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First 5000 Characters:Chloroquine and hydroxychloroquine are commonly used drugs in the treatment of malaria as well as chronic diseases, such as rheumatoid arthritis, and systemic lupus erythematosus. Although various reports on possible psychiatric side effects of these drugs exist, the nature and extent of these effects remain poorly understood. Moreover, the relevance of these drugs in the treatment of early stages of COVID-19 necessitates a careful estimation of their side effects. Here, we provide a systematic review of the psychiatric side effects associated with chloroquine and hydroxychloroquine. We used PubMed, Scopus, and Web of Science platforms to identify relevant literature published between 1962 and 2020. Search terms included chloroquine, hydroxychloroquine, psychiatry, psychosis, depression, anxiety, bipolar disorder, delirium, and psychotic disorders. Only case reports and clinical trials were included. All studies included records of psychiatric side effects induced by either chloroquine or hydroxychloroquine or both. Both retrospective and prospective, randomized as well as non-randomized population studies were included. Overall, the psychiatric side effects are dose-and sex-independent. The most common psychiatric side effects reported are increased speech output/ excessive talking, increased psychomotor activity, irritable mood, auditory hallucinations, delusion of grandiosity, and suicide attempts, likely due to brain intoxicationbe of chloroquine or hydroxychloroquine. The symptoms can develop in a few hours to 11 weeks after drug intake and are normally reversed within a week after the drug withdrawal. We conclude that CQ and HCQ have the potential to induce psychiatric side effects. This study calls for further investigation of psychiatric symptoms induced by these drugs in the short and long term.
On April 4th, 2020, the US Food and Drugs Administration (FDA) issued an emergency use of HCQ to treat adults and adolescents hospitalized with COVID-19 and cannot participate in or do not have clinical trials available (https://www.fda.gov/media/136537/download). Although some psychiatric side effects were discussed in the document ("Psychosis, delirium, agitation, confusion, suicidal behavior, and hallucinations"), the contraindications mentioned were only for patients with retinal or visual field changes, and cardiac problems. However, previous studies looking at psychiatric side effects induced by CQ and HCQ suggest that these drugs should be prescribed with caution to patients with a previous diagnosis of mental illnesses or individuals with a family history of psychiatric disorders (Gonzalez-Nieto J. A. & Costa-Juan E., 2015; Good M.I. & Shader R.I., 1977; Lovestone S., 1991; Mascolo A. et al., 2018) . Even though the FDA revoked its emergency use authorization on June 15th, 2020, it was evident that there is little information for physicians about the psychiatric side effects induced by HCQ and CQ. As there are still clinical-trials on these drugs being conducted, it is fundamental to bring up the attention for the induced psychiatric side effects. Therefore, the objective of this study is to focus on increasing the awareness of the CQ/HCQ induced psychiatric side effects by performing a systematic review of the topic. This will provide guidance of CQ/HCQ usage potentially not only on COVID-19, but other disorders.
Studies were identified by searching four electronic databases in the following order: PubMed, Scopus, Web of Science, and Embase. The following Medical Subject Heading (MeSH) term filters were applied: ("Chloroquine" OR "Hydroxychloroquine") AND ("Psychiatry" OR "Psychosis" OR "Depression" OR "Anxiety" OR "Bipolar Disorder" OR "Delirium" OR "Psychotic Disorders"). All four database searches were done in April 2020. A study was deemed relevant if it included a report of psychiatric side effects as well as a report of CQ or HCQ use. This encompassed both case reports and population studies. The relevance of a study was independently assessed by two authors (FT and SC) and the article contents were saved in an Excel spreadsheet. In case of a lack of agreement between these two authors, referral to a third author was planned. We excluded duplicate articles, articles that did not report any psychiatric side effects, did not report use of CQ or HCQ, were in vitro or animal studies, the full article was not available online, or was a comment to the journal (i.e., not an article). No language-based criterion was used for exclusion. We also excluded the review studies, since all of the relevant references in these reviews were either case reports or population studies that were already included (Alisky J.M. et al., 2006; Andrews R., 1985; Baird J.K., 2005; Berman J., 2004; Bhatia M.S. & Malik S.C., 1994; Bogaczewicz A. & Sobow T., 2017; Breuer O. & Schultz A., 2018; Chattopadhyay R. et al., 2007; Cooper R.G., 2008; Evans R.L. et al., 1984; Farhangian M.E. et al., 2015; Good M.I. & Shader R.I., 197