Some aspects of genetic polymorphism in the biotransformation of antidepressants

Tricyclic antidepressants are all hydroxylated by cytochrome P450 (CYP) 2D6, but the tertiary amines, amitriptyline, clomipramine and imipramine, are also N-demethylated to the active metabolites, nortriptyline, N-desmethylclomipramine and desipramine, by several CYPs, including the polymorphic CYP2C19, CYP1A2 and CYP3A4. The five selective serotonin reuptake inhibitors, citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline are also oxidised by the CYP enzyme system. Thus, fluoxetine, fluvoxamine and paroxetine are partially metabolised by CYP2D6, citalopram by CYP2C19 and sertraline by at least five different CYPs. Paroxetine and fluoxetine are very potent inhibitors of CYP2D6 while citalopram, fluvoxamine and sertraline are moderate inhibitors of this enzyme. Fluvoxamine is a potent inhibitor of CYP1A2 and CYP2C19 and a moderate inhibitor of CYP2C9. Since the termination of the human genome project, there is no longer a technical hindrance to the identification of all of the genes involved in the clinical response to antidepressants. Research in the future will involve modern technologies and new scientific disciplines, including DNA-micro-array technology and bioinformatics. The research ultimately aims at developing better and safer antidepressants and/or better and safer use of currently available antidepressants.