Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017.

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.

Gene expression and proliferation biomarkers for antidepressant treatment resistance.

The neurotrophic hypothesis of depression suggests an association between effects on neuroplasticity and clinical response to antidepressant drug therapy. We studied individual variability in antidepressant drug effects on cell proliferation in lymphoblastoid cell lines (LCLs) from n=25 therapy-resistant patients versus n=25 first-line therapy responders from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Furthermore, the variability in gene expression of genes associated with cell proliferation was analyzed for tentative candidate genes for prediction of individual LCL donor's treatment response. Cell proliferation was quantified by EdU (5-ethynyl-2'-deoxyuridine) assays after 21-day incubation of LCLs with fluoxetine (0.5 ng µl-1) and citalopram (0.3 ng µl-1) as developed and described earlier. Gene expression of a panel of candidate genes derived from genome-wide expression analyses of antidepressant effects on cell proliferation of LCLs from the Munich Antidepressant Response Signature (MARS) study was analyzed by real-time PCR. Significant differences in in vitro cell proliferation effects were detected between the group of LCLs from first-line therapy responders and LCLs from treatment-resistant patients. Gene expression analysis of the candidate gene panel revealed and confirmed influence of the candidate genes ABCB1, FZD7 and WNT2B on antidepressant drug resistance. The potential of these genes as tentative biomarkers for antidepressant drug resistance was confirmed. In vitro cell proliferation testing may serve as functional biomarker for individual neuroplasticity effects of antidepressants.

Proliferation rates and gene expression profiles in human lymphoblastoid cell lines from patients with depression characterized in response to antidepressant drug therapy.

The current therapy success of depressive disorders remains in need of improvement due to low response rates and a delay in symptomatic improvement. Reliable functional biomarkers would be necessary to predict the individual treatment outcome. On the basis of the neurotrophic hypothesis of antidepressant's action, effects of antidepressant drugs on proliferation may serve as tentative individual markers for treatment efficacy. We studied individual differences in antidepressant drug effects on cell proliferation and gene expression in lymphoblastoid cell lines (LCLs) derived from patients treated for depression with documented clinical treatment outcome. Cell proliferation was characterized by EdU (5-ethynyl-2'-deoxyuridine) incorporation assays following a 3-week incubation with therapeutic concentrations of fluoxetine. Genome-wide expression profiling was conducted by microarrays, and candidate genes such as betacellulin-a gene involved in neuronal stem cell regeneration-were validated by quantitative real-time PCR. Ex vivo assessment of proliferation revealed large differences in fluoxetine-induced proliferation inhibition between donor LCLs, but no association with clinical response was observed. Genome-wide expression analyses followed by pathway and gene ontology analyses identified genes with different expression before vs after 21-day incubation with fluoxetine. Significant correlations between proliferation and gene expression of WNT2B, FZD7, TCF7L2, SULT4A1 and ABCB1 (all involved in neurogenesis or brain protection) were also found. Basal gene expression of SULT4A1 (P=0.029), and gene expression fold changes of WNT2B by ex vivo fluoxetine (P=0.025) correlated with clinical response and clinical remission, respectively. Thus, we identified potential gene expression biomarkers eventually being useful as baseline predictors or as longitudinal targets in antidepressant therapy.

[Personalized drug therapy based on genetics. Possibilities and examples from clinical practice]. / Personalisierte Arzneitherapie auf genetischer Grundlage. Möglichkeiten und Beispiele aus der Praxis.

BACKGROUND: Pharmacogenetics are an important component in the individualization of treatment; however, pharmacogenetic diagnostics have so far not been used to any great extent in clinical practice. A consistent consideration of individual patient factors, such as pharmacogenetics may help to improve drug therapy and increase individual safety and efficacy aspects. OBJECTIVE: A brief summary of structures and effects of genetic variations on drug efficacy is presented. Some frequently prescribed pharmaceuticals are specified. Furthermore, the feasibility of pharmacogenetic diagnostics and dose recommendations in the clinical practice are described. CURRENT DATA: The European Medicines Agency (EMA) as the European approval authority has already extended the drug labels of more than 70 pharmaceuticals by information on pharmacogenetic biomarkers and the U.S. Food and Drug Administration (FDA) more than 150. This is a crucial step towards targeted medicine. Guidelines on dose and therapy adjustments are provided by the Clinical Pharmacogenetics Implementation Consortium of the Pharmacogenomics Research Network. CONCLUSION: It is fundamental to consider individual patient factors for successful drug therapy. Dose and therapy recommendations based on pharmacogenetic diagnostics are highly important for individualization as well as improvement of safety and efficiency of drug therapy.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors.

