The search for a drug or vaccine continues as the COVID-19 continues to wreak havoc in countries around the world. A new research paper published in the journal L'Encéphale in May 2020 reports on the planned ReCoVery Study, which will examine the possibility of repurposing the antipsychotic drug chlorpromazine for the treatment of COVID-19.
The study is motivated by the observation that patients in a Parisian psychiatric hospital had remarkably fewer new cases than the hospital staff (an incidence of 4% vs. 14%, respectively). The researchers want to explore the usefulness of psychotropic drugs in the prevention of progression of COVID-19 infection, especially to the symptomatic and severe forms.
The drug used in the ReCoVery trial is chlorpromazine, a psychotropic drug first used in 1952 by Jean Delay and Pierre Deniker, psychiatrists who were working at Sainte Anne Hospital (GHU PARIS Psychiatrie & Neuroscience, Paris, France). This is the same hospital where the authors of the current research work.
Chlorpromazine (CPZ) has been found to have antiviral activity in vitro against the influenza virus, HIV, Japanese Encephalitis (JE), and Chikungunya alphavirus. It was first found to block antiviral activity in coronaviruses in 2014, and listed among "the most promising molecules for inhibiting coronaviruses in human cells." Another study confirmed its ability to block MERS and SARS CoV replication in human cells.
CPZ interacts with the cell membrane protein called dynamin to block clathrin-dependent endocytosis that is essential for coronavirus entry into the host cell. This is one mechanism being explored currently to block severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
Novel Coronavirus SARS-CoV-2 Colorized scanning electron micrograph of an apoptotic cell (pink) heavily infected with SARS-COV-2 virus particles (green), isolated from a patient sample. Image captured at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. Credit: NIAID
There could also be other mechanisms of action because it appears that CPZ can inhibit CoV in many ways.
Moreover, CPZ has immunomodulatory potential acting through various mechanisms, such as increasing the blood levels of IgM, and, in mice, protecting against endotoxin-induced septic shock. Simultaneously, it reduces the levels of multiple pro-inflammatory chemicals like IL-2, IL-4, and TNF, while boosting the anti-inflammatory chemical IL-10.
Extensive and Concentrated Biodistribution
CPZ also achieves very high biodistribution in saliva and lung tissue, as well as crossing the blood-brain barrier. Animal models, confirmed by autopsy studies on people with schizophrenia treated with this drug, demonstrate that a single injection leads to the detection of CPZ and its metabolites in the lungs, with a lung: blood ratio of 20-200.
Safety Profile and Tolerability
CPZ has an excellent safety profile. It has been widely used for almost 7 decades, has known side effects, and is easy to manage. The common adverse effects include anticholinergic effects, namely, dryness of the mouth, sedation, constipation, and urinary retention.
It is used among pregnant women, cancer patients, and many neurological conditions. It also does not cause respiratory depression and can, therefore, be used even in patients with acute respiratory distress syndrome (ARDS).
The ReCoVery Study
The current challenge is to confirm its antiviral activity against SARS-CoV-2 in vivo and to arrive at a clinically relevant dosage. In vitro data does not typically translate directly into in vivo dosages, and dosage data from animal experiments are lacking. However, the in vitro studies do show that the effective inhibitory concentrations are lower than the toxic dose for human cells.
In order to help evaluate the actual clinical usefulness of CPZ, the authors plan a pilot study comparing standard vs. CPZ therapy.
The ReCoVery Trial is based on the theory that if CPZ is given at the onset of respiratory symptoms, it can prevent the progression of the disease to a severe stage while reducing its infectivity. It is designed as a single-blinded randomized controlled trial over multiple centers. The participants will be ill COVID-19 patients who do not need intensive care but require supplemental oxygen.
The basis for this selection criterion is that CPZ appears to inhibit viral replication during early infection, which may indicate its greater efficacy at early stages. The clinical observation that symptomatic and virulent COVID-19 was rare among these patients is a piece of supporting evidence. However, its immunomodulatory effect could also mean that it can reduce the severity of later stages of the disease.
One group of patients will receive standard care for COVID-19 while the other will additionally receive CPZ at up to 300 mg per day for up to 21 days, or until they meet criteria for recovery.
The outcome measures are, primarily, a shorter time to a response by WHO criteria, and secondarily, greater clinical improvement and decrease in biomarkers of viral attack and inflammation. In addition, chest CT findings at the seventh day will be recorded. The optimal dosage of CPZ will also be examined, with its tolerance.
How Will the ReCoVery Study Help in COVID-19?
Repurposing CPZ may result in a fast-acting intervention to reduce respiratory distress and the severity of infection. It avoids the expensive and time-consuming pipeline of drug development while using a drug that is proven to be safe, with adverse effects that are known, are limited, and can be managed easily.
If proven to be useful, it could reduce the distress of respiratory difficulty in symptomatic COVID-19, reduce the hospital load as well as the need for mechanical ventilation and ICU care.
RECOVERY Trial - Randomised Evaluation of COVID-19 Therapy