Approaches to the development of antidepressants targeting non-monoaminergic components. Chronic stress can cause hypercortisolemia which results in neuronal damages in the hippocampus, thereby weakening the feedback inhibition on HPA axis. Chronic stress also can inhibit the expression of neurotrophic factors through epigenetic mechanisms. On the other hand, chronic treatment of antidepressants and mood stabilizers can establish epigenomic environments that favor the expression of anti-depression genes. The targets may include genes for neurotrophic factors which prevent neuronal damages and enhance hippocampal neurogenesis. Some of approaches to the development of antidepressants targeting non-monoaminergic components are also shown.