{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T12:32:08Z","timestamp":1776429128113,"version":"3.51.2"},"reference-count":79,"publisher":"Springer Science and Business Media LLC","issue":"8","license":[{"start":{"date-parts":[[2020,6,5]],"date-time":"2020-06-05T00:00:00Z","timestamp":1591315200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,6,5]],"date-time":"2020-06-05T00:00:00Z","timestamp":1591315200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100010767","name":"Innovative Medicines Initiative","doi-asserted-by":"publisher","award":["H2020-JTI-IMI2-2017-13-two-stage, ID 821528"],"award-info":[{"award-number":["H2020-JTI-IMI2-2017-13-two-stage, ID 821528"]}],"id":[{"id":"10.13039\/501100010767","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Arch Toxicol"],"published-print":{"date-parts":[[2020,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>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.<\/jats:p>","DOI":"10.1007\/s00204-020-02788-1","type":"journal-article","created":{"date-parts":[[2020,6,5]],"date-time":"2020-06-05T18:03:06Z","timestamp":1591380186000},"page":"2829-2845","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Molecular basis of mood and cognitive adverse events elucidated via a combination of pharmacovigilance data mining and functional enrichment analysis"],"prefix":"10.1007","volume":"94","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6174-579X","authenticated-orcid":false,"given":"Christos","family":"Andronis","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5656-0897","authenticated-orcid":false,"given":"Jo\u00e3o Pedro","family":"Silva","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4416-0148","authenticated-orcid":false,"given":"Eftychia","family":"Lekka","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4573-0501","authenticated-orcid":false,"given":"Vassilis","family":"Virvilis","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6650-5285","authenticated-orcid":false,"given":"Helena","family":"Carmo","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5063-4675","authenticated-orcid":false,"given":"Konstantina","family":"Bampali","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9809-2649","authenticated-orcid":false,"given":"Margot","family":"Ernst","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8702-6654","authenticated-orcid":false,"given":"Yang","family":"Hu","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1557-4416","authenticated-orcid":false,"given":"Irena","family":"Loryan","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5286-9088","authenticated-orcid":false,"given":"Jacques","family":"Richard","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3858-3494","authenticated-orcid":false,"given":"F\u00e9lix","family":"Carvalho","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6934-9193","authenticated-orcid":false,"given":"Miroslav M.","family":"Savi\u0107","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2020,6,5]]},"reference":[{"key":"2788_CR1","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1055\/s-0036-1584935","volume":"6","author":"KI Afzal","year":"2017","unstructured":"Afzal KI, Anam S, Hunter SJ (2017) The effects of antiepileptic drugs on pediatric cognition, mood, and behavior. J Pediatr Epilepsy 6:3\u201318. https:\/\/doi.org\/10.1055\/s-0036-1584935","journal-title":"J Pediatr Epilepsy"},{"key":"2788_CR2","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1038\/nbt.2083","volume":"30","author":"M Allison","year":"2012","unstructured":"Allison M (2012) Reinventing clinical trials. Nature Biotechnol 30:41\u201349. https:\/\/doi.org\/10.1038\/nbt.2083","journal-title":"Nature Biotechnol"},{"key":"2788_CR3","doi-asserted-by":"publisher","first-page":"824","DOI":"10.1053\/jhep.2002.32099","volume":"35","author":"MdL Alvarez","year":"2002","unstructured":"Alvarez MdL et al (2002) The in vivo apoptotic effect of interferon alfa-2b on rat preneoplastic liver involves Bax protein. Hepatology 35:824\u2013833. https:\/\/doi.org\/10.1053\/jhep.2002.32099","journal-title":"Hepatology"},{"key":"2788_CR4","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1038\/nn992","volume":"6","author":"SG Anagnostaras","year":"2003","unstructured":"Anagnostaras SG, Murphy GG, Hamilton SE, Mitchell SL, Rahnama NP, Nathanson NM, Silva AJ (2003) Selective cognitive dysfunction in acetylcholine M1 muscarinic receptor mutant mice. Nature Neurosci 6:51\u201358. https:\/\/doi.org\/10.1038\/nn992","journal-title":"Nature Neurosci"},{"key":"2788_CR5","doi-asserted-by":"publisher","unstructured":"Andronis