Molecular basis of mood and cognitive adverse events elucidated via a combination of pharmacovigilance data mining and functional enrichment analysis

Abstract

Drug-induced Mood- and Cognition-related adverse events (MCAEs) are often only detected during the clinical trial phases of drug development, or even after marketing, thus posing a major safety concern and a challenge for both pharmaceutical companies and clinicians. To fill some gaps in the understanding and elucidate potential biological mechanisms of action frequently associated with MCAEs, we present a unique workflow linking observational population data with the available knowledge at molecular, cellular, and psychopharmacology levels. It is based on statistical analysis of pharmacovigilance reports and subsequent signaling pathway analyses, followed by evidence-based expert manual curation of the outcomes. Our analysis: (a) ranked pharmaceuticals with high occurrence of such adverse events (AEs), based on disproportionality analysis of the FDA Adverse Event Reporting System (FAERS) database, and (b) identified 120 associated genes and common pathway nodes possibly underlying MCAEs. Nearly two-thirds of the identified genes were related to immune modulation, which supports the critical involvement of immune cells and their responses in the regulation of the central nervous system function. This finding also means that pharmaceuticals with a negligible central nervous system exposure may induce MCAEs through dysregulation of the peripheral immune system. Knowledge gained through this workflow unravels putative hallmark biological targets and mediators of drug-induced mood and cognitive disorders that need to be further assessed and validated in experimental models. Thereafter, they can be used to substantially improve in silico/in vitro/in vivo tools for predicting these adversities at a preclinical stage.

Behavioural interaction of pyrazoloquinolinone positive allosteric modulators at α6GABAA receptors and diazepam in rats: Anti‐diazepam‐induced ataxia action as a structure‐dependent feature

“…CNS safety pharmacology and neurotoxicology considerations are of utmost importance for timely assessment of prospects for successful drug development (cf. Andronis et al 17 ). Several deuterated PQs, discovered as functionally selective positive modulators of α6‐containing GABAARs via the PQ site, 6 hold promise of developing medicines with a novel mechanism of action for a number of undertreated chronic conditions in neurology and psychiatry connected with this subtype of ionotropic receptors for GABA 7 .…”

Gene Expression Profile as a Predictor of Seizure Liability

“…The 11 tool compounds were selected based on their known ictogenic properties and different mechanisms of action. The 13 FAERS-positive test compounds included those frequently associated with seizures based on the FAERS database and the VigiAccess adverse event records [ 29 ] followed by the disproportionality analysis [ 43 ]. The 10 FAERS-negative compounds exhibited very low or no linkage with seizures in the analysis.…”

GABAA receptor-mediated seizure liabilities: a mixed-methods screening approach

“…All records meeting commonly used criteria, specifically proportional reporting ratio (PRR) ≥ 2, the lower boundary of the CI 95% of the information component (IC025) had to be positive, and at least 5 reports in the dataset were used for further analysis. Except for the number of reports, these criteria correspond to those used in Andronis et al (2020).…”