Amitriptyline metabolism in relation to antidepressive effect

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Abstract
The relationship between amitriptyline (AT) metabolism and clinical response was studied in 14 outpatients treated with a daily dose of 150 mg AT. Riboflavin was added to the medication to check compliance. On days 0, 2 and 7 and at 3, 6, 9 and 13 wk after onset of therapy, blood samples were drawn from the patients 3 (.+-. 0.5) h after the 1st morning dose and a sample of the 1st morning urine was taken to check riboflavin. Serum levels of AT and its metabolites nortriptyline (NT), E- and Z-10-hydroxynortriptyline (E- and Z-10-OH-NT), total (E + Z) 10-hydroxyamitriptyline (tot-10-OH-AT) and demethylnortriptyline (DNT) were measured by HPLC [high performance liquid chromatography] while minimizing adsorption onto glass. On day 0 and after 6 and 13 wk, the severity of the depressive disorder was scored by means of the self-rating depression scale of Zung. Mean steady-state concentrations of AT, NT and E-10-OH-NT were in the order of 100 .mu.g/l and tot-10-OH-AT and Z-10-OH-NT approximated 20 .mu.g/l. DNT concentrations were < 15 .mu.g/l. There was great variation in metabolic pattern between patients. After 6 wk, concentrations of all compounds were .apprx. 15% lower than at 3 wk, indicating a weak autoinducible effect of AT or its metabolites. Steady-state concentrations of AT correlated well with that of NT (r = 0.64; P < 0.05) but not with that of E-10-OH-NT. The means of the Zung score at 6 and 13 wk were lower than the mean of the baseline score (P < 0.0001). Correlation coefficients between the mean percentage improvement in Zung score and the steady-state concentrations of AT, NT, E-10-OH-NT and age were -0.06, 0.10, -0.46 and -0.64, respectively.