C, Sharma A, Deftereos S, Virvilis V, Konstanti O, Persidis A, Persidis A (2012) Mining Scientific and Clinical Databases to Identify Novel Uses for Existing Drugs. In: Drug Repositioning. John Wiley & Sons, Ltd, pp 137\u2013161. https:\/\/doi.org\/10.1002\/9781118274408.ch6","DOI":"10.1002\/9781118274408.ch6"},{"key":"2788_CR6","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1016\/j.pharmthera.2017.05.006","volume":"179","author":"A Bal-Price","year":"2017","unstructured":"Bal-Price A, Meek ME (2017) Adverse outcome pathways: Application to enhance mechanistic understanding of neurotoxicity. Pharmacol Therapeut 179:84\u201395. https:\/\/doi.org\/10.1016\/j.pharmthera.2017.05.006","journal-title":"Pharmacol Therapeut"},{"key":"2788_CR7","doi-asserted-by":"publisher","first-page":"83","DOI":"10.3109\/10408444.2014.981331","volume":"45","author":"A Bal-Price","year":"2015","unstructured":"Bal-Price A, Crofton KM, Sachana M, Shafer TJ, Behl M, Forsby A et al (2015) Putative adverse outcome pathways relevant to neurotoxicity. Crit Rev Toxicol 45:83\u201391. https:\/\/doi.org\/10.3109\/10408444.2014.981331","journal-title":"Crit Rev Toxicol"},{"key":"2788_CR8","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1016\/j.neuro.2016.05.010","volume":"59","author":"A Bal-Price","year":"2017","unstructured":"Bal-Price A, Lein PJ, Keil KP, Sethi S, Shafer T, Barenys M et al (2017) Developing and applying the adverse outcome pathway concept for understanding and predicting neurotoxicity. Neurotoxicol 59:240\u2013255. https:\/\/doi.org\/10.1016\/j.neuro.2016.05.010","journal-title":"Neurotoxicol"},{"key":"2788_CR9","doi-asserted-by":"publisher","first-page":"160026","DOI":"10.1038\/sdata.2016.26","volume":"3","author":"JM Banda","year":"2016","unstructured":"Banda JM, Evans L, Vanguri RS, Tatonetti NP, Ryan PB, Shah NH (2016) A curated and standardized adverse drug event resource to accelerate drug safety research. Sci Data 3:160026\u2013160026. https:\/\/doi.org\/10.1038\/sdata.2016.26","journal-title":"Sci Data"},{"key":"2788_CR10","unstructured":"Adverse Outcome Pathway Knowledge Base (AOP-KB). Available at: https:\/\/aopkb.oecd.org\/index.html. Accessed on 11\/2019"},{"key":"2788_CR11","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1002\/pds.1742","volume":"18","author":"A Bate","year":"2009","unstructured":"Bate A, Evans SJW (2009) Quantitative signal detection using spontaneous ADR reporting. Pharmacoepidemiol Drug Saf 18:427\u2013436. https:\/\/doi.org\/10.1002\/pds.1742","journal-title":"Pharmacoepidemiol Drug Saf"},{"key":"2788_CR12","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1177\/153537020523000206","volume":"230","author":"B Bauer","year":"2005","unstructured":"Bauer B, Hartz AMS, Fricker G, Miller DS (2005) Modulation of p-glycoprotein transport function at the blood-brain barrier. Exp Biol Med 230:118\u2013127. https:\/\/doi.org\/10.1177\/153537020523000206","journal-title":"Exp Biol Med"},{"key":"2788_CR13","doi-asserted-by":"publisher","first-page":"1888","DOI":"10.1038\/sj.npp.1301312","volume":"32","author":"M Beneyto","year":"2007","unstructured":"Beneyto M, Kristiansen LV, Oni-Orisan A, McCullumsmith RE, Meador-Woodruff JH (2007) Abnormal glutamate receptor expression in the medial temporal lobe in schizophrenia and mood disorders. Neuropsychopharmacol 32:1888\u20131902. https:\/\/doi.org\/10.1038\/sj.npp.1301312","journal-title":"Neuropsychopharmacol"},{"key":"2788_CR14","doi-asserted-by":"publisher","first-page":"1055","DOI":"10.1080\/14740338.2019.1665022","volume":"18","author":"AC Bennett","year":"2019","unstructured":"Bennett AC, Bennett CL, Witherspoon BJ, Knopf KB (2019) An evaluation of reports of ciprofloxacin, levofloxacin, and moxifloxacin-association neuropsychiatric toxicities, long-term disability, and aortic aneurysms\/dissections disseminated by the food and drug administration and the european medicines agency. Expert Opin Drug Saf 18:1055\u20131063. https:\/\/doi.org\/10.1080\/14740338.2019.1665022","journal-title":"Expert Opin Drug Saf"},{"key":"2788_CR15","doi-asserted-by":"publisher","first-page":"180015","DOI":"10.1038\/sdata.2018.15","volume":"5","author":"S Bhattacharya","year":"2018","unstructured":"Bhattacharya S et al (2018) ImmPort, toward repurposing of open access immunological assay data for translational and clinical research. Sci Data 5:180015. https:\/\/doi.org\/10.1038\/sdata.2018.15","journal-title":"Sci Data"},{"key":"2788_CR16","doi-asserted-by":"publisher","first-page":"D267","DOI":"10.1093\/nar\/gkh061","volume":"32","author":"O