Implications of Off‐Target Serotoninergic Drug Activity: An Analysis of Serotonin Syndrome Reports Using a Systematic Bioinformatics Approach

Culbertson, Vaughn L.; Rahman, Shaikh Emdadur; Bosen, Grayson C.; Caylor, Matthew L.; Echevarria, Megan M.; Xu, Dong

doi:10.1002/phar.2163

Cited by 15 publications

(30 citation statements)

References 37 publications

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“…Analysis of the FDA Adverse Event Reporting System (FAERS) of serotonin syndrome cases by our group suggests that the two criteria differ substantially in their clinical application. This was evident from an additional 1100 FAERS cases identified by Sternbach but not Hunter's criteria 4 . Thus, Sternbach's inclusion of more nonspecific symptoms may result in identification of milder toxicity cases.…”

Section: Severe Versus Mild Serotonin Toxicitymentioning

confidence: 96%

“…This study builds on our earlier work in which the Serotonin Expanded Biomedical Matrix (SEBM) was developed to characterize serotonergic drug interactions at 13 serotonin receptor subtypes, serotonin and norepinephrine transporter proteins, and antimuscarinic receptors 4 . An in-house bioinformatics Web service, TargetSearch (http://dxulab.org/ software) was developed to mine publicly available ChEMBL, a pharmacologic database for relevant drug-receptor interactions and functional activity 8 .…”

Section: Serotonin Receptor Interactionsmentioning

confidence: 99%

“…This computational approach efficiently accounts for the interaction of drugs at these receptors and has been shown to effectively capture drug off-target interactions 11 and measure drug-induced toxic burden 12,13 . The concordence of documented versus experimentally derived receptor interactions as been previsouly described 4 .…”

Section: Serotonin Receptor Interactionsmentioning

confidence: 99%

“…Very little is known, however, about less serious forms of serotonin-mediated toxicity that may include milder manifestations of agitation, tremor, irritability, muscular incoordination, diarrhea, or confusion. Our previous work has characterized the potential interactions of 71 United States Food and Drug Administration-approved drugs at one or more serotonin receptor subtypes and off-target neurotransmitter activity 4 . These drugs encompass multiple therapeutic categories and tend to be commonly prescribed.…”

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confidence: 99%

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Use of a Bioinformatics‐Based Toxicity Scoring System to Assess Serotonin Burden and Predict Population‐Level Adverse Drug Events from Concomitant Serotonergic Drug Therapy

et al. 2019

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Study Objective-Numerous medications interact at serotonin (5-hydroxytryptamine [5-HT]) receptors directly or through off-target interactions, causing mild to severe serotonergic adverse drug events (ADEs), particularly among the elderly. Our objective was to develop a novel molecular-based toxicity scoring system to assess serotonergic burden resulting from concurrently administered drugs. Quantitative methods to assess serotonergic burden may provide a useful clinical tool for improving pharmacotherapy. Design-Retrospective cohort study.

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Section: Severe Versus Mild Serotonin Toxicitymentioning

confidence: 96%

Section: Serotonin Receptor Interactionsmentioning

confidence: 99%

Section: Serotonin Receptor Interactionsmentioning

confidence: 99%

mentioning

confidence: 99%

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Use of a Bioinformatics‐Based Toxicity Scoring System to Assess Serotonin Burden and Predict Population‐Level Adverse Drug Events from Concomitant Serotonergic Drug Therapy

et al. 2019

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“…43 Pharmacokinetic drug interactions are also implicated through the inhibition of the cytochrome P450 pathway, a pathway that SSRIs themselves inhibit (in particular CYP2D6 and CYP3A4. 56,57 At least 25 serotonergic drugs are metabolised by the cytochrome P450 pathway, 19 and a recent study has shown that 50% of the top 20 drugs associated with SS have known pharmacokinetic interactions in which coadministration of cytochrome P-450 inhibitors may elevate drug concentrations to toxic levels. These drugs collectively were shown to participate in > 70% of all the reported SS reports in their study.…”

Section: Drugs Commonly Associated With Ssmentioning

confidence: 99%

Serotonin Syndrome: Pathophysiology, Clinical Features, Management, and Potential Future Directions

