{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T11:36:58Z","timestamp":1792237018501,"version":"4.4.0"},"reference-count":42,"publisher":"Springer Science and Business Media LLC","issue":"7","license":[{"start":{"date-parts":[[2025,5,25]],"date-time":"2025-05-25T00:00:00Z","timestamp":1748131200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0"},{"start":{"date-parts":[[2025,5,25]],"date-time":"2025-05-25T00:00:00Z","timestamp":1748131200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0"}],"funder":[{"DOI":"10.13039\/501100001826","name":"ZonMw","doi-asserted-by":"publisher","award":["848016004"],"award-info":[{"award-number":["848016004"]}],"id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Clin Pharmacokinet"],"published-print":{"date-parts":[[2025,7]]},"DOI":"10.1007\/s40262-025-01528-x","type":"journal-article","created":{"date-parts":[[2025,5,25]],"date-time":"2025-05-25T12:13:27Z","timestamp":1748175207000},"page":"1071-1078","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Optimizing Nortriptyline Dosing: A Comparison between Pharmacogenetics-Based, Phenotype-Based, and Standard Dosing"],"prefix":"10.1007","volume":"64","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6760-1474","authenticated-orcid":false,"given":"Cornelis F.","family":"Vos","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marieke J. H.","family":"Coenen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie E.","family":"ter Hark","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnt F. A.","family":"Schellekens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rob E.","family":"Aarnoutse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joost G. E.","family":"Janzing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rob","family":"ter Heine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,25]]},"reference":[{"key":"1528_CR1","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1007\/164_2018_133","volume":"250","author":"R Chockalingam","year":"2019","unstructured":"Chockalingam R, Gott BM, Conway CR. Tricyclic antidepressants and monoamine oxidase inhibitors: are they too old for a new look? Handb Exp Pharmacol. 2019;250:37\u201348.","journal-title":"Handb Exp Pharmacol"},{"key":"1528_CR2","unstructured":"Medicines Evaluation Board. Nortriptyline hydrochloride: summary of product characteristics. 2017. https:\/\/www.geneesmiddeleninformatiebank.nl\/smpc\/h11407_smpc.pdf. Accessed 1 Dec 2024."},{"issue":"1","key":"1528_CR3","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1186\/s12888-021-03490-x","volume":"21","author":"CF Vos","year":"2021","unstructured":"Vos CF, et al. Tricyclic antidepressants for major depressive disorder: a comprehensive evaluation of current practice in the Netherlands. BMC Psychiatry. 2021;21(1):481.","journal-title":"BMC Psychiatry"},{"issue":"4","key":"1528_CR4","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1007\/BF02246640","volume":"123","author":"ML Dahl","year":"1996","unstructured":"Dahl ML, Bertilsson L, Nordin C. Steady-state plasma levels of nortriptyline and its 10-hydroxy metabolite: relationship to the CYP2D6 genotype. Psychopharmacology. 1996;123(4):315\u20139.","journal-title":"Psychopharmacology"},{"issue":"5770","key":"1528_CR5","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1136\/bmj.3.5770.331","volume":"3","author":"M Asberg","year":"1971","unstructured":"Asberg M, et al. Relationship between plasma level and therapeutic effect of nortriptyline. Br Med J. 1971;3(5770):331\u20134.","journal-title":"Br Med J"},{"issue":"8","key":"1528_CR6","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1080\/15622975.2021.1878427","volume":"22","author":"CB Eap","year":"2021","unstructured":"Eap CB, et al. Tools for optimising pharmacotherapy in psychiatry (therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests): focus on antidepressants. World J Biol Psychiatry. 2021;22(8):561\u2013628.","journal-title":"World J Biol Psychiatry"},{"issue":"5726","key":"1528_CR7","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1136\/bmj.4.5726.18","volume":"4","author":"M Asberg","year":"1970","unstructured":"Asberg M, et al. Correlation of subjective side effects with plasma concentrations of nortriptyline. Br Med J. 1970;4(5726):18\u201321.","journal-title":"Br Med J"},{"issue":"1","key":"1528_CR8","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.jad.2012.07.008","volume":"145","author":"JD Bukh","year":"2013","unstructured":"Bukh JD, et al. The effect of prolonged duration of untreated depression on antidepressant treatment outcome. J Affect Disord. 