Negative Impact of Olanzapine on ICU Delirium Resolution: An Emulated Clinical Trial

Introduction: Delirium is a common and debilitating clinical complication among ICU patients. Despite the prevalence of this condition, 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 within 24 h of ICU admission. We exluded 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 delirium 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 5070 patients with a positive delirium screening within 24 h and no exposure to other antipsychotics met the 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 (HR = 1.0024 per unit of age × log(time), p = 0.023), translating to a 2.4% increase in the risk of prolonged delirium resolution for every 10-year increase in age per log(time). There was no modification of the association according to gender. Discussion: The negative effect of olanzapine on ICU delirium resolution, particularly among the elderly, presented in this study is in line with the results of our earlier study showing a negative effect (i.e., prolonged ICU stay) among patients receiving quetiapine relative to both control and haloperidol conditions. Distinctly strong anticholinergic effects of both olanzapine and quetiapine relative to the other antipsychotic agents may be driving the identified negative outcomes. Conclusions: Results of this emulated clinical trial do not support the use of olanzapine for the treatment of ICU delirium because the agent prolongs time to resolution of the condition.