Why nobody discusses the adverse psychiatric effects of chloroquine in case it might become the future treatment against COVID-19?
Chloroquine represents at least a basic prototype antimalarial drug, widely applied in several branches of medicine. This antimalarial medication is commonly associated with the treatment of various immunological, rheumatological, dermato- logical, and infectious diseases. Among the non-labeled examples can be cited sarcoidosis, dermatomyositis, polymorphic light eruption, disseminated annular granuloma, and other cases involving chloroquine analogs like in porfiria cutanea tarda (PCT) and also recently against a new zoonotic origin coronavirus that appeared in China in late 2019 and has rapidly spread in this territory, incidentally affecting more than over 100 countries in the world around March 2020. This COVID- 19 contamination is due to a virus called coronavirus 2 (SARS-CoV-2), responsible for an acute respiratory syndrome stated by the World Health Organization (WHO). The first cases emerged as a group of pneumonia patients who were all linked to a live animal business, which tested positive for a previously unknown coronavirus other than his medication.1 The Chi- nese government and researchers are to be praised for their rapid sharing of viral sequences with laboratories around the world, making a significant contribution to diagnostic, therapeutic, and vaccine development efforts in the weeks following the detection of the pathogen. Undoubtedly, one of the most promising recommendations will be that of Professor Didier Raoult, describing chloroquine being an effective method or treatment against the virus in question since there are a rela- tively small number of adverse effects related to chloroquine analogs used at standard doses, such as headaches, gastroin- testinal disorders, hypotension, convulsions, skin reactions, visual disorders, and extrapyramidal symptoms.2
Could chloroquine be one of the miracle cures for the coronavirus? An article published in the journal Cell Research on February 4 showed that chloroquine prevented the entry and exit stages of the SARS-CoV-2 virus in cells cultured in vitro, thus effectively stopping its replication and spread. Several Chinese clinical trials have also demonstrated how well chloroquine performs. The authors mentioned the apparent efficacy and acceptable tolerance of this treatment based on data from 15 clinical studies in 10 hospitals in Beijing, Wuhan, Guangzhou, Shanghai, Jingzhou, Ningbo, and Chongqing, which are still unpublished. According to Prof. Didier Raoult, chloroquine is the best remedy to treat coro- navirus sufferers. So, he administered it on March 16, 2020 to 20 sick patients in his department at a dose of 600 mg of hydroxychloroquine per day combined with azithromycin (an antibiotic from the macrolide family).3 After oral intake, chloroquine is absorbed rapidly and almost completely in the small intestine. The peak concentration in the blood reaches on average between 2 and 6 hours following administration. So, it is clear that chloroquine does not act directly on the virus, but on the cells themselves infected through the virus, reducing their viral load. Therefore, it could also harm the binding between the virus and its receptor in the cells to be contaminated.4
Still, at present, there is little awareness of chloroquine’s psychiatric side effects, which appear to be overlooked by the Scientific Committee, although they may manifest in a worryingly wide range of symptoms, for instance, agita- tion, disorientation, confusion, feelings of sadness, persecution, violent outbursts, loss of judgment, and suicidal idea- tion. A manic episode with psychotic traits has also been describing in bipolar disorder, and another case of persecutory delusions, anxiety, derealization, and visual illusions triggered by chloroquine. Symptoms last 1 to 2 weeks and usually disappear within days of stopping chloroquine therapy and beginning psychiatric help.5 This is likely to interfere with the course of specifically long-term (high-dose) COVID-19 treatment in some aggravated forms (25% of coronavirus patients were still carrying the virus 6 days after taking hydroxychloroquine).
On the other hand, those patients with confirmed or suspected SARS-CoV-2 may be afraid of the consequences if infected as a result of a potentially fatal new virus. Those in the quarantine may experience boredom, loneliness, and anger as well. Many authors describe how a pandemic like a coronavirus is not just a medical phenomenon; it affects individuals and society causing disruption, anxiety, stress, stigma, xenophobia and so on. The reason for that is so sample say Calum Paton, “science” has had to follow policy both past and present (A deadly combination). Instead of a sufficient number of tests; we applied restricted stressful measures, for example, the wearing of facemasks, isolation, social distancing, and closure of educational institutes, workplaces, and entertainment venues consigned people to stay in their homes to help break the chain of transmission (no scientific evidence).6,7 Besides, symptoms of infection, such as fever, hypoxia, and cough, or adverse effects from the 600 mg hydroxychloroquine daily plus azithromycin, including insomnia, headaches, skin reactions, digestive upset with nausea, vomiting, and diarrhea, blurred vision, and local pain, may lead to increased anxiety and mental distress. Also, during the first phase of the SARS epidemic, a series of psychiatric morbidities, among them persistent depression, anxiety, panic attacks, psychomotor arousal, psychotic symptoms, delirium, and even suicide, were noted. As part of the public health response to the 2019 pneumonia outbreak, mandatory contact tracing and prolonged quarantine before receiving any chloroquine drugs could lead to a fragile psychotic state causing more anxiety and guilt-related feelings about the effects of the contagion, quarantine, and stigmatization of family and friends.8
The molecular mechanisms behind the psychiatric side effects of chloroquine therapy are not fully understood. Early reports were based on speculation about how it would act on the brain. The interference between chloroquine and muscarinic cholinergic systems was discovered over 30 years ago, at the time when H. Schmidt, realized that chloroquine replaced a specific muscarinic ligand from its receptor and functioned effectively the same way as a muscarinic antagonist.9 A further animal study showed that chloroquine enhanced the locomotion to the extent of causing dose-related stereotypic behavior in rats, suggesting that chloroquine exerts excitatory effects through dopaminergic pathways. However, it would be an over-simplification to look for the possible psychiatric side effects generated by chloroquine through muscarinic and/or dopaminergic routes exclusively. According to a recent analysis, chloroquine has occurred set as an antagonist for both 5-HT3A and 5-HT3AB sites, with no evidence that 5-hydroxytryptamine-3 receptors are inhibited in patients taking chloroquine, despite the fact that blood and/or tis- sue measurements indicate a potential for this to occur.5 In this context, researchers proposed that nausea, one sec- ondary adverse effect of chloroquine, could be caused by an effect modeled via those serotonin receptors.10
Finally, during any biological emergency, topics like fear, anxiety, insecurity, and trauma are common. They can be barriers to medical treatment, like in the case concerning chloroquine, particularly if the medication itself poses adverse consequences upon the mental health of patients who are already experiencing psychological fragility fol- lowing the impact of COVID-19 on their lives. Considering the experience acquired following serious new pneumo- nia epidemics around the world and the psychosocial implications of viral epidemics, the development and implementation of assessment, support, mental care, and treatment services are crucial with the same urgency as the development of new experimental molecules to combat the COVID-19 epidemic.