Arbeitsgemeinschaft Für Neuropsychopharmakologie Und Pharmakopsychiatrie Research Articles

Automated Interlaboratory Comparison of Therapeutic Drug Monitoring Data and Its Use for Evaluation of Published Therapeutic Reference Ranges.

Therapeutic drug monitoring is a tool for optimising the pharmacological treatment of diseases where the therapeutic effect is difficult to measure or monitor. Therapeutic reference ranges and dose-effect relation are the main requirements for this drug titration tool. Defining and updating therapeutic reference ranges are difficult, and there is no standardised method for the calculation and clinical qualification of these. The study presents a basic model for validating and selecting routine laboratory data. The programmed algorithm was applied on data sets of antidepressants and antipsychotics from three public hospitals in Denmark. Therapeutic analytical ranges were compared with the published therapeutic reference ranges by the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) and in additional literature. For most of the drugs, the calculated therapeutic analytical ranges showed good concordance between the laboratories and to published therapeutic reference ranges. The exceptions were flupentixol, haloperidol, paroxetine, perphenazine, and venlafaxine + o-desmethyl-venlafaxine (total plasma concentration), where the range was considerably higher for the laboratory data, while the calculated range of desipramine, sertraline, ziprasidone, and zuclopenthixol was considerably lower. In most cases, we identified additional literature supporting our data, highlighting the need of a critical re-examination of current therapeutic reference ranges in Denmark. An automated approach can aid in the evaluation of current and future therapeutic reference ranges by providing additional information based on big data from multiple laboratories.

Therapeutic drug monitoring of LAI antipsychotics as a predictor of clinical relapse: a one-year follow-up

IntroductionClinical relapses in schizophrenia remain a frequent event. Long-acting injectable (LAI) antipsychotics enhance adherence, but low blood levels can sometimes be observed despite an adequate posology. Nonetheless, the evaluation of this parameter is uncommon in clinical practice.ObjectivesTo explore the potential advantages of therapeutic drug monitoring (TDM) of LAIs as a predictor of relapse in clinically stable outpatients with schizophrenia.Methods44 individuals who had reached the pharmacokinetic steady state of LAI treatment (paliperidone, olanzapine, aripiprazole) underwent an anamnestic and psychopathological assessment. LAI blood levels were measured using liquid chromatography-mass spectrometry and classified as “in range” or “under range” according to the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) guideline values. Individuals who relapsed during the one-year follow-up were compared to non-relapsers (Fisher’s exact test, χ2 or Mann-Whitney U). An exploratory binary logistic regression tested the role of other possible relevant predictors of relapse.ResultsNo differences were observed in baseline use of mood stabilisers (p=0.211), antidepressants (p=0.530), or prescribed LAI (p=0.563). Other comparisons are presented in the table: among these variables, in-range LAI levels were the only significant predictor of relapse (F=5.95, p=0.015; OR 0.04, 95%CI 0.02-0.56).Relapse (n=6)No relapse (n=38)pAge (years)41.33±10.7843.95±12.980.667Male4 (66.7%)21 (55.3%)0.600Illness duration (years)21.83±2.6419.13±11.820.289Previous acute episodes3.50±1.053.29±1.470.652PANSS-total49.33±14.8342.74±14.140.231In-range LAI2 (33.3%)32 (84.2%)0.006ConclusionsTDM of LAIs may optimise the clinical management of schizophrenia by highlighting a suboptimal dosage and a consequent higher relapse risk. Large-scale, drug-specific assessments are needed to confirm these findings.DisclosureNo significant relationships.

Use of Antidepressants in Older People during a 10-Year Period: An Observational Study on Prescribed Doses and Serum Levels.

