Valentin A. Pavlov1,2,3*- 1The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
- 2Department of Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States
- 3Elmezzi Graduate School of Molecular Medicine, Manhasset, NY, United States
Introduction
Schizophrenia is a multifactorial chronic and frequently disabling mental disorder that reportedly affects about one percent of the world’s population (1, 2). Until recently, the pharmacological treatment of schizophrenia was almost entirely based on blocking brain dopamine D2 receptor signaling (2). While the approved therapeutics that act through this mechanism are efficacious in improving the positive symptoms in schizophrenia, they have considerable side effects including sedation, weight gain and motor impairment (2). They also have limited effectiveness in improving the negative and cognitive symptoms in patients with this disease (3). In addition to dopaminergic mechanisms, abundant experimental evidence reveals the important role of the brain cholinergic system and muscarinic acetylcholine receptors (mAChRs) as a therapeutic target in schizophrenia (4–6). Xanomeline is a centrally acting agonist of the M1 and M4 subtype of mAChRs with beneficial antipsychotic and cognitive effects (6, 7). Decades of research in preclinical and clinical settings and a series of recent clinical trials led to the FDA approval in September 2024 of xanomeline together with trospium for the treatment of schizophrenia (8). Trospium is a peripherally restricted nonspecific mAChR antagonist, which when given together with xanomeline mitigates the undesirable peripheral, mainly gastrointestinal effects of xanomeline. A recent review summarized the chronology and major findings from the clinical trials with xanomeline/trospium in schizophrenia (9). The approval of xanomeline/trospium is paradigm shifting, because for the first time in over 70 years a novel treatment which is not based on the mainstream concept of modulating D2 dopamine receptor signaling is available for schizophrenia. These recent developments may have broader implications: for reasons we summarize and discuss below, this drug combination can be explored in the future treatment of other complex neuropsychiatric and neurocognitive conditions such as Alzheimer’s disease (AD) and sepsis-associated encephalopathy (SAE) and long-term cognitive impairment.
Xanomeline in the treatment of schizophrenia
There has been a substantial interest during the last few decades in studying the role of brain mAChRs in the pathogenesis of schizophrenia and targeting these receptors using pharmacological modalities for therapeutic benefit. Accumulated experimental evidence from preclinical and human brain imaging and post mortem studies was summarized in 2007 as a “muscarinic hypothesis of schizophrenia” (5). Studies in murine and non-human primate models have indicated the therapeutic potential of the centrally acting M1/M4 mAChR agonist xanomeline for treating psychosis and the mediating role of brain mAChRs (10–12). A small double-blind, placebo-controlled pilot study published in 2008, demonstrated the effectiveness of xanomeline in improving multiple symptom domains in patients with schizophrenia (13). However, side effects associated with xanomeline treatment, including gastrointestinal disturbances were also reported in this study. More recently, to mitigate these peripheral side effects in clinical studies with schizophrenia patients, xanomeline was combined with the peripherally acting mAChR antagonist trospium. A series of Phase 2 (14) and Phase 3 clinical trials (15, 16) demonstrated that treatment with xanomeline/trospium significantly decreased the positive and negative symptoms in people with schizophrenia who experience acute psychosis. These successful clinical trials led to the approval of xanomeline/trospium by the FDA for the treatment of adult patients with schizophrenia. Cognitive impairment, which may precede the onset of psychosis, is a core feature of schizophrenia (17). Importantly, xanomeline/trospium treatment significantly improved cognitive deficits in patients with acute schizophrenia who had preexisting cognitive deterioration as revealed by analysis of data pulled from the Phase 3 trials (18). These observations revealing the cognitive benefit of xanomeline/trospium among participants who had substantial impairment at baseline are consistent with the Phase 2 study data. Of note, as in the Phase 2 study, the beneficial cognitive effects of xanomeline/trospium were independent of changes in positive and negative symptoms, indicating that the cognitive improvements were not pseudo-specific (18).
Xanomeline in the treatment of Alzheimer’s disease
The brain cholinergic system plays a key role in the regulation of attention, learning and memory (19). Characteristic neurodegeneration of brain (forebrain) neurons, with associated cognitive impairment is one of the cardinal features of AD, a debilitating and lethal brain neurodegenerative and neuropsychiatric disease and the most prevalent form of dementia (20, 21). In addition to schizophrenia, xanomeline has also been explored in the treatment of patients with AD. Almost 30 years ago (in 1997), in a large-scale multicenter, 6-month placebo-controlled clinical trial, xanomeline was found to significantly improve the cognitive function in AD patients (22). Intriguingly, xanomeline also improved psychosis in these patients (22). However, adverse, predominantly gastrointestinal events of xanomeline resulted in discontinued treatment of 52% of patients (22). Therefore, because of its peripheral side effects no further studies with xanomeline were performed despite its significant efficacy in counteracting the cognitive decline and neuropsychiatric symptoms in patients with AD.
