• A previous study reported that unipolar depressives excrete significantly lower amounts of urinary tyramine-O-sulfate following oral administration of a tyramine hydrochloride load than do normal control subjects. This study replicates and extends those findings by showing that within the heterogeneous group of unipolar depressives, patients with melancholia and bipolar patients with a history of melancholia manifest a tyramine excretion deficit. A small subgroup of medication-free patients in remission from episodes of melancholia had abnormally low tyramine sulfate excretion levels while they were euthymic, supporting the suggestion that reduced tyramine sulfate excretion following oral tyramine loading is a trait marker for depression. Further study of the role of trace amines in affective illness is warranted. Clinical application is not warranted until further evaluation of the sensitivity, specificity, and reproducibility of this oral tyramine challenge test.