The serological identification of syphilis is the model of a specific laboratory test for a general medical disorder. The test separates the behavioral syndrome of neurosyphilis from phenotypically similar but etiologically diverse conditions of mood and psychotic disorders. No such assessment exists for psychiatric disorders, despite more than a century of effort. A major hurdle in this quest has been the inability to define syndromes with biological homogeneity, thus confounding samples and eliciting conflicting findings. The dexamethasone suppression test (DST) was positive (non-suppression) in about 50% of depressed patients but was deemed unsuitable as a laboratory test in depressive illness, despite the evidence that samples of depressed patients were heterogeneous. Severely depressed patients, however, have substantial perturbations in their neuroendocrine functioning and measures of the endocrine system remain the best laboratory-based opportunity to demarcate mood disorders.