Re-titration rates after clozapine-induced neutropenia or agranulocytosis: A case report and literature review

Abstract

Clozapine-induced neutropenia occurs in 3-5% of individuals treated with clozapine. Current US guidelines require interruption of clozapine when the absolute neutrophil count (ANC) drops below 1000 cells/mm. There is minimal available guidance for what dosing schedule to use when restarting clozapine after an episode of neutropenia. Here, we present a case of a 50-year-old Caucasian female with a history of schizoaffective disorder who was successfully rechallenged on clozapine one month after developing clozapine-induced neutropenia (ANC 600 cells/mm). To understand published re-titration rates of clozapine after neutropenia, we conducted a literature review using a using the PubMed database and found only seven case reports that unambiguously reported a clozapine dosing schedule during re-challenge. All were successful except one, a case of clozapine rechallenge after agranulocytosis. Including this case presentation, six out of eight cases restarted clozapine more cautiously than recommended by the US guidelines for a new clozapine initiation. We cannot comment what role a slower or more rapid titration plays in a successful rechallenge after neutropenia with the available evidence. We encourage researchers to publish their dosing schedule in detail after an episode of neutropenia or agranulocytosis.

Clozapine in the treatment of refractory schizophrenia: a practical guide for healthcare professionals

“…Thus cautious reintroduction of clozapine may be deemed appropriate in conjunction with haematological advice. 47 However, if clozapine was the cause of the (impending) agranulocytosis, progression to agranulocytosis is likely to be more rapid and more severe than in the initial episode. 48 …”

Continuation of Treatment With Clozapine After an Episode of Neutropenia

“…It contrasted from several clozapine "rechallenge" studies reporting treatment restarting after an extended period of discontinuation. [11][12][13][14][15][16] Rechallenge studies used medications like lithium and granulocyte colony stimulating factor to manage neutropenia. 8,11,13,14 This report did not involve the use of such treatments to manage neutropenia.…”

“…This report's most significant aspect was the clozapine treatment continuation with little or no interruption after a neutropenic episode. It contrasted from several clozapine “rechallenge” studies reporting treatment restarting after an extended period of discontinuation 11–16 . Rechallenge studies used medications like lithium and granulocyte colony stimulating factor to manage neutropenia 8,11,13,14 .…”

Clozapine rechallenge and initiation despite neutropenia- a practical, step-by-step guide

“…c. Retitration rates. Given the probable contribution of an immune mechanism, a slower clozapine titration may be useful; as yet there is no evidence to support this [79]. d. How long to continue Lithium or G-CSF.…”