{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T22:11:40Z","timestamp":1783030300814,"version":"3.54.6"},"reference-count":70,"publisher":"Georg Thieme Verlag KG","issue":"01","license":[{"start":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T00:00:00Z","timestamp":1762128000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmacopsychiatry"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Attention deficit-\/hyperactivity disorder (ADHD) medications are commonly\n                        prescribed to children and adolescents, but therapeutic reference ranges\n                        have not been systematically evaluated yet. This study aimed to establish\n                        preliminary therapeutic reference ranges for methylphenidate (MPH),\n                        d-amphetamine (d-AMP), atomoxetine (ATX), and guanfacine\n                        (GFC), based on a systematic review of the existing relevant literature.<\/jats:p>\n                  <jats:p>Therapeutic reference ranges were calculated based on blood concentrations\n                        measured in responder children and adolescents with ADHD. Therapeutic ranges\n                        were determined both as mean values plus one standard deviation (SD) and\n                        using the 25th\/75th IQRs.<\/jats:p>\n                  <jats:p>For MPH, a therapeutic reference range was calculated according to the mean\n                        maximum concentration (Cmax)\u00b1SD (8.8\u00b17.7\u2009ng\/mL) as 1.1\u201316.6\u2009ng\/mL\n                        and according to the 25th\/75th IQR as 7.2\u201311.3\u2009ng\/mL.\n                        The mean d-AMP Cmax concentration\u00b1SD was 31.9\u00b115.2\u2009ng\/mL,\n                        resulting in a range of 16.6\u201347.1\u2009ng\/mL, and the calculated range according\n                        to IQR 25th\/75th was 18.4\u201332.5\u2009ng\/mL. For ATX, mean\n                        maximum concentration at steady state (Cmax,ss)\u00b1SD was\n                        589.7\u00b1656.3\u2009ng\/mL, resulting in a range of 0.0\u20131245.9\u2009ng\/mL, and according\n                        to 25th\/75th IQR, the range was calculated as\n                        537.0\u2013635.5\u2009ng\/mL. For GFC, only one study was eligible, with a mean blood\n                        concentration of 7.5\u2009ng\/mL in responders.<\/jats:p>\n                  <jats:p>The results provide preliminary recommendations that can serve as reference\n                        values for therapeutic drug monitoring in children and adolescents treated\n                        with MPH, AMP, ATX, and GFC. Further research is needed to validate or\n                        refine the proposed therapeutic ranges.<\/jats:p>","DOI":"10.1055\/a-2689-4911","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T23:44:07Z","timestamp":1762213447000},"page":"15-34","source":"Crossref","is-referenced-by-count":2,"title":["Therapeutic Reference Ranges for ADHD Drugs in Blood of Children and\n                    Adolescents: A Systematic Review by the AGNP TDM-Task Force"],"prefix":"10.1055","volume":"59","author":[{"given":"Sarah S.","family":"Hagenk\u00f6tter","sequence":"additional","affiliation":[{"name":"Department of Child and Adolescent Psychiatry, Psychotherapy and\n                    Psychosomatics, Medical Center, University Hospital of Freiburg, Freiburg,\n                    Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"Egberts","sequence":"additional","affiliation":[{"name":"Department of Child and Adolescent Psychiatry, GGZ Reinier van Arkel,\n                    \u2018s-Hertogenbosch, The Netherlands"},{"name":"AGNP TDM-Task Force, Arbeitsgemeinschaft f\u00fcr Neuropsychopharmakologie\n                    und Pharmacopsychiatrie,\n                    https:\/\/agnp.de\/die-agnp\/arbeitsgruppen\/therapeutisches-drug-monitoring\/"},{"name":"Competence network TDM in child and adolescent psychiatry,\n                    https:\/\/tdm-kjp.com"},{"name":"Department Child and Adolescent Psychiatry, Psychosomatics and\n                    Psychotherapy, University Hospital of Wuerzburg, Wuerzburg,\n                    Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Fekete","sequence":"additional","affiliation":[{"name":"AGNP TDM-Task Force, Arbeitsgemeinschaft f\u00fcr Neuropsychopharmakologie\n                    und Pharmacopsychiatrie,\n                    https:\/\/agnp.de\/die-agnp\/arbeitsgruppen\/therapeutisches-drug-monitoring\/"},{"name":"Competence network TDM in child and adolescent psychiatry,\n                    https:\/\/tdm-kjp.com"},{"name":"Department Child and Adolescent Psychiatry, Psychosomatics and\n                    Psychotherapy, University Hospital of Wuerzburg, Wuerzburg,\n                    Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Hiemke","sequence":"additional","affiliation":[{"name":"AGNP TDM-Task