Lower Muscarinic M₁ Receptor Availability in Schizophrenia: In Vivo Positron Emission Tomography Evidence

There is growing interest in the contributions of brain muscarinic M₁ receptors to the neurobiology of schizophrenia (SZ). Postmortem evidence strongly indicates M₁ deficits in patients with SZ. Recently, the U.S. Food and Drug Administration approved xanomeline and trospium chloride, which contains the M₁/M₄ agonist xanomeline, as the first nondopaminergic medication for SZ. The development of the positron emission tomography ligand ¹¹C-LSN3172176 enables in vivo quantification of brain M₁ availability in SZ and its relationship to clinical features.

M₁ availability in patients with SZ (n = 16) was compared with age- and sex-matched healthy control (HC) participants (n = 16) using ¹¹C-LSN3172176 and high-resolution research tomography. Distribution volume ratio relative to the centrum semiovale (DVR_CS) and distribution volume (V_T) were measured. Regional variation in percent gray matter fraction was included as a covariate to account for potential atrophy.

Compared with HCs, patients with SZ showed significantly lower M₁ availability across several cortical and subcortical regions, with large effect sizes: frontal (DVR_CS: -13%), temporal (DVR_CS: -15%, V_T: -12%), parietal (DVR_CS: -14%, V_T: -11%), and occipital (DVR_CS: -16%, V_T: -13%) cortices; caudate (DVR_CS: -19%, V_T: -15%); putamen (DVR_CS: -19%, V_T: -17%); hippocampus (DVR_CS: -13%); and amygdala (DVR_CS: -19%, V_T: -16%). A subgroup of patients (DVR_CS: 44%, V_T: 27%) showed larger whole-brain M₁ deficits (>20% from the mean of HCs). Exploratory analyses suggested associations between M₁ availability and selected clinical measures.

Together with postmortem data, these in vivo findings warrant further characterization of M₁ deficits in SZ and highlight M₁ as a therapeutic target and potential biomarker for muscarinic-based treatments.