Muscarinic agonists and antagonists in schizophrenia: recent therapeutic advances and future directions

Existing therapies for schizophrenia have limited efficacy, and significant residual positive, negative, and cognitive symptoms remain in many individuals with the disorder even after treatment with the current arsenal of antipsychotic drugs. Preclinical and clinical data suggest that selective activation of the muscarinic cholinergic system may represent novel therapeutic mechanisms for the treatment of schizophrenia. The therapeutic relevance of earlier muscarinic agonists was limited by their lack of receptor selectivity and adverse event profile arising from activation of nontarget muscarinic receptors. Recent advances in developing compounds that are selective to muscarinic receptor subtypes or activate allosteric receptor sites offer tremendous promise for therapeutic targeting of specific muscarinic receptor subtypes in schizophrenia.