Bodenreider","year":"2004","unstructured":"Bodenreider O (2004) The Unified Medical Language System (UMLS): integrating biomedical terminology. Nucleic Acids Res 32:D267\u2013D270. https:\/\/doi.org\/10.1093\/nar\/gkh061","journal-title":"Nucleic Acids Res"},{"key":"2788_CR17","doi-asserted-by":"publisher","first-page":"D1228","DOI":"10.1093\/nar\/gks1147","volume":"41","author":"K Breuer","year":"2013","unstructured":"Breuer K et al (2013) InnateDB: systems biology of innate immunity and beyond\u2013recent updates and continuing curation. Nucleic Acids Res 41:D1228\u2013D1233. https:\/\/doi.org\/10.1093\/nar\/gks1147","journal-title":"Nucleic Acids Res"},{"key":"2788_CR18","doi-asserted-by":"publisher","first-page":"2681","DOI":"10.4049\/jimmunol.1601546","volume":"198","author":"TM Brombacher","year":"2017","unstructured":"Brombacher TM et al (2017) IL-13\u2013mediated regulation of learning and memory. J Immunol 198:2681\u20132688. https:\/\/doi.org\/10.4049\/jimmunol.1601546","journal-title":"J Immunol"},{"key":"2788_CR19","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1016\/j.pharmthera.2011.01.014","volume":"130","author":"L Capuron","year":"2011","unstructured":"Capuron L, Miller AH (2011) Immune system to brain signaling: neuropsychopharmacological implications. Pharmacol Ther 130:226\u2013238. https:\/\/doi.org\/10.1016\/j.pharmthera.2011.01.014","journal-title":"Pharmacol Ther"},{"key":"2788_CR20","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1007\/s40264-014-0204-5","volume":"37","author":"O Caster","year":"2014","unstructured":"Caster O, Juhlin K, Watson S, Nor\u00e9n GN (2014) Improved statistical signal detection in pharmacovigilance by combining multiple strength-of-evidence aspects in vigiRank. Drug Saf 37:617\u2013628. https:\/\/doi.org\/10.1007\/s40264-014-0204-5","journal-title":"Drug Saf"},{"key":"2788_CR21","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1038\/nrd4309","volume":"13","author":"D Cook","year":"2014","unstructured":"Cook D, Brown D, Alexander R, March R, Morgan P, Satterthwaite G, Pangalos MN (2014) Lessons learned from the fate of AstraZeneca's drug pipeline: a five-dimensional framework. Nature Rev Drug Discov 13:419\u2013431. https:\/\/doi.org\/10.1038\/nrd4309","journal-title":"Nature Rev Drug Discov"},{"key":"2788_CR22","doi-asserted-by":"publisher","first-page":"D1068","DOI":"10.1093\/nar\/gkx1143","volume":"46","author":"KC Cotto","year":"2018","unstructured":"Cotto KC et al (2018) DGIdb 3.0: a redesign and expansion of the drug-gene interaction database. Nucleic Acids Res 46:D1068\u2013D1073. https:\/\/doi.org\/10.1093\/nar\/gkx1143","journal-title":"Nucleic Acids Res"},{"key":"2788_CR23","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1182\/asheducation-2013.1.15","volume":"2013","author":"M Crowther","year":"2013","unstructured":"Crowther M (2013) Phase 4 research: what happens when the rubber meets the road? Hematol Am Soc Hematol Educ Program 2013:15\u201318. https:\/\/doi.org\/10.1182\/asheducation-2013.1.15","journal-title":"Hematol Am Soc Hematol Educ Program"},{"key":"2788_CR24","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1002\/wsbm.147","volume":"3","author":"SN Deftereos","year":"2011","unstructured":"Deftereos SN, Andronis C, Friedla EJ, Persidis A, Persidis A (2011) Drug repurposing and adverse event prediction using high-throughput literature analysis. Wiley Interdiscip Rev Syst Biol Med 3:323\u2013334. https:\/\/doi.org\/10.1002\/wsbm.147","journal-title":"Wiley Interdiscip Rev Syst Biol Med"},{"key":"2788_CR25","doi-asserted-by":"publisher","first-page":"1067","DOI":"10.1084\/jem.20091419","volume":"207","author":"NC Derecki","year":"2010","unstructured":"Derecki NC, Cardani AN, Yang CH, Quinnies KM, Crihfield A, Lynch KR, Kipnis J (2010) Regulation of learning and memory by meningeal immunity: a key role for IL-4. J Exp Med 207:1067\u20131080. https:\/\/doi.org\/10.1084\/jem.20091419","journal-title":"J Exp Med"},{"key":"2788_CR26","unstructured":"Duggirala H et al. (2018) Data Mining at FDA - Data Mining at FDA - White Paper"},{"key":"2788_CR27","doi-asserted-by":"publisher","first-page":"1255","DOI":"10.1016\/S0140-6736(00)02799-9","volume":"356","author":"IR Edwards","year":"2000","unstructured":"Edwards IR, Aronson JK (2000) Adverse drug reactions: definitions, diagnosis, and management. Lancet 356:1255\u20131259. https:\/\/doi.org\/10.1016\/S0140-6736(00)02799-9","journal-title":"Lancet"},{"key":"2788_CR28","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1124\/pr.117.014647","volume":"70","author":"MA