KarXT combines the partial benefits of haloperidol for positive symptoms and sulpiride for negative symptoms: Evidence from computational biology

Abstract

Objective:

The new drug KarXT targets muscarinic receptors to reduce the positive and negative symptoms of schizophrenia. Haloperidol is effective in treating the positive symptoms of schizophrenia, while sulpiride has shown modest efficacy in alleviating negative symptoms. The shared and distinct molecular mechanisms of these drugs are unclear. This study aimed to determine if the mechanism for KarXT overlaps with the benefits of haloperidol for positive symptoms and sulpiride for negative symptoms.

Methods:

The putative target genes for the three drugs were identified, and a protein-protein interaction network was constructed to identify core targets. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses of the top 20 core targets were conducted. A drug-pathway-target-disease network was constructed.

Results:

The search yielded 179 common targets for haloperidol against positive symptoms, 96 targets for sulpiride against negative symptoms, and 99 targets for KarXT against schizophrenia. Haloperidol affects positive symptoms by targeting the IL-17 signaling pathway via TNF, IL6, IL1B, MAPK3, and CASP3, and sulpiride affects negative symptoms by targeting the PI3K-AKT signaling pathway via BDNF, INS, AKT1, IGF1, and BCL2. KarXT affects schizophrenia by targeting the MAPK signaling pathway via AKT1, FOS, CASP3, NFKB1, and IGF1. Molecular docking revealed good binding affinities between the drugs and the potential core targets.

Conclusions:

This study provides insights into the distinct molecular mechanisms by which haloperidol and sulpiride affect distinct symptoms of schizophrenia. KarXT integrates the partial effects of both drugs, including CASP3 with haloperidol and AKT1 and IGF1 with sulpiride. Our results provide a theoretical basis for clinical applications and new directions for drug development.