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Yo U Are P Ro H Ib Ited from M Aking Th Is P D F P U B Licly Availab Le. It Is

You are prohibited from making this PDF publicly available. isIt illegal to post this copyrighted PDF on any website. J ClinPsychiatry 81:3,May/June 2020 For [email protected]. reprints orpermissions, contact ♦ article. Facultythe financialdisclosure appearsat theendof anyreported relevant personalfinancialrelationships. staff CME Institute the Health.Nomemberof of Mental pharmaceutical companies andtheNational Institute and Institute, whichreceives research funding from multiple Sunovion, andworks withtheMGHClinical Trials Network is sponsored by Teva, Actavis, and Alkermes, Otsuka, works with theMGHNational Pregnancy Registry, which GeneralHospital(MGH)employee,as aMassachusetts Committee for Educational for Activities and, Medscape; Steering the Committee for Janssen;hasbeenamemberof Data Safety andMonitoring Independent the member of Alkermes, andSunovion;boards hasbeena for Otsuka, advisory the from hasbeenamemberof JayMac and Sage; Freeman, MD, Editor inChief, hasreceived research funding interest that were identified. thepastyear, In P. Marlene interest. The hasresolved CMEInstitute any of conflicts andany commercialthemselves ortheirspouse/partner all relevant personalfinancial relationships between were askedtoactivity complete astatement regarding this All individualsinapositionto influence thecontent of Financial Disclosure material was2022. 2020. April this The latest review of is eligible 1Credit for™ through Category AMAPRA June30, was publishedinMay 2020and This educational activity Release, Expiration, andReview Dates IcreditCategory for completing thisprogram. Physician assistants may receive amaximumof1hour accredited by ACCME orarecognized state medicalsociety. 1Credit for™ from Category AMAPRA organizationscertified for educationalaccepts activities ofparticipation certificates Note: The Academy American ofPhysician Assistants (AAPA) intheactivity. participation their only thecredit commensurate withtheextent of 1Credit™. Physicians Category of 1AMAPRA shouldclaim fordesignates amaximum CMEactivity thisjournal-based The ofPhysicians CMEInstitute Postgraduate Press, Inc., Credit Designation physicians. to provide continuing medicaleducation for Council for Continuing Education Medical Press, Inc.,isaccredited by theAccreditation The ofPhysicians CMEInstitute Postgraduate Accreditation Statement youAfter shouldbeableto: studyingthisarticle, CME Objective $10 processing fee willapply. questions inthePosttest, andcomplete theEvaluation. A To obtaincredit, answer correctly read the thearticle, needs withdesired results. areActivities plannedusingaprocess that linksidentified throughout eachvolume.topics of onavariety CME articles ofprovidingwith thepurpose readers of withacurriculum educational needsofCMEparticipants, the assessment of are for selected creditArticles designation basedonan CME Background • process andsafety of to helpoptimize theefficacy oftheclinicaldecision-making indications aspart Use therapeutic drugmonitoring withappropriate Focus on : Consensus Statement Oliver Freudenreich, MD Michael Paulzen, MDMichael Neuropsychopharmakologie undPharmakopsychiatrie Monitoring Task für Force Arbeitsgemeinschaft the of Clinical Psychopharmacology andthe Therapeutic Drug Pierre Baumann, PhD Georgios Schoretsanitis, MD, PhD Pharmakopsychiatrie Neuropsychopharmakologiefür und Arbeitsgemeinschaft Forcethe of Therapeutic Monitoring Drug Task Psychopharmacology and the of Clinical American Society the A Joint Consensus Statement of Practice: Clinical Treatment in to Optimize Levels Blood antipsychotics. although forTDM isnotequallyrecommended/supported all which patients are mostlikelyto respond andtolerate treatment, therapeutic reference ranges for blood antipsychotic levels, within to provide with algorithm a condensed clinicaldecision-making Evidence: TDM literature onantipsychotics reviewed was critically and Pharmacopsychiatry). Pharmakopsychiatrie (Association ofNeuropsychopharmacology fürNeuropsychopharmakologieArbeitsgemeinschaft und and the Therapeutic Drug Monitoring Task the Force of ofClinicalPsychopharmacology, Society American the members of Participants wereParticipants: cliniciansandresearchers, antipsychotics.those andsafety of efficacy apply TDM inroutine inorder clinicalpractice to helpoptimize the aid clinicianswhoroutinely prescribe antipsychotics to successfully pregnant isto women, andtheelderly. article this The mainaim of vulnerable patient subgroups,highly suchaschildren, adolescents, The benefitsof evident inthetreatmentTDM may of beparticularly adverse (ADRs) drugreactions related to antipsychotic treatment. response,therapeutic relapse, or clinical scenarios, suchaslackof of TDM for antipsychotics canbehelpfulinnumerous challenging augment antipsychotic useanddosingdecisions. The application useful tool personalized ofmodern therapy that canbeappliedto isapotentially astherapeutic drugmonitoring (TDM), also known Objective: The quantification ofantipsychotic levels inblood, Goff, MD John M.Kane, MD Newcomer, MD Gerald Zernig, MD and Gerhard Gründer, MD R. Marder, MD ABSTRACT g ; Deanna L.Kelly, PhD; Deanna © 2020Copyright Physicians Postgraduate Press, Inc. d ; Leslie Citrome, MD, MPH f ; Delbert G.Robinson, MD ; Delbert a,b m ; Ekkehard Haen, MD, PhD; Ekkehard ; Christoph U. Correll, MD k o ; Andreas Conca, MD ; Christoph Hiemke, PhD i ; Daria Piacentino, MD, PhD; Daria q ; for the American Society of; for Society theAmerican h ;