Erickson","year":"2018","unstructured":"Erickson MA, Banks WA (2018) Neuroimmune axes of the blood\u2013brain barriers and blood\u2013brain interfaces: Bases for physiological regulation, disease states, and pharmacological interventions. Pharmacol Rev 70:278\u2013314. https:\/\/doi.org\/10.1124\/pr.117.014647","journal-title":"Pharmacol Rev"},{"key":"2788_CR29","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1002\/pds.677","volume":"10","author":"SJ Evans","year":"2001","unstructured":"Evans SJ, Waller PC, Davis S (2001) Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports. Pharmacoepidemiol Drug Saf 10:483\u2013486. https:\/\/doi.org\/10.1002\/pds.677","journal-title":"Pharmacoepidemiol Drug Saf"},{"key":"2788_CR30","unstructured":"Food and Drug Administration (FDA) (2018) Questions and Answers on FDA's Adverse Event Reporting System (FAERS). https:\/\/www.fda.gov\/drugs\/surveillance\/questions-and-answers-fdas-adverse-event-reporting-system-faers. Accessed on 11\/2019"},{"key":"2788_CR31","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1097\/WNF.0b013e3181f8d513","volume":"33","author":"YD Fragoso","year":"2010","unstructured":"Fragoso YD et al (2010) Severe depression, suicide attempts, and ideation during the use of interferon beta by patients with multiple sclerosis. Clin Neuropharmacol 33:312\u2013316. https:\/\/doi.org\/10.1097\/WNF.0b013e3181f8d513","journal-title":"Clin Neuropharmacol"},{"key":"2788_CR32","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.seizure.2019.02.009","volume":"67","author":"H Goji","year":"2019","unstructured":"Goji H, Kanemoto K (2019) The effect of perampanel on aggression and depression in patients with epilepsy: A short-term prospective study. Seizure 67:1\u20134. https:\/\/doi.org\/10.1016\/j.seizure.2019.02.009","journal-title":"Seizure"},{"key":"2788_CR33","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1192\/apt.bp.115.015735","volume":"22","author":"A Gupta","year":"2016","unstructured":"Gupta A, Chadda RK (2016) Adverse psychiatric effects of non-psychotropic medications. BJPsych Adv 22:325\u2013334. https:\/\/doi.org\/10.1192\/apt.bp.115.015735","journal-title":"BJPsych Adv"},{"key":"2788_CR34","doi-asserted-by":"publisher","first-page":"462","DOI":"10.1124\/mol.105.017954","volume":"69","author":"AMS Hartz","year":"2006","unstructured":"Hartz AMS, Bauer B, Fricker G, Miller DS (2006) Rapid modulation of p-glycoprotein-mediated transport at the blood-brain barrier by tumor necrosis factor-\u03b1 and lipopolysaccharide. Mol Pharmacol 69:462\u2013470. https:\/\/doi.org\/10.1124\/mol.105.017954","journal-title":"Mol Pharmacol"},{"key":"2788_CR35","doi-asserted-by":"publisher","first-page":"1310","DOI":"10.1016\/j.biopsych.2007.03.017","volume":"62","author":"K Hashimoto","year":"2007","unstructured":"Hashimoto K, Sawa A, Iyo M (2007) Increased levels of glutamate in brains from patients with mood disorders. Biol Psychiatry 62:1310\u20131316. https:\/\/doi.org\/10.1016\/j.biopsych.2007.03.017","journal-title":"Biol Psychiatry"},{"key":"2788_CR36","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1016\/j.bbapap.2005.08.017","volume":"1754","author":"B Kaminska","year":"2005","unstructured":"Kaminska B (2005) MAPK signalling pathways as molecular targets for anti-inflammatory therapy - from molecular mechanisms to therapeutic benefits. Biochim Biophys Acta 1754:253\u2013262. https:\/\/doi.org\/10.1016\/j.bbapap.2005.08.017","journal-title":"Biochim Biophys Acta"},{"key":"2788_CR37","unstructured":"Labonte B, Turecki G (2012) Epigenetic effects of childhood adversity in the brain and suicide risk. In: The neurobiological basis of suicide. 2012. Dwivedi Y (ed): Boca Raton (FL, USA)"},{"key":"2788_CR38","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1177\/009286150804200501","volume":"42","author":"M Lindquist","year":"2008","unstructured":"Lindquist M (2008) VigiBase, the WHO Global ICSR Database System: Basic Facts. Drug Inf J 42:409\u2013419. https:\/\/doi.org\/10.1177\/009286150804200501","journal-title":"Drug Inf J"},{"key":"2788_CR39","doi-asserted-by":"publisher","first-page":"533","DOI":"10.2165\/00002018-200023060-00004","volume":"23","author":"M Lindquist","year":"2000","unstructured":"Lindquist M, St\u00e5hl M, Bate A, Edwards IR, Meyboom RH (2000) A retrospective evaluation of a data mining approach to aid finding new adverse drug reaction signals in the WHO international database. Drug Saf 23:533\u2013542. https:\/\/doi.org\/10.2165\/00002018-200023060-00004","journal-title":"Drug