Pharmacogenetics in Child and Adolescent Psychiatry: Background and Evidence-Based Clinical Applications.

The efficacy and tolerability of psychotropic medications can vary significantly among children and adolescents, and some of this variability relates to pharmacogenetic factors. Pharmacogenetics (PGx) in child and adolescent psychiatry can potentially improve treatment outcomes and minimize adverse drug reactions. This article reviews key pharmacokinetic and pharmacodynamic genes and principles of pharmacogenetic testing and discusses the evidence base for clinical decision-making concerning PGx testing. This article reviews current guidelines from the United States Food and Drug Administration (FDA), the Clinical Pharmacogenetics Implementation Consortium (CPIC), and the Dutch Pharmacogenetics Working Group (DPWG) and explores potential future directions. This review discusses key clinical considerations for clinicians prescribing psychotropic medications in children and adolescents, focusing on antidepressants, antipsychotics, stimulants, norepinephrine reuptake inhibitors, and alpha-2 agonists. Finally, this review synthesizes the practical use of pharmacogenetic testing and clinical decision support systems.

Implementing a Pharmacogenomic-driven Algorithm to Guide Antiplatelet Therapy among Caribbean Hispanics: A non-randomized prospective cohort study.

Background: After percutaneous coronary intervention (PCI), clopidogrel resistant patients are at an increased risk of major adverse cardiovascular and cerebrovascular events (MACCEs). We aimed to assess whether genotype-guided selection of oral antiplatelet drugs using a clinical decision support (CDS) algorithm reduces the occurrence of these ischemic events and improves outcomes among Caribbean Hispanic patients from Puerto Rico, who are underrepresented in clinical pharmacogenomic (PGx)-guided implementation studies. Methods: Individual platelet function testing (PRU) measures, CYP2C19*2 and PON1 rs662 genotypes, clinical and demographic data from 8 medical facilities were included. Patients were separated into standard of care (SoC) and genotype-guided groups (150 each). Risk scores were calculated based on a previously developed CDS risk prediction algorithm designed to make actionable treatment recommendations for each patient. Alternative therapy with ticagrelor was recommended for patients with a high risk score ≥2. Statistical associations between patient time free of MACCEs and predictor variables (i.e., treatment groups, risk scores) were tested in this population using Kaplan-Meier survival analyses and Cox proportional-hazards regression models. Results: Median age of participants is 67 years; BMI: 27.8; 48% women; 14% smokers; 59% with type-2 diabetes mellitus (T2DM). Among patients with high-risk scores who were free from MACCE events 6 months after coronary stenting, genotype-driven guidance of antiplatelet therapy showed superiority over SoC in terms of reducing the incidence rate of atherothrombotic events. Conclusions: The clinical utility of our PGx-driven CDS algorithm to reduce the incidence rate of MACCEs among post-PCI Caribbean Hispanic patients on clopidogrel was externally demonstrated. Clinical Trial Registration Unique Identifier: NCT03419325.

Discovery of Ancestry-specific Variants Associated with Clopidogrel Response among Caribbean Hispanics.

Background: High on-treatment platelet reactivity (HTPR) with clopidogrel is predictive of ischemic events in adults with coronary artery disease. Despite strong data suggesting HTPR varies with ethnicity, including clinical and genetic variables, no genome-wide association study (GWAS) of clopidogrel response has been performed among Caribbean Hispanics. This study aimed to identify genetic predictors of HTPR in a cohort of Caribbean Hispanic cardiovascular patients from Puerto Rico. Methods: Local Ancestry inference (LAI) and traditional GWASs were performed on a cohort of 511 clopidogrel-treated patients, stratified based on their P2Y12 reaction units (PRU) into responders and non-responders (HTPR). Results: The LAI GWAS identified variants within the CYP2C19 region associated with HTPR, predominantly driven by individuals of European ancestry and absent in those with native ancestry. Incorporating local ancestry adjustment notably enhanced our ability to detect associations. While no loci reached traditional GWAS significance, three variants showed suggestive significance at chromosomes 3, 14 and 22 (OSBPL10 rs1376606, DERL3 rs5030613, and RGS6 rs9323567). In addition, a variant in the UNC5C gene on chromosome 4 was associated with an increased risk of HTPR. These findings were not identified in other cohorts, highlighting the unique genetic landscape of Caribbean Hispanics. Conclusion: This is the first GWAS of clopidogrel response in Hispanics, confirming the relevance of the CYP2C19 cluster, particularly among those with European ancestry, and also identifying novel markers in a diverse patient population. Further studies are warranted to replicate our findings in other diverse cohorts and meta-analyses.