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r e1 Baltimore, Maryland Practice for Psychotherapy and Court-Certified Witness, Hall in Tirol, Tirol, in Hall Witness, Court-Certified and Psychotherapy for Practice Private and Innsbruck, Innsbruck, of University Medical Psychotherapy, University, Faculty Mannheim, Heidelberg Health, Mannheim, Medical Medical School, Boston, Massachusetts Boston, School, Medical Schoretsanitis etal Switzerland Mainz, Germany Mainz, Mainz, of Center Medical University Medicine, Laboratory and Chemistry Brain Medicine, Aachen, Germany JARA–Translational and University; Aachen RWTH Psychosomatics, and e2 For [email protected]. reprints orpermissions, contact ♦ r q p o n m l k j i h g f e d c b a © Copyright 2020Physicians Postgraduate Press, Inc. To https://doi.org/10.4088/JCP.19cs13169 share: 2020;81(3):19cs13169. und Pharmakopsychiatrie. Psychiatry JClin für Neuropsychopharmakologie Arbeitsgemeinschaft Task the of Force Monitoring Drug Therapeutic the and Psychopharmacology Clinical of Society American the of statement consensus ajoint practice: clinical in treatment antipsychotic optimize cite: To 2020;81(3):19cs13169 J ClinPsychiatry process. clinicaldecision-making the of indications aspart encourages cliniciansto perform TDM withthe appropriate information ontheroutine useof TDM for antipsychotics and safety andefficacy. This consensus statement summarizes essential in antipsychotic treatment offers a uniquemethodto improve Conclusions: The utilization of TDM asatool for problem solving levels, issues, practical andinterpretation, aswell aslimitations. indications, therapeutic reference alert ranges andlaboratory areas: steady-state andsamplingtime, levels ofrecommendations, in allcases, andresulting recommendations focused onfollowing circulated to group thewriting members. Consensus was achieved was prepared draft Consensus Process: Apreliminary and Psychiatry, Germany Berlin, Regensburg, Germany Regensburg, Regensburg, of University Toxicology, and Pharmacology of Department Institutes Maryland of Health, Bethesda, Intramural Research Program, National Institute Abuse, on Drug National and Alcoholism, and Abuse on Institute National Research, ofNeuropsychopharmacology, Division Intramural Clinical and Biological Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York New Hempstead, Hofstra/Northwell, at Medicine of School Zucker College, Valhalla, New York Nathan New York Institute, Kline Orangeburg, Medical Research, Manhasset, New Research, York Manhasset, Medical andGlen Oaks, Center for Psychiatric Neuroscience, Feinstein Institute for St Missouri Louis, Medicine, of School University Washington Psychiatry, of Department and 263rd St, Glen Oaks, NY 11004 NY ([email protected]) Oaks, Glen St, 263rd 75-59 Health, Northwell Hospital, Hillside Zucker The Research, Psychiatry * article. the of end the at listed are Pharmakopsychiatrie und für Neuropsychopharmakologie Arbeitsgemeinschaft the Angeles, David Geffen School of Medicine, Los Angeles, California Angeles, Los Medicine, of School Geffen David Angeles, Servizio PsichiatricoServizio del Comprensorio Sanitario di Bolzano, Bolzano, Italy Section onSection Clinical Psychoneuroendocrinology and Thriving Mind South Florida Behavioral Health Network, Miami, Florida; Florida; Miami, Network, Health Behavioral Florida South Mind Thriving Department of Psychiatry, Massachusetts General Hospital, Harvard Harvard Hospital, General of Psychiatry, Massachusetts Department It isIt illegal to post this copyrighted PDF on any website. Members of the Therapeutic Drug Monitoring Task of Force Monitoring Drug Therapeutic the of Members Charité Universitätsmedizin, Department of Child and Adolescent Adolescent and Child of Department Universitätsmedizin, Charité Department of Psychiatry, The Zucker Hillside Hospital, Northwell Health, Health, Northwell Hospital, Hillside Zucker The Psychiatry, of Department Alexianer Hospital Aachen; and Department of Psychiatry, Psychotherapy Psychotherapy Psychiatry, of Department and Aachen; Hospital Alexianer Department of Psychiatry and Behavioral Sciences, New York Medical York Medical New Sciences, Behavioral and Psychiatry of Department Clinical Pharmacology, Department of Psychiatry and Psychotherapy, and and Psychotherapy, and Psychiatry of Department Pharmacology, Clinical Department of Psychiatry, University of Lausanne, Prilly-Lausanne, Prilly-Lausanne, Lausanne, of University Psychiatry, of Department Department of Psychiatry, University of Maryland School of Medicine, Medicine, of School Maryland of University Psychiatry, of Department Department of Psychiatry, NYU Langone Medical Center, New York, and and York, Center, New Medical Langone NYU Psychiatry, of Department Department of Molecular Neuroimaging, Central Neuroimaging, of Institute Molecular of Mental Department Psychiatry and Biobehavioral Sciences, University of California Los Los California of University Sciences, Biobehavioral and Psychiatry Department of Psychiatry and Molecular Medicine, Donald and Barbara and Barbara Donald Medicine, and of Molecular Psychiatry Department Department of Psychiatry and Psychotherapy and Institute of Clinical Clinical of Institute and Psychotherapy and Psychiatry of Department Corresponding author: Experimental Psychiatry Unit, Department of Psychiatry and and Psychiatry of Department Unit, Psychiatry Experimental

Schoretsanitis G, Kane JM, Correll CU, et al. Blood levels to to levels Blood al. CU, et Correll JM, Kane G, Schoretsanitis Georgios Schoretsanitis, MD, PhD, Department of of MD, PhD, Department Schoretsanitis, Georgios . . M . and stabilizers, mood such as , valproate, and therapeutic monitoring drug (TDM) for in psychopharmacotherapy there is an established role for toxicology,clinical and pediatrics, psychiatry. Specifically, including oncology, immunology, infectious diseases, prescribed antipsychotic agents, is increasingly available for majority the of widely the utilitythe of TDM of as part routine pharmacotherapy Pharmacopsychiatry), Association of Neuropsychopharmacology and und Pharmakopsychiatrie (AGNP; inEnglish, Arbeitsgemeinschaftthe Neuropsychopharmakologie für encouraged to read previous work of TDM the taskforce of (ADRs). antipsychotic-relatedof several adverse reactions drug context inthe meaningful of prevention and treatment outcomes. Specifically, of use the TDM is particularly ofas part antipsychotic treatment to improve therapeutic statement is to guideclinicians application inthe of TDM TDM and treatment as usual. The aim of consensus this directly performed comparingbeen outcomes between and drug-drug interactions.and drug-drug treatment. and/or tolerabilityefficacy related to antipsychotic severe mental disorders may help overcome suboptimal like TDM pharmacologic inthe treatment of patients with ranges, treatmentpoor response within therapeutic the dose of patient profiles, indications specific for TDM include patterns. on patients’of based drugs individual pharmacokinetic antipsychotic levels allows tailoring in blood dosage the html/10.1055/s-0043-116492. at latest update of AGNP the consensus is publicly available and safetyenhancing of pharmacotherapy. efficacy the The theoretical framework for of use the TDM practice inclinical substance disorders, use and forensic patients. as patients with intellectual disabilities, patients with adolescents, pregnant women, and elderly, the as well management subgroups, of specific such as children and ■ ■ ■ https://www.thieme-connect.com/products/ejournals/ ■ ■ ■ TDM as part ofantipsychotic treatment.TDM aspart This work provides aframework for theimplementation of efficiently guidecliniciansinclinicalroutine. subgroups andunderappropriate indications can inseveral patient therapeutic drugmonitoring (TDM), bloodlevelsMeasuring ofantipsychotics, as alsoknown response andsafety for antipsychotic treatment. There isanurgenttreatment needfor improvement of © 2020Copyright Physicians Postgraduate Press, Inc. 7 valuable insight areas inseveral of medicine easurement of provides levels in drug blood evaluation of adherence, drug tolerability issues, 9–11 3,4 5 Implementation of precision medicine tools TDM may valuable particularly be in the Cliniciansinterested further in TDM are 1,2 Additionally, quantification the of Clinical PointsClinical 6,12,13 J ClinPsychiatry 81:3,May/June 2020 which provides which details on the 5 Evidence insupport of 8 although few trials have although few trials 6 Regardless

