SPECIAL ISSUE Boldizsa ´r Cze ´h Æ Paul J. Lucassen What causes the hippocampal volume decrease in depression? Are neurogenesis, glial changes and apoptosis implicated? Published online: 1 April 2007 j Abstract Even though in vivo imaging studies document significant reductions of hippocampal volume in depressed patients, the exact underlying cellular mechanisms are unclear. Since stressful life events are associated with an increased risk of developing depression, preclinical studies in which animals are exposed to chronic stress have been used to understand the hippocampal shrinkage in de- pressed patients. Based on morphometrical studies in these models, parameters like dendritic retraction, suppressed adult neurogenesis and neuronal death, all due to elevated levels of glucocorticoids, have been suggested as major causative factors in hippocampal shrinkage. However, histopathological studies exam- ining hippocampi of depressed individuals have so far failed to confirm either a massive neuronal loss or a suppression of dentate neurogenesis, an event that is notably very rare in adult or elderly humans. In fact, many of the structural changes and the volume reduction appear to be reversible. Clearly, more his- topathological studies are needed; especially ones that (a) employ stereological quantification, (b) focus on specific cellular elements and populations, and (c) are performed in nonmedicated depressed patients. We conclude that mainly other factors, like alterations in the somatodendritic, axonal, and synaptic compo- nents and putative glial changes are most likely to explain the hippocampal shrinkage in depression, while shifts in fluid balance or changes in the extra- cellular space cannot be excluded either. j Key words hippocampus Æ depression Æ mood disorder Æ neuroplasticity Æ glia Introduction Major depressive disorder (MDD) is a common and life-threatening illness, but despite extensive investi- gations, little is known about its underlying funda- mental biology [74]. The traditional neurobiological concept on the etiology of depressive disorders has been the monoamine hypothesis, but during recent years, it has become evident that factors other than monoamine deficiency or imbalances between various neurotransmitter systems must be taken into account when describing the neurobiological basis of major depression. Contemporary theories place emphasis on the intracellular and structural changes, and suggest that disturbed neuroplasticity, including impaired adult hippocampal neurogenesis, might be implicated in the biological basis of major depression [9, 24, 66]. These novel theories are based on a number of clinical and preclinical observations. Numerous in vivo imaging studies report selective functional and structural changes in limbic structures such as the prefrontal cortex and hippocampus in patients with major depressive disorder [5, 22, 67, 91, 92]. Probably the most reproduced finding is a small (10–15%) but significant reduction in hippocampal volume as doc- umented by in vivo magnetic resonance imaging (MRI) studies [6, 106]. Moreover, duration of the depressive episode is closely paralleled by volumetric changes, with longer periods of depression generally corresponding to smaller hippocampi [92, 93, 61]. EAPCN 728 Dr. B. Cze ´h (&) Clinical Neurobiology Laboratory German Primate Center Kellnerweg 4 37077 Go ¨ttingen, Germany Tel.: +49-551/3851-134 Fax: +49-551/3851-307 E-Mail: bczeh@cnl-dpz.de P.J. Lucassen Swammerdam Institute for Life Sciences Center for Neuroscience University of Amsterdam 1098 SM Amsterdam, The Netherlands Eur Arch Psychiatry Clin Neurosci (2007) 257:250–260 DOI 10.1007/s00406-007-0728-0