Therapeutic drug monitoring (TDM) is the quantification and interpretation of drug concentrations in blood to optimize pharmacotherapy. It considers the interindividual variability of pharmacokinetics and thus enables personalized pharmacotherapy. In psychiatry and neurology, patient populations that may particularly benefit from TDM are children and adolescents, pregnant women, elderly patients, individuals with intellectual disabilities, patients with substance abuse disorders, forensic psychiatric patients or patients with known or suspected pharmacokinetic abnormalities. Non-response at therapeutic doses, uncertain drug adherence, suboptimal tolerability, or pharmacokinetic drug-drug interactions are typical indications for TDM. However, the potential benefits of TDM to optimize pharmacotherapy can only be obtained if the method is adequately integrated in the clinical treatment process. To supply treating physicians and laboratories with valid information on TDM, the TDM task force of the Arbeitsgemeinschaft fur Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued their first guidelines for TDM in psychiatry in 2004. After an update in 2011, it was time for the next update. Following the new guidelines holds the potential to improve neuropsychopharmacotherapy, accelerate the recovery of many patients, and reduce health care costs.

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Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017.

Therapeutic drug monitoring (TDM), i. e., the quantification of serum or plasma concentrations of medications for dose optimization, has proven a valuable tool for the patient-matched psychopharmacotherapy. Uncertain drug adherence, suboptimal tolerability, non-response at therapeutic doses, or pharmacokinetic drug-drug interactions are typical situations when measurement of medication concentrations is helpful. Patient populations that may predominantly benefit from TDM in psychiatry are children, pregnant women, elderly patients, individuals with intelligence disabilities, forensic patients, patients with known or suspected genetically determined pharmacokinetic abnormalities or individuals with pharmacokinetically relevant comorbidities. However, the potential benefits of TDM for optimization of pharmacotherapy can only be obtained if the method is adequately integrated into the clinical treatment process. To promote an appropriate use of TDM, the TDM expert group of the Arbeitsgemeinschaft fur Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued guidelines for TDM in psychiatry in 2004. Since then, knowledge has advanced significantly, and new psychopharmacologic agents have been introduced that are also candidates for TDM. Therefore the TDM consensus guidelines were updated and extended to 128 neuropsychiatric drugs. 4 levels of recommendation for using TDM were defined ranging from “strongly recommended” to “potentially useful”. Evidence-based “therapeutic reference ranges” and “dose related reference ranges” were elaborated after an extensive literature search and a structured internal review process. A “laboratory alert level” was introduced, i. e., a plasma level at or above which the laboratory should immediately inform the treating physician. Supportive information such as cytochrome P450 substrate- and inhibitor properties of medications, normal ranges of ratios of concentrations of drug metabolite to parent drug and recommendations for the interpretative services are given. Recommendations when to combine TDM with pharmacogenetic tests are also provided. Following the guidelines will help to improve the outcomes of psychopharmacotherapy of many patients especially in case of pharmacokinetic problems. Thereby, one should never forget that TDM is an interdisciplinary task that sometimes requires the respectful discussion of apparently discrepant data so that, ultimately, the patient can profit from such a joint effort.

/pdf/agnp-consensus-guidelines-for-therapeutic-drug-monitoring-in-18q2ciintb.pdf

AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Psychiatry: Update 2011

Therapeutic drug monitoring (TDM), i. e., the quantification of serum or plasma concentrations of medications for dose optimization, has proven a valuable tool for the patient-matched psychopharmacotherapy. Uncertain drug adherence, suboptimal tolerability, non-response at therapeutic doses, or pharmacokinetic drug-drug interactions are typical situations when measurement of medication concentrations is helpful. Patient populations that may predominantly benefit from TDM in psychiatry are children, pregnant women, elderly patients, individuals with intelligence disabilities, forensic patients, patients with known or suspected genetically determined pharmacokinetic abnormalities or individuals with pharmacokinetically relevant comorbidities. However, the potential benefits of TDM for optimization of pharmacotherapy can only be obtained if the method is adequately integrated into the clinical treatment process. To promote an appropriate use of TDM, the TDM expert group of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued guidelines for TDM in psychiatry in 2004. Since then, knowledge has advanced significantly, and new psychopharmacologic agents have been introduced that are also candidates for TDM. Therefore the TDM consensus guidelines were updated and extended to 128 neuropsychiatric drugs. 4 levels of recommendation for using TDM were defined ranging from “strongly recommended” to “potentially useful”. Evidence-based “therapeutic reference ranges” and “dose related reference ranges” were elaborated after an extensive literature search and a structured internal review process. A “laboratory alert level” was introduced, i. e., a plasma level at or above which the laboratory should immediately inform the treating physician. Supportive information such as cytochrome P450 substrate and inhibitor properties of medications, normal ranges of ratios of concentrations of drug metabolite to parent drug and recommendations for the interpretative services are given. Recommendations when to combine TDM with pharmacogenetic tests are also provided. Following the guidelines will help to improve the outcomes of psychopharmacotherapy of many patients especially in case of pharmacokinetic problems. Thereby, one should never forget that TDM is an interdisciplinary task that sometimes requires the respectful discussion of apparently discrepant data so that, ultimately, the patient can profit from such a joint eff ort.