You are prohibited from making this PDF publicly available. You are prohibited from making this PDF publicly available. from similar or different pharmacologic classes. antipsychotic levels include interactions with comedications passage acrossmodify BBB. the blood determinants Other of variability inbioavailability related to transporters that related to transporters gut,in the it not does overcome TDM can circumvent of effects variations the in metabolism as the ABC transporters,as ABC the including P-glycoprotein. genes encoding(BBB) blood-brain transporters, barrier such (CYP1A2, CYP2C19,CYP2D6,and CYP3A4). majoritythe of antipsychotics phasethe 1metabolism of antipsychotics, with involved 4CYPenzymes being in of pharmacokinetic variability of , including system embraced hasisoenzyme been as amajor source antipsychotics. Particularly, cytochrome the P450(CYP) transporters mediating metabolism the and distribution of attention with identification the of enzymes and efflux attainment. Pharmacokinetic pathways have received pharmacokinetic/pharmacodynamicthe (PK/PD) target mainly uponhas been based increasing the knowledge of 2.2. TDM for Antipsychotics: Theoretical Framework limitations. issues, levels, practical andalert interpretation, as well as indications, therapeutic reference ranges and laboratory steady-state and sampling time, levels of recommendations, careclinical are centered around following the areas: framework of TDM, resulting the recommendations for theoretical Following cases. the in all abrief of review manuscript accordingly. was revised Consensus was achieved writing group. Revision suggestions were received, and the draft was prepared andthe circulated to members the of prescribing appropriate via of use TDM. Apreliminary offocusing on enhanced aspects antipsychotic practical the principlesbasic to prescribing the of antipsychotics and relevant the reviewed literature on TDM, applying practice. with integration the of pharmacogenetic tests inclinical variants, by determined activity isCYP2D6), their genetic crucially regards polymorphic (CYP2C19, isoenzymes so-called the Pharmacopsychiatry (AGNP), Associationthe of Neuropsychopharmacology and 2.1. Participants, Evidence, andConsensus Process J ClinPsychiatry 81:3,May/June 2020 For [email protected]. reprints orpermissions, contact ♦ Interactions at apharmacodynamic level comprise provides alist of metabolic pathway inducers and inhibitors. properties, known also as “perpetrator” Table drugs. 1 coprescribed medications with inducing or inhibiting antipsychotic concentrations requires information on the metabolic pathways. Therefore, interpretation the blood of administered antipsychotics overlapping affecting when alter metabolismthe and levels blood of concomitantly metabolizing enzymes or transporters and can ultimately medications inhibiting exert or inducing on effects drug METHODS It isIt illegal to post this copyrighted PDF on any website. In development the past decades, the of TDM science Drawing on prior work by TDM the task force of 16 15 Genetic variants Genetic impact encompass of also crucial which are which increasingly tested routine inclinical 6,12,13 this group of authors authors of group this 17 Numerous 10 While 14 As As respectively. 84–95 and 118–139 days for deltoid and gluteal injection, days 30 and 33, with median half-lives ranging between 3-monthlythe palmitate are reached between days. hours and second at the 10to 14days, with ahalf-life of 9–11 single-injection data first at the reported 2plasma 4–6 peaks, injection displays different pharmacokinetic characteristics; reached 5–7days after injection, with apparent the t days. is approximately elimination the 4–5times half-life (t loss. Practically, to time the reach steady state rate the when of medication input is to equal rate the of concentration refers for inblood adrug to point time the Steady-State andSampling Time 3.1. TDM for Antipsychotics: injection, and apparent the t arein blood reached within 1–14 days after LAI the immediately before next the injection. Peak concentrations In LAI-treated patients, appropriate the sampling is time antipsychotics (LAIs) differ from their oral formulations. drawevening, is blood 12hours. the interval morning. For antipsychotics inthe taken to prescribed be antipsychoticthe is prescribed once if dose, daily inthe morning or, dose the inother words, 24hours after last the appropriate sampling is time immediately before intake of ), and stable During . dosing, the cariprazine (and its principal active metabolite, didesmethyl- particularly long half-life, such as , , majority of antipsychotics. Exceptions are compounds with a is reached within 1week of maintenance dosing for the antipsychoticthe Tableof (see 2), and, thus, steady state and supported by data. Specificity and sensitivity vary reliability such that TDM strongly can be recommended with treatment response with sufficient trials inclinical ranges have established on association their been based Levels ofRecommendations 3.2. TDM for Antipsychotics: respectively. 400 or 300mg aripiprazole monthly 47and being 30days, into TDM. antipsychotics and have not sufficiently integrated yet been more complicated challenges for clinicians prescribing days after last injection. and 57.2days, with maximum concentrations reached 20–34 it has a substantially longer half-life ranging 53.9 between formulation that differs interms of inthat concentrations are reached after 4 weeks, and its t once-monthly. first-generation LAIs, as well as for paliperidone palmitate RESULTS In area the of pharmacokinetics, term the The pharmacokinetics of long-acting injectablelong-acting The pharmacokinetics of For antipsychotics, several therapeutic reference 19 21 © 2020Copyright Physicians Postgraduate Press, Inc. A newly available Anewly risperidonesubcutaneous monthly For aripiprazole monohydrate, levels are peak LAI Therapeutic Consensus Drug Monitoring: Statement 18 22 6 For microspheres, LAI peak is another aripiprazole 19,20 The maximal plasma concentrations for 23 1/2 is about 2–3weeks for steady-state steady-state 1/2 1/2 is 4–6

after e3 1/2 ) increased risk of intolerance or adverse effects. supratherapeutic concentrations may related be to an may associated with be risk of response, poor whereas in that subtherapeutic antipsychotic blood concentrations probabilitythe of response or remission innonresponders, Schoretsanitis etal =UDP-glucuronosyltransferase.UGT oxidase, MAO =monoamine P450, CYP =cytochrome Abbreviations: e4 For [email protected]. reprints orpermissions, contact ♦ Evidence is less supportive for TDM application for athird either or benefit harm. due to fewer data therapeuticlinking level ranges blood to lower level of confidence clinical (level 2recommendation), andsertindole, , TDM is recommended with a flupenthixol, paliperidone, , risperidone, antipsychotics, including aripiprazole, , as well as safety and tolerability. For a second group of efficacy, such as response, remission, and relapse prevention, range are to linked favorable outcomes clinical interms of antipsychoticblood concentrations therapeutic within the asdose, well as for indications special (Table 2).Specifically, , TDM is recommended for titration to target , , , , and For and some other antipsychotics, including thresholds.defining positron emission tomography helpful very when has been but fromand trials, evidence drugs the between between UGT1A1 UGT P-glycoprotein MAO-A MAO CYP3A4 CYP2E1 CYP2D6 CYP2C19 CYP2C9 CYP2C8 CYP2B6 CYP2A6 CYP1A2 Transporters and Enzymes Metabolic Table and Enzymes 1.Inhibitors andInducers ofMetabolic Transporters a of clozapine and provided rigorous data validating TDM. that randomized patients to 3different level ranges blood clozapine on 1 landmarkbased has been prospective trial It isIt illegal to post this copyrighted PDF on any website. Inhibitors of enzymes indicated increase inboldmarkedly concentrations indicated ofenzymes Inhibitors drugs, inbolddecrease whileinducers ofvictim ofenzymes concentrations drugsby more ofvictim than50%.