Saf"},{"key":"2788_CR40","doi-asserted-by":"publisher","first-page":"3210","DOI":"10.1172\/JCI90603","volume":"127","author":"A Louveau","year":"2017","unstructured":"Louveau A, Plog BA, Antila S, Alitalo K, Nedergaard M, Kipnis J (2017) Understanding the functions and relationships of the glymphatic system and meningeal lymphatics. J Clin Invest 127:3210\u20133219. https:\/\/doi.org\/10.1172\/JCI90603","journal-title":"J Clin Invest"},{"key":"2788_CR41","doi-asserted-by":"publisher","first-page":"2104","DOI":"10.1016\/j.celrep.2017.10.094","volume":"21","author":"SE Lutz","year":"2017","unstructured":"Lutz SE et al (2017) Caveolin Is Required for Th1 Cell Infiltration, but Not Tight Junction Remodeling, at the Blood-Brain Barrier in Autoimmune Neuroinflammation. Cell Rep 21:2104\u20132117. https:\/\/doi.org\/10.1016\/j.celrep.2017.10.094","journal-title":"Cell Rep"},{"key":"2788_CR42","doi-asserted-by":"publisher","first-page":"e25818","DOI":"10.7554\/eLife.25818","volume":"6","author":"M Maciejewski","year":"2017","unstructured":"Maciejewski M, Lounkine E, Whitebread S, Farmer P, DuMouchel W, Shoichet BK, Urban L (2017) Reverse translation of adverse event reports paves the way for de-risking preclinical off-targets. Elife 6:e25818. https:\/\/doi.org\/10.7554\/eLife.25818","journal-title":"Elife"},{"key":"2788_CR43","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1007\/s11920-007-0063-1","volume":"9","author":"S Maeng","year":"2007","unstructured":"Maeng S, Zarate CA Jr (2007) The role of glutamate in mood disorders: results from the ketamine in major depression study and the presumed cellular mechanism underlying its antidepressant effects. Curr Psychiatry Rep 9:467\u2013474. https:\/\/doi.org\/10.1007\/s11920-007-0063-1","journal-title":"Curr Psychiatry Rep"},{"key":"2788_CR44","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1016\/j.schres.2006.02.001","volume":"84","author":"L Martucci","year":"2006","unstructured":"Martucci L, Wong AH, De Luca V, Likhodi O, Wong GW, King N, Kennedy JL (2006) N-methyl-D-aspartate receptor NR2B subunit gene GRIN2B in schizophrenia and bipolar disorder: Polymorphisms and mRNA levels. Schizophr Res 84:214\u2013221. https:\/\/doi.org\/10.1016\/j.schres.2006.02.001","journal-title":"Schizophr Res"},{"key":"2788_CR45","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1016\/s0361-9230(01)00523-8","volume":"55","author":"JH Meador-Woodruff","year":"2001","unstructured":"Meador-Woodruff JH, Hogg AJ Jr, Smith RE (2001) Striatal ionotropic glutamate receptor expression in schizophrenia, bipolar disorder, and major depressive disorder. Brain Res Bull 55:631\u2013640. https:\/\/doi.org\/10.1016\/s0361-9230(01)00523-8","journal-title":"Brain Res Bull"},{"key":"2788_CR46","doi-asserted-by":"publisher","first-page":"e13984","DOI":"10.1371\/journal.pone.0013984","volume":"5","author":"D Merico","year":"2010","unstructured":"Merico D, Isserlin R, Stueker O, Emili A, Bader GD (2010) Enrichment map: a network-based method for gene-set enrichment visualization and interpretation. PLoS ONE 5:e13984\u2013e13984. https:\/\/doi.org\/10.1371\/journal.pone.0013984","journal-title":"PLoS ONE"},{"key":"2788_CR47","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1016\/j.pnpbp.2017.04.021","volume":"80","author":"B Misiak","year":"2018","unstructured":"Misiak B, Besz\u0142ej JA, Kotowicz K, Szewczuk-Bogus\u0142awska M, Samochowiec J, Kucharska-Mazur J, Frydecka D (2018) Cytokine alterations and cognitive impairment in major depressive disorder: From putative mechanisms to novel treatment targets. Progr Neuro-Psychopharmacol Biol Psychiatry 80:177\u2013188. https:\/\/doi.org\/10.1016\/j.pnpbp.2017.04.021","journal-title":"Progr Neuro-Psychopharmacol Biol Psychiatry"},{"key":"2788_CR48","doi-asserted-by":"publisher","first-page":"905","DOI":"10.1111\/j.1365-2125.2011.04037.x","volume":"72","author":"J-L Montastruc","year":"2011","unstructured":"Montastruc J-L, Sommet A, Bagheri H, Lapeyre-Mestre M (2011) Benefits and strengths of the disproportionality analysis for identification of adverse drug reactions in a pharmacovigilance database. Br J Clin Pharmacol 72:905\u2013908. https:\/\/doi.org\/10.1111\/j.1365-2125.2011.04037.x","journal-title":"Br J Clin Pharmacol"},{"key":"2788_CR49","doi-asserted-by":"publisher","first-page":"915","DOI":"10.1080\/14740338.2019.1652269","volume":"18","author":"AE Muderrisoglu","year":"2019","unstructured":"Muderrisoglu AE, Becher KF, Madersbacher S, Michel MC (2019) Cognitive and mood side effects of lower urinary tract medication. Expert Opin Drug Saf 