PharmVar Tutorial on CYP2D6 Structural Variation Testing and Recommendations on Reporting.

The Pharmacogene Variation Consortium (PharmVar) provides nomenclature for the highly polymorphic human CYP2D6 gene locus and a comprehensive summary of structural variation. CYP2D6 contributes to the metabolism of numerous drugs and, thus, genetic variation in its gene impacts drug efficacy and safety. To accurately predict a patient's CYP2D6 phenotype, testing must include structural variants including gene deletions, duplications, hybrid genes, and combinations thereof. This tutorial offers a comprehensive overview of CYP2D6 structural variation, terms, and definitions, a review of methods suitable for their detection and characterization, and practical examples to address the lack of standards to describe CYP2D6 structural variants or any other pharmacogene. This PharmVar tutorial offers practical guidance on how to detect the many, often complex, structural variants, as well as recommends terms and definitions for clinical and research reporting. Uniform reporting is not only essential for electronic health record-keeping but also for accurate translation of a patient's genotype into phenotype which is typically utilized to guide drug therapy.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A Genotypes and Serotonin Reuptake Inhibitor Antidepressants.

Serotonin reuptake inhibitor antidepressants, including selective serotonin reuptake inhibitors (SSRIs; i.e., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline), serotonin and norepinephrine reuptake inhibitors (i.e., desvenlafaxine, duloxetine, levomilnacipran, milnacipran, and venlafaxine), and serotonin modulators with SSRI-like properties (i.e., vilazodone and vortioxetine) are primary pharmacologic treatments for major depressive and anxiety disorders. Genetic variation in CYP2D6, CYP2C19, and CYP2B6 influences the metabolism of many of these antidepressants, which may potentially affect dosing, efficacy, and tolerability. In addition, the pharmacodynamic genes SLC6A4 (serotonin transporter) and HTR2A (serotonin-2A receptor) have been examined in relation to efficacy and side effect profiles of these drugs. This guideline updates and expands the 2015 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 and CYP2C19 genotypes and SSRI dosing and summarizes the impact of CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A genotypes on antidepressant dosing, efficacy, and tolerability. We provide recommendations for using CYP2D6, CYP2C19, and CYP2B6 genotype results to help inform prescribing these antidepressants and describe the existing data for SLC6A4 and HTR2A, which do not support their clinical use in antidepressant prescribing.

Contrasting ABCB1 pharmacogenetics and psychotropic responses in child and adolescent psychiatry: a case comparison.

This case comparison illustrates pharmacogenetic testing in psychotropic and clinical management in relation to the ABCB1 gene, which encodes the P-glycoprotein transporter affecting blood-brain barrier (BBB) permeability. Two pediatric patients (9 and 11 years old) were selected for similar clinical presentations with opposing ABCB1 genotype, while they were identically matched for key CYP450, dopaminergic and serotonergic genes (CYP2C9, CYP2C19, DRD2, SLC6A4, 5HTR2A). Case A was functional for the ABCB1 gene (G/G rs1045642), suggesting that the BBB had a functional P-glycoprotein transporter. Case B was subfunctional for the ABCB1 gene (A/A rs1045642), suggesting that the patient's BBB may be permeable to psychotropic drugs. Case A had more medication trials and dose adjustments than Case B. Case A had two inpatient admissions and interspersed emergency room visits, while case B had none.

