The Effect of Valproic Acid on Olanzapine Serum Concentration: A Study Including 2791 Patients Treated With Olanzapine Tablets or Long-Acting Injections

J Clin Psychopharmacol. 2019 Nov/Dec;39(6):561-566. doi: 10.1097/JCP.0000000000001126.


Background: The combination of olanzapine and valproic acid (VPA) is regularly prescribed in the treatment of bipolar or schizoaffective disorders. The VPA has been shown to reduce olanzapine concentration, but the mechanism behind this interaction remains unknown. We aimed to investigate the effect of VPA on olanzapine concentration during oral versus long-acting injectable (LAI) formulation in a real-life setting.

Methods: From a therapeutic drug monitoring service, prescribed doses and serum concentrations from 2791 olanzapine-treated patients (9433 measurements) were included.

Results: The number of patients on olanzapine-LAI treatment was 328, whereas 2463 were using oral olanzapine. The frequency of patients comedicated with VPA was 9.4% for olanzapine tablets and 5.8% for olanzapine-LAI. The VPA had no effect on olanzapine dose-adjusted concentrations in LAI users (1.6 vs 1.7 [ng/mL]/[mg/d]; P = 0.38), whereas in the oral group the dose-adjusted olanzapine concentration was lower in VPA users (2.2 vs 2.7 [ng/mL]/[mg/d]; P < 0.001). For smokers in the oral olanzapine group using VPA, 8.7% of the measurements were in the subtherapeutic range (<10 ng/mL) compared with 6.0% in nonusers (P = 0.003).

Implications: These findings show that the VPA-olanzapine interaction involves a presystemic mechanism and is therefore restricted to oral olanzapine treatment. For oral treatment of olanzapine, comedication with VPA implies a risk of insufficient effect, which may be of clinical relevance in smokers in particular. Thus, it is important to be aware of the interaction potential with VPA during oral olanzapine use, whereas for LAI-treated patients fewer precautions are required from a pharmacokinetic point of view.

MeSH terms

  • Administration, Oral
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Antimanic Agents / pharmacology*
  • Antipsychotic Agents / administration & dosage*
  • Antipsychotic Agents / blood*
  • Bipolar Disorder / drug therapy*
  • Delayed-Action Preparations
  • Drug Interactions*
  • Drug Monitoring
  • Drug Therapy, Combination
  • Female
  • Humans
  • Injections
  • Male
  • Middle Aged
  • Olanzapine / administration & dosage*
  • Olanzapine / blood*
  • Psychotic Disorders / drug therapy*
  • Smoking / blood*
  • Valproic Acid / pharmacology*
  • Young Adult


  • Antimanic Agents
  • Antipsychotic Agents
  • Delayed-Action Preparations
  • Valproic Acid
  • Olanzapine