1. Context
The coronavirus disease 2019 (COVID-19) has had numerous side effects on mental health status (1, 2). Several medications have been considered for the treatment of COVID-19. However, the efficacy of these medications is unclear (3-6). In a study, the neuropsychiatric side effects of oseltamivir have been addressed (7). Another medication in this regard is chloroquine, introduced by the World Health Organization (WHO) in 2020 (8) and the Food and Drug Administration (FDA) (9) as an essential medicine for the prevention and treatment of COVID-19 pneumonia (8-12). Numerous articles have been published at the same time since the start of the COVID-19 outbreak. These studies have demonstrated that chloroquine could effectively diminish the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As such, other studies have also supported this statement (11-14), but the psychiatric side effects of chloroquine have not been taken into account. Chloroquine phosphate administration for COVID-19 patients has been highlighted in the first version of the flowchart published on February 27, 2020, by the Ministry of Health and Medical Education in Iran. The protocol of chloroquine was a single dose of 500 mg for inpatients and 250 mg for outpatients twice a day for five days. Then, in the sixth version, published on April 29, 2020, the protocol of this medicine for high-risk individuals and outpatients was 500 mg twice a day on the first day and then 250 mg twice a day for at least five days. It should be noted that this dose of medicine should be continued for up to ten days if the initial symptoms remain. For inpatients, chloroquine can be administered 500 mg twice a day on the first day and then 250 mg twice a day for one to two weeks (15).
2. Objectives
The present study aimed to briefly review and discuss the safety of chloroquine. In fact, we sought to answer the following questions:
- What is the possible mechanism of psychiatric side effects of chloroquine?
- Is chloroquine a safe choice in COVID-19 management?
- What should we do regarding psychiatric side effects following chloroquine treatment?
The results of this narrative review will provide a comprehensive view for healthcare providers on COVID-19 patient management to support them against psychiatric side effects induced by chloroquine.
3. Methods
3.1. Search Strategy
A narrative literature search on the databases of Web of Science (WoS), Scopus, PubMed, and Google Scholar was carried out on studies without time limitations. The search strategy consisted of combining MeSH terms and keywords of chloroquine toxicity, psychiatry, delusion, psychotic disorder, and depression. A manual search was also performed to find the relevant articles.
3.2. Inclusion Criteria
The inclusion criteria included the English and Persian language case reports containing relevant data to this review.
3.3. Exclusion Criteria
Exclusion criteria included the lack of access to the full texts of articles.
3.4. Selection Strategy
Two authors (M. K. and M. A.) performed the literature search and reviewed the titles and abstracts of the articles independently. Then, the articles were assessed based on the inclusion and exclusion criteria, and disagreements were solved by a psychiatrist (F. E.). Also, the critical opinion of the psychiatrist (F. E.) was used in all stages of the review process.
3.5. Data Extraction
Data were extracted in the table containing the age of patients, a history of psychiatric disorders, the dose of chloroquine administration, other concomitant medications, comorbidities, psychiatric side effects, and treatment by narrative synthesis.
4. Results
Search in databases resulted in retrieving 280 articles. After removing 100 duplicated articles, 180 studies were screened using titles and abstracts. Then, review studies (46), letters to the editor/commentaries (25), and clinical trials (94) were excluded. Finally, 15 articles were reviewed (Table 1).
