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, fluoxetine, fluvoxamine, paroxetine, and sertraline and they differ from each other in chemical structure, by pharmacokinetic properties and, most importantly, with respect to enzyme-specific metabolism and interactions. Citalopram is administered as a racemic mixture. The drug is oxidated to desmethylcitalopram in the liver, partially by CYP2C19 and partially by CYP3A4. Fluoxetine is administered as a racemate of R- and S-fluoxetine. Both R- and S-fluoxetine are metabolized by CYP2D6 to the active metabolites R- and S-norfluoxetine. Fluvoxamine is metabolized to inactive metabolites by CYP1A2 and CYP2D6. Paroxetine is metabolized to inactive metabolites partially by CYP2D6, and accordingly the metabolism of paroxetine is dependent on the genetic polymorphism of CYP2D6. Sertraline is metabolized to desmethylsertraline, probably by CYP3A4. Several analytical methods have been described for all SSRIs. Most assays are based on separation by high-performance liquid chromatography or gas chromatography. Stereoselective methods for the analysis of racemic citalopram and fluoxetine have been published. The SSRIs are generally well tolerated and their therapeutic indices are large. In several studies there has not been found a clear relationship between clinical efficacy and plasma concentration, nor any threshold that defines toxic concentrations. The available data do not suggest that any benefit be obtained from routine monitoring of SSRI plasma levels. Therefore therapeutic drug monitoring (TDM) of the SSRIs may be useful mainly in situations where poor compliance is suspected and when therapeutic failure or toxic events are experienced at clinically relevant dosages. Further, in special populations, such as in elderly patients, poor metabolizers of sparteine (CYP2D6) or mephenytoin (CYP2C19), and patients with liver impairment, the measurement of plasma concentrations may be useful.