Simultaneous Analysis of Fluoxetine, Norfluoxetine, Citalopram, and Haloperidol in Plasma by LC–ESI-IT-MS Abdul-Wahab El-Rjoob 1 , Munther Tahtamouni 2 , Yahya R. Tahboub 1,2,& 1 Department of Applied Chemistry, Jordan University of Science and Technology, Irbid 22110, Jordan 2 Princess Haya Center of Biotechnology, Jordan University of Science and Technology, Irbid 22110, Jordan; E-Mail: tahboub@just.edu.jo Received: 31 March 2009 / Revised: 7 September 2009 / Accepted: 11 December 2009 Online publication: 30 January 2010 Abstract A reliable and simple method has been developed for simultaneous analysis of fluoxetine, its metabolite norfluoxetine, citalopram, and haloperidol with lamotrigine as internal standard. The method is based on solid-phase extraction on mixed-mode cation-exchange cartridges followed by LC separation on a C 18 column at ambient temperature with a gradient prepared from acetonitrile and 5 mM ammonium acetate in 0.1% (v/v) aqueous formic acid. The flow rate was 0.5 mL min -1 . Eluted compounds were ionized by the electrospray ionization ion source of an ion-trap mass spectrometer and were detected by selected ion monitoring. Co-extracted endogenous compounds from plasma were eluted in the first 5 min and discarded by valve-switching. The target drugs were eluted in the period 5.5–11 min. Calibration plots were linear in the ranges 5 (or 10)–400 ng mL -1 with correlation coefficients >0.999. Other statistical and validation results were within accepted ranges for clinical analysis. Keywords Column liquid chromatography–mass spectrometry Fluoxetine Norfluoxetine Citalopram Haloperidol Introduction Depression is a widespread disease especially in developed countries [1]. Depression requires long-term treat- ment, usually for the patient’s entire life, with antidepressant drugs (ADDs). Therapeutic drug monitoring (TDM) is used to optimize the therapeutic effects of ADDs while minimizing side effects. Quantitative analysis of ADDs in bio- logical fluids is an important way of facilitating individualization of dosage [2]. There is evidence of therapeutic and economic benefits of monitoring these drugs to avoid adverse events, intoxica- tion, lack of response, or noncompli- ance. The drugs fluoxetine, its metabolite norfluoxetine, and citalopram (Fig. 1) are selective serotonin reuptake inhibi- tors (SSRIs) which have recently been introduced in addition to other SSRIs, for example fluvoxamine, paroxetine, and sertraline. Although no therapeutic window has been defined for SSRIs, in contrast with tricyclic antidepressants, analytical methods for therapeutic monitoring of SSRIs are useful in several instances. SSRIs differ widely in their chemical structure and metabolism. Be- cause some SSRIs have N-demethylated metabolites, which are also SSRIs, methods must be available which enable therapeutic monitoring of both the par- ent compounds and the active metabo- lites [3]. Haloperidol (Fig. 1) is still one of the most widely used antipsychotic drugs in the treatment of schizophrenic and other psychiatric disorders. Al- though reduced haloperidol has little effect as a dopamine D2 antagonist, an animal study suggests that reduced hal- operidol acts as a potent inhibitor of 2010, 71, 423–430 DOI: 10.1365/s10337-010-1483-3 0009-5893/10/03 Ó 2010 Vieweg+Teubner | GWV Fachverlage GmbH Original Chromatographia 2010, 71, March (No. 5/6) 423