Antipsychotics Beyond Dopamine: The Muscarinic Turn

Introduction

For more than half a century, antipsychotic treatment has rested on the pharmacological foundation of dopamine D2 antagonism: the idea that attenuating hyperdopaminergic signaling in striatal circuits would quell hallucinations, delusions, and acute agitation. This approach, from haloperidol to risperidone and beyond, remains the most reliable way to suppress acute psychotic symptoms, yet its limitations remain stark. Even when positive symptoms abate, many patients continue to struggle with cognitive and negative symptom domains that constrain social and occupational recovery and drive long-term disability. In addition, tolerability and safety constraints—extrapyramidal side effects (EPS), metabolic complications, hyperprolactinemia—limit durability of benefit and quality of life. These realities have fueled a sustained search for non-dopaminergic mechanisms that can engage the core pathophysiology more directly and, ideally, improve function in domains that have eluded previous generations of antipsychotics.

The approval of Cobenfy (xanomeline–trospium, KarXT) by the U.S. Food and Drug Administration in 2024 (FDA, 2024) was widely heralded as the first credible departure from the D2-blocking orthodoxy. Xanomeline is a centrally acting muscarinic agonist with preferential activity at M1 and M4 receptors, while trospium is a peripherally restricted antagonism strategy designed to curb cholinergic adverse effects outside the central nervous system. Together, the combination aims to deliver central muscarinic efficacy with a manageable side-effect profile.

The following review examines the evidence and implications of this muscarinic turn. We consider the rationale behind cholinergic modulation, summarize the acute and maintenance efficacy data, examine safety and tolerability trade-offs, explore real-world implications for function and adherence, and sketch an initial positioning within current treatment algorithms. Throughout, we highlight what is known, what remains uncertain, and where future research should focus if muscarinic agents are to address the enduring problems Dopamine D2 antagonism has failed to solve.

Unmet Clinical Needs and the Rationale for Muscarinic Modulation

The dopamine hypothesis has carried antipsychotic development for decades, but its cracks are visible. Standard D2 blockade reliably attenuates positive symptoms yet does little for negative symptoms and cognitive impairments, which are the strongest predictors of functional outcomes and long-term disability. These symptom clusters—amotivation, anhedonia, blunted affect, working memory deficits, processing speed—are less responsive to dopaminergic strategies and account for much of the functional burden in schizophrenia.

It is here that muscarinic receptor modulation enters the conversation. Central M1 and M4 receptors are abundant in cortical and striatal circuits that govern learning, salience assignment, and top–down control. Preclinical and early clinical work has suggested that M1 activation can enhance cortical plasticity and cognitive processes, while M4 activation may dampen aberrant dopaminergic signaling in striatum indirectly. This dual action offers a mechanistic bridge between symptom domains, with the potential to move beyond pure positive symptom relief toward measurable gains in motivation, learning, and executive function. In simple terms, the muscarinic system provides a plausible route to improving Negative symptoms and Cognitive impairments that blunt recovery.

Another part of the rationale lies in side-effect trade-offs. Extrapyramidal symptoms, hyperprolactinemia, and weight gain are major liabilities of dopaminergic antagonists. By eschewing direct D2 blockade, muscarinic agonists avoid EPS and prolactin elevation and, to date, show a relatively neutral Metabolic profile. The trade-off, however, is cholinergic burden—nausea, vomiting, sweating, dyspepsia, dizziness—which must remain manageable for long-term adherence. Notably, the trospium component is designed to attenuate peripheral cholinergic effects, in contrast to agents such as olanzapine or risperidone.

Skeptics point out, however, that psychiatry has been promised “next-generation” breakthroughs before. The label atypical once suggested freedom from EPS and better negative symptom control, but many expectations were tempered by real-world outcomes. The muscarinic story will only be compelling if cognitive and functional benefits are demonstrable beyond acute symptom control, and if tolerability is confirmed in diverse populations and real-world settings.

Efficacy Across Acute and Maintenance Settings

What makes this striking is that efficacy was reached with no D2 receptor blockade. The key evidence for muscarinic antipsychotics comes from the EMERGENT-2 and EMERGENT-3 trials. Both phase III studies showed significant improvements on the Positive and Negative Syndrome Scale (PANSS) versus placebo, with robust separation emerging early. In pooled analyses, Xanomeline–trospium demonstrated meaningful reductions in PANSS total scores, with effect sizes similar to leading second-generation antipsychotics. In EMERGENT-2, the mean change in PANSS was –17.4 from baseline versus –11.6 for placebo (Brannan et al., 2023).

