The pharmacogenetics of the selective serotonin reuptake inhibitors

Citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline are selective serotonin reuptake inhibitors (SSRIs), which are thought to act as antidepressants through their ability to inhibit presynaptic serotonin reuptake in the brain. The elimination of the SSRIs proceeds predominantly via oxidation catalyzed by cytochrome P450 in the liver. Paroxetine and fluoxetine are potent inhibitors of cytochrome P4502D6 and hence may cause serious interactions with drugs metabolized by this isozyme, notably tricyclic antidepressants, some neuroleptics, and some antiarrhythmics. Citalopram, fluvoxamine and sertraline do not share this property. Fluvoxamine is the only SSRI that is a potent inhibitor of cytochrome P4501A2 and hence causes serious pharmacokinetic interactions with amitriptyline, clomipramine, imipramine, theophylline, and presumably caffeine and other drugs which are metabolized by the isozyme. Citalopram and fluoxetine are administered as racemates, but practically nothing is known about the stereoselective metabolism of the two drugs. Citalopram is partially metabolized via the mephenytoin oxidation polymorphism, and paroxetine is partially metabolized via the sparteine/debrisoquine oxidation polymorphism. The pharmacogenetic differences in the oxidation of the SSRIs themselves are probably of no clinical relevance.