moclobemide isoniazid, tranylcypromine telithromycin, verapamil, voriconazole miconazole, nelfinavir, , ritonavir, saquinavir, telaprevir, grapefruit juice, indinavir, isoniazid, , ketoconazole, fluconazole, fluvoxamine, (norfluoxetine), fosamprenavir, , clarithromycin, crizotinib, diltiazem, erythromycin, amiodarone, amprenavir, aprepitant, atazanavir , boceprevir, , clomethiazole, disulfiram , paroxetinemoclobemide , , ,ritonavir (norfluoxetine), , , , amiodarone, , cimetidine, duloxetine, fluoxetine isoniazid,, omeprazole moclobemide , ticlopidinevoriconazole esomeprazole, felbamate, fluoxetine (norfluoxetine), fluvoxamine, voriconazole amiodarone, fluconazole, fluvoxamine, isoniazid, miconazole, valproate, fluvoxamine, gemfibrozil clopidogrel, ticlopidine, voriconazole isoniazid, tranylcypromine perazine, , propafenone, zileuton cimetidine, ciprofloxacin, enoxacin, fluvoxamine, isoniazid, norfloxacine, 6 For example, reference the range for 8,25 Nevertheless, TDM increase will Inhibitors 8,10,26–30 24

absence. Large-scale evidence from evidence absence. patients Large-scale with chronic However,trials. absence of is evidence not of evidence supporting TDM varies from reports case to clinical situationsclinical for availability the which of evidence indications.of specific indications These challenging reflect antipsychotic, TDM is strongly recommended for aseries 3.3. TDM for Antipsychotics: Indications decision-making. information that can have astrong influence on clinical absencethe important of level adetectable is very blood patientthe arelapse experiencing of psychotic symptoms, establishment of atherapeutic range. dose For example, in for TDM donot on necessarily depend definitive the below,that, as discussed strong some very indications considered potentially It useful. is important to emphasize concentrationsblood is available, and, thus, TDM is only for , and associating no evidence effects clinical but potentially useful, still be more data are Lastly, needed. case reports. case addressed yet or only inaretrospective fashion or insingle antipsychotic concentrations hasand not effects clinical been melperone, and , blood where between link the , , , , group of antipsychotics, such as brexpiprazole, cariprazine, Regardless of recommendation levels for any specific a © 2020Copyright Physicians Postgraduate Press, Inc. phenobarbital carbamazepine, lamotriginephenytoin, ritonavir carbamazepine, St John’s wort rifabutin, rifampicinritonavir (highdose),St John’s wort , phenobarbital, phenytoin, primidone bosentan, carbamazepine, , , ethanol, isoniazid phenobarbital, phenytoin, primidone, rifampicin rifampicin, ritonavir, St John’s wort carbamazepine, phenobarbital, phenytoin, primidone, phenytoin, rifampicin carbamazepine, efavirenz, modafinil, phenobarbital, cigarette smoke) (aromaticrifampicin, smoking hydrocarbons found in carbamazepine, modafinil, phenobarbital, phenytoin, 31–36 For group this of antipsychotics, TDM can J ClinPsychiatry 81:3,May/June 2020 Inducers

You are prohibited from making this PDF publicly available. You are prohibited from making this PDF publicly available. J ClinPsychiatry 81:3,May/June 2020 For [email protected]. reprints orpermissions, contact ♦ antipsychotic.the titration,dose such or as dose target change switching of patients dictatethe additional will actions apart of fromhalf has shown that treatmentthe of almost the the decision-makingthe process (Figure 1). error approach, TDM can provide valuable information for It isIt illegal to post this copyrighted PDF on any website. 5. 4. 3. 2. 1. TDM may valuable be following inthe situations: inducing or inhibiting properties Combination treatment with medication(s) with Adverse reactions drug (ADRs) treatment Symptom recurrence or relapse during maintenance rangesdose No response clinical within established therapeutic Uncertain adherence to antipsychotics Antipsychotic drugfor which TDM ispotentially useful(level 4) Pimozide Iloperidone Loxapine Lurasidone Melperone Risperidone plus9-hydroxyrisperidoneRisperidone Sertindole Ziprasidone Antipsychotic drugsfor which TDM isuseful(level 3) Major CYP Enzymes Involved, CYP Applicable)Major Enzymes (When Ratios andMetabolite-to-Parent Aripiprazole Clozapine Drug orActive Metabolite Table 2. Therapeutic Levels Reference Alert andLaboratory (inng/mL),Elimination Ranges Half-Lives (t h g f e d c b a Asenapine Chlorprothixene Brexpiprazole Cariprazine Abbreviations: ADR Antipsychotic drugsfor which TDM isstrongly recommended (level 1) Chlorpromazine N-desalkylquetiapine Quetiapine Flupenthixol Fluphenazine Haloperidol Olanzapine Antipsychotic drugsfor which TDM isrecommended (level 2) Perphenazine Perazine Paliperidone For intake of the extended release extended formulation intheeveningthe andbloodwithdrawalFor inthemorning, concentrations expected intake of are 2-fold For the definition of the levels ofrecommendation, 3.2. the see section For thedefinitionof Data from etal. Hiemke 150–500 ng/mL. (aripiprazole +dehydroaripiprazole) =150–500 moiety active For Refers to didesmethyl-cariprazine. Based on AUC data, 73% of the circulating moietiesat active steady statethe are didesmethyl-Based onAUC anddesmethyl-cariprazine. data, 73%of The half-lives of Alternatively, athreshold of1,200ng/mLfor clozapine plusnorclozapine canbeconsidered, asnorclozapine seemsto beimplicated in Elimination half-lives refer to theoral formulations ofantipsychotics. For flupenthixol decanoate t higher thantrough levels. several ADRssuchasseizures. t desmethyl-cariprazine and didesmethyl-cariprazine are anddidesmethyl-cariprazine desmethyl-cariprazine 29.7–37.5and314–446hours, respectively. decanoate t MPR 1/2

= = 4–6 days, andfor LAIt risperidone metabolite-to-parent ratio, TDM metabolite-to-parent 39 g 37 8 1/2 Instead of applying trial-and- aso-called

= 14 days, for olanzapinepamoate t = adverse AUC drugreaction, 6 9 37 40 = 1/2 therapeutic drugmonitoring, t Therapeutic Reference

= 26 days, ratio 1.2–4.3. andmetabolite-to-parent Range inBlood Range 38 (cis-isomer) = 100–350 350–600 100–250 100–500 100–230 (ng/mL) 0.5–5 0.6–2.4 area CYP underthecurve, 15–20 15–40 30–100 20–60 50–100 50–200 20–300 40–140 30–300 20–80 20–60 1/2 5–10 5–10 1–5 5–15 1–10 1–10 c

= 30 days, for palmitate paliperidone t f e c c Laboratory Laboratory Alert LevelAlert (ng/mL) c 1,000 1,000 1,000 120 200 120 200 400 400 280 600 100 460 120 1/2 20 20 20 10 40 15 15 15 12. 11. 10. 9. 8. 7. 6.

