HMN 2026: What is the receptor dysfunction in living patients with schizophrenia

A study using positron emission tomography (PET) imaging has found that patients with schizophrenia had significantly lower muscarinic acetylcholine M1 receptor availability (about 13%–19%) across multiple brain regions than healthy individuals. Reduced M1 receptor availability affects several brain regions involved in cognition, learning, memory and executive function. The findings in Biological Psychiatry provide the first in vivo evidence supporting widespread M1 receptor deficits in schizophrenia.

Schizophrenia is a serious mental disorder that is heterogeneous in its expression and biology. For many years, abnormalities in the brain’s muscarinic acetylcholine system, particularly the M1 receptor, have been implicated in the pathophysiology of schizophrenia. However, nearly all the evidence came from postmortem studies, making it impossible to determine whether these abnormalities were present in living patients or how they related to clinical symptoms.

Confirming a long-suspected deficit

“The development of a novel PET radiotracer for the M1 receptor provided a unique opportunity to directly measure M1 receptor availability in the living brain,” explains co-lead investigator Deepak C. D’Souza, MBBS, MD, Department of Psychiatry, Yale University School of Medicine; Psychiatry Service, VA Connecticut Healthcare System; and Abraham Ribicoff Research Facilities, Connecticut Mental Health Center. “Although receptor availability is not identical to receptor density, it is widely accepted as a useful proxy for the brain’s functional M1 receptor system. This allowed us, for the first time, to confirm that muscarinic dysfunction is a feature of schizophrenia in living patients.”

“The study’s findings were robust across multiple methods of PET quantification and remained significant after accounting for potential confounding factors, including gray matter differences and partial-volume effects,” says co-first author Tommaso Volpi, MD, Ph.D., associate research scientist in radiology and biomedical imaging, Yale University School of Medicine.

Stronger ties to cognition

Researchers highlighted that M1 receptor availability was more strongly associated with measures of cognition than with the severity of psychotic symptoms, suggesting that M1 dysfunction may be particularly relevant to the cognitive impairments that are among the most disabling aspects of schizophrenia.

The pharmacological treatment of schizophrenia has been dominated by dopamine D2 receptor antagonists/agonists commonly referred to as antipsychotics. Their limited efficacy, especially for negative and cognitive symptoms, and significant side effects have spurred the search for drugs with alternative mechanisms of action. M1 receptors are G-protein-coupled receptors that are present throughout the cortex and subcortical regions. They are now considered an important focus of the underlying neurobiology and treatment of schizophrenia.

Momentum for muscarinic therapies

John Krystal, MD, editor of Biological Psychiatry, comments, “This study is particularly interesting in light of the emergence of M1 and M4 muscarinic agonist drugs as pharmacotherapies in schizophrenia. These findings are particularly timely given the recent approval of xanomeline–trospium (COBENFY), the first antipsychotic medication in more than 70 years to treat schizophrenia through a primarily nondopaminergic mechanism of action.”

“Although our study did not evaluate treatment response, it strengthens the biological rationale for developing muscarinic-based therapies and raises the possibility that M1 receptor imaging could eventually help identify biologically distinct subgroups of patients and inform future precision medicine approaches,” concludes co-lead investigator Rajiv Radhakrishnan, MBBS, MD, Department of Radiology and Biomedical Engineering and Department of Psychiatry, Yale University School of Medicine; Psychiatry Service, VA Connecticut Healthcare System; and Abraham Ribicoff Research Facilities, Connecticut Mental Health Center.

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