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Introduction: Sedatives and analgesics are commonly utilized as continuous infusions in the ICU but have complications, including an increase in mechanical ventilation days, ICU length of stay, and delirium. Atypical antipsychotics (AAPs) affect several receptors including muscarinic, histamine, and α-1 adrenergic receptors, which may allow them to act as adjunctive agents to facilitate weaning of continuous infusions. Objective: To determine if there is a decrease in sedatives/analgesics requirements with the use of quetiapine and olanzapine in mechanically ventilated critically ill patients. Methods: A single-center, retrospective study conducted at Brigham and Women's Hospital from 1/1/2018 to 12/31/2019. Patients were included if they were mechanically ventilated for at least 48 hours before and following AAP initiation, were receiving at least one sedative/analgesic by continuous infusion and received AAP for at least 48 hours. The major endpoint was the percentage of patients with ≥20% reduction in the cumulative dose (CD) of midazolam, propofol, or opioids using morphine mg equivalent (MME), 48 hours from AAP initiation. Minor endpoints included median changes in CD at 24 and 48 hours, and Richmond Agitation–Sedation Scale (RASS), and Critical Care Pain Observation Tool (CPOT) changes at 48 hours. Results: A total of 1177 encounters were screened and 107 were included. Within the 48 hours after AAP initiation, 77.6% had ≥20% reduction in the CD of a sedative/analgesic. There was a significant reduction in propofol, no change in MME, and significant increase in dexmedetomidine median CD at 48 hours from AAP start. No difference was found in pain scores, but patients had significantly lighter sedation scores in the 48 hours after AAP initiation. A multivariate analysis showed that earlier initiation of antipsychotics was associated with a higher likelihood of achieving a 20% reduction in a sedative/analgesic. Conclusion: AAP use was associated with a significant reduction in sedatives/analgesics doses. Future studies are warranted to confirm the results. [ABSTRACT FROM AUTHOR]

Schizophrenia is a severe mental illness that has its onset in late adolescence or early adulthood and is associated with significant dysfunction across multiple domains. The pathogenesis of schizophrenia remains unknown, but physiologic understanding of the illness has been driven by the dopamine hypothesis. However, acetylcholine (ACh) clearly plays a role with mixed results regarding effect on psychosis. Selective muscarinic M1 and M4 agonists, such as xanomeline, originally developed to aid in cognitive loss with Alzheimer's, showed promise in proof-of-concept study in 20 patients with schizophrenia. Unfortunately, tolerability problems made muscarinic agonists impractical in either condition. However, coadministration of trospium, a lipophobic, non-selective muscarinic antagonist previously used for the treatment of overactive bladder, with xanomeline resulted in a significant reduction of cholinergic adverse effects. A recent randomized, placebo-controlled study of the antipsychotic effects of this combination in 182 patients with acute psychosis revealed improved tolerability with 80% of subjects staying to the end of the 5 weeks study. At the end of the trial, the treatment group saw a − 17.4 change in the positive and negative symptom scale (PANSS) score from baseline compared to a − 5.9 change in the placebo arm (P < 0.001). Furthermore, the negative symptom subscore, was also superior in the active arm (P < 0.001). These early studies are exciting because they suggest that the cholinergic system may be recruited to treat a severe and disabling disorder with suboptimal treatment options. Xanomeline-trospium combination is currently in phase III studies. [ABSTRACT FROM AUTHOR]