Is therapeutic drug monitoring a case for optimizing clinical outcome and avoiding interactions of the selective serotonin reuptake inhibitors?

The selective serotonin reuptake inhibitors (SSRIs) comprise citalopram, fl uoxetine, fluvoxamine, paroxetine, and sertraline and they differ from each other in chemical structure, by pharmacokinetic properties and, most impor tantly, with respect to enzyme-specific metabolism and interactions. Citalo pram is administered as a racemic mixture. The drug is oxidated to desmethy lcitalopram in the liver, partially by CYP2C19 and partially by CYP3A4. Flu oxetine is administered as a racemate of Rand S-fluoxetine. Both R- and S-f luoxetine are metabolized by CYP2D6 to the active metabolites R- and S-norf luoxetine. Fluvoxamine is metabolized to inactive metabolites by CYP1A2 and CYP2D6. Paroxetine is metabolized to inactive metabolites partially by CYP 2D6, and accordingly the metabolism of paroxetine is dependent on the genet ic polymorphism of CYP2D6. Sertraline is metabolized to desmethylsertraline , probably by CYP3A4. Several analytical methods have been described for al l SSRIs. Most assays are based on separation by high-performance liquid chr omatography or gas chromatography. Stereoselective methods for the analysis of racemic citalopram and fluoxetine have been published. The SSRIs are ge nerally well tolerated and their therapeutic indices are large. In several studies there has not been found a clear relationship between clinical effi cacy and plasma concentration, nor any threshold that defines toxic concent rations. The available data do not suggest that any benefit be obtained fro m routine monitoring of SSRI plasma levels. Therefore therapeutic drug moni toring (TDM) of the SSRIs may be useful mainly in situations where poor com pliance is suspected and when therapeutic failure or toxic events are exper ienced at clinically relevant dosages. Further, in special populations, suc h as in elderly patients, poor metabolizers of sparteine (CYP2D6) or mephen ytoin (CYP2C19), and patients with liver impairment, the measurement of pla sma concentrations may be useful.