New antidepressants and the cytochrome P450 system: focus on venlafaxine, nefazodone, and mirtazapine

Abstract

Objective: This review critically evaluates recent information on the cytochrome P450 system, with an emphasis on drug interactions involving antidepressant medications, particularly venlafaxine, nefazodone, and mirtazapine.

Methods: International literature on the cytochrome P450 system and related drug interactions from 1995-1997 were critically examined.

Results: Venlafaxine, nefazodone, and mirtazapine have different effects on the cytochrome P450 system. In vitro, venlafaxine is a weaker CYP2D6 inhibitor than most of the selective serotonin reuptake inhibitors (SSRIs) by a factor of 1-3 orders of magnitude. In vivo drug interaction studies generally confirm in vitro results. However, some exceptions exist. The clinical significance of such interactions remains unknown. Venlafaxine had minimal or no demonstratable inhibition of CYP1A2, CYP3A4, or CYP2C. Nefazodone is a potent inhibitor of CYP3A4 and is therefore absolutely contraindicated with concurrent administration of terfenadine, astemizole, and cisapride. It is a weak inhibitor of CYP1A2, 3A4, and 2D6. A metabolite of nefazodone, mCPP, is a weak and probably clinically insignificant inhibitor of CYP2D6. Mirtazapine has minimal inhibitory effects on CYP1A2, CYP3A4, and CYP2D6 in vitro. Little is known about its interactions with other drugs.

Conclusions: With the addition of the latest antidepressant medications, the clinician may now choose antidepressants with little liability for drug-drug interactions. Venlafaxine and mirtazapine are associated with a lower risk of clinically significant drug interactions than SSRIs. Nefazodone is a potent inhibitor of CYP3A4 and therefore may not be suitable for all patient populations. It is, however, a much weaker CYP2D6 inhibitor than the SSRIs. More studies are needed to assess more accurately and precisely the risk of such untoward drug-drug interactions with these novel antidepressants, particularly in more diverse ethnic patient populations.