18:915\u2013923. https:\/\/doi.org\/10.1080\/14740338.2019.1652269","journal-title":"Expert Opin Drug Saf"},{"key":"2788_CR50","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1016\/S2215-0366(18)30255-4","volume":"6","author":"L Nerurkar","year":"2019","unstructured":"Nerurkar L, Siebert S, McInnes IB, Cavanagh J (2019) Rheumatoid arthritis and depression: an inflammatory perspective. Lancet Psychiatry 6:164\u2013173. https:\/\/doi.org\/10.1016\/S2215-0366(18)30255-4","journal-title":"Lancet Psychiatry"},{"key":"2788_CR51","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1006\/exnr.2002.7871","volume":"174","author":"W Pan","year":"2002","unstructured":"Pan W, Kastin AJ (2002) TNF\u03b1 transport across the blood\u2013brain barrier is abolished in receptor knockout mice. Exp Neurol 174:193\u2013200. https:\/\/doi.org\/10.1006\/exnr.2002.7871","journal-title":"Exp Neurol"},{"key":"2788_CR52","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/S0165-5728(97)00034-9","volume":"76","author":"W Pan","year":"1997","unstructured":"Pan W, Banks WA, Kastin AJ (1997) Permeability of the blood-brain and blood-spinal cord barriers to interferons. J Neuroimmunol 76:105\u2013111. https:\/\/doi.org\/10.1016\/S0165-5728(97)00034-9","journal-title":"J Neuroimmunol"},{"key":"2788_CR53","doi-asserted-by":"publisher","first-page":"e41623","DOI":"10.1371\/journal.pone.0041623","volume":"7","author":"A Patel","year":"2012","unstructured":"Patel A, Zhu Y, Kuzhikandathil EV, Banks WA, Siegel A, Zalcman SS (2012) Soluble interleukin-6 receptor induces motor stereotypies and co-localizes with gp130 in regions linked to cortico-striato-thalamo-cortical circuits. PLoS ONE 7:e41623. https:\/\/doi.org\/10.1371\/journal.pone.0041623","journal-title":"PLoS ONE"},{"key":"2788_CR54","unstructured":"Adverse Outcome Pathway -Wiki (AOP-Wiki). Available at: https:\/\/aopwiki.org. Accessed on 11\/2019"},{"key":"2788_CR55","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1016\/j.neuropharm.2014.12.028","volume":"96","author":"MR Picciotto","year":"2015","unstructured":"Picciotto MR, Lewis AS, van Schalkwyk GI, Mineur YS (2015) Mood and anxiety regulation by nicotinic acetylcholine receptors: A potential pathway to modulate aggression and related behavioral states. Neuropharmacol 96:235\u2013243. https:\/\/doi.org\/10.1016\/j.neuropharm.2014.12.028","journal-title":"Neuropharmacol"},{"key":"2788_CR56","doi-asserted-by":"publisher","first-page":"1225","DOI":"10.1080\/17425255.2018.1539076","volume":"14","author":"J Pletz","year":"2018","unstructured":"Pletz J et al (2018) A critical review of adverse effects to the kidney: mechanisms, data sources, and in silico tools to assist prediction. Expert Opin Drug Metab Toxicol 14:1225\u20131253. https:\/\/doi.org\/10.1080\/17425255.2018.1539076","journal-title":"Expert Opin Drug Metab Toxicol"},{"key":"2788_CR57","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1007\/s10571-009-9431-1","volume":"30","author":"B Poller","year":"2010","unstructured":"Poller B, Drewe J, Kr\u00e4henb\u00fchl S, Huwyler J, Gutmann H (2010) Regulation of bcrp (ABCG2) and p-glycoprotein (ABCB1) by cytokines in a model of the human blood\u2013brain barrier. Cell Mol Neurobiol 30:63\u201370. https:\/\/doi.org\/10.1007\/s10571-009-9431-1","journal-title":"Cell Mol Neurobiol"},{"key":"2788_CR58","doi-asserted-by":"publisher","unstructured":"Poluzzi E, Raschi E, Piccinni C, De Ponti F (2012) Data mining techniques in pharmacovigilance: Analysis of the publicly accessible FDA adverse event reporting system (AERS) N2 - data mining applications in engineering and medicine targets to help data miners who wish to apply different data mining techniques. 2012. Karahoca, E (ed): IntechOpen CY, Rijeka. https:\/\/doi.org\/10.5772\/50095","DOI":"10.5772\/50095"},{"key":"2788_CR59","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1007\/s40264-018-0647-1","volume":"41","author":"R Postigo","year":"2018","unstructured":"Postigo R et al (2018) Eudravigilance medicines safety database: Publicly accessible data for research and public health protection. Drug Saf 41:665\u2013675. https:\/\/doi.org\/10.1007\/s40264-018-0647-1","journal-title":"Drug Saf"},{"key":"2788_CR60","doi-asserted-by":"publisher","first-page":"W191","DOI":"10.1093\/nar\/gkz369","volume":"47","author":"U Raudvere","year":"2019","unstructured":"Raudvere U, Kolberg L, Kuzmin I, Arak T, Adler P, Peterson H, Vilo J (2019) g:Profiler: a web server for functional enrichment analysis and conversions of gene lists (2019 update). Nucleic Acids Res 47:W191\u2013W198. https:\/\/doi.org\/10.1093\/nar\/gkz369","journal-title":"Nucleic