| Authors | Year | Patient | A History of Psychiatric Disorders | Dose of Chloroquine Administration | Other Concomitant Medications | Comorbidities | Psychiatric Side Effects | Treatment |
|---|---|---|---|---|---|---|---|---|
| Das and Mohan (16) | 1981 | A 40-year-old woman | Patient (no), family (no) | Chloroquine 1.5 g, frequency (unknown) | None | Malaria | Four days after drug ingestion: Sleeplessness, loss of interest in doing any work, feeling sad, suicidal ideas, weeping spells, impaired insight | Amitriptyline 100 mg per day |
| Das and Mohan (16) | 1981 | A 32-year-old woman | Patient (no), family (no) | Chloroquine 1.8 g, frequency (unknown) | None | Malaria | Five days after drug ingestion: Depressive mood, psychomotor retardation, suicidal and paranoid ideas | Tricyclic antidepressant, dose and frequency (unknown) |
| Bhatia et al. (17) | 1988 | A 9-year-old girl | Patient (no), family (no) | Chloroquine 0.5 mg followed by 250 mg chloroquine six hours later. On the second day, 125 mg chloroquine was given | None | Malaria | Three days later: Restless, outburst of abusive, violent behavior, irrelevant talks, poor judgment, lack of insight, disorientation to time, mild impairment of recent memory | Chlorpromazine 300 mg daily in divided doses |
| Lovestone (18) | 1991 | A 33-year-old man | Patient (no), family (no) | Chloroquine 300 mg weekly | Proguanil 200 mg daily | Antimalarial prophylaxis | The drug onset was unknown: Mildly irritable, overactive, irritable, talkative, experiencing racing thoughts, expressing delusions of reference and grandeur | Single dose of 5 mg haloperidol |
| Telgt et al. (19) | 2005 | A 34-year-old woman | Patient (no), family (no) | Chloroquine 600 mg, followed by 3 more doses of 300 mg after 6, 24, and 48 hours (total dose 25 mg/kg). | None | Malaria | After the third dose of chloroquine: Complaining of “losing her mind” and “feeling like a robot.” Signs of paranoid delusions suffer repeatedly from vivid and unpleasant dreams, by day 12: The idea that there was a “short circuit” in her head, constant headache photophobia, dizziness, difficulty focusing, out-of-body experience, not able to control her thoughts, a panic-struck preoccupation with "going mad." Memory disturbances, language difficulties, attention deficit, concentrations of chloroquine were in the therapeutic range (20 - 300 μg/L) | Oxazepam 10 mg at bedtime to alleviate insomnia, all complaints gradually subsided over the next 4 months |
| Sahoo et al. (20) | 2007 | A 40-year-old man | Patient (no), family (no) | Chloroquine 1.8 g, frequency (unknown) | None | Malaria | Two days after chloroquine administration: Delusions, auditory hallucinations, agitation, hostility, disturbed sleep, disturbed appetite, stereotypic hand and feet movements, rocking of the body hallucinatory behavior, his speech was loud and punctuated with grunting, expressing the fear that he might be killed and that the world is coming to an end | Intravenous diazepam, injectable antipsychotics, then oral antipsychotics |
| Zaki et al. (21) | 2009 | A 7-year-old girl | Patient (unknown), family (unknown) | Chloroquine (base: 150 mg) 10 mg/kg followed by 5 mg/kg at 6, 24, and 48 hours. However, as the parents did not understand the dosing schedule, the total dose of chloroquine received by the child was approximately 100 mg/kg of base as against the total therapeutic dose of 25 mg/kg of base. | Paracetamol, dose (unknown) | High-grade fever, chills, vomiting | Excessive talking, restlessness | olanzapine olanzapine 10 mg/day, discharged on the fourth hospital day |
| Gulec et al. (22) | 2009 | A 39-year-old woman | Patient (no), family (no) | Chloroquine 250 mg daily | Sulfasalazine 2 g daily | Rheumatoid arthritis | Two months after initiating chloroquine and sulfasalazine: Insomnia, suicidal tendency, increased energy, behavioral changes, auditory hallucinations, grandiose, persecutive and erotomanic type delusions | Risperidone 2 mg daily and quetiapine 200 mg/day |
| Plesnicar et al. (23) | 2013 | A 72-year-old man | Patient (no), family (unknown) | Chloroquine 250 mg daily | Etoricoxib, Gliquidone, Candesartan, Diltiazem, dose (unknown) | Diabetes mellitus, seronegative polyarthritis, arterial hypertension, cured prostate cancer | Two weeks after drug administration that aggravated one month later: Anxiety, delusions of grandeur, flight of ideas, overflow of energy, distractibility with attention deficit, talkative, irritable, feeling extremely well, starting chloroquine on the same dose and after three weeks: Talkative, distractible, delusions of grandeur, no need for sleep, irritable, his attention deficit was pretty pronounced | Risperidone 2 mg daily, then 0.5 mg daily in the follow-up visit |
