J Lab Med 2014; aop Review Katharina M. Rentsch* An update on therapeutic drug monitoring and pharmacogenetic testing for the optimization of therapy with psychiatric medication DOI 10.1515/labmed-2014-0032 Keywords: antidepressants; antipsychotic drugs; cyto- Received September 28, 2013; accepted January 28, 2014 chrome; pharmacogenetics; psychiatric medication. Abstract: Therapeutic drug monitoring of psychiatric medication as well as pharmacogenetic testing is per- formed more and more frequently in numerous labora- Introduction tories. In this review, a summary of the literature in the years 2011 and 2012 has been completed. The guidelines The Therapeutic Drug Monitoring (TDM) of psychophar- of the German AGNP (Association for Neuropsychop- maceutical drugs is carried out in numerous laboratories harmacology and Pharmacopsychiatry) contain all the to an ever more frequent extent, as are pharmacogenetic information needed for the interpretation of drug concen- studies. Based on numerous studies that have shown that trations. The determination of serotonin in urine could pharmacogenetic polymorphisms, among other factors, be a marker for the assessment of the response of antide- cause large inter-individual differences in the pharma- pressants, and correlations between the occupancy of the cokinetics of psychopharmaceutical drugs, doctors who target receptors in the brain and drug concentration have prescribe such drugs increasingly order TDM tests. As part been established using positron emission tomography. of the diagnostics updates 2013 [1] a compilation of the The influence of age on drug concentrations has been literature on the above topics published in 2011 and 2012 controversially described, and additionally females have was prepared, and the individual papers and studies were always showed a slower metabolism and higher serum evaluated. This review article is based on this literature concentrations. Several liquid chromatography-mass compilation. spectrometry (LC-MS)/MS multi-analyte procedures for the quantification of psychiatric medication have been described. All methods showed good validation data, but there have always been some compounds with less good Basis for the therapeutic drug moni- validation results due to the fact that not all compounds toring of psychopharmaceutical of a multi-analyte procedure can be analyzed optimally. Pharmacogenetic testing is not routinely performed drugs prior to the prescription of psychiatric medication. This The Association for Neuropsychopharmacology and Phar- relies, among other things, on missing large randomized macopsychiatry (AGNP) published an update of its con- trials and the absence of standardized analytical meth- sensus guidelines on TDM in psychiatry at the end of 2011 ods, which allow the identification of the whole genetic [2]. These guidelines contained recommendations for all variability. steps of TDM with respect to psychoactive substances. The guidelines defined the term “therapeutic ref- erence range”. When falling below the lower limit, a response to treatment is improbable, and when the upper *Corresponding author: Katharina M. Rentsch, Clinical Chemistry, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland, limit is exceeded, any further therapeutic improvement Phone: +0041-61-265-42-36, Fax: +0041-61-265-53-33, E-Mail: becomes impossible. In addition, warning limits were [email protected] specified for laboratories, above which the doctor should 2 Rentsch: TDM and pharmacogenetic testing of psychopharmaceutical drugs be informed immediately that an overdose has occurred. before the next dose). Any order should always contain It was further specified for all drugs described whether information on the patient, the diagnosis, medication therapeutic drug monitoring was highly recommended, and therapeutic outcome. Laboratories should use a recommended, useful or maybe useful. The “highly rec- validated method for analysis, which is used to conduct ommended” category was set aside for all drugs for which both internal and external quality checks. The findings controlled clinical studies had demonstrated beneficial report should list the concentration of the drug (and any effects of TDM. In case of a sub- or supertherapeutic level, active metabolites), the unit, a reference range, as well as the dose should be adjusted until it is within the therapeu- an interpretation of the results. The ordering physician tic reference range again. The concentrations for drugs in should then incorporate the results into the further treat- the “recommended” category were arrived at by way of ment of the patient. If necessary, the dose may be adjusted plasma concentration measurements in connection with or the medication may be changed. Finally, recommenda- therapeutic