Force, Arbeitsgemeinschaft f\u00fcr Neuropsychopharmakologie\n                    und Pharmacopsychiatrie,\n                    https:\/\/agnp.de\/die-agnp\/arbeitsgruppen\/therapeutisches-drug-monitoring\/"},{"name":"Department of Psychiatry and Psychotherapy, University Medical Center\n                    of Mainz, Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reinhold","family":"Rauh","sequence":"additional","affiliation":[{"name":"Department of Child and Adolescent Psychiatry, Psychotherapy and\n                    Psychosomatics, Medical Center, University Hospital of Freiburg, Freiburg,\n                    Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans-Willi","family":"Clement","sequence":"additional","affiliation":[{"name":"Department of Child and Adolescent Psychiatry, Psychotherapy and\n                    Psychosomatics, Medical Center, University Hospital of Freiburg, Freiburg,\n                    Germany"},{"name":"AGNP TDM-Task Force, Arbeitsgemeinschaft f\u00fcr Neuropsychopharmakologie\n                    und Pharmacopsychiatrie,\n                    https:\/\/agnp.de\/die-agnp\/arbeitsgruppen\/therapeutisches-drug-monitoring\/"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Biscaldi","sequence":"additional","affiliation":[{"name":"Department of Child and Adolescent Psychiatry, Psychotherapy and\n                    Psychosomatics, Medical Center, University Hospital of Freiburg, Freiburg,\n                    Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Fleischhaker","sequence":"additional","affiliation":[{"name":"Department of Child and Adolescent Psychiatry, Psychotherapy and\n                    Psychosomatics, Medical Center, University Hospital of Freiburg, Freiburg,\n                    Germany"},{"name":"Competence network TDM in child and adolescent psychiatry,\n                    https:\/\/tdm-kjp.com"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manfred","family":"Gerlach","sequence":"additional","affiliation":[{"name":"AGNP TDM-Task Force, Arbeitsgemeinschaft f\u00fcr Neuropsychopharmakologie\n                    und Pharmacopsychiatrie,\n                    https:\/\/agnp.de\/die-agnp\/arbeitsgruppen\/therapeutisches-drug-monitoring\/"},{"name":"Competence network TDM in child and adolescent psychiatry,\n                    https:\/\/tdm-kjp.com"},{"name":"Department Child and Adolescent Psychiatry, Psychosomatics and\n                    Psychotherapy, University Hospital of Wuerzburg, Wuerzburg,\n                    Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"194","published-online":{"date-parts":[[2025,11,3]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1337","DOI":"10.1007\/s00787-021-01871-x","article-title":"The management of ADHD in children and adolescents: Bringing evidence 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Wolraich","year":"2004","journal-title":"CNS Drugs"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"457","DOI":"10.2165\/00003088-199937060-00002","article-title":"Pharmacokinetics and clinical effectiveness of methylphenidate","volume":"37","author":"H C Kimko","year":"1999","journal-title":"Clin Pharmacokinet"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1169","DOI":"10.1517\/17425255.2014.922542","article-title":"An evaluation of the pharmacokinetics of methylphenidate for the treatment of\n                    attention-deficit\/ hyperactivity disorder","volume":"10","author":"J Fr\u00f6lich","year":"2014","journal-title":"Expert Opin Drug Metab Toxicol"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"S62","DOI":"10.1097\/JCP.0b013e3181744aa6","article-title":"Does chirality matter? Pharmacodynamics of enantiomers of methylphenidate in\n                    patients with attention-deficit\/hyperactivity disorder","volume":"28","author":"D Quinn","year":"2008","journal-title":"J Clin Psychopharmacol"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1023\/A:1018956526016","article-title":"Enantioselective pharmacokinetics of dl-threo-methylphenidate in humans","volume":"10","author":"N R Srinivas","year":"1993","journal-title":"Pharm Res"},{"key":"ref12","doi-asserted-by":"crossref","DOI":"10.1007\/978-3-662-65267-1","volume-title":"Neuro-\/Psychopharmaka im Kindes-und Jugendalter. Grundlagen und Therapie. 4.