Causality of stem cell based neurogenesis and depression - To be or not to be, is that the question?

Mood disorders compose a considerable portion of the worldwide prevailing diseases with high suicide rates and urgent demand for novel therapeutic interventions as efficacious treatment is still lacking. Depression is thought to feature distinct morphological correlatives in the brain and has recently been linked to adult neurogenesis (NG) in the hippocampal formation. Numerous findings give rise to the hypothesis that depression and declining NG in the hippocampus may be causally connected. This implies that depressive symptoms could originate from impairments in NG and, vice versa, that improved NG could mediate antidepressant action and alleviate symptoms. Thus, great hopes rest on the question whether the observed increase in NG following antidepression treatment may have the potential to become a novel drug target and specific mechanism in the development of the next generation of antidepressants that specifically involves targeting of neuropoetic factors in addition to their "traditional" effects as modulators of synaptic transmission. Along the still hypothetical association of depression and NG, however, several controversies and unresolved questions exist with respect to the presently available data and interpretation. This article highlights and summarizes some of the most pressing issues and identifies the crucial ones that await urgent clarification and resolving. Without their reliable answering, the fascinating notion of a neurogenic basis for depression will remain to be greatly speculative.