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<p class="ltrs-br-ltr-br-title"><span class="bold">Psychiatric Side Effects of Chloroquine</span></p>
<p class="ltrs-br-ltr-br-body-text"><span class="semibold">To the Editor:</span> There is considerable interest in the use of chloroquine and hydroxychloroquine for treatment and prevention of coronavirus disease 2019 (COVID-19). Whereas contradictory results have been reported about their efficacy against COVID-19, potentially serious adverse effects, such as cardiac, kidney, liver, and ophthalmologic effects, have been reported.<span class="htm-cite"><a href="#ref1">1</a></span></p>
<p class="ltrs-br-ltr-br-body-text">This letter will emphasize additional potentially serious psychiatric side effects that may be induced by chloroquine. Indeed, in a recent study<span class="htm-cite"><a href="#ref2">2</a></span> based on data from the FDA Adverse Event Reporting System database, there were 4,336 adverse event cases following the use of chloroquine, of which 520 (12.0%) reported neuropsychiatric adverse events. Exposure to chloroquine was associated with high reporting of amnesia, delirium, hallucinations, depression, and loss of consciousness but somewhat surprisingly not with suicide, psychosis, confusion, or agitation.</p>
<p class="ltrs-br-ltr-br-body-text">However, the incidence of these and other psychiatric adverse effects with the use of chloroquine is unclear in the absence of high-quality, randomized placebo-controlled trials of its safety. In prophylaxis of malaria, whereas the frequency of serious adverse effects was rare (1/13,600),<span class="htm-cite"><a href="#ref3">3</a></span> insomnia and depression were more common, reported in, respectively, 4.5% and 1.4% of individuals at 300 mg/wk (n<span class="thinspace"> </span>=<span class="thinspace"> </span>3,827) and 5% and 1% at 600 mg/wk (n<span class="thinspace"> </span>=<span class="thinspace"> </span>48,970).<span class="htm-cite"><a href="#ref3">3</a></span></p>
<p class="ltrs-br-ltr-br-body-text">These rates may be comparable to the rates of these effects observed with the use of mefloquine,<span class="htm-cite"><a href="#ref4">4</a></span> as early randomized studies that used chloroquine as a comparator revealed approximately similar rates of insomnia and abnormal dreams between drugs.<span class="htm-cite"><a href="#ref5">5</a>,<a href="#ref6">6</a></span></p>
<p class="ltrs-br-ltr-br-body-text">In curative treatment of malaria and in use as an anti-inflammatory drug for lupus erythematosus and rheumatoid arthritis, most of the literature regarding psychiatric adverse effects of chloroquine is based on case reports or case series reporting symptoms such as depression, anxiety, agitation, outbursts of violence, and suicidal ideation, as well as symptoms of psychosis including hallucinations, paranoia, and persecutory delusions.<span class="htm-cite"><a href="#ref7">7</a></span> In contrast to many other psychoses, chloroquine-induced psychosis may be more affective and include prominent visual hallucinations, symptoms of derealization, and disorders of thought, but with preserved insight.<span class="htm-cite"><a href="#ref8">8</a></span></p>
<p class="ltrs-br-ltr-br-body-text">Chloroquine-induced psychiatric symptoms can occur in patients with no familial predisposition or personal mental disorders.<span class="htm-cite"><a href="#ref8">8</a></span> The frequency of these symptoms does not seem to be related to the cumulative dose or to the duration of treatment.<span class="htm-cite"><a href="#ref8">8</a></span> However, the onset of psychosis and other potentially serious effects is usually sudden, and while this typically occurs during the early days to weeks of treatment, there may be delayed recognition of more subtle psychiatric symptoms, which may persist even after stopping the drug. While such persistence has been attributed to chloroquine’s extremely long half-life (10–30 days), long-term psychiatric effects extending beyond the drug’s persistence in the body cannot be excluded.<span class="htm-cite"><a href="#ref4">4</a></span> Of note is that severe COVID-19 has been associated with reports of sleep disturbance, anxiety, agitation, depression, cognitive impairment, and symptoms of psychosis,<span class="htm-cite"><a href="#ref9">9</a></span> since these symptoms may resemble those caused by chloroquine and may potentially confound causal attribution.</p>
