Markers of muscarinic deficit for individualized treatment in schizophrenia

Abstract

Recent clinical studies have shown that agonists at muscarinic acetylcholine receptors effectively reduce schizophrenia symptoms. It is thus conceivable that, for the first time, a second substance class of procholinergic antipsychotics could become established alongside the usual antidopaminergic antipsychotics. In addition, various basic science studies suggest that there may be a subgroup of schizophrenia in which hypofunction of muscarinic acetylcholine receptors is of etiological importance. This could represent a major opportunity for individualized treatment of schizophrenia if markers can be identified that predict response to procholinergic vs. antidopaminergic interventions. In this perspective, non-response to antidopaminergic antipsychotics, specific symptom patterns like visual hallucinations and strong disorganization, the presence of antimuscarinic antibodies, ERP markers such as mismatch negativity, and radiotracers are presented as possible in vivo markers of muscarinic deficit and thus potentially of response to procholinergic therapeutics. Finally, open questions and further research steps are outlined.

New Developments in the Treatment of Schizophrenia: An Expert Roundtable

“…Many recent attempts at developing drugs with novel MOAs have failed ( Downing et al, 2014 ; Bugarski-Kirola et al, 2017 ), with results from animal models not translating to benefits in humans. Potential reasons for failure include increasingly high placebo response rates ( Kemp et al, 2010 ), limitations in trial design or execution ( Javitt and Kantrowitz, 2022 ), and, importantly, the lack of biomarkers to identify subpopulations whose neuropathology is likely to respond to the MOA of a drug ( Kantrowitz, 2019 ; Stuke, 2023 ). However, this situation may be changing with numerous novel therapies with unique MOAs in late-stage clinical development ( Correll et al, 2023 ).…”