There is ample evidence that depression and stress can be ameliorated through the use of physical exercise and/or antidepressant drugs. Both have been shown to promote neuroprotection against atrophy of dendrites and neuronal death through the activation of pro-survival signaling pathways, such as that of phosphatidyl inositol 3′ kinase (PI-3K) and mitogen-activated protein kinase (MAPK). Depriving neurons in culture of several vital nutrients provides a viable model of neuronal stress, trauma or insult that occurs in vivo. Therefore, we sought to evaluate if various antidepressants are indeed neuroprotective in this model of nutrient deprivation stress. In addition, we evaluated if three key pro-survival pathways (PI-3K, MAPK, protein kinase A) are necessary for such neuroprotection. We used quantitative Western blotting to evaluate the immunoreactivity levels of brain-derived neurotrophic factor, PI-3K, phospho-protein kinase B (P-Akt), phospho-MAPK and phospho-cyclic AMP response element-binding protein, and live/dead cytotoxicity assay to evaluate cell survival. We demonstrate that in the ideal conditions of nutrient supplement, norepinephrine, serotonin and three antidepressants increased all six outcome measures; however, in the absence of such nutrients, only P-Akt levels showed signs of decreasing. In the presence of pro-survival pathway inhibitor, however, five out of the six outcome measures decreased (not P-Akt), relative to those of the ideal conditions of nutrient supplement. Thus, pro-survival pathway integrity, which more directly affects gene expression, is more important than the presence of externally placed nutrients for cell survival. We discuss our results in the context of receptor and pathway cross-talk, indicating that pharmacological rescue of neuronal atrophy/death in the face of mood disorders requires that pro-survival pathways remain intact.