The fact that the selective JAK-3 inhibitor tofacitinib improves SF-36 scores the most raise the speculative expectation that depression is mostly induced by a JAK-3 phosphorylation downstream mediated axis.33 In support of this, there is direct evidence that stress-induced JAK3 activation is partly accomplished through the acid sphingomyelinase. This evidence concerns the gene JAK3 and depressive disorder.