Abstract

Observed interindividual differences in tricyclic antidepressant (TCA) pharmacokinetic parameters and treatment outcomes are associated with CYP2D6 and/or CYP2C19 genetic variation. The purpose of this guideline is to provide information to allow the interpretation of existing CYP2D6 and/or CYP2C19 genotyping results to guide TCA dosing and selection. Other clinical variables that may influence TCA therapy as well as genotyping cost-effectiveness are beyond the scope of this article. CPIC guidelines are periodically updated at https://cpicpgx.org/guidelines/ and http://www.pharmgkb.org. A systematic literature review focused on CYP2D6 and CYP2C19 genetic variations and their relevance to gene-based dosing of TCAs was conducted (see Supplementary Data online). This guideline was developed based on interpretation of the literature by the authors and by experts in the field. The CYP2D6 gene is highly polymorphic. Over 100 known allelic variants and subvariants have been identified, and there are substantial ethnic differences in observed allele frequencies (CYP2D6 Allele Definition Table and CYP2D6 Frequency Table1). The most commonly reported alleles are categorized into functional groups as follows: normal function (e.g., CYP2D6*1 and *2), decreased function (e.g., CYP2D6*9, *10, and *41), and no function (e.g., CYP2D6*3-*6).2, 3 Because CYP2D6 is subject to deletions or duplications, many clinical laboratories also report copy number. Deletions are indicated by the CYP2D6*5 allele, and gene duplications are denoted by an "xN" following the allele (e.g., CYP2D6*1xN, where xN represents the number of CYP2D6 gene copies). Similar to CYP2D6, the CYP2C19 gene is highly polymorphic; over 35 known allelic variants and subvariants have been identified3 (CYP2C19 Allele Definition Table4). Although there are ethnic differences in allele frequencies (CYP2C19 Frequency Table4), the majority of patients will carry a CYP2C19*1,*2,*3 or *17 allele.5 CYP2C19*1 is the wildtype allele encoding a fully functional enzyme. CYP2C19*2-*8 are no function alleles of which CYP2C19*2 is the most frequently observed, although CYP2C19*3 is more common among individuals of Asian ancestry.3, 5 The CYP2C19*17 allele, defined by a variant in the gene promoter region, causes enhanced gene transcription resulting in greater metabolic capacity6 and is therefore classified as an increased function allele. Clinical laboratories usually interrogate for the more frequently observed CYP2D6 and CYP2C19 genetic variants and translate the results into star-allele (*) nomenclature. Each star-allele, or haplotype, is defined by a specific combination of single-nucleotide polymorphisms and/or other genetic variants within the gene locus of either CYP2D6 or CYP2C19.5 Genetic test results are reported as the summary of inherited maternal and paternal star-alleles referred to as a diplotype (e.g., CYP2D6*1/*2 and CYP2C19*1/*1). The more frequently observed alleles and their functional status can be found in the CYP2D61 and CYP2C19 Allele Definition Tables.4 Scoring systems have been developed in an attempt to provide a uniform approach to quantitate the predicted functional status of CYP2D6 alleles as follows: 1 for normal function, 0.5 for decreased function, and 0 for no function alleles (see Supplemental Material; CYP2D6 Allele Definition Table1).2, 7 The activity value for each allele of the diplotype is totaled to provide a CYP2D6 activity score. If CYP2D6 gene duplications are detected, the activity value of the duplicated allele is multiplied by the number of duplications present before calculating the activity score (Table 1, Supplemental Tables S1 and S2). (See the Supplement for further explanation.) Ultrarapid metabolizer (∼1-20% of patients)a Normal metabolizer (∼72-88% of patients) Intermediate metabolizer (∼1-13% of patients) Poor metabolizer (∼1-10% of patients) Ultrarapid metabolizer (∼2-5% of patients)a Rapid metabolizer (∼2-30% of patients) Normal metabolizer (∼35-50% of patients) Intermediate metabolizer (∼18-45% of patients) Poor metabolizer (∼2-15% of patients) Patients with two normal function CYP2C19 alleles are categorized as normal metabolizers and individuals carrying one or two no function alleles are considered intermediate and poor metabolizers, respectively (Table 1). Limited data suggest that CYP2C19*17 may not compensate for no function alleles such as the CYP2C19*2 allele.8 Therefore, patients carrying the CYP2C19*17 increased function allele in combination with a no function allele are considered intermediate metabolizers. These phenotype assignments are analogous to the CPIC guideline for selective serotonin reuptake inhibitors.3 (See the Supplement for discussion regarding CYP2C19 rapid metabolizer phenotype.) Reference laboratories use varying methods to assign phenotypes. Before pharmacotherapy modifications are made based upon this guideline, it is advisable to determine a patient's phenotype as described above. Commercially available genetic testing options change over time. Additional information about pharmacogenetic testing can be found at the Genetic Testing Registry website (http://www.ncbi.nlm.nih.gov/gtr/). Independent of drug metabolism and response, there are currently no diseases or conditions that have been convincingly linked to variants in the CYP2D6 or CYP2C19 genes.5, 7 Tricyclic antidepressants (TCAs) are mixed serotonin and norepinephrine reuptake inhibitors used to treat several disease states including depression, obsessive-compulsive disorder, and neuropathic pain in addition to migraine prophylaxis. The TCAs have similar but distinct chemical structures referred to as tertiary and secondary amines. The pharmacological properties of the tertiary and secondary amines differ, with tertiary amines having a more pronounced serotonergic effect and secondary amines having a greater noradrenergic effect (Supplemental Tables S3, and S4).9, 10 The tertiary amines (e.g., amitriptyline) are mainly metabolized by CYP2C19 to desmethyl-metabolites (Figure 1), also referred to as secondary amines (e.g., nortriptyline). It should be noted that the desmethyl-metabolites nortriptyline as well as desipramine are pharmacologically active, with antidepressant properties as well as with distinct clinical features that differ from the parent drugs amitriptyline and imipramine. Both the tertiary and secondary amines are metabolized by CYP2D6 to less active hydroxy-metabolites (Figure 1, Supplemental Table S3). CYP2C19 impacts the ratio of tertiary to secondary amine plasma concentrations, but may have less influence on overall drug clearance than CYP2D6.11 Although the total concentration of amitriptyline and nortriptyline may be unchanged for a CYP2C19 ultrarapid or poor metabolizer in certain instances, an imbalance between serotonergic and noradrenergic affect could influence clinical response or toxicities. There is limited evidence demonstrating that a serotonergic/noradrenergic imbalance influences outcomes, thus contributing to the optional recommendations in Table 3. Serotonin reuptake inhibition is expected to be more pronounced in CYP2C19 poor metabolizers due to the decreased conversion of parent tertiary amines to their respective metabolites.10 Major metabolic pathway of the tertiary amine amitriptyline and the secondary amine nortriptyline. For the structural representation the following 2D images from the National Center for Biotechnology Information PubChem Compound Database are used: amitriptyline – CID=2160 (https://pubchem.ncbi.nlm.nih.gov/compound/2160); nortriptyline – CID=4543 (https://pubchem.ncbi.nlm.nih.gov/compound/4543); 10-hydroxyamitriptyline – CID=6420900 (https://pubchem.ncbi.nlm.nih.gov/compound/6420900); 10-hydroxynortriptyline – CID=6420504 (https://pubchem.ncbi.nlm.nih.gov/compound/6420504).37 All entries were accessed Nov. 8, 2016. The use of TCAs to treat psychiatric disorders has declined in part due to the occurrence of undesirable side effects along with the growing availability of alternatives with more acceptable side effect profiles. Although TCAs are still used to treat depression,12 they are now more often used in the context of pain management.13, 14 Interindividual differences in side effects and treatment response have been associated with variability of tricyclic plasma concentrations.15, 16 Patients may be predisposed to treatment failure or adverse effects due to genetic variation in CYP2D6 altering drug clearance or in CYP2C19 altering the ratio of parent drug to metabolites. Common adverse effects include anticholinergic, central nervous system, and cardiac effects. Tertiary and secondary amines along with their metabolites each have unique side effect profiles, as detailed in Supplemental Table S4. Both amitriptyline and nortriptyline are used as representative TCAs for this guideline because the majority of pharmacogenomic studies have focused on these two drugs. However, the results of these studies may apply to other TCAs because these drugs have comparable pharmacokinetic properties.15, 17 TCAs are well absorbed from the gastrointestinal tract, and the average extent of first-pass metabolism is ∼50%, although the average first-pass metabolism of doxepin may be closer to 70%.15 The clearance of TCAs is mostly a linear process, but saturation of the hydroxylation pathway may occur at higher