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<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 K_m 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 K_m and the plasma concentration of NT after 1 week of treatment (r=0.88, P<0.01) but not after 3 weeks of treatment (r=0.48; ns). There was no uniform effect of NT treatment on V_max. It is concluded that clinical NT treatment results in uptake inhibition not only in norepinephrine but also in serotonin neurons.