Abstract
<jats:title>Abstract</jats:title> <jats:p>The results of a 40-year three-generation study of families at high and low risk for major depression are presented. Clinical outcomes, including diagnosis, medical, and social functioning, with case descriptions, as well as preliminary efforts to understand brain functioning using electrophysiology and magnetic resonance imaging are presented. The roles of religion/spirituality as protections for some individuals is described. The clinical samples include the biological offspring and the grandchildren of the first generation high (depressed) or low risk (not depressed) probands. The clinical findings on the offspring and grandchildren are considered in light of our current understanding from animal model studies as well as their final implementation and translation in larger populations. The study began when there was limited research on clinical depression. Now with a rich understanding of the presentation and course of depression, future directions of research and clinical care are considered. Included are discussion of early detection, prevention, and treatment. The limitations of this study include its lack of social diversity and the fact that genetic studies are limited as efforts to replicate findings in separate studies, including large diverse samples. The next phase of research is diverse, rich, and promising.</jats:p>