5 = d = elimination half-life. cytochrome P450,h cytochrome © 2020Copyright Physicians Postgraduate Press, Inc. tracking and mitigating nonadherence challenges thatspecial underscore for need the as treatment the of patient this subgroup presents Forensic patients or court mandated individuals, Patients with intellectual disabilities Elderly patients orChild adolescent patients Pregnant or lactating patients or mass body index Patients with abnormally or high low weight body of world) the Caucasian versus Asian, rest vsthe Eastern middle indifferentmay highly vary groups, ethnic eg, genetic variantsspecific metabolism drug affecting metabolismthe of antipsychotics prevalence (the of for peculiarities pathways the Genetic involved in 48–120 h 10–13h 23–43 h 18–33 h 20–40 h 17–23 h 55–90 h 13–39 h 60–80 h 15–30 h 12–16 h 12–36 h 30–60 h 20–40 h 17–23 h Therapeutic Consensus Drug Monitoring: Statement 8–12 h 6–11 h 8–12 h 8–16 h t 6–8 h 4–6 h 2–4 h 4–8 h 1/2 91 h 16 h b g 1/2

= CYP3A4, CYP1A2 CYP3A4, CYP2D6 CYP1A2, CYP3A4, CYP2D6 CYP3A4 CYP3A4 CYP2D6, CYP3A4 CYP2D6 CYP3A4 CYP1A2 CYP2D6, CYP3A4 CYP3A4 CYP3A4, CYP2D6 CYP1A2, CYP2D6 CYP1A2, CYP2C19 CYP2D6 CYP2D6 CYP1A2 CYP2D6 CYP2C19 CYP2D6 41 25–49 days, for enanthate perphenazine 1/2 CYP Enzymes InvolvedCYP Enzymes = 6

hours, LAI = a 17 days, for fluphenazine 42 Major = long-acting injectable, injectable, long-acting 44 43 45 0.54–3.1 0.14–0.42 3.6–22.77 1.1–2.7 0.3–0.5 0.5–0.6 0.1–0.3 0.6–2.8 1.1–3.3 1/2 3–6 MPR ), h

46 e5

Schoretsanitis etal e6 For [email protected]. reprints orpermissions, contact ♦ to occur dizziness/orthostasis, QTc prolongation, are more likely dependent ADRs such as sedation, , antipsychotic) specific the other dose- properties of seizures, but (depending on also nondopaminergic the extrapyramidal ADRs,which especially symptoms or response is relatively unlikely, and an upper limit, above consistsin blood of alower limit, below therapeutic which Levels Alert andLaboratory Ranges 3.4. TDM for Antipsychotics: Therapeutic Reference (eg, active(eg, moiety active metabolite, as latter the is pharmacologically active moiety to thresholds. determine efficacy/tolerability used Active risperidone, where active moiety concentrations are also parentmost the cases compound, with exception the of addressed. Reference ranges for antipsychotics involve in or renal and functioning detected can rationally be interactions,drug-drug intercurrent or illness, changes in variations antipsychotic inblood levels due to, among others, individualthe patient. This way, nonadherence partial or dose-concentration-efficacy-tolerability relationship for ingested target inorder dose to havethe abenchmark of antipsychoticblood level at an and efficacious well-tolerated within ameasurement-baseduseful framework to obtain a clearly indicates complete nonadherence, it may be indeed regularly. For example, since only level of ablood zero unique therapeutic concentrations measured when TDM can assist clinicians inidentifying individual’s the range and tolerate levels without blood those ADRs. In fact, may respond only at levels above therapeutic the reference levels below therapeutic the reference range, others while patients may respond despite having antipsychotic blood not always applicable be patient. to every For example, some that ranges are an orienting, population-based tool that may dosages.effective However, clinicians to in mind need bear antipsychotic monotherapy at presumed therapeutically invariablybeen obtained from studies of patients receiving therapeutic response occur. will Reference ranges have It isIt illegal to post this copyrighted PDF on any website. The therapeutic reference range for antipsychotic levels 16. 15. 14. 13. 19. 18. 17.

related adherence aspects therapeutic equivalence differences, as well as generic forms of antipsychotics due to potential Switching preparation original the between and surgery restrictive gastrointestinal resection or bariatric Postoperative care for patients undergoing conditions and infections Patients with acute or chronic inflammatory and renal flow) blood and severe cardiovascular hepatic (affecting disease comorbidities, such as hepatic or renal dysfunction Patients with pharmacokinetically relevant Research Pharmacovigilance programs Switching oral antipsychotics between and LAIs refers to sum the of parent compound and its 56,57 or above it which is relatively unlikely that 50 55 = risperidone plus 9-OH-risperidone 47,48 49 51,52 54 53 that patient the antipsychotic the is taking as prescribed, antipsychotics)evening-dosed after last assure the dose, hours (for morning-dosed antipsychotics) or 12hours (for level obtained was indeed blood at 24the first check if If ADRs are not or suspected present, clinicians to need adjustmenta dose ADRs when are present or suspected. laboratory to prescribing the clinicians, may who consider immediately levels to need be alert the reported by the to increase. Antipsychoticis expected levels than higher represent threshold levels above risk for the which ADRs levelslaboratory (Table alert levels 2).Laboratory alert patients with schizophrenia. to providing reference diagnosis-specific ranges only for TDM isspecific rarely available. Therefore, we are limited gluteal injections) and sampling times. injections, butconcentration peak higher after deltoid than schizophrenia. increasingly prescribed for other indications apart from antipsychotic prescription. However, antipsychotics are ranges applythe indication of to primary/specific the Symbols: ↑ = increase; a for Decision-Making and onResponse Based Tolerability Suggestions Including Figure 1.Estimates ofPercentages for Patient Categories debate as to precision their latter inthe context. applied for LAIs as well, although there some has been antipsychotic studies. Nevertheless, effectively can be they decision-makingclinical for efficacy. added, but target the level of clozapine should determine the clozapine, and the 2 reported levels should not simply be as well. However, norclozapine has only 10%activity of though active the metabolite norclozapine is often reported level monitoring on is clozapine based levels alone, even [paliperidone]). such as injection sites (longer t is wrongly into placed fat tissue) and study issues, design intramuscular injection (with lower levels medication when likely attributed to variations correctly inthe applied, deep LAIs from suggested the reference ranges may more be a pharmacokinetic point of view, potential deviations of Adapted etal. from withpermission Horvitz-Lennon Insu cient Su cient Along with therapeutic reference ranges, provide we also Further, reference the ranges derive mainly from oral © 2020Copyright Physicians Postgraduate Press, Inc. Clinical Response Tolerable 59 Nevertheless, regarding evidence diagnosis- 6 The literature regarding clozapine blood ↓ =decrease. Dose, assess adherence, adherence, assess ↑ Dose, a Su cient response response Su cient switch drug (~25%) J ClinPsychiatry 81:3,May/June 2020 (~52%) Tolerability 1/2 after gluteal than deltoid 6 Lastly, therapeutic 37 Switch drug switch drug Intolerable (~8%) Dose, ↓ Dose, (~15%) 58 From From