| Bogaczewicz et al. (24) | 2014 | A 31-year-old man | Patient (no), family (no) | Chloroquine 250 mg daily | Methylprednisolone 12 mg daily | SLE | Three months later: Depressed mood, psychomotor retardation feelings of pessimism, worthlessness, loss of interest, excitation, suicidal thoughts | Perazine 200 mg daily in three divided doses, sertraline 150 mg daily, mirtazapine 15 mg daily, hydroxyzine 25 mg twice a day, methylprednisolone 4 mg daily for 11 months |
| Anonymous (25) | 2016 | A 29-year-old woman | Patient (unknown), family (unknown) | Chloroquine 250 mg daily | Topical treatment with clobetasol propionate | SLE | Three days after drug onset: Persecutory delusions, feelings of de-realization, general feelings of paranoia, delusional perceptions, strong anxiety, occasional visual illusions | Only discontinuation of chloroquine |
| Choughule and Salunkhe (26) | 2019 | A 32-year-old man | Patient (no), family (unknown) | Chloroquine 600 mg in divided doses | None | Amoebic liver abscess | On the fifth day: Feeling that there is some supernatural power in his room, feeling that became extremely fearful, pleading for the constant company of family members, irrelevant talk, muttering, aggression, suspiciousness, having a firm belief that some supernatural force is going to harm him, fearful mood, perplexed affect, delusion of persecution against unknown forces or people, auditory hallucinations, illusions and visual imagery related to a devil’s shadow, impaired personal and social judgment | Olanzapine 10 mg in divided doses for two weeks |
| Emmanuel and Ostlundh (27) | 2020 | A 25-year-old woman | Patient (unknown), family (unknown) | Chloroquine 300 mg, frequency (unknown) | None | Coronavirus disease 2019 | Thirty days after chloroquine administration: Behavioral problems, agitation, temporal disorientation, tachypsychia, incoherent speech, delusional syndrome, logorrhoea with: Echolalia, insomnia, psychomotor agitation, chloroquine level was found to be 0.5 mg/L. | Olanzapine, dose and frequency (unknown) |
| Benjelloun et al. (28) | 2020 | A 35-year-old woman | Patient (no), family (no) | Chloroquine, dose and frequency (unknown) | Azithromycin dose (unknown) | Coronavirus disease 2019 | Three days after treatment: Insomnia, recurrent panic attacks with palpitations, the sensation of imminent death feeling of not being able to control her thoughts, depersonalization derealization, persistent sadness with permanent negative thoughts, fear of dying herself and her loved ones | 2.5 mg of lorazepam spread over 24 hours, anxiety symptoms disappeared rapidly after interrupting azithromycin-chloroquine |
| Benjelloun et al. (28) | 2020 | A 46-year-old man | Patient (mild depressive episode treated with vortioxetine), family (no) | Chloroquine, dose and frequency (unknown) | Azithromycin dose (unknown) | Coronavirus disease 2019 | Nine days after treatment: Symptoms of distress and insomnia, visual hallucinations incoherent speech, the outburst of odd behavior, repeated attempts to run away from hospital | Amisulpride 100 mg per day for a week, psychotic symptoms disappeared totally after 48 hours. |
The Sample Case Report Studies Concerning Psychiatric Side Effects Following Chloroquine Administration
4.1. Pharmaceutical Characteristics of Chloroquine
Considering the pharmacokinetics of chloroquine, this medicine has a cumulative feature in the body with a long-term plasma half-life whose concentration in plasma is not an appropriate predictor of brain concentration, estimated to be 10-30 times higher than plasma (19). This high concentration may lead to adverse drug events (ADEs) such as psychiatric symptoms varying from insomnia (29) to catatonia (30), toxic psychosis (31, 32), suicidal attempts (33), as well as behavioral manifestations including most frequently extreme irritability, restlessness, abusiveness, distractibility, pressured speech, flight of ideas, grandiosity delusion, and auditory and visual hallucinations (34). It should be emphasized that the neuropsychiatric side effects of chloroquine may emerge even in cases receiving therapeutic doses. However, acute psychosis has occurred at high doses (2 - 6 g/day) (35, 36) and therapeutic antimalarial doses (total dose of 1500 mg) (19, 37).