/pdf/agnp-consensus-guidelines-for-therapeutic-drug-monitoring-in-57afwyxg8p.pdf

AGNP consensus guidelines for therapeutic drug monitoring in psychiatry: update 2011

Summary of ﬁndings for the main comparison CLOZAPINE versus TYPICAL ANTIPSYCHOTICS -OVERALL for schizophrenia; Summary of ﬁndings 2 CLOZAPINEversusTYPICALANTIPSYCHOTICS forpeoplewithschizophreniawhose illnesshasprovedresistant totreatment1. COMPARISON 1. CLOZAPINE versus TYPICAL AN-TIPSYCHOTIC DRUGS - OVERALLAll data are derived from 50 studies.1.1 DeathFour deathsoccurredin614peopletreatedwithtypicalneurolep-tics compared with three deaths in 629 people treatedwith cloza-pine. There were no signiﬁcant differences in mortality betweengroups (n=1243, 12 RCTs, RR 0.56 CI 0.1 to 2.3).1.2 Relapse rateWe included 19 short-term studies, and found incidences of re-lapse werelowerin theclozapine group (n=1303, RR 0.62 CI0.5to0.8,NNT21CI15to49)comparedwithtypicalantipsychoticdrugs. Long-term data (4 RCTs, n=578) also favoured clozapinebut data were heterogeneous (I-squared =76%) (RR 0.22 CI 0.1to 0.3).1.3 Global impression1.3.1 Clinical improvement as deﬁned by study authorsWefound thatthenumber ofparticipants whohadnot improvedwere lower in the clozapine group (n=1119, 14 RCTs, RR 0.72CI 0.7 to 0.8, NNT 6 CI 5 to 8). Three long-term studies alsofavoured clozapine (n=719, RR 0.81 CI 0.7 to 0.9) but the dataare heterogeneous (I-squared statistic 81%).1.3.2 Readiness for hospital dischargeThere were no signiﬁcant differences between treatment groupsfor the number of participants who were judged to be not readyfordischarge(short-term,n=447,5RCTs,RR0.88CI0.8to1.0).Long-termdataalsofailedtoshowasigniﬁcant difference(n=648,2 RCTs, RR 0.82 CI 0.6 to 1.1).1.4 Hospitalisation - Not discharged or readmitted within oneyear after dischargeData were available from two long-term studies (Essock 1996(H/CPZ/Flu),Rosenheck1993(H)),andwefoundnosigniﬁcantadvantageforclozapine(n=648,RR0.94CI0.9to1.0)comparedwith typical antipsychotic drugs.1.5 Unable to workWe found no signiﬁcant difference in the number of participantswho were assessed as being unable to work (n=416, 4 RCTs, RR0.87CI0.8to1.0),althoughthedatasuggestedatrendfavouringclozapine (p=0.06).1.6 Participant dissatisfactionNosigniﬁcantdifferenceswerefoundfordissatisfactionwithtreat-mentintwoshort-termstudies(n=114,RR0.72CI0.4to1.3).Wefoundlonger-termdatain(Rosenheck1993(H)).Thesefavouredtheclozapinegroupwhowerelessdissatisﬁedwiththeirtreatmentcomparedwithconventionalantipsychoticdrugs(n=423,RR0.45CI 0.3 to 0.8, NNT 13 CI 9 to 37).1.7 Leaving the study early - acceptability of treatmentWe used leaving the study early data as a proxy measure for theacceptability of treatment. Short-term data from 32 studies in-volving 2316 participants indicated that signiﬁcantly more par-ticipantsgivenclozapinefoundtreatmentacceptable(RR0.81CI0.7 to 1.0, NNT 35 CI 20 to 217). Longer-term data from sixstudies showed a signiﬁcant beneﬁt in the clozapine group (n=982,RR0.60CI0.5to0.7,NNT15CI12to20).Thelong-termattrition rate fromclozapine treatment isapproximately 33% and56% when treated with typical antipsychotic drugs.1.8 Mental state1.8.1 BPRS and PANSSWe found BPRS mental state scores favoured clozapine duringshort-termassessmentin16studies(n=1205,WMD-3.79CI-4.9to -2.7), although the data were heterogeneous (I squared=69%).Longer-term BPRS data (Lee 1994 (mainly H)) were equivocal(n=52, WMD 0.80 CI -5.7 to 7.3). PANSS scores from threeChinesetrialsfavouredtheclozapinegroups(n=163,WMD-3.82CI -7.4 to -0.3) during short-term analysis. Also, PANSS scoresassessed over the long-term favoured clozapine (Rosenheck 1993(H), n=235, WMD -6.90 CI -10.7 to -3.1).1.8.2 Negative symptomsShort-termcontinuous data on negative symptom scores from sixshort-termtrialswith236participantsfavouredclozapine(SANS,WMD -7.12 CI -8.8 to -5.5) but these are heterogeneous data(Isquared=92%). Longer-termnegativesymptomsscoresassessedwiththePANSSnegativesubscorewerenotsigniﬁcantlydifferent(Rosenheck 1993 (H), n=235, WMD -0.90 CI -6.6 to 4.8).1.8.3 Positive symptomsWe found short-term SAPS scores were equivocal (Wang 2001(CPZ), n=60, WMD 4.39 CI -12.2 to 20.9). Longer-term datafrom the PANSS positive scores favoured clozapine (Rosenheck1993 (H), n=235, WMD -2.20 CI -3.3 to -1.1).1.9 Cognitive functionCognitive impairment from one small study (n=82) favoured theclozapine group who experienced less impairment (Klieser 1990(H),RR0.56CI0.3to0.9,NNT4CI3to21)whenassessedwiththe SKT scale compared with those given typical antipsychoticdrugs.Onesmallstudy(Lee1994(mainlyH),n=54)reporteddataon aseriesof cognitive functioning tests(verbal,memory or exec-utive functions etc.) and we found outcomes to be equivocal, ex-cept for ’psychomotor speedand attention’ scoreswhich favouredthe clozapine-treated participants over the three pre-stated cut-off points (short-term, WMD 1.40 CI 0.2 to 2.6, medium-term,WMD1.30CI0.01to3.0,long-term,WMD2.10CI0.8to3.4).Clozapine versus typical neuroleptic medication for schizophrenia (Review)

