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Final Program


Delirium

PO-117

(PO-117) (PO-117) Novel agents for treatment of delirium: A proposal for a multimodal approach

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Background:

Delirium, a syndrome characterized by impairment in attention and consciousness, commonly occurs in hospital setting and is associated with higher mortality and poor long-term outcomes. With precise etiology of delirium yet to be elucidated, our current understanding describes delirium as a state of multifactorial global brain dysfunction occurring in susceptible elderly and critically ill patients. (Maldonado, 2008) To treat such a multimodal disorder, we propose investigating two novel multimodal pharmacological approaches: Granulocyte-macrophage colony stimulating factor (GM-CSF) inhibitors and pro-cholinergic muscarinic-receptor agonists.





Discussion:

Neuroinflammation is a focus of inquiry in a number of neuropsychiatric diseases. Unlike individual cytokine (TNF, IL-6) inhibitors, GM-CSF inhibitors combat the entire inflammatory cascade implicated in delirium: blunting the cytokine response (IL-1, IL-6, TNF) to reduce inflammation, limiting chemotaxis (IL-8 inhibition), reducing cell degradation (H2O2, MMPs), and dulling the T- and B-cell response. (Patel, 2021) GC-CSF inhibitors (otilimab and TMJ2) have already been shown to be effective in and approved for the treatment of inflammatory conditions, such as Rheumatoid Arthritis, and have been effective in treatment of inflammatory processes of COVID-19. (Patel, 2021) Given the role of the neuroinflammatory cascade in delirium, we propose investigating the GM-CSF inhibitors to treat delirium.

Acetylcholine dysregulation (‘anticholinergic surge’), on the other hand, has long been implicated in delirium and studies suggest some efficacy of acetylcholinesterase inhibitors in treatment of delirium. Novel schizophrenia treatment studies combine xanomeline, a M-receptor agonist, with trospium, a peripheral anticholinergic, to create a net-positive pro-cholinergic state in the brain while minimizing systemic side-effects. (Brannan, 2020) In addition to treating schizophrenia and cognitive impairment, this combination (KarXT), may be useful in reversing the anti-cholinergic state of the delirious brain. Currently in Phase III clinical trials, KarXT should be considered a viable candidate for delirium treatment, once FDA-approved.





Conclusions:

Pharmacological approaches to delirium have been limited to managing behavioral dysregulation and sleep-wake cycle disturbances. Presently, we are looking at two potential additional approaches to delirium treatment. One is limited to cholinergic circuitry and aims to restore AcH balance via direct M-receptor agonism. The other, based on Systems Integration Failure Hypothesis, addresses the entire inflammatory cascade via GM-CSF inhibition. As agents from both classes are either approved or are close to FDA-approval, we should consider them as candidates for delirium management.



References:

Maldonado, J, Kapinos, G. (2008). Pathoetiological Model of Delirium, Critical care clinics. 24. 789-856, ix. 10.1016/j.ccc.2008.06.004.

Brannan, S, Sawchak, S, et al.(2020). Efficacy and Safety of Xanomeline, a M1/M4 Receptor Preferencing Agonist, Plus Trospium, a Peripheral Muscarinic Antagonist, in Schizophrenia. Biological Psychiatry, 87(9), S169. doi: 10.1016/j.biopsych.2020.02.446

Patel, S, Saxena, B., Mehta, P. (2021). Recent updates in the clinical trials of therapeutic monoclonal antibodies targeting cytokine storm for the management of COVID-19. Heliyon, 7(2), e06158. doi: 10.1016/j.heliyon.2021.e06158

Learning Objectives:

  • Evaluate anti-inflammatory agents and muscarinic agonists as potential pharmacological approaches to treating delirium.
  • Gain further understanding of the pathophysiology of delirium utilizing the systems integration failure hypothesis.