Absolute and Dose-Adjusted Serum Concentrations of Clozapine in Patients Switching vs. Maintaining Treatment: An Observational Study of 1979 Patients

CNS Drugs. 2021 Sep;35(9):999-1008. doi: 10.1007/s40263-021-00847-4. Epub 2021 Aug 20.


Background: Clozapine is an effective drug for the management of schizophrenia that has not responded to other agents, but some patients experience insufficient or adverse effects and discontinue treatment.

Objective: We investigated a potential association between clozapine serum concentrations and switching to other antipsychotics in a large real-world patient population from a therapeutic drug monitoring service.

Methods: Absolute and dose-adjusted serum concentrations (concentration-to-dose ratios [C/D ratios]) of clozapine during dosing between 100 and 1000 mg/day were measured in 1979 Norwegian patients during the period 2005-2019. These variables were compared in patients switching to other antipsychotic drugs versus maintaining clozapine treatment using linear mixed models. Smoking habits were known for 49% of the patients. To prevent potential nonadherence affecting clozapine switching, only patients with serum concentrations above 50% of the lower reference range were included.

Results: In total, 190 patients (9.6%) switched from clozapine to another antipsychotic drug during the study period, whereas the remaining patients were not detected as switchers and were interpreted as maintaining treatment. Patients switching treatment had 23.5% lower absolute concentrations (954 vs. 1245 nmol/L; p < 0.001) and 15.7% lower daily doses (305 vs. 362 mg/day; p < 0.001) of clozapine than did nonswitchers, making the clozapine C/D ratio 9.7% lower in switchers than in nonswitchers after correcting for smoking habits (2.80 vs. 3.10 nmol/L/mg/day; p = 0.032).

Conclusions: The present study suggests that decreased absolute and dose-adjusted serum concentrations of clozapine were associated with clozapine discontinuation. The significantly reduced clozapine concentrations regardless of prescribed dose in switchers versus nonswitchers may indicate a pharmacokinetic mechanism underlying the risk of clozapine discontinuation.

Publication types

  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antipsychotic Agents / administration & dosage
  • Antipsychotic Agents / blood*
  • Clozapine / administration & dosage
  • Clozapine / blood*
  • Dose-Response Relationship, Drug
  • Drug Monitoring / methods
  • Drug Substitution / methods*
  • Female
  • Humans
  • Longitudinal Studies
  • Maintenance Chemotherapy / methods*
  • Male
  • Norway / epidemiology
  • Retrospective Studies
  • Schizophrenia / blood*
  • Schizophrenia / drug therapy*
  • Schizophrenia / epidemiology


  • Antipsychotic Agents
  • Clozapine