doses of the drugs that were assigned to clini- tions on and help with interpretation were provided, as cal effects. The “useful” category contained therapeutic well as recommendations regarding the combination of reference ranges where drug concentrations were derived TDM with pharmacokinetic tests [2]. from pharmacokinetic studies. The “maybe useful” cat- These guidelines represent an extensive and widely- egory, finally, listed the drugs for which plasma concen- covered compilation of the literature published on this trations did not correlate with the clinical effects due to broad topic. They should be read by every laboratory the unique pharmacological effect of the drug or for which that analyzes psychopharmaceutical drugs and by every the dose could be clearly derived from clinical symptoms doctor ordering such analyses, and become part of clinical (e.g., sedatives inducing sleep) [2]. daily routine. In the case of psychopharmaceutical drugs, the drug concentration should be determined at the start of therapy or at the time of dose modifications if the therapeutic ref- erence range is well defined or if the therapeutic index Pharmacokinetic parameters of psy- is narrow. In the event of suspected non-compliance, a chopharmaceutical drugs determination of all psychopharmaceutical drugs may be useful, regardless of the recommendations for TDM. This The article by Patteet et al. [3] contains a compilation is also true if the therapeutic effect is absent. If the drug of the most important pharmacokinetic parameters of concentration is within the therapeutic reference range in common antipsychotics, which are necessary for the such a situation, a different treatment should be consid- determination of drug concentrations and also the inter- ered. In the presence of adverse drug reactions, a deter- pretation. The effect of the first-generation antipsychot- mination of the drug concentration can show whether ics was traced back mainly to the strong antagonism of the dose is too high and should be reduced. If a patient the dopamine D2 receptor. An antipsychotic effect was requires various drugs that are metabolized by the same achieved with an occupancy of the D2 receptor in the stri- cytochrome enzymes, interactions in terms of induction atum of 65%–70%; with an occupancy of > 80%, the risk or inhibition of the metabolism can occur relative to the of extrapyramidal side effects (EPS) increased. Thus, the individual drugs prescribed. If one of the drugs involved therapeutic window with a minimal risk of EPS was at a D2 affects the metabolism of another drug, the concentra- occupancy of between 65% and 80%. The second-genera- tion of the affected drug should be analyzed in order to tion antipsychotics were different mainly due to the block- detect levels of the active ingredient that are either too ing of various dopamine or serotonergic receptors (with high or too low. The working group of AGNP recommends the exception of amisulpride and sulpiride). Here, too, an that the drug concentration should be determined every occupancy of the dopamine receptors of between 65% and 3–6 months in connection with long-term psychophar- 80% resulted in therapeutic success without adverse side maceutical treatment to prevent a recurrence. Apart from effects of the drug. Clozapine was given as an exception, that, TDM should be performed for special patient groups, where a receptor occupancy of as little as 30%–40% was such as pregnant women, children and adolescents or associated with a therapeutic effect (Table 1). older patients [2]. According to the authors [3], the psychotic symptoms AGNP recommended TDM as routine monitoring change after the initiation of treatment with antipsychot- according to the above indications and also when specific ics only slowly. If there has been no improvement after 1–4 problems occur. Blood samples should always be taken weeks from the start of therapy, an increased dose or a as steady-state trough concentrations (i.e., immediately change of drug will have to be considered. Antipsychotics Rentsch: TDM and pharmacogenetic testing of psychopharmaceutical drugs 3 Table 1 Main pharmacokinetic parameters of antipsychotics (adapted from [3]). Antipsychotic Therapeutic range, ng/mL Protein binding, % Half-life, h Bioavailability, % Amisulpride 100–320 17 12–20 48 Aripiprazole 150–500 > 99 60–80 87 Asenapine 2–5 – 24 35 Bromperidol 12–15 90 20–36 30 Clozapine 350–600 95 12–16 24–50 Flupentixol 1–10 99 20–40 40 Haloperidol 1–10 90 12–36 60–70 Iloperidone 5–10 93 18–33 96 Lurasidone – > 99 12–37 9–19 Olanzapine 20–80 93 30–60 60 Paliperidone 20–60 74 23 28 Perphenazine 0.6–2.4 – 8–12 60–80 Pimozide 15–20 – 23–43 50 Pipamperone 100–400 – 17–22 – Quetiapine 100–500 83 7 70 Risperidone