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Risk of depression, suicide and psychosis with hydroxychloroquine treatment for rheumatoid arthritis: a multinational network cohort study


Rheumatology (Oxford). 2020 Dec 25;keaa771. doi: 10.1093/rheumatology/keaa771.Online ahead of print.

Jennifer C E Lane 1James Weaver 2Kristin Kostka 3Talita Duarte-Salles 4Maria Tereza F Abrahao 5Heba Alghoul 6Osaid Alser 7Thamir M Alshammari 8Carlos Areia 9Patricia Biedermann 10Juan M Banda 11Edward Burn 1 4Paula Casajust 12Kristina Fister 13Jill Hardin 2Laura Hester 2George Hripcsak 14 15Benjamin Skov Kaas-Hansen 16 17Sajan Khosla 18Spyros Kolovos 1Kristine E Lynch 19 20Rupa Makadia 2Paras P Mehta 21Daniel R Morales 22Henry Morgan-Stewart 3Mees Mosseveld 23Danielle Newby 24Fredrik Nyberg 25Anna Ostropolets 14Rae Woong Park 26Albert Prats-Uribe 1Gowtham A Rao 2Christian Reich 3Peter Rijnbeek 23Anthony G Sena 2 23Azza Shoaibi 2Matthew Spotnitz 14Subbian Vignesh 27Marc A Suchard 28David Vizcaya 29Haini Wen 30Marcel de Wilde 23Junqing Xie 1Seng Chan You 26Lin Zhang 31 32Simon Lovestone 33Patrick Ryan 2 14Daniel Prieto-Alhambra 1OHDSI-COVID-19 consortium

Author Information

1 Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences (NDORMS), University of Oxford, Oxford, UK.

2 Janssen Research and Development, Titusville, NJ, USA.

3 Real World Solutions, IQVIA, Cambridge, MA, USA.

4 Fundació Institut Universitari per a la recerca a l'Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Barcelona, Spain.

5 Faculty of Medicine, University of Sao Paulo, Sao Paulo, Brazil.

6 Faculty of Medicine, Islamic University of Gaza, Gaza, Palestine.

7 Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

8 Medication Safety Research Chair, King Saud University, Riyadh, Saudi Arabia.

9 Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.

10 Actelion Pharmaceuticals, Allschwil, Switzerland.

11 Georgia State University, Atlanta, GA, USA.

12 Real-World Evidence, Trial Form Support, Barcelona,Spain.

13 School of Medicine, Andrija Štampar School of Public Health, University of Zagreb, Zagreb, Croatia.

 14 Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, NY, USA.

15 New York-Presbyterian Hospital, New York, NY, USA.

16 Clinical Pharmacology Unit, Zealand University Hospital, Roskilde, Denmark.

17 NNF Centre for Protein Research, University of Copenhagen, Copenhagen, Denmark.

18 Real World Science & Digital, AstraZeneca, Cambridge, UK.

19 Department of Veterans Affairs, Salt Lake City, UT, USA.

20 University of Utah School of Medicine, Salt Lake City, UT, USA.

21 College of Medicine, University of Arizona, Tucson, AZ, USA.

22 Division of Population Health and Genomics, University of Dundee, Dundee, UK.

23 Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, The Netherlands.

24 Department of Psychiatry, University of Oxford, Oxford, UK.

25 School of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

26 Department of Biomedical Informatics, Ajou University School of Medicine, Suwon-si, Gyeonggi-do, South Korea.

27 College of Engineering, University of Arizona, Tucson, AZ, USA.

28 Departments of Biomathematics and Human Genetics David Geffen School of Medicine at UCLA, and Department of Biostatistics, UCLA School of Public Health, South Los Angeles, CA, USA.

29 Bayer Pharmaceuticals, Sant Joan Despi, Barcelona, Spain.

30 Department of Pharmacy, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, P.R. China.

31 School of Public Health, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, P.R. China.

32 Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia.

33 Janssen-Cilag, 50-100 Holmers Farm Way, High Wycombe HP12 4EG, UK.


Objectives: Concern has been raised in the rheumatology community regarding recent regulatory warnings that HCQ used in the coronavirus disease 2019 pandemic could cause acute psychiatric events. We aimed to study whether there is risk of incident depression, suicidal ideation or psychosis associated with HCQ as used for RA.

Methods: We performed a new-user cohort study using claims and electronic medical records from 10 sources and 3 countries (Germany, UK and USA). RA patients ≥18 years of age and initiating HCQ were compared with those initiating SSZ (active comparator) and followed up in the short (30 days) and long term (on treatment). Study outcomes included depression, suicide/suicidal ideation and hospitalization for psychosis. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate database-specific calibrated hazard ratios (HRs), with estimates pooled where I2 <40%.

Results: A total of 918 144 and 290 383 users of HCQ and SSZ, respectively, were included. No consistent risk of psychiatric events was observed with short-term HCQ (compared with SSZ) use, with meta-analytic HRs of 0.96 (95% CI 0.79, 1.16) for depression, 0.94 (95% CI 0.49, 1.77) for suicide/suicidal ideation and 1.03 (95% CI 0.66, 1.60) for psychosis. No consistent long-term risk was seen, with meta-analytic HRs of 0.94 (95% CI 0.71, 1.26) for depression, 0.77 (95% CI 0.56, 1.07) for suicide/suicidal ideation and 0.99 (95% CI 0.72, 1.35) for psychosis.

Conclusion: HCQ as used to treat RA does not appear to increase the risk of depression, suicide/suicidal ideation or psychosis compared with SSZ. No effects were seen in the short or long term. Use at a higher dose or for different indications needs further investigation.

Trial registration: Registered with EU PAS (reference no. EUPAS34497; http://www.encepp.eu/encepp/viewResource.htm? id=34498). The full study protocol and analysis source code can be found at https://github.com/ohdsi-studies/Covid19EstimationHydroxychloroquine2.