The accurate mechanism of psychiatric manifestations by this drug has still remained unknown. Various hypothesized mechanisms have been reported. Chloroquine acts as a muscarinic antagonist, and a chloroquine-muscarinic cholinergic system interaction has been reported (33). It is supposed that neurotransmitter systems such as polyamines (particularly spermidine), imbalances in acetylcholine, and prostaglandin E-antagonist activity may play the main roles in its mechanism (33). Also, chloroquine acts as N-methyl-D-aspartate (NMDA), gamma-aminobutyric acid (GABA), and dopamine-serotonin antagonist (38, 39). According to the related literature, chloroquine might induce imbalances in cholinergic receptors (40) and initiate glucose-6-phosphate dehydrogenase (G6PD) deficiency (41). All these neurotransmitters play major roles in cognition, perception, and mood pathway. Therefore, they may provoke psychiatric symptoms (42). On the other hand, chloroquine may cause cell death (43). A possible mechanism is the relationship between chloroquine and altered gene expression in cell death pathways, including inhibition of poly (ADP-ribose) polymerase (PARP1) and PARP2, as well as metabolomics perturbations that lead to failure in nicotinamide adenine dinucleotide (NAD+) balance and aspartate availability (44). Also, encephalopathy and psychiatric symptoms may occur following inflammatory responses to influenza (45). Of course, COVID-19 patients may present neuropsychiatric symptoms, and chloroquine may aggravate or initiate the neuropsychiatric symptoms (46). It is supposed that behavioral symptoms, hallucinations, delirium, or abnormal behaviors arise in patients with encephalitis or encephalopathy. In addition, patients infected with influenza may manifest psychiatric symptoms attributable to immunological reactions rather than virus effectiveness on the central nervous system (CNS) (47). In addition, chloroquine affects the lipid bilayer membranes and interacts with lysosomal activity. Also, it prevents the expression of pro-inflammatory cytokines via toll-like receptor (TLR) activation (48). They lead to CNS toxicity which may appear with nausea, vomiting, dizziness, headache, and delirium (49).
4.2. The Safety of Chloroquine
According to the results of several studies, extensive psychiatric manifestations have been reported following chloroquine use (16-22, 24, 26-28, 50, 51) (Table 1). Chloroquine has a narrow therapeutic window, and CNS toxicity and neuropsychiatric symptoms may occur at therapeutic doses (19, 27). However, 10 - 35% of mortality cases have occurred in overdose conditions (46). Based on the results of a study in 2014, 76.2% of psychiatric symptoms were mood disorders. The results of this study demonstrated no significant relationship between the prescribed dose of chloroquine and the severity of psychosis. In this study, the group with psychosis following chloroquine (i.e., the PFC group) exposure was compared with equal-age patients suffering from brief psychotic disorders (i.e., the BPD group). The findings of this study revealed that the PFC group had an early manifestation of psychosis, including mixed affective psychosis, higher levels of restlessness, irritability, agitation, and more disturbed thought content and orientation but better insight compared with the BPD group. Also, the patients in the PFC group showed prominent positive symptoms with visual hallucinations and de-realization experiences (43).
Another case report with the regime of chloroquine due to malaria revealed that all disease symptoms were alleviated on the third day of therapy, but the patient manifested hyperactivity, excessive talking, argumentativeness, extreme irritability, grandiosity, abusiveness, and lack of sleep. According to the history of manic episodes three years ago, the patient was prescribed haloperidol 20 mg daily, and the manic symptoms were remitted within two weeks. The patient continued that treatment for at least three months and then ceased on his own (52). Another case with manic manifestations has been reported who was treated with chloroquine 250 mg per day. One month later, other psychiatric symptoms such as anxiety, flight of ideas, attention deficit disorder (20), delusions of grandeur, distractibility, and an overflow of energy appeared (51). In another case report with the diagnosis of systemic lupus erythematosus (SLE), chloroquine was administered for three episodes of the disease. In two episodes, the patient's symptoms were relieved without any manifestations of psychiatric symptoms; however, the patient showed symptoms of severe depression, including low mood, psychomotor retardation, feelings of pessimism and worthlessness, loss of interest, excitation, and suicidal thoughts in the first prescription of chloroquine in the third episode. It should be noted that this patient had a history of bipolar disorder (24).
4.3. Management of Chloroquine Side Effects
Once psychiatric side effects of chloroquine appear, the best treatment choice is to discontinue chloroquine if possible and prescribe specific medications according to the clinical manifestations of the psychiatric disorders (38). In this regard, a study reported that a sub-acute paranoid-like disorder was resolved two days after chloroquine discontinuation (50). Psychiatric manifestations usually occur from one to two weeks with chloroquine treatment, and symptoms are commonly resolved within several days following discontinuation of this agent and prescription of psychiatric treatment. It should be reminded that other diagnoses of psychiatric complications following chloroquine use, including comorbidities such as metabolic disorders, primary psychiatric disorders, influenza virus-associated encephalopathy, glucocorticoid-induced psychotic disorders, and other antiretroviral psychiatric side effects, should be ruled out (38).