You are prohibited from making this PDF publicly available. You are prohibited from making this PDF publicly available. metabolizer status, adherence, interactions. and drug-drug indirectly provide information crucial for or poor ultrarapid antipsychotics.the metabolismin the Hence, of they enzymatic the The MPRs activity implicated reflect drug. majorthe metabolite by parentof concentrations the the of (MPRs). The latter is calculated by dividing the concentrations CYP enzymes implicated and metabolite-to-parent the ratios J ClinPsychiatry 81:3,May/June 2020 For [email protected]. reprints orpermissions, contact ♦ pharmacologic advice, recent developments inteam-based to apply TDM practice. clinical ineveryday Regarding Table 2. metabolic pathwaysthe ofof antipsychotics, as reported in antipsychotics predicted can drugs) be as victim in light interactionsDrug-drug antipsychotics affecting (ie, and elimination half-life (t therapeuticthe reference ranges, laboratory levels, alert Practical IssuesandInterpretation 3.5. TDM for Antipsychotics: antipsychotic levels and accordingly. act for signs clinical indicative of an overdose/excessive blood antipsychotic,the alter metabolism the of and vigilant be by other providers or purchased over counter) the that can nonadherence), out rule of use comedications (prescribed ingested draw blood context inthe inanticipationthe of of possibilitythe of white coat compliance (ie, medications outrule accidental or intentional overdose, eliminate It isIt illegal to post this copyrighted PDF on any website. In Figure 2, we providehow a schematic of overview Table 2provides information, clinically useful including Abbreviations: ADR A. Decide whether/why TDM is indicated B. Check availability of and laboratory pharmacologic advice c b a Figure 2. Therapeutic Monitoring Process Drug inEveryday Clinical Practice Pharmacologic ofpharmacotherapy advice needsto aswell beprovided including assupervision by experts Adapted frometal. withpermission Hiemke See section 3.3for section specificindications.See clinical pharmacists and/ortrainedclinical pharmacists experts. Request TDM Speci c indicationSpeci c (see 3.3) section Further supervision ofFurther pharmacotherapy supervision D ac Pro D St s os eay e 1/2 e o s

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inc r at at luing ion TDM is strongly recommended (Table 2) Treatment with antipsychotics where ion psychiatrist inTDM applications. such as psychiatric can who assist pharmacy specialists, the care provide opportunity the to include other professionals, clozapine level of the therapeuticclozapine range).the level of reported elsewhere (although with a slightly lower upper example for clinical decision-making the process previously more robust for clozapine, we provide aframework as an draw blood must considered.the be point As of data are formulation, change since time last the dose and time the remission, as well as ADRs. Further, antipsychotic the information regarding symptom and severity response or understood/interpreted to be need inrelationship to clinical TDMthe request. antipsychotic In blood fact, levels always diagnosis, and smoking habits, as well as indication the for demographic and characteristics, clinical including age, sex, Moreover, contextual information is necessary, such as metabolic pathways inhibiting or inducing properties. consideration, focusing on medications with antipsychotic are required. First, comedications taken into to need be antipsychoticthe levels, pieces several of information can provide additional assistance. When interpreting been publishedbeen previously. that can inform clinicians on how to utilize TDM best have Additionally, patients’ vignettes case with examples of TDM considering response and tolerability (Table aspects 3). structured processlogically as an aid for practice clinical the framework, algorithm this this proposesfor a each step of note that evenifrigorous data are trial clinical not available

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therapeutic drugmonitoring. or relaps e pre 6 a ent ion 61 Electronic databases 62 It is important to

e7 Schoretsanitis etal Symbols: ↓ monitoring. drug TDM =therapeutic Abbreviation: of the recentlythe approved of antipsychotics have therapeutic conducted controlled inhighly inpatient settings), for none other studies for at leastlast the 15years (including studies PK assessments antipsychotic intheir registration and trials although has pharmaceutical the routinely industry included respond to different antipsychotic blood level ranges. In fact, severe/chronic psychiatric disorders that may possibly receive multiple comedications and may who have more likely to have psychiatric and physical comorbidities and might not generalize to care usual patients, are who more from groups of patients agree who studied. to be Their data mentioned above, therapeutic level ranges blood are derived regarding utility the of TDM practice. inclinical First, as limitations may account for potential differences of opinion care, limitations several must acknowledged. be These tool to improve effectiveness the of antipsychotics in clinical Limitations andFuture Directions 4.1. TDM for Antipsychotics: e8 For [email protected]. reprints orpermissions, contact ♦ b a Clozapine Level Clozapine-Treated Patients Table 3. Algorithm for Decision Making TDM-Based (< Subtherapeutic (350–600 ng/mL) reference range Within the (> Supratherapeutic DISCUSSION It isIt illegal to post this copyrighted PDF on any website. Based on Taylor etal. Refers to clozapine levels onlyandnotto clozapine plusnorclozapine. For the supratherapeutic algorithms. 3.4)whileapplying clinicians needto beadditionallycautious(seesection patients’ levels (> levelsalert higherthanthelaboratory 350 ng/mL) 600 ng/mL) Despite promise the of TDM as a measurement-based

= decrease, ↑ b Insufficient Insufficient Sufficient Sufficient Insufficient Insufficient Sufficient Sufficient Insufficient Insufficient Sufficient Sufficient Response 62 = increase. Intolerable Tolerable Tolerability Intolerable Tolerable Intolerable Tolerable Intolerable Tolerable Intolerable Tolerable Intolerable Tolerable a reach reference range ↑ Clozapine doseslowly to reference range ↑ Clozapine doseto reach Consider ↓clozapine dose Continue to monitor tolerability range accordingly to remain withinthereference ↑ Clozapine doseslowly to range ifpossible remain withinthereference ↑ Clozapine doseslowly to range ifpossible monitor to remain withinthe improve, ↓clozapine dose, tolerability doesnot If Continue to monitor prophylactic dose, monitor. Consider Consider ↓clozapine prophylactic anticonvulsant Consider augmentation/ range ifpossible monitor to bewithinthe ↓ Clozapine doseslowly, anticonvulsant consider prophylactic vigilantBe for tolerability/ Monitor concentrations. Action 1,000 ng/mL), adolescents, such as olanzapine levels wereblood reported for some antipsychotics in used others, such as risperidone with antipsychotics. increasing, prevalence of around 4%for TDM intreatment someis transdiagnostic unclear; data suggest alow, however treated patients with schizophrenia where TDM is applied with schizophrenia. In percentage the fact, of antipsychotic- applied TDM are almost exclusively derived from patients antipsychoticblood level ranges available for clinically estimated referencethe precisionthe ranges. of Second, maintenance treatment), with patients in different treatment phases acute (eg, vs data has resultedthe data inpooling from of samples available to groups for analysis. further In scarcity the fact, as key safety/tolerability parameters or to make data these data antipsychotic between as well levels and blood efficacy companies either to publish (even negative) correlational data exist, our group strongly urges pharmaceutical the antipsychoticblood level ranges published. been Since these of antipsychotics in minors. safety,the indication, the prescription and evidence-based the over recent years relate and to PK/PD concern peculiarities psychopharmacology of children and adolescents discussed elderly, as well as children and adolescents. Ethical issues in example of urgent for need more refers evidence to the analyzedbe and published gap. evidence this to fill Atypical more research Additionally, is needed. available data should to limited the of use TDM practice. inclinical Thus, clearly, outcomes and antipsychotic blood levels likely contributes and tolerability. data treatment linking the The scarcity of level ranges for antipsychotics specific and efficacy clinical establishcould firmly arelationship explicit between blood quite limited for many, ifnot most, antipsychotics that adherence. increasingly available technologies for assessment the of to decision-makingthe integrate need process also will and antipsychotic blood levels. Apart from levels, blood interpretation of future variations picture clinical inthe giventhe patient that as abenchmark used can for be the dose-concentration-efficacy-tolerability relationship for an and efficacious well-tolerated target to dose provide a antipsychotica blood level is obtained at steady state of help antipsychotic of incases partial nonadherence, unless results.interpretation Fourth,the TDM is of of only limited data are provided to laboratory the and for used acareful 12-hour trough level is obtained and sufficient contextual are Third, used. TDM results are only helpful if a true and off-label, even indications for antipsychotics which data many inthe should collected be additional approved, schizophrenia treated with antipsychotics. Thus, more TDM is of applied fraction patients small inavery with legislative efforts to improve safety and discourage “off-label” perform TDM. age groups volume and amounts the requiredblood to of limited knowledge on therapeutic ranges dose for younger for antipsychotics in adolescents and children relates also to © 2020Copyright Physicians Postgraduate Press, Inc. 65,66 Fifth, as mentioned Fifth, above, data are still 68 However, age-dependent patterns for 64 Therefore, it is most likely that J ClinPsychiatry 81:3,May/June 2020 63 which may which limitations pose for 69 67 and aripiprazole. The complexity of using TDM 69 and quetiapine, 71 70 Apart from but not for for not but

