Clinically significant interactions with antidepressants

Depression is one of the most frequent and severe mental disorders, and concurrent medical conditions commonly coexist in depressed patients. This presents numerous potentials for interactions between antidepressants and other nonpsychotropics prescribed for the same patient. Many selective serotonin reuptake inhibitors and selective serotonin and norepinephrine reuptake inhibitors possess various extent of inhibition towards different cytochrome P-450 isoenzymes, which constitute the primary mechanism of reported antidepressant drug interactions in the literature. Most of the antidepressants are also metabolized by the cytochrome P-450 enzyme system. As such, modulation of their hepatic elimination can occur with concurrently administered substrates, inhibitors, or inducers of the same cytochrome P-450 isoenzyme. In addition, the basal enzyme activity and genetic polymorphism affecting specific cytochrome P-450 isoenzyme can affect the magnitude and clinical significance of the cytochrome P-450-mediated drugantidepressant interaction. In addition to drug-metabolizing enzymes, uptake and efflux drug transporters that are present at many biological membranes, including the blood-brain barrier, the intestinal epithelial cells, the hepatocytes, and the renal tubular cells, can also affect systemic exposure and central nervous system penetration of most antidepressants, and hence pharmacological response. Although cytochrome P-450- mediated drug interactions still constitute the majority of the reported literature data, more recent studies have focused on these drug transporters in mediating drug interactions, including the antidepressants. In contrast to pharmacokinetic interactions, pharmacodynamic drug interactions involving the antidepressants mostly are derived from case reports and less well documented. Nevertheless, the more relevant and clinically significant pharmacodynamic interactions will also be reviewed.