The electrospray ionisation ion trap tandem mass spectrometry (ESI-MSn) of selected antidepressant drugs, i.e., citalopram, fluoxetine, mirtazapine, paroxetine, sertraline, and venlafaxine, has been investigated. Sequential product ion fragmentation experiments (MSn) have been performed in order to elucidate the degradation pathways for the [M+H](+) ions and their predominant product ions. These MSn experiments show certain characteristic fragmentations in that functional groups are generally cleaved from the ring systems as molecules such as H2O, amines and phenols. When an aromatic entity is present in a drug molecule together with a nitrogen-containing saturated ring structure as with mirtazapine, fragmentation initially occurs at the latter ring with the former being predictably resistant to fragmentation. Also, when an amine-containing drug molecule such as fluoxetine also contains a functional group, which liberates a phenol with a significantly lower Delta H-f(0) value than that of the corresponding amine, the phenol is preferentially liberated. The structures of product ions proposed for ESI-MSn can be supported by electrospray ionisation quadrupole-time-of-flight tandem mass spectrometry (ESI-QToF-MS/MS). These molecules can be identified and determined in mixtures at low ng/mL concentrations by the application of high-performance liquid chromatography/electrospray ionisation tandem mass spectrometry (HPLC/ESI-MS2), which can also be used for their analysis in hair samples. Copyright (c) 2006 John Wiley & Sons, Ltd.