- Victor M Castro, team lead1,
- Caitlin C Clements, clinical research coordinator23,
- Shawn N Murphy, associate professor of neurology4,
- Vivian S Gainer, team lead1,
- Maurizio Fava, Slater Family professor of psychiatry 5,
- Jeffrey B Weilburg, assistant professor of psychiatry 5,
- Jane L Erb, assistant professor of psychiatry6,
- Susanne E Churchill, executive director, i2b2 National Center for Biomedical Computing7,
- Isaac S Kohane, director, i2b2 National Center for Biomedical Computing8,
- Dan V Iosifescu, associate professor of psychiatry 9,
- Jordan W Smoller, associate professor of psychiatry2,
- Roy H Perlis, associate professor of psychiatry3
- 1Partners Research Computing, Partners HealthCare System, One Constitution Center, Boston, MA 02129, USA
- 2Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02114, USA
- 3Center for Experimental Drugs and Diagnostics, Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02114, USA
- 4Laboratory of Computer Science and Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA
- 5Depression Clinic and Research Program, Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02114, USA
- 6Department of Psychiatry, Brigham and Women’s Hospital, Boston, MA 02215, USA
- 7Information Systems, Partners HealthCare System, New Research Building 255, Boston, MA 02215, USA
- 8Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02215, USA
- 9Mood and Anxiety Disorders Program, Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA
- Correspondence to: R H Perlis, Simches Research Building/MGH, 185 Cambridge St, Boston, MA 02114, USA
- Accepted 18 December 2012
Objective To quantify the impact of citalopram and other selective serotonin reuptake inhibitors on corrected QT interval (QTc), a marker of risk for ventricular arrhythmia, in a large and diverse clinical population.
Design A cross sectional study using electrocardiographic, prescribing, and clinical data from electronic health records to explore the relation between antidepressant dose and QTc. Methadone, an opioid known to prolong QT, was included to demonstrate assay sensitivity.
Setting A large New England healthcare system comprising two academic medical centres and outpatient clinics.
Participants 38 397 adult patients with an electrocardiogram recorded after prescription of antidepressant or methadone between February 1990 and August 2011.
Main outcome measures Relation between antidepressant dose and QTc interval in linear regression, adjusting for potential clinical and demographic confounding variables. For a subset of patients, change in QTc after drug dose was also examined.
Results Dose-response association with QTc prolongation was identified for citalopram (adjusted beta 0.10 (SE 0.04), P<0.01), escitalopram (adjusted beta 0.58 (0.15), P<0.001), and amitriptyline (adjusted beta 0.11 (0.03), P<0.001), but not for other antidepressants examined. An association with QTc shortening was identified for bupropion (adjusted beta 0.02 (0.01) P<0.05). Within-subject paired observations supported the QTc prolonging effect of citalopram (10 mg to 20 mg, mean QTc increase 7.8 (SE 3.6) ms, adjusted P<0.05; and 20 mg to 40 mg, mean QTc increase 10.3 (4.0) ms, adjusted P<0.01).
Conclusions This study confirmed a modest prolongation of QT interval with citalopram, and identified additional antidepressants with similar observed risk. Pharmacovigilance studies using electronic health record data may be a useful method of identifying potential risk associated with treatments.
Contributors: VMC designed the tools for collecting data, cleaned and analysed the data, and drafted and revised the manuscript. CCC contributed to preparation of the manuscript. SNM designed the tools for collecting data and contributed to interpretation of analysis and preparation of the manuscript. VSG, MF, JBW, JLE, SEC, ISK, and DVI contributed to interpretation of the analysis and preparation of the manuscript. JWS designed the study and contributed to interpretation of the analysis and preparation of the manuscript. RHP initiated the project, designed the study, monitored the analyses and drafted and revised the manuscript. VMC and RHP are guarantors for the study. All authors had full access to all of the data (including statistical reports and tables) in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis.
Funding: The project was supported by the NIH/National Library of Medicine (award No 2U54LM008748 to ISK) and the National Institute of Mental Health (award No R01MH086026 to RHP). 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.
Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: RHP has received consulting fees from or served on scientific advisory boards for Proteus Biomedical, Pamlab, Genomind, and RIDventures, and has received 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 Massachusetts General Hospital Psychiatry Academy and has served as a consultant for CNS Response. MF has received consulting fees from or served on scientific advisor boards for Abbott Laboratories, Affectis Pharmaceuticals AG, Alkermes, Amarin Pharma, Aspect Medical Systems, AstraZeneca, Auspex Pharmaceuticals, Bayer AG, Best Practice Project Management, BioMarin Pharmaceuticals, Biovail Corporation, BrainCells, Bristol-Myers Squibb, CeNeRx BioPharma, Cephalon, CNS Response, Compellis Pharmaceuticals, Cypress Pharmaceutical, DiagnoSearch Life Sciences, Dinippon Sumitomo Pharma, Dov Pharmaceuticals, Edgemont Pharmaceuticals, Eisai, Eli Lilly, EnVivo Pharmaceuticals, ePharmaSolutions, EPIX Pharmaceuticals, Euthymics Bioscience, Fabre-Kramer Pharmaceuticals, Forest Pharmaceuticals, GenOmind, GlaxoSmithKline, Grunenthal GmbH, i3 Innovus/Ingenis, Janssen Pharmaceutica, Jazz Pharmaceuticals, Johnson & Johnson Pharmaceutical Research & Development, Knoll Pharmaceuticals, Labopharm, Lorex Pharmaceuticals, Lundbeck, MedAvante, Merck, MSI Methylation Sciences, Naurex, Neuralstem, Neuronetics, NextWave Pharmaceuticals, Novartis AG, Nutrition 21, Orexigen Therapeutics, Organon Pharmaceuticals, Otsuka Pharmaceuticals, Pamlab, Pfizer, PharmaStar, Pharmavite, PharmoRx Therapeutics, Precision Human Biolaboratory, Prexa Pharmaceuticals, Puretech Ventures, PsychoGenics, Psylin Neurosciences, Rexahn Pharmaceuticals, Ridge Diagnostics, Roche, Sanofi-Aventis US, Sepracor, Servier Laboratories, Schering-Plough, Solvay Pharmaceuticals, Somaxon Pharmaceuticals, Somerset Pharmaceuticals, Sunovion Pharmaceuticals, Supernus Pharmaceuticals, Synthelabo, Takeda Pharmaceutical, Tal Medical, Tetragenex Pharmaceuticals, TransForm Pharmaceuticals, Transcept Pharmaceuticals, Vanda Pharmaceuticals. MF has equity holdings in Compellis and has received research grant support from Abbot Laboratories, Alkermes, Aspect Medical Systems, AstraZeneca, BioResearch, BrainCells, Bristol-Myers Squibb, CeNeRx BioPharma, Cephalon, Clintara, Covance, Covidien, Eli Lilly, ElMindA, EnVivo Pharmaceuticals, Euthymics Bioscience, Forest Pharmaceuticals, Ganeden Biotech, GlaxoSmithKline, Icon Clinical Research, i3 Innovus/Ingenix, Johnson & Johnson Pharmaceutical Research & Development, Lichtwer Pharma GmbH, Lorex Pharmaceuticals, National Alliance for Research on Schizophrenia & Depression (NARSAD), National Center for Complementary and Alternative Medicine (NCCAM), National Institute of Drug Abuse (NIDA), National Institute of Mental Health (NIMH), Novartis AG, Organon Pharmaceuticals, PamLab, Pfizer, Pharmavite, Photothera, Roche Pharmaceuticals, RCT Logic (formerly Clinical Trials Solutions), Sanofi-Aventis, Shire, Solvay Pharmaceuticals, Synthelabo, Wyeth-Ayerst Laboratories. MF also holds a patent for Sequential Parallel Comparison Design (SPCD), which is licensed by MGH to RCT Logic, and copyright for the MGH Cognitive & Physical Functioning Questionnaire (CPFQ), Sexual Functioning Inventory (SFI), Antidepressant Treatment Response Questionnaire (ATRQ), Discontinuation-Emergent Signs & Symptoms (DESS), and SAFER; Lippincott, Williams & Wilkins; Wolkers Kluwer; World Scientific Publishing.
Ethical approval: This study obtained IRB approval from the Partners Human Research Committee (protocol No 2011-P-002314). No informed consent was required (this project was a retrospective study involving thousands of patients and multiple years of data, so consent could not feasibly be obtained from all subjects).
Data sharing: Additional data can be found in the supplementary figures and tables on bmj.com.
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