Brain functional impairment during sepsis
Sepsis is a multifactorial disorder that remains a number one killer in the intensive care units. According to its latest 2016 definition, sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection (23). One organ that is frequently, profoundly, and progressively affected during sepsis is the brain. The brain functional impairment and neuropsychiatric manifestations during sepsis, which include cognitive impairment and progression into delirium and coma, are characterized as sepsis-associated encephalopathy (SAE) (24–27). SAE can be defined as a diffuse cerebral dysfunction due to the dysregulated host response during sepsis secondary to infection which does not directly involve the central nervous system (24, 27). Brain alterations, including cognitive impairment and delirium occur very early during sepsis and are associated with increased hospital mortality (27–30). While the pathogenesis of SAE is not well understood, there is evidence from preclinical (31–33) and clinical studies for brain cholinergic alterations and hypofunction among the brain neurotransmitter changes that occur during sepsis (32, 34). As the brain cholinergic system plays a key role in the regulation of cognition, this cholinergic hypofunction may play a causative role in the severe cognitive impairment and delirium during sepsis (35).
Brain dysfunction and persistent cognitive impairment are also profound manifestations of sepsis long-term sequelae (36–38). Findings from a multicenter prospective cohort study revealed that one in four patients had cognitive impairment 12 months after critical illness comparable to that of mild AD (39). There is a correlation between SAE and especially delirium and the development of long-term cognitive dysfunction following hospital discharge (39, 40). Neuropsychiatric symptoms, including depression, anxiety, and post-traumatic stress disorder have also been documented in sepsis survivors (41, 42). In addition, an increased risk of suicide has been revealed in patients with prior hospitalization with infection, including sepsis (43). The long-term cognitive impairment and neuropsychiatric symptoms are key components of functional disability of sepsis survivors severely worsening their quality of life and associated with increased morbidity and mortality (38). While treating SAE encephalopathy and preventing and treating long-term cognitive impairment and neuropsychiatric manifestations in sepsis survivors are of fundamental value, there is a lack of targeted pharmacological modalities, and no specific guidelines have been currently implemented.
Discussion of possibilities for using xanomeline/trospium in the treatment of AD and SAE
Psychosis and agitation are major and challenging to manage neuropsychiatric symptoms in AD (44, 45). Therefore, it is not surprising that based on accumulated evidence for its antipsychotic effects, clinical trials exploring the efficacy of xanomeline/trospium in treating AD psychosis are underway (46). Also, very recently, the emergence of psychosis in AD was correlated with increased plasma levels of p-tau phosphorylated at threonine 181 (p-tau181) and neurofilament light chain protein (NfL) and their utility as biomarkers of neuropsychiatric illness in AD was suggested (47). Therefore, it would be intriguing to determine whether plasma p-tau181 and NfL levels are altered in AD patients treated with xanomeline/trospium and corelate with antipsychotic drug effects in these trials.
The effects of xanomeline/trospium in AD might be far reaching and not just restricted to treating psychosis. This speculation is strongly supported by the prior study which showed that xanomeline monotherapy significantly improved cognitive domains in AD patients (22). It appears that the main obstacle for its use, i.e., severe peripheral side effects that for a long-time hampered progress, can now be addressed by including trospium. Hence, evaluating the effects of xanomeline on cognitive function in patients with AD, utilizing the double-blind placebo-controlled design in the 1997 study but with the addition of trospium is warranted. The use of this therapy can also be considered for treating cognitive impairment in the context of other disorders.
As previously noted, xanomeline is an M1/M4 m AChR agonist. It is not clear whether xanomeline beneficial effects in schizophrenia are due to the action on the brain M1 or the M4 subtype or both. The brain M1 and M4 mAChRs have different synaptic location and different function (48–50). The M1 subtype is predominantly postsynaptic and plays a major role in processing cholinergic neurotransmission in the cortex and the hippocampus with an essential function in the regulation of cognition (48). Of note, studies with mice lacking specific mAChR subtypes have shown no direct involvement of the M1 subtype in the control of brain (striatal) dopamine release (51). The brain M4 subtype is predominantly presynaptic and associated with modulation of neurotransmitter, including dopaminergic system (50–53). There is some evidence linking the antipsychotic-like effects of xanomeline and its efficacy in treating positive and negative symptoms in patients with schizophrenia to its action on the M4 subtype, while the cognitive effects might be mainly associated with activation of M1 mAChR signaling (6, 54).
