New Drug Treatments for Schizophrenia: A Review of Approaches to Target Circuit Dysfunction

Abstract

Schizophrenia is a leading cause of global disease burden. Current drug treatments are associated with significant side-effects and have limited efficacy for many patients; highlighting the need to develop new approaches that target other aspects of the neurobiology of schizophrenia. Preclinical, in vivo imaging, post-mortem, genetic and pharmacological studies have highlighted the key role of cortical GABA-glutamatergic microcircuits and their projections to subcortical dopaminergic circuits in the pathoetiology of negative, cognitive and psychotic symptoms. Antipsychotics primarily act downstream of the dopaminergic component of this circuit. However, multiple drugs are currently in development that could target other elements of this circuit to treat schizophrenia. These include drugs for GABA or glutamatergic targets, including glycine transporters, d-amino acid oxidase, sodium channels or potassium channels. Other drugs in development are likely to primarily act on pathways that regulate the dopaminergic system such as muscarinic or trace amine receptors or serotonin 2A receptors, whilst phosphodiesterase 10 A inhibitors are being developed to modulate the downstream consequences of dopaminergic dysfunction. Our review considers where new drugs may act on this circuit and their latest clinical trial evidence in terms of indication, efficacy and side-effects. Limitations of the circuit model, including whether there are neurobiologically distinct subgroups of patients, and future directions are also considered. Several drugs based on the mechanisms reviewed have promising clinical data, with the muscarinic agonist KarXT most advanced. If they are approved for clinical use, they have the potential to revolutionise understanding of the pathophysiology and treatment of schizophrenia.

Topics & Concepts