The slow onset of traditional antidepressants has become an urgent clinical issue, researchers are constantly exploring new antidepressants with prompt action. Previous studies have found that zinc levels were decreased in serum and brain of depressed patients or animal models. Zinc treatment can improve depressive symptoms and enhance the antidepressant effects of monoamine antidepressants. However, its mechanism of action is still unclear. This present study aims to investigate whether the zinc can enhance the rapid action of traditional antidepressant imipramine and to explore the potential mechanisms of action through the rapid antidepressant targets CREB (cAMP-response element binding protein) and mTOR (mammalian target of the rapamycin). Drug treatment included intraperitoneal injection of imipramine or zinc alone and imipramine plus zinc. Zinc had a rapid enhanced antidepressive effect on the imipramine and achieved a rapid antidepressant effect similar to ketamine. Combination of zinc with imipramine rapidly enhanced the phosphorylation of mTOR Ser2448 and CREB Ser133, and increased the expression of mTOR and CREB, which were dependent on the activation of PIGS. In conclusion, combination therapy with zinc and monoamine antidepressants may overcome the problem of slow-onset action of traditional antidepressants in clinical uses. (C) 2019 Elsevier Inc. All rights reserved.