Antidepressant-elicited changes in gene expression: remodeling of neuronal circuits as a new hypothesis for drug efficacy

Although antidepressants have been used clinically for more than 50 years, no consensus has been reached concerning their precise molecular mechanism of action. Pharmacogenomics is a powerful tool that can be used to identify genes affected by antidepressants or by other effective therapeutic manipulations. Using this tool, others and we have identified as candidate molecular targets several genes or expressed sequence tags (ESTs) that are induced by chronic antidepressant treatment. In this article, we review antidepressant-elicited changes in gene expression, focusing especially on the remodeling of neuronal circuits that results. This refocusing motivates our hypothesis that this plasticity represents the mechanism for drug efficacy, and thus a causal event for clinical improvement. Defining the roles of these molecules in drug-induced neural plasticity is likely to transform the course of research on the biological basis of antidepressants. Such detailed knowledge will have profound effects on the diagnosis, prevention, and treatment of depression. Consideration of novel biological approaches beyond the "monoamine hypothesis" of depression is expected to evoke paradigm shifts in the future of antidepressant research.