Muscarinic Cholinergic Receptor Agonist and Peripheral Antagonist for Schizophrenia

Brannan, Stephen K.; Sawchak, Sharon; Miller, Andrew; Lieberman, Jeffrey A.; Paul, Steven M.; Breier, Alan

doi:10.1056/nejmoa2017015

Cited by 205 publications

(177 citation statements)

References 24 publications

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“…Most recently, the M1/M4 agonist xanomeline was combined with a peripheral acetylcholine antagonist trospium to reduce treatment limiting gastrointestinal side effects. A Phase II study found significant improvement across multiple symptom domains, including negative symptoms [15]. Similar to SEP-363,856, this study was conducted in acutely ill schizophrenia group that was not specifically enriched for negative symptoms.…”

Section: Acetylcholinergic-based Treatmentsmentioning

confidence: 89%

How do we address treating the negative symptoms of schizophrenia pharmacologically?

Kantrowitz

2021

Expert Opinion on Pharmacotherapy

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Section: Acetylcholinergic-based Treatmentsmentioning

confidence: 89%

How do we address treating the negative symptoms of schizophrenia pharmacologically?

Kantrowitz

2021

Expert Opinion on Pharmacotherapy

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“…In a phase 2 clinical trial, xanomeline/trospium demonstrated significant antipsychotic efficacy with an improved safety profile, lowering rates of cholinergic adverse events. It is still unclear if both mAChR M1 and M4 agonism are required for xanomeline efficacy [ 121 ]. Several mechanisms have been proposed to explain how agonists of mAChR M4 could counteract a hyperdopaminergic state.…”

Section: New Targets To Treat Sczmentioning

confidence: 99%

Beyond Dopamine Receptor Antagonism: New Targets for Schizophrenia Treatment and Prevention

Gomes

Grace

2021

IJMS

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Treatment of schizophrenia (SCZ) historically relies on the use of antipsychotic drugs to treat psychosis, with all of the currently available antipsychotics acting through the antagonism of dopamine D2 receptors. Although antipsychotics reduce psychotic symptoms in many patients, they induce numerous undesirable effects and are not effective against negative and cognitive symptoms. These highlight the need to develop new drugs to treat SCZ. An advanced understanding of the circuitry of SCZ has pointed to pathological origins in the excitation/inhibition balance in regions such as the hippocampus, and restoring function in this region, particularly as a means to compensate for parvalbumin (PV) interneuron loss and resultant hippocampal hyperactivity, may be a more efficacious approach to relieve a broad range of SCZ symptoms. Other targets, such as cholinergic receptors and the trace amine-associated receptor 1 (TAAR1), have also shown some promise for the treatment of SCZ. Importantly, assessing efficacy of novel compounds must take into consideration treatment history of the patient, as preclinical studies suggest prior antipsychotic treatment may interfere with the efficacy of these novel agents. However, while novel therapeutic targets may be more effective in treating SCZ, a more effective approach would be to prevent the transition to SCZ in susceptible individuals. A focus on stress, which has been shown to be a predisposing factor in risk for SCZ, is a possible avenue that has shown promise in preclinical studies. Therefore, therapeutic approaches based on our current understanding of the circuitry of SCZ and its etiology are likely to enable development of more effective therapeutic interventions for this complex disorder.

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“…Indeed, xanomeline revealed its potential for a novel treatment of schizophrenia with improved short-term memory and verbal learning function [52]. Despite its gastrointestinal adverse effects, xanomeline still remains an interesting drug for further studies [53]. According to the above-mentioned studies, targeting mAChRs can be considered as an interesting approach for both cognitive and psychotic disturbances therapies [51].…”

Section: Muscarinic Acetylcholine Receptors and Cognitionmentioning

confidence: 99%

Neuropharmacology of Cevimeline and Muscarinic Drugs—Focus on Cognition and Neurodegeneration

Olekšák

Novotný

Patočka

et al. 2021

IJMS

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At present, Alzheimer’s disease (AD) and related dementias cannot be cured. Therefore, scientists all over the world are trying to find a new approach to prolong an active life of patients with initial dementia. Both pharmacological and non-pharmacological pathways are investigated to improve the key symptom of the disease, memory loss. In this respect, influencing the neuromodulator acetylcholine via muscarinic receptors, such as cevimeline, might be one of the therapeutic alternatives. The purpose of this study is to explore the potential of cevimeline on the cognitive functions of AD patients. The methodology is based on a systematic literature review of available studies found in Web of Science, PubMed, Springer, and Scopus on the research topic. The findings indicate that cevimeline has shown an improvement in experimentally induced cognitive deficits in animal models. Furthermore, it has demonstrated to positively influence tau pathology and reduce the levels of amyloid-β (Aβ) peptide in the cerebral spinal fluid of Alzheimer's patients. Although this drug has not been approved by the FDA for its use among AD patients and there is a lack of clinical studies confirming and extending this finding, cevimeline might represent a breakthrough in the treatment of AD.

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Muscarinic Cholinergic Receptor Agonist and Peripheral Antagonist for Schizophrenia

Cited by 205 publications

References 24 publications

How do we address treating the negative symptoms of schizophrenia pharmacologically?

How do we address treating the negative symptoms of schizophrenia pharmacologically?

Beyond Dopamine Receptor Antagonism: New Targets for Schizophrenia Treatment and Prevention

Neuropharmacology of Cevimeline and Muscarinic Drugs—Focus on Cognition and Neurodegeneration

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