Valproate-related neutropenia and lithium-related leukocytosis in patients treated with clozapine: a retrospective cohort study

BACKGROUND: Neutropenia is a noteworthy side effect of clozapine, which might warrant this drugs’ discontinuance for safety. Studies have revealed that the risk of neutropenia increases with concurrent administration of valproate, but the evidence was limited. Conversely, lithium may have an ameliorating effect on clozapine-induced neutropenia. This study explored the effects of valproate and lithium on white blood cell counts in patients treated with clozapine. METHODS: We retrospectively investigated the electronic medical records from one tertiary psychiatric hospital in Taiwan and enrolled patients discharged between January 1, 2006, and December 31, 2017, with clozapine prescriptions. We scrutinized their demographic data, medications, and hematological results at discharge and during follow-up outpatient clinic visits over the subsequent 3 years. Patients were classified into four groups: clozapine only (CLO), clozapine and valproate (CLO + VAL), clozapine and lithium (CLO + Li), and clozapine, valproate, and lithium (CLO + VAL + Li). We also identified hematological events (neutropenia or leukocytosis) of these patients during outpatient follow-ups. RESULTS: Of the included 1084 patients, 55(5.1%) developed neutropenia. Concurrent valproate use (odds ratio [OR] = 3.49) and older age (p = .007) were identified as risk factors. Moreover, 453 (41.79%) patients developed leukocytosis. Younger age; male sex; and concurrent use of lithium (OR = 3.39, p < .001), clozapine daily dosage, and benzodiazepines were the risk factors for leukocytosis. CONCLUSION: Concurrent valproate use and older age are associated with the development of neutropenia in patients treated with clozapine. Concurrent lithium usage, younger age, male sex, and concurrent benzodiazepine use might be related to leukocytosis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12888-023-04659-2.