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Muscarinic Agonists in Schizophrenia
The Muscarinic Revolution: A Novel Treatment Paradigm for Schizophrenia

Released: December 18, 2025

Jonathan M. Meyer
Jonathan M. Meyer, MD, DLFAPA
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Key Takeaways
  • Xanomeline/trospium (X/T) is a first-in-class, FDA-approved M1/M4 agonist for schizophrenia, demonstrating efficacy comparable to risperidone and olanzapine while avoiding motor, metabolic, and endocrine adverse effects associated with traditional antipsychotics.
  • X/T may offer particular benefit for patients with baseline cognitive deficits or prominent negative symptoms, such as those with muscarinic receptor deficit syndrome (approximately 25% of patients with schizophrenia).
  • Successful use of X/T in clinical practice requires careful attention to twice-daily dosing (1 hour before breakfast, 2 hours after dinner); procholinergic adverse events can be managed with ondansetron or additional trospium, and advancing to the 125 mg/30 mg dose provides relatively greater trospium exposure.

Schizophrenia is a complex disorder that presents with variable manifestations of 3 core features: positive symptoms of psychosis, negative symptoms, and cognitive deficits. With the exception of cariprazine’s superiority to risperidone for persistent negative symptoms, antipsychotics have not been effective for remediation of negative symptoms or cognitive deficits, and 25% to 30% of individuals with schizophrenia remain treatment resistant. Among those who are not treatment resistant, animal models and human imaging studies indicate that positive symptoms correlate with excessive presynaptic dopamine release. Therefore, postsynaptic D2 receptor antagonism is valuable for these patients.

Preclinical models used for antipsychotic drug development employed amphetamine to mimic positive symptoms, and NMDA glutamate antagonists such as PCP or MK-801 to induce cognitive disruption, but these studies with adult animals provided limited insight into the biological origins of schizophrenia, especially the presynaptic dopamine dysfunction underlying positive symptoms. Over the past 20 years, Professor Anthony Grace has been studying a neurodevelopmental model of schizophrenia, using prenatal exposure of rats to the neurotoxin methylazoxymethanol acetate (MAM) at gestational Day 17, equivalent to the second human trimester. MAM-exposed offspring exhibit all the behavioral and cognitive aspects of schizophrenia, with neuroanatomic functional studies indicating that positive symptoms are associated with loss of GABAergic interneurons in the hippocampus. Dopamine neuron activity in the striatum is driven by a hippocampal pacemaker that is regulated by GABA interneurons in the striatum. The absence of the usual GABA tone reduces inhibition of dopamine neurons, leaving the entire population active and responsive, resulting in greater striatal dopamine release. The MAM model cements the concept of positive symptoms being a presynaptic problem and will facilitate the discovery of novel mechanisms that treat schizophrenia at its origins, not just postsynaptically, and perhaps more completely than existing therapies.

Chlorpromazine was discovered by accident, but once its primary mechanism was understood, the limitations of postsynaptic D2 receptor antagonism became immediately clear because of the nonselective mode of action and associated off-target effects in the motor striatum and in the pituitary. Although clozapine was considered revolutionary, it too was discovered by accident, and the unique properties that conferred efficacy for resistant schizophrenia, suicidality, and impulsive aggression could not be replicated. As we wait for novel treatments to be discovered based on the MAM model, another fortuitous discovery has instigated the muscarinic revolution for schizophrenia treatment, and an FDA-approved therapy, xanomeline/trospium (X/T).