BackgroundAccording to previous studies, older patients frequently have serum concentrations of antidepressant medication above the recommended reference range.ObjectiveThe aim of this study was to investigate whether prescribed doses of antidepressants and the proportion of individuals with serum concentrations above the recommended reference range in older individuals (≥ 65 years) have changed over a 10-year period in Norway.MethodsSerum concentration measurements and prescribed daily doses of antidepressants in 2007 and 2017 were extracted from a therapeutic drug monitoring (TDM) database at the Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway. The database contains routine follow-up serum concentration measurements of psychotropic drugs for patients from all parts of the country. For citalopram, escitalopram, sertraline, mirtazapine and venlafaxine, the differences between 2007 and 2017 in mean prescribed doses and the proportion of patients with at least one serum concentration above the reference range, according to the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) guidelines, were compared. For the proportion of patients with serum concentrations above the recommended reference range, differences between individuals aged 65–79 and ≥ 80 years were also examined.ResultsThe analyses of prescribed doses included 806 patients from 2007 and 1932 patients from 2017, with 972 and 2441 TDM samples, respectively. Between 2007 and 2017, modest reductions in prescribed daily doses were observed for citalopram (20 vs. 17 mg/day) and escitalopram (11 vs. 10 mg/day), but the proportion of patients with serum concentrations above the recommended reference range was unchanged for both drugs, i.e. 11.5% vs. 12.4% for citalopram and 3.6% vs. 2.9% for escitalopram. For mirtazapine and venlafaxine, prescribed doses were reduced from 28 to 25 mg/day and 150 to 125 mg/day, respectively. A significant reduction in the proportion of individuals with serum concentrations above the recommended reference range was observed for mirtazapine (27.1% vs. 11.5%) and for individuals aged ≥ 80 years using venlafaxine (60.0% vs. 30.0%). For sertraline, no differences in prescribed doses or serum concentrations above the recommended reference range were observed.ConclusionsOver a 10-year period, prescribed doses of antidepressants have been slightly reduced in older Norwegian patients, but a considerable proportion is still exposed to high serum concentrations of antidepressants.Electronic supplementary materialThe online version of this article (10.1007/s40266-020-00784-9) contains supplementary material, which is available to authorized users.

A review of a recently published guidelines' "strong recommendation" for therapeutic drug monitoring of olanzapine, haloperidol, perphenazine, and fluphenazine.

IntroductionIn addition to clozapine, there is a growing body of evidence that supports therapeutic drug monitoring (TDM) for additional antipsychotics commonly used in the United States.MethodsThe Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) published TDM guidelines for several psychiatric medications. Sources were identified that the authors used to establish therapeutic reference ranges for haloperidol, fluphenazine, perphenazine, and olanzapine—4 antipsychotics commonly used in the United States with a “strong recommendation” for TDM. The sources were then reviewed for content and appropriateness for utilization in establishing the reference ranges.ResultsOlanzapine had 15 citations, haloperidol had 9, perphenazine had 4, and fluphenazine had 2. The studies' methods were reviewed along with the proposed therapeutic reference ranges.DiscussionSeveral limitations of the guidelines were identified. Reference ranges were suggested based on studies of patients with various diagnoses; some patients had an acute exacerbation, and others were in a maintenance phase. An additional publication was identified that reviewed similar (and additional) TDM studies; those conclusions were in slight contrast with those of the AGNP guidelines. In the future, guidance should be given to those looking to conduct TDM studies to standardize methods and make meta-analysis of this data more feasible.

A Critical Commentary on the 2017 AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology.

In 2004, 2011, and 2017, the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP), a group of German-speaking psychiatric researchers and psychiatrists, published successive versions of therapeutic drug monitoring (TDM) expert group consensus guidelines. The 2017 version has as a major strength its encyclopedic nature, including 1358 references. The guideline has 3 major sections: 1) theoretical aspects of TDM, 2) drug concentration levels in blood to guide neuropsychopharmacotherapy, and 3) practical aspects of TDM in psychiatry and neurology. The writer hopes the time is right for a TDM guideline in psychiatry, which is indicated for: 1) psychiatric researchers ready to value how TDM can contribute to moving psychopharmacology forward, 2) flexible clinicians ready to improve their patient care by personalizing dosing, and 3) today's psychiatry residents prepared as a new generation ready to be trained in TDM and willing to continue incorporating TDM as new psychiatric drugs are marketed.

