In contrast to tricyclic antidepressants (TCAs), the selective serotonin reuptake inhibitors (SSRIs) have a high affinity for the serotonin uptake site with little or no affinity for α-adrenergic, cholinergic or histaminic receptors. SSRIs, again in contrast to TCAs, do not slow intracardiac conduction. These differences between TCAs and SSRIs are important in terms of both discomforting and more serious adverse effects. Despite their more focused effects, the SSRIs are as effective as TCAs in treating major depression. The SSRIs have similar properties in terms of their pharmacodynamics, but important differences in terms of pharmacokinetics and their effects on hepatic function. Sertraline, and the starting dose of paroxetine have an elimination half-life (t1/2) of approximately 24 h. However, the half-life of paroxetine, but not of sertraline, becomes longer at higher doses due to paroxetine's inhibition of its own clearance. A t1/2 of 24 h makes once-daily dosing feasible and allows for new steady-state concentrations and wash-out within a reasonable time after dose adjustment. Fluoxetine has a t1/2 of 2–4 days and has an active metabolite with a t1/2 of 7–15 days. Such a half-life makes dose titration more difficult, and can result in prolonged effects even after dose reduction or drug discontinuation. Sertraline has dose-proportional changes in plasma concentrations, in contrast to fluoxetine and paroxetine. Thus, dose increases with fluoxetine and paroxetine produce greater than expected changes in plasma drug concentration, and hence, in concentration-dependent effects. Both fluoxetine and paroxetine at their usually effective minimum dose can inhibit the hepatic isoenzyme CYP2D6, which is important in the oxidative metabolism of a variety of drugs. Fluoxetine also inhibits another hepatic isoenzyme, CYP3A4, which is also important in oxidative drug metabolism. Additional research is required to understand the differential effects of the various SSRIs on this and other hepatic isoenzymes. Currently, sertraline is notable for having few clinically meaningful drug interactions at its usually effective, minimum dose.