Quality of Evidence Supporting Major Psychotropic Drug‐Drug Interaction Warnings: A Systematic Literature Review

Abstract

Among pharmacodynamic and pharmacokinetic drug-drug interactions (DDIs), psychotropic drug-drug interactions (pDDIs) are of particular interest because psychopharmacologic agents mark one of the fastest growing therapeutic drug classes over the past 2 decades, and prescribing multiple psychotropic drugs has become increasingly prevalent in clinical practice. However, the documentation of pDDIs across drug references has lacked consistency. Thus we set out to review the primary evidence directly supporting 58 pDDIs that were uniformly reported as "major" or "contraindicated" in three prominent drug references: Clinical Pharmacology, Micromedex, and Lexicomp. We identified 134 citations from Micromedex in December 2017 and 4251 citations from Medline in March 2018 involving any of the 58 pDDIs. The included articles directly observed a clinical adverse effect or effects on drug plasma concentrations from the concomitant use of the two listed drugs in each pDDI. These articles were classified as controlled studies (e.g., randomized controlled trials, clinical trials, or observational studies) or uncontrolled studies (case reports). A total of 124 studies with 2716 patients were included in this review. Commonly evaluated adverse effects related to the studied pDDIs included decreased effectiveness, central nervous system depression, neurotoxicity, QT-interval prolongation, and serotonin syndrome. Among the 58 pDDIs, 18 (31%) were not supported by any primary studies. Among the remaining 35 pDDIs supported by studies on clinical adverse effects, only 14 (40%) included evidence from controlled study designs. Only 7 (12.1%) of the 58 pDDIs had evidence from studies with a combined sample size of more than 100 patients. This literature review highlights the poor quality of evidence supporting major or contraindicated psychotropic DDI warnings. Most DDIs lacked support from controlled studies that evaluated clinically significant adverse effects, leaving uncertainty about the clinical relevance of the warning. More postmarketing studies are needed to evaluate the safety of psychotropic combination therapy.

Comparison of potential psychiatric drug interactions in six drug interaction database programs: A replication study after 2 years of updates

“…For example, the potential for DDI between psychiatric drugs and the current and experimental drugs used to treat COVID‐19 may not be covered in standard drug interaction database programs (Bishara et al., 2020; Luykx et al., 2020; University of Liverpool, 2020). Many disagree with the clinical relevance of DDI alerts from drug interaction database programs (Poly et al., 2020; Roblek et al., 2015; Tamblyn et al., 2008), including alerts involving psychiatric drug pairs (Nguyen et al., 2020; Phillips & Citrome, 2018). Alert fatigue remains a major problem.…”

“…However, there are frequent discrepancies in the clinical information provided by drug interaction database programs, including for potential DDI involving psychiatric drugs (Boyce et al., 2012; Liu et al., 2017; Monteith & Glenn, 2019; Monteith et al., 2020; Schjøtt et al., 2020; Zorina et al., 2013). Without international standards to define DDI (Kongsholm et al., 2015; Payne et al., 2015; Scheife et al., 2015; Tilson et al., 2016), the experts who maintain the drug interaction database programs use different sources and methodologies to find and assess evidence, and inconsistent criteria to classify risk (Grizzle et al., 2019, 2020; Nguyen et al., 2020; Romagnoli et al., 2017).…”

“…sources and methodologies to find and assess evidence, and inconsistent criteria to classify risk (Grizzle et al, 2019(Grizzle et al, , 2020Nguyen et al, 2020;Romagnoli et al, 2017).…”

Review of Questions Concerning Clinical Drug Interactions in ADHD Treatment From Physicians in Norway

“…Thus, documentation and handling are important elements in assessment of interactions. Only seven (12%) of 58 psychotropic drug interactions had evidence from studies with a sample size of more than 100 patients according to a recent study (Nguyen et al, 2020). The possibility to detect consequences of an interaction is important as it relates potential risk of adverse effects to individual patients.…”

Editorial: Drug-drug interactions in pharmacology

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Editorial on the Research Topic Drug-drug interactions in pharmacologyIn pharmacology, drug-drug interactions result in unintended reactions, toxic side effects, or a lack of clinical efficacy in an individual body when multiple medications are simultaneously administered for one or more diseases (Molenaar-Kuijsten et al, 2021). These are usually considered in terms of two principal classes of underlying mechanisms: pharmacodynamics and pharmacokinetics (Nguyen et al, 2020). Indeed, the pharmacological effect of one or both drugs may be enhanced or suppressed, or a new and unanticipated adverse effect may occur, even leading to fatal consequences (Barbera et al, 2013;Karch et al, 2016).Concerning pharmacokinetics, drug absorption, distribution, metabolism, and excretion (ADME cycle) variations may result in a plasma concentration fluctuation, influencing drug bioavailability.

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