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 effort.

This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas’ original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300–600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75–150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175–300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100–200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250–400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150–300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300–600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration.

Objectives: Therapeutic drug monitoring (TDM) combines the quantification of drug concentrations in blood, pharmacological interpretation and treatment guidance. TDM introduces a precision medicine tool in times of increasing awareness of the need for personalized treatment. In neurology and psychiatry, TDM can guide pharmacotherapy for patient subgroups such as children, adolescents, pregnant women, elderly patients, patients with intellectual disabilities, patients with substance use disorders, individuals with pharmacokinetic peculiarities and forensic patients. Clear indications for TDM include lack of clinical response in the therapeutic dose range, assessment of drug adherence, tolerability issues and drug–drug interactions. Methods: Based upon existing literature, recommended therapeutic reference ranges, laboratory alert levels, and levels of recommendation to use TDM for dosage optimization without specific indications, conversion factors, factors for calculation of dose-related drug concentrations and metabolite-to-parent ratios were calculated. Results: This summary of the updated consensus guidelines by the TDM task force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie offers the practical and theoretical knowledge for the integration of TDM as part of pharmacotherapy with neuropsychiatric agents into clinical routine. Conclusions: The present guidelines for TDM application for neuropsychiatric agents aim to assist clinicians in enhancing safety and efficacy of treatment.

Introduction: This article comprehensively reviews the clinical utility of the serum clozapine/norclozapine (CLO/NCLO) ratio. Areas covered: Fifty-four published studies used this ratio (21 from a PubMed search from onset to 10/21/18 and 33 identified by the authors). To estimate a combined mean of the CLO/NCLO ratio in published studies, a PubMed search on 10/21/18 identified 422 articles leading to 19 included. The systematic review focused on: 1) the combined analysis, 2) CYP1A2 activity, 3) clinical response, 4) cognition, and 5) renal function. Expert opinion: Our combined analysis provided a weighted mean CLO/NCLO ratio of 1.73 in 2,317 adult patients from 19 studies but the range in the studies varied widely from 1.19 to 3.37. No study provided data on variability of the CLO/NCLO ratios within individual patients. The CLO/NCLO ratio is not a measure of CYP1A2 activity and is not associated with clinical response. The association of the CLO/NCLO ratio with cognitive measures is unclear (4 cross-sectional studies were positive and post-hoc analysis of a randomized clinical trial was negative). Future studies must replicate the finding of a case report that gemfibrozil may invert the CLO/NCLO ratio (making it <1), indicating that gemfibrozil inhibit the renal transporter that excretes NCLO.

Aripiprazole, a novel antipsychotic drug, is metabolized by CYP3A4 and CYP2D6 forming mainly its active metabolite dehydroaripiprazole. In this study, aripiprazole and dehydroaripiprazole serum levels of psychiatric patients were measured and related to dose, comedication, and clinical effects including therapeutic and side effects. Patients were treated with mean doses of 20±8 mg/day of aripiprazole (median 15 mg, range 7.5–60 mg). Serum levels correlated significantly with the dose (r=0.419; P<0.01), with a mean value of aripiprazole of 214±140 ng/ml. Mean concentrations of the active metabolite dehydroaripiprazole amounted to 40% of the parent compound. Comedication with CYP3A4 and CYP2D6 inducers or inhibitors changed serum levels up to 51%. Improvement was best in patients with a serum level between 150 to 300 ng/ml. No or only mild side effects were detected in patients, with aripiprazole plasma concentrations between 110 and 249 ng/ml. A total of 32% of the patients who received no other antipsychotic drug besides aripiprazole reported side effects; tension being the most frequent one. Since serum levels of aripiprazole and dehydroaripiprazole were highly variable between individuals, and distinct ranges were associated with good therapeutic response and minimal side effects, it seems likely that therapeutic drug monitoring can be helpful to improve the antipsychotic drug therapy.