The postsynaptically located M1 mAChR is largely preserved during the neurodegenerative alterations in AD (21, 55, 56). Thus, the M1 mAChR presents a viable target for therapeutic strategies aimed at counteracting cognitive impairment in AD by activating M1 mAChR signaling (21, 48, 57, 58). Preclinical studies have also demonstrated a role for activation of M1 mAChR signaling in reducing other characteristic features of AD pathology, including amyloid plaques, mainly composed of the amyloid-β peptide and neurofibrillary tangles, comprised of hyperphosphorylated aggregates of the tau protein (59, 60). These findings have a provided a rationale for proposing the use of M1 mAChR agonists in potentially disease-modifying therapies for AD (57, 58). Therefore, xanomeline acting on the brain M1 mAChR may have additional beneficial effects in AD.
In addition to regulation of cognition, brain (forebrain) mAChR and specifically the M1 mAChR are implicated in the regulation of peripheral cytokine levels and inflammation (61–66). Administration of xanomeline or BQCA, a selective positive allosteric modulator of the M1 mAChR with demonstrated pro-cognitive effects (67) significantly suppresses circulating pro-inflammatory cytokine levels in mice with endotoxemia (62, 65). Xanomeline reduces serum pro-inflammatory cytokine levels, ameliorates sickness behavior, and improves survival in endotoxemia and in a preclinical mouse model of sepsis (62, 68). The anti-inflammatory effects of xanomeline are mediated through brain mAChRs, because they are inhibited in mice with pharmacological blockade of these receptors (62). These effects also require signaling through the vagus nerve (62). The vagus nerve is a key constituent of a major physiological mechanism termed the inflammatory reflex that links the brain and the immune system and controls peripheral cytokine responses (62, 69, 70).
Accumulated experimental evidence during the last 20 years has revealed a role for systemic inflammation in the pathogenesis of schizophrenia and as a new therapeutic target in the treatment of this disease (7, 71). As we have recently proposed, the anti-inflammatory activity of xanomeline may contribute to its remarkable efficacy in alleviating multiple symptoms in patients with schizophrenia (7). Such a possibility can be evaluated in future clinical studies in which subclusters of patients with increased inflammation can be reliably identified using machine learning, and additional analysis of xanomeline anti-inflammatory effects in this subset of patients is performed (7).
There is also evidence for systemic inflammation that is linked with brain inflammation in the pathophysiology of AD (72–74). It has also been reported that both acute and chronic inflammation and increased levels of pro-inflammatory cytokines are associated with exacerbated cognitive decline in patients with AD (75). Therefore, it is intriguing to consider that the beneficial effects of xanomeline on cognition in patients with AD will be amplified by its anti-inflammatory effects. Such a possibility can be experimentally and more specifically tested in AD patients with increased peripheral cytokine levels by implementing the same approach as proposed for patients with schizophrenia.
Increased circulating pro-inflammatory cytokine levels and systemic inflammation linked to brain inflammation (neuroinflammation) and brain cholinergic hypofunction have been implicated in SAE (25, 32, 76, 77). Of note, administration of xanomeline in a murine model of sepsis improves survival and ameliorates markers of immune dysregulation and inflammation (62, 68). There is also evidence for immune dysregulation and increased levels of pro-inflammatory cytokines and inflammation in sepsis survivors (31, 78, 79). Long-term cognitive impairment with symptoms that are similar to those in patients with mild AD has also been reported in sepsis survivors (38, 39). Importantly, for most patients, this profound cognitive deterioration in sepsis survivors was not related to cognitive impairment before their admission to the intensive care unit (39). It was also documented in both old and young patients, regardless of the burden of coexisting conditions at baseline (39). While of primary clinical significance, treating SAE is challenging as no targeted treatments are currently available. The anti-inflammatory and beneficial cognitive efficacy of xanomeline (together with trospium) can be explored in new therapies for SAE and the long-term cognitive impairment in sepsis survivors.
In conclusion, based on evidence and reasoning we outline here, xanomeline/trospium - a therapeutic modality that was very recently approved for schizophrenia - can also be considered in novel therapeutic strategies for AD and SAE and long-term cognitive deficits.
