The biological components of depressive mood disorders are the theme of thousands of articles. Despite recognition that mood disorders are clinically and physiologically heterogeneous, few studies assess the biology of different forms of depressive illness. Our knowledge about melancholia is therefore limited, and is based largely on interpolation from hospital samples or patients identified as “severely depressed,” the groups most likely to include an abundance of melancholic patients. This chapter examines the neurobiology of melancholia. The association of melancholia with vegetative, psychomotor, and mood disturbances that result from the characteristic hypothalamic–pituitary–adrenal (HPA) axis dysfunction are the basis for the clinical features of melancholia. Their usefulness as diagnostic criteria is discussed in Chapter 4. Biological studies picture a mood disorder as an abnormal physiologic stress response. The neurochemical, electrophysiologic, and cognitive deviations are considered secondary to an abnormal stress response. Melancholic patients also demonstrate abnormal brain metabolism and structure that worsen with increasing numbers of episodes. Most abnormalities, however, resolve with proper treatment. When prolonged, the risk increases for future episodes of the illness.

A genetic predisposition for melancholia has been sought in genomic mapping.