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

Abstract

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 pre-specified. 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 experts' opinions.

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

“…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 .…”

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

“…By performing exploratory analyses (meta-regression and ANOVAs) of the impact of previously described potential moderators of concentration-efficacy relationships, we were able to identify two methodological properties of primary studies which significantly moderate the association between antidepressant concentration and efficacy: First, we could demonstrate a substantial impact of the dose design used in primary studies on the association between antidepressant concentration and efficacy. The use of a fixed dose design has already been described as the best way to address the question whether there is a relationship between concentration and effect, not only in antidepressant treatment, but in pharmacological treatment in general (32,41). Flexible dose studies are often designed to provide evidence for antidepressant efficacy in comparison to placebo or active control groups.…”

“…First, we could demonstrate a substantial impact of the dose design used in primary studies on the association between antidepressant concentration and efficacy. The use of a fixed dose design has already been described as the best way to address the question whether there is a relationship between concentration and effect, not only in antidepressant treatment, but in pharmacological treatment in general ( 32 , 41 ). Flexible dose studies are often designed to provide evidence for antidepressant efficacy in comparison to placebo or active control groups.…”

“…To validate previous research on the influence of methodological shortcomings of primary studies as moderators of the antidepressant concentration-effect relationship, proposed criteria from three studies were included (22)(23)(24) and adapted to the specific purpose of this study. The inclusion of these criteria has also been recommended in a recent protocol guideline for systematic reviews for the development of therapeutic reference ranges in psychotropic drugs (32). In total, 14 criteria were formulated to assess the quality of primary studies, shown in detail in Table 2.…”

Escitalopram: Drug monitoring for dose titration? Systematic literature review on the therapeutic and the dose-related reference range

“…Methods Four databases were searched (Update March 2022) for relevant articles following our previously published protocol 2 . Evidence for a certain concentration/effect relationship was graded into a level.…”