591. MUSCARINIC RECEPTORS AND THE MOLECULAR PATHOLOGY OF SCHIZOPHRENIA

Abstract Background The licencing of Cobenfy, a co-formulation of the muscarinic receptor agonist xanomeline and the peripherally active muscarinic receptor antagonist trospium, for the treatment of schizophrenia means the first drug not acting on the dopaminergic system of the CNS to treat the disorder will be available to clinicians. Notably, the discovery that drugs targeting the dopaminergic systems of the CNS could be used to treat schizophrenia preceded an understanding of how that system was involved in the molecular pathology of the disorder. By contrast, an understanding of how muscarinic receptors were affected by the molecular pathology of schizophrenia supported the rationale for the development of Cobenfy. Aims & Objectives To explain how data from the study of muscarinic receptors in the human CNS support the notion that treating people with schizophrenia with muscarinic M1 and M4 receptor agonists would have beneficial therapeutic effects. Method This presentation will mainly focus on data from postmortem and neuroimaging studies of muscarinic receptors in the human CNS. Results Data showing that levels of the muscarinic M1 and M4 receptors are lower in the cortex, caudate and hippocampus, but not that thalamus, from people with schizophrenia will be reviewed. Notably, in the cortex, available data suggests people with schizophrenia have lower levels of muscarinic M1 receptors and that a sub-group of people with the disorder have a marked loss of that receptor. However, it will also be shown that a loss of muscarinic M1 receptor positive pyramidal cells in the cortex is common across all people with schizophrenia. The loss of muscarinic M1 receptors on cortical pyramidal cells in people with schizophrenia would be predicted to affect glutamatergic neurotransmission with a feed down effect on GABAergic neurons. Finally, data will be presented that suggests that those in the sub-group with a marked loss of cortical muscarinic M1 receptors may have less severe cognitive deficits. Discussion & Conclusions The findings showing lower levels of muscarinic receptors in multiple CNS region supported the hypothesis that activating those receptors would be beneficial in treating the disorder. Moreover, given the role of muscarinic M1 and M4 receptors in sub-cortical functioning, activating those receptors would be predicted to down-regulate dopaminergic systems in the CNS and, by doing so, act on the severity of psychoses. Finally, activating cortical muscarinic M1 and M4 receptors would be predicted to impact on the severity of negative and cognitive symptoms. Data from clinical trials of Cobenfy provides support for all the proposed outcomes of activating muscarinic M1 and M4 receptors in people with schizophrenia. However, these early data need to be confirmed by using the drug in clinical practice. In addition, it would be of value to use neuroimaging techniques to confirm the presence of a sub-group of people with schizophrenia with markedly lower levels of muscarinic M1 receptors as data from postmortem CNS suggests they may be resistant to treatment with muscarinic M1 receptor agonists or positive allosteric modulators.