Abstract
BackgroundIt is still unclear which underlying mechanisms are involved in cognitive deficits of psychotic disorders. Pro-cognitive effects of muscarinic M1 receptor agonists suggest alterations in M1 receptor functioning may modulate these symptoms. Post mortem studies in patients with schizophrenia have shown significantly reduced M1 receptor expression rates in the dorsolateral prefrontal cortex (DLPFC) compared to controls. To date no in-vivo examinations of M1 receptor 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 M1 receptor binding in the DLPFC and hippocampus in relation to cognitive functioning.MethodsMuscarinic M1 receptor binding potential (BPND) was measured using 123I-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.ResultsAssessment of cognitive domains showed that lower M1 BPND in the DLPFC was related to overall lower performance in verbal learning and memory. In addition, lower M1 BPND in the DLPFC was related to greater negative symptom severity. Lastly, lower M1 BPND in the hippocampus was related to worse delayed recognition of verbal memory.ConclusionThis is the first study to show that variation in M1 receptors in the DLPFC is related to cognitive and negative symptom outcome in psychotic disorders. The M1 receptor may be an important biomarker in biological stratification of patients with psychotic disorders.
Highlights
An estimated 80% of subjects with psychotic disorders suffer from cognitive deficits, scoring 1–2 standard deviations below their peers (Green et al, 2004; Woodberry et al, 2008)
The data supports that the efficacy of xanomeline to improve verbal learning and memory in psychotic disorders may be more attributable to its M1 agonist properties, rather than M4
We investigated the broader spectrum of psychotic disorders rather than solely schizophrenia
Summary
An estimated 80% of subjects with psychotic disorders suffer from cognitive deficits, scoring 1–2 standard deviations below their peers (Green et al, 2004; Woodberry et al, 2008). Severity of cognitive deficits best predict poor functional outcome and relapse, this finding is supported primarily by studies done in schizophrenia (Kahn and Keefe, 2013) These symptoms cannot be treated adequately with available antipsychotics giving an urgent need to understand their underlying neuropathology (Vingerhoets et al, 2013). Aggravation of cognitive impairments in patients with psychotic disorders by anti-muscarinic agents given to reduce antipsychotic-induced extrapyramidal side effects, has suggested involvement of the muscarinic neurotransmitter system in cognitive symptoms of psychosis (Everitt and Robbins, 1997). Administration of these anti-muscarinic agents in healthy volunteers induces pronounced cognitive. The M1 receptor may be an important biomarker in biological stratification of patients with psychotic disorders
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