Author contributions
VP: Conceptualization, Writing – review & editing, Writing – original draft.
Funding
The author(s) declare that financial support was received for the research and/or publication of this article. This work was supported by the National Institutes of Health (NIH), National Institute of General Medical Sciences grants: RO1GM128008 and RO1GM121102 (to VP).
Acknowledgments
The author thanks Dr. Michael Brines, Dr. Christine Metz, Dr. Jeremy Koppel, and Dr. Kevin Tracey for their helpful comments. The manuscript format requirements and word count limitations did not allow expanding the discussion of certain aspects and we would direct the reader to relevant studies cited here.
Conflict of interest
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
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References
2. Howes OD, Bukala BR, and Beck K. Schizophrenia: from neurochemistry to circuits, symptoms and treatments. Nat Rev Neurol. (2023) 20:22–35. doi: 10.1038/s41582-023-00904-0
3. Galderisi S, Mucci A, Buchanan RW, and Arango C. Negative symptoms of schizophrenia: new developments and unanswered research questions. Lancet Psychiatry. (2018) 5:664–77. doi: 10.1016/S2215-0366(18)30050-6
4. Gibbons A and Dean B. The cholinergic system: an emerging drug target for schizophrenia. Curr pharmaceutical design. (2016) 22:2124–33. doi: 10.2174/1381612822666160127114010
5. Raedler TJ, Bymaster FP, Tandon R, Copolov D, and Dean B. Towards a muscarinic hypothesis of schizophrenia. Mol Psychiatry. (2007) 12:232–46. doi: 10.1038/sj.mp.4001924
6. Foster DJ, Bryant ZK, and Conn PJ. Targeting muscarinic receptors to treat schizophrenia. Behav Brain Res. (2021) 405:113201. doi: 10.1016/j.bbr.2021.113201
7. Metz CN, Brines M, and Pavlov VA. Bridging cholinergic signalling and inflammation in schizophrenia. Schizophrenia. (2024) 10:51. doi: 10.1038/s41537-024-00472-2
8. Kingwell K. FDA approves first schizophrenia drug with new mechanism of action since 1950s. Nat Rev Drug Discov. (2024) 23:803. doi: 10.1038/d41573-024-00155-8
9. Smith CM, Augustine MS, Dorrough J, Szabo ST, Shadaram S, Hoffman EOG, et al. Xanomeline-trospium (Cobenfy(TM)) for schizophrenia: A review of the literature. Clin Psychopharmacol Neurosci. (2025) 23:2–14. doi: 10.9758/cpn.24.1253
10. Shannon HE, Rasmussen K, Bymaster FP, Hart JC, Peters SC, Swedberg MDB, et al. Xanomeline, an M1/M4 preferring muscarinic cholinergic receptor agonist, produces antipsychotic-like activity in rats and mice. Schizophr Res. (2000) 42:249–59. doi: 10.1016/S0920-9964(99)00138-3
11. Stanhope KJ, Mirza NR, Bickerdike MJ, Bright JL, Harrington NR, Hesselink MB, et al. The muscarinic receptor agonist xanomeline has an antipsychotic-like profile in the rat. J Pharmacol Exp Ther. (2001) 299:782–92. doi: 10.1016/S0022-3565(24)29291-0
12. Andersen MB, Fink-Jensen A, Peacock L, Gerlach J, Bymaster F, Lundbæk JA, et al. The muscarinic M1/M4 receptor agonist xanomeline exhibits antipsychotic-like activity in cebus apella monkeys. Neuropsychopharmacology. (2003) 28:1168–75. doi: 10.1038/sj.npp.1300151
13. Shekhar A, Potter WZ, Lightfoot J, Lienemann J, Dubé S, Mallinckrodt C, et al. Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia. Am J Psychiatry. (2008) 165:1033–9. doi: 10.1176/appi.ajp.2008.06091591
14. Brannan SK, Sawchak S, Miller AC, Lieberman JA, Paul SM, and Breier A. Muscarinic cholinergic receptor agonist and peripheral antagonist for schizophrenia. New Engl J medicine. (2021) 384:717–26. doi: 10.1056/NEJMoa2017015
