Zhang et al. conducted a preclinical study in which they demonstrated that bone inflammatory markers (including OPN) may play a role in the antidepressant effect of (R)-ketamine, as mice with major depressive disorder (MDD) showed a significant increase in OPN (and OPN/RANKL) in response to (R,S)-ketamine on days 1 and 3 after a single infusion [39]. This evidence concerns the gene SPP1 and major depressive disorder.