Depression and the hippocampus: cause or effect?

f d f h l s R esearch examining the relationship between major depressive disorder (MDD) and hippocampal volume has long wrestled with the chicken and egg question. From the time the rst report was published finding smaller hippocampal volumes in atients with MDD compared with healthy control subjects (1), here have been hundreds of studies in the literature, with the ajority, but not all, finding smaller hippocampal volumes in MDD 2). The direction of a potential causal arrow, however, remains nresolved. Studies supporting a role for episodes of MDD leading o smaller hippocampal volumes have found that longer cumulaive duration of lifetime depression, total number of recurrent epiodes, and earlier age of onset of depression are associated with ippocampal volume loss (2,3). On the other hand, evidence also upports the causality arrow pointing in the opposite direction. tudies supporting the role of hippocampal structural impairment n the etiology of depression have found that a smaller hippocamus predicts worse clinical outcome, and genetic influences on rain structures, including the hippocampus, have been identified n twin studies (4). One explanation for the relation between MDD and smaller ippocampal volumes is the neurotoxicity hypothesis (5), which uggests that prolonged exposure to glucocorticoids increases euronal susceptibility to insults, thereby increasing the rate of amage from toxic challenges or ordinary attrition. According to his hypothesis, the reduction in hippocampal volumes is a cumuative process from many years of depression, posttraumatic stress isorder, or chronic stress. In addition to abnormalities in the hypohalamic-pituitary-adrenal (HPA) axis, other biological abnormaliies have been recently shown to contribute to hippocampal volme loss: stress-induced reduction in neurotrophic factors, in articular brain-derived neurotrophic factor (BDNF), and stress-inuced reduction in neurogenesis. In preclinical studies, several orms of stress reduce BDNF-mediated signaling in hippocampus, hereas chronic treatment with antidepressants increases BDNF ignaling (6). Similar changes are observed in postmortem hipocampi of humans with depression, as well as in serum BDNF oncentration, although this remains controversial. Another imporant source of plasticity is the induction or downregulation of adult ippocampal neurogenesis, by which neural progenitors of the ippocampal subgranular zone divide to form new neurons that ifferentiate and integrate into the dentate gyrus (7). These addiional mechanisms may be additive or synergistic with glucocortioid neurotoxicity and there appear to be important developmenal windows in these effects (8). At the time the neurotoxicity ypothesis was proposed, the effects of stress on BDNF and neuroenesis had not been described and there persists some tendency n the literature to oversimplify the connection between stressnduced neurotoxicity and hippocampal volume loss. An alternaive explanation for the relationship is the vulnerability hypothesis, hich suggests, in contrast to the neurotoxicity hypothesis, that