Transcription-Driven Repurposing of Cardiotonic Steroids for Lithium Treatment of Severe Depression.

Lithium is prescribed as a mood stabilizer for bipolar disorder and severe depression. However, the mechanism of action of lithium is unknown and there are major side effects associated with prolonged medication. This motivates a search for safer alternative drug repurposing candidates. Given that the drug mechanism may be encoded in transcriptional changes, we generated the gene expression profile for acute lithium treatment of cortical neuronal cultures. We found that the lithium-associated transcription response harbors a significant component that is the reverse of that seen in human brain samples from patients with major depression, bipolar disorder, and a mouse model of depression. Interrogating publicly available drug-driven expression data, we found that cardiotonic steroids drive gene expression in a correlated manner to our acute lithium profile. An analysis of the psychiatric medication cohort of the Norwegian Prescription Database showed that cardiotonic prescription is associated with a lower incidence of lithium prescription. Our transcriptional and epidemiological observations point towards cardiotonic steroids as possible repurposing candidates for lithium. These observations motivate a controlled trial to establish a causal connection and genuine therapeutic benefit in the context of depression.