Relevant issues in the monitoring and the toxicology of antidepressants.

This review provides specific information concerning the interpretation and usefulness of antidepressant drug monitoring. Fifteen antidepressants (ADs) were selected based on their importance in the 7 major markets (Japan, USA, France, United Kingdom, Italy, Spain, Germany) according to the Cognos Plus Study #11. Literature data were reviewed concerning monitoring of the tricyclic ADs amitriptyline, clomipramine, imipramine, and new generation antidepressants such as citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine, mianserin, mirtazapine, bupropion, and milnacipran. In addition, St.-John's Wort was added as this natural antidepressant is very popular in Europe. The objectives of therapeutic drug monitoring (TDM) for old and new generation ADs differs, as older ADs have narrow therapeutic windows with higher risks of severe drug interactions, while the new ADs have a wide therapeutic range, but an unclear plasma concentration-effect relationship. Therefore, the purpose of TDM for new-generation ADs leads more to the monitoring of patient compliance and special patient groups such as the elderly, patients with liver and kidney impairment, patients with poor metabolism by CYP 450 and comedication with inhibitors and inducers of those enzymes.

Comparison of electron and chemical ionization modes by validation of a quantitative gas chromatographic-mass spectrometric assay of new generation antidepressants and their active metabolites in plasma.

A gas chromatographic-mass spectrometric method (GC-MS) for the simultaneous determination of the 'new' antidepressants (mirtazapine, viloxazine, venlafaxine, trazodone, citalopram, mianserin, reboxetine, fluoxetine, fluvoxamine, sertraline, maprotiline, melitracen, paroxetine) and their active metabolites (desmethylmirtazapine, O-desmethylvenlafaxine, m-chlorophenylpiperazine, desmethylcitalopram, didesmethylcitalopram, desmethylmianserin, desmethylfluoxetine, desmethylsertraline, desmethylmaprotiline) in plasma using different ionization modes was developed and validated. Sample preparation consisted of a strong cation exchange mechanism and derivatisation with heptafluorobutyrylimidazole. The GC separation was performed in 24.8 min. Identification and quantification were based on selected ion monitoring in electron (EI) and chemical ionization (CI) modes. Calibration by linear and quadratic regression for electron and chemical ionization, respectively, utilized deuterated internal standards and a weighing factor 1/x(2). Limits of quantitation were established between 5 and 12.5 ng/ml in EI and positive ionization CI (PICI), and 1 and 6.25 ng/ml in negative ionization CI (NICI). During validation stability, sensitivity, precision, accuracy, recovery, and selectivity were evaluated for each ionization mode and were demonstrated to be acceptable for most compounds. While it is clear that not all compounds can be quantitated either due to chromatographic (trazodone) or derivatisation problems (O-desmethylvenlafaxine), this method can quantitate most new antidepressants (ADs) in the therapeutic range using EI. PICI and NICI lead to higher selectivity. Moreover, NICI is of interest for small sample volumes and high sensitivity requirements. This paper draws the attention to the pros and cons of the different ionization modes in the GC-MS analysis of these antidepressants in plasma.

Therapeutic drug monitoring of old and newer anti-epileptic drugs.

The aim of the present paper is to provide information concerning the setting up and interpretation of therapeutic drug monitoring (TDM) for anti-epileptic drugs. The potential value of TDM for these drugs (including carbamazepine, clobazam, clonazepam, ethosuximide, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pheneturide, phenobarbital, phenytoin, primidone, tiagabine, topiramate, valproic acid, vigabatrin and zonisamide) is discussed in relation to their mode of action, drug interactions and their pharmacokinetic properties. The review is based upon available literature data and on observations from our clinical practice. Up until approximately 15 years ago anti-epileptic therapeutics were restricted to a very few drugs that were developed in the first half of the 20th century. Unfortunately, many patients were refractory to these drugs and a new generation of drugs has been developed, mostly as add-on therapy. Although the efficacy of the newer drugs is no better, there is an apparent improvement in drug tolerance, combined with a diminished potential for adverse drug interactions. All new anticonvulsant drugs have undergone extensive clinical studies, but information on the relationship between plasma concentrations and effects is scarce for many of these drugs. Wide ranges in concentrations have been published for seizure control and toxicity. Few studies have been undertaken to establish the concentration-effect relationship. This review shows that TDM may be helpful for a number of these newer drugs.