Uncovering novel therapeutics for schizophrenia: a multitarget approach using the CANDO platform

Schizophrenia is a complex and debilitating neuropsychiatric disorder characterized by positive, negative, and cognitive symptoms, many remaining insufficiently addressed by current treatments. High rates of treatment resistance and heterogeneous pathophysiology pose significant challenges to traditional single-target drug discovery. To address this, we applied the CANDO platform to identify repurposable drugs for schizophrenia using a multitarget strategy. The platform evaluates how compounds interact with the entire human proteome, generating interaction signatures that capture a compound’s effect across all targets. By comparing these signatures, CANDO computes compound similarity scores and enables consensus prediction of novel therapeutics. Benchmarking experiments across all indications and specific to schizophrenia demonstrated that CANDO significantly outperformed controls across multiple evaluation metrics, recovering known drug indication associations with orders of magnitude better accuracy. Using prediction methodology validated through benchmarking, we generated a ranked list of repurposable compounds. Literature review confirmed clinical or biochemical evidence supporting 25 top ranked drug candidates, including phenothiazine and benzamide antipsychotics, tricyclic antidepressants, benzodiazepines, and monoamine oxidase inhibitors. We identified protein targets with the highest likelihood of interaction with these top drugs and assessed prediction quality through overlap analysis with gold standards, showing significantly better concordance with established schizophrenia related biology than controls. Among these protein are corroborated targets such as canonical neurotransmitter receptors, dopamine, serotonin, and adrenergic, as well as monoamine transporters, tyrosine aminotransferase, and lysine specific histone demethylase 1A. Enrichment of calcium-binding proteins among the phenothiazine antipsychotic triethylperazine’s top predicted targets highlights a potential role for dysregulated calcium signaling, including calmodulin–CaMKK2 pathways, in schizophrenia pathology and treatment response. Another phenothiazine antipsychotic, triflupromazine, binds the serotonin transporter in addition to its canonical dopamine D2 receptor interaction, warranting further research into its potential effects on depressive symptoms. These findings demonstrate the utility of the CANDO platform in elucidating multitarget pharmacological mechanisms and accelerating the identification of effective repurposable treatments for schizophrenia.