Antidepressant-drug interactions are potentially but rarely clinically significant

The salient pharmacologic features of the selective serotonin reuptake inhibitors (SSRIs) discovered in the late 1980s included an in vitro ability to inhibit various Cytochrome P450 enzymes (CYPs). Differences in potency among the SSRIs for CYP inhibition formed the basis of a marketing focus based largely on predictions of in vivo pharmacokinetic drug interactions from in vitro data, conclusions derived from case reports, and the extrapolation of the results of pharmacokinetic studies conducted in healthy volunteers to patients. Subsequently introduced antidepressants have undergone a similar post hoc scrutiny for potential drug-drug interactions. Concern for the untoward consequences of drug interactions led the FDA to publish guidance for the pharmaceutical industry in 1997 recommending that in vitro metabolic studies be conducted early in the drug development process to evaluate inhibitory properties toward the major CYPs. However, the prevalence of clinically significant Enzyme inhibition interactions occurring during antidepressant treatment remains poorly defined despite millions of exposures. Although lack of evidence does not equate to evidence of absence, sparse epidemiological and post-marketing surveillance data do not substantiate a conclusion that widespread morbidity results from antidepressant-induced drug interactions. This commentary discusses points of uncertainty and controversy in the field of drug interactions, notes areas where inadequate data exist, and suggests explanations for a low prevalence of serious interactions. The conclusion is drawn that drug interactions from CYP inhibition caused by the newer antidepressants are potentially, but rarely, clinically significant.