A complex set of biological processes has been implicated in the etiology and course of depression—although such research has not always clarified whether such processes are underlying causal factors, correlates, or consequences of depression. These include interrelated mechanisms of genetic vulnerabilities, brain structure and function, neurotransmitter and neuroendocrine processes, and immune system processes. Discussion of the details and transactions among these processes given the vastly expanding research literature in recent years is beyond the scope of this report (but see Thase, 2008, for a review). Advances have been made in each of these areas as well as in studies of interactions among these biological mechanisms and environmental and personal factors that confer increased risk for depression. In light of the heterogeneity of depression, it is not surprising that the research evidence to date has failed to converge on a single set of biological processes that is related to the onset and course of depression. However, evidence supports the role of several important aspects of functioning in the brain, the central nervous system, and the periphery. A theme throughout these various lines of research is the importance of considering the interaction between biology and exposure to stress, particularly chronic or recurring stress, in the etiology and course of depression.

Genetic Vulnerability

It is well known that depression runs in families, a phenomenon implicating both genetic and environmental processes. A review of twin studies finds that about one-third of the risk for major depression in adults derives from genetic differences between individuals (Kendler et al., 2006; Sullivan, Neale, and Kendler, 2000). This figure is substantially lower than for some other psychological disorders, such as schizophrenia or bipolar disorder (McGuffin et al., 2003; Sullivan, Kendler, and Neale, 2003). Similarly, the risk of developing major depression increases about 2.5–3 times for those who have a first-degree relative with depression, whereas having a highly threatening life event increases risk from 5 to 16 times in a few months after the event (Kendler, Karkowski, and Prescott, 1998; Sullivan, Neale, and Kendler, 2000). Genetic influences appear to be modified by gender and developmental phase, and they may influence not only internal biological and psychological characteristics but also the nature of the person’s effects on the environment (Kendler et al., 2001, 2006; Kendler and Karkowski-Shuman, 1997; Kendler, Gardner, and Prescott, 2003; Kendler, Gardner, and Lichtenstein, 2008).

Several genetic polymorphisms have been linked to increased risk of depression in response to stress. Foremost among these are genes of the

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