Psychiatric Effects of COVID-19 Treatment

Chloroquine has been in the news lately, with President Trump extolling its effectiveness against coronavirus, and the demurral of his experts. There have been allegations of doctors stockpiling the drug, and even a case of a man who died after ingesting a form of chloroquine found in a fish tank cleaning product.

Health agencies in Italy, China, and South Korea have endorsed chloroquine for COVID-19. Whether it will be used in the U.S. will be determined after it has been systematically studied. But because it is a possibility, and because it is very much in the news, it’s worthwhile to be aware that it has a significant side effect profile of psychiatric symptoms, which we may be seeing if it becomes widely used.

What, then, is chloroquine, and where does it come from? The story goes back to World War II. At that time, malaria was rampant in our troops in the South Pacific and Africa. General Douglas MacArthur was quoted as saying that for every division fighting the enemy, another was sick with malaria and yet another was recovering. The difficulty was that after Pearl Harbor, the source of bark of the cinchona tree, and the quinine which is derived from it, were effectively cut off. The result was a scramble to find new drugs.

Several appeared, primarily as derivatives of the synthetic dye industry. The first of these, methylene blue, was originally made as a fabric dye in 1876, and later found to be a useful histological stain aiding in differentiating white blood cells as well as the axons of neurons. It turned out to be toxic to the microscopic parasites which cause malaria, and was developed into a drug. Ultimately it was less effective than quinine, and was understandably unpopular with the troops because it turned the urine and the sclerae of the eyes blue. This was followed by quinacrine, a yellow acridine dye that had been synthesized in 1931, and which was widely used as the drug Atabrine.

It too had an array of side effects including anemia and damage to the retina and liver. It turned the skin yellow, so reliably that some American spies infiltrating Japanese-controlled China took quinacrine to make their Caucasian skin appear more like that of Asians. More importantly for our purposes, it caused mood changes and hallucinations, and 0.1-1.5 percent of persons taking it had psychotic reactions which could last several weeks (likely not a desirable quality in the practice of spy-craft).

Chloroquine came along in an effort to find an alternative to quinacrine. It had been first discovered in Germany in 1934, but initially was considered to have too many side effects. It was re-evaluated in the U.S. in the later part of World War II, and by 1947 moved into general use. Today it continues to be prescribed for the suppressive treatment of malaria, though use is more limited due to the development of resistance. It is also indicated for a form of amebiasis. Its medical side effect profile is ample, but improved over quinacrine, and changes in skin coloration are less common. The potential psychiatric effects, however, appear to be significant and well worth considering.

The official FDA patient package insert for chloroquine refers to ‘psychosis, delirium, anxiety, agitation, insomnia, confusion, hallucinations, personality changes, and depression’, though frequencies are not given. The large body of literature documenting side effects, summarized in a 2016 article by Nevin and Croft, is very impressive. Reports variously describe insomnia, impulsivity, flight of ideas, a condition resembling mania, visual and auditory hallucinations, brief psychotic or delusional disorder, and suicidality.

Chloroquine 3D structure

Source: BaptisteGrandGrand/Wikimedia Commons Public Domain

By way of illustration, Telgt and colleagues in 2005 provided this case history of a 34-year-old woman given a three-day course of chloroquine. She developed depersonalization and anxiety, and ultimately was considered to have a psychotic disorder not otherwise specified. (She was not thought to have delirium due to clear consciousness, and the absence of diurnal fluctuations.) After three weeks, symptoms had largely subsided, though she still had difficulty concentrating and did not seem fully recovered until four months had passed.

In summary, we know there is a substantial body of data describing psychiatric complications of chloroquine. Admittedly, their frequency is not fully established, but in a sense that is part of the worry—we don’t yet have all the information we need to make good judgments about its safety if given widely in the general population. But if it should come to be approved for COVID-19, it would be prudent to be on the lookout for drug-related mental health consequences.