AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Psychiatry: Update 2011
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Review 195 AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Psychiatry: Update 2011 Authors C. Hiemke 1 , P. Baumann 2 , N. Bergemann3 , A. Conca 4 , O. Dietmaier 5 , K. Egberts 6 , M. Fric 7 , M. Gerlach 6 , C. Greiner 8 , G. Gründer 9 , E. Haen 10 , U. Havemann-Reinecke 11 , E. Jaquenoud Sirot 12 , H. Kirchherr 13 , G. Laux 7 , U. C. Lutz 14 , T. Messer 15 , M. J. Müller 16 , B. Pfuhlmann 17 , B. Rambeck 18 , P. Riederer 17 , B. Schoppek 19 , J. Stingl 20 , M. Uhr 21 , S. Ulrich 22 , R. Waschgler 23 , G. Zernig 24 Affi liations Affi liation addresses are listed at the end of the article Key words Abstract cologic agents have been introduced that are also ● ▶ consensus guidelines ▼ candidates for TDM. Therefore the TDM consen- ● ▶ drug analysis Therapeutic drug monitoring (TDM), i. e., the sus guidelines were updated and extended to 128 ▶ ● pharmacokinetics quantifi cation of serum or plasma concentra- neuropsychiatric drugs. 4 levels of recommenda- ● ▶ psychotropic drugs tions of medications for dose optimization, has tion for using TDM were defi ned ranging from ● ▶ reference ranges ● ▶ therapeutic drug monitoring proven a valuable tool for the patient-matched “strongly recommended” to “potentially useful”. ● ▶ therapeutic window psychopharmacotherapy. Uncertain drug adher- Evidence-based “therapeutic reference ranges” ence, suboptimal tolerability, non-response at and “dose related reference ranges” were elabo- therapeutic doses, or pharmacokinetic drug-drug rated after an extensive literature search and a interactions are typical situations when meas- structured internal review process. A “laboratory urement of medication concentrations is help- alert level” was introduced, i. e., a plasma level at ful. Patient populations that may predominantly or above which the laboratory should immedi- benefi t from TDM in psychiatry are children, ately inform the treating physician. Supportive pregnant women, elderly patients, individuals information such as cytochrome P450 substrate- with intelligence disabilities, forensic patients, and inhibitor properties of medications, nor- patients with known or suspected genetically mal ranges of ratios of concentrations of drug determined pharmacokinetic abnormalities or metabolite to parent drug and recommendations individuals with pharmacokinetically relevant for the interpretative services are given. Recom- comorbidities. However, the potential benefi ts mendations when to combine TDM with phar- of TDM for optimization of pharmacotherapy macogenetic tests are also provided. Following can only be obtained if the method is adequately the guidelines will help to improve the outcomes integrated into the clinical treatment process. To of psychopharmacotherapy of many patients promote an appropriate use of TDM, the TDM especially in case of pharmacokinetic problems. expert group of the Arbeitsgemeinschaft für Thereby, one should never forget that TDM is an Bibliography Neuropsychopharmakologie und Pharmakopsy- interdisciplinary task that sometimes requires DOI http://dx.doi.org/ chiatrie (AGNP) issued guidelines for TDM in the respectful discussion of apparently discrep- 10.1055/s-0031-1286287 psychiatry in 2004. Since then, knowledge has ant data so that, ultimately, the patient can profi t This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Pharmacopsychiatry 2011; advanced signifi cantly, and new psychopharma- from such a joint eff ort. 44: 195–235 © Georg Thieme Verlag KG Stuttgart · New York than 5 decades [ 521 , 522 ] , growing evidence sug- ISSN 0176-3679 Introduction ▼ gests that improving the way the available medi- Correspondence In psychiatry, around 130 drugs are now availa- cations are administered may bring substantial C. Hiemke, PhD, Univ.-Prof. ble which have been detected and developed benefi t to patients [ 45 ] . Evidence-based guidelines Department of Psychiatry and during the last 60 years [ 54 ] . These drugs are for optimum treatment have been published dur- Psychotherapy eff ective and essential for the treatment of many ing the last decade [ 23 , 46 , 101 , 204 , 205 , 221 , 234 , University Medical Center, psychiatric disorders and symptoms. Despite 254 , 276 , 284 , 582 , 585 ,748]. Mainz enormous medical and economic benefi ts, how- A valuable tool for tailoring the dosage of the D-55101 Mainz ever, therapeutic outcomes are still far from prescribed medication(s) to the individual char- Germany Tel.: +49/6131/177 131 satis factory for many patients [ 5 , 6 , 396 , 661 ] . acteristics of a patient is therapeutic drug moni- Fax: +49/6131/176 789 Therefore, after having focused clinical research toring (TDM). The major reason to use TDM for [email protected] on the