plasma concentrations for certain TCAs, including imipramine and desipramine.15, 18 Additionally, extrapolated dose adjustments based on metabolizer status are similar across the tricyclic class.17 Because some studies investigating the influence of CYP2D6 and/or CYP2C19 genotype/phenotype on the pharmacokinetics of TCAs used a single dose, it should be noted that in this guideline tricyclic metabolism was assumed to be similar after single or multiple dosing, and no differentiation was made between evidence from single-dose studies or from multiple-dose studies.16 There is substantial evidence linking CYP2D6 and CYP2C19 genotypes to phenotypic variability in tricyclic side effects and pharmacokinetic profiles. Modifying pharmacotherapy for patients who have CYP2D6 or CYP2C19 genetic variants that affect drug efficacy and safety could potentially improve clinical outcomes, and reduce the failure rate of initial treatment. The application of a grading system to the evidence linking CYP2D6 and CYP2C19 genotypic variations to phenotypic variability in the response to amitriptyline or nortriptyline indicates a high quality of evidence in the majority of cases (Supplemental Tables S5–S7). This body of evidence, rather than randomized clinical trials, provides the basis for amitriptyline and nortriptyline dosing recommendations in Tables 2 and 3, respectively. Optimal therapeutic plasma concentrations for the TCAs have been defined.19 CYP2D6 and CYP2C19 poor or ultrarapid metabolizers may have tricyclic plasma concentrations outside the recommended therapeutic range, thus increasing the risk of treatment failure or side effects.17, 20-22 TCA plasma concentrations have been shown to be predictive of toxicity and efficacy, with guidelines defining therapeutic ranges for TCAs.19 However, there are less data supporting a direct correlation between genotype and response when compared to the correlation between genotype and plasma concentrations. Some studies describe a relationship between genotype and response,23-25 while other studies do not.26 Therefore, this guideline takes into consideration both clinical outcomes and observed tricyclic plasma concentrations based on genotype/phenotype characteristics. Increased metabolism of TCAs to less active compounds compared to normal metabolizers Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers).e Utilize therapeutic drug monitoring to guide dose adjustments. Reduced metabolism of TCAs to less active compounds compared to normal metabolizers Higher plasma concentrations of active drug will increase the probability of side effects Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers Higher plasma concentrations of active drug will increase the probability of side effects Avoid tricyclic use due to potential for side effects. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider a 50% reduction of recommended starting dose.f Utilize therapeutic drug monitoring to guide dose adjustments.e Increased metabolism of tertiary amines compared to normal metabolizers Greater conversion of tertiary amines to secondary amines may affect response or side effects Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments.e Greatly reduced metabolism of tertiary amines compared to normal metabolizers Decreased conversion of tertiary amines to secondary amines may affect response or side effects Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. For tertiary amines, consider a 50% reduction of the recommended starting dose.f Utilize therapeutic drug monitoring to guide dose adjustments.e For neuropathic pain treatment, where lower initial doses of TCAs are used, gene-based dosing recommendations are found in the subsection Gene-based dosing recommendations for neuropathic pain treatment (below). Table 2 summarizes the gene-based dosing recommendations for CYP2D6 and amitriptyline and nortriptyline for situations in which a higher initial dose is warranted, such as depression treatment. The recommended starting dose of amitriptyline or nortriptyline does not need adjustment for those with genotypes predictive of CYP2D6 normal metabolism. A 25% reduction of the recommended dose may be considered for CYP2D6 intermediate metabolizers.27 The strength of this recommendation is classified as "moderate" because patients with a CYP2D6 activity score of 1.0 are inconsistently categorized as intermediate or normal metabolizers in the literature, making these studies difficult to evaluate. CYP2D6 ultrarapid metabolizers have a higher probability of failing amitriptyline or nortriptyline pharmacotherapy due to subtherapeutic plasma concentrations, and alternate agents are preferred. There are documented cases