Major depression is one of the leading causes of disability and psychosocial impairment worldwide. Although
many advances have been made in the neurobiology of this complex disorder, the pathophysiological mechanisms are still
unclear. Among the proposed theories, impaired neuroplasticity and hippocampal neurogenesis have received
considerable attention. The possible association between hippocampal neurogenesis, neurotrophic factors, major
depression, and antidepressant responses was critically analyzed using a comprehensive search of articles/book chapters in
English language between 1980 and 2014. One common emerging theme was that chronic stress and major depression are
associated with structural brain changes such as a loss of dendritic spines and synapses, as well as reduced dendritic
arborisation, together with diminished glial cells in the hippocampus. Both central monoamines and neurotrophic factors
were associated with a modulation of hippocampal progenitor proliferation and cell survival. Accordingly, antidepressants
are generally suggested to reverse stress-induced structural changes augmenting dendritic arborisation and synaptogenesis.
Such antidepressant consequences are supposed to stem from their stimulatory effects on neurotrophic factors, and
possibly modulation of glial cells. Of course, accumulating evidence also suggested that glutamatergic systems are
implicated in not only basic neuroplastic processes, but also in the core features of depression. Hence, it is critical that
antidepressant strategies focus on links between the various neurotransmitter systems, neurotrophic processes of
hippocampal neurogenesis, and neurotrophic factors with regards to depressive symptomology. The identification of novel
alternative antidepressant medications that target these systems is discussed in this review.