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On 8–9 November 2022, the European Society of Pharmacogenomics and Personalised Therapy organized its sixth biennial congress, in Belgrade, Serbia (congress website: www.sspt.rs ). The congress aimed to address the current status and future perspectives of pharmacogenomics, share latest knowledge in the field of precision medicine and showcase the implementation of clinical applications in pharmacogenomics/pharmacogenetics. The 2 day congress consisted of 17 lectures given by key-opinion leaders and included a poster session plus discussions. The meeting was a great success by generating an informal environment and enabling the exchange of information between 162 participants from 16 different countries.

Supplementary Figure 1. CYP3A4.25 protein stability assessment

Supplementary Figure 3. CYP3A4*22 association with paclitaxel-induced neuropathy and paclitaxel dose modifications.

Supplementary Figure 2. Neuropathy risk conditions confer an increased risk of paclitaxel-induced neuropathy and a trend towards treatment modifications.

Supplementary Figure 1 - PDF file 89K, Structures of the compounds used in the study

Supplementary Table 1 - PDF file 24K, Pharmacokinetic data

Purpose: Paclitaxel, a widely used chemotherapeutic drug, can cause peripheral neuropathies leading to dose reductions and treatment suspensions and decreasing the quality of life of patients. It has been suggested that genetic variants altering paclitaxel pharmacokinetics increase neuropathy risk, but the major causes of interindividual differences in susceptibility to paclitaxel toxicity remain unexplained. We carried out a whole-exome sequencing (WES) study to identify genetic susceptibility variants associated with paclitaxel neuropathy.Experimental Design: Blood samples from 8 patients with severe paclitaxel-induced peripheral neuropathy were selected for WES. An independent cohort of 228 cancer patients with complete paclitaxel neuropathy data was used for variant screening by DHPLC and association analysis. HEK293 cells were used for heterologous expression and characterization of two novel CYP3A4 enzymes.Results: WES revealed 2 patients with rare CYP3A4 variants, a premature stop codon (CYP3A4*20 allele) and a novel missense variant (CYP3A4*25, p.P389S) causing reduced enzyme expression. Screening for CYP3A4 variants in the independent cohort revealed three additional CYP3A4*20 carriers, and two patients with missense variants exhibiting diminished enzyme activity (CYP3A4*8 and the novel CYP3A4*27 allele, p.L475V). Relative to CYP3A4 wild-type patients, those carrying CYP3A4 defective variants had more severe neuropathy (2- and 1.3-fold higher risk of neuropathy for loss-of-function and missense variants, respectively, P = 0.045) and higher probability of neuropathy-induced paclitaxel treatment modifications (7- and 3-fold higher risk for loss-of-function and missense variants, respectively, P = 5.9 × 10−5).Conclusion: This is the first description of a genetic marker associated with paclitaxel treatment modifications caused by neuropathy. CYP3A4 defective variants may provide a basis for paclitaxel treatment individualization. Clin Cancer Res; 21(2); 322–8. ©2014 AACR.

Supplementary data. Supplementary figure legends and supplementary tables

Purpose: Cytochrome P450 2W1 (CYP2W1) is a monooxygenase detected in 30% of colon cancers, whereas its expression in nontransformed adult tissues is absent, rendering it a tumor-specific drug target for development of novel colon cancer chemotherapy. Previously, we have identified duocarmycin synthetic derivatives as CYP2W1 substrates. In this study, we investigated whether two of these compounds, ICT2705 and ICT2706, could be activated by CYP2W1 into potent antitumor agents.Experimental Design: The cytotoxic activity of ICT2705 and ICT2706 in vitro was tested in colon cancer cell lines expressing CYP2W1, and in vivo studies with ICT2706 were conducted on severe combined immunodeficient mice bearing CYP2W1-positive colon cancer xenografts.Results: Cells expressing CYP2W1 suffer rapid loss of viability following treatment with ICT2705 and ICT2706, whereas the CYP2W1-positive human colon cancer xenografts display arrested growth in the mice treated with ICT2706. The specific cytotoxic metabolite generated by CYP2W1 metabolism of ICT2706 was identified in vitro. The cytotoxic events were accompanied by an accumulation of phosphorylated H2A.X histone, indicating DNA damage as a mechanism for cancer cell toxicity. This cytotoxic effect is most likely propagated by a bystander killing mechanism shown in colon cancer cells. Pharmacokinetic analysis of ICT2706 in mice identified higher concentration of the compound in tumor than in plasma, indicating preferential accumulation of drug in the target tissue.Conclusion: Our findings suggest a novel approach for treatment of colon cancer that uses a locoregional activation of systemically inactive prodrug by the tumor-specific activator enzyme CYP2W1. Clin Cancer Res; 19(11); 2952–61. ©2013 AACR.