of CYP2D6 ultrarapid metabolizers receiving large doses of nortriptyline in order to achieve therapeutic concentrations.22 However, very high plasma concentrations of the nortriptyline hydroxy-metabolite were present, which may increase the risk for cardiotoxicity. If a tricyclic is warranted, there are insufficient data in the literature to calculate a starting dose for a patient with CYP2D6 ultrarapid metabolizer status, and therapeutic drug monitoring is strongly recommended. Adverse effects are more likely in CYP2D6 poor metabolizers due to elevated tricyclic plasma concentrations28; therefore, alternate agents are preferred. If a tricyclic is warranted, consider a 50% reduction of the usual dose, and therapeutic drug monitoring is strongly recommended. Dosing recommendations for neuropathic pain treatment with amitriptyline are found in the subsection Gene-based dosing recommendations for neuropathic pain treatment. Table 3 summarizes the gene-based dosing recommendations for CYP2C19 and amitriptyline when higher initial starting doses are warranted. The usual starting dose of amitriptyline may be used in CYP2C19 normal and intermediate metabolizers. Although CYP2C19 intermediate metabolizers would be expected to have a modest increase in the ratio of amitriptyline to nortriptyline plasma concentrations, the evidence does not indicate that CYP2C19 intermediate metabolizers should receive an alternate dose. Patients taking amitriptyline who are CYP2C19 rapid or ultrarapid metabolizers may be at risk for having low plasma concentrations and an imbalance between parent drug and metabolites causing treatment failure and/or adverse events. Although the CYP2C19*17 allele did not alter the sum of amitriptyline plus nortriptyline plasma concentrations, it was associated with higher nortriptyline plasma concentrations, possibly increasing the risk of adverse events.8 For patients taking amitriptyline, extrapolated pharmacokinetic data suggest that CYP2C19 rapid or ultrarapid metabolizers may need a dose increase.17 Due to the need for further studies investigating the clinical importance of CYP2C19*17 regarding tricyclic metabolism and the possibility of altered concentrations, we recommend considering an alternative tricyclic or other drug not affected by CYP2C19. This recommendation is classified as optional due to limited available data. If amitriptyline is administered to a CYP2C19 rapid or ultrarapid metabolizer, therapeutic drug monitoring is recommended. CYP2C19 poor metabolizers are expected to have a greater ratio of amitriptyline to nortriptyline plasma concentrations.29 The elevated amitriptyline plasma concentrations may increase the chance of a patient experiencing side effects. Consider a 50% reduction of the usual amitriptyline starting dose along with therapeutic drug monitoring.17 Because the TCAs have comparable pharmacokinetic properties, it may be reasonable to extrapolate this guideline to other TCAs, including clomipramine, desipramine, doxepin, imipramine, and trimipramine (Tables 2, 3; Supplemental Tables S8–S16), with the acknowledgment that there are fewer data supporting dose adjustments for these drugs than for amitriptyline or nortriptyline. Although specific combinations of CYP2D6 and CYP2C19 alleles are likely to result in additive effects on the pharmacokinetic properties of TCAs, little information is available on how to adjust initial doses based on combined genotype information. Patients carrying at least one CYP2D6 no function allele and two CYP2C19 normal function alleles had an increased risk of experiencing side effects when administered amitriptyline, while patients with at least one CYP2C19 no function allele and two CYP2D6 normal function alleles had a lower risk of experiencing side effects.22, 30 Combinatorial gene-based recommendations are provided in Table 4. Therapeutic drug monitoring may be advised if a tricyclic is prescribed to a patient with CYP2D6 ultrarapid, intermediate, or poor metabolism in combination with CYP2C19 ultrarapid, rapid, intermediate, or poor metabolism. There are sparse data in patients with a combinatorial CYP2C19 ultrarapid/rapid/intermediate/poor metabolizer phenotype and CYP2D6 ultrarapid/intermediate/poor phenotype. Because there are limited clinical or pharmacokinetic data regarding these combinatorial phenotypes, pharmacotherapy recommendations are classified as optional. Avoid amitriptyline usec Classification of recommendationd: Optional Consider alternative drug not metabolized by CYP2C19c, e Classification of recommendationd: Optional Consider alternative drug not metabolized by CYP2C19c,e Classification of recommendationd: Optional Avoid amitriptyline