Depression and the Hippocampus: Cause or Effect?

Research examining the relationship between major depressivedisorder(MDD)andhippocampalvolumehaslongwrestled with the chicken and egg question. From the time the first report was published finding smaller hippocampal volumes in patients with MDD compared with healthy control subjects (1), there have been hundreds of studies in the literature, with the majority, but not all, finding smaller hippocampal volumes in MDD (2). The direction of a potential causal arrow, however, remains unresolved. Studies supporting a role for episodes of MDD leading to smaller hippocampal volumes have found that longer cumulative duration of lifetime depression, total number of recurrent episodes, and earlier age of onset of depression are associated with hippocampal volume loss (2,3). On the other hand, evidence also supports the causality arrow pointing in the opposite direction. Studies supporting the role of hippocampal structural impairment in the etiology of depression have found that a smaller hippocampus predicts worse clinical outcome, and genetic influences on brain structures, including the hippocampus, have been identified in twin studies (4). One explanation for the relation between MDD and smaller hippocampal volumes is the neurotoxicity hypothesis (5), which suggests that prolonged exposure to glucocorticoids increases neuronal susceptibility to insults, thereby increasing the rate of damage from toxic challenges or ordinary attrition. According to this hypothesis, the reduction in hippocampal volumes is a cumulative process from many years of depression, posttraumatic stress disorder,orchronicstress.Inadditiontoabnormalitiesinthehypothalamic-pituitary-adrenal (HPA) axis, other biological abnormalities have been recently shown to contribute to hippocampal volume loss: stress-induced reduction in neurotrophic factors, in particular brain-derived neurotrophic factor (BDNF), and stress-induced reduction in neurogenesis. In preclinical studies, several forms of stress reduce BDNF-mediated signaling in hippocampus, whereas chronic treatment with antidepressants increases BDNF signaling (6). Similar changes are observed in postmortem hippocampi of humans with depression, as well as in serum BDNF concentration,althoughthisremainscontroversial.Anotherimportantsourceofplasticityistheinductionordownregulationofadult hippocampal neurogenesis, by which neural progenitors of the hippocampal subgranular zone divide to form new neurons that differentiate and integrate into the dentate gyrus (7). These additional mechanisms may be additive or synergistic with glucocorticoid neurotoxicity and there appear to be important developmental windows in these effects (8). At the time the neurotoxicity hypothesis was proposed, the effects of stress on BDNF and neurogenesis had not been described and there persists some tendency in the literature to oversimplify the connection between stressinduced neurotoxicity and hippocampal volume loss. An alternativeexplanationfortherelationshipisthevulnerabilityhypothesis, which suggests, in contrast to the neurotoxicity hypothesis, that reducedadulthippocampalvolumeisnotduetocumulativeexposure to MDD, posttraumatic stress disorder, or chronic stress, but rather that reduced hippocampal volume is a pre-existing risk factor for stress-related disorders induced by genetics and early exposure to stress (9). The report by Gerritsen et al. (10) in this issue of Biological Psychiatry investigated the role of dysregulated HPA axis function in the association between depression and smaller hippocampal volumes. The report is remarkable for several reasons. It used the largest sample (n 636) to date to study both hippocampal and entorhinal cortex volumes in depression. The sample consisted of well-characterizedlate-lifedepressionparticipants,subcategorized into those with early-onset depression (50 years) (EOD) versus late-onset depression (50 years) (LOD). The sample was also divided into those with current depression (defined as having been depressed within the past year), remitted depression, and never depressed. The extension to examining structural differences in both the hippocampus and entorhinal cortex is novel, having only rarely been examined together in investigations of depression. Most importantly, given their findings in late-life depression, the studyrevealsthattherelationshipbetweenMDDandhippocampal volumes is even more complicated than previous studies have indicated. The study found that one or more episodes of depression were associated with smaller hippocampal volumes but not entorhinal cortex volumes. Early-onset depression was associated with smaller hippocampal volumes but not entorhinal cortex volumes, whereas LOD was associated with smaller entorhinal cortex volumesbutnotsmallerhippocampusvolumes.Smallerhippocampal volume was not associated with HPA abnormalities. The finding that participants with one or more episodes of depression and those with EOD had smaller hippocampal volumes is consistent with the large number of studies that have identified hippocampal volume abnormalities in MDD, particularly in participants with greater numbers of depressive episodes, as would be expected in older people with EOD who would have experienced multiple depressive episodes. The finding that the LOD group had smallerentorhinalcortexvolumesisfascinatingbecausethisregion