2013;145(1):42\u20138.","journal-title":"J Affect Disord"},{"issue":"1","key":"1528_CR9","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1038\/s41398-019-0460-3","volume":"9","author":"C Kraus","year":"2019","unstructured":"Kraus C, et al. Prognosis and improved outcomes in major depression: a review. Transl Psychiatry. 2019;9(1):127.","journal-title":"Transl Psychiatry"},{"key":"1528_CR10","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1016\/j.jad.2015.01.014","volume":"175","author":"L Ghio","year":"2015","unstructured":"Ghio L, et al. Duration of untreated depression influences clinical outcomes and disability. J Affect Disord. 2015;175:224\u20138.","journal-title":"J Affect Disord"},{"issue":"5","key":"1528_CR11","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1017\/S1092852923002213","volume":"28","author":"G Alva","year":"2023","unstructured":"Alva G. Importance of achieving rapid treatment response in major depressive disorder. CNS Spectr. 2023;28(5):521\u20135.","journal-title":"CNS Spectr"},{"issue":"5","key":"1528_CR12","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2023.12443","volume":"6","author":"CF Vos","year":"2023","unstructured":"Vos CF, et al. Effectiveness of genotype-specific tricyclic antidepressant dosing in patients with major depressive disorder: a randomized clinical trial. JAMA Netw Open. 2023;6(5): e2312443.","journal-title":"JAMA Netw Open"},{"issue":"1","key":"1528_CR13","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1002\/cpt.597","volume":"102","author":"JK Hicks","year":"2017","unstructured":"Hicks JK, et al. Clinical pharmacogenetics implementation consortium guideline (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update. Clin Pharmacol Ther. 2017;102(1):37\u201344.","journal-title":"Clin Pharmacol Ther"},{"key":"1528_CR14","doi-asserted-by":"crossref","unstructured":"Curry SHWR. Factors affecting plasma concentrations, in drug disposition and pharmacokinetics. Wiley; 2010.","DOI":"10.1002\/9780470665190"},{"issue":"6","key":"1528_CR15","doi-asserted-by":"publisher","first-page":"796","DOI":"10.1038\/clpt.1980.237","volume":"28","author":"P Kragh-S\u00f8rensen","year":"1980","unstructured":"Kragh-S\u00f8rensen P, Larsen NE. Factors influencing nortriptyline steady-state kinetics: plasma and saliva levels. Clin Pharmacol Ther. 1980;28(6):796\u2013803.","journal-title":"Clin Pharmacol Ther"},{"issue":"2","key":"1528_CR16","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1007\/BF00562502","volume":"4","author":"B Alexanderson","year":"1972","unstructured":"Alexanderson B. Pharmacokinetics of nortriptyline in man after single and multiple oral doses: the predictability of steady-state plasma concentrations from single-dose plasma-level data. Eur J Clin Pharmacol. 1972;4(2):82\u201391.","journal-title":"Eur J Clin Pharmacol"},{"issue":"5","key":"1528_CR17","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1097\/00004714-198710000-00003","volume":"7","author":"LS Schneider","year":"1987","unstructured":"Schneider LS, et al. Prediction of individual dosage of nortriptyline in depressed elderly outpatients. J Clin Psychopharmacol. 1987;7(5):311\u20134.","journal-title":"J Clin Psychopharmacol"},{"issue":"2","key":"1528_CR18","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1007\/BF00561582","volume":"18","author":"S Dawling","year":"1980","unstructured":"Dawling S, et al. Nortriptyline therapy in elderly patients: dosage prediction after single dose pharmacokinetic study. Eur J Clin Pharmacol. 1980;18(2):147\u201350.","journal-title":"Eur J Clin Pharmacol"},{"issue":"11","key":"1528_CR19","doi-asserted-by":"publisher","first-page":"869","DOI":"10.2165\/00003088-200140110-00005","volume":"40","author":"EE Kvist","year":"2001","unstructured":"Kvist EE, et al. Quantitative pharmacogenetics of nortriptyline: a novel approach. Clin Pharmacokinet. 2001;40(11):869\u201377.","journal-title":"Clin Pharmacokinet"},{"issue":"3","key":"1528_CR20","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1016\/0893-133X(89)90026-2","volume":"2","author":"IR Katz","year":"1989","unstructured":"Katz IR, et al. Steady state pharmacokinetics of nortriptyline in the frail elderly. Neuropsychopharmacology. 1989;2(3):229\u201336.","journal-title":"Neuropsychopharmacology"},{"issue":"1","key":"1528_CR21","doi-asserted-by":"publisher","first-page":"61","DOI":"10.3109\/10401239109147969","volume":"3","author":"SJ Bupp","year":"1991","unstructured":"Bupp SJ. The effect of age on plasma levels of nortriptyline. Ann Clin Psychiatry. 