usec Classification of recommendationd: Optional Avoid amitriptyline use. If amitriptyline is warranted, consider titrating to a higher target dose (compared to normal metabolizers)f, g Classification of recommendationd: Strong Initiate therapy with recommended starting doseh Classification of recommendationd: Strong Consider a 25% reduction of recommended starting dosef, h Classification of recommendationd: Moderate Avoid amitriptyline use. If amitriptyline is warranted, consider a 50% reduction of recommended starting dosef, h Classification of recommendationd: Strong Avoid amitriptyline usec Classification of recommendationd: Optional Initiate therapy with recommended starting doseh Classification of recommendationd: Strong Consider a 25% reduction of recommended starting dosef, h Classification of recommendationd: Optional Avoid amitriptyline use. If amitriptyline is warranted, consider a 50% reduction of recommended starting dosef, h Classification of recommendationd: Optional Avoid amitriptyline usec Classification of recommendationd: Optional Avoid amitriptyline use. If amitriptyline is warranted, consider a 50% reduction of recommended starting dosef, h Classification of recommendationd: Moderate Avoid amitriptyline usec Classification of recommendationd: Optional Avoid amitriptyline usec Classification of recommendationd: Optional Amitriptyline is often used at lower dosages (e.g., 0.1 mg/kg/day in pediatric patients; initial doses of 25 mg daily may be prescribed to adults) for treatment of neuropathic pain compared to treatment for depressive disorders.13, 14 Because of the lower dosage, it is less likely that CYP2D6 or CYP2C19 poor or intermediate metabolizers will experience adverse effects due to supratherapeutic plasma concentrations of amitriptyline.31 Therefore, we recommend no dose modifications for poor or intermediate metabolizers when prescribed amitriptyline at a lower dose for treatment of neuropathic pain, but these patients should be monitored closely for side effects. If larger doses of amitriptyline are warranted, we recommend following the gene-based dosing guidelines presented in Tables 2-4. There are limited data to support dose recommendations for CYP2C19*17 carriers who are prescribed amitriptyline at lower doses for neuropathic pain treatment. There are also few data describing the use of amitriptyline for neuropathic pain in CYP2D6 ultrarapid metabolizers. Based on predicted and observed pharmacokinetic data in those with depression, CYP2D6 ultrarapid metabolizers may be at an increased risk of failing amitriptyline therapy for neuropathic pain due to lower than expected drug concentrations, and thus alternative agents should be considered.32 Although there is sparse information on how to adjust initial amitriptyline doses based on combined CYP2D6 and CYP2C19 genetic results when treating neuropathic pain, caution should be used when patients have a combination of poor or ultrarapid phenotypes (e.g., a CYP2D6 poor metabolizer also having CYP2C19 ultrarapid or poor metabolism). There are scarce studies focusing solely on CYP2D6 or CYP2C19 genotype and association with pharmacokinetic parameters or treatment outcomes of TCAs in pediatric patients. CYP2D6 activity is fully mature by early childhood, but CYP2C19 activity may be increased in children relative to adults.3 Although further genomic ontogeny studies are needed, there is a lack of evidence suggesting that this guideline cannot be extrapolated to pediatric patients. Patients treated for psychiatric disorders often require multiple medications, which can influence tricyclic plasma concentrations, side effects, and therapeutic failure.15 Recent data indicate that up to 20% of patients treated for depression may be converted to CYP2D6 poor metabolizer status.33 For example, patients taking amitriptyline in combination with a potent CYP2D6 inhibitor, such as fluoxetine, may have dramatic increases in amitriptyline plasma concentrations.34 It has been suggested that patients taking strong CYP2D6 inhibitors should be treated similarly to CYP2D6 poor metabolizers.7 Additionally, patients with increased age, liver disease, and reduced renal function may require reduced doses of TCAs.15 Drug–drug interactions along with patient characteristics should be considered in addition to the gene-based dosing recommendations presented herein. Other cytochrome P450 enzymes including CYP3A4 and CYP1A2 metabolize TCAs to a lesser extent.15, 31, 35, 36 There is currently no strong evidence supporting gene-based dosing recommendations for other CYP enzymes that metabolize TCAs. The guideline supplement contains resources that can be used within electronic