27,30 In fact, several instances of neurobiological changes reported in MDD may be more attributable to histories of early-life adversity,30,32 which are over-represented among individuals with MDD, than to the MDD itself. Thus, early-life adversity seems capable of “reprogramming” the individual to a certain lifetime repertoire of altered physiological responses to stress and to vulnerability to psychiatric and physical illness. This reprogramming toward stress arousal Inhibitors,research,lifescience,medical and preparedness may be adaptive when the individual is likely to be confronted with a lifetime of continuous adversity, but is clearly disadvantageous otherwise. The causes of early adversity-induced

namely behavioral and biochemical changes, and the Inhibitors,research,lifescience,medical explanation for the very long-lasting effects of such adversity, are the subject of intense investigation. One explanation that has attracted much attention is epigenetic changes,45,46 discussed in the next section. Genetic and epigenetic moderators A number of variants in candidate genes have been

implicated in contributing to maladaptive and resilient responses that underlie alterations in neuronal plasticity and subsequent behavioral depression.47 Evidence is strongest for genes involved in HPA regulation and stress (corticotrophin-releasing hormone [CRH]1; glucocorticoid receptor Inhibitors,research,lifescience,medical [GR]), regulatory neurotransmitters, transporters, and receptors (serotonin (5-HT)1A, 5HT2, 5-HTTLPR, NET), neurotrophic factors, (brain-derived neurotrophic factor [BDNF], nuclear factor-kappaB, mitogen-activated protein kinase-1) and transcription factors (cAMP response element binding, Re-1 silencing transcription factor, delta Inhibitors,research,lifescience,medical FosB), but variations in other secondary modulatory

factors (g-aminobutyric acid [GABA], catechol-O-methyl transferase, monoamine oxidase, dynorphin, neuropeptide-Y) have also been hypothesized to be important in determining individual differences in stress response.48 Studies of the CRH-1 gene in humans, for example, have shown that specific Inhibitors,research,lifescience,medical variants are associated with differential hormonal responses to stress, and with differing rates of depression and suicidal behavior.49 Increasingly, such genetic effects have themselves been found to be modulated by individual variation in environmental context and history Entinostat (gene x environment, GxE).45 Epigenetics, which focuses on nongenomic alterations of gene expression, provides a mechanism for understanding such findings, through alteration of DNA methylation and subsequent silencing of gene expression or through physical changes in DNA packaging into histones.50 A comprehensive review of this literature is beyond the scope of this article, but the findings of selective recent studies in these areas are illustrative of the regulatory complexity that influences the possible translation of stressful experiences into depression.