It was known that only phosphorylated proteins exhibit full enzymatic activity, and ERK1/2 phosphorylation was hypothesized to be an intracellular signaling mechanism mediating antidepressant efficacy in patients with depression and in animal models of depression, with supporting evidence coming mainly from studies in rodent or in vitro models [55–57] and postmortem studies of suicidal individuals with depression [58]. This evidence concerns the gene MAPK3 and depressive disorder.