A postmortem study of patients with depression suggests that neurons and glia form a network in the pathophysiology and treatment of depression, where there is a reduction of glial cells and altered expression of glia-related genes in certain areas of the brain. Glia, especially astrocytes, play a major role in the CNS and in the storage of several types of neurotrophic factors, such as GDNF and BDNF. The expression of neurotrophic factors in glia by antidepressants is regulated by a monoamine-independent mechanism. Multiple neurotrophic/growth factors might be systematically associated with the pathophysiology and treatment of depression as an intermediate phenotype. Although tricyclic antidepressants (TCA)are an established class of drug, TCAs have been clinically observed to cause previously-unknown effects. The current study focuses on novel effects of TCA on glia,which may lead to drug discovery.