Acids Res"},{"key":"2788_CR61","doi-asserted-by":"publisher","first-page":"1577","DOI":"10.1001\/archinte.1987.00370090055011","volume":"147","author":"PF Renault","year":"1987","unstructured":"Renault PF et al (1987) Psychiatric complications of long-term interferon alfa therapy. Arch Intern Med 147:1577\u20131580","journal-title":"Arch Intern Med"},{"key":"2788_CR62","doi-asserted-by":"publisher","first-page":"796","DOI":"10.7150\/ijms.6048","volume":"10","author":"T Sakaeda","year":"2013","unstructured":"Sakaeda T, Tamon A, Kadoyama K, Okuno Y (2013) Data mining of the public version of the FDA Adverse Event Reporting System. Int J Med Sci 10:796\u2013803. https:\/\/doi.org\/10.7150\/ijms.6048","journal-title":"Int J Med Sci"},{"key":"2788_CR63","doi-asserted-by":"publisher","unstructured":"Samanen J (2013) Chapter 5 - Similarities and differences in\u00a0the\u00a0discovery and use of\u00a0biopharmaceuticals and\u00a0small-molecule chemotherapeutics. In: Ganellin R, Roberts S, Jefferis R (eds) Introduction to Biological and Small Molecule Drug Research and Development. Elsevier, Oxford, pp 161\u2013203. https:\/\/doi.org\/10.1016\/B978-0-12-397176-0.00005-4","DOI":"10.1016\/B978-0-12-397176-0.00005-4"},{"key":"2788_CR64","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1159\/000231896","volume":"17","author":"E Scarr","year":"2009","unstructured":"Scarr E (2009) Muscarinic Receptors in Psychiatric Disorders \u2013 Can We Mimic \u2018Health\u2019? Neurosignals 17:298\u2013310. https:\/\/doi.org\/10.1159\/000231896","journal-title":"Neurosignals"},{"key":"2788_CR65","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1034\/j.1399-5618.2003.00024.x","volume":"5","author":"E Scarr","year":"2003","unstructured":"Scarr E, Pavey G, Sundram S, MacKinnon A, Dean B (2003) Decreased hippocampal NMDA, but not kainate or AMPA receptors in bipolar disorder. Bipolar Disord 5:257\u2013264. https:\/\/doi.org\/10.1034\/j.1399-5618.2003.00024.x","journal-title":"Bipolar Disord"},{"key":"2788_CR66","doi-asserted-by":"publisher","first-page":"e6585","DOI":"10.1371\/journal.pone.0006585","volume":"4","author":"A Sequeira","year":"2009","unstructured":"Sequeira A et al (2009) Global brain gene expression analysis links glutamatergic and GABAergic alterations to suicide and major depression. PLoS ONE 4:e6585. https:\/\/doi.org\/10.1371\/journal.pone.0006585","journal-title":"PLoS ONE"},{"key":"2788_CR67","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyt.2019.00138","author":"B Sessa","year":"2019","unstructured":"Sessa B, Higbed L, Nutt D (2019) A Review of 3,4-methylenedioxymethamphetamine (MDMA)-Assisted Psychotherapy. Front Psychiatry. https:\/\/doi.org\/10.3389\/fpsyt.2019.00138","journal-title":"Front Psychiatry"},{"key":"2788_CR68","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1038\/sj.mp.4001035","volume":"7","author":"RD Shytle","year":"2002","unstructured":"Shytle RD, Silver AA, Lukas RJ, Newman MB, Sheehan DV, Sanberg PR (2002) Nicotinic acetylcholine receptors as targets for antidepressants. Mol Psychiatry 7:525\u2013535. https:\/\/doi.org\/10.1038\/sj.mp.4001035","journal-title":"Mol Psychiatry"},{"key":"2788_CR69","doi-asserted-by":"publisher","first-page":"336","DOI":"10.1176\/appi.ajp.2017.17060616","volume":"175","author":"CW Skovlund","year":"2018","unstructured":"Skovlund CW, M\u00f8rch LS, Kessing LV, Lange T, Lidegaard \u00d8 (2018) Association of hormonal contraception with suicide attempts and suicides. Am J Psychiatry 175:336\u2013342. https:\/\/doi.org\/10.1176\/appi.ajp.2017.17060616","journal-title":"Am J Psychiatry"},{"key":"2788_CR70","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1016\/j.schres.2008.12.017","volume":"109","author":"SH Stephens","year":"2009","unstructured":"Stephens SH et al (2009) Association of the 5'-upstream regulatory region of the alpha7 nicotinic acetylcholine receptor subunit gene (CHRNA7) with schizophrenia. Schizophr Res 109:102\u2013112. https:\/\/doi.org\/10.1016\/j.schres.2008.12.017","journal-title":"Schizophr Res"},{"key":"2788_CR71","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1016\/s0028-3908(01)00122-8","volume":"41","author":"YP Tang","year":"2001","unstructured":"Tang YP, Wang H, Feng R, Kyin M, Tsien JZ (2001) Differential effects of enrichment on learning and memory function in NR2B transgenic mice. Neuropharmacol 41:779\u2013790. https:\/\/doi.org\/10.1016\/s0028-3908(01)00122-8","journal-title":"Neuropharmacol"},{"key":"2788_CR72","doi-asserted-by":"publisher","first-page":"809","DOI":"10.1016\/j.pnpbp.2010.10.014","volume":"35","author":"S-J