Clozapine and COVID‐19 Vaccination: Effects on blood levels and leukocytes. An observational cohort study

Abstract

Objective To investigate the safety of COVID‐19 vaccination in patients on clozapine as regards plasma clozapine concentration and haematological parameters. Methods We conducted a multicentre observational cohort study from 22 February 2021 to 2 September 2021. Primary outcomes were clinically relevant increase in clozapine blood levels (>100 μg/L increase compared to baseline) and clozapine alert levels (>1000 μg/L). Secondary outcomes were granulocytopenia, leukocytopenia and lymphocytopenia. Outcomes were measured approximately 5 days after the first and (where applicable) second dose of COVID‐19 vaccine. Results This study included 139 patients. Compared to baseline, clozapine blood levels increased significantly (ES = 0.28, p = 0.003) after the second vaccination. Clinically relevant increases in clozapine blood levels occurred in 20/92 patients (22%) and in 16/56 patients (29%) during the first and second phases, respectively. Clozapine alert levels developed in one patient (1%) following the first dose and in three patients (5%) after the second dose. In both phases, changes in white blood cells (WBC) were limited to mild granulocytopenia (3% and 5%), moderate granulocytopenia (1% and 0%) and leukocytopenia (2% and 3%) without cause for extra monitoring according to the guideline. Conclusion In general, as regards WBC counts COVID‐19 vaccination seems to be safe in patients with SMI. Changes in WBC had no clinical implications. Psychoeducation on the symptoms of clozapine intoxication is recommended, especially in patients with clozapine blood levels approaching the upper limit of the therapeutic range. Increase in the C‐reactive protein (CRP) level can signal inflammation rapidly and help to prevent clozapine intoxication following vaccination.

COVID-19 Vaccines and the Virus: Impact on Drug Metabolism and Pharmacokinetics

“…Observations from case studies need to be supported or discounted based on findings in larger cohort studies. A report of the effects of SARS-CoV-2 vaccines in 139 patients treated with clozapine found no clinically significant changes in symptoms or hematological parameters, but did support the observation from the present case of an increase in median clozapine level (after second dose) of effect size 0.28 and p=0.003 (Veerman et al, 2022). Larger studies such as this could provide the opportunity to investigate potentially complex interactions that could occur with CYP1A2 activity depending on concurrent exposures, such as the smoking status of patients.…”

“…However, case reports indicated clozapine levels could rise as much as three-fold during SARS-CoV-2 infection, with an increase in the clozapine:norclozapine ratio (Tio et al, 2021). Dose reduction was recommended for clozapine-treated patients experiencing signs and symptoms consistent with clozapine toxicity (Siskind et al, 2020;Veerman et al, 2022).…”

Haematological changes and adverse events associated with BNT162b2 mRNA COVID‐19 vaccine in patients receiving clozapine—Findings from an audit

“…We found one (0.8%) and two cases (1.7%) of asymptomatic mild neutropenia after the first and second dose respectively with spontaneous recovery, and all three cases had a history of granulocytopenia. Veerman et al similarly reported a low incidence of mild granulocytopenia (3% and 5%), after the first and second dose of the COVID‐19 vaccinations respectively, without cause for additional monitoring 5 …”

“…Veerman et al similarly reported a low incidence of mild granulocytopenia (3% and 5%), after the first and second dose of the COVID-19 vaccinations respectively, without cause for additional monitoring. 5 The strength of our audit is the inclusion of a baseline FBC and 72 hours post-vaccination monitoring for any adverse effects. We drew blood samples 1 week postvaccination with considerations to the case report described by Thompson et al 4 However, it was possible to have underestimated the incidence and severity of haematological or other adverse events as we only obtained 2 follow-up FBCs and captured adverse events only for 72 hours post-vaccination.…”

“…Veerman et al similarly reported a low incidence of mild granulocytopenia (3% and 5%), after the first and second dose of the COVID‐19 vaccinations respectively, without cause for additional monitoring. 5 …”