The focus of this case comparison report is the ABCB1 gene in child psychiatry and its role in drug efficacy and side effects. ABCB1 encodes the P-glycoprotein transporter of the blood­brain barrier (BBB). As antidepressants must cross the BBB to act on the brain, differences in the functionality of ABCB1 may lead to variable brain concentrations of antidepressants and subsequent variability in therapeutic response. Selecting the cases for comparison with opposing functionality at the ABCB1 gene, while matching for key CYP450, dopaminergic and serotonergic genes (CYP2C9, CYP2C19, DRD2, SLC6A4, 5HTR2A), was the approach utilized. The outcomes of case A and case B reflected pharmacogenetic and clinical contrasts, including patient responses to antidepressants and antipsychotics, susceptibility to adverse effects and differences in the severity of symptoms. These effects on antidepressants and antipsychotics are important because a permeable BBB will allow these drugs to cross into the brain to exert their effect, thus improving clinical outcomes, reducing hospitalizations and emergency room visits and minimizing drug trials and dosage changes. More clinical attention and research are needed for the BBB's involvement in psychiatric disease and for the P-glycoprotein transporter as a chemical gatekeeper to the brain. Pharmacogenetic testing for ABCB1 polymorphisms could be considered to inform psychotropic prescribing for the most vulnerable patients in child and adolescent psychiatry in the near future.

Automated Extraction of Pain Symptoms: A Natural Language Approach using Electronic Health Records.

BACKGROUND: Pain costs more than $600 billion annually and affects more than 100 million Americans, but is still a poorly understood problem and one for which there is very often limited effective treatment. Electronic health records (EHRs) are the only databases with a high volume of granular pain information that allows for documentation of detailed clinical notes on a patient's subjective experience. OBJECTIVES: This study applied natural language processing (NLP) technology to an EHR dataset as part of a pilot study to capture pain information from clinical notes and prove its feasibility as an efficient method. STUDY DESIGN: Retrospective study. SETTING: All data were from UConn Health John Dempsey Hospital (JDH) in Farmington, CT. METHODS: The JDH EHR dataset contains 611,355 clinical narratives from 359,854 patients from diverse demographic backgrounds from 2010 through 2019. These data were processed through a customized NLP pipeline. A training set of 100 notes was annotated based on focus group-generated ontology and used to generate and evaluate an NLP model that was later tested on the remaining notes. Validation of the model was evaluated externally and performance was analyzed. RESULTS: The model identified back pain as the most common location of experienced pain with 40,369 term frequencies. Patients most commonly experienced decreased mobility with their pain with 7,375 term frequencies. Pain was most commonly found to be radiating with 26,967 term frequencies and patients most commonly rated their pain as 8/10 with 2,375 term frequencies. All parameters studied had statistical F-scores greater than 0.85. LIMITATIONS: A single-center, pilot study subject to reporting bias, recording bias, and missing patient data. CONCLUSIONS: Our customized NLP model demonstrated good and successful performance in extracting granular pain information from clinical notes in electronic health records.

Pharmacogenomic polygenic risk score for clopidogrel responsiveness among Caribbean Hispanics: A candidate gene approach.

This multicenter clinical study was aimed at conducting a targeted pharmacogenomic association analysis of residual on-clopidogrel platelet reactivity in 474 Caribbean Hispanic patients. Platelet reactivity was measured using the VerifyNow P2Y12 assay and clopidogrel resistance was defined as P2Y12 reaction units (PRUs) greater than or equal to 208. Genotyping was performed using the whole-genome Infinium MEGA BeadChip array. An ancestry-adjusted, weighted polygenic risk score (wPGxRS) was developed to account for the effect of multiple variants on PRU and compared between clopidogrel responders and nonresponders. The mean PRU across the study cohort was 173.8 ± 68.5 and 33.5% of patients were defined as clopidogrel resistant. Multivariate linear regression showed that 19% of PRU variability was attributed to nine independent predictors, with CYP2C19*2 (rs4244285) accounting for ~ 7% of observed PRU variation (p < 0.001). PON1 rs662, ABCB1/MDR1 rs2032582, PEAR1 rs12041331 carrier status, and the interaction between African ancestry and rs12041331 carriers also predicted PRU among the participants (p ≤ 0.05). A clear gene-dose effect was detected between PRU and CYP2C19*2 genotype, consistent with previous studies in European patient populations, as well as rs12777823. Importantly, a significant positive correlation was detected between our novel wPGxRS (4 variants) and PRU among the Hispanic patient population (rp  = 0.35, p < 0.001). Moreover, the wPGxRS discriminated between nonresponders and responders (p = 0.003), indicating that this multigene-based score is a useful predictor of clopidogrel resistance among Caribbean Hispanics. Taken together, these results help close the gap of knowledge on clopidogrel pharmacogenomics and its potential clinical implementation in this under-represented population.

