Relationship between muscarinic M ₁ receptor binding and cognition in medication-free subjects with psychosis

Background: It is still unclear which underlying mechanisms are involved in cognitive deficits of psychotic disorders. Pro-cognitive effects of muscarinic M1receptor agonists suggest alterations in M1receptor functioning may modulate these symptoms. Post mortem studies in patients with schizophrenia have shown significantly reduced M1receptor expression rates in the dorsolateral prefrontal cortex (DLPFC) compared to controls. To date no in-vivo examinations of M1receptor binding in relation to cognitive impairments have been done. As cognitive deficits have similar course and prognostic relevance across psychotic disorders, the current study assessed M1receptor binding in the DLPFC and hippocampus in relation to cognitive functioning.

Methods: Muscarinic M1receptor binding potential (BPND) was measured using123I-IDEX, single photon emission computed tomography (SPECT) in 30 medication-free subjects diagnosed with a psychotic disorder. A computerized neuropsychological test battery was used to assess cognition, and the positive and negative syndrome scale (PANSS) to assess severity of psychotic symptoms.

Results: Assessment of cognitive domains showed that lower M1BPNDin the DLPFC was related to overall lower performance in verbal learning and memory. In addition, lower M1BPNDin the DLPFC was related to greater negative symptom severity. Lastly, lower M1BPNDin the hippocampus was related to worse delayed recognition of verbal memory.

Conclusion: This is the first study to show that variation in M1receptors in the DLPFC is related to cognitive and negative symptom outcome in psychotic disorders. The M1receptor may be an important biomarker in biological stratification of patients with psychotic disorders.