[Muscarinic M1 and/or M4 receptor agonists as potential novel treatments for psychoses]

Research suggests that cholinergic muscarinic 1 (M₁) and/or muscarinic 4 (M₄) receptors may be involved in the pathophysiology of psychotic disorders. Agonistic modulation of these receptors can offer new treatment options.

To provide an overview of current research on the role of cholinergic M₁ and M₄ receptors in the development and treatment of psychoses, with special attention to the development of new drugs such as xanomeline and emraclidine.

To obtain an overview, we searched for English-language studies published in PubMed, Embase, and PsycInfo up until June 1, 2023. We examined the role and effects of M₁ and/or M₄ agonists in schizophrenia. Additionally, we consulted clinical trial registers.

Our search strategy resulted in nine published articles on five clinical studies. These studies revealed that reduced presence of M₁ receptors, primarily in the frontal cortex, and M₄ receptors, primarily in the basal ganglia, are associated with psychoses. M₁ and M₄ receptors modulate dopaminergic activity in the ventral tegmentum and striatum through various pathways. Several M₁ and/or M₄ agonists, partial agonists, and positive allosteric modulators (PAMs) have been developed. Drugs exhibiting agonistic activity on M₁ and/or M₄ receptors, such as xanomeline-trospium (phase 2 and 3 studies) and emraclidine (phase 1b studies), have shown positive effects on cognitive and potentially negative symptoms in patients with schizophrenia.

M₁ and/or M₄ receptor agonists show potential as new treatment strategies for individuals with psychotic disorders. Although initial studies with xanomeline-trospium and emraclidine have shown positive results, further research is needed to assess their long-term efficacy, safety, and tolerability before these new medications can be evaluated.