The newer antidepressants are a diverse group of compounds with distinct pharmacokinetic properties. The selective serotonin reuptake inhibitors (SSRIs)--paroxetine, sertraline, and fluvoxamine--have elimination half-lives of 15-26 hours. The extended half-life of fluoxetine (4-6 days) and its active metabolite, norfluoxetine (4-16 days), results in an extended time to steady-state and a prolonged washout period when dosing is discontinued. The SSRIs are administered as a single daily dose. Venlafaxine and nefazodone have short half-lives, 2-5 hours, and are dosed > or = 2 times daily. The newer antidepressants are all highly cleared from the body through hepatic metabolism. The biotransformation of all the drugs except paroxetine and fluvoxamine results in the formation of pharmacologically active metabolites. The newer antidepressants display a broad variability similar to the tricyclic antidepressants (TCAs) in steady-state drug concentrations. Due largely to a safer toxicity profile, the variability in clearance is of lesser importance with the newer antidepressants than with the TCAs. No useable concentration versus therapeutic effect relationship has been found with the newer drugs, and widely varying concentrations appear to have little relationship to adverse effects. Knowledge of kinetic characteristics is important for designing dosage regimens and avoiding potentially serious drug-drug interactions that are mediated through inhibition of specific hepatic cytochrome P450 enzyme pathways. Each of the SSRIs inhibits at least one cytochrome P450 enzyme, and all of the SSRIs increase serum concentrations of concomitantly administered TCAs.