What makes this striking is that efficacy was reached with no D2 receptor blockade. For decades, antipsychotic action was assumed to require some degree of D2 antagonism, and agents without this property largely failed. KarXT’s performance challenges the field’s core assumptions and opens the door to a more pluralistic view of antipsychotic pharmacology—one in which multiple pathways can achieve symptom relief without the liabilities of dopamine antagonism. The clinical implication is subtle but important: patients may experience both symptomatic benefit and relief from EPS-related anxieties, which can enhance engagement and adherence.

Symptom breakdown paints a more cautious picture. The strongest benefits remain in Positive symptoms like hallucinations and delusions, while effects on negative and cognitive domains are more modest and variable. Some exploratory endpoints suggest signal in motivation and processing speed, but these require prospective confirmation with dedicated cognitive batteries and functional assessments. It’s plausible that muscarinic effects on cortical networks require time and practice effects to translate into everyday gains, and trials in early psychosis may be needed to test these domains.

Maintenance data are only beginning to emerge. The EMERGENT program’s open-label extension suggests sustained benefits over months, but formal relapse-prevention trials are still pending. Without head-to-head maintenance studies against standard D2 antagonists, it is premature to claim parity in long-term outcomes. The question is not only whether relapse rates are comparable but whether time to relapse, functional stability, and quality of life are improved to a clinically meaningful degree.

Effect sizes also temper expectations. KarXT’s placebo-adjusted differences on PANSS and other scales are in the moderate range and may be driven less by superior efficacy than by its tolerability and safety profile. In other words, the advantage may lie in what is avoided rather than dramatic gains over existing agents. This is not a trivial point: in practice, drugs that patients can tolerate and trust often perform better than more “potent” agents that come with adherence-sapping adverse effects.

In general, muscarinic agents have cleared the first test: delivering acute symptom relief without D2 antagonism. The second test—maintenance of effect, prevention of relapse, and demonstrable gains in everyday function across diverse populations, remains to be seen.

Safety, Tolerability, and Mitigation of Cholinergic Burden

Every new mechanism carries its own liabilities, and for muscarinic agonists the challenge is their cholinergic side-effect profile. Early studies raised concerns about nausea, vomiting, dyspepsia, sweating, and dizziness, which can undermine adherence. The trospium component and dosing strategies (e.g., titration, with-food administration) reduce peripheral cholinergic effects and improve tolerability, and this mitigation has been vital to KarXT’s success and underpins its clinical viability (Bristol Myers Squibb, 2024).

In phase III studies, discontinuation due to adverse events was modest and driven largely by gastrointestinal symptoms. Rates of EPS and prolactin elevation were near placebo, and weight gain appeared limited—a profile that may appeal to clinicians treating patients with metabolic risk or comorbid cardiovascular disease, i.e., groups often poorly served by existing drugs.

Still, uncertainties remain. Reports of blurred vision, urinary retention, and heart rate changes, while infrequent, require vigilance in susceptible populations. Patient education, slow titration, and straightforward management algorithms (e.g., antiemetics, hydration guidance) are important tools for clinicians managing tolerability in practice.

Overall, the safety story is cautiously optimistic. KarXT appears to offer a combination of efficacy without EPS and a neutral metabolic profile, but longer-term surveillance and broader population data will be critical to confirm whether these benefits hold up in real-world use.

Real-World Signals and Functional Outcomes

The transition from trial efficacy to everyday psychiatry is often where new agents are tested most harshly. Early open-label and naturalistic reports suggest improvements in adherence and engagement when patients experience symptom relief without movement-related anxieties or sedation. The reduced need for concomitant anticholinergics may also simplify regimens. Functional measures—employment, social participation—are harder to shift quickly and require sustained support, but anecdotal and preliminary cohort data are encouraging.

In pragmatic settings, tolerability often drives outcomes as much as efficacy. By avoiding EPS and minimizing metabolic liabilities, muscarinic agents may foster better therapeutic alliances and reduce discontinuations. It’s notable that gastrointestinal side effects, while common, were often transient and manageable with simple strategies; their presence remains a counseling issue, but in most series they did not lead to high dropout rates.

Positioning in the Treatment Landscape

The arrival of a first-in-class muscarinic antipsychotic invites a re-examination of where it fits within the established sequencing of treatments for schizophrenia? For patients in acute episodes, KarXT has shown efficacy and could be considered alongside standard SGAs when EPS, prolactin, or metabolic risks are paramount. In partial responders, a switch may be justified when side-effect burdens impede adherence or function, especially for younger patients or those with cardiometabolic risk factors.

