128 IGF-1 levels are also reported to be elevated in major depression, and this may reflect elevated growth hormone release as a result of the hypercortisolemia.129 Each of these patterns of elevation constitutes an “allostatic state,” and represents a pathway for the development of allostatic load

in the brain and in other organs throughout the body. Regarding the brain, we already noted the studies Inhibitors,research,lifescience,medical showing that hippocampal volume loss in major depressive illness is related to duration of the depression rather than to age per se of the patients.130-132 Not all studies report such changes (see, for example, references 133 and 134); the reasons for these different results are beyond Inhibitors,research,lifescience,medical the scope of this discussion, but they may be explained by differences in the duration of depression, as well as gender and age. It should

be noted that hippocampal size in elderly twins shows only 40% genetic contribution, with the predominant influence being environmental.135 This emphasizes the importance of experimental factors and allostatic load in determining Inhibitors,research,lifescience,medical hippocampal volume. Hippocampal atrophy has been found in relation to depression in the elderly,136 with an association detected with presence of the ApoE4 genotype.137 In subjects with a long-term history of depression, Sheline and colleagues described magnetic resonance imaging (MRI) evidence for discontinuities that might represent sites of damage.130 Although some recent postmortem studies on brains from depressed individuals Inhibitors,research,lifescience,medical did not show neuron loss in hippocampus,138,139 the duration of the depression and the subtype of depression were not carefully controlled. Thus, the possibility that neural damage may ultimately occur in major depression cannot be disregarded, particularly when depression lasts a long time. However, in a recent study in young depressed subjects, hippocampal volume was not smaller in first-episode depression, but declined rapidly over several years.140 ‘Ihc key,

unanswered question is whether such changes can be prevented or even reversed. It Inhibitors,research,lifescience,medical is important to note that other brain regions besides hippocampus are affected in depressive illness and undergo structural changes. One region is the prefrontal below cortex, and structural AZD5363 imaging141 showed loss of volume in familial pure depressive disorder, whereas autopsy studies142-144 have shown loss of volume and glial cells, as well as neuronal density in both unipolar and bipolar disorder. There is one animal study showing that chronic glucocorticoid treatment induces loss of dendrites in the rat prefrontal cortex.4 However, much more work needs to be done on this brain region. Depressive illness is associated with a hyperactivation of the amygdala,145,146 and more recently, with an actual enlargement of the amygdala in the first episode of major depression.147 This is reminiscent of the increased dendritic branching reported in rats after repeated immoblization stress (see above and reference 148).