Pharmacokinetically designed double-blind placebo-controlled study of nortriptyline in 6- to 12-year-olds with major depressive disorder.

A random assignment, double-blind, placebo-controlled study of nortriptyline in 50 prepubertal 6- to 12-year-olds with Research Diagnostic Criteria and DSM-III major depressive disorder was performed. The protocol included a 2-week placebo wash-out phase and an 8-week double-blind, placebo-controlled phase with weekly plasma level monitoring. Active subjects had their plasma level pharmacokinetically placed at 80 +/- 20 ng/ml by using previously developed tables to determine the starting dose from a plasma level 24 hours after a single dose administered at baseline. The mean plasma level was 89.9 ng/ml. The study population was severely depressed, had a chronic, unremitting course of long duration before the study, had a high percentage of family histories with affective disorder, alcoholism and suicidality, and had a high rate of comorbidity. None of the subjects had ever received tricyclic antidepressants before this study. There was a poor rate of response in both treatment groups (30.8% active, 16.7% placebo). Active subjects did not evidence the anticholinergic side effects reported in adult samples. The implications of these findings for future pharmacotherapy studies of depressed children are discussed.

Lithium and tricyclic antidepressants.

Pharmacokinetic studies of lithium and tricyclic antidepressants (TCAs) in children and adolescents report similarities to adults with respect to a wide interindividual genetic variation in the rate of elimination and with regard to the linear nature of the system. Children may eliminate these medications more rapidly; therefore, more frequent dosing may be necessary to maintain steady state serum lithium or plasma TCA levels. Doses of these medications necessary for desired blood levels can be obtained from tables based on nomograms (i.e., one-step dosage adjustment determined from a single serum lithium or plasma TCA level drawn 24 hours after administration of a single dose). Use of these dose prediction tables avoids toxicity due to excessively high blood levels in genetically slow metabolizers in whom medication regimes that use mg/kg dose schedules may produce toxic blood levels.