1991;3(1):61\u20135.","journal-title":"Ann Clin Psychiatry"},{"issue":"1\u201302","key":"1528_CR22","first-page":"9","volume":"51","author":"E Hiemke","year":"2018","unstructured":"Hiemke E, et al. Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology: update 2017. Pharmacopsychiatry. 2018;51(1\u201302):9\u201362.","journal-title":"Pharmacopsychiatry"},{"key":"1528_CR23","unstructured":"The Dutch Pharmacogenomic Working Group. Phamacogenomic recommendations, farmacogenetica\u2014update. 2022. www.knmp.nl\/. Accessed 1 Dec 2024."},{"key":"1528_CR24","unstructured":"Health Institute the Netherlands. Pharmacotherapeutic compass. 2020. https:\/\/farmacotherapeutischkompas.nl. Accessed 1 Dec 2024."},{"key":"1528_CR25","unstructured":"European Medicines Agency. Guideline on bioanalytical method validation. 2015. https:\/\/www.ema.europa.eu\/en\/documents\/scientific-guideline\/guideline-bioanalytical-method-validation_en.pdf. Accessed 1 Dec 2024."},{"key":"1528_CR26","unstructured":"Icon (2020). NONMEM (version 7.5). Dublin, Ireland."},{"key":"1528_CR27","unstructured":"IBM Corp. IBM SPSS statistics for Windows (version 30), Armonk; 2024."},{"issue":"6","key":"1528_CR28","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1097\/JCP.0000000000001129","volume":"39","author":"J van der Schans","year":"2019","unstructured":"van der Schans J, et al. Effects of pharmacogenetic screening for CYP2D6 among elderly starting therapy with nortriptyline or venlafaxine: a pragmatic randomized controlled trial (CYSCE trial). J Clin Psychopharmacol. 2019;39(6):583\u201390.","journal-title":"J Clin Psychopharmacol"},{"issue":"5","key":"1528_CR29","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1055\/s-0042-105443","volume":"49","author":"E Berm","year":"2016","unstructured":"Berm E, et al. Relation between CYP2D6 genotype, phenotype and therapeutic drug concentrations among nortriptyline and venlafaxine users in old age psychiatry. Pharmacopsychiatry. 2016;49(5):186\u201390.","journal-title":"Pharmacopsychiatry"},{"issue":"4","key":"1528_CR30","first-page":"117","volume":"34","author":"Z Nakad","year":"2024","unstructured":"Nakad Z, Saab Y. Precision dosing for patients on tricyclic antidepressants. Pharmacogenet Genom. 2024;34(4):117\u201325.","journal-title":"Pharmacogenet Genom"},{"issue":"6","key":"1528_CR31","doi-asserted-by":"publisher","first-page":"871","DOI":"10.1007\/s40262-024-01382-3","volume":"63","author":"M Centanni","year":"2024","unstructured":"Centanni M, et al. Pharmacogenetic testing or therapeutic drug monitoring: a quantitative framework. Clin Pharmacokinet. 2024;63(6):871\u201384.","journal-title":"Clin Pharmacokinet"},{"issue":"15","key":"1528_CR32","doi-asserted-by":"publisher","first-page":"857","DOI":"10.2217\/pgs-2022-0104","volume":"23","author":"S Mostafa","year":"2022","unstructured":"Mostafa S, et al. Pharmacogenomics in psychiatry\u2014the challenge of cytochrome P450 enzyme phenoconversion and solutions to assist precision dosing. Pharmacogenomics. 2022;23(15):857\u201367.","journal-title":"Pharmacogenomics"},{"issue":"5","key":"1528_CR33","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1111\/imj.13412","volume":"47","author":"J Donagher","year":"2017","unstructured":"Donagher J, Martin JH, Barras MA. Individualised medicine: why we need Bayesian dosing. Intern Med J. 2017;47(5):593\u2013600.","journal-title":"Intern Med J"},{"issue":"1","key":"1528_CR34","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1023\/A:1020634813296","volume":"27","author":"Y Merl\u00e9","year":"1999","unstructured":"Merl\u00e9 Y, Mentr\u00e9 F. Optimal sampling times for Bayesian estimation of the pharmacokinetic parameters of nortriptyline during therapeutic drug monitoring. J Pharmacokinet Biopharm. 1999;27(1):85\u2013101.","journal-title":"J Pharmacokinet Biopharm"},{"issue":"12","key":"1528_CR35","doi-asserted-by":"publisher","first-page":"1368","DOI":"10.1177\/106002809102501216","volume":"25","author":"WA Kehoe","year":"1991","unstructured":"Kehoe WA, et al. Early individualization of tricyclic antidepressant dosing using a Bayesian pharmacokinetic model. DICP. 1991;25(12):1368\u201373.","journal-title":"DICP"},{"issue":"8","key":"1528_CR36","doi-asserted-by":"publisher","first-page":"842","DOI":"10.1002\/j.1552-4604.1994.tb02049.x","volume":"34","author":"WA Kehoe","year":"1994","unstructured":"Kehoe WA, et al. Sources of prediction error when using a Bayesian method to evaluate nortriptyline serum concentrations. J Clin Pharmacol. 