Evaluation of 96 cases of apparent clozapine-induced severe neutropenia

Background

Clozapine remains underused despite its unparalleled efficacy in treatment-refractory schizophrenia. One of the reasons for its underuse is the fear of severe neutropenia and its consequences.

Aims

To scrutinise the association between severe neutropenia and clozapine in a cohort of patients clinically diagnosed with clozapine-induced severe neutropenia.

Method

We used data from the South London and Maudsley National Health Service Foundation Trust’s anonymised case register, known as the Clinical Record Interactive Search. We extracted details of cases where clozapine use was associated with two consecutive neutrophil counts below 1.5 × 109/L. A panel of clinicians independently assessed each case. Agreement was reached on which cases clozapine was the likely or definite cause of the severe neutropenia, the risk to life and whether or not rechallenge with clozapine could be attempted.

Results

There were 96 cases where two consecutive neutrophil counts below 1.5 × 109/L were registered. The panel judged that 9 (9.4%) were definitely caused by clozapine and a further 11 (11.5%) were probably caused by clozapine. Overall, 18 (18.8%) patients should be precluded from ever receiving clozapine again according to the panel (all from the 20 cases where clozapine was the definite or probable cause). Of the remaining 76 cases of severe neutropenia the cause could not be determined in 60 cases, but in 11 cases the cause was benign ethnic neutropenia, in 2 others the cause was cancer chemotherapy, in 2 it was infections and in 1 it was laboratory error. In almost 80% of cases, clozapine was not the clear cause of the neutropenia observed.

Conclusions

The large majority of severe neutropenia episodes mandating cessation of clozapine may not be caused by clozapine. Threshold-based monitoring systems cause unnecessary stopping of clozapine because they lack the necessary specificity for clozapine-related blood disorders.