development of new drugs during more the guidance of psychopharmacotherapy is the Hiemke C et al. AGNP Consensus Guidelines for … Pharmacopsychiatry 2011; 44: 195–235 196 Review considerable interindividual variability in the pharmacokinetic aspects of monitoring drug plasma concentrations. The second properties of the patient [ 524 , 526 ] . At the very same dose, a part defi nes indications for TDM and gives reference drug plasma more than 20-fold interindividual variation in the medication’s concentrations for dose optimization. The third part describes steady state concentration in the body may result, as patients the best practice of the process of TDM, which starts with the diff er in their ability to absorb, distribute, metabolize and request and ends with the clinical decision to either continue or excrete drugs due to concurrent disease, age, concomitant medi- change the pre-TDM pharmacotherapy. cation or genetic peculiarities [ 61 , 94 , 310 , 311 , 334 , 335 , 374 ] . Aiming to optimise the practice of TDM the following topics Diff erent formulations of the same medication may also infl u- were addressed: ence the degree and temporal pattern of absorption and, hence, ▶ d e fi nition of indications to utilize TDM in psychiatry medication concentrations in the body. TDM uses the quantifi - ▶ d e fi nition of graded levels of recommendations to use TDM cation of drug concentrations in blood plasma or serum to titrate ▶ d e fi nition of therapeutic reference ranges (“therapeutic win- the dose of individual patients so that a drug concentration dows”) and dose-related reference ranges that laboratories associated with highest possible probability of response and can quote and clinicians can use to guide the psychopharma- tolerability and a low risk of toxicity can be obtained. Moreover, cotherapy TDM has the possible and widely unexploited potential to ▶ d e fi nition of alert levels for laboratories to warn the treating improve cost-eff ectiveness of psychopharmacotherapy [ 527 , 660 ] . physician when plasma concentrations are considered to be For a considerable number of psychopharmacologic compounds, too high and potentially harmful the quantifi cation of the medications’ plasma concentration has ▶ recommendations and help for interpretative services become clinical routine for dose adjustment. Clear evidence of ▶ recommendations concerning the combination of TDM with the benefi ts of TDM has been given for tricyclic antidepressants, pharmacogenetic tests a number of old and new antipsychotic drugs and for conven- tional mood stabilizing drugs [ 51 , 459 , 505 ] . For lithium, TDM has become a standard of care due to its narrow therapeutic Preparation of the Consensus Document range [ 133 , 395 ] . ▼ The benefi ts of TDM regarding the optimization of pharmaco- The updated consensus guidelines were prepared by the inter- therapy, however, can only be obtained if the method is ade- disciplinary TDM group of the AGNP consisting of clinical psy- quately integrated into the clinical treatment process. Current chiatrists, pharmacologists, biochemists, pharmacists and TDM use in psychiatric care is obviously suboptimal chemists from academic and non academic hospitals and insti- [ 134 , 700 , 742 ] . Similar to other medical disciplines, systematic tutions of Germany, Switzerland, Austria and Italy, who have studies have demonstrated that the inappropiate use of TDM is been involved for many years in the development and imple- widespread. Inappropriate TDM testing wastes laboratory mentation of TDM for psychotropic medications in everyday resources and also bears the risk that misleading results will clinical practice. The experts compiled information from the lit- adversely infl uence clinical decision making [ 122 ] . A study on erature and worked out the present best practice guidelines the clinical use of TDM for tricyclic antidepressants in psychiat- aiming at promoting the appropriate use of TDM in psychiatry. ric university hospital settings showed that between 25 and 40 % Because TDM is widely used in daily clinical practice for antide- of the requests for TDM were inappropriate and the interpreta- pressant, antipsychotic and mood stabilizing drugs, these 3 tion of the results led to about 20 % of inappropriate therapeutic pharmacologic classes are extensively represented in the present adjustments [ 700 , 742 ] . Other typical errors were absence of guidelines. Anxiolytic and hypnotic drugs, antidementia drugs, steady-state conditions and transcription errors on the request drugs for treatment of substance abuse related disorders and form [ 700,743 ] . Studies on TDM for antidepressant and mood other psychotropic drugs are also candidates for TDM and are stabilizing drugs further specifi ed the information on the inap- thus covered in the present guidelines.