Personalized health and the coronavirus vaccines-Do individual genetics matter?

Vaccines represent preventative interventions amenable to immunogenetic prediction of how human variability will influence their safety and efficacy. The genetic polymorphism among individuals within any population can render possible that the immunity elicited by a vaccine is variable in length and strength. The same immune challenge (virus and/or vaccine) could provoke partial, complete or even failed protection for some individuals treated under the same conditions. We review genetic variants and mechanistic relationships among chemokines, chemokine receptors, interleukins, interferons, interferon receptors, toll-like receptors, histocompatibility antigens, various immunoglobulins and major histocompatibility complex antigens. These are the targets for variation among macrophages, dendritic cells, natural killer cells, T- and B-lymphocytes, and complement. The technology platforms (mRNA, viral vectors, proteins) utilized to produce vaccines against SARS-CoV-2 infections may each trigger genetically distinct immune reactogenic profiles. With DNA biobanking and immunoprofiling of recipients, global COVID-19 vaccinations could launch a new era of personalized healthcare.

Subanalysis of the CYP-GUIDES Trial: CYP2D6 Functional Stratification and Operational Timeline Selection.

CYP-GUIDES (Cytochrome Psychotropic Genotyping Under Investigation for Decision Support) was a Randomized Controlled Trial comparing 2 outcomes in hospitalized patients with major depressive disorder treated according to the patient's CYP2D6 genotype and functional status versus standard psychotropic therapy. The primary outcome was hospital Length of Stay (LOS) and the secondary was Re-Admission Rate (RAR) 30 days after discharge. Methodology, total results and database of the trial have been published. Here we present a subanalysis that isolated 3 confounders to assess the impact of CYP2D6 therapeutic guidance on LOS: a single Electronic Medical Record, a minimum 3-day LOS, and CYP2D6 functional stratification of patients. CYP2D6 functional stratification enabled subgrouping patients and comparing outcomes according to CYP2D6 functionality within Group G and Group S. Subfunctional patients evidenced a 2-day shorter LOS in Group G compared to Group S. Drug administration for subfunctional patients in Group S evidenced a higher percentage of CYP2D6 substrate psychotropics being prescribed as well as a greater number of prescriptions than in functional patients. We conclude that there was an effect of pharmacogenetic clinical decision support that reduced LOS in patients with CYP2D6 subfunctional status and reduced prescribing of CYP2D6 substrate dependent drugs.

Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6, OPRM1, and COMT Genotypes and Select Opioid Therapy.

Opioids are mainly used to treat both acute and chronic pain. Several opioids are metabolized to some extent by CYP2D6 (codeine, tramadol, hydrocodone, oxycodone, and methadone). Polymorphisms in CYP2D6 have been studied for an association with the clinical effect and safety of these drugs. Other genes that have been studied for their association with opioid clinical effect or adverse events include OPRM1 (mu receptor) and COMT (catechol-O-methyltransferase). This guideline updates and expands the 2014 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 genotype and codeine therapy and includes a summation of the evidence describing the impact of CYP2D6, OPRM1, and COMT on opioid analgesia and adverse events. We provide therapeutic recommendations for the use of CYP2D6 genotype results for prescribing codeine and tramadol and describe the limited and/or weak data for CYP2D6 and hydrocodone, oxycodone, and methadone, and for OPRM1 and COMT for clinical use.

Living with respiratory viruses: The next saga in human/viral coexistence?

Testing for respiratory viruses and SARS-CoV-2 in clinical and epidemiological settings has contrasting purposes and utility. Symptomatic patients are best tested with respiratory virus panels to establish the pathogen and guide personalized treatment. Asymptomatic patients are tested for a single infectious pathogen to establish carrier status and guide containment.

Assessment of the clinical utility of pharmacogenetic guidance in a comprehensive medication management service.

