Cobenfy, a co-formulation of xanomeline and trospium, is the first drug not acting on the dopaminergic system of the CNS approved for the treatment of schizophrenia by the FDA. Xanomeline is a muscarinic M1 and M4 receptor (CHRM1 and CHRM4) agonist whilst trospium is a peripherally active CHRM antagonist that reduces the unwanted peripheral side-effects of xanomeline. Relevant to this exciting development, this review details the human CNS cholinergic systems and how those systems are affected by the molecular pathology of schizophrenia in a way suggesting activating the CHRM1 and 4 would be beneficial in treating the disorder. The CNS distribution of CHRMs is presented along with findings using CHRM knockout mice and mice treated with drugs that activate the CHRM1 and / or M4, these data explain why these CHRMs could be involved in the genesis of the symptoms of schizophrenia. Next, the process leading to the formulation of Cobenfy and the preclinical data on xanomeline are reviewed showing why Cobenfy was expected to be useful in treating schizophrenia. The pipeline of drugs targeting CHRM1 and /or M4 receptors to treat schizophrenia are discussed. Finally, the molecular pathology of two sub-groups within schizophrenia, separated based on the presence or absence of a deficit of cortical CHRM1, are reviewed to show how such approaches could identify new drug targets. In conclusion, the history of the development of Cobenfy highlights how a growing understanding the pathophysiology of schizophrenia will suggest new treatment targets for the disorder and that pharmacologists can synthesise drugs to target these sites.

In a previous study on ionotropic glutamate receptors, we have shown that [3H]kainate, but not [3H]AMPA or [3H]NMDA, receptor binding was lower in Brodmann's area (BA) 9 from people with schizophrenia. Subsequently, we defined a subgroup within the syndrome of schizophrenia who are termed the Muscarinic Receptor Deficit subgroup of Schizophrenia (MRDS) as they have markedly lower levels of [3H]pirenzepine binding to the muscarinic M1 receptor. The previous glutamate receptor study did not contain enough people with MRDS and other forms of schizophrenia (non-MRDS) to study any subgroup-specific differences. Hence, in this study we first measured [3H]pirenzepine binding to the muscarinic M1 receptor to confirm the MRDS subgroup, then measured [3H]kainate, [3H]AMPA and [3H]NMDA receptor binding using autoradiography in BA 9 from people with MRDS, non-MRDS and controls. We also measured binding in BA 10 as our gene expression study indicated that BA 10 is disproportionally affected by the molecular pathology of schizophrenia. As expected, due to case-selection criteria, [3H]pirenzepine binding to the M1 receptor was lower in BA 9 and BA 10 from people with MRDS, although more profound in BA 10. [3H]kainate receptor binding was lower only in BA 9 from people with MRDS, while [3H]AMPA and [3H]NMDA receptor binding was not altered in either region. Muscarinic M1 receptors and kainate receptors are both located on glutamatergic pyramidal neurons so a perturbation in both receptors could indicate altered excitatory neurotransmission in BA 9 from people with MRDS.

Schizophrenia is a neuropsychiatric disorder characterized by various symptoms such as hallucinations, delusions, and disordered thinking. The etiology of this disease is unknown; however, it has been linked to many microdeletion syndromes that are likely to contribute to the pathology of schizophrenia. In this review we have comprehensively analyzed the role of various microdeletion syndromes, like 3q29, 15q13.3, and 22q11.2, which are known to be involved with schizophrenia. A variety of factors lead to schizophrenia phenotypes, but copy number variants that disrupt gene regulation and impair brain function and cognition are one of the causes that have been identified. Multiple case studies have shown that loss of one or more genes in the microdeletion regions lead to brain activity defects. In this article, we present a coherent paradigm that connects copy number variations (CNVs) to numerous neurological and behavioral abnormalities associated with schizophrenia. It would be helpful in understanding the different aspects of the microdeletions and how they contribute in the pathophysiology of schizophrenia.

Successful phase 3 trials of KarXT in people with schizophrenia herald a new era of treating the disorder with drugs that do not target the dopamine D2 receptor. The active component of KarXT is xanomeline, a muscarinic (CHRM) M1 and M4 agonist, making muscarinic receptors a viable target for treating schizophrenia.

This review covers the process of taking drugs that activate the muscarinic M1 and M4 receptors from conceptualization to the clinic and details the mechanisms by which activating the CHRM1 and 4 can affect the broad spectrum of symptoms experienced by people with schizophrenia.

Schizophrenia is a syndrome which means drugs that activate muscarinic M1 and M4 receptors, as was the case for antipsychotic drugs acting on the dopamine D2 receptor, will not give optimal outcomes in everyone within the syndrome. Thus, it would be ideal to identify people who are responsive to drugs activating the CHRM1 and 4. Given knowledge of the actions of these receptors, it is possible treatment non-response could be restricted to sub-groups within the syndrome who have deficits in cortical CHRM1 or those with one of the cognitive endophenotypes that may be identifiable by changes in the blood transcriptome.

Multiple lines of evidence argue for lower levels of cortical muscarinic M1 receptors (CHRM1) in people with schizophrenia which is possibly due to a sub-group within the disorder who have a marked loss of CHRM1 (muscarinic receptor deficit sub-group (MRDS)). In this study we sought to determine if the lower levels of CHRM1 was apparent in older people with schizophrenia and whether the loss of CHRM1 was associated with symptom severity by measuring levels of cortical [³H]pirenzepine binding to CHRM1 from 56 people with schizophrenia and 43 controls. Compared to controls (173 ± 6.3 fmol / mg protein), there were lower levels of cortical [³H]pirenzepine binding in the people with schizophrenia (mean ± SEM: 153 ± 6.0 fmol / mg protein; p = 0.02; Cohen's d = - 0.46). [³H]pirenzepine binding in the people with schizophrenia, but not controls, was not normally distributed and best fitted a two-population solution. The nadir of binding separating the two groups of people with schizophrenia was 121 fmol / mg protein and levels of [³H]pirenzepine binding below this value had a 90.7 % specificity for the disorder. Compared to controls, the score from the Clinical Dementia Rating Scale (CDR) did not differ significantly in MRDS but were significantly higher in the sub-group with normal radioligand binding. Positive and Negative Syndrome Scale scores did not differ between the two sub-groups with schizophrenia. Our current study replicates and earlier finding showing a MRDS within schizophrenia and, for the first time, suggest this sub-group have less severe cognitive deficits others with schizophrenia.

Pre-clinical models, postmortem and neuroimaging studies all support a role for muscarinic receptors in the molecular pathology of schizophrenia. From these data it was proposed that activation of the muscarinic M1 and/or M4 receptor would reduce the severity of the symptoms of schizophrenia. This hypothesis is now supported by results from two clinical trials which indicate that activating central muscarinic M1 and M4 receptors can reduce the severity of positive, negative and cognitive symptoms of the disorder. This review will provide an update on a growing body of evidence that argues the muscarinic M1 and M4 receptors have critical roles in CNS functions that are dysregulated by the pathophysiology of schizophrenia. This realization has been made possible, in part, by the growing ability to visualize and quantify muscarinic M1 and M4 receptors in the human CNS using molecular neuroimaging. We will discuss how these advances have provided evidence to support the notion that there is a sub-group of patients within the syndrome of schizophrenia that have a unique molecular pathology driven by a marked loss of muscarinic M1 receptors. This review is timely, as drugs targeting muscarinic receptors approach clinical use for the treatment of schizophrenia and here we outline the background biology that supported development of such drugs to treat the disorder.