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

Abstract

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.

Relationship between parameters of serotonin transport and antidepressant plasma levels or therapeutic response in depressive patients treated with paroxetine and amitriptyline

“…Lingjaerde et al (22) described a positive correlation between plate-let 5-HT uptake inhibition and zimelidine plasma levels after 3 weeks of treatment. Corresponding results have been reported for desipramine after 3 or 4 weeks of treatment respectively (22,23) and for nortriptyline after one, but not after 3 weeks of treatment (24).…”

The Platelet and The Neuron: Two Cells in Focus in Migraine

“…Their efficacy is, however, not likely to be due to an inhibition of platelet functions. Several pieces of indirect evidence support the assumption that an inhibition of platelet functions, in response to drug treatment, reflects a similar pharmacologic effect on serotonergic neurons (76,101,148,149). Thus, the effect of these drugs on platelets reflects their interference with similar processes in the serotonergic neurons.…”

Nortriptyline, a tricyclic antidepressant, inhibits voltage-dependent K+channels in coronary arterial smooth muscle cells

“…First, the IC 50 value of nortriptyline for Kv current inhibition was 2.86±0.52 µM, which was much greater than the IC 50 value of nortriptyline for serotonin uptake inhibition (0.94 µM) [16]. This difference suggests that the nortriptyline-induced inhibition of Kv channels is independent of serotonin uptake inhibition.…”