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The Neural Foundations of Major Depression: Classical Approaches and New Frontiers J. Paul Hamilton, Daniella J. Furman, Ian H. Gotlib Department of Psychology, Stanford University Running Head: Neural Foundations of Depression Preparation of this chapter was supported by NIMH Grants MH59259 and MH74849 to Ian H. Gotlib. The Neural Foundations of Major Depression: Classical Approaches and New Frontiers Major Depressive Disorder (MDD) is among the most prevalent of all psychiatric disorders. Recent estimates indicate that almost 20% of the American population, or more than 30 million adults, will experience a clinically significant episode of depression during their lifetime (Kessler Wang, 2009). Moreover, depression is frequently comorbid with other mental and physical difficulties, including anxiety disorders, cardiac problems, and smoking (e.g., Friedland Carney, 2009). Depression also has significant economic and social costs. Kessler et al. (2006), for example, estimated that the annual salary-equivalent costs of depression-related lost productivity in the United States exceed $36 billion. Given the high prevalence, comorbidity, and costs of depression, it is not surprising that the World Health Organization Global Burden of Disease Study ranked this disorder as the single most burdensome disease world-wide (Murray Lopez, 1996). Finally, it is important to note that depression is a highly recurrent disorder. More than 75% of depressed patients have more than one depressive episode, often relapsing within two years of recovery from a depressive episode (Boland Keller, 2009). Indeed, between one-half and two-thirds of people who have ever been clinically depressed will be in an episode in any given year over the remainder of their lives (Kessler Wang, 2009). Although MDD is primarily a disorder of emotion and its regulation, it is important to recognize that this disorder can be characterized by a full constellation of behavioral, emoti