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

Abstract

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.

Can lithium be used in the setting of clozapine commencement in patients with COVID‐19 associated neutropenia: A case report

“…Considering the temporal association between the onset of neutropenia and COVID‐19 infection in this scenario, ostensibly COVID‐19 was suggested to be a key factor. The true causality of neutropenia in this scenario was clouded by the presence of confounding factors such as clozapine, sodium valproate, and olanzapine; medications known to be associated with neutropenia and the inherent known increased risk of CAN in the initial period following clozapine commencement 5,23,38,39 . Moreover, a cohort study has suggested that concurrent use of sodium valproate is a significant additional risk factor for CAN (up to 5‐fold higher compared to clozapine alone) 39 .…”

“…The true causality of neutropenia in this scenario was clouded by the presence of confounding factors such as clozapine, sodium valproate, and olanzapine; medications known to be associated with neutropenia and the inherent known increased risk of CAN in the initial period following clozapine commencement. 5,23,38,39 Moreover, a cohort study has suggested that concurrent use of sodium valproate is a significant additional risk factor for CAN (up to 5-fold higher compared to clozapine alone). 39 We were also unable to confirm if the improvements in WCC and ANC counts occurred purely because of lithium (immunomodulating and/or neutrophilic effects), temporary cessation of clozapine, or natural recovery from COVID-19 infection.…”

“…5,23,38,39 Moreover, a cohort study has suggested that concurrent use of sodium valproate is a significant additional risk factor for CAN (up to 5-fold higher compared to clozapine alone). 39 We were also unable to confirm if the improvements in WCC and ANC counts occurred purely because of lithium (immunomodulating and/or neutrophilic effects), temporary cessation of clozapine, or natural recovery from COVID-19 infection.…”

Severe Clozapine-Induced Agranulocytosis, Pharmacodynamic Synergism, and Lithium Promyelocytic Effects in Granulocyte Colony-Stimulating Factor (G-CSF) Resistance or Delayed Response: A Case Report

“…Though all these medications individually can cause agranulocytosis, the simultaneous use of all 3 drugs plus a haldol decanoate injection may explain the patient's absolute neutropenia count of zero. Concurrent valproate use and older age are associated with the development of neutropenia in patients treated with clozapine [10].…”

Data Mining for Risks of Clozapine Side Effects, Including Neutropenia, Associated with Lithium Carbonate Administration: Analysis Using the Japanese Adverse Drug Event Report Database

“…No association of the use of lithium carbonate with the risk of hematopoietic leukopenia was represented by the analyses with the data of 2453 clozapine users (Table 3 ). A retrospective cohort study using the medical record from a tertiary psychiatric hospital in Taiwan reported that neutropenia did not occur in 45 patients receiving clozapine and lithium, and that it developed in 20 (2.9%) out of 700 lithium-untreated clozapine users [ 28 ]. Our study used a spontaneous reporting database, and analyzed 530 patients exposed to clozapine and lithium carbonate.…”