15. Kaul I, Sawchak S, Correll CU, Kakar R, Breier A, Zhu H, et al. Efficacy and safety of the muscarinic receptor agonist KarXT (xanomeline-trospium) in schizophrenia (EMERGENT-2) in the USA: results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trial. Lancet (London England). (2024) 403:160–70. doi: 10.1016/S0140-6736(23)02190-6
16. Kaul I, Sawchak S, Walling DP, Tamminga CA, Breier A, Zhu H, et al. Efficacy and safety of xanomeline-trospium chloride in schizophrenia: A randomized clinical trial. JAMA Psychiatry. (2024) 81:749–56. doi: 10.1001/jamapsychiatry.2024.0785
17. McCutcheon RA, Keefe RS, and McGuire PK. Cognitive impairment in schizophrenia: aetiology, pathophysiology, and treatment. Mol Psychiatry. (2023) 28:1902–18. doi: 10.1038/s41380-023-01949-9
18. Horan WP, Sauder C, Harvey PD, Ramsay IS, Yohn SE, Keefe RSE, et al. The impact of xanomeline and trospium chloride on cognitive impairment in acute schizophrenia: replication in pooled data from two phase 3 trials. Am J Psychiatry. (2024) 182:297–306. doi: 10.1176/appi.ajp.20240076
19. Ananth MR, Rajebhosale P, Kim R, Talmage DA, and Role LW. Basal forebrain cholinergic signalling: development, connectivity and roles in cognition. Nat Rev Neurosci. (2023) 24:233–51. doi: 10.1038/s41583-023-00677-x
20. Ballinger EC, Ananth M, Talmage DA, and Role LW. Basal forebrain cholinergic circuits and signaling in cognition and cognitive decline. Neuron. (2016) 91:1199–218. doi: 10.1016/j.neuron.2016.09.006
21. Hampel H, Mesulam MM, Cuello AC, Farlow MR, Giacobini E, Grossberg GT, et al. The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease. Brain: A J Neurol. (2018) 141:1917–33. doi: 10.1093/brain/awy132
22. Bodick NC, Offen WW, Levey AI, Cutler NR, Gauthier SG, Satlin A, et al. Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in alzheimer disease. Arch Neurol. (1997) 54:465–73. doi: 10.1001/archneur.1997.00550160091022
23. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). Jama. (2016) 315:801–10. doi: 10.1001/jama.2016.0287
24. Gofton TE and Young GB. Sepsis-associated encephalopathy. Nat Rev Neurol. (2012) 8:557–66. doi: 10.1038/nrneurol.2012.183
25. Carter BL and Underwood J. Sepsis and the brain: a review for acute and general physicians. Clin Med (Lond). (2022) 22:392–5. doi: 10.7861/clinmed.2022-0346
26. Sonneville R, Verdonk F, Rauturier C, Klein IF, Wolff M, Annane D, et al. Understanding brain dysfunction in sepsis. Ann Intensive Care. (2013) 3:15. doi: 10.1186/2110-5820-3-15
27. Chung H-Y, Wickel J, Brunkhorst FM, and Geis C. Sepsis-associated encephalopathy: from delirium to dementia? J Clin Med. (2020) 9:703. doi: 10.3390/jcm9030703
28. Martin B-J, Buth KJ, Arora RC, and Baskett RJ. Delirium as a predictor of sepsis in post-coronary artery bypass grafting patients: a retrospective cohort study. Crit Care. (2010) 14:1–6. doi: 10.1186/cc9273
29. Eidelman LA, Putterman D, Putterman C, and Sprung CL. The spectrum of septic encephalopathy: definitions, etiologies, and mortalities. Jama. (1996) 275:470–3. doi: 10.1001/jama.1996.03530300054040
30. Sonneville R, de Montmollin E, Poujade J, Garrouste-Orgeas M, Souweine B, Darmon M, et al. Potentially modifiable factors contributing to sepsis-associated encephalopathy. Intensive Care Med. (2017) 43:1075–84. doi: 10.1007/s00134-017-4807-z
31. Zaghloul N, Addorisio ME, Silverman HA, Patel HL, Valdes-Ferrer SI, Ayasolla KR, et al. Forebrain cholinergic dysfunction and systemic and brain inflammation in murine sepsis survivors. Front Immunol. (2017) 8:1673. doi: 10.3389/fimmu.2017.01673
32. Zhang Q-H, Sheng Z-Y, and Yao Y-M. Septic encephalopathy: when cytokines interact with acetylcholine in the brain. Military Med Res. (2014) 1:20. doi: 10.1186/2054-9369-1-20
