis of 0.33%. Clozapine was withdrawn worldwide and later reintroduced with strict haematological monitoring
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