{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T23:04:15Z","timestamp":1774307055184,"version":"3.50.1"},"reference-count":23,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,7,9]],"date-time":"2025-07-09T00:00:00Z","timestamp":1752019200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>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 &lt; 0.1), and no multicollinearity was detected (all VIFs &lt; 2). Pre-ICU olanzapine use was associated with a 27% decrease in the likelihood of delirium resolution (HR = 0.73; 95% CI: 0.63\u20130.86; p &lt; 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 \u00d7 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.<\/jats:p>","DOI":"10.3390\/ph18071019","type":"journal-article","created":{"date-parts":[[2025,7,10]],"date-time":"2025-07-10T07:38:27Z","timestamp":1752133107000},"page":"1019","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Negative Impact of Olanzapine on ICU Delirium Resolution: An Emulated Clinical Trial"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8975-5674","authenticated-orcid":false,"given":"Ajna","family":"Hamidovic","sequence":"first","affiliation":[{"name":"College of Pharmacy, University of Illinois Chicago, Chicago, IL 60607, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3963-1654","authenticated-orcid":false,"given":"John","family":"Davis","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Illinois Chicago, Chicago, IL 60607, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/j.aucc.2022.08.005","article-title":"A Nurse-Led Intervention to Reduce the Incidence and Duration of Delirium among Adults Admitted to Intensive Care: A Stepped-Wedge Cluster Randomised Trial","volume":"36","author":"Brennan","year":"2023","journal-title":"Aust. Crit. Care"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"American Psychiatric Association (2013). Diagnostic and Statistical Manual of Mental Disorders, American Psychiatric Association. [5th ed.].","DOI":"10.1176\/appi.books.9780890425596"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1097\/CCM.0b013e3181fd66e5","article-title":"Long-Term Complications of Critical Care","volume":"39","author":"Desai","year":"2011","journal-title":"Crit. Care Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.1056\/NEJMoa1301372","article-title":"Long-Term Cognitive Impairment after Critical Illness","volume":"369","author":"Pandharipande","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Fan, Y.-Y., Luo, R.-Y., Wang, M.-T., Yuan, C.-Y., Sun, Y.-Y., and Jing, J.-Y. (2024). Mechanisms Underlying Delirium in Patients with Critical Illness. Front. Aging Neurosci., 16.","DOI":"10.3389\/fnagi.2024.1446523"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e711","DOI":"10.1097\/CCM.0000000000006574","article-title":"A Focused Update to the Clinical Practice Guidelines for the Prevention and Management of Pain, Anxiety, Agitation\/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU","volume":"53","author":"Lewis","year":"2025","journal-title":"Crit. Care Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3083","DOI":"10.1002\/sim.3697","article-title":"Balance Diagnostics for Comparing the Distribution of Baseline Covariates between Treatment Groups in Propensity-score Matched Samples","volume":"28","author":"Austin","year":"2009","journal-title":"Stat. Med."},{"key":"ref_8","first-page":"5","article-title":"Receptor Pharmacology of Neuroleptics: Relation to Clinical Effects","volume":"60","author":"Richelson","year":"1999","journal-title":"J. Clin. Psychiatry"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/0893-133X(94)00129-N","article-title":"Radioreceptor Binding Profile of the Atypical Antipsychotic Olanzapine","volume":"14","author":"Bymaster","year":"1996","journal-title":"Neuropsychopharmacology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4077","DOI":"10.1523\/JNEUROSCI.15-05-04077.1995","article-title":"Expression of M1-M4 Muscarinic Acetylcholine Receptor Proteins in Rat Hippocampus and Regulation by Cholinergic Innervation","volume":"15","author":"Levey","year":"1995","journal-title":"J. Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"11194","DOI":"10.1523\/JNEUROSCI.2338-05.2005","article-title":"Modulation of Synaptic Plasticity by Physiological Activation of M1 Muscarinic Acetylcholine Receptors in the Mouse Hippocampus","volume":"25","author":"Shinoe","year":"2005","journal-title":"J. Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1146\/annurev.pharmtox.44.101802.121622","article-title":"Muscarinic Acetylcholine Receptor Knockout Mice: Novel Phenotypes and Clinical Implications","volume":"44","author":"Wess","year":"2004","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1038\/nn992","article-title":"Selective Cognitive Dysfunction in Acetylcholine M1 Muscarinic Receptor Mutant Mice","volume":"6","author":"Anagnostaras","year":"2003","journal-title":"Nat. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.pharmthera.2007.09.009","article-title":"Muscarinic Acetylcholine Receptors as CNS Drug Targets","volume":"117","author":"Langmead","year":"2008","journal-title":"Pharmacol. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"14096","DOI":"10.1073\/pnas.251542998","article-title":"Cholinergic Dilation of Cerebral Blood Vessels Is Abolished in M5 Muscarinic Acetylcholine Receptor Knockout Mice","volume":"98","author":"Yamada","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Hamidovic, A. (2025). Quetiapine Use Is Associated with Longer ICU Stay Compared to Control and Haloperidol: A Propensity Score\u2013Matched Analysis Using the MIMIC-IV Database. J. Clin. Med., 14.","DOI":"10.3390\/jcm14134438"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3491","DOI":"10.1007\/s10072-021-05339-3","article-title":"Why Is Delirium More Frequent in the Elderly?","volume":"42","author":"Bugiani","year":"2021","journal-title":"Neurol. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1186\/s13054-022-04260-1","article-title":"Association between Cholinesterase Activity and Critical Illness Brain Dysfunction","volume":"26","author":"Hughes","year":"2022","journal-title":"Crit. Care"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1428","DOI":"10.1002\/gps.4823","article-title":"Delirium Pathophysiology: An Updated Hypothesis of the Etiology of Acute Brain Failure","volume":"33","author":"Maldonado","year":"2018","journal-title":"Int. J. Geriatr. Psychiatry"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"20451253231152113","DOI":"10.1177\/20451253231152113","article-title":"Olanzapine for the Treatment of ICU Delirium: A Systematic Review and Meta-Analysis","volume":"13","author":"Liu","year":"2023","journal-title":"Ther. Adv. Psychopharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1370","DOI":"10.1097\/00003246-200107000-00012","article-title":"Evaluation of Delirium in Critically Ill Patients: Validation of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU)","volume":"29","author":"Ely","year":"2001","journal-title":"Crit. Care Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v042.i08","article-title":"MatchIt: Nonparametric Preprocessing for Parametric Causal Inference","volume":"42","author":"Ho","year":"2011","journal-title":"J. Stat. Soft."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1093\/biomet\/81.3.515","article-title":"Proportional Hazards Tests and Diagnostics Based on Weighted Residuals","volume":"81","author":"Grambsch","year":"1994","journal-title":"Biometrika"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/7\/1019\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:07:06Z","timestamp":1760033226000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/7\/1019"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,9]]},"references-count":23,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["ph18071019"],"URL":"https:\/\/doi.org\/10.3390\/ph18071019","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,9]]}}}