Supplementary Methods - PDF file 82K, Detailed experimental procedures

Aims: CYP2C19 transgenic mouse expresses the human CYP2C19 gene in the liver and developing brain, and it exhibits altered neurodevelopment associated with impairments in emotionality and locomotion. Because the validation of new animal models is essential for the understanding of the aetiology and pathophysiology of movement disorders, the objective was to characterise motoric phenotype in CYP2C19 transgenic mice and to investigate its validity as a new animal model of ataxia. Methods: The rotarod, paw-print and beam-walking tests were utilised to characterise the motoric phenotype. The volumes of 20 brain regions in CYP2C19 transgenic and wild-type mice were quantified by 9.4T gadolinium-enhanced post-mortem structural neuroimaging. Antioxidative enzymatic activity was quantified biochemically. Dopaminergic alterations were characterised by chromatographic quantification of concentrations of dopamine and its metabolites and by subsequent immunohistochemical analyses. The beam-walking test was repeated after the treatment with dopamine receptor antagonists ecopipam and raclopride. Results: CYP2C19 transgenic mice exhibit abnormal, unilateral ataxia-like gait, clasping reflex and 5.6-fold more paw-slips in the beam-walking test; the motoric phenotype was more pronounced in youth. Transgenic mice exhibited a profound reduction of 12% in cerebellar volume and a moderate reduction of 4% in hippocampal volume; both regions exhibited an increased antioxidative enzyme activity. CYP2C19 mice were hyperdopaminergic; however, the motoric impairment was not ameliorated by dopamine receptor antagonists, and there was no alteration in the number of midbrain dopaminergic neurons in CYP2C19 mice. Conclusions: Humanised CYP2C19 transgenic mice exhibit altered gait and functional motoric impairments; this phenotype is likely caused by an aberrant cerebellar development.

The metabolic activity of the polymorphic CYP2D6 enzyme is dependent on the CYP2D6 genotype; however, the guidelines for translating the genotype into phenotype, which are of relevance for adequate drug dose personalization, are ambiguous. In the present study, retrospective therapeutic drug monitoring data from 4,700 CYP2D6 genotyped patients treated with risperidone, venlafaxine, and/or aripiprazole were analyzed to quantify the effect of CYP2D6 genotype on the CYP2D6 metabolic activities, as measured by metabolic ratios of these substrates. The patients were categorized into diplotypes based on the presence of normal function (CYP2D6Norm), nonfunctional (CYP2D6Nonf), and decreased function (CYP2D6Decr; i.e., CYP2D6*9, CYP2D6*10, and CYP2D6*41) CYP2D6 haplotypes. Significant correlations between the metabolic ratios were observed in patients (n = 77-103) cotreated with risperidone and venlafaxine, risperidone and aripiprazole, or venlafaxine and aripiprazole (ρ = 0.874, 0.785, and 0.644, respectively; P

Genetic variation in genes encoding cytochrome P450 enzymes influences the metabolism of drugs and endogenous compounds. The locus containing the cytochrome genes CYP2C8 and CYP2C9 on chromosome 10 exhibits linkage disequilibrium between the CYP2C8*3 and CYP2C9*2 alleles, forming a haplotype of ~300 kilobases. This haplotype is associated with altered metabolism of several drugs, most notably reduced metabolism of warfarin and phenytoin, leading to toxicity at otherwise therapeutic doses. Here we show that this haplotype is inherited from Neandertals.

