Hydroxychloroquine Increased Anxiety-Like Behaviors and Disrupted the Expression of Some Related Genes in the Mouse Brain

Abstract

Hydroxychloroquine (HCQ), which has been proposed as a therapeutic or prophylactic drug for COVID-19, has been administered to thousands of individuals with varying efficacy; however, our understanding of its adverse effects is insufficient. It was reported that HCQ induced psychiatric symptoms in a few patients with autoimmune diseases, but it is still uncertain whether HCQ poses a risk to mental health. Therefore, in this study, we treated healthy mice with two different doses of HCQ that are comparable to clinically administered doses for 7 days. Psychiatric-like behaviors and the expression of related molecules in the brain were evaluated at two time points, i.e., 24 h and 10 days after drug administration. We found that HCQ increased anxiety behavior at both 24 h and 10 days. Furthermore, HCQ decreased the mRNA expression of interleukin-1beta, corticotropin-releasing hormone (Crh), a serotonin transporter (Slc6a4), and a microglia maker (Aif1) in the hippocampus and decreased the mRNA expression of brain-derived neurotrophic factor (Bdnf) in both the hippocampus and amygdala. Lots of these behavioral and molecular changes were sustained beyond 10 days after drug administration, and some of them were dose-dependent. Although this animal study does not prove that HCQ has a similar effect in humans, it indicates that HCQ poses a significant risk to mental health and suggests that further clinical investigation is essential. According to our data, we recommend that HCQ be carefully used as a prophylactic drug in people who are susceptible to mental disorders.

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“…A study reported that CQ crosses the BBB easily and potentially accumulates in the brain, 32 whereas another study indicated that the ability of CQ to cross the BBB is quite limited. 33 Therefore, this issue is controversial. Several clinical trials of CQ have been conducted for various cancers, but the results have not been encouraging.…”

“…While there is no information on the efficiency of penetration across the BBB regarding bafilomycin and MRT68921, CQ is clinically available and data on CQ have been reported in several studies. A study reported that CQ crosses the BBB easily and potentially accumulates in the brain, 32 whereas another study indicated that the ability of CQ to cross the BBB is quite limited 33 . Therefore, this issue is controversial.…”