Therapeutic drug monitoring (TDM) is the quantification and interpretation of drug concentrations in blood to optimize pharmacotherapy. It considers the interindividual variability of pharmacokinetics and thus enables personalized pharmacotherapy. In psychiatry and neurology, patient populations that may particularly benefit from TDM are children and adolescents, pregnant women, elderly patients, individuals with intellectual disabilities, patients with substance abuse disorders, forensic psychiatric patients or patients with known or suspected pharmacokinetic abnormalities. Non-response at therapeutic doses, uncertain drug adherence, suboptimal tolerability, or pharmacokinetic drug-drug interactions are typical indications for TDM. However, the potential benefits of TDM to optimize pharmacotherapy can only be obtained if the method is adequately integrated in the clinical treatment process. To supply treating physicians and laboratories with valid information on TDM, the TDM task force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued their first guidelines for TDM in psychiatry in 2004. After an update in 2011, it was time for the next update. Following the new guidelines holds the potential to improve neuropsychopharmacotherapy, accelerate the recovery of many patients, and reduce health care costs.

Selective Serotonin Reuptake Inhibitors (SSRIs) are primary treatment options for major depressive and anxiety disorders. CYP2D6 and CYP2C19 polymorphisms can influence the metabolism of SSRIs thereby affecting drug efficacy and safety. We summarize evidence from the published literature supporting these associations and provide dosing recommendations for fluvoxamine, paroxetine, citalopram, escitalopram and sertraline based on CYP2D6 and/or CYP2C19 genotype (updates at www.pharmgkb.org).

than 5 decades [ 521 , 522 ] , growing evidence suggests that improving the way the available medications are administered may bring substantial benefi t to patients [ 45 ] . Evidence-based guidelines for optimum treatment have been published during the last decade [ 23 , 46 , 101 , 204 , 205 , 221 , 234 , 254 , 276 , 284 , 582 , 585 ,748]. A valuable tool for tailoring the dosage of the prescribed medication(s) to the individual characteristics of a patient is therapeutic drug monitoring (TDM). The major reason to use TDM for the guidance of psychopharmacotherapy is the Introduction ▼ In psychiatry, around 130 drugs are now available which have been detected and developed during the last 60 years [ 54 ] . These drugs are eff ective and essential for the treatment of many psychiatric disorders and symptoms. Despite enormous medical and economic benefi ts, however, therapeutic outcomes are still far from satis factory for many patients [ 5 , 6 , 396 , 661 ] . Therefore, after having focused clinical research on the development of new drugs during more Therefore the TDM consensus guidelines were updated and extended to 128 neuropsychiatric drugs. 4 levels of recommendation for using TDM were defi ned ranging from "strongly recommended" to "potentially useful". Evidence-based "therapeutic reference ranges" and "dose related reference ranges" were elaborated after an extensive literature search and a structured internal review process. A "laboratory alert level" was introduced, i. e., a plasma level at or above which the laboratory should immediately inform the treating physician. Supportive information such as cytochrome P450 substrateand inhibitor properties of medications, normal ranges of ratios of concentrations of drug metabolite to parent drug and recommendations for the interpretative services are given. Recommendations when to combine TDM with pharmacogenetic tests are also provided. Following the guidelines will help to improve the outcomes of psychopharmacotherapy of many patients especially in case of pharmacokinetic problems. Thereby, one should never forget that TDM is an interdisciplinary task that sometimes requires the respectful discussion of apparently discrepant data so that, ultimately, the patient can profi t from such a joint eff ort. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. considerable interindividual variability in the pharmacokinetic properties of the patient [ 524 , 526 ] . At the very same dose, a more than 20-fold interindividual variation in the medication's steady state concentration in the body may result, as patients diff er in their ability to absorb, distribute, metabolize and excrete drugs due to concurrent disease, age, concomitant medication or genetic peculiarities [ 61 , 94 , 310 , 311 , 334 , 335 , 374 ] . Diff erent formulations of the same medication may also infl uence the degree and temporal pattern of absorption and, hence, medication concentrations in the body. TDM uses the quantification of drug concent...

CYP2D6 and CYP2C19 polymorphisms affect the exposure, efficacy and safety of tricyclic antidepressants (TCAs), with some drugs being affected by CYP2D6 only (e.g., nortriptyline and desipramine) and others by both polymorphic enzymes (e.g., amitriptyline, clomipramine, doxepin, imipramine, and trimipramine). Evidence is presented for CYP2D6 and CYP2C19 genotype-directed dosing of TCAs. This document is an update to the 2012 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic Antidepressants.