During pharmacotherapy, knowledge about the actual drug and metabolite concentrations in plasma is often critical. Individual dose adjustments can be performed based on pre-emptive genotyping of certain absorption, distribution, metabolism, and excretion (ADME) genes but also using therapeutic drug monitoring (TDM). Analyses of liquid biopsies for tumor-derived components are well-established and have been found to be a good complement to biopsy examinations. Recently, liquid biopsy-based quantification of cell-free RNA (cfRNA) in plasma exosomes was proposed as a proxy measurement for the expression of different hepatic ADME genes and for the rate of drug metabolism, constituting an alternative to TDM. In this study, we validated these findings by examining the correlation between mRNA expression of eight different CYP genes in liver and the corresponding rate of enzyme-specific drug metabolism in 96 donor-matched liver samples. Analyses of CYP-dependent drug metabolism in liver microsomes in comparison to the level of mRNA expression for the different CYP genes revealed a mean Pearson correlation coefficient of 0.28. The highest correlations (0.33-0.34) were obtained for CYP2D6 and CYP3A4 and the weakest correlations were observed for CYP1A2 and CYP2B6 (0.18-0.21). In all cases, the correlations obtained were too weak to demonstrate a predictive relationship, likely due to different regulatory and post-translational events controlling the rate of enzyme activity. Our results reinforce the notion that, whilst liquid biopsy-based approaches might have utility for prediction of hepatic CYP protein expression, they are not currently an important substitute for TDM.

BackgroundAnimal models are essential for understanding etiology and pathophysiology of movement disorders. Previously, we have found that mice transgenic for the human CYP2C19 gene, expressed in the liver and developing brain, exhibit altered neurodevelopment associated with impairments of their motor function and emotionality.ObjectivesTo characterize motoric phenotype of the CYP2C19 transgenic mice and validate its usefulness as an animal model of ataxia.MethodsThe rotarod and beam-walking tests were utilized to quantify the functional alterations induced by motoric phenotype. Dopaminergic system was assessed by tyrosine hydroxylase immunohistochemistry and by chromatographic quantification of the whole-brain dopamine levels. Beam-walking test was also repeated after the treatment with the dopamine receptor antagonists, ecopipam and raclopride. The volumes of 20 brain regions in the CYP2C19 transgenic mice and controls were quantified by 9.4T gadolinium-enhanced postmortem structural neuroimaging.ResultsCYP2C19 transgenic mice were found to exhibit abnormal, unilateral ataxia-like gait, clasping reflex and 5.6-fold more paw-slips using the beam-walking test (pCYP2C19 mice; however, the motoric impairment was not ameliorated by dopamine receptor antagonists and there was also no midbrain dopamine neuron loss in CYP2C19 mice. However, in these mice, cerebellar volume was drastically decreased (11.8% [95%CI: −14.7, −9.0], qq=0.015, n=59).ConclusionsHumanized CYP2C19 transgenic mice exhibit altered motoric function and functional motoric impairments; this phenotype is likely caused by an aberrant cerebellar development.

Genetic factors can, to a certain extent, successfully predict the therapeutic effects, metabolism, and adverse reactions of drugs. This research field, pharmacogenomics, is well developed in oncology and is currently expanding in psychiatry. Here, we summarize the latest development in pharmacogenomic psychiatry, where results of several recent large studies indicate a true benefit and cost-effectiveness of pre-emptive genotyping for more successful psychotherapy. However, it is apparent that we still lack knowledge of many additional heritable genetic factors of importance for explanation of the interindividual differences in response to psychiatric drugs. Thus, more effort to further develop pharmacogenomic psychiatry should be invested to achieve a broader clinical implementation.

Pharmacogenomic drug labels in the Summary of Product Characteristics (SmPC) provide an instrument for clinical implementation of pharmacogenomics. We compared pharmacogenomic guidance by Clinical Pharmacogenetics Implementation Consortium (CPIC), Dutch Pharmacogenetics Working Group (DPWG), the US Food and Drug Administration (FDA), and by the European agencies the European Medicines Agency (EMA), College ter Beoordeling van Geneesmiddelen Medicines Evaluation Board (CBG-MEB), and Federal Institute for Drugs and Medical Devices (FIDMD), collectively assigned as EMA/FIDMD+MEB shortened as EMA/FM. Of 54 drugs with an actionable gene-drug interaction in the CPIC and DPWG guidelines, only 50% had actionable pharmacogenomic information in the SmPCs and the agencies were in agreement in only 18% of the cases. We further compared 450 additional drugs, lacking CPIC or DPWG guidance, and found 126 actionable gene-drug labels by the FDA and/or the EMA/FM. Based on these 126 drugs in addition to the 54 above, the consensus of actionable pharmacogenomic labeling between the FDA and the EMA/FM was only 54%. In conclusion, guidelines provided by CPIC/DPWG are only partly implemented into the SmPCs and the implementation of pharmacogenomic drug labels into the clinics would strongly gain from a higher extent of consensus between agencies.