33. Semmler A, Frisch C, Debeir T, Ramanathan M, Okulla T, Klockgether T, et al. Long-term cognitive impairment, neuronal loss and reduced cortical cholinergic innervation after recovery from sepsis in a rodent model. Exp Neurol. (2007) 204:733–40. doi: 10.1016/j.expneurol.2007.01.003
34. Trzepacz PT. Is there a final common neural pathway in delirium? Focus on acetylcholine and dopamine. Semin Clin Neuropsychiatry. (2000) 5:132–48. doi: 10.153/SCNP00500132
35. Hshieh TT, Fong TG, Marcantonio ER, and Inouye SK. Cholinergic deficiency hypothesis in delirium: a synthesis of current evidence. journals gerontology Ser A Biol Sci Med Sci. (2008) 63:764–72. doi: 10.1093/gerona/63.7.764
36. Annane D and Sharshar T. Cognitive decline after sepsis. Lancet Respiratory Med. (2015) 3:61–9. doi: 10.1016/S2213-2600(14)70246-2
37. Rengel KF, Hayhurst CJ, Pandharipande PP, and Hughes CG. Long-term cognitive and functional impairments after critical illness. Anesthesia analgesia. (2019) 128:772–80. doi: 10.1213/ANE.0000000000004066
38. Iwashyna TJ, Ely EW, Smith DM, and Langa KM. Long-term cognitive impairment and functional disability among survivors of severe sepsis. Jama. (2010) 304:1787–94. doi: 10.1001/jama.2010.1553
39. Pandharipande PP, Girard TD, Jackson JC, Morandi A, Thompson JL, Pun BT, et al. Long-term cognitive impairment after critical illness. New Engl J Med. (2013) 369:1306–16. doi: 10.1056/NEJMoa1301372
40. Girard TD, Jackson JC, Pandharipande PP, Pun BT, Thompson JL, Shintani AK, et al. Delirium as a predictor of long-term cognitive impairment in survivors of critical illness. Crit Care Med. (2010) 38:1513–20. doi: 10.1097/CCM.0b013e3181e47be1
41. Wintermann G-B, Brunkhorst FM, Petrowski K, Strauss B, Oehmichen F, Pohl M, et al. Stress disorders following prolonged critical illness in survivors of severe sepsis. Crit Care Med. (2015) 43:1213–22. doi: 10.1097/CCM.0000000000000936
42. Mostel Z, Perl A, Marck M, Mehdi SF, Lowell B, Bathija S, et al. Post-sepsis syndrome - an evolving entity that afflicts survivors of sepsis. Mol Med. (2019) 26:6. doi: 10.1186/s10020-019-0132-z
43. Lund-Sørensen H, Benros ME, Madsen T, Sørensen HJ, Eaton WW, Postolache TT, et al. A nationwide cohort study of the association between hospitalization with infection and risk of death by suicide. JAMA Psychiatry. (2016) 73:912–9. doi: 10.1001/jamapsychiatry.2016.1594
44. Murray PS, Kumar S, DeMichele-Sweet MAA, and Sweet RA. Psychosis in alzheimer’s disease. Biol Psychiatry. (2014) 75:542–52. doi: 10.1016/j.biopsych.2013.08.020
45. Halpern R, Seare J, Tong J, Hartry A, Olaoye A, and Aigbogun MS. Using electronic health records to estimate the prevalence of agitation in Alzheimer disease/dementia. Int J geriatric Psychiatry. (2019) 34:420–31. doi: 10.1002/gps.v34.3
46. Watson C, Cummings J, Grossberg G, Kang M, and Marcus R. P20: Evaluating xanomeline and trospium as a treatment for psychosis associated with Alzheimer’s disease: design of the phase 3, ADEPT-1, relapse prevention study. Int Psychogeriatrics. (2024) 36:93–4. doi: 10.1017/S1041610224002035
47. Gomar JJ and Koppel J. Psychosis in alzheimer disease and elevations in disease-relevant biomarkers. JAMA Psychiatry. (2024) 81:834–9. doi: 10.1001/jamapsychiatry.2024.1389
48. Metz CN and Pavlov VA. Treating disorders across the lifespan by modulating cholinergic signaling with galantamine. J neurochemistry. (2021) 158:1359–80. doi: 10.1111/jnc.v158.6
49. Volpicelli LA and Levey AI. Muscarinic acetylcholine receptor subtypes in cerebral cortex and hippocampus. Prog Brain Res. (2004) 145:59–66. doi: 10.1016/S0079-6123(03)45003-6
50. Levey AI. Muscarinic acetylcholine receptor expression in memory circuits: implications for treatment of Alzheimer disease. Proc Natl Acad Sci. (1996) 93:13541–6. doi: 10.1073/pnas.93.24.13541
