Intron retention: a novel method for evaluating the response to ketamine in patients with treatment-resistant depression

In response to stress, the body attempts to maintain protein homeostasis through intron retention (IR). By identifying the genes that undergo IR in response to stress, possibly we can identify what type of stress the body is experiencing. Using this principle, we reanalyzed RNA sequencing data of patients with treatment-resistant depression and examined IR genes to investigate their characteristics to ketamine. The ketamine nonresponders were characterized by a state of elevated viral infection. Several IR genes related to viral infection were restored to a healthy state by ketamine, regardless of whether the individual was a nonresponder or a responder. Accordingly, it was more reasonable to describe nonresponders not as individuals for whom ketamine is ineffective but rather as individuals for whom ketamine is insufficient to overcome the extremely elevated inflammatory state of these individuals. This study is pioneering in its exploration of the molecular underpinnings that differentiate between nonresponders and responders.