**2.1 Antidepressants and monoamine axon regeneration/sprouting**

Recent animal and human studies have demonstrated that depression is a neurodegenerative disease characterized by the degeneration of monoamine axons without cell death, and the delayed clinical efficacy of antidepressants is due to their regenerative action on damaged monoamine axons. In 1990, it was reported for the first time that antidepressants that increase the extracellular concentration of NA, such as desipramine, maprotiline, and mianserin, have the ability to induce regeneration of NA axons, but fluoxetine, a potent selective serotonin reuptake inhibitor (SSRI), does not [6, 7]. The regenerative effects of antidepressants on NA axons lesioned by 6-hydroxydopamine (6-OHDA) could be induced by antidepressant infusions in the rat cerebral cortex for more than 2 weeks but not for less than 1 week. Furthermore, the ability of antidepressants to induce axonal sprouting of 5-HT neurons has been demonstrated by systemic injections of antidepressants for 4 weeks daily in rats without damaging 5-HT axons [9]. In this study, fluoxetine and the 5-HT reuptake enhancer tianeptine, but not the NA reuptake inhibitor desipramine, increased the density of 5-HT axons in the cerebral cortex and some limbic forebrain areas. These findings indicate that antidepressants associated with 5-HT reuptake, but not NA reuptake, induce axonal sprouting of 5-HT neurons. Based on the sprouting or regenerative effects of antidepressants on NA and 5-HT axons, the axonal degeneration of monoamine neurons has been suggested to be involved in the pathophysiology of depression and antidepressants exert their action by inducing the regeneration of monoamine axons. In addition, it is suggested that the pathophysiology of depression includes NA-axon and/or 5-HT-axon degeneration, and NA- and 5-HT-specific antidepressants are effective in inducing NA and 5-HT axon regeneration, respectively.