<p class="ltrs-br-ltr-br-body-text">Thus, the public should be better informed about the psychiatric risks of chloroquine. Considering the poor risk/benefit ratio of chloroquine and hydroxychloroquine, and taking into account the fact that their use for COVID-19 may impact their availability for disorders for which they are known to alleviate symptoms and improve quality of life or course of illness, the FDA revoked on June 15, 2020, the emergency use authorization of chloroquine and hydroxychloroquine for the treatment of COVID-19.</p>
<p class="references_references-heading"><span class="bold">References</span></p>
<p class="references-references-text-1-9"><a name="ref1"></a><span class="htm-ref"> 1. </span>Ferner RE, Aronson JK. Chloroquine and hydroxychloroquine in COVID-19. <span class="italic">BMJ</span>. 2020;369:m1432. <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=32269046&dopt=Abstract" target="_blank"><span class="pubmed-crossref">PubMed</span></a> <a href="https://doi.org/10.1136/bmj.m1432" target="_blank"><span class="pubmed-crossref">CrossRef</span></a></p>
<p class="references-references-text-1-9"><a name="ref2"></a><span class="htm-ref"> 2. </span>Sato K, Mano T, Iwata A, et al. Neuropsychiatric adverse events of chloroquine: a real-world pharmacovigilance study using the FDA Adverse Event Reporting System (FAERS) database. <span class="italic">Biosci Trends</span>. 2020;14(2):139–143. <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=32321905&dopt=Abstract" target="_blank"><span class="pubmed-crossref">PubMed</span></a> <a href="https://doi.org/10.5582/bst.2020.03082" target="_blank"><span class="pubmed-crossref">CrossRef</span></a></p>
<p class="references-references-text-1-9"><a name="ref3"></a><span class="htm-ref"> 3. </span>Steffen R, Fuchs E, Schildknecht J, et al. Mefloquine compared with other malaria chemoprophylactic regimens in tourists visiting east Africa. <span class="italic">Lancet</span>. 1993;341(8856):1299–1303. <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8098447&dopt=Abstract" target="_blank"><span class="pubmed-crossref">PubMed</span></a> <a href="https://doi.org/10.1016/0140-6736(93)90814-W" target="_blank"><span class="pubmed-crossref">CrossRef</span></a></p>
<p class="references-references-text-1-9"><a name="ref4"></a><span class="htm-ref"> 4. </span>Nevin RL. A serious nightmare: psychiatric and neurologic adverse reactions to mefloquine are serious adverse reactions. <span class="italic">Pharmacol Res Perspect</span>. 2017;5(4):e00328. <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=28805982&dopt=Abstract" target="_blank"><span class="pubmed-crossref">PubMed</span></a> <a href="https://doi.org/10.1002/prp2.328" target="_blank"><span class="pubmed-crossref">CrossRef</span></a></p>
<p class="references-references-text-1-9"><a name="ref5"></a><span class="htm-ref"> 5. </span>Lobel HO, Miani M, Eng T, et al. Long-term malaria prophylaxis with weekly mefloquine. <span class="italic">Lancet</span>. 1993;341(8849):848–851. <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8096560&dopt=Abstract" target="_blank"><span class="pubmed-crossref">PubMed</span></a> <a href="https://doi.org/10.1016/0140-6736(93)93058-9" target="_blank"><span class="pubmed-crossref">CrossRef</span></a></p>
<p class="references-references-text-1-9"><a name="ref6"></a><span class="htm-ref"> 6. </span>Boudreau E, Schuster B, Sanchez J, et al. Tolerability of prophylactic lariam regimens. <span class="italic">Trop Med Parasitol</span>. 1993;44(3):257–265. <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8256107&dopt=Abstract" target="_blank"><span class="pubmed-crossref">PubMed</span></a></p>