INTRODUCTION: Pharmacists are poised to be the health care professionals best suited to provide medication-related consults and services based on a patient's genetics. Despite its potential benefits, the implementation of pharmacogenetic (PGx) testing into primary clinical settings has been slow among medically underserved populations. To our knowledge, this is the first time that PGx-driven recommendations have been incorporated into a Comprehensive Medication Management (CMM) service in a Hispanic population. OBJECTIVES: The aim of this study is to evaluate the clinical utility of adding PGx guidance into pharmacist-driven CMM. METHODS: This is a pre- and post-interventional design study. Patients were recruited from a psychologist's clinic. A total of 24 patients had a face-to-face interview with a pharmacist to complete a CMM, Personal Medication Record, and Medication-Related Action Plan (MAP) blind to PGx findings. Collected buccal DNA samples were genotyped using drug-metabolizing enzymes and transporters (DMET) Plus Array. RESULTS: The pharmacist generated new MAPs for each patient based on PGx results. Genetic variants that could potentially affect the safety and effectiveness of at least one drug in the pharmacotherapy were identified in 96% of patients, for whom the pharmacist changed the initial recommendations. Polymorphisms in genes encoding for isoenzymes CYP2D6, CYP2C19, and CYP2C9 were identified in 83%, 52%, and 41% of patients, respectively. Pharmacists performing CMM identified 22 additional medication problems after PGx determinations. Moreover, they agreed with the clinical utility of PGx in the studied sample based on perceived value of adding PGx to traditional CMM and its utility in the decision-making process of pharmacists. CONCLUSIONS: The study confirmed the critical role to be played by pharmacists in facilitating the clinical usage of relevant genetic information to optimize drug therapy decisions as well as their involvement on many levels of these multidisciplinary implementation efforts, including championing and leading PGx-guided CMM services.

Implementing a pharmacogenetic-driven algorithm to guide dual antiplatelet therapy (DAPT) in Caribbean Hispanics: protocol for a non-randomised clinical trial.

INTRODUCTION: Minority populations in the USA are disproportionately affected by cardiovascular conditions. Reduced responsiveness to clopidogrel among carriers of CYP2C19 variants has been reported in patients with either coronary artery disease (CAD) or acute coronary syndrome (ACS) after the percutaneous coronary intervention (PCI). Previous studies have evaluated CYP2C19 genotyping-guided antiplatelet therapy in selected populations; however, this has yet to be tested among Hispanics. Given the paucity of clinical research on CYP2C19 and antiplatelet clinical outcomes in Hispanics, our study will test the safety and efficacy of a genetic-driven treatment algorithm to guide dual antiplatelet therapy (DAPT) in Caribbean Hispanics. METHODS AND ANALYSIS: This is a multicentre, prospective, non-randomised clinical trial that proposes an assessment of pharmacogenomic-guided DAPT in post-PCI Caribbean Hispanic patients with ACS or CAD. We will recruit 250 patients to be compared with a matched non-concurrent cohort of 250 clopidogrel-treated patients (standard-of-care). Major adverse cardiovascular events (MACEs) such as all-cause death, myocardial infarction (MI), stroke, coronary revascularisation, stent thrombosis and bleedings over 6 months will be the study endpoints. Among the recruited, high-risk patients will be escalated to ticagrelor and low-risk patients will remain on clopidogrel. The primary objective is to determine whether genetic-guided therapy is superior to standard of care. The secondary objective will determine if clopidogrel treatment in low-risk patients is not associated with a higher rate of MACEs compared with escalated antiplatelet therapy in high-risk patients. Patients will be enrolled up to the group's completion. ETHICS AND DISSEMINATION: Approval was obtained from the Institutional Review Board of the University of Puerto Rico Medical Sciences Campus (protocol # A4070417). The study will be carried out in compliance with the Declaration of Helsinki and International Conference on Harmonization Good Clinical Practice Guidelines. Findings will be published in a peer-reviewed journal and controlled access to experimental data will be available. TRIAL REGISTRATION NUMBER: NCT03419325; Pre-results.

Pharmacogenomics: an Update for Child and Adolescent Psychiatry.

PURPOSE OF REVIEW: This paper aims to acquaint child and adolescent psychiatrists with the field of pharmacogenomics (PGX) and review the most up-to-date evidence-based practices to guide the application of this field in clinical care. RECENT FINDINGS: Despite much research being done in this area, the field of PGX continues to yield controversial findings. In the adult world, studies have focused on the impact of combinatorial gene panels that guide medication selection by providing reports that estimate the impact of multiple pharmacodynamic and pharmacokinetic genes, but to date, these have not been directly examined in younger patient populations. Pharmacokinetic genes, CYP2D6 and CYP2C19, and hypersensitivity genes, HLA-A and HLA-B, have the strongest evidence base for application to pharmacotherapy in children. Although the field is evolving, and the evidence is mixed, there may be a role for PGX testing in children to help guide dosing and monitoring strategies. However, evidence-based medicine, rather than PGX testing, continues to play the lead role in guiding medication selection in pediatric psychopharmacology.