At the other end of the algorithm lies Clozapine, still the gold standard for treatment-resistant schizophrenia. Muscarinic agonists are not a substitute for clozapine’s unique efficacy, particularly in suicidality, but they may play a role earlier in the pathway for patients who cannot tolerate D2 antagonists or for whom cognitive/negative domains are priority targets. The lack of Long-acting injectables (LAI) formulations is a practical limitation for patients with adherence challenges; until available, oral regimens must be supported by assertive follow-up and shared decision-making.

Another practical limitation is the absence of long-acting formulations and limited data in special populations (older adults, severe hepatic/renal impairment). Health-system factors—costs, access, clinician familiarity—will also determine uptake. Ultimately, muscarinic antipsychotics are best viewed as a complementary option rather than a wholesale replacement for dopamine antagonists, at least until long-term comparative data accumulate.

Future Directions and Research Priorities

The next steps will determine whether this mechanism can scale from proof-of-concept to durable public health impact, and whether muscarinic agents will reshape schizophrenia treatment or settle into a narrow niche. Long-term safety registries and post-marketing surveillance will be crucial to detect rare events and to understand safety in patients with multimorbidity and polypharmacy.

Long-term safety monitoring is essential. While early data are reassuring on EPS and metabolic parameters, cholinergic effects across years of treatment need systematic tracking; small liabilities may accumulate into discontinuation if not carefully managed.

On the efficacy side, trials are expanding into early psychosis, negative symptom–focused cohorts, and comorbid conditions. Mechanistic studies in cognition, motivation, and functional capacity—including digital phenotyping and ecologically valid tasks—are warranted. Exploratory indications in bipolar disorder or dementia could further test the versatility of this mechanism.

Another frontier is biomarker development. Imaging of muscarinic receptor occupancy, electrophysiologic markers of cholinergic tone, and cognitive/neurophysiologic task batteries could guide dosing and patient selection. Genetic or transcriptomic signatures of cholinergic pathway engagement might enrich trials and accelerate learning curves, ultimately integrating these drugs into personalized treatment strategies.

Finally, the field will need head-to-head comparative studies against established SGAs and clozapine. Without such trials, we will not know where muscarinic agents perform best, for whom they offer the greatest advantage, and for how long they deliver value beyond the dopamine paradigm.

Conclusion

The evidence from phase II and III trials confirms that xanomeline–trospium (KarXT) can deliver clinically meaningful improvements in schizophrenia without direct D2 antagonism, challenging a foundational assumption in antipsychotic pharmacology and offering a tolerability profile that sidesteps many of the liabilities typically associated with dopamine blockade. The development and approval of xanomeline–trospium (KarXT) represent a notable advance in the treatment of schizophrenia, not because it outperforms every existing antipsychotic on all outcomes, but because it proves acute efficacy without the trade-offs inherent to dopaminergic strategies.

The therapeutic profile to date is characterized by a combination of robust effects on positive symptoms, a neutral weight and metabolic signature, and a manageable cholinergic burden that appears to attenuate with mitigation strategies. The magnitude and durability of benefits outside acute positive symptoms, particularly in negative and cognitive domains and across longer treatment horizons, remains to be established.

The broader clinical significance of muscarinic agonists will ultimately depend on whether benefits extend beyond the core acute outcomes into functional recovery and quality of life. This will require careful patient selection, vigilant management of Gastrointestinal side effects, and systematic assessment of cognitive and functional domains in routine practice.

Muscarinic agonists should at present be viewed as a promising addition to the therapeutic armamentarium rather than a disruptive replacement. Their role will be refined through comparative effectiveness studies, maintenance trials, and pragmatic implementation work that clarifies where they fit best in real-world care.

References

Brannan, S. K., Pikalov, A., Deng, L., Zhang, Y., Riesenberg, R. A., Morozova, M., … & Correll, C. U. (2023). Efficacy and safety of xanomeline–trospium in schizophrenia (EMERGENT-2): A randomized, double-blind, placebo-controlled phase 3 trial. The American Journal of Psychiatry, 180(11), 993–1004. https://doi.org/10.1176/appi.ajp.2023.23030229

Bristol Myers Squibb. (2024, September 26). U.S. Food and Drug Administration approves Bristol Myers Squibb’s COBENFY (xanomeline and trospium) muscarinic receptor agonist for the Treatment of Schizophrenia in Adults. https://news.bms.com/news/corporate-financial/2024/U.S.-Food-and-Drug-Administration-approves-Bristol-Myers-Squibbs-COBENFY-xanomeline-and-trospium-muscarinic-receptor-agonist-for-the-Treatment-of-Schizophrenia-in-Adults/default.aspx

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