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).

The International SSRI Pharmacogenomics Consortium (ISPC): a genome-wide association study of antidepressant treatment response.

Response to treatment with selective serotonin reuptake inhibitors (SSRIs) varies considerably between patients. The International SSRI Pharmacogenomics Consortium (ISPC) was formed with the primary goal of identifying genetic variation that may contribute to response to SSRI treatment of major depressive disorder. A genome-wide association study of 4-week treatment outcomes, measured using the 17-item Hamilton Rating Scale for Depression (HRSD-17), was performed using data from 865 subjects from seven sites. The primary outcomes were percent change in HRSD-17 score and response, defined as at least 50% reduction in HRSD-17. Data from two prior studies, the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study (PGRN-AMPS) and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, were used for replication, and a meta-analysis of the three studies was performed (N=2394). Although many top association signals in the ISPC analysis map to interesting candidate genes, none were significant at the genome-wide level and the associations were not replicated using PGRN-AMPS and STAR*D data. The top association result in the meta-analysis of response represents SNPs 5' upstream of the neuregulin-1 gene, NRG1 (P = 1.20E - 06). NRG1 is involved in many aspects of brain development, including neuronal maturation and variations in this gene have been shown to be associated with increased risk for mental disorders, particularly schizophrenia. Replication and functional studies of these findings are warranted.

Relevance of UDP-glucuronosyltransferase polymorphisms for drug dosing: A quantitative systematic review.

UDP-glucuronosyltransferases (UGT) catalyze the biotransformation of many endobiotics and xenobiotics, and are coded by polymorphic genes. However, knowledge about the effects of these polymorphisms is rarely used for the individualization of drug therapy. Here, we present a quantitative systematic review of clinical studies on the impact of UGT variants on drug metabolism to clarify the potential for genotype-adjusted therapy recommendations. Data on UGT polymorphisms and dose-related pharmacokinetic parameters in man were retrieved by a systematic search in public databases. Mean estimates of pharmacokinetic parameters were extracted for each group of carriers of UGT variants to assess their effect size. Pooled estimates and relative confidence bounds were computed with a random-effects meta-analytic approach whenever multiple studies on the same variant, ethnic group, and substrate were available. Information was retrieved on 30 polymorphic metabolic pathways involving 10 UGT enzymes. For irinotecan and mycophenolic acid a wealth of data was available for assessing the impact of genetic polymorphisms on pharmacokinetics under different dosages, between ethnicities, under comedication, and under toxicity. Evidence for effects of potential clinical relevance exists for 19 drugs, but the data are not sufficient to assess effect size with the precision required to issue dose recommendations. In conclusion, compared to other drug metabolizing enzymes much less systematic research has been conducted on the polymorphisms of UGT enzymes. However, there is evidence of the existence of large monogenetic functional polymorphisms affecting pharmacokinetics and suggesting a potential use of UGT polymorphisms for the individualization of drug therapy.

CYP2D6 genotype and adjuvant tamoxifen: meta-analysis of heterogeneous study populations.

The International Tamoxifen Pharmacogenomics Consortium was established to address the controversy regarding cytochrome P450 2D6 (CYP2D6) status and clinical outcomes in tamoxifen therapy. We performed a meta-analysis on data from 4,973 tamoxifen-treated patients (12 globally distributed sites). Using strict eligibility requirements (postmenopausal women with estrogen receptor-positive breast cancer, receiving 20 mg/day tamoxifen for 5 years, criterion 1); CYP2D6 poor metabolizer status was associated with poorer invasive disease-free survival (IDFS: hazard ratio = 1.25; 95% confidence interval = 1.06, 1.47; P = 0.009). However, CYP2D6 status was not statistically significant when tamoxifen duration, menopausal status, and annual follow-up were not specified (criterion 2, n = 2,443; P = 0.25) or when no exclusions were applied (criterion 3, n = 4,935; P = 0.38). Although CYP2D6 is a strong predictor of IDFS using strict inclusion criteria, because the results are not robust to inclusion criteria (these were not defined a priori), prospective studies are necessary to fully establish the value of CYP2D6 genotyping in tamoxifen therapy.

