Objective To examine the association between exposure to newer antidepressants and risk of gastrointestinal (GI) and other bleeding complications among individuals with major depressive disorder (MDD).
Design This study uses an incident user cohort design to compare associations between incidence of vascular/bleeding events and the relative affinity (low, moderate or high) of the antidepressant for the serotonin transporter during an exposure risk period for each patient.
Setting New England healthcare system electronic medical record database.
Participants 36 389 individuals with a diagnosis of MDD and monotherapy with a selective serotonin reuptake inhibitor, serotonin–norepinephrine reuptake inhibitor or other new-generation antidepressant were identified from among 3.1 million patients in a New England healthcare system.
Primary and secondary outcome measures Rates of bleeding or other vascular complications, including acute liver failure, acute renal failure, asthma, breast cancer and hip fractures.
Results 601 GI bleeds were observed in the 21 462 subjects in the high-affinity group versus 333 among the 14 927 subjects in the lower affinity group (adjusted RR: 1.17, 95% CI 1.02 to 1.34). Similarly, 776 strokes were observed in the high-affinity group versus 434 in the lower affinity treatment group (adjusted RR: 1.18, 95% CI 1.06 to 1.32). No significant association with risk for a priori negative control outcomes, including acute liver failure, acute renal failure, asthma, breast cancer and hip fractures, was identified.
Conclusions Use of antidepressants with high affinity for the serotonin transporter may confer modestly elevated risk for GI and other bleeding complications. While multiple methodologic limitations must be considered, these results suggest that antidepressants with lower serotonin receptor affinity may be preferred in patients at greater risk for such complications.
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To cite: Castro V, Gallagher PJ, Clements CC, et al. Incident user cohort study of risk for gastrointestinal bleed and stroke in individuals with major depressive disorder treated with antidepressants. BMJ Open 2012;2:e000544. doi:10.1136/bmjopen-2011-000544
Contributors VC designed the tools for collecting data, cleaned and analysed the data and drafted and revised the manuscript. He is a guarantor. PJG contributed to interpretation of analysis and drafted and revised the manuscript. CCC contributed to preparation of the manuscript. SM designed the tools for collecting data and contributed to interpretation of analysis and preparation of manuscript. VG, MF, JW, SC, IK and DVI contributed to interpretation of analysis and preparation of manuscript. JWS designed the study and contributed to interpretation of analysis and preparation of manuscript. RP initiated the project, designed the study, monitored the analyses and drafted and revised the manuscript. He is a guarantor. All authors have approved the final version.
Funding The project described was supported by Award # 2U54LM008748 from the NIH/National Library of Medicine (to IK) and R01MH086026 from the National Institute of Mental Health (to RP). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Library of Medicine or the National Institutes of Health.
Disclosures Maurizio Fava—Lifetime Disclosures. Abbott Laboratories; Alkermes, Inc.; Aspect Medical Systems; AstraZeneca; BioResearch; BrainCells Inc.; Bristol-Myers Squibb; Cephalon, Inc.; Clinical Trials Solutions, LLC; Covidien; Eli Lilly and Company; EnVivo Pharmaceuticals, Inc.; Forest Pharmaceuticals, Inc.; Ganeden Biotech, Inc.; GlaxoSmithKline; Johnson & Johnson Pharmaceutical Research & Development; Lichtwer Pharma GmbH; Lorex Pharmaceuticals; Novartis AG; Organon Pharmaceuticals; PamLab, LLC; Pfizer Inc.; Pharmavite® LLC; Roche; RTC Logic, LLC; Sanofi-Aventis US LLC; Shire; Solvay Pharmaceuticals, Inc.; Synthelabo; Wyeth-Ayerst Laboratories. Advisory/Consulting: Abbott Laboratories; Affectis Pharmaceuticals AG; Amarin Pharma Inc.; Aspect Medical Systems; AstraZeneca; Auspex Pharmaceuticals; Bayer AG; Best Practice Project Management, Inc.; BioMarin Pharmaceuticals, Inc.; Biovail Corporation; BrainCells Inc; Bristol-Myers Squibb; CeNeRx BioPharma; Cephalon, Inc.; Clinical Trials Solutions, LLC; CNS Response, Inc.; Compellis Pharmaceuticals; Cypress Pharmaceutical, Inc.; Dov Pharmaceuticals, Inc.; Eisai Inc.; Eli Lilly and Company; EPIX Pharmaceuticals, Inc.; Euthymics Bioscience, Inc.; Fabre-Kramer Pharmaceuticals, Inc.; Forest Pharmaceuticals, Inc.; GenOmind, LLC; GlaxoSmithKline; Gruenthal GmbH; Janssen Pharmaceutica; Jazz Pharmaceuticals, Inc.; Johnson & Johnson Pharmaceutical Research & Development, LLC.; Knoll Pharmaceuticals Corp.; Labopharm Inc.; Lorex Pharmaceuticals; Lundbeck Inc.; MedAvante, Inc.; Merck & Co., Inc.; Methylation Sciences; Neuronetics, Inc.; Novartis AG; Nutrition 21; Organon Pharmaceuticals; PamLab, LLC.; Pfizer Inc.; PharmaStar; Pharmavite® LLC.; Precision Human Biolaboratory; Prexa Pharmaceuticals, Inc.; PsychoGenics; Psylin Neurosciences, Inc.; Ridge Diagnostics, Inc.; Roche; RCT Logic, LLC; Sanofi-Aventis US LLC.; Sepracor Inc.; Schering-Plough Corporation; Solvay Pharmaceuticals, Inc.; Somaxon Pharmaceuticals, Inc.; Somerset Pharmaceuticals, Inc.; Synthelabo; Takeda Pharmaceutical Company Limited; Tetragenex Pharmaceuticals, Inc.; TransForm Pharmaceuticals, Inc.; Transcept Pharmaceuticals, Inc.; Vanda Pharmaceuticals, Inc.; Wyeth-Ayerst Laboratories. Speaking/Publishing: Adamed, Co; Advanced Meeting Partners; American Psychiatric Association; American Society of Clinical Psychopharmacology; AstraZeneca; Belvoir Media Group; Boehringer Ingelheim GmbH; Bristol-Myers Squibb; Cephalon, Inc.; Eli Lilly and Company; Forest Pharmaceuticals, Inc.; GlaxoSmithKline; Imedex, LLC; MGH Psychiatry Academy/Primedia; MGH Psychiatry Academy/Reed Elsevier; Novartis AG; Organon Pharmaceuticals; Pfizer Inc.; PharmaStar; United BioSource, Corp.; Wyeth-Ayerst Laboratories. Equity Holdings: Compellis Royalty/patent, other income: Patent for SPCD and patent application for a combination of azapirones and bupropion in major depressive disorder, copyright royalties for the MGH CPFQ, SFI, ATRQ, DESS and SAFER. RHP has received consulting fees or served on scientific advisory boards for Proteus Biomedical, Concordant Rater Systems, Genomind and RIDventures; research grant support from Proteus Biomedical and royalties from Concordant Rater Systems. JWS has served as a consultant for The Medical Letter. DVI has received payment for lectures including service on speakers' bureaus from the MGH Psychiatry Academy and has served as a consultant for CNS Response, Inc.
Competing interests None.
Patient consent This is a retrospective health care utilization/clinical study involving potentially hundreds of thousands of patients and multiple years of data—that is, consent could not feasibly be obtained from all subjects.
Ethics approval Partners Institutional Review Board.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Additional data can be found in tables S1–S4.