PMID- 32504122
OWN - NLM
STAT- MEDLINE
DCOM- 20210712
LR  - 20210712
IS  - 1432-0738 (Electronic)
IS  - 0340-5761 (Print)
IS  - 0340-5761 (Linking)
VI  - 94
IP  - 8
DP  - 2020 Aug
TI  - Molecular basis of mood and cognitive adverse events elucidated via a combination 
      of pharmacovigilance data mining and functional enrichment analysis.
PG  - 2829-2845
LID - 10.1007/s00204-020-02788-1 [doi]
AB  - 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.
FAU - Andronis, Christos
AU  - Andronis C
AUID- ORCID: 0000-0002-6174-579X
AD  - Biovista, 34 Rodopoleos Street, 16777, Athens, Greece.
FAU - Silva, Joao Pedro
AU  - Silva JP
AUID- ORCID: 0000-0002-5656-0897
AD  - UCIBIO, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, 
      Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal.
FAU - Lekka, Eftychia
AU  - Lekka E
AUID- ORCID: 0000-0003-4416-0148
AD  - Biovista, 34 Rodopoleos Street, 16777, Athens, Greece.
FAU - Virvilis, Vassilis
AU  - Virvilis V
AUID- ORCID: 0000-0003-4573-0501
AD  - Biovista, 34 Rodopoleos Street, 16777, Athens, Greece.
FAU - Carmo, Helena
AU  - Carmo H
AUID- ORCID: 0000-0002-6650-5285
AD  - UCIBIO, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, 
      Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal.
FAU - Bampali, Konstantina
AU  - Bampali K
AUID- ORCID: 0000-0001-5063-4675
AD  - Department of Molecular Neurosciences, Medical University of Vienna, Spitalgasse 
      4, 1090, Vienna, Austria.
FAU - Ernst, Margot
AU  - Ernst M
AUID- ORCID: 0000-0002-9809-2649
AD  - Department of Molecular Neurosciences, Medical University of Vienna, Spitalgasse 
      4, 1090, Vienna, Austria.
FAU - Hu, Yang
AU  - Hu Y
AUID- ORCID: 0000-0002-8702-6654
AD  - Translational PKPD Group, Department of Pharmaceutical Biosciences, Associate 
      Member of SciLifeLab, Uppsala University, Uppsala, Sweden.
FAU - Loryan, Irena
AU  - Loryan I
AUID- ORCID: 0000-0002-1557-4416
AD  - Translational PKPD Group, Department of Pharmaceutical Biosciences, Associate 
      Member of SciLifeLab, Uppsala University, Uppsala, Sweden.
FAU - Richard, Jacques
AU  - Richard J
AUID- ORCID: 0000-0002-5286-9088
AD  - Sanofi R&D, 371 avenue Professeur Blayac, 34000, Montpellier, France.
FAU - Carvalho, Felix
AU  - Carvalho F
AUID- ORCID: 0000-0003-3858-3494
AD  - UCIBIO, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, 
      Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal. 
      felixdc@ff.up.pt.
FAU - Savic, Miroslav M
AU  - Savic MM
AUID- ORCID: 0000-0002-6934-9193
AD  - Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Vojvode 
      Stepe 450, 11000, Belgrade, Serbia. miroslav@pharmacy.bg.ac.rs.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200605
PL  - Germany
TA  - Arch Toxicol
JT  - Archives of toxicology
JID - 0417615
SB  - IM
MH  - *Adverse Drug Reaction Reporting Systems
MH  - Affect/*drug effects
MH  - Brain/*drug effects/metabolism/physiopathology
MH  - Cognition/*drug effects
MH  - Cognitive Dysfunction/*chemically induced/genetics/metabolism/psychology
MH  - *Data Mining
MH  - Gene Expression Regulation
MH  - Gene Regulatory Networks
MH  - Humans
MH  - Mood Disorders/*chemically induced/genetics/metabolism/psychology
MH  - *Pharmacovigilance
MH  - Protein Interaction Maps
MH  - Risk Assessment
MH  - Signal Transduction
PMC - PMC7395038
OTO - NOTNLM
OT  - Adverse outcome pathways
OT  - Cross-talk analysis
OT  - Neurotoxicity
OT  - Pharmaceuticals' safety
OT  - Psychiatric/psychological adverse events
COIS- We declare no competing interests.
EDAT- 2020/06/07 06:00
MHDA- 2021/07/13 06:00
PMCR- 2020/06/05
CRDT- 2020/06/07 06:00
PHST- 2020/05/07 00:00 [received]
PHST- 2020/05/20 00:00 [accepted]
PHST- 2020/06/07 06:00 [pubmed]
PHST- 2021/07/13 06:00 [medline]
PHST- 2020/06/07 06:00 [entrez]
PHST- 2020/06/05 00:00 [pmc-release]
AID - 10.1007/s00204-020-02788-1 [pii]
AID - 2788 [pii]
AID - 10.1007/s00204-020-02788-1 [doi]
PST - ppublish
SO  - Arch Toxicol. 2020 Aug;94(8):2829-2845. doi: 10.1007/s00204-020-02788-1. Epub 
      2020 Jun 5.