The TCAs, such as imipramine, desipramine, clomipramine, amitriptyline, and nortriptyline, are dibenzapine derivatives. Because they undergo significant first-pass metabolism by the liver and are less bound to proteins,4 these agents are metabolized significantly more rapidly in children and adolescents than in adults. This faster metabolism is true of all compounds with primary hepatic metabolism because of the greater liver mass in relation to body size in children and adolescents. Children and adolescents, like adults, can show a more than 30-fold difference in heterocyclic blood levels at a particular dose,8-10 and steady-state TCA levels can vary widely in children receiving fixed daily doses of medication. ll Liver biotransformation of TCAs primarily involves oxidation, aromatic hydroxylation, and demethylation. Approximately 5% of the population are "slow hydroxylators" and will have significantly longer half-lives and higher plasma blood levels. 12 These are persons who metabolize TCAs slowly and may develop CNS side effects, which need to be differentiated from worsening of depression or ADHD.13 As severe cardiotoxicity and deaths have been reported,13 close monitoring of TCA blood levels is required.