International audience; Drug-induced liver injury (DILI) is a patient-specific, temporal, multifactorial pathophysiological process that cannot yet be recapitulated in a single in vitro model. Current preclinical testing regimes for the detection of human DILI thus remain inadequate. A systematic and concerted research effort is required to address the deficiencies in current models and to present a defined approach towards the development of new or adapted model systems for DILI prediction. This Perspective defines the current status of available models and the mechanistic understanding of DILI, and proposes our vision of a roadmap for the development of predictive preclinical models of human DILI.

The genetic background for interindividual variability of the polymorphic CYP2D6 enzyme activity remains incompletely understood and the role of NFIB genetic polymorphism for this variability was evaluated in this translational study. We investigated the effect of NFIB expression in vitro using 3D liver spheroids, Huh7 cells, and the influence of the NFIB polymorphism on metabolism of risperidone in patients in vivo. We found that NFIB regulates several important pharmacogenes, including CYP2D6. NFIB inhibited CYP2D6 gene expression in Huh7 cells and NFIB expression in livers was predominantly nuclear and reduced at the mRNA and protein level in carriers of the NFIB rs28379954 T>C allele. Based on 604 risperidone treated patients genotyped for CYP2D6 and NFIB, we found that the rate of risperidone hydroxylation was elevated in NFIB rs28379954 T>C carriers among CYP2D6 normal metabolizers, resulting in a similar rate of drug metabolism to what is observed in CYP2D6 ultrarapid metabolizers, with no such effect observed in CYP2D6 poor metabolizers lacking functional enzyme. The results indicate that NFIB constitutes a novel nuclear factor in the regulation of cytochrome P450 genes, and that its polymorphism is a predictor for the rate of CYP2D6 dependent drug metabolism in vivo.

There is a high unmet need for developing treatments for nonalcoholic fatty liver disease (NAFLD), for which there are no approved drugs today. Here, we used a human in vitro disease model to understand mechanisms linked to genetic risk variants associated with NAFLD. The model is based on 3D spheroids from primary human hepatocytes from five different donors. Across these donors, we observed highly reproducible differences in the extent of steatosis induction, demonstrating that inter-donor variability is reflected in the in vitro model. Importantly, our data indicates that the genetic variant TM6SF2 E167K, previously associated with increased risk for NAFLD, induces increased hepatocyte fat content by reducing APOB particle secretion. Finally, differences in gene expression pathways involved in cholesterol, fatty acid and glucose metabolism between wild type and TM6SF2 E167K mutation carriers (N = 125) were confirmed in the in vitro model. Our data suggest that the 3D in vitro spheroids can be used to investigate the mechanisms underlying the association of human genetic variants associated with NAFLD. This model may also be suitable to discover new treatments against NAFLD.

Academic, industry, regulatory leaders and patient advocates in cancer clinical research met in November 2018 at the Innovation and Biomarkers in Cancer Drug Development meeting in Brussels to address the existing dichotomy between increasing calls for personalised oncology approaches based on individual molecular profiles and the need to make resource and regulatory decisions at the societal level in differing health-care delivery systems around the globe. Novel clinical trial designs, the utility and limitations of real-world evidence (RWE) and emerging technologies for profiling patient tumours and tumour-derived DNA in plasma were discussed. While randomised clinical trials remain the gold standard approach to defining clinical utility of local and systemic therapeutic interventions, the broader adoption of comprehensive tumour profiling and novel trial designs coupled with RWE may allow patient and physician autonomy to be appropriately balanced with broader assessments of safety and overall societal benefit. (C) 2019 Published by Elsevier Ltd.

Individuals differ substantially in their response to pharmacological treatment. Personalized medicine aspires to embrace these inter-individual differences and customize therapy by taking a wealth of patient-specific data into account. Pharmacogenomic constitutes a cornerstone of personalized medicine that provides therapeutic guidance based on the genomic profile of a given patient. Pharmacogenomics already has applications in the clinics, particularly in oncology, whereas future development in this area is needed in order to establish pharmacogenomic biomarkers as useful clinical tools. In this review we present an updated overview of current and emerging pharmacogenomic biomarkers in different therapeutic areas and critically discuss their potential to transform clinical care. Furthermore, we discuss opportunities of technological, methodological and institutional advances to improve biomarker discovery. We also summarize recent progress in our understanding of epigenetic effects on drug disposition and response, including a discussion of the only few pharmacogenomic biomarkers implemented into routine care. We anticipate, in part due to exciting rapid developments in Next Generation Sequencing technologies, machine learning methods and national biobanks, that the field will make great advances in the upcoming years towards unlocking the full potential of genomic data.

