Recently, clinical and animal studies have shown that neuronal and glial plasticity are important for the therapeutic action of antidepressants. Thus, it has been suggested that neurotrophic factors or growth factors, which are potent regulators for neuronal and glial plasticity, might be involved in the effect of antidepressants. Post-mortem studies provide evidence for glial reduction in different brain areas in mood disorders. Therefore, we focused on glial cell line-derived neurotrophic factor (GDNF) in mood disorders, because GDNF plays an important role in neurogenesis and high-ordered brain function, such as learning and memory. GDNF family ligands have shown promise of efficacy for neurodegenerative disorders such as Parkinson's disease, suggesting that GDNF family ligands exist in the closest position to clinical development for treatment of diseases of the central nervous system. We reported that total GDNF levels in whole blood in patients with mood disorders were significantly lower than those in healthy control subjects (Takebayashi et al, 2006), and antidepressants increased GDNF production through monoamine-independent activation of protein tyrosine kinase (PTK) and extracellular signal-regulated kinase (ERK) in glial cells (Hisaoka et al, 2007). Clarifying the monoamine-independent novel target of antidepressants in glia might contribute to the development of more efficient therapeutics for depression.