In a double-blind controlled study lasting 4 weeks 25 newly admitted severely depressed patients were randomly assigned to tryptophan-nicotinamide or imipramine or tryptophan-nicotinamide-imipramine combination. Nicotinamide was given to reduce peripheral breakdown of tryptophan. Although there were no substantial differences between the three treatments, the efficacy of tryptophan-nicotinamide tended to diminish after 2 weeks when the dose of tryptophan was increased from 4 g/day to 6 g/day and that of nicotinamide from 1.0 g/day to 1.5 g/day. The therapeutic response of patients treated with tryptophan-nicotinamide was significantly correlated with the rise in plasma tryptophan. For the tryptophan-nicotinamide-imipramine group, however, therapeutic response and rise in plasma tryptophan were negatively correlated, implying that tryptophan levels were too high in some patients. The data suggest that tryptophan-nicotamide may be as effective as imipramine in unipolar patients providing the dose is kept within the therapeutic window, and that at low doses it could also potentiate the action of tricyclic antidepressants. Bipolar patients seem to require higher doses of tryptophan than unipolar patients.