10-hydroxyamitriptyline and Depressive-Disorder

As part of a double-blind clinical trial comparing phenelzine and amitriptyline in outpatients with predominantly major depressive disorder, plasma tricyclic antidepressant drug concentrations were measured in 83 amitriptyline-treated patients. In 29 of these patients, hydroxymetabolites were also assayed. Patients were treated for 6 weeks at a fixed dose of 150 mg/day of amitriptyline after the first 5 days. Therapeutic outcome was assessed with a structured depression interview schedule, the Symptom Checklist-90, a side effects checklist, and a global improvement scale. Steady state plasma levels of 10-hydroxynortriptyline were in the same range as amitriptyline or nortriptyline concentrations. Clinical response did not relate significantly to plasma levels of either the parent drug, its metabolites, or the sum of all four pharmacologically active substances. Minimum threshold tricyclic antidepressant levels for therapeutic effect were not found. Assay of its active hydroxymetabolites does not appear to improve the clinical utility of routine amitriptyline level monitoring in patients with major depression in an outpatient setting.

Topics: Adult; Aged; Amitriptyline; Depressive Disorder; Humans; Kinetics; Middle Aged; Nortriptyline

The serum concentrations of amitriptyline and its 3 metabolites--nortriptyline, 10-hydroxy-amitriptyline and 10-hydroxy-nortriptyline were determined in 18 depressive patients treated with amitriptyline for 6 weeks. The relationships between the serum concentrations and the clinical effects were statistically analyzed and showed significant correlations. The authors suggest that the total TAD serum concentration (280 ng/ml) can be used as the index for clinical efficacy, so far as the above data are concerned.

Topics: Adult; Aged; Amitriptyline; Depressive Disorder; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Nortriptyline

A subgroup of 16 out of 30 endogenous depressive inpatients (cf. part I), treated for 3 weeks with 150 mg amitriptyline (AT) daily, participated in a pharmacogenetic study: all were phenotyped with debrisoquine and 3 of them with mephenytoin. Four patients were found to be poor metabolizers (PMs) of debrisoquine and one of mephenytoin. Plasma levels of AT + NT (nortriptyline) were highest in the PMs of debrisoquine, but the ratio of hydroxylated metabolites to the parent compounds appeared to be lower in these subjects. From these data, it is speculated that, in the PM of mephenytoin, the demethylation of AT is impaired. In 12 patients, free plasma 10-hydroxy-AT (ATOH) and 10-hydroxy-NT (NTOH) were found to be bound to a similar extent to plasma proteins, but not so firmly as their parent compounds, by a factor of 6 and 4 respectively. While mean total plasma ATOH reached only 15% of the value of AT, total plasma NTOH was as high as NT. ATOH correlated significantly with its parent compound, but NTOH did not correlate with NT. No drug plasma levels/clinical relationship was found in this small group of patients, even when the hydroxylated metabolites were taken into account. Both poor and extensive metabolizers of debrisoquine responded to treatment. The debrisoquine-test appears to be a useful clinical tool for detecting in patients a genetic deficiency in the hydroxylation of AT-type drugs.

Topics: Adult; Amitriptyline; Debrisoquin; Depressive Disorder; Female; Humans; Hydantoins; Hydroxylation; Isoquinolines; Kinetics; Male; Mephenytoin; Middle Aged; Nortriptyline; Phenotype; Polymorphism, Genetic