Tsai","year":"2011","unstructured":"Tsai S-J, Hong C-J, Liou Y-J (2011) Recent molecular genetic studies and methodological issues in suicide research. Progr Neuro-Psychopharmacol Biol Psychiatry 35:809\u2013817. https:\/\/doi.org\/10.1016\/j.pnpbp.2010.10.014","journal-title":"Progr Neuro-Psychopharmacol Biol Psychiatry"},{"key":"2788_CR73","doi-asserted-by":"publisher","first-page":"468","DOI":"10.1002\/ajmg.b.31002","volume":"153","author":"S Utge","year":"2010","unstructured":"Utge S et al (2010) A population-based association study of candidate genes for depression and sleep disturbance. Am J Med Genet B Neuropsychiatr Genet 153:468\u2013476. https:\/\/doi.org\/10.1002\/ajmg.b.31002","journal-title":"Am J Med Genet B Neuropsychiatr Genet"},{"key":"2788_CR74","first-page":"39","volume":"25","author":"AD Valentine","year":"1998","unstructured":"Valentine AD, Meyers CA, Kling MA, Richelson E, Hauser P (1998) Mood and cognitive side effects of interferon-alpha therapy. Semin Oncol 25:39\u201347","journal-title":"Semin Oncol"},{"key":"2788_CR75","doi-asserted-by":"publisher","first-page":"1067","DOI":"10.1111\/j.1471-4159.2004.02774.x","volume":"91","author":"A Wick","year":"2004","unstructured":"Wick A et al (2004) Chemotherapy-induced cell death in primary cerebellar granule neurons but not in astrocytes: in vitro paradigm of differential neurotoxicity. J Neurochem 91:1067\u20131074. https:\/\/doi.org\/10.1111\/j.1471-4159.2004.02774.x","journal-title":"J Neurochem"},{"key":"2788_CR76","doi-asserted-by":"publisher","first-page":"87","DOI":"10.2174\/187152707780363302","volume":"6","author":"JM Witkin","year":"2007","unstructured":"Witkin JM, Marek GJ, Johnson BG, Schoepp DD (2007) Metabotropic glutamate receptors in the control of mood disorders. CNS Neurol Disord Drug Targets 6:87\u2013100. https:\/\/doi.org\/10.2174\/187152707780363302","journal-title":"CNS Neurol Disord Drug Targets"},{"key":"2788_CR77","doi-asserted-by":"publisher","first-page":"293","DOI":"10.3109\/10673229.2010.511059","volume":"18","author":"C Zarate Jr","year":"2010","unstructured":"Zarate C Jr, Machado-Vieira R, Henter I, Ibrahim L, Diazgranados N, Salvadore G (2010) Glutamatergic modulators: The future of treating mood disorders? Harv Rev Psychiatry 18:293\u2013303. https:\/\/doi.org\/10.3109\/10673229.2010.511059","journal-title":"Harv Rev Psychiatry"},{"key":"2788_CR78","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1007\/s00213-013-3297-0","volume":"231","author":"C Zhang","year":"2014","unstructured":"Zhang C et al (2014) A study of N-methyl-D-aspartate receptor gene (GRIN2B) variants as predictors of treatment-resistant major depression. Psychopharmacol 231:685\u2013693. https:\/\/doi.org\/10.1007\/s00213-013-3297-0","journal-title":"Psychopharmacol"},{"key":"2788_CR79","doi-asserted-by":"publisher","first-page":"314","DOI":"10.1016\/S1875-5364(13)60035-7","volume":"11","author":"RC Zink","year":"2013","unstructured":"Zink RC, Huang Q, Zhang L-Y, Bao W-J (2013) Statistical and graphical approaches for disproportionality analysis of spontaneously-reported adverse events in pharmacovigilance. Chin J Nat Med 11:314\u2013320. https:\/\/doi.org\/10.1016\/S1875-5364(13)60035-7","journal-title":"Chin J Nat Med"}],"container-title":["Archives of Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00204-020-02788-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00204-020-02788-1\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00204-020-02788-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,6,4]],"date-time":"2021-06-04T23:14:09Z","timestamp":1622848449000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00204-020-02788-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,5]]},"references-count":79,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2020,8]]}},"alternative-id":["2788"],"URL":"https:\/\/doi.org\/10.1007\/s00204-020-02788-1","relation":{},"ISSN":["0340-5761","1432-0738"],"issn-type":[{"value":"0340-5761","type":"print"},{"value":"1432-0738","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,5]]},"assertion":[{"value":"7 May 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 May 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 June 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"We declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"All data and materials, as well as software applications support the published claims and comply with field standards.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data transparency"}}]}}