Genetic and physiological. First-degree family members of individuals with major de-
pressive disorder have a risk for major depres sive disorder two- to  fourfold higher than
that of the general population. Relative risks appear to be higher for early-onset and re-
current forms. Heritability is a pproximately 40%, and the personality trait neuroticism ac-
counts for a substantial port ion of this genetic liability.
Course modifiers. Essentially all major nonm ood disorders increase the risk of an indi-
vidual developing depression. Major depressive episodes th at develop against the back-
ground of another disorder of ten follow a more refractory course. Substance use, anxiety,
and borderline personality diso rders are among the most common of these, and the pre-
senting depressive symptoms may obscure an d delay their recognition. However, sus-
tained clinical improvement in depressive  symptoms may depend on the appropriate
treatment of underlying illnesses. Chronic or  disabling medical conditions also increase
risks for major depressive episod es. Such prevalent illnesses as diabetes, morbid obesity,
and cardiovascular disease are often complicated by depressive episodes, and these epi-
sodes are more likely to become chronic than are depressive episodes in medically healthy
individuals.
Culture-Related Diagnostic Issues
Surveys of major depressive disorder across diverse cultures have shown sevenfold dif-
ferences in 12-month prevalen ce rates but much more consistency in female-to-male ratio,
mean ages at onset, and the degree to which presence of the disorder raises the likelihood
of comorbid substance abuse. While these findings suggest substantial cultural differences
in the expression of major depressive disord er, they do not permit simple linkages be-
tween particular cultures and the likelihoo d of specific symptoms. Rather, clinicians