Significance Liver steatosis, or fatty liver, is the most common liver disease in the world, affecting up to 25% of all Americans. There is currently no approved drug available for this condition, which may progress to serious disease, including steatohepatitis, fibrosis, and cirrhosis. Here, we show in rodent and human models of metabolic syndrome that steatosis can be prevented by a simple dietary approach. Inorganic nitrate, present in green leafy vegetables, is converted in vivo to nitric oxide (NO) in a process involving symbiotic host bacteria. NO then induces key metabolic regulatory pathways to ultimately reduce oxidative stress and improve cardiometabolic functions. Clinical trials would be helpful to tell if dietary nitrate is useful in treatment and prevention of fatty liver disease., Advanced age and unhealthy dietary habits contribute to the increasing incidence of obesity and type 2 diabetes. These metabolic disorders, which are often accompanied by oxidative stress and compromised nitric oxide (NO) signaling, increase the risk of adverse cardiovascular complications and development of fatty liver disease. Here, we investigated the therapeutic effects of dietary nitrate, which is found in high levels in green leafy vegetables, on liver steatosis associated with metabolic syndrome. Dietary nitrate fuels a nitrate–nitrite–NO signaling pathway, which prevented many features of metabolic syndrome and liver steatosis that developed in mice fed a high-fat diet, with or without combination with an inhibitor of NOS (l-NAME). These favorable effects of nitrate were absent in germ-free mice, demonstrating the central importance of host microbiota in bioactivation of nitrate. In a human liver cell line (HepG2) and in a validated hepatic 3D model with primary human hepatocyte spheroids, nitrite treatment reduced the degree of metabolically induced steatosis (i.e., high glucose, insulin, and free fatty acids), as well as drug-induced steatosis (i.e., amiodarone). Mechanistically, the salutary metabolic effects of nitrate and nitrite can be ascribed to nitrite-derived formation of NO species and activation of soluble guanylyl cyclase, where xanthine oxidoreductase is proposed to mediate the reduction of nitrite. Boosting this nitrate–nitrite–NO pathway results in attenuation of NADPH oxidase-derived oxidative stress and stimulation of AMP-activated protein kinase and downstream signaling pathways regulating lipogenesis, fatty acid oxidation, and glucose homeostasis. These findings may have implications for novel nutrition-based preventive and therapeutic strategies against liver steatosis associated with metabolic dysfunction.

AIMS CYP2D6*9, CYP2D6*10 and CYP2D6*41 are the most frequent reduced-function CYP2D6 alleles in Caucasians. Despite lacking in vivo evidence, they are collectively classified with an enzyme activity score of 0.5. Thus, the aim of this study was to compare the functional impact of CYP2D6*9, CYP2D6*10 and CYP2D6*41 on CYP2D6 metabolism in a large patient population. METHODS A total of 1003 patients (mainly Caucasians) with data on CYP2D6 genotype and serum concentrations of venlafaxine and metabolites were included from a therapeutic drug monitoring service in Oslo, Norway. The O-desmethyl-to-N-desmethyl-venlafaxine metabolic ratio (MR) was applied as CYP2D6 biomarker and compared (Mann-Whitney) between carriers of CYP2D6*9-10 (merged) and CYP2D6*41, either combined with CYP2D6*1 or non-coding (null) alleles. MR subgroup estimates were obtained by multiple linear regression for calculations of CYP2D6*9-10 and CYP2D6*41 activity scores. RESULTS MR was significantly lower in carriers of CYP2D6*41 than CYP2D6*9-10 (P