Scotton

Hill

Williams

et al. 2019

Int J�Tryptophan�Res

157

161

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Serotonin syndrome (SS) (also referred to as serotonin toxicity) is a potentially life-threatening drug-induced toxidrome associated with increased serotonergic activity in both the peripheral (PNS) and central nervous systems (CNS). It is characterised by a dose-relevant spectrum of clinical findings related to the level of free serotonin (5-hydroxytryptamine [5-HT]), or 5-HT receptor activation (predominantly the 5-HT1Aand 5-HT2Asubtypes), which include neuromuscular abnormalities, autonomic hyperactivity, and mental state changes. Severe SS is only usually precipitated by the simultaneous initiation of 2 or more serotonergic drugs, but the syndrome can also occur after the initiation of a single serotonergic drug in a susceptible individual, the addition of a second or third agent to long-standing doses of a maintenance serotonergic drug, or after an overdose. The combination of a monoamine oxidase inhibitor (MAOI), in particular MAO-A inhibitors that preferentially inhibit the metabolism of 5-HT, with serotonergic drugs is especially dangerous, and may lead to the most severe form of the syndrome, and occasionally death. This review describes our current understanding of the pathophysiology, clinical presentation and management of SS, and summarises some of the drugs and interactions that may precipitate the condition. We also discuss the newer novel psychoactive substances (NPSs), a growing public health concern due to their increased availability and use, and their potential risk to evoke the syndrome. Finally, we discuss whether the inhibition of tryptophan hydroxylase (TPH), in particular the neuronal isoform (TPH2), may provide an opportunity to pharmacologically target central 5-HT synthesis, and so develop new treatments for severe, life-threatening SS.

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Advancing drug safety science by integrating molecular knowledge with post‐marketing adverse event reports

Soldatos¹,

Kim

Schmidt

et al. 2022

CPT Pharmacom & Syst Pharma

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Promising drug development efforts may frequently fail due to unintended adverse reactions. Several methods have been developed to analyze such data, aiming to improve pharmacovigilance and drug safety. In this work, we provide a brief review of key directions to quantitatively analyzing adverse events and explore the potential of augmenting these methods using additional molecular data descriptors. We argue that molecular expansion of adverse event data may provide a path to improving the insights gained through more traditional pharmacovigilance approaches. Examples include the ability to assess statistical relevance with respect to underlying biomolecular mechanisms, the ability to generate plausible causative hypotheses and/or confirmation where possible, the ability to computationally study potential clinical trial designs and/or results, as well as the further provision of advanced features incorporated in innovative methods, such as machine learning. In summary, molecular data expansion provides an elegant way to extend mechanistic modeling, systems pharmacology, and patient-centered approaches for the assessment of drug safety. We anticipate that such advances in real-world data informatics and outcome analytics will help to better inform public health, via the improved ability to prospectively understand and predict various types of drug-induced molecular perturbations and adverse events. | 541 MOLECULAR KNOWLEDGE FOR ADVANCED DRUG SAFETY (inter-)national regulatory authorities worldwide. Major instances of such safety data collections include: • The Sentinel Initiative of the US Food and Drug Administration (FDA), 2,3 • The FDA Adverse Event Reporting System (FAERS; formerly AERS), maintained by the FDA, 4 • The Vaccine Adverse Event Reporting System (VAERS), maintained by the FDA, co-managed by the Centers for Disease Control and Prevention, 5 • The European database of suspected adverse drug reaction reports (EudraVigilance), maintained by the European Medicines Agency (EMA), 6 and • VigiBase -the global database of individual case safety reports (ICSRs), maintained by the World Health Organization's (WHO) Uppsala Monitoring Center (UMC). 7How to cite this article: Soldatos TG, Kim S, Schmidt S, Lesko LJ, Jackson DB. Advancing drug safety science by integrating molecular knowledge with post-marketing adverse event reports. CPT

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Implications of Off‐Target Serotoninergic Drug Activity: An Analysis of Serotonin Syndrome Reports Using a Systematic Bioinformatics Approach

Cited by 15 publications

References 37 publications

Use of a Bioinformatics‐Based Toxicity Scoring System to Assess Serotonin Burden and Predict Population‐Level Adverse Drug Events from Concomitant Serotonergic Drug Therapy

Use of a Bioinformatics‐Based Toxicity Scoring System to Assess Serotonin Burden and Predict Population‐Level Adverse Drug Events from Concomitant Serotonergic Drug Therapy

Serotonin Syndrome: Pathophysiology, Clinical Features, Management, and Potential Future Directions

Advancing drug safety science by integrating molecular knowledge with post‐marketing adverse event reports

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