51. Zhang W, Yamada M, Gomeza J, Basile AS, and Wess J. Multiple muscarinic acetylcholine receptor subtypes modulate striatal dopamine release, as studied with M1–M5 muscarinic receptor knock-out mice. J Neurosci. (2002) 22:6347–52. doi: 10.1523/JNEUROSCI.22-15-06347.2002
52. Jeon J, Dencker D, Wörtwein G, Woldbye DP, Cui Y, Davis AA, et al. A subpopulation of neuronal M4 muscarinic acetylcholine receptors plays a critical role in modulating dopamine-dependent behaviors. J Neurosci. (2010) 30:2396–405. doi: 10.1523/JNEUROSCI.3843-09.2010
53. Nunes EJ, Addy NA, Conn PJ, and Foster DJ. Targeting the actions of muscarinic receptors on dopamine systems: new strategies for treating neuropsychiatric disorders. Annu Rev Pharmacol Toxicol. (2024) 64:277–89. doi: 10.1146/annurev-pharmtox-051921-023858
54. Woolley ML, Carter HJ, Gartlon JE, Watson JM, and Dawson LA. Attenuation of amphetamine-induced activity by the non-selective muscarinic receptor agonist, xanomeline, is absent in muscarinic M4 receptor knockout mice and attenuated in muscarinic M1 receptor knockout mice. Eur J Pharmacol. (2009) 603:147–9. doi: 10.1016/j.ejphar.2008.12.020
55. Pearce BD and Potter LT. Coupling of ml muscarinic receptors to G protein in alzheimer disease. Alzheimer Dis Associated Disord. (1991) 5:163–72. doi: 10.1097/00002093-199100530-00002
56. Overk CR, Felder CC, Tu Y, Schober DA, Bales KR, Wuu J, et al. Cortical M1 receptor concentration increases without a concomitant change in function in Alzheimer’s disease. J Chem neuroanatomy. (2010) 40:63–70. doi: 10.1016/j.jchemneu.2010.03.005
57. Caccamo A, Fisher A, and LaFerla FM. M1 agonists as a potential disease-modifying therapy for Alzheimer’s disease. Curr Alzheimer Res. (2009) 6:112–7. doi: 10.2174/156720509787602915
58. Scarpa M, Hesse S, and Bradley SJ. Chapter Ten - M1 muscarinic acetylcholine receptors: A therapeutic strategy for symptomatic and disease-modifying effects in Alzheimer’s disease? In: Langmead CJ, editor. Advances in Pharmacol, vol. 88. Cambridge, Massachusetts, USA: Academic Press (2020). p. 277–310.
59. Fisher A. Cholinergic modulation of amyloid precursor protein processing with emphasis on M1 muscarinic receptor: perspectives and challenges in treatment of Alzheimer’s disease. J neurochemistry. (2012) 120 Suppl 1:22–33. doi: 10.1111/j.1471-4159.2011.07507.x
60. Caccamo A, Oddo S, Billings LM, Green KN, Martinez-Coria H, Fisher A, et al. M1 receptors play a central role in modulating AD-like pathology in transgenic mice. Neuron. (2006) 49:671–82. doi: 10.1016/j.neuron.2006.01.020
61. Pavlov VA, Ochani M, Gallowitsch-Puerta M, Ochani K, Huston JM, Czura CJ, et al. Central muscarinic cholinergic regulation of the systemic inflammatory response during endotoxemia. Proc Natl Acad Sci U S A. (2006) 103:5219–23. doi: 10.1073/pnas.0600506103
62. Rosas-Ballina M, Valdes-Ferrer SI, Dancho ME, Ochani M, Katz D, Cheng KF, et al. Xanomeline suppresses excessive pro-inflammatory cytokine responses through neural signal-mediated pathways and improves survival in lethal inflammation. Brain behavior immunity. (2015) 44:19–27. doi: 10.1016/j.bbi.2014.07.010
63. Pavlov VA, Parrish WR, Rosas-Ballina M, Ochani M, Puerta M, Ochani K, et al. Brain acetylcholinesterase activity controls systemic cytokine levels through the cholinergic anti-inflammatory pathway. Brain behavior immunity. (2009) 23:41–5. doi: 10.1016/j.bbi.2008.06.011
64. Pavlov VA and Tracey KJ. Bioelectronic medicine: Preclinical insights and clinical advances. Neuron. (2022) 110:3627–44. doi: 10.1016/j.neuron.2022.09.003