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Clozapine versus typical neuroleptic medication for schizophrenia.

Serotonin Subtype 2 Receptor Genes and Clinical Response to Clozapine in Schizophrenia Patients

Clozapine plasma levels were monitored in 16 patients during a series of three consecutive treatments (single dose-multiple dose-single dose). Each patient received a single 75-mg dose (3 x 25 mg) with clozapine tablets, and serial plasma samples were collected over 48 hr after the dose. At 48 hr, a multiple-dose regimen was started, consisting of an initial dose escalation period followed by dosing at a constant regimen for at least 6 days. After the last dose, serial plasma samples were again obtained over 72 hr. Drug was then withheld for at least 7 days, a final single 75-mg dose was given, and plasma sampling was repeated. A subset of the patient population (N = 7) was used to test for a food effect during the single-dose treatments. The pharmacokinetic parameters between the initial and the final single dose periods were not significantly different. Similarly, there were no differences within patients when given the dose after fasting (fed 1 hr after dose) or with a meal. In contrast, the terminal elimination rate differed between the single-dose and the multiple-dose treatments (t1/2 m3 = 7.9 hr single dose and 14.2 hr multiple dose) (P less than 0.05) and the dose-normalized area under the plasma concentration/time curves increased 27% with multiple dosing. Since a previous study in patients (Choc et al., Pharm. Res. 4:402-405, 1987) showed dose proportionality of clozapine plasma concentrations during multiple-dose regimens, the present results cannot be described by Michaelis-Menten kinetics.

Jack Hirschowitz

Papers

Single- vs multiple-dose pharmacokinetics of clozapine in psychiatric patients