Cholinergic system in schizophrenia: A systematic review and meta-analysis

Studies have shown widespread alterations in different components of the cholinergic system in schizophrenia, but to date the evidence has not been systematically reviewed and summarized. Here, we systematically review imaging and post-mortem studies on the central cholinergic system in schizophrenia/schizoaffective disorder.

Searches were performed in Embase and Medline. Study designs included cross-sectional case control studies comparing individuals with schizophrenia/schizoaffective disorder to control population. Risk of bias was assessed with the NIH/NHLBI tool for Quality Assessment of Case-Control Studies. The current study followed the PRISMA 2020 guidelines (PROSPERO: CRD42023402126).

A total of 3259 studies were screened and 61 met eligibility criteria for the systematic review, including 8 in vivo neuroimaging and 53 post-mortem studies. About 74% of these studies described significant alterations, most often reductions in either muscarinic or nicotinic receptor levels in schizophrenia. We also conducted 3 meta-analyses showing reductions in M1/M4 muscarinic receptors in the striatum (g = -0.809, k = 3, n = 108), hippocampus (g = -0.872, k = 3, n = 84), and fronto-cingulate cortex (g = -0.438, k = 4, n = 295). Six neuroimaging studies reported associations with clinical symptom severity measures, and four investigations with cognitive dysfunction.

Our review demonstrates a widespread decrease in muscarinic and nicotinic receptor levels in schizophrenia, evident in both neuroimaging and post-mortem studies. Our meta-analyses show large to moderate effects for the reductions in M1/M4 muscarinic receptors in the striatum, hippocampus, and fronto-cingulate cortex. Limitations and future directions for the field are discussed.