65. Lehner KR, Silverman HA, Addorisio ME, Roy A, Al-Onaizi MA, Levine Y, et al. Forebrain cholinergic signaling regulates innate immune responses and inflammation. Front Immunol. (2019) 10:585. doi: 10.3389/fimmu.2019.00585
66. Munyaka P, Rabbi MF, Pavlov VA, Tracey KJ, Khafipour E, and Ghia JE. Central muscarinic cholinergic activation alters interaction between splenic dendritic cell and CD4+CD25- T cells in experimental colitis. PLoS One. (2014) 9:e109272. doi: 10.1371/journal.pone.0109272
67. Ma L, Seager MA, Wittmann M, Jacobson M, Bickel D, Burno M, et al. Selective activation of the M1 muscarinic acetylcholine receptor achieved by allosteric potentiation. Proc Natl Acad Sci. (2009) 106:15950–5. doi: 10.1073/pnas.0900903106
68. Abraham MN, Nedeljkovic-Kurepa A, Fernandes TD, Yaipen O, Brewer MR, Leisman DE, et al. M1 cholinergic signaling in the brain modulates cytokine levels and splenic cell sub-phenotypes following cecal ligation and puncture. Mol Medicine. (2024) 30:22. doi: 10.1186/s10020-024-00787-x
70. Pavlov VA and Tracey KJ. Neural regulation of immunity: molecular mechanisms and clinical translation. Nat Neurosci. (2017) 20:156–66. doi: 10.1038/nn.4477
71. Khandaker GM, Cousins L, Deakin J, Lennox BR, Yolken R, and Jones PB. Inflammation and immunity in schizophrenia: implications for pathophysiology and treatment. Lancet Psychiatry. (2015) 2:258–70. doi: 10.1016/S2215-0366(14)00122-9
72. Walker KA, Ficek BN, and Westbrook R. Understanding the role of systemic inflammation in alzheimer’s disease. ACS Chem Neurosci. (2019) 10:3340–2. doi: 10.1021/acschemneuro.9b00333
73. Kinney JW, Bemiller SM, Murtishaw AS, Leisgang AM, Salazar AM, and Lamb BT. Inflammation as a central mechanism in Alzheimer’s disease. Alzheimer’s dementia (New York N Y). (2018) 4:575–90. doi: 10.1016/j.trci.2018.06.014
74. Walker KA, Le Page LM, Terrando N, Duggan MR, Heneka MT, and Bettcher BM. The role of peripheral inflammatory insults in Alzheimer’s disease: a review and research roadmap. Mol Neurodegeneration. (2023) 18:37. doi: 10.1186/s13024-023-00627-2
75. Holmes C, Cunningham C, Zotova E, Woolford J, Dean C, Kerr S, et al. Systemic inflammation and disease progression in Alzheimer disease. Neurology. (2009) 73:768–74. doi: 10.1212/WNL.0b013e3181b6bb95
76. Pavlov VA, Chavan SS, and Tracey KJ. Molecular and functional neuroscience in immunity. Annu Rev Immunol. (2018) 36:783–812. doi: 10.1146/annurev-immunol-042617-053158
77. Catarina AV, Branchini G, Bettoni L, De Oliveira JR, and Nunes FB. Sepsis-associated encephalopathy: from pathophysiology to progress in experimental studies. Mol Neurobiol. (2021) 58:2770–9. doi: 10.1007/s12035-021-02303-2
78. Nomellini V, Kaplan LJ, Sims CA, and Caldwell CC. Chronic Critical Illness and Persistent Inflammation: What can we Learn from the Elderly, Injured, Septic, and Malnourished? Shock (Augusta Ga). (2018) 49:4–14. doi: 10.1097/SHK.0000000000000939
Keywords: schizophrenia, xanomeline, brain muscarinic receptors, Alzheimer’s disease, sepsis-associated encephalopathy, inflammation
Citation: Pavlov VA (2025) Novel opportunities for treating complex neuropsychiatric and neurocognitive conditions based on recent developments with xanomeline. Front. Psychiatry 16:1593341. doi: 10.3389/fpsyt.2025.1593341
Received: 13 March 2025; Accepted: 24 April 2025;
Published: 15 May 2025.
Edited by:
Massimo Tusconi, University of Cagliari, ItalyReviewed by:
Eva Ceskova, Masaryk University, CzechiaYuji Ozeki, Shiga University of Medical Science, Japan
Lawrence Maayan, New York State Psychiatric Institute (NYSPI), United States
Copyright © 2025 Pavlov. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Valentin A. Pavlov, dnBhdmxvdkBub3J0aHdlbGwuZWR1