Structural alterations in the limbic system, neuronal cell loss, and low levels of neurotrophins have been implicated in the pathogenesis of depression. While it is generally accepted that increasing monoamine levels in the brain can effectively alleviate depression, the precise neurobiological mechanisms involved are unclear. In the present study, we examined the effects of two antidepressants, duloxetine and mirtazapine, on the expression of apoptotic and neurotrophic proteins in the cerebral cortex and hippocampus of mice. Duloxetine (10 mg/kg) and mirtazapine (3 mg/kg) were chronically administered for 21 days, and qRT-PCR analysis was carried for the following: neurotrophins (BDNF, NGF, FGF-2, and NT-3); anti-apoptotic proteins (Bcl-2 and Bcl-xL) and pro-apoptotic proteins (Bax, Bad, and p53). Both duloxetine and mirtazapine produced antidepressant activity in the forced swimming test and induced increased cortical and hippocampal mRNA expression of BDNF. Duloxetine also increased Bcl-2, Bcl-xL, FGF-2, and NT-3 expression in the cerebral cortex, and FGF-2 expression in the hippocampus. Moreover, duloxetine reduced Bax and p53 expression in the hippocampus, and Bad expression in the cerebral cortex. Mirtazapine decreased Bcl-xL and Bax expression in the hippocampus, and Bad and p53 expression in both the hippocampus and cerebral cortex. Mirtazapine also increased the expression of neurotrophins, NGF and NT-3, in the cerebral cortex. These results suggest that duloxetine and mirtazapine could elicit their therapeutic effect by modulating the activity of apoptotic and neurotrophic pathways, thus enhancing plasticity and cell survival in depressive patients.