It does not propose that

each component is necessary or sufficient, or that the specified mediators are the sole routes to MDD. It also does not speak to the directions of causality between depression and physical pathology. Further, many of the specified mediators may serve either protective or destructive functions depending on their context and chronicity.11-13 Nonetheless, the model presented here provides testable hypotheses for further investigation and provides rationales for considering novel treatment approaches. Earlier reviews of this model have been published elsewhere.5,6,10 Figure 1. Model of multiple pathways leading to psychiatric and physical llness and cell aging. In Inhibitors,research,lifescience,medical conjunction with genetic and epigenetic moderators, elevated cortisol levels, associated with downregulation of glucocorticoid receptor (GC) function (GC resistance) … In brief, psychological and physical stressors trigger physiological responses that are acutely important for successful adaptation to the stress (“stress arousal”).

However, when stress responses Inhibitors,research,lifescience,medical are disrupted or inappropriately prolonged, endangering effects may supersede the protective ones. The “cost” to the organism of maintaining these physiological responses over prolonged periods has been termed “allostatic load”13 or “arousal pathology,”14 and it has check details repeatedly been associated with poor medical outcomes.12 Inhibitors,research,lifescience,medical In addition to chronicity of the stress response, certain psychological, environmental, genetic, and epigenetic circumstances (discussed below) favor dysregulation of two main stress response effectors, Inhibitors,research,lifescience,medical the limbic-hypothalamic -pituitaryadrenal (LHPA) axis and the

locus coeruleus noradrenergic (NE) system.15 A particular problem may arise when these two systems, which are generally Inhibitors,research,lifescience,medical counterregulatory, activate one another for prolonged periods of time (as may be seen in melancholic depression).15 The failure of glucocorticoids (GCs) to effectively counter-regulate stress-induced NE and LHPA activity may underlie critical aspects of MDD.15 Prolonged LHPA axis dysregulation can lead to neuroendangering or neurotoxic effects in vulnerable brain regions (eg, prefrontal cortex and hippocampus).16 It can also lead to energetic disturbances (decreased intracellular glucose availability and insulin resistance), glutamatergic hyperactivity/excitotoxicity, all increased intracellular calcium concentrations, mitochondrial damage, free radical generation and oxidative stress, immune alterations (leading to a proinflammatory milieu), and accelerated cell aging (via effects on the telomere/telomerase maintenance system). The nature of cortisol abnormalities in MDD is complex, however, and will be discussed below. Prolonged activation of central NE systems, as often seen in melancholic depression, may be associated with worsened outcome in cardiovascular diseases and with accelerated cell aging at the level of the telomere.