Depression, antidepressants, and neurogenesis: a critical reappraisal

Abstract

The neurogenesis hypothesis of depression posits (1) that neurogenesis in the subgranular zone of the dentate gyrus is regulated negatively by stressful experiences and positively by treatment with antidepressant drugs and (2) that alterations in the rate of neurogenesis play a fundamental role in the pathology and treatment of major depression. This hypothesis is supported by important experimental observations, but is challenged by equally compelling contradictory reports. This review summarizes the phenomenon of adult hippocampal neurogenesis, the initial and continued evidence leading to the development of the neurogenesis hypothesis of depression, and the recent studies that have disputed and/or qualified those findings, to conclude that it can be affected by stress and antidepressants under certain conditions, but that these effects do not appear in all cases of psychological stress, depression, and antidepressant treatment.

Figure 1

Areas of neurogenesis in the adult rat brain. Red – confirmed neurogenesis; pink – possible neurogenesis. (reproduced from Gould, 2007).

Figure 2

Stages of neurogenesis in the dentate gyrus. Type-1 cells (radial-glia-like stem cells) in the subgranular zone divide asymmetrically, maintaining their population while producing Type-2 daughter cells (neural progenitor cells). These continue to divide symmetrically as they mature into Type-3 cells (neuroblasts) and migrate into the granule cell layer. Type-4 cells, which have ceased mitosis, extend axons toward the CA3, leading to the development of mature granule cells that integrate with the mossy fiber pathway. SGZ, subgranular zone; GCL, granule cell layer; ML, molecular layer.