5. Discussion
The present study aimed to briefly review and discuss the safety of chloroquine and subsequent psychiatric side effects. The results showed that chloroquine had been prescribed in patients following malaria (7 studies), COVID-19 (3 studies), SLE (2 studies), rheumatoid arthritis (2 studies), and amoebic liver abscess (1 study). Chloroquine as an antimalarial agent was discovered by Bayer A.G. in Germany in 1934 (53). Chloroquine inhibits the polymerization and detoxification of hematin. So, the accumulation of free hematin that is highly toxic to Plasmodium contributes to the dissolution of the cell membrane and, finally, the death of the parasites (54, 55). Therefore, chloroquine has been used as an effective antimalarial management for decades (56). Another indication of chloroquine is in the treatment of inflammatory rheumatic diseases such as SLE and rheumatoid arthritis (57, 58). Chloroquine has direct immunomodulatory effects, so it can protect patients against infections following inflammatory rheumatic diseases (59). The new indication of chloroquine, COVID-19 management, was controversial. Multiple theories have been proposed, including increasing the endosomal pH level and its essential role in the division of SARS-CoV-2 spike proteins, inhibiting quinine reductase-2, and then reducing the sialic acid synthesis (60, 61).
The literature review showed that most patients were 25-46-year-old. A clinical trial reported the mean age of patients who received 300 mg chloroquine over a 12-weeks period to be 25.7 years and showed CNS complications (62). In another study, the mean age of patients with post-chloroquine psychosis was shown to be 31 years (43). The present review revealed that most patients were female (10 cases). This finding was also obtained in another review study investigating the neuropsychiatric side effects of chloroquine (63). The results of the current literature review showed that most patients had no family or personal history of psychiatric disorders, although the risk of psychiatric events may be influenced by familial risk (64). It can be a practical warning notice for healthcare providers that expect psychiatric manifestations following chloroquine therapy in patients with no previous history. The present case review revealed the psychiatric side effects that may be observed in the therapeutic dose of chloroquine. This issue should be considered a clinical notice to frequently assess psychiatric symptoms.
The present narrative review reported a wide range of chloroquine-to-side effects times, ranging from two days to three months following chloroquine administration. It can be due to the slow terminal half-life of the plasma concentration concerning time, approximately 3 - 5 days, after a single dose of 300 mg chloroquine (65). The results of a study revealed that most side effects following chloroquine administration were observed between 0.2 and 0.4 µg/mL. So, we can consider this criterion regarding the psychiatric side effects of chloroquine (66). In the cases reported in our study, the dose was wide-ranging, from 125 mg to 1800 mg. Unfortunately, the frequency of medication was unknown.
The most commonly reported psychiatric side effects were mood disorders, psychosis, and insomnia. The results of a study revealed that 76.2% of psychiatric symptoms following chloroquine administration were mood disorders (43). A multi-transmitter hypothesis of chloroquine-induced psychiatric disorders has been proposed considering central dopamine, glutamate, and acetylcholine pathways involved in psychosis and depression (67).
In all cases of the current literature review, symptomatic therapy, including heterocyclic antidepressants (amitriptyline and mirtazapine), selective serotonin reuptake inhibitors (SSRIs), sertraline, phenothiazine (chlorpromazine), benzodiazepine (oxazepam, diazepam, and lorazepam), antipsychotic agents (haloperidol, olanzapine, risperidone, amisulpride, and perazine), antihistamines (hydroxyzine), and corticosteroids (methylprednisolone) treatment, were used. Side effect management is important to avoid abandoning treatment (68).
5.1. Conclusions
Given the probability of a wide range of unknown interactions and mechanisms due to the co-administration of antiretroviral and other drugs, physicians should cautiously choose antiviral agents. Considering the large number of patients with COVID-19 receiving chloroquine as a part of their therapeutic plan, psychiatrists and other healthcare professionals need to reflect on the adverse effects of chloroquine administration on patients’ mental health status.