You are prohibited from making this PDF publicly available. You are prohibited from making this PDF publicly available. several monthsseveral after titration success. dose limited were of to unravel pharmacokinetic correlates of response clinical framework. Thus, it is nothat surprise previous attempts TDM of part to aclear needs be temporal and contextual a tool for problem solving is unanimously embraced. In fact, ofas part routine. clinical However, potential the of TDM as regardingviews proven the of benefits TDM for drugs specific consensus statementthis members of may hold different years. neuropsychopharmacology, AGNP published afirst consensus statement on TDM in J ClinPsychiatry 81:3,May/June 2020 For [email protected]. reprints orpermissions, contact ♦ Association. dating back to 1985from American the Psychiatric in psychiatry, first attempt with the to establish guidelines antipsychotic treatment. In TDM fact, has along tradition leveraged canwhich be to of enhance safety and efficacy that considers interindividual pharmacokinetic variability, scarce. TDM presents method aunique, evidence-based available relevant tools instandard psychiatric care are publication data. of needed still to demand increased lead will practice for and collection the greater appreciation potential utility ofthe TDM inclinical of requires more attention and application. It likely is also that measurement-based care and precision medicine tool that data indicate that TDM is an important yet underutilized limitations that are mostly addressable by more research, data supportingthe TDM use. Nevertheless, despiteof these limitationsThese some justify skepticism regarding rigor the review.cost-effectivenessthis of TDM is beyond of scope the in general and of TDM of antipsychotics inparticular. The of cost-effectiveness data mandatory area inthe of TDM TDM insome care clinical settings, collection making the Finally, cost may a considerable be to barrier conducting facilitatefurther TDM the integration practice. inclinical ranges for antipsychotic levels in electronic databases will to TDM, availability the of constantly updated reference level of any antipsychotics. or specific Parallel to access the on availability the laboratories that analyze of blood the medications. of Sixth, use these TDM depends of side effects antipsychotic levels and documentation and the of efficacy system including standardized both measurementsblood of European countries. The Network amulticenter uses TDM 12 departments of child and adolescent in3 psychiatry tdm-kjp.de ofuse antipsychotics inyouth, patients presenting with clozapine-related myocarditis at clozapine blood Likewise, levels measured at in baseline Drug MonitoringDrug and inChild Adolescent Psychiatry ( Toeffects. aim, this aCompetence Network on Therapeutic under- or overdosing side long-term and delayed the risk of to guidecliniciansis expected to reduce direct the risk of are reports of TDM underutilization. practice hasclinical not progressed sufficiently and there CONCLUSION It isIt illegal to post this copyrighted PDF on any website. Despite for general the therapy, call personalized 6,12 Nevertheless, implementation the of TDM into ) was established 2007, including in December 1 Two later, decades TDM the the taskforce of 13 updated past inthe twice 72 additional TDM evidence 73 The writing group http:// 74

Targacept, Forum, Abbvie, and Allergan, has and Neurocrine received research Boehringer-Ingelheim, Takeda, Otsuka, , Teva, Roche, Genentech, Dr Marder Pharma. LB of ashareholder is Takeda; and and Janssen from support UpToDate grant from and royalties Teva; received and has Supernus, Rovi, Lundbeck, Boehringer-Ingelheim, for board monitoring safety adata on served has Otsuka; and Janssen, Squibb, Bristol-Myers for testimony expert Teva; provided Takeda, and has Supernus, Sunovion, Dainippon, Sumitomo Servier, Rovi, Recordati, Pfizer, Otsuka, Noven, Neurocrine, Merck, Medscape, MedAvante-ProPhase, Group, Indivior, Janssen/J&J, IntraCellular Therapies, LB Pharma, Lundbeck, Allergan, Angelini, Boehringer-Ingelheim, Richter, Gedeon Lehrman Gerson Alkermes, from honoraria received has or to advisor and/or a consultant been has Vanguard Research Group and Correll LB Pharmaceuticals, Dr Inc. in Teva; ashareholder is Takeda, and Fabre, and Pierre Otsuka, Neurocrine, for Sumitomo, Alkermes, Dainippon Lundbeck, Intracellular Therapies, boards advisory in participated has Janssen; and Lundbeck, Otsuka, from support grant Teva; received Takeda, and has Sunovion, Roche, Reviva, Fabre, Pierre Otsuka, Neurocrine, Minerva, Merck, Pharmaceuticals, LB Johnson, and Johnson Pharmaceutica, Janssen Therapies, Intracellular Lundbeck, H. Genentech, Allergan, Forum, Lilly, Eli Sumitomo, Dainippon Alkermes, from Financial disclosure: manuscript. the revised and read critically authors the All draft. article first the wrote Kane and Schoretsanitis, Kelly, Author contributions: activity. this in presented been has labeling approved Administration– Drug and USFood outside is that therapies device or agents pharmaceutical about information investigational no knowledge, their of best the to that, determined have Disclosure of authors off-labelusage: The Published online: Submitted: the risk the of a clozapine-related myocarditis. various later points time may less accurate be inestimating further improved.further research important inthis area, patient outcomes can be psychiatric disorders, reinforced by much additional needed TDM treatment inthe of schizophrenia and other severe It is that hoped with broader implementation clinical of of other psychotropic medications pursued. should be also parallel, increasing database the on utility the of TDM for use antipsychotic prescription in patients with schizophrenia. In order to inform decision-making clinical algorithms for to perform TDM under appropriate the indications in Specifically, joint this consensus aims to encourage clinicians including implementing and interpreting TDM results. antipsychotic treatment of patients with schizophrenia, essential information on routine the of use TDM inthe of this tool. this of therefore help to encourage and implement appropriate use an extensive on TDM section and inpsychiatry should during postgraduate training. inEuropecurriculum for teaching psychopharmacology pharmacotherapy objectives andlearning a catalog of Psychiatric Association created apsychopharmacology- European Psychopharmacologythe authors the of section of TDM as atool for optimizing psychopharmacotherapy. The pharmacogenetics of psychotropic and of drugs, use the psychiatry, including pharmacokinetics, metabolism, and for postgraduatecurricula training of in specialists educational programs, for example, psychopharmacology area. To end, this TDM to needs receive more attention in as well as stimulate further, much research needed inthis AGNP to implementation, lead a wider Forcethe will of Psychopharmacology of Clinical Society and TDM the Task that present the collaborative work American the between © 2020Copyright Physicians Postgraduate Press, Inc. November 16, 2019; accepted February 12, 2020. 16, 2019; February November accepted Therapeutic Consensus Drug Monitoring: Statement 74 May 19, May 2020. In consensus this statement, we summarize has been a consultant for or received honoraria honoraria received or for aconsultant been has Kane Dr Drs Hiemke, Goff, Gründer, Paulzen, Correll, Citrome, Citrome, Correll, Paulzen, Gründer, Goff, Hiemke, Drs has received consulting fees from from fees consulting received has 76 This document contains 75 Thus, we hope