<p class="references-references-text-1-9"><a name="ref7"></a><span class="htm-ref"> 7. </span>Bogaczewicz A, Sobów T. Psychiatric adverse effects of chloroquine. <span class="italic">Psychiatr Psychol Klin.</span> 2017;17(2):111–114. <a href="https://doi.org/10.15557/PiPK.2017.0012" target="_blank"><span class="pubmed-crossref">CrossRef</span></a></p>
<p class="references-references-text-1-9"><a name="ref8"></a><span class="htm-ref"> 8. </span>Biswas PS, Sen D, Majumdar R. Psychosis following chloroquine ingestion: a 10-year comparative study from a malaria-hyperendemic district of India. <span class="italic">Gen Hosp Psychiatry</span>. 2014;36(2):181–186. <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=24290896&dopt=Abstract" target="_blank"><span class="pubmed-crossref">PubMed</span></a> <a href="https://doi.org/10.1016/j.genhosppsych.2013.07.012" target="_blank"><span class="pubmed-crossref">CrossRef</span></a></p>
<p class="references-references-text-1-9"><a name="ref9"></a><span class="htm-ref"> 9. </span>Rogers JP, Chesney E, Oliver D, et al. Psychiatric and neuropsychiatric presentations associated with severe coronavirus infections: a systematic review and meta-analysis with comparison to the COVID-19 pandemic. <span class="italic">Lancet Psychiatry</span>. 2020;7(7):611–627. <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=32437679&dopt=Abstract" target="_blank"><span class="pubmed-crossref">PubMed</span></a> <a href="https://doi.org/10.1016/S2215-0366(20)30203-0" target="_blank"><span class="pubmed-crossref">CrossRef</span></a></p>
<p class="ltrs-br-ltr-br-author" style="margin-top:15px;"><span class="bold">Florence Gressier, MD, PhD</span><span class="superscript">a,b</span></p>
<p class="ltrs-br-ltr-br-author"><a href="mailto:florence.gressier@aphp.fr">florence.gressier@aphp.fr</a></p>
<p class="ltrs-br-ltr-br-author"><span class="bold">Céline Verstuyft, MD, PhD</span><span class="superscript">b,c</span></p>
<p class="ltrs-br-ltr-br-author"><span class="bold">Laurent Becquemont, MD, PhD</span><span class="superscript">b,c</span></p>
<p class="ltrs-br-ltr-br-author"><span class="bold">Bruno Falissard, MD, PhD</span><span class="superscript">d</span></p>
<p class="ltrs-br-ltr-br-author"><span class="bold">Emmanuelle Corruble, MD, PhD</span><span class="superscript">a,b</span></p>
<p class="end-matter"><span class="superscript">a</span>Department of Psychiatry, Bicêtre University Hospital, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Sud, Le Kremlin Bicêtre, France</p>
<p class="end-matter"><span class="superscript">b</span>MOODS team, CESP, Inserm, Université Paris-Saclay, Faculté de Médecine Paris-Sud, Le Kremlin Bicêtre, France</p>
<p class="end-matter"><span class="superscript">c</span>Molecular Genetics, Pharmacogenetics and Hormonology Department, Paris-Saclay University Hospitals, AP-HP, Le Kremlin Bicêtre, France</p>
<p class="end-matter"><span class="superscript">d</span>Department of Biostatistics, Maison de Solenn, Université Paris-Saclay, Univ. Paris-Sud, UVSQ, CESP, Paris, France</p>
<p class="end-matter"><span class="bold-italic">Published online:</span> July 28, 2020.</p>
<p class="end-matter"><span class="bold-italic">Author contributions:</span> All authors contributed to and approved the final manuscript.</p>
<p class="end-matter"><span class="bold-italic">Potential conflicts of interest:</span> The authors reported no conflict of interest regarding this letter.</p>
<p class="end-matter"><span class="bold-italic">Funding/support:</span> None.</p>
<p class="front-matter"><span class="italic">J Clin Psychiatry 2020;81(5):20l13476</span></p>
<p class="front-matter-rule"><span class="bold-italic">To cite:</span> Gressier F, Verstuyft C, Becquemont L, et al. Psychiatric side effects of chloroquine. <span class="italic">J Clin Psychiatry</span>. 2020;81(5):20l13476.</p>
<p class="doi-line"><span class="bold-italic">To share:</span> https://doi.org/<span class="doi">10.4088/JCP.20l13476</span></p>
<p class="end-matter">© <span class="italic">Copyright 2020 Physicians Postgraduate Press, Inc.</span></p>
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