Fotheringham_2025_Clin.Toxicol.(Phila)__1

INTRODUCTION: Post-injection delirium/sedation syndrome is a rare but serious adverse effect of depot olanzapine, typically managed with supportive care and benzodiazepines. CASE REPORTS: We report two cases of post-injection delirium/sedation syndrome following long-acting olanzapine intramuscular depot administration and describe the use of the acetylcholinesterase inhibitors, physostigmine and rivastigmine, in their management. Both patients showed rapid resolution of delirium within minutes of physostigmine administration, with no recurrence after rivastigmine maintenance therapy. The response was achieved with lower physostigmine doses than typically used in patients with pure antimuscarinic delirium. Olanzapine plasma concentrations were collected in one patient and were significantly elevated. DISCUSSION: Intravenous physostigmine produced rapid and sustained resolution of delirium symptoms. Transdermal rivastigmine prevented recurrence. Benzodiazepines were ineffective prior to acetylcholinesterase inhibitor use. CONCLUSIONS: Our patients support the hypothesis that post-injection delirium/sedation syndrome includes an antimuscarinic mechanism responsive to acetylcholinesterase inhibitors. Early administration of physostigmine, followed by rivastigmine, may be an effective, targeted approach. We propose their use should be first-line when treating antimuscarinic delirium in post-injection delirium/sedation syndrome.