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.
Highlights
Serious safety concerns contribute to a significant proportion of clinical trial failures, heavily increasing the costs associated with drug development (Allison 2012)
Following expert curation of the 232 genes associated with the FDA Adverse Event Reporting System (FAERS)-selected drugs, we identified altogether 120 candidate pathway elements (CPEs) directly associated with Mood and/or Cognition adverse events (AEs) (MCAEs): 58 associated with Mood- and 99 with Cognition-related AEs, while 30 CPEs were related to both Mood and Cognition AEs
: (i) the identified Adverse Outcome Pathways (AOPs) mostly focused on brain-occurring Molecular Initiating Event (MIE)/KEs, despite growing evidence that MCAEs may result from the modulation of molecules outside the Central Nervous System (CNS) (Capuron and Miller 2011); (ii) AOPs often fail to clearly associate a drug’s pharmacological action with a MIE, as they do not account for either targets’ subunits, site-specific regulation, nor possible off-targets; (iii) AOPs do not specify the molecules involved in a particular KE
Summary
Serious safety concerns contribute to a significant proportion of clinical trial failures, heavily increasing the costs associated with drug development (Allison 2012). The United States’ Food and Drug Administration has recently authorized the use of methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder (PTSD), MDMA may induce suicidal ideation and behavior (Sessa et al 2019) Such AEs, which show a likely causality to a drug, are known in clinical practice as adverse reactions or adverse effects (Edwards and Aronson 2000). A recent cohort study performed in Danish women with no previous psychiatric diagnoses identified a positive association of hormonal contraception with suicidal ideation and attempt (Skovlund et al 2018) Antiepileptic drugs such as perampanel have been associated with adverse mood changes (e.g. depression) and effects on cognition (Afzal et al 2017; Goji and Kanemoto 2019). Both the United States and European regulators issued a warning about the potential of neuropsychiatric AEs of fluoroquinolones, including suicidal ideation (Bennett et al 2019)
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