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

Acta Psychiatr Scand. 2022 Aug;146(2):168-178. doi: 10.1111/acps.13428. Epub 2022 Apr 1.


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.

Keywords: COVID-19 vaccine; clozapine; plasma concentration; safety.

Publication types

  • Observational Study

MeSH terms

  • Agranulocytosis / chemically induced
  • Agranulocytosis / drug therapy
  • Antipsychotic Agents* / adverse effects
  • Antipsychotic Agents* / blood
  • COVID-19 Vaccines* / adverse effects
  • COVID-19* / prevention & control
  • Clozapine* / adverse effects
  • Clozapine* / blood
  • Cohort Studies
  • Humans
  • Leukocytes
  • Leukopenia* / chemically induced
  • Leukopenia* / drug therapy
  • Vaccination


  • Antipsychotic Agents
  • COVID-19 Vaccines
  • Clozapine