Clinical Effectiveness of Muscarinic Receptor-Targeted Interventions in Neuropsychiatric Disorders: A Systematic Review

Abstract

Background For decades, treatment of mood disorders, psychoses, anxiety and dementia have been confounded by limited efficacy and high rates of treatment resistance. Preclinical and clinical evidence have highlighted disruption of cholinergic signalling in several neuropsychiatric conditions and examined intervention strategies including acetylcholinesterase inhibitors and nicotinic receptor-targeted intervention. However, the effectiveness of these approaches is often curtailed by ontarget side effects. Post mortem studies implicate muscarinic receptor dysregulation in neuropsychiatric pathophysiology; therefore, we conducted a systematic review and meta-analysis to investigate the therapeutic efficacy and safety of muscarinic receptor-targeted interventions in adults with neuropsychiatric disorders. Methods PubMed, EMBASE, PsycINFO, EBSCO and Web of Science were searched using relevant keywords from database inception to 7 August 2022. Randomised, double-blind, placebo-controlled studies were included if they investigated the effect of muscarinic receptor-targeted intervention in adults with a diagnosis of a neuropsychiatric disorder and were published in English. A narrative synthesis approach was adopted to describe the findings. Wherever three or more studies with a similar intervention were available, effect sizes were calculated, and a meta-analysis was performed. Cochrane riskof-bias-2 tool was utilised to assess the risk of bias, and sensitivity analyses were performed to identify publication bias. Certainty analysis (high, moderate, low and/or very low) was conducted using GRADE criteria. Results Overall, 33 studies met the inclusion criteria and 5 were included in the meta-analysis. Despite a limited pool with several different interventions, we found therapeutic efficacy of xanomeline (M 1 /M 4 agonist) in primary psychotic disorders plus behavioural and psychological symptoms of dementia. Scopolamine showed a significant antidepressant effect in a combined cohort of major depressive and bipolar disorders in the short-term outcome measure, but no effect following cessation of treatment. Results from bias assessments suggest "very low" certainty in the antidepressant effect of scopolamine. Critical limitations of the current literature included low power, high heterogeneity in the patient population and a lack of active comparators. Conclusion While the results are not definitive, findings on muscarinic receptor-targeted interventions in several mental disorders are promising in terms of efficacy and safety, specifically in treating schizophrenia, mood disorders, and behavioural and psychiatric symptoms of Alzheimer's disease. However, orthosteric muscarinic receptor-targeted interventions are associated with a range of peripheral adverse effects that are thought to be mediated via M 2 /M 3 receptors. The orthosteric binding site of muscarinic acetylcholine receptors is remarkably conserved, posing a challenge for subtype-selective interventions; nonetheless allosteric ligands with biased signalling pa...

The New Horizon of Antipsychotics beyond the Classic Dopaminergic Hypothesis—The Case of the Xanomeline–Trospium Combination: A Systematic Review

“…Another review was published in Dutch by Spoelstra et al, in 2023 [98], and included nine published articles on five clinical studies; however, this review explored muscarinic M1 and/or M4 receptor agonists, partial agonists, and positive allosteric modulators, and therefore included not just KarXT and, again, did not include further directions on research in this field. Other reviews dedicated to new antipsychotic agents did not detail KarXT efficacy and tolerability, but they still concluded the need to develop new drugs that support the non-dopaminergic pathogenetic mechanisms of SSDs [25,[99][100][101][102].…”

The New Horizon of Antipsychotics beyond the Classic Dopaminergic Hypothesis—The Case of the Xanomeline-Trospium Combination: A Systematic Review

“…Another review was published in Dutch by Spoelstra et al, in 2023 [98], and included nine published articles on five clinical studies; however, this review explored muscarinic M1 and/or M4 receptor agonists, partial agonists, and positive allosteric modulators and included not only KarXT, and, again, did not include further directions on research in this field. Other reviews dedicated to new antipsychotic agents did not detail KarXT efficacy and tolerability, but they still concluded the need to develop new drugs that support the nondopaminergic pathogenetic mechanisms of SSD [25,[99][100][101][102].…”