Clinical database of the CYP-guides trial: An open data resource on psychiatric hospitalization for severe depression.

CYP-GUIDES (Cytochrome Psychotropic Genotyping Under Investigation for Decision Support ) is a randomized controlled trial (RCT) of pharmacogenetic decision support in the psychotropic treatment of hospitalized patients with major depressive disorder or severe depression. Patients were treated according to their CYP2D6 functional status or empirically and compared for both their Length of Stay (LOS, primary outcome) at the hospital and Re-Admission Rate (RAR, secondary outcome) 30 days after discharge. The trial was conducted at the Institute of Living (Hartford Hospital, Hartford CT). CYP2D6 genotyping was implemented to infer the functional status of the CYP2D6 enzyme and classify it as sub-normal, normal or supra-normal. The electronic medical record (EMR) transmitted to the physician the indicated drug prescribing guidance. During the RCT, 1500 patients were recruited and 1459 genotyped for CYP2D6. A 1:2 randomization assigned 477 patients to standard therapy (Group S) and 982 to genetically-guided therapy (Group G). In Group S, standard empiric treatment was indicated for all patients. In Group G, medications primarily metabolized by the CYP2D6 enzyme were proscribed for patients with sub- or supra-normal CYP2D6 function. The clinical course, therapeutic guidance, and drug treatment for each patient are being published in this article and deposited in Mendeley Data. These data should be valuable to assess the impact of clinical decision support on utilization of psychiatric resources for treatment of severe depression requiring hospitalization.

PharmVar GeneFocus: CYP2D6.

The Pharmacogene Variation Consortium (PharmVar) provides nomenclature for the highly polymorphic human CYP2D6 gene locus. CYP2D6 genetic variation impacts the metabolism of numerous drugs and, thus, can impact drug efficacy and safety. This GeneFocus provides a comprehensive overview and summary of CYP2D6 genetic variation and describes how the information provided by PharmVar is utilized by the Pharmacogenomics Knowledgebase (PharmGKB) and the Clinical Pharmacogenetics Implementation Consortium (CPIC).

Results of the CYP-GUIDES randomized controlled trial: Total cohort and primary endpoints.

CYP-GUIDES (Cytochrome Psychotropic Genotyping Under Investigation for Decision Support) is a randomized controlled trial (RCT) comparing 2 outcomes in hospitalized patients with major depressive disorder (MDD) treated according to the patient's CYP2D6 genotype and functional status versus standard psychotropic therapy. The primary outcome was hospital Length of Stay (LOS) and the secondary outcome was the Re-Admission Rate (RAR) 30 days after discharge. The trial setting was the Institute of Living at Hartford Hospital. CYP2D6 genotyping was implemented to detect common polymorphisms resulting in an enzyme with sub-normal, normal or supra-normal function. The electronic medical record (EMR) was utilized to transmit clinically actionable drug prescribing guidance based on the patient's CYP2D6 genotype to the physician. The RCT recruited 1500 patients, genotyped CYP2D6 in 1459, and randomized 477 to standard therapy (Group S), for whom treatment-as-usual guidance was delivered without consideration of patient CYP2D6 genotype, and 982 to genetically-guided therapy (Group G) where CYP2D6-based treatment recommendations were provided via EMR to physicians. For inpatients in Group G whose CYP2D6 function was sub- or supra-normal, medications primarily metabolized by the CYP2D6 enzyme were proscribed. The RCT developed a database of potential benefit to the field. The genetic, pharmacologic and clinical information is being simultaneously published. Results did not reveal differences in LOS or RAR between Group G and Group S, but confounders may have obscured the effects of pharmacogenetic guidance. We present strategies to assess effects of pharmacogenetic guidance on the most vulnerable patients at either extreme of CYP2D6 function treated with multiple psychotropics.