title: Impact of varying outcomes and definitions of suicidality on the associations of antiepileptic drugs and suicidality: comparisons from UK Clinical Practice Research Datalink (CPRD) and Danish national registries (DNR).
abstract: OBJECTIVE
  The purpose of this study is to quantify the impact of the different outcomes and definitions of suicidality on the association between antiepileptic drugs (AEDs) and suicidality.
  
  
  METHODS
  Retrospective cohort studies of selected AEDs (carbamazepine, gabapentin, lamotrigine, phenytoin, pregabalin, topiramate and valproate) using data from UK Clinical Practice Research Datalink (CPRD) alone and linked to UK Hospital Episode Statistics (HES) and UK Office of National Statistics (ONS), and from Danish national registries (DNR). Follow-up started at initiation of one of the study AEDs, divided into exposure periods, a maximum 90-day post-exposure period, and the reference period starting the day after the 90-day post-exposure period ended. Primary outcomes were completed suicide (SUI)/suicide attempt (SA) for CPRD and SUI/deliberate self-harm (DSH) for DNR. We applied adjusted Cox regression analyses and sensitivity analyses with varying outcome definitions.
  
  
  RESULTS
  We analyzed 84,524 AED users from CPRD-HES-ONS (1188 SUI/SA; 96 SUI) and 258,180 users from DNR (7561 SUI/DSH; 781 SUI). The adjusted hazard ratios (HRs) on SUI/SA ranged between 1.3 (95% confidence interval (CI): 0.84-2.00) for lamotrigine and 2.7 (1.24-5.81) for phenytoin in CPRD-HES-ONS, and between 0.9 (0.78-1.00) for valproate and 1.8 (1.10-3.07) for phenytoin on SUI/DSH in DNR. HRs for the primary outcomes varied consistently across exposure periods and data sources. HRs for SUI were in general lower, more stable and similar for periods of exposure and the 90-day post-exposure period.
  
  
  CONCLUSIONS
  Applying different outcomes and definitions of suicidality had an impact on the relative risks of suicidality associated with the investigated AEDs with results for SUI being most consistent and reliable.
authors.affiliation: Real World Data Science, F. Hoffmann-La Roche, Basel, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Schuerch
authors.affiliation: National Center for Register-based Research, Aarhus University, Aarhus V, Denmark.
authors.forename: Christiane
authors.initials: C
authors.lastname: Gasse
authors.affiliation: Real World Data Science, F. Hoffmann-La Roche, Basel, Switzerland.
authors.forename: Noah Jamie
authors.initials: NJ
authors.lastname: Robinson
authors.affiliation: European Medicines Agency, London, UK.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Alvarez
authors.affiliation: Real World Data Science, F. Hoffmann-La Roche, Basel, Switzerland.
authors.forename: Robert
authors.initials: R
authors.lastname: Walls
authors.affiliation: CIRRAU-Centre for Integrated Register-Based Research, Aarhus University, Aarhus V, Denmark.|Department P, Research Unit, Aarhus University Hospital Risskov, Aarhus, Denmark.
authors.forename: Ole
authors.initials: O
authors.lastname: Mors
authors.affiliation: CIRRAU-Centre for Integrated Register-Based Research, Aarhus University, Aarhus V, Denmark.|Department of Neurology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Jakob
authors.initials: J
authors.lastname: Christensen
authors.affiliation: National Institute for Health Data and Disease Control, Copenhagen, Denmark.
authors.forename: Ulrik
authors.initials: U
authors.lastname: Hesse
authors.affiliation: Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands.
authors.forename: Mark
authors.identifier: http://orcid.org/0000-0002-5764-5788
authors.initials: M
authors.lastname: de Groot
authors.affiliation: Global Clinical Epidemiology, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Raymond
authors.initials: R
authors.lastname: Schlienger
authors.affiliation: Epidemiology, Pfizer Inc., New York, NY, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Reynolds
authors.affiliation: Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands.
authors.forename: Olaf
authors.initials: O
authors.lastname: Klungel
authors.affiliation: Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands.|Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Frank
authors.initials: F
authors.lastname: de Vries
mesh_terms: D000328:Adult; D000927:Anticonvulsants / Q000009:adverse effects*; D003718:Denmark; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D063868:Patient Outcome Assessment; D012042:Registries; D012189:Retrospective Studies; D013405:Suicide / Q000706:statistics & numerical data*; D006113:United Kingdom
chemical_list: D000927:Anticonvulsants
keywords: CPRD; Danish national registries; antiepileptic drugs; deliberate self-harm; pharmacoepidemiology; suicide; suicide attempt