title: The use of antidepressants and the risk of idiopathic pulmonary arterial hypertension.
abstract: BACKGROUND
  Serotonin has been implicated in the development of idiopathic pulmonary arterial hypertension (IPAH). Drugs modulating serotonin pathways, including antidepressants, have been associated with the incidence of IPAH, with conflicting reports as to the direction of the effect. We aimed to determine whether antidepressant exposure is associated with the incidence of IPAH.
  
  
  METHODS
  A nested case-control study was conducted using the United Kingdom Clinical Practice Research Datalink and the Hospital Episodes Statistics repository between January 1, 1988 and September 30, 2011. Incident cases of IPAH were identified and matched to all controls in the case's risk set on age, sex, general practice, and date of registration with the practice. Rate ratios (RRs) and 95% confidence intervals (CIs) were estimated for the use of antidepressants on the risk of IPAH, with an 18-month lag period before the diagnosis.
  
  
  RESULTS
  One hundred ninety-five IPAH cases were identified (incidence 3.84/million per year). Use of any antidepressant was associated with a 67% increased risk of IPAH (RR, 1.67; 95% CI, 1.17-2.37). The rate of IPAH was similar across antidepressant classes, whether with selective serotonin reuptake inhibitors (SSRIs) (RR, 1.67; 95% CI, 1.09-2.57) or non-SSRI antidepressants (RR, 1.66; 95% CI, 1.07-2.59). In sensitivity and exploratory analyses, no change in risk was observed with different lag times, serotonin transporter affinities, or durations of exposure.
  
  
  CONCLUSIONS
  The use of antidepressants was associated with a significantly increased risk of IPAH. However, the consistency of this risk across all antidepressants and absence of a dose-response relationship suggests a noncausal association.
authors.affiliation: Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Québec, Canada; Center for Pulmonary Vascular Diseases, Division of Cardiology, Jewish General Hospital, Montreal, Québec, Canada; Department of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Fox
authors.affiliation: Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Québec, Canada; Department of Oncology, McGill University, Montreal, Québec, Canada.
authors.forename: Laurent
authors.initials: L
authors.lastname: Azoulay
authors.affiliation: Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Québec, Canada.
authors.forename: Sophie
authors.initials: S
authors.lastname: Dell'Aniello
authors.affiliation: Center for Pulmonary Vascular Diseases, Division of Cardiology, Jewish General Hospital, Montreal, Québec, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Langleben
authors.affiliation: Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Québec, Canada; Department of Preclinical and Clinical Pharmacology, University of Florence, Florence; Agency for Healthcare Services of Tuscany, Florence, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Lapi
authors.affiliation: Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Québec, Canada.
authors.forename: Jacques
authors.initials: J
authors.lastname: Benisty
authors.affiliation: Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Québec, Canada. Electronic address: samy.suissa@mcgill.ca.
authors.forename: Samy
authors.initials: S
authors.lastname: Suissa
mesh_terms: D000928:Antidepressive Agents / Q000009:adverse effects* / Q000627:therapeutic use; D016001:Confidence Intervals; D003863:Depression / Q000188:drug therapy*; D065627:Familial Primary Pulmonary Hypertension / Q000139:chemically induced* / Q000453:epidemiology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors; D006113:United Kingdom / Q000453:epidemiology
chemical_list: D000928:Antidepressive Agents