Risk of depression, suicidal ideation, suicide and psychosis with hydroxychloroquine treatment for rheumatoid arthritis: a multi-national network cohort study
Authors: Lane Jennifer C.E. , Weaver James , Kostka Kristin , Duarte-Salles Talita , Abrahao Maria Tereza F. , Alghoul Heba , Alser Osaid , Alshammari Thamir M , Areia Carlos , Biedermann Patricia , Banda Juan M. , Burn Edward , Casajust Paula , Fišer Kristina , Hardin Jill , Hester Laura , Hripcsak George , Kaas-Hansen Benjamin Skov , Khosla Sajan , Kolovos Spyros , Lynch Kristine E. , Makadia Rupa , Mehta Paras P. , Morales Daniel R. , Morgan-Stewart Henry , Mosseveld Mees , Newby Danielle , Nyberg Fredrik , Ostropolets Anna , Park Rae Woong , Prats-Uribe Albert , Rao Gowtham A. , Reich Christian , Rijnbeek Peter , Sena Anthony G. , Shoaibi Azza , Spotnitz Matthew , Subbian Vignesh , Suchard Marc A. , Vizcaya David , Wen Haini , de Wilde Marcel , Xie Junqing , You Seng Chan , Zhang Lin , Lovestone Simon , Ryan Patrick , Prieto-Alhambra Daniel 
Published: July 2020

ABSTRACTObjectivesConcern has been raised in the rheumatological community regarding recent regulatory warnings that hydroxychloroquine used in the COVID-19 pandemic could cause acute psychiatric events. We aimed to study whether there is risk of incident depression, suicidal ideation, or psychosis associated with hydroxychloroquine as used for rheumatoid arthritis (RA).MethodsNew user cohort study using claims and electronic medical records from 10 sources and 3 countries (Germany, UK and US). RA patients aged 18+ and initiating hydroxychloroquine were compared to those initiating sulfasalazine (active comparator) and followed up in the short (30-day) 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 (HR), with estimates pooled where I2<40%.Results918,144 and 290,383 users of hydroxychloroquine and sulfasalazine, respectively, were included. No consistent risk of psychiatric events was observed with short-term hydroxychloroquine (compared to sulfasalazine) use, with meta-analytic HRs of 0.96 [0.79-1.16] for depression, 0.94 [0.49-1.77] for suicide/suicidal ideation, and 1.03 [0.66-1.60] for psychosis. No consistent long-term risk was seen, with meta-analytic HRs 0.94 [0.71-1.26] for depression, 0.77 [0.56-1.07] for suicide/suicidal ideation, and 0.99 [0.72-1.35] for psychosis.ConclusionsHydroxychloroquine as used to treat RA does not appear to increase the risk of depression, suicide/suicidal ideation, or psychosis compared to sulfasalazine. No effects were seen in the short or long term. Use at higher dose or for different indications needs further investigation.TRIAL REGISTRATIONRegistered with EU PAS; Reference number 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/Covid19EstimationHydroxychloroquine.WHAT IS ALREADY KNOWN ON THIS TOPICRecent regulatory warnings have raised concerns of potential psychiatric side effects of hydroxychloroquine at the doses used to treat COVID-19, generating concern in the rheumatological communitySerious psychiatric adverse events such as suicide, acute psychosis, and depressive episodes have been identified by the US Food and Drug Administration (FDA) adverse events reporting system and at case report levelWHAT THIS STUDY ADDSThis is the largest study on the neuro-psychiatric safety of hydroxychloroquine to date, including >900,000 users treated for their RA in country-level or private health care systems in Germany, the UK, and the USWe find no association between the use of hydroxychloroquine and the risk of depression, suicide/suicidal ideation, or severe psychosis compared to sulfasalazineHOW MIGHT THIS IMPACT ON CLINICAL PRACTICEOur data shows no association between hydroxychloroquine treatment for RA and risk of depression, suicide or psychosis compared to sulfasalazine. These findings do not support stopping or switching hydroxychloroquine treatment as used for RA due to recent concerns based on COVID-19 treated patients.