Serotonin uptake inhibition during treatment of depression with nortriptyline caused by parent drug and not by 10-hydroxymetabolites.

Treatment of endogenous depression with nortriptyline (NT), at a daily dose of 150 mg, resulted in a pronounced improvement of seven of ten patients investigated. The concentration of the norepinephrine metabolite HMPG in cerebrospinal fluid (CSF) decreased by 29% (P less than 0.01) after 3 weeks of treatment. There was no significant effect of treatment on the serotonin and dopamine metabolites 5-HIAA and HVA. In previous larger materials, however, a decrease of 5-HIAA in CSF has been demonstrated. Platelets from the patients showed an increase in Km for serotonin uptake in response to NT treatment. The IC50 value of NT for serotonin uptake inhibition was 940 nM, while the corresponding value of the major metabolite of NT, i.e. E-10-OH-NT, was much higher (6700 nM). Thus, during treatment, the parent drug and not the metabolite was responsible for the serotonin uptake inhibition in platelets. There was a close correlation between Km and the plasma concentration of NT after 1 week of treatment (r = 0.88, P less than 0.01) but not after 3 weeks of treatment (r = 0.48; ns). There was no uniform effect of NT treatment on Vmax. It is concluded that clinical NT treatment results in uptake inhibition not only in norepinephrine but also in serotonin neurons.