In delirium, which neurotransmitter deficiency is most consistently implicated in the pathophysiology?

Explanation

## Neurochemistry of Delirium: The Cholinergic Hypothesis **Key Point:** The **cholinergic deficiency hypothesis** is the most widely accepted neurochemical model of delirium pathophysiology. ### The Cholinergic Hypothesis 1. **Acetylcholine (ACh) depletion** in the basal forebrain and cortex is the core mechanism 2. Occurs in response to systemic insults (infection, hypoxia, metabolic derangement, drugs) 3. Results in: - Impaired attention and executive function - Disorganized thinking - Fluctuating consciousness - Sleep–wake cycle disruption ### Supporting Evidence **High-Yield:** - Anticholinergic drugs (atropine, antihistamines, tricyclic antidepressants) **precipitate or worsen delirium** - Cholinesterase inhibitors (physostigmine, donepezil) can **improve delirium** in some cases - Delirium is common in conditions that reduce ACh (sepsis, hypoxia, liver failure, uremia) ### Clinical Pearl **Warning:** Anticholinergic medications are a major iatrogenic cause of delirium in hospitalized elderly patients. Benztropine, diphenhydramine, and tricyclic antidepressants should be avoided or minimized in delirious patients. ### Why Other Neurotransmitters Are Less Central | Neurotransmitter | Role in Delirium | Evidence | | --- | --- | --- | | **Acetylcholine** | Primary deficiency | Anticholinergics worsen; cholinesterase inhibitors improve | | **Dopamine** | Excess (secondary) | Antipsychotics help, but dopamine excess is not primary | | **Serotonin** | Unclear role | Not a primary target; serotonin syndrome ≠ delirium | | **GABA** | Excess (secondary) | Benzodiazepine excess can worsen delirium | ### Mnemonic: ACh = Attention & Cognition - **A**cetylcholine = **A**ttention (the core deficit in delirium) [cite:Harrison 21e Ch 28]