**1. Introduction**

It has long been known that the pathophysiology of depression is associated with a reduction in the concentration of monoamines, that is, serotonin (5-HT), noradrenaline (NA), and dopamine (DA), in the brain [1, 2]. Conventional antidepressant drugs for clinical use increase monoamine contents immediately after their administration, whereas it takes several weeks or more before their clinical efficacy becomes evident. The delayed onset of action of antidepressants suggests that antidepressants exert their effects by inducing slowly occurring changes in the brain. Furthermore, over 30–50% of patients with depression show resistance to antidepressant drug treatment [3–5]. Thus, two major questions remain to be resolved—(1) How do the delayed clinical effects of antidepressant drugs occur, and (2) why does a large percentage of patients with depression show resistance to antidepressant treatment. This review article focuses on addressing these questions based on the evidence that depression is not a disease caused simply by the deficiency of neurotransmitters, but a neurodegenerative disease characterized by axonal degeneration of monoamine neurons without cell death [6–11].