[Personalised pharmacogenetics. Evidence-based guidelines and clinical application of pharmacogenetic diagnostics]. / Personalisierte Pharmakotherapie. Evidenzbasierte Leitlinien und klinische Anwendung pharmakogenetischer Diagnostik.

The broad clinical application of pharmacogenetic diagnostics for individualised drug treatment is still limited. With the exception of oncological therapies where molecular tumor makers are frequently used to decide upon individual drug therapies, pharmacogenetic testing is not generally offered in clinical laboratory diagnostics, because the costs are not covered by general health insurance and it is not evident what consequences the results of a genotyping test may have for the individual drug treatment. Especially in the context of pharmacokinetics, bioequivalence-based concepts have been developed that allow the individual drug dosage or therapy to be adjusted to genetic polymorphisms in drug metabolism, drug transport that affect drug absorption, metabolism and elimination. Pharmacogenetic aspects are increasingly included in the product information (e.g., on its website the FDA lists more than 60 drug labels that include pharmacogenetic information). However, most pharmacogenetic information on drug labels does not give recommendations for clinical decisions to be made based on individual genotypes. This gap is currently being closed by the development of international consortia aiming to base clinical recommendations on the best available evidence by systematic review of the existing data. The Clinical Pharmacogenetics Implementation Consortium of the Pharmacogenomics Research Network (CPIC) is an international community-driven organisation that is developing peer-reviewed, freely available gene/drug guidelines that are published in full at PharmGKB (http://www.pharmgkb.org). The aim of these guidelines is to give therapeutic recommendations such as dose adjustments or suggestions for the choice of an alternative drug in the case of specific genotypes (phenotypes) that predict slow metabolism or transport of drugs or safety risks or risks of therapeutic failure. These guidelines are not mandatory but serve to facilitate the translation of pharmacogenetic knowledge from bench to bedside.

Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants.

Polymorphisms 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.

Pharmacogenetic predictors for EGFR-inhibitor-associated skin toxicity.

The aim of this study was to investigate pharmacogenetic determinants of skin rash associated with epidermal growth factor receptor (EGFR) inhibitor treatment. A total of 109 prospectively sampled cancer patients, receiving the first treatment with an EGFR inhibitor, were genotyped for functional EGFR polymorphisms and tagging variants in genes involved in receptor downstream signaling. Skin rash was absent in 26 (23.9%) patients and associated with shorter overall survival compared with patients presenting skin rash (P=0.005). The EGFR polymorphisms, 497G/A (P=0.008), and the haplotypes of the promoter variants, EGFR-216G/T and -191C/A (P=0.029), were associated with the appearance of skin rash. In addition, a common haplotype in the PIK3CA gene was associated with skin rash (P=0.045) and overall survival (P=0.009). In conclusion, genetic variation within the EGFR gene and its downstream signaling partner PIK3CA might predict EGFR-inhibitor-related skin rash.

Genetic variability of drug-metabolizing enzymes: the dual impact on psychiatric therapy and regulation of brain function.

Polymorphic drug-metabolizing enzymes (DMEs) are responsible for the metabolism of the majority of psychotropic drugs. By explaining a large portion of variability in individual drug metabolism, pharmacogenetics offers a diagnostic tool in the burgeoning era of personalized medicine. This review updates existing evidence on the influence of pharmacogenetic variants on drug exposure and discusses the rationale for genetic testing in the clinical context. Dose adjustments based on pharmacogenetic knowledge are the first step to translate pharmacogenetics into clinical practice. However, also clinical factors, such as the consequences on toxicity and therapeutic failure, must be considered to provide clinical recommendations and assess the cost-effectiveness of pharmacogenetic treatment strategies. DME polymorphisms are relevant not only for clinical pharmacology and practice but also for research in psychiatry and neuroscience. Several DMEs, above all the cytochrome P (CYP) enzymes, are expressed in the brain, where they may contribute to the local biochemical homeostasis. Of particular interest is the possibility of DMEs playing a physiological role through their action on endogenous substrates, which may underlie the reported associations between genetic polymorphisms and cognitive function, personality and vulnerability to mental disorders. Neuroimaging studies have recently presented evidence of an effect of the CYP2D6 polymorphism on basic brain function. This review summarizes evidence on the effect of DME polymorphisms on brain function that adds to the well-known effects of DME polymorphisms on pharmacokinetics in explaining the range of phenotypes that are relevant to psychiatric practice.

Genetically polymorphic OCT1: another piece in the puzzle of the variable pharmacokinetics and pharmacodynamics of the opioidergic drug tramadol.

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.