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

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 für 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.

Consensus Guideline Based Therapeutic Drug Monitoring (TDM) in Psychiatry and Neurology.

Therapeutic drug monitoring (TDM) is a valuable tool for tailoring the dosage of the prescribed medication(s) to the individual pharmacokinetic characteristics of a patient. In psychiatry and neurology, however, proven evidence that TDM should be used for treatment with the multiple neuropsychiatric medications is restricted to few compounds. Well-designed clinical trials on medical and economic benefits of TDM are rare. The use of TDM is limited in most countries to few antiepileptics, especially carbamazepine, phenobarbital and phenytoin, some mood stabilizers, especially lithium and valproic acid, some antidepressants, especially tricyclic antidepressants and some antipsychotics, primarily clozapine because these drugs have a narrow therapeutic index. On the other hand, specific indications and distinct problems can make TDM most useful for individualized pharmacotherapy with almost any neuropsychiatric drug. Potential benefits of TDM can, however, only be reaped if the method is adequately integrated into the clinical treatment process. The TDM expert group of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued consensus guidelines for the best practice of TDM in psychiatry and neurology. A first version was published in 2004. These guidelines were extended in 2011 and are actually updated (see: www.agnp.de). Exemplified by single cases it is shown here how to use TDM consensus guidelines for problem solving in psychiatry and neurology. Studies on depressed patients give evidence for tricyclic antidepressants, venlafaxine and citalopram that TDM could become a standard of care in psychiatry and neurology. There is potential to accelerate improvement. Reducing phases of suffering will not only have medical benefits for the patients but also an impact on costs for the health system which needs to be clarified by controlled studies.

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.

The AGNP-TDM Expert Group Consensus Guidelines: focus on therapeutic monitoring of antidepressants

Therapeutic drug monitoring (TDM) of psychotropic drugs such as antidepressants has been widely introduced for optimization of pharmacotherapy in psychiatric patients. The interdisciplinary TDM group of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) has worked out consensus guidelines with the aim of providing psychiatrists and TDM laboratories with a tool to optimize the use of TDM. Five research-based levels of recommendation were defined with regard to routine monitoring of drug plasma concentrations: (i) strongly recommended; (ii) recommended; (iii) useful; (iv) probably useful; and (v) not recommended. In addition, a list of indications that justify the use of TDM is presented, eg, control of compliance, lack of clinical response or adverse effects at recommended doses, drug interactions, pharmacovigilance programs, presence of a genetic particularity concerning drug metabolism, and children, adolescents, and elderly patients. For some drugs, studies on therapeutic ranges are lacking, but target ranges for clinically relevant plasma concentrations are presented for most drugs, based on pharmacokinetic studies reported in the literature. For many antidepressants, a thorough analysis of the literature on studies dealing with the plasma concentration-clinical effectiveness relationship allowed inclusion of therapeutic ranges of plasma concentrations. In addition, recommendations are made with regard to the combination of pharmacogenetic (phenotyping or genotyping) tests with TDM. Finally, practical instructions are given for the laboratory practitioners and the treating physicians how to use TDM: preparation of TDM, drug analysis, reporting and interpretation of results, and adequate use of information for patient treatment TDM is a complex process that needs optimal interdisciplinary coordination of a procedure implicating patients, treating physicians, clinical pharmacologists, and clinical laboratory specialists. These consensus guidelines should be helpful for optimizing TDM of antidepressants.

Therapeutic monitoring of psychotropic drugs: an outline of the AGNP-TDM expert group consensus guideline.

TDM of psychotropic drugs is widely used, but there is little consensus regarding its optimal use in the clinical context. This prompted a multidisciplinary group comprised of clinical biochemists, clinical pharmacologists, and psychiatrists of the AGNP (Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie) to provide a consensus guideline. This will allow clinical psychiatrists, practitioners, and laboratory directors involved in psychopharmacotherapy to optimize TDM of antidepressants, antipsychotics, and opioid substituents. Recommendations are also given on the combined use of TDM and pharmacogenetic tests.