Background: The second-generation antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and other compounds with different mechanisms of action. All second-generation antidepressants are metabolized in the liver by the cytochrome P450 (CYP) enzyme system. Concomitant intake of inhibitors or inducers of the CYP isozymes involved in the biotransformation of specific antidepressants may alter plasma concentrations of these agents, although this effect is unlikely to be associated with clinically relevant interactions. Rather, concern about drug interactions with second-generation antidepressants is based on their in vitro potential to inhibit > or = 1 CYP isozyme.

Objective: The goal of this article was to review the current literature on clinically relevant pharmacokinetic drug interactions with second-generation antidepressants.

Methods: A search of MEDLINE and EMBASE was conducted for original research and review articles published in English between January 1985 and February 2008. Among the search terms were drug interactions, second-generation antidepressants, newer antidepressants, SSRIs, SNRIs, fluoxetine, paroxetine, fluvoxamine, sertraline, citalopram, escitalopram, venlafaxine, duloxetine, mirtazapine, reboxetine, bupropion, nefazodone, pharmacokinetics, drug metabolism, and cytochrome P450. Only articles published in peer-reviewed journals were included, and meeting abstracts were excluded. The reference lists of relevant articles were hand-searched for additional publications.

Results: Second-generation antidepressants differ in their potential for pharmacokinetic drug interactions. Fluoxetine and paroxetine are potent inhibitors of CYP2D6, fluvoxamine markedly inhibits CYP1A2 and CYP2C19, and nefazodone is a substantial inhibitor of CYP3A4. Therefore, clinically relevant interactions may be expected when these antidepressants are coadministered with substrates of the pertinent isozymes, particularly those with a narrow therapeutic index. Duloxetine and bupropion are moderate inhibitors of CYP2D6, and sertraline may cause significant inhibition of this isoform, but only at high doses. Citalopram, escitalopram, venlafaxine, mirtazapine, and reboxetine are weak or negligible inhibitors of CYP isozymes in vitro and are less likely than other second-generation antidepressants to interact with co-administered medications.

Conclusions: Second-generation antidepressants are not equivalent in their potential for pharmacokinetic drug interactions. Although interactions may be predictable in specific circumstances, use of an antidepressant with a more favorable drug-interaction profile may be justified.