Chloroquine Linked to Serious Psychiatric Side Effects

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Chloroquine may be associated with serious psychiatric side effects, even in patients with no family or personal history of psychiatric disorders, a new review suggests.

In a letter to the editor published online July 28 in The Journal of Clinical Psychiatry, the authors summarize data from several studies published as far back as 1993 and as recently as May 2020.

"In addition to previously reported side effects, chloroquine could also induce psychiatric side effects which are polymorphic and can persist even after stopping the drug," lead author Florence Gressier, MD, PhD, CESP, Inserm, Department of Psychiatry, Le Kremlin Bicêtre, France, told Medscape Medical News.

"In COVID-19 patients who may still be [undergoing treatment] with chloroquine, close psychiatric assessment and monitoring should be performed," she said.

Heated Controversy

Chloroquine and hydroxychloroquine have been at the center of heated controversy for their potential role in preventing or treating COVID-19.

Following findings of a small French study that suggested efficacy in lowering the viral load in patients with COVID-19, President Donald Trump expressed optimism regarding the role of hydroxychloroquine in treating COVID-19, calling it a "game changer."

Other studies, however, have called into question both the efficacy and the safety of hydroxychloroquine in treating COVID-19. On June 15, the US Food and Drug Administration (FDA) revoked the emergency use authorization it had given in March to chloroquine and hydroxychloroquine for the treatment of COVID-19.

Nevertheless, hydroxychloroquine continues to be prescribed for COVID-19. For example, an article that appeared in Click2Houston on June 15 quoted the chief medical officer of Houston's United Memorial Center as saying he plans to continue prescribing hydroxychloroquine for patients with COVID-19 until he finds a better alternative.

As discussed in a Medscape expert commentary, a group of physicians who held a "white coat summit" in front of the US Supreme Court building promoted the use of hydroxychloroquine for the treatment of COVID-19. The video of their summit was retweeted by President Trump and garnered millions of views before it was taken down by Twitter, Facebook, and YouTube.

Sudden Onset

For the new review, "we wanted to alert the public and practitioners on the potentially psychiatric risks induced by chloroquine, as it could be taken as self-medication or potentially still prescribed," Gressier said.

"We think the format of the letter to the editor allows information to be provided in a concise and clear manner," she added.

According to the FDA's Adverse Event Reporting System database, 12% of reported adverse events (520 of 4336) following the use of chloroquine that occurred between the fourth quarter of 2012 and the fourth quarter of 2019 were neuropsychiatric. These events included amnesia, delirium, hallucinations, depression, and loss of consciousness, the authors write.

They acknowledge that the incidence of psychiatric adverse effects associated with the use of chloroquine is "unclear in the absence of high-quality, randomized placebo-controlled trials of its safety." Nevertheless, they point out that there have been reports of insomnia and depression when the drug was used as prophylaxis against malaria.

Moreover, some case series or case reports describe symptoms such as depression, anxiety, agitation, violent outburst, suicidal ideation, and psychosis in patients who have been treated with chloroquine for malaria, lupus erythematosus, and rheumatoid arthritis.

"In contrast to many other psychoses, chloroquine psychosis may be more affective and include prominent visual hallucinations, symptoms of derealization, and disorders of thought, with preserved insight," the authors write.

They note that the frequency of symptoms does not appear to be connected to the cumulative dose or the duration of treatment, and the onset of psychosis or other adverse effects is usually "sudden."

In addition, they warn that the drug's psychiatric effects may go unnoticed, especially because COVID-19 itself has been associated with neuropsychiatric symptoms, making it hard to distinguish between symptoms caused by the illness and those caused by the drug.

Although the psychiatric symptoms typically occur early after treatment initiation, some "subtle" symptoms might persist after stopping the drug, possibly owing to its "extremely long" half-life, the authors state.

Gressier noted that practicing clinicians should look up reports about self-medication with chloroquine "and warn their patients about the risk induced by chloroquine."

Safe but "Not Benign"

Nilanjana Bose, MD, MBA, a rheumatologist at the Rheumatology Center of Houston, Texas, said she uses hydroxychloroquine "all the time" in clinical practice to treat patients with rheumatic conditions.

"I cannot comment on whether it [hydroxychloroquine or chloroquine] is a potential prophylactic or treatment for COVID-19, but I can say that, from a safety point of view, as a rheumatologist who uses hydroxychloroquine at a dose of 400 mg/day, I do not think we need to worry about serious [psychiatric] side effects," Bose told Medscape Medical News when asked to comment.

Because clinicians are trying all types of possible treatments for COVD-19, "if this medication has possible efficacy, it is a great medicine from a rheumatologic perspective and is safe," she added.

Nevertheless, the drug is "not benign, and regular side effects will be there, and of course, higher doses will cause more side effects," said Bose, who was not involved in authoring the letter.

She counsels patients about potential psychiatric side effects of hydroxychloroquine because some of her patients have complained about irritability, worsening anxiety and depression, and difficulty sleeping.

Be Wary

Also commenting on the letter for Medscape Medical News, James "Jimmy" Potash, MD, MPH, Henry Phipps professor of psychiatry and behavioral sciences, Johns Hopkins Medicine, Baltimore, Maryland, said the "take-home message of this letter is that serious psychiatric effects, psychotic illness in particular," can occur in individuals who take chloroquine and hydroxychloroquine.

In addition, "these are potentially very concerning side effects that psychiatrists should be aware of," noted Potash, who is also the department director and psychiatrist-in-chief at Johns Hopkins.

He said that one of his patients who had been "completely psychiatrically healthy" took chloroquine prophylactically prior to traveling overseas. After she began taking the drug, she had an episode of mania that resolved once she discontinued the medication and received treatment for the mania.

"If you add potential psychiatric side effects to the other side effects that can result from these medications, that adds up to a pretty important reason to be wary of taking them, particularly for the indication of COVID-19, where the level of evidence that it helps in any way is still quite weak," Potash said.

Remington Nevin, MD, MPH, DrPH, executive director at the Quinism Foundation, White River Junction, Vermont, and faculty associate in the Department of Mental Health at the Johns Hopkins Bloomberg School of Public Health, agreed.

"The authors of this letter are to be commended for their efforts in raising awareness of the potentially lasting and disabling psychiatric effects of chloroquine and hydroxychloroquine, which, as with similar effects from other synthetic quinoline antimalarials, have occasionally been overlooked or misattributed to other conditions," Nevin told Medscape Medical News.

"I have proposed that the chronic neuropsychiatric effects of this class of drug are best considered not as side effects but as signs and symptoms of a disorder known as chronic quinoline encephalopathy caused by poisoning of the central nervous system," he said.

Gressier and the other letter authors, Bose, and Potash have reported no relevant financial relationships. Nevin reviewed the letter to the editor and serves as the executive director of the Quinism Foundation, a nonprofit organization that supports and promotes education and research on disorders caused by poisoning by quinoline drugs. He has also been retained as a consultant and expert witness in legal cases involving claims of adverse effects from quinoline antimalarial drugs.

J Clin Psychiatry. Published online July 28, 2020. Full text

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