e9 program ( program editor of an Internet-based interaction drug-drug is and Servier and Stada, Janssen, from fees Hiemke Dr Switzerland. in drugs psychotropic selling companies pharmaceutical all almost from fees Dr Baumann an Internet-based interaction drug-drug program. Schoretsanitis etal PhD; Hans-Willi Clement, PhD; Jürgen Deckert, Deckert, Jürgen PhD; Clement, Hans-Willi PhD; Pharmakopsychiatrie: Neuropsychopharmakologie und für Arbeitsgemeinschaft the of Task Force Monitoring Drug Group information: the Therapeutic work. this of completion the in role any had Funding/support: article. the to relative disclose to withfinancial relationships any interest commercial and Schoretsanitis Drs GmbH. Institute Brain and Mind and GmbH, InMedicon GmbH, Brainfoods of ashareholder and founder the is and and Saladax; Lundbeck, Ingelheim, Boehringer from trials clinical for funding received has and Recordati; Otsuka, Neuraxpharma, Lundbeck, Janssen-Cilag, Gedeon-Richter, for aspeaker as honoraria received Takeda; has and SAGE Recordati, Otsuka, Lundbeck, Janssen-Cilag, IQWiG, Lilly, Eli and institutions: Allergan, Boehringer Ingelheim, companies following the for years three last the during member board advisory and consultant as e10 For [email protected]. reprints orpermissions, contact ♦ Neurocrine. fromsupport Boehringer-Ingelheim, Takeda, and the psiac GmbH ( GmbH psiac the of shareholder is and therapy drug economic and ( AGATE the of director managing and chairman is Pfizer, Novartis, Wyeth. and Mundipharma, Lundbeck, Lilly, Eli Squibb, Bristol-Myers Bio-Rad, AstraZeneca, AlcaSynn, from grants educational or Zernig and Janssen. Dr Italfarma, Lundbeck, Zeneca, Astra BMS, Lilly, of bureau speakers’ the on served has and Pfizer and Squibb, Bristol-Myers Lilly, for aconsultant as UpToDate. served has Conca Dr and Kluwer Wolters from royalties received and content developer for Global Medical Education; a as served Saladax; and Otsuka, Avanir, Janssen, from grants research received Roche; and Novartis, Janssen, Neurocrine, Alkermes, to aconsultant as Freudenreich Dr Alkermes. and Therapeutics HLS for consultant a as and Lundbeck for board advisory the on Dr Kelly honoraria. accepted not has but reimbursement travel accepted he which for for Avanirboards Pharmaceuticals and Takeda advisory in participated has and Pharmaceuticals ResearchStanley Foundation, and Medical Avanir Health, of Institutes National the from support Goff Dr Otsuka. and Janssen, Squibb, Bristol-Myers from grants received has and Shire and Otsuka, Asubio, for aconsultant as Dr Robinson litigation. for and Sunovion Auris, Intracellular and Therapies, Otsuka, Alkermes, for aconsultant as acted and Amgen for board monitoring safety adata on served has Dr (book). and Healthcare Springer Newcomer Journal of Clinical Practice International (Editor-in-Chief, Wiley from royalties received has and ago; > years 10 purchased Pfizer and Merck, J&J, Lilly, Eli Squibb, Bristol-Myers of stock) common of shares of number (small stocks and holds Teva; Takeda, Sunovion, Shire, Pfizer, Otsuka, Neurocrine, Merck, Lundbeck, Janssen, a speakerbeen for Acadia, Alkermes, Allergan, 12 also past months the in has Vanda; Teva, and Takeda, Sunovion, Shire, Pfizer, Otsuka, Osmotica, Noven, Neurocrine, Merck, Lundbeck, Janssen, Indivior, Therapies, Allergan, Impel, Intra-Cellular Alkermes, Acadia, 12 for past months the in It isIt illegal to post this copyrighted PDF on any website. www.amuep-agate.de Paulzen has received speaker’s or consultancy fees fees consultancy or speaker’s received has

has received speaker’s and consultancy consultancy and speaker’s received has

www.psiac.de Dr Citrome have no personal affiliations or affiliations personal no have has received speaker’s or consultancy consultancy or speaker’s received has has served on advisory boards or or boards advisory on served has www.psiac.de No commercial organizations ) that supports reasonable reasonable ) that supports Niels Bergemann, MD, Bergemann, Niels has been a consultant aconsultant been has ). Dr Gründer ). ), UpToDate (reviewer), has received research research received has ), which provides provides ), which , Piacentino has served served has has served served has served served Dr Haen

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as authors. listed are statement consensus this with involved were who members ASCP PhD. The Zurek, Gabriela and MSc; Waschgler, MD, Roland Unterecker Stefan PhD; Uhr, Sven Ulrich, MD, PhD; Manfred MD; Steimer, Werner PhD; Stegmann, Benedikt PhD; Gracia, Silva Margarete MD; Schwarz, Markus PhD; Schoppek, Bernd MD; Saria, Alois PhD; Riederer, Peter MD; Pfuhlmann, Bruno MD, PhD; Müller, J. Matthias MD; Mössner, Rainald MD; Messer, Thomas MD; Laux, Gerd PhD; Helmer, Renate PhD; Hefner, Gudrun MD, PhD; Havemann-Reinecke, Ursula PhD; Greiner, Christine PhD; Gerlach, Manfred MD; Egberts, Karin MD; Eckermann, Gabriel MD; 13 12 11 10 9. 8. 7. 6. 3. 2. 1. 5. 4. REFERENCES . . . .

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3. 2. 1. To obtaincredit, goto P to take thisPosttest andcomplete theEvaluation. osttest d. c. b. a. Therapeutic reference range refers to: d. c. b. a. in his currently good treatment outcome? says that he wishes to quit smoking. should youWhat take action to avoid changes Jackson, who has been receivingMr a stable clozapine dosefor the past few years, d. c. b. a. except: antipsychotics in routine clinical practice include all of the following scenarios Clear with patients indications for taking therapeutic drug monitoring (TDM) A range of antipsychotic that doses are unlikely related to be with adverse reactions A range of antipsychotic that doses are most effective relatively unlikely and above adverse which reactions are more likely to occur A range of antipsychotic blood concentrations, below therapeutic which response is have adverse reactions A range of antipsychotic blood concentrations, within patients which are more likely to Cardiovascular monitoring to improve is needed Mr Jackson’s somatic outcomes. health clozapine. cessation may to lead elevated clozapine levels due to inducing the effects of smoking on Clozapine levels should monitored be closely adjustment, to guidedose as smoking patches should not considered, be are as they likely to interact with clozapine. considerable amount of time. adjustmentDose Mr because Jackson is unlikely necessary to be stable has been over a Antipsychotic-induced adverse reactions Presence of somatic comorbidities affecting clearance of antipsychotics Discontinuation of antipsychotics Assessment of adherence (Keyword: JuneCME) © 2020Copyright Physicians Postgraduate Press, Inc. A $10processing fee is required. J ClinPsychiatry 81:3,May/June 2020

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