Zimelidine, a bicyclic compound, which in animal experiments causes specific inhibition of the uptake of 5-HT, was tried on 15 patients with depression of endogenous type. It produced considerable and highly significant 5-HT uptake inhibition in rat brain slices incubated in blood plasma from the patient under treatment, but no inhibition of NA uptake. Depressive symptoms were effectively relieved or entirely abolished in about two thirds of the patients. Only four patients did not react to the drug, and three of these were probably in need of NA uptake inhibitors, which on other occasions had worked well on their depressions. These three patients showed an extreme degree or retardation. During zimelidine treatment they were not just unaffected but showed signs of excitation, impatience and desperate feelings. These preliminary findings strongly indicate the true existence of depressive cases in need of an NA uptake inhibitor, but completely resistant to a specific 5-HT uptake inhibitor. The final dose of zimelidine was 75 mg b.i.d. This dose, although sufficient in most cases, was obviously somewhat low for a few of our patients. The concentration in blood plasma of zimelidine should probably reach a minimum level of 250 nmol/l and norzimelidine 500 nmol/l, and to achieve this a general dosage of 100 mg b.i.d. is recommended.