From the Guidelines
The therapeutic potential of acetylcholine agonists in treating psychosis is primarily related to their effects on dopaminergic neurotransmission, as evidenced by the most recent and highest quality study 1.
Mechanism of Action
These agents work by modulating cholinergic activity, which indirectly influences dopamine release in key brain regions implicated in psychosis, particularly the mesolimbic pathway.
- Acetylcholine agonists can reduce excessive dopaminergic signaling that contributes to positive symptoms of psychosis such as hallucinations and delusions.
- Additionally, they affect glutamatergic transmission, which is another neurotransmitter system implicated in psychotic disorders.
Clinical Implications
The mechanism involves stimulation of muscarinic and nicotinic acetylcholine receptors, leading to normalization of aberrant neural activity in cortical and subcortical regions.
- This dual action on both cholinergic and dopaminergic systems provides a unique approach to managing psychotic symptoms, potentially with fewer extrapyramidal side effects compared to traditional antipsychotics that directly block dopamine receptors, as noted in 1 and 1.
- However, it is essential to consider the potential risks and benefits of antipsychotic polypharmacy, as discussed in 1 and 1, and to prioritize treatment strategies that minimize harm and optimize patient outcomes, in line with the recommendations of 1.
From the Research
Therapeutic Potential of Acetylcholine Agonists
The therapeutic potential of acetylcholine agonists in treating psychosis is related to their effects on:
- Cognitive processes such as memory and attention, as evidenced by the role of α7 nicotinic acetylcholine receptors (α7 nAChRs) in regulating these processes 2
- Negative and cognitive symptoms of schizophrenia, which are targeted by muscarinic acetylcholine receptor (mAChR) agonists 3
- Pro-cognitive effects and other properties beneficial to schizophrenia patients, as shown by α7-nAChR ligands 4
Mechanisms of Action
The mechanisms of action of acetylcholine agonists in treating psychosis include:
- Enhancement of neuronal transmission by increasing the availability of acetylcholine in muscarinic and nicotinic receptors, as seen with acetylcholinesterase inhibitors (ChEIs) 5
- Activation of the central cholinergic transmission and enhancement of the survival of newborn neurons in the hippocampal dentate gyrus, as demonstrated by donepezil 6
Receptor Subtypes
The therapeutic potential of acetylcholine agonists is also related to their effects on specific receptor subtypes, including:
- α7 nAChRs, which have implications in the regulation of cognitive processes and have shown promise as a therapeutic target for the treatment of cognitive deficits associated with schizophrenia 2, 4
- mAChRs, which have been targeted by agonists such as xanomeline, which has been shown to reduce psychotic symptoms and improve cognition in patients with Alzheimer's disease and schizophrenia 3