Background: Nonadherence to antipsychotics may cause relapse and hospitalizations in patients with psychotic disorders. The purpose was to quantify and compare the outpatient's nonadherence rates of atypical antipsychotics by objective detection in blood samples. Methods: Totally, 13,217 outpatients with therapeutic drug monitoring (TDM) data of atypical antipsychotics were included. An event of complete nonadherence was defined as an occurrence of undetectable level of a prescribed antipsychotic in the blood sample submitted for TDM. Patients with such an event(s) were defined as nonadherent of the respective drug treatment (outcome). The rates of nonadherence patients were compared between the drugs by logistic regression. Results: In the study population, 70.2% of the patients were prescribed doses compliant with a schizophrenia diagnosis. The mean olanzapine equivalent dose in the population was 13.4 mg (95% confidence interval (CI): 13.3, 13.6). The frequency of nonadherence patients, regardless of drug, was 3.7% (CI: 3.4–4.0). The nonadherence patient rate was lowest in clozapine-treated patients (2.2%; CI: 1.5–2.8), followed by aripiprazole (2.3%; 1.7–2.8), risperidone (2.4%; 1.6–3.0), quetiapine (2.8%; 2.3–3.2) and olanzapine (4.9%; 4.1–5.3). Users of olanzapine had significantly higher risk of complete nonadherence (Odds ratio: 1.9; CI: 1.6–2.3, p < 0.001) compared to patients treated with other antipsychotics as a group. Conclusions: In this study, complete nonadherence of atypical antipsychotics, measured as undetectable blood level, was disclosed for ~5% of outpatients with psychotic disorders. The rate of complete nonadherence was significantly higher during olanzapine treatment compared to other atypical antipsychotics. Further studies should investigate if this reflects drug differences in tolerability or other causal relationships.

IMPORTANCE: Precise estimation of the drug metabolism capacity for individual patients is crucial for adequate dose personalization. OBJECTIVE: To quantify the difference in the antipsychotic and antidepressant exposure among patients with genetically associated CYP2C19 and CYP2D6 poor (PM), intermediate (IM), and normal (NM) metabolizers. DATA SOURCES: PubMed, Clinicaltrialsregister.eu, ClinicalTrials.gov, International Clinical Trials Registry Platform, and CENTRAL databases were screened for studies from January 1, 1990, to June 30, 2020, with no language restrictions. STUDY SELECTION: Two independent reviewers performed study screening and assessed the following inclusion criteria: (1) appropriate CYP2C19 or CYP2D6 genotyping was performed, (2) genotype-based classification into CYP2C19 or CYP2D6 NM, IM, and PM categories was possible, and (3) 3 patients per metabolizer category were available. DATA EXTRACTION AND SYNTHESIS: The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed for extracting data and quality, validity, and risk of bias assessments. A fixed-effects model was used for pooling the effect sizes of the included studies. MAIN OUTCOMES AND MEASURES: Drug exposure was measured as (1) dose-normalized area under the plasma level (time) curve, (2) dose-normalized steady-state plasma level, or (3) reciprocal apparent total drug clearance. The ratio of means (RoM) was calculated by dividing the mean drug exposure for PM, IM, or pooled PM plus IM categories by the mean drug exposure for the NM category. RESULTS: Based on the data derived from 94 unique studies and 8379 unique individuals, the most profound differences were observed in the patients treated with aripiprazole (CYP2D6 PM plus IM vs NM RoM, 1.48; 95% CI, 1.41-1.57; 12 studies; 1038 patients), haloperidol lactate (CYP2D6 PM vs NM RoM, 1.68; 95% CI, 1.40-2.02; 9 studies; 423 patients), risperidone (CYP2D6 PM plus IM vs NM RoM, 1.36; 95% CI, 1.28-1.44; 23 studies; 1492 patients), escitalopram oxalate (CYP2C19 PM vs NM, RoM, 2.63; 95% CI, 2.40-2.89; 4 studies; 1262 patients), and sertraline hydrochloride (CYP2C19 IM vs NM RoM, 1.38; 95% CI, 1.27-1.51; 3 studies; 917 patients). Exposure differences were also observed for clozapine, quetiapine fumarate, amitriptyline hydrochloride, mirtazapine, nortriptyline hydrochloride, fluoxetine hydrochloride, fluvoxamine maleate, paroxetine hydrochloride, and venlafaxine hydrochloride; however, these differences were marginal, ambiguous, or based on less than 3 independent studies. CONCLUSIONS AND RELEVANCE: In this systematic review and meta-analysis, the association between CYP2C19/CYP2D6 genotype and drug levels of several psychiatric drugs was quantified with sufficient precision as to be useful as a scientific foundation for CYP2D6/CYP2C19 genotype-based dosing recommendations.