nature publishing groupPolymorphisms in CYP2D6 and CYP2C19 affect the efficacy and safety of tricyclics, with some drugs being affected by CYP2D6 only, and others by both polymorphic enzymes. Amitriptyline, clomipramine, doxepin, imipramine, and trimipramine are demethylated by CYP2C19 to pharmacologically active metabolites. These drugs and their metabolites, along with desipramine and nortriptyline, undergo hydroxylation by CYP2D6 to less active metabolites. Evidence from published literature is presented for CYP2D6 and CYP2C19 genotype-directed dosing of tricyclic antidepressants.The use of tricyclics to treat psychological disorders has declined in part because of the occurrence of undesirable side effects. Although tricyclics are still used to treat depression, 1 their main therapeutic use is often for pain management. 2,3 Interindividual differences in side effects and treatment response have been associated with variability of tricyclic plasma concentrations. 4,5 Because both enzymes influence plasma concentrations, the effectiveness and tolerability of tricyclics are affected by CYP2D6 metabolism and partially by CYP2C19 metabolism. 4 The purpose of this guideline is to provide information regarding how to use existing CYP2D6 and/or CYP2C19 genotyping test results to guide dosing of tricyclics for psychological disorders and pain management, focusing particularly on amitriptyline and nortriptyline.Optimal therapeutic plasma concentrations for the tricyclics have been defined. 6 Poor or ultrarapid metabolizers of CYP2D6 and CYP2C19 may have tricyclic plasma concentrations outside the recommended therapeutic range, thereby increasing the risk of treatment failure or side effects. 7-10 Therefore, this guideline takes into consideration both clinical outcomes and observed tricyclic plasma concentrations based on genotype/phenotype characteristics. Detailed guidelines for use of other laboratory tests including therapeutic drug monitoring of tricyclics are beyond the scope of this article. The Clinical Pharmacogenetics Implementation Consortium (CPIC) of the National Institutes of Health's Pharmacogenomics Research Network develops peer-reviewed gene-drug guidelines that are published and updated periodically at http://www.pharmgkb.org based on new developments in the field. FOCUSED LITERATURE REVIEWA systematic literature review focused on CYP2D6 and CYP2C19 genotyping and its relevance to gene-based dosing of tricyclics was conducted (see Supplementary Data online). This guideline was developed based on interpretation of the literature by the authors and experts in the field. GENES: CYP2D6 AND CYP2C19 CYP2D6 backgroundThe CYP2D6 gene is highly polymorphic. 11 More than 100 known allelic variants and subvariants have been identified, and there are substantial ethnic differences in observed allele frequencies (Supplementary Data online). The most commonly reported CYP2C19 backgroundSimilar to CYP2D6, the CYP2C19 gene is highly polymorphic; more than 30 known allelic variants and subvariants have been identif...

We investigated whether morphine and its pro-drug codeine are substrates of the highly genetically polymorphic organic cation transporter OCT1 and whether OCT1 polymorphisms may affect morphine and codeine pharmacokinetics in humans. Morphine showed low transporter-independent membrane permeability (0.5 × 10⁻⁶ cm/s). Morphine uptake was increased up to 4-fold in HEK293 cells overexpressing human OCT1. The increase was concentration-dependent and followed Michaelis-Menten kinetics (KM = 3.4 μM, VMAX = 27 pmol/min/mg protein). OCT1-mediated morphine uptake was abolished by common loss-of-function polymorphisms in the OCT1 gene and was strongly inhibited by drug-drug interactions with irinotecan, verapamil and ondansetron. Morphine uptake in primary human hepatocytes was strongly reduced by MPP⁺, an inhibitor of organic cation transporters, and morphine was not a substrate of OCT3, the other organic cation transporter expressed in human hepatocytes. In concordance with the in vitro data, morphine plasma concentrations in healthy volunteers were significantly dependent on OCT1 polymorphisms. After codeine administration, the mean AUC of morphine was 56% higher in carriers of loss-of-function OCT1 polymorphisms compared to non-carriers (P = 0.005). The difference remained significant after adjustment for CYP2D6 genotype (P = 0.03). Codeine itself had high transporter-independent membrane permeability (8.2 × 10⁻⁶ cm/s). Codeine uptake in HEK293 cells was not affected by OCT1 overexpression and OCT1 polymorphisms did not affect codeine AUCs. In conclusion, OCT1 plays an important role in the hepatocellular uptake of morphine. Carriers of loss-of-function OCT1 polymorphisms may be at higher risk of adverse effects after codeine administration, especially if they are also ultra-rapid CYP2D6 metabolizers.

Despite scientific and clinical advances in the field of pharmacogenomics (PGx), application into routine care remains limited. Opportunely, several implementation studies and programs have been initiated over recent years. This article presents an overview of these studies and identifies current research gaps. Importantly, one such gap is the undetermined collective clinical utility of implementing a panel of PGx-markers into routine care, because the evidence base is currently limited to specific, individual drug-gene pairs. The Ubiquitous Pharmacogenomics (U-PGx) Consortium, which has been funded by the European Commission's Horizon-2020 program, aims to address this unmet need. In a prospective, block-randomized, controlled clinical study (PREemptive Pharmacogenomic testing for prevention of Adverse drug REactions [PREPARE]), pre-emptive genotyping of a panel of clinically relevant PGx-markers, for which guidelines are available, will be implemented across healthcare institutions in seven European countries. The impact on patient outcomes and cost-effectiveness will be investigated. The program is unique in its multicenter, multigene, multidrug, multi-ethnic, and multihealthcare system approach.

We investigated whether tramadol or its active metabolite, O-desmethyltramadol, are substrates of the organic cation transporter OCT1 and whether polymorphisms in OCT1 affect tramadol and O-desmethyltramadol pharmacokinetics. Tramadol showed high permeability through parallel artificial membrane permeability assays (PAMPAs). Tramadol uptake in HEK293 cells did not change after OCT1 overexpression, and the concentrations of tramadol in the plasma of healthy volunteers were independent of their OCT1 genotypes. In contrast, O-desmethyltramadol showed low membrane permeability, and OCT1 overexpression increased O-desmethyltramadol uptake 2.4-fold. This increase in uptake was reversed by OCT1 inhibitors and absent when loss-of-function OCT1 variants were overexpressed. Volunteers carrying loss-of-function OCT1 polymorphisms had significantly higher plasma concentrations of O-desmethyltramadol (P = 0.002, n = 41) and significantly prolonged miosis, a surrogate marker of opioidergic effects (P = 0.005, n = 24). In conclusion, polymorphisms in OCT1 influence the pharmacokinetics of O-desmethyltramadol, presumably by affecting its uptake into liver cells, and thus may modulate the efficacy of tramadol treatment.