\n                    Aufl.","author":"M Gerlach","year":"2023"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1007\/978-3-7091-1501-5_12","volume-title":"Attention-Deficit\/Hyperactivity Disorders. In: Gerlach M, ed. Psychiatric drugs\n                    in children and adolescents: Basic pharmacology and practical applications","author":"S Walitza","year":"2014"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1177\/108705470000300403","article-title":"Methyiphenidate vs. amphetamine: Comparative review","volume":"3","author":"L E Arnold","year":"2000","journal-title":"J Atten Disord"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"1487","DOI":"10.1126\/science.168.3938.1487","article-title":"Amphetamine: Differentiation by d and l isomers of behavior involving brain\n                    norepinephrine or dopamine","volume":"168","author":"K M Taylor","year":"1970","journal-title":"Science"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"317","DOI":"10.2147\/ndt.s9749","article-title":"Absorption of lisdexamfetamine dimesylate and its enzymatic conversion to\n                    d-amphetamine","volume":"6","author":"M Pennick","year":"2010","journal-title":"Neuropsychiatr Dis Treat"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1097\/01.chi.0000246056.83791.b6","article-title":"CYP2D6 and clinical response to atomoxetine in children and adolescents with\n                    ADHD","volume":"46","author":"D Michelson","year":"2007","journal-title":"J Am Acad Child Adolesc Psychiatry"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1089\/104454603321666199","article-title":"Atomoxetine pharmacokinetics in children and adolescents with attention deficit\n                    hyperactivity disorder","volume":"13","author":"J W Witcher","year":"2003","journal-title":"J Child Adolesc Psychopharmacol"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1055\/s-0043-116492","article-title":"Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology:\n                    Update 2017","volume":"51","author":"C Hiemke","year":"2018","journal-title":"Pharmacopsychiatry"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1097\/FTD.0000000000001264","article-title":"How to determine a therapeutic reference range for a psychotropic drug\n                    systematically? Recommendations of the TDM Task Force of the AGNP","volume":"47","author":"X M Hart","year":"2025","journal-title":"Ther Drug Monit"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"787043","DOI":"10.3389\/fpsyt.2021.787043","article-title":"Therapeutic reference ranges for psychotropic drugs: A protocol for systematic\n                    reviews","volume":"12","author":"X M Hart","year":"2021","journal-title":"Front Psychiatry"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1002\/jrsm.1260","article-title":"Introduction, comparison, and validation of meta-essentials: A free and simple\n                    tool for meta-analysis","volume":"8","author":"R Suurmond","year":"2017","journal-title":"Res Synth Methods"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1097\/FTD.0000000000000582","article-title":"Concentration-effect relationships of psychoactive drugs and the problem to\n                    calculate therapeutic reference ranges","volume":"41","author":"C Hiemke","year":"2019","journal-title":"Ther Drug Monit"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: An updated guideline for reporting systematic\n                    reviews","volume":"372","author":"M J Page","year":"2021","journal-title":"BMJ"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1111\/j.1365-2125.1979.tb01046.x","article-title":"Pharmacokinetics of methylphenidate in hyperkinetic children","volume":"8","author":"B L Hungund","year":"1979","journal-title":"Br J Clin Pharmacol"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1016\/S0009-9120(80)80007-5","article-title":"Gas chromatographic\/mass spectrometric analysis of methylphenidate (ritalin) in\n                    serum","volume":"13","author":"Y M Chan","year":"1980","journal-title":"Clin Biochem"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1097\/00004583-198201000-00005","article-title":"Clinical studies of methylphenidate serum levels in children and adults","volume":"21","author":"C T Gualtieri","year":"1982","journal-title":"J Am Acad Child Psychiatry"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1097\/00004583-198201000-00006","article-title":"Learning ability and methylphenidate (Ritalin) plasma concentration in\n                    hyperkinetic children. A preliminary investigation","volume":"21","author":"S S Kupietz","year":"1982","journal-title":"J Am Acad Child Psychiatry"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"688","DOI":"10.1542\/peds.69.6.688","article-title":"Psychopharmacology of attention deficit disorder: Pharmacokinetic,\n                    neuroendocrine, and behavioral measures following acute and chronic treatment\n                    with methylphenidate","volume":"69","author":"S E Shaywitz","year":"1982","journal-title":"Pediatrics"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1007\/BF00449120","article-title":"Methylphenidate oral dose plasma concentrations and behavioral response in\n                    children","volume":"76","author":"B G Winsberg","year":"1982","journal-title":"Psychopharmacology"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1542\/peds.72.1.56","article-title":"Methylphenidate hydrochloride given with or before breakfast: II. 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