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

Jennifer C.E. Lane, James Weaver, Kristin Kostka, Talita Duarte-Salles, Maria Tereza F. Abrahao, Heba Alghoul, Osaid Alser, Thamir M. Alshammari, Carlos Areia, Patricia Biedermann, Juan M. Banda, Edward Burn, Paula Casajust, Kristina Fister, Jill Hardin, Laura Hester, George Hripcsak, Benjamin Skov Kaas-Hansen, Sajan Khosla, Spyros KolovosKristine E. Lynch, Rupa Makadia, Paras P. Mehta, Daniel R. Morales, Henry Morgan-Stewart, Mees Mosseveld, Danielle Newby, Fredrik Nyberg, Anna Ostropolets, Rae Woong Park, Albert Prats-Uribe, Gowtham A. Rao, Christian Reich, Peter Rijnbeek, Anthony G. Sena, Azza Shoaibi, Matthew Spotnitz, Vignesh Subbian, Marc A. Suchard, David Vizcaya, Haini Wen, Marcel De Wilde, Junqing Xie, Seng Chan You, Lin Zhang, Simon Lovestone, Patrick Ryan, Daniel Prieto-Alhambra

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)3222-3234
Number of pages13
JournalRheumatology and Rehabilitation
Issue number7
StatePublished - Jul 1 2021


  • HCQ
  • depression
  • epidemiology, RA
  • psychosis
  • safety

ASJC Scopus subject areas

  • Rheumatology
  • Pharmacology (medical)


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