key: cord-1041312-446buunz
authors: Nobile, B.; Durand, M.; Courtet, P.; Van de Perre, P.; Nagot, N.; Molès, J.P.; Olié, E.
title: Could the antipsychotic chlorpromazine be a potential treatment for SARS-CoV-2?
date: 2020-07-25
journal: Schizophr Res
DOI: 10.1016/j.schres.2020.07.015
sha: cd4e00e9dce47fd1e89fec88b9eed122588a0c38
doc_id: 1041312
cord_uid: 446buunz

nan

A list of drugs with antiviral effects has been suggested against Severe Acute Respiratory Syndrome-Coronavirus type 2 (SARS-CoV-2) (Lythgoe and Middleton 2020) .

Until recently, chlorpromazine (CPZ), a cationic amphiphilic drug, has been neglected.

Enveloped viruses, such as SARS-CoV-2, use different ways to enter the host cell. Inoue et al. showed that SARS-CoV (a coronavirus similar to SARS-CoV-2) mainly uses Clathrin-Mediated Endocytosis (CME) (Inoue et al. 2007) . During this process, the S protein of coronaviruses (necessary for the fusion between the virus and the cell) is activated by proteases (in a low pH-dependent manner) located in the endosome. Recently, a Chinese study showed that the endocytic pathway is essential for SARS-CoV-2 invasion of host cells, although they could not demonstrate that CME is the major pathway (Ou et al. 2020) . CPZ, mainly used as antipsychotic medication, blocks CME by inhibiting the formation of clathrincoated vesicles (Dyall et al. 2014 ). In addition, in vitro studies demonstrated that CPZ can efficiently inhibit SARS-CoV and MERS-CoV replication (see Table 1 for their description).

It was also suggested that CPZ can increase the intra-vesicular pH and consequently inhibit S protein activation due to its cationic amphiphilic properties. Indeed, cationic amphiphilic drugs accumulate in acidic compartments where their tertiary amine groups are protonated.

Thus, they act as mild bases, can neutralize the low pH of the acidic environment of endo/lysosomes, and block S protein activation (Dyall et al. 2017) .

Moreover, patients with SARS-CoV-2 infection can present a hyper-inflammation phase, called "cytokine storm". High concentrations of inflammatory markers have been associated with poor disease prognosis (Ye, Wang, and Mao 2020) . Interestingly, CPZ has also immune-modulatory effects. For instance, in mice, CPZ increases the concentration of the anti-inflammatory cytokines IL-10 and decreases that of pro-the inflammatory cytokines IL-6 and TNFα after administration of endotoxins (Mengozzi et al. 1994; Plaze et al. 2020 ).

Altogether, CPZ properties suggest that it could be active at different stages of the disease: at the beginning (by inhibiting CME) and later during the hyper-inflammation phase (due to its anti-inflammatory properties).

On the basis of these data, two randomized controlled trials (RCT) have been designed to test CPZ in patients with SARS-CoV-2 infection (i.e. either psychiatrics and nonpsychiatrics patients): the reCoVery study in France (NTC 04366739) and one study in Egypt (NTC 04354805). Patients' enrollment has not started yet (July 2020). (Table 1) .

However, the finding that CPZ concentration is 20-to 200-fold higher in human lungs than in plasma (Forrest, Bolt, and Serra 1968; Plaze et al. 2020) suggests that antiviral effective drug concentrations could be reached. Moreover, some studies in cultured cells showed that CPZ at therapeutic concentrations significantly reduces infection by other viruses (e.g. JC virus and adenovirus) (Atwood 2001; Kanerva et al. 2007 ). Finally, CPZ can pass through the blood brain barrier and diffuses largely in the CNS where SARS-CoV-2 has deleterious effects (e.g. encephalitis) with negative consequences for survivors (Nobile et al. 2020) .

Another major question concerns the timing of CZP administration in patients with COVID-19. CPZ use in COVID-19 should be first investigated: i) in hospitalized patients with mild or moderate disease at the beginning of the infection (as proposed by the reCoVery study with a dosage of 300mg/day) to reduce the viral load and decrease the risk of disease J o u r n a l P r e -p r o o f 4 worsening; ii) in patients in intensive care units to reduce inflammation, with or without corticoids (to date, no RCT on CPZ in this population), and also to reduce confusion or during extubation. In a second time, CPZ could also be considered as a pre-exposure prophylaxis, or to prevent the long-term neurological consequences.

Obviously, CPZ use could expose patients to adverse effects (e.g. QT interval elongation). Yet, if the recommendations of use (electrocardiogram before prescription, and treatment under medical supervision only) are respected, side effects can be rapidly corrected by clinicians. Furthermore, CPZ is used not only for psychiatric patients, but also in anesthesia, and in pregnant women with treatment-resistant nausea; its use is safe (Plaze et al. 2020 ).

Given the emergency of the situation worldwide, several drugs are considered for repurposing on the basis of in vitro data. CPZ is readily available and inexpensive and might be worth testing. Moreover, collecting clinical data on the SARS-CoV-2 infection rate and disease severity among psychiatric patients currently on CPZ could be useful. The results of the newly launched RCTs will give robust information on CPZ place in COVID-19 management. (Cong et al. 2018; Dyall et al. 2014 Dyall et al. , 2017 de Wilde et al. 2014 J o u r n a l P r e -p r o o f

A Combination of Low-Dose Chlorpromazine and Neutralizing Antibodies Inhibits the Spread of JC Virus (JCV) in a Tissue Culture Model: Implications for Prophylactic and Therapeutic Treatment of Progressive Multifocal Leukencephalopathy

MERS-CoV Pathogenesis and Antiviral Efficacy of Licensed Drugs in Human Monocyte-Derived Antigen-Presenting Cells

Repurposing of Clinically Developed Drugs for Treatment of Middle East Respiratory Syndrome Coronavirus Infection

Middle East Respiratory Syndrome and Severe Acute Respiratory Syndrome: Current Therapeutic Options and Potential Targets for Novel Therapies

Distribution of Chlorpromazine Metabolites in Selected Organs of Psychiatric Patients Chronically Dosed up to the Time of Death

Clathrin-Dependent Entry of Severe Acute Respiratory Syndrome Coronavirus into Target Cells Expressing ACE2 with the Cytoplasmic Tail Deleted

Chlorpromazine and Apigenin Reduce Adenovirus Replication and Decrease Replication Associated Toxicity

Ongoing Clinical Trials for the Management of the COVID-19 Pandemic

Chlorpromazine Specifically Inhibits Peripheral and Brain TNF Production, and up-Regulates IL-10 Production, in Mice

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The Pathogenesis and Treatment of the `Cytokine Storm' in COVID-19

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