health records (EHRs) to assist clinicians in applying genetic information to patient care for the purpose of drug therapy optimization (see Resources to incorporate pharmacogenetics into an electronic health record with clinical decision support sections of the Supplement). For patients who have existing CYP2D6 and/or CYP2C19 genotyping test results, the potential benefit is identifying those patients who are at an elevated risk of experiencing side effects or therapeutic failure. For those patients, dose adjustments can be made or an alternative agent selected. A limitation inherent to most commercially available genotyping tests is that rare or de novo variants are not detected. Additionally, some alleles are not well characterized, resulting in uncertainty when predicting the phenotype from some genetic test results. Genotyping is reliable when performed in qualified clinical laboratories, but as with any laboratory test, an error can occur. Any errors in genotyping or phenotype prediction, along with the presence of a rare genomic variant not tested for, could potentially have lifelong implications for the patient's drug therapy. The application of genotype-based dosing is most appropriate when initiating therapy with a tricyclic. Obtaining a pharmacogenetic test after months of drug therapy may be less helpful in some instances, as the drug dose may have already been adjusted based on plasma concentrations, response, or side effects. Similar to all diagnostic tests, genetic tests are one of several pieces of clinical information that should be considered before initiating drug therapy. CPIC guidelines reflect expert consensus based on clinical evidence and peer-reviewed literature available at the time they are written and are intended only to assist clinicians in decision making and to identify questions for further research. New evidence may have emerged since the time a guideline was submitted for publication. Guidelines are limited in scope and are not applicable to interventions or diseases not specifically identified. Guidelines do not account for all individual variations among patients and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It remains the responsibility of the healthcare provider to determine the best course of treatment for a patient. Adherence to any guidelines is voluntary, with the ultimate determination regarding its application to be made solely by the clinician and the patient. CPIC assumes no responsibility for any injury to persons or damage to persons or property arising out of or related to any use of CPIC's guidelines, or for any errors or omissions. CPIC is a registered service mark of the US Department of Health & Human Services (HHS). We acknowledge the critical input of Dr. M. Relling and members of the Clinical Pharmacogenetics Implementation Consortium of the Pharmacogenomics Research Network, funded by the National Institutes of Health. This work was funded by the National Institutes of Health (NIH) for CPIC (R24GM115264) and PharmGKB (R24GM61374). E.D.K. is supported by R01 GM63674 and R01 DA14211. T.C.S. is supported by R01 GM088076 and the Agency for Healthcare Research and Quality (R01 HS19818-01). The content is solely the responsibility of the authors and does not necessarily represent the official views of the Agency for Healthcare Research and Quality. V.L.E. is supported by the NIMH (R01 MH082784). D.J.M. is supported by a New Investigator Salary Award from the Canadian Institutes of Health Research, a New Investigator Fellowship Award from the Ontario Mental Health Foundation, and an Early Researcher Award by the Ministry of Research and Innovation of Ontario. A.G. is supported by R01 GM088076-05. A.G. is a paid consultant of Millennium Laboratories. T.E.K is a paid scientific advisor to the Rxight Pharmacogenetic Program. K.S. has received research support from Shionogi & Co., Ltd., Eli Lilly Japan, K.K., Yoshitomi Pharmaceutical Industries, Ltd., Meiji Seika Pharma Co., Ltd., Eisai Co., Ltd., Pfizer Inc., GlaxoSmithKlein K.K., Otsuka Pharmaceutical Co., Ltd., Daiichi Sankyo Co., and Takeda Pharmaceutical Co., Ltd., and honoraria from Kowa Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Meiji Seika Pharma Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Ono Pharmaceutical Co., Ltd., GlaxoSmithKlein K.K., and Eisai Co., Ltd. All other authors declare no conflict of interest. Additional Supporting Information may be found in the online version of this article. Supplement to: Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC®) for CYP2D6 and CYP2C19 Genotypes and Tricyclic Antidepressants: 2016 Update Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.