1994;34(8):842\u20137.","journal-title":"J Clin Pharmacol"},{"issue":"4","key":"1528_CR37","doi-asserted-by":"publisher","first-page":"1418","DOI":"10.1111\/bcp.14426","volume":"88","author":"T Mizuno","year":"2022","unstructured":"Mizuno T, et al. Clinical implementation of pharmacogenetics and model-informed precision dosing to improve patient care. Br J Clin Pharmacol. 2022;88(4):1418\u201326.","journal-title":"Br J Clin Pharmacol"},{"key":"1528_CR38","doi-asserted-by":"crossref","unstructured":"Minichmayr IK et al. Model-informed precision dosing: state of the art and future perspectives. Adv Drug Deliv Rev. 2024:115421.","DOI":"10.1016\/j.addr.2024.115421"},{"issue":"4","key":"1528_CR39","doi-asserted-by":"publisher","first-page":"928","DOI":"10.1002\/cpt.2202","volume":"109","author":"SG Wicha","year":"2021","unstructured":"Wicha SG, et al. From therapeutic drug monitoring to model-informed precision dosing for antibiotics. Clin Pharmacol Ther. 2021;109(4):928\u201341.","journal-title":"Clin Pharmacol Ther"},{"issue":"12","key":"1528_CR40","doi-asserted-by":"publisher","first-page":"1054","DOI":"10.1177\/02698811241275630","volume":"38","author":"A Lereclus","year":"2024","unstructured":"Lereclus A, et al. Towards precision dosing in psychiatry: population pharmacokinetics meta-modelling of clozapine and lithium. J Psychopharmacol. 2024;38(12):1054\u201362.","journal-title":"J Psychopharmacol"},{"issue":"5","key":"1528_CR41","doi-asserted-by":"publisher","first-page":"674","DOI":"10.1097\/FTD.0000000000000987","volume":"44","author":"A Lereclus","year":"2022","unstructured":"Lereclus A, et al. Towards precision dosing of clozapine in schizophrenia: external evaluation of population pharmacokinetic models and Bayesian forecasting. Ther Drug Monit. 2022;44(5):674\u201382.","journal-title":"Ther Drug Monit"},{"issue":"8","key":"1528_CR42","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1007\/s00228-010-0857-7","volume":"66","author":"G Gervasini","year":"2010","unstructured":"Gervasini G, Ben\u00edtez J, Carrillo JA. Pharmacogenetic testing and therapeutic drug monitoring are complementary tools for optimal individualization of drug therapy. Eur J Clin Pharmacol. 2010;66(8):755\u201374.","journal-title":"Eur J Clin Pharmacol"}],"container-title":["Clinical Pharmacokinetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s40262-025-01528-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s40262-025-01528-x\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s40262-025-01528-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T14:56:47Z","timestamp":1750690607000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s40262-025-01528-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,25]]},"references-count":42,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2025,7]]}},"alternative-id":["1528"],"URL":"https:\/\/doi.org\/10.1007\/s40262-025-01528-x","relation":{},"ISSN":["0312-5963","1179-1926"],"issn-type":[{"value":"0312-5963","type":"print"},{"value":"1179-1926","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,25]]},"assertion":[{"value":"11 May 2025","order":1,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 May 2025","order":2,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The study and the appointment of C.V. and S.t.H. were funded by the Netherlands Organization for Health Research and Development (ZonMW), project no. 848016004. The funding body had no role in the design of the study, collection of data, or decision to publish the study.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"We report no conflicts of interest.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"Ethical approval for the original study was obtained from the Commissie Mensgebonden Onderzoek (CMO) Medical Ethical Review Board in Arnhem-Nijmegen, the Netherlands, and from local ethical review boards. The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"All patients provided written informed consent.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"Not applicable.","order":6,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"Data are available upon reasonable request.","order":7,"name":"Ethics","group":{"name":"EthicsHeading","label":"Availability of data and material"}},{"value":"Not applicable.","order":8,"name":"Ethics","group":{"name":"EthicsHeading","label":"Code availability"}},{"value":"C.V., R.A., J.J., and R.t.H. initiated the idea for the study and conducted the statistical analyses. C.V. was the primary author of the study. M.C., S.t.H., R.A., A.S., J.J., and R.t.H. made important contributions. All authors read and approved the final manuscript.","order":9,"name":"Ethics","group":{"name":"EthicsHeading","label":"Author contributions"}}]}}