Abstract Rationale While one of the basic axioms of pharmacology postulates that there is a relationship between the concentration and effects of a drug, the value of measuring blood levels is questioned by many clinicians. This is due to the often-missing validation of therapeutic reference ranges. Objectives Here, we present a prototypical meta-analysis of the relationships between blood levels of aripiprazole, its target engagement in the human brain, and clinical effects and side effects in patients with schizophrenia and related disorders. Methods The relevant literature was systematically searched and reviewed for aripiprazole oral and injectable formulations. Population-based concentration ranges were computed ( N = 3,373) and pharmacokinetic influences investigated. Results Fifty-three study cohorts met the eligibility criteria. Twenty-nine studies report blood level after oral, 15 after injectable formulations, and nine were positron emission tomography studies. Conflicting evidence for a relationship between concentration, efficacy, and side effects exists (assigned level of evidence low, C; and absent, D). Population-based reference ranges are well in-line with findings from neuroimaging data and individual efficacy studies. We suggest a therapeutic reference range of 120–270 ng/ml and 180–380 ng/ml, respectively, for aripiprazole and its active moiety for the treatment of schizophrenia and related disorders. Conclusions High interindividual variability and the influence of CYP2D6 genotypes gives a special indication for Therapeutic Drug Monitoring of oral and long-acting aripiprazole. A starting dose of 10 mg will in most patients result in effective concentrations in blood and brain. 5 mg will be sufficient for known poor metabolizers. 

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Therapeutic Reference Range for Aripiprazole in Schizophrenia Revised: a Systematic Review and Metaanalysis

Pharmacogenomics in treatment of depression and psychosis: an update.

Inter-individual differences in antidepressant drug concentrations attained in blood may limit the efficacy of pharmacological treatment of depressive disorders. Therapeutic drug monitoring (TDM) enables to determine drug concentrations in blood and adjust antidepressant dosage accordingly. However, research on the underlying assumption of TDM, association between concentration and clinical effect, has yielded ambiguous results for antidepressants. It has been proposed that this ambiguity may be caused by methodological shortcomings in studies investigating the concentration-effect relationship. Guidelines recommend the use of TDM in antidepressant treatment as expert opinion. This reflects the lack of research, particularly systematic reviews and meta-analyses of randomized controlled trials, on the relationship between concentration and effect as well as on the benefits of the use of TDM in clinical practice. In this study, a systematic review and meta-analysis of randomized controlled trials has been performed to investigate the relationship between antidepressant concentration, efficacy, and side effects. It is the first meta-analytical approach to this subject and additionally considers methodological properties of primary studies as moderators of effect in quantitative analysis. Our results identified methodological shortcomings, namely the use of a flexible dose design and the exclusion of concentrations in lower- or subtherapeutic ranges, which significantly moderate the relationship between antidepressant concentration and efficacy. Such shortcomings obscure the evidence base of using TDM in clinical practice to guide antidepressant drug therapy. Further research should consider these findings to determine the relationship between concentration and efficacy and safety of antidepressant treatments, especially for newer antidepressants. Systematic Review Registration https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=246149, identifier: CRD42021246149.

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Is Therapeutic Drug Monitoring Relevant for Antidepressant Drug Therapy? Implications From a Systematic Review and Meta-Analysis With Focus on Moderating Factors

Introduction A titration within a certain therapeutic reference range presupposes a relationship between the blood concentration and the therapeutic effect of a drug. However, this has not been systematically investigated for escitalopram. Furthermore, the recommended reference range disagrees with mean steady state concentrations (11–21 ng/ml) that are expected under the approved dose range (10–20 mg/day). This work systematically investigated the relationships between escitalopram dose, blood levels, clinical effects, and serotonin transporter occupancy. Methods Following our previously published methodology, relevant articles were systematically searched and reviewed for escitalopram. Results Of 1,032 articles screened, a total of 30 studies met the eligibility criteria. The included studies investigated escitalopram blood levels in relationship to clinical effects (9 studies) or moderating factors on escitalopram metabolism (12 studies) or serotonin transporter occupancy (9 studies). Overall, the evidence for an escitalopram concentration/effect relationship is low (level C). Conclusion Based on our findings, we propose a target range of 20–40 ng/ml for antidepressant efficacy of escitalopram. In maintenance treatment, therapeutic response is expected, when titrating patients above the lower limit. The lower concentration threshold is strongly supported by findings from neuroimaging studies. The upper limit for escitalopram’s reference range rather reflects a therapeutic maximum than a tolerability threshold, since the incidence of side effects in general is low. Concentrations above 40 ng/ml should not necessarily result in dose reductions in case of good clinical efficacy and tolerability. Dose-related escitalopram concentrations in different trials were more than twice the expected concentrations from guideline reports. Systematic review registration [https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=215873], identifier [CRD42020215873].

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Systematic review and meta-analysis on the therapeutic reference range for escitalopram: Blood concentrations, clinical effects and serotonin transporter occupancy

Introduction The current reference range for the atypical antipsychotic aripiprazole is 100-350 ng/mL (150-500 ng/mL for the sum of aripiprazole+active metabolite) [1]. The range(s) might be transferable to aripiprazole’s long-acting injectable (LAI) formulation [2]. As published previously, valid reference ranges derive from systematic evaluation of up-to-date literature of the relationship between blood levels, clinical outcomes and receptor occupancy, not solely from experts opinions [3]. 

Therapeutic reference range for aripiprazole revised: A systematic
 review and combined analysis

Background: For many psychotropic drugs, monitoring of drug concentrations in the blood (Therapeutic Drug Monitoring; TDM) has been proven useful to individualize treatments and optimize drug effects. Clinicians hereby compare individual drug concentrations to population-based reference ranges for a titration of prescribed doses. Thus, established reference ranges are pre-requisite for TDM. For psychotropic drugs, guideline-based ranges are mostly expert recommendations derived from a conglomerate of cohort and cross-sectional studies. A systematic approach for identifying therapeutic reference ranges has not been published yet. This paper describes how to search, evaluate and grade the available literature and validate published therapeutic reference ranges for psychotropic drugs. Methods/Results: Following PRISMA guidelines, relevant databases have to be systematically searched using search terms for the specific psychotropic drug, blood concentrations, drug monitoring, positron emission tomography (PET) and single photon emission computed tomography (SPECT). The search should be restricted to humans, and diagnoses should be prespecified. Therapeutic references ranges will not only base upon studies that report blood concentrations in relation to clinical effects, but will also include implications from neuroimaging studies on target engagement. Furthermore, studies reporting concentrations in representative patient populations are used to support identified ranges. Each range will be assigned a level of underlying evidence according to a systematic grading system. Discussion: Following this protocol allows a comprehensive overview of TDM literature that supports a certain reference range for a psychotropic drug. The assigned level of evidence reflects the validity of a reported range rather than expert opinions.

Luzie Eichentopf

Papers

Therapeutic Reference Ranges for Psychotropic Drugs: A Protocol for Systematic Reviews