Xanomeline is a muscarinic M1/M4 agonist synthesized in the early 1990s as a cognitive enhancer for patients with dementia due to Alzheimer’s disease. Despite lacking any binding to dopamine D2 receptors, xanomeline was noted to possess antipsychotic properties in the dementia trials. This unexpected discovery was at odds with the predominant paradigm that antipsychotics must function as postsynaptic D2 receptor antagonists. The primary exceptions to that rule were clozapine, whose mechanism was not fully understood, and the nonselective VMAT1 and VMAT2 inhibitor reserpine, which decreased presynaptic dopamine release to the extent that it reduced positive symptoms, but also induced significant motor adverse events (AEs) because of  activity in the motor striatum. Unlike reserpine, xanomeline also reduced presynaptic dopamine release by decreasing stimulatory inputs to striatal dopamine neurons, but it did so selectively, with no actions on motor pathways. Despite the absence of motor, endocrine, or metabolic AEs, when administered by itself, xanomeline was associated with procholinergic AEs such as nausea and vomiting, necessitating its pairing with trospium, a peripheral anticholinergic medication approved in the United States in 2004 for overactive bladder, but with very limited brain penetration so as not to interfere with the central muscarinic agonism of xanomeline. Trospium significantly reduced (but did not eliminate) procholinergic AEs, and X/T was approved by the FDA in September 2024 for the treatment of schizophrenia on the basis of 3 registrational trials of acutely exacerbated adults with schizophrenia that used an 8-day titration to the maximal dose. The X/T prescribing information not only lacks the typical antipsychotic class warnings but also does not contain the word “antipsychotic” at all. Of importance, the effect size calculated using the meta-analysis method is 0.56, among the highest of any antipsychotic approved since clozapine (eg, risperidone 0.56, olanzapine 0.59).

The unique aspects of X/T pharmacology necessitate that X/T be dosed twice daily, and on an empty stomach (ie, 1 hour before breakfast, 2 hours after dinner), to maximize trospium absorption and minimize procholinergic AEs. Taking X/T with food results in loss of 85% to 90% of trospium exposure, necessitating that healthcare professionals clearly communicate with patients and decide to what extent a patient can be adherent with an oral twice-daily medication. The use of ondansetron (as was done in the clinical trials) and possibly an additional 20 mg dose of trospium daily may be necessary in certain patients to manage procholinergic AEs. Moreover, advancing to the highest twice-daily X/T dose containing 125 mg xanomeline and 30 mg trospium provides more relative trospium exposure than the 100 mg/20 mg twice-daily dose.

Although the unusual aspects of X/T pharmacology mandate flexibility to improve tolerability, clinical trials not only found an absence of weight gain, endocrine, and motor AEs, but also signaled cognitive benefits in those whose baseline function was at least 1 standard deviation below norms. The hypothesis for this effect, which was noted in each of the 3 phase IIb/III studies, relates to markedly diminished muscarinic M1 receptor expression seen in 25% of patients with schizophrenia. This muscarinic receptor deficit syndrome is associated with cognitive deficits and negative symptoms. Therefore, M1 receptor stimulation from xanomeline is postulated to improve cognition on this basis. Moreover, a post hoc analysis of these trials also indicated benefit for negative symptoms, again among those patients with higher baseline levels of those symptoms. X/T is not necessarily a replacement for clozapine as it works to decrease presynaptic dopamine release, but many patients with treatment-resistant schizophrenia do not appear to have a presynaptic dopamine overproduction problem underlying their positive symptoms. X/T may also not necessarily confer marked benefit when used adjunctively as noted in a dedicated clinical trial, but there may be improvement in symptoms among those with less severe psychopathology (ie, baseline PANSS total score <90), those receiving a partial agonist like aripiprazole, with a signal for impact on positive symptoms among all subjects in that study, although the effect was modest.

Insight provided by X/T has spurred studies of numerous muscarinic receptor–stimulating agents that act on M1, M4, or both, with the goal of replicating the efficacy of X/T while perhaps mitigating some of the procholinergic AEs. Assuming their studies are positive, these medications are still many years away from being clinically available, so those who treat patients with schizophrenia must become adept at using X/T and confer its unique advantages (eg, efficacy, procognitive impact, lack of tardive dyskinesia risk, minimal acute motor AEs, weight gain, or endocrine AEs).

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