Targeting disrupted networks in schizophrenia: Can muscarinic drugs make a fundamental difference?

New treatments for schizophrenia are urgently needed because existing antipsychotic drugs mainly improve positive symptoms, with minimal effect on cognitive deficits and negative symptoms. The approval of Karuna Therapeutics (KarXT) in 2024 marked a significant milestone, as it became the first antipsychotic drug to target muscarinic acetylcholine receptors (mAChRs) rather than dopamine receptors. Here, we provide a perspective on how targeting mAChRs might improve the positive, negative and cognitive symptoms of schizophrenia. First, we revisit the prevailing view that xanomeline acts primarily as a M1 and M4 mAChR partial agonist. Next, we examine potential pharmacological overlap with clozapine, focusing on actions at 5-HT1A, 5-HT2A and 5-HT7 receptors and consider whether 5-HT receptor subtype agonism, inverse agonism or antagonism could be important for therapeutic efficacy. We then review the brain systems and networks impacted by muscarinic receptor subtypes in the context of Research Domain Criteria (RDoC) domains. We propose that, based on their cellular and regional expression, muscarinic receptor subtypes impact several cortico-striatal-thalamo-cortical loops and interrelated networks to improve RDoC-informed sensorimotor, positive valence, social processes, arousal and regulation, and cognitive systems. Taken together, these data suggest that there are neurobiological reasons for optimism for muscarinic agents to improve the classically described positive, negative and cognitive symptoms of schizophrenia, although the relative contribution of each mAChR subtype (M1-M5) remains unclear. We propose that a multi-targeted approach combining actions at 5-HT1A and 5-HT7 receptors could provide additional therapeutic benefits across a range of RDoC domains and hence be of clinical benefit trans-diagonistically beyond schizophrenia.