Association Between Serotonin Syndrome and Second‐Generation Antipsychotics via Pharmacological Target‐Adverse Event Analysis

Racz, Rebecca; Soldatos, Theodoros; Jackson, David B.; Burkhart, Keith

doi:10.1111/cts.12543

Cited by 40 publications

(51 citation statements)

References 28 publications

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“…Thus, rather than simply blocking 5‐HT actions, inverse agonism at constitutive 5‐HT receptors may result in an opposite action that may serve to further augment or alternatively mitigate 5‐HT toxicity. A growing body of experimental evidence suggests that 5‐HT 1A agonism and 5‐HT 2A antagonism may contribute to serotonin toxicity . Of interest, both chlorpromazine and olanzapine have been shown to antagonize serotonin toxicity.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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Study Objective Serotonergic adverse drug events (ADEs) are caused by enhanced intra-synaptic concentrations of 5-hydroxytryptamine (5-HT). No systematic process currently exists for evaluating cumulative 5-HT and off-target toxicity of serotonergic drugs. The primary study aim was to create a Serotonergic Expanded Bioactivity Matrix (SEBM) employing a molecular bioinformatics, poly-pharmacologic approach for assessing the participation of individual 5-HT drugs in serotonin syndrome (SS) reports. Data Sources Publicly available databases including the Food and Drug Association (FDA) Adverse Event Reporting System (FAERS), ChEMBL, DrugBank, PubChem, and Kyoto Encyclopedia of Genes and Genomes (KEGG) were queried for computational and pharmacologic data. Design An in-house bioinformatics TargetSearch program was used to characterize 71 serotonergic drugs interacting at 13 serotonin receptor subtypes, and serotonin re-uptake transporter protein (SERT). Additionally, off-target interactions at norepinephrine transporter (NET), monoamine oxidase (MAO), and muscarinic receptors were included to define 7 poly-pharmacologic drug cohorts. Serotonin syndrome reports for each serotonergic drug were extracted from FAERS using Sternbach’s and Hunter’s criteria. Measurements and Main Results A proportional reporting adverse drug reaction (ADR) ratio (PRR) was calculated from each drug’s total ADEs and SS case reports and aggregated by drug bioactivity cohorts. Triple receptor interactions had a disproportionately higher number of SS cases using both Hunter’s criteria (mean PRR 1.72; 95% C.I. 1.05 to 2.39) and Sternbach’s (mean PRR 1.54, 95% C.I. 1.29 to 1.79). 5-Hydroxtryptamine agonists were associated with a significantly lower proportion of SS cases using Hunter’s and Sternbach’s criteria, respectively (mean PRR 0.49, 95% C.I. 0.17 to 0.81 and mean PRR 0.49, 95% C.I. 0.15 to 0.83). Drugs with disproportionately higher participation in SS vary considerably between the 2 diagnostic criteria. Conclusion The SEBM model suggests a possible poly-pharmacologic role in SS. Although further research is needed, off-target receptor activity may help explain differences in severity of toxicity and clinical presentation.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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“…A case report in 2006 mentioned increased adverse drug reactions in clomipramine and quetiapine combination for a patient with CYP2D6 poor metabolizer and low CYP3A4/5 activity status [ 27 ]. Quetiapine along with other second-generation antipsychotics such as lurasidone and ziprasidone has been associated with SS using the FDA Adverse Event Reporting System [ 28 ]. Thus, our patient is also predisposed to quetiapine toxicity considering his genetic finding.…”

Section: Discussionmentioning

confidence: 99%

Clinical Relevance of Pharmacogenetics in Serotonin Syndrome

Pandya

Tran

Verduzco‐Gutierrez

2020

Case Reports in Psychiatry

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Serotonin syndrome is a predictable life-threatening condition that is caused by serotonergic stimulation of the central and peripheral nervous systems. A patient’s genetic profile can amplify exposure risk as many serotonergic drugs are metabolized by CYP450 enzymes, and these enzymes may be altered in functionality. We report a case of an elderly man who presented with serotonin syndrome after a dose change in valproic acid 5 weeks prior. His medication list consisted of low-dose serotonergic agents, which is unusual as most cases of serotonin syndrome involve higher doses. A review of his pharmacogenetic profile is presented to retrospectively evaluate the additive risk for serotonin syndrome and implications on resuming serotonergic agents.

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“…When available, AE analytics can further benefit from the examination of additional data regarding laboratory and clinical parameters. For example, molecular dissection of AEs has been shown to effectively improve clinical insights, as well as inform about potential drug-drug interactions or other mechanisms underlying observed outcome phenotypes e.g., [41,42]. Such information could be important within the broader context of immunotherapy, potentially providing useful markers for the use of these agents in NHL patients.…”

Section: Discussionmentioning

confidence: 99%

Radioimmunotherapy in Non-Hodgkin’s Lymphoma: Retrospective Adverse Event Profiling of Zevalin and Bexxar

Sachpekidis

Jackson²,

Soldatos³

2019

Pharmaceuticals

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The development of monoclonal antibodies has dramatically changed the outcome of patients with non-Hodgkin’s lymphoma (NHL), the most common hematological malignancy. However, despite the satisfying results of monoclonal antibody treatment, only few NHL patients are permanently cured with single-agent therapies. In this context, radioimmunotherapy, the administration of radionuclides conjugated to monoclonal antibodies, is aimed to augment the single-agent efficacy of immunotherapy in order to deliver targeted radiation to tumors, particularly CD20+ B-cell lymphomas. Based on evidence from several trials in NHL, the radiolabeled antibodies 90Y-ibritumomab tiuxetan (Zevalin, Spectrum Pharmaceuticals) and 131I-tositumomab (Bexxar, GlaxoSmithKline) received FDA approval in 2002 and 2003, respectively. However, none of the two radioimmunotherapeutic agents has been broadly applied in clinical practice. The main reason for the under-utilization of radioimmunotherapy includes economic and logistic considerations. However, concerns about potential side effects have also been raised. Driven by these developments, we performed retrospective analysis of adverse events reporting Zevalin or Bexxar, extracted from the FDA’s Adverse Event Reporting System (FAERS) and the World Health Organization’s VigiBase repository. Our results indicate that the two radioimmunotherapeutic agents have both related and distinct side effect profiles and confirm their known toxicological considerations. Our work also suggests that computational analysis of real-world post-marketing data can provide informative clinical insights. While more prospective studies are necessary to fully characterize the efficacy and safety of radioimmunotherapy, we expect that it has not yet reached its full therapeutic potential in modern hematological oncology.

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Association Between Serotonin Syndrome and Second‐Generation Antipsychotics via Pharmacological Target‐Adverse Event Analysis

Cited by 40 publications

References 28 publications

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

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

Clinical Relevance of Pharmacogenetics in Serotonin Syndrome

Radioimmunotherapy in Non-Hodgkin’s Lymphoma: Retrospective Adverse Event Profiling of Zevalin and Bexxar

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