PET imaging reveals widespread brain receptor deficits in schizophrenia

A groundbreaking study using positron emission tomography (PET) imaging has found that patients with schizophrenia had significantly lower muscarinic acetylcholine M1 receptor availability (~13% to 19%) across multiple brain regions compared with healthy individuals. Reductions in M1 receptors affect several brain regions involved in cognition, learning, memory, and executive function. The findings in Biological Psychiatry, published by Elsevier, 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 of 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.

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. 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."

Deepak C. D'Souza, MBBS, MD, co-lead investigator, Department of Psychiatry, Yale University School of Medicine; Psychiatry Service, VA Connecticut Healthcare System; and Abraham Ribicoff Research Facilities, Connecticut Mental Health Center

"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, PhD, Associate Research Scientist in Radiology and Biomedical Imaging, Yale University School of Medicine.

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 antagonist/agonists commonly referred to as antipsychotics. Their limited efficacy, especially for negative and cognitive symptoms, and their 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.

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 non-dopaminergic 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.