Negative Impact of Olanzapine on ICU Delirium Resolution: A Real-World Data Study

Introduction: Delirium is a common and debilitating clinical complication among ICU patients. Despite its prevalence, there are insufficient data to support or refute the routine use of atypical antipsychotics since the existing evidence remains sparse and inconclusive. The objective of the present study was to evaluate whether pre-ICU administration of the atypical antipsychotic olanzapine is associated with a differential time to delirium resolution relative to the control condition. Methods: In this emulated clinical trial, we utilized the MIMIC-IV v3.1 database, which contains deidentified health records from approximately 65,000 ICU patients, to derive a cohort of patients with a positive delirium screening (CAM-ICU) within 24 hours of ICU admission. We excluded patients who received any antipsychotic other than olanzapine prior to ICU admission. We performed propensity score matching using logistic regression and nearest-neighbor matching (1:1, caliper = 0.2) to balance covariates between the olanzapine and control groups. The primary outcome was time to delirium resolution, defined as the first negative CAM-ICU assessment. A Cox proportional hazards model, adjusted for multiple covariates and incorporating age as a time-dependent variable, was used to examine the association between olanzapine use and delirium resolution. Interaction terms were included to evaluate effect modification by age and gender. Results: A total of 5,070 patients with a positive delirium screening within 24 hours and no exposure to other antipsychotics met eligibility criteria; 421 olanzapine users were matched to 421 controls using propensity score matching. Covariate balance was achieved (all standardized mean differences < 0.1), and no multicollinearity was detected (all VIFs < 2). Pre-ICU olanzapine use was associated with a 27% decrease in the likelihood of delirium resolution (HR = 0.73; 95% CI: 0.63–0.86; p < 0.001). A significant interaction with age indicated that the negative impact of olanzapine on delirium resolution increased with advancing age, translating to a 2.4% increase in the risk of prolonged delirium resolution for every 10-year increase in age. There was no modification of the association according to gender. Discussion: The negative effect of olanzapine on ICU delirium resolution - in the elderly in particular - presented in this study is in line with the results of our earlier study showing a negative effect (i.e., prolonged ICU stay) in patients receiving quetiapine relative to the control condition. As both olanzapine and quetiapine have a distinctly strong anticholinergic effect relative to the other antipsychotic agents used in the ICU, their use is not advised for the treatment of delirium.