A machine learning approach to drug repositioning based on drug expression profiles: Applications in psychiatry

Development of new medications is a very lengthy and costly process. Finding novel indications for existing drugs, or drug repositioning, can serve as a useful strategy to shorten the development cycle. In this study, we present an approach to drug discovery or repositioning by predicting indication for a particular disease based on expression profiles of drugs, with a focus on applications in psychiatry. Drugs that are not originally indicated for the disease but with high predicted probabilities serve as good candidates for repurposing. This framework is widely applicable to any chemicals or drugs with expression profiles measured, even if the drug targets are unknown. It is also highly flexible as virtually any supervised learning algorithms can be used. We applied this approach to identify repositioning opportunities for schizophrenia as well as depression and anxiety disorders. We applied various state-of-the-art machine learning (ML) approaches for prediction, including deep neural networks, support vector machines (SVM), elastic net, random forest and gradient boosted machines. The performance of the five approaches did not differ substantially, with SVM slightly outperformed the others. However, methods with lower predictive accuracy can still reveal literature-supported candidates that are of different mechanisms of actions. As a further validation, we showed that the repositioning hits are enriched for psychiatric medications considered in clinical trials. Notably, many top repositioning hits are supported by previous preclinical or clinical studies. Finally, we propose that ML approaches may provide a new avenue to explore drug mechanisms via examining the variable importance of gene features.