Central serotonin (5-hydroxytryptamine; 5-HT) metabolism can be disturbed in a subgroup of patients with vital (endogenous, primary) depression. Presumably these disturbances do not result from the depression and have a predisposing rather than a causative relationship to it. This latter statement is based on two observations. First, in a majority of patients, the 5-HT disturbances persist after depression has abated. Secondly, 5-hydroxytryptophan seems to have prophylactic value, in particular in patients with persistent abnormalities in central 5-HT metabolism. In this study we approached the hypothesis that 5-HT disturbances are a predisposing factor to the occurrence of depression from still another perspective. If this hypothesis is correct, then depressive patients with persistent 5-HT disturbances should have higher frequencies of depression than depressive patients without demonstrable 5-HT disturbances. This was indeed demonstrated. The same was true for family members of probands with low levels of 5-hydroxyindoleacetic acid. No cerebrospinal fluid data are available for family members. The reported findings strongly support the predisposition hypothesis.