Structural dynamics of chlorpromazine (CPZ) drug with dipalmitoylphosphatidylcholine (DPPC) lipid: a potential drug for SARS-CoV-2.

There is an urgent requirement for drug discovery and more importantly drug repositioning due to infectious new Severe Acute Respiratory Syndrome coronavirus 2. As per the recent report published in the journal L'Encéphale in May 2020, there is a planned ReCoVery Study examining the repurposing the chlorpromazine for the treatment of COVID-19. Here, we apply a combined Raman microspectroscopy and DFT-MD approach to investigate the structural dynamics of the Chlorpromazine (CPZ) drug with dipalmitoylphosphatidylcholine (DPPC) lipid bilayer, identifying the specific position of the drug in the DPPC lipid bilayer. The intensity ratios of the Raman peaks I2935/I2880, I1097/I1064 and I1097/I1129 are representative of the interaction of drugs with lipid alkyl chains and furnish conformation of lipid alkyl chains. Raman imaging microscopy for the study of the distribution of CPZ inside the lipid vesicles is reported. We also investigated the influence of order and disorder ratio in the CPZ on the DPPC liposomes prepared on phase transition temperature. HIGHLIGHTSDrug-membrane interactions using micromolar concentrations of both lipid and drugs.Neuroleptic drug and DPPC vesicles composed of DPPC/drug mixtures reveal qualitative differences between the Raman spectraThe temperature-controlled Raman microspectroscopic study has demonstrated that below phase-transition temperature, the fatty acid chains of the phospholipids are stiff and packed in a highly ordered array.DFT and MD simulations to understand molecular interactions, structural dynamics, and Raman spectra.Above phase-transition temperature, the chains are disordered and possess more motional freedom.Communicated by Ramaswamy H. Sarma.

Increased Mental Health Needs in Pediatric Admissions During COVID-19: The Epidemic Within the Pandemic

Background: Pediatric patients with increasing psychiatric needs introduce a substantial challenge for inpatient care. This study illustrates how the COVID-19 pandemic has influenced the number and acuity of psychiatry and psychology consults among pediatric inpatients at a tertiary care hospital. Methods: The study population included all pediatric patients (ages 0-25) admitted to University of Michigan's C.S. Mott Children's Hospital between March 2019 and March 2021 who received a psychology and/or psychiatry consult. Three time periods were defined: pre-pandemic, 3/1/19-3/15/20;early pandemic, 3/16/20-6/30/20;and steady-state pandemic, 7/1/20-2/28/21. The patients were described demographically and clinically. To assess differences among time periods, ANOVA testing was conducted for numeric variables and chi-square tests were used for categorical variables. The number of pediatric inpatients receiving psychiatry and/or psychology consults was reported for each month of the study period as a count and as a percent of all pediatric admissions. Psychiatric acuity was described in terms of length of stay and use of restraints and as-needed medication. Logistic regression was used to estimate the odds of requiring restraints based on time period, controlling for relevant demographic and clinical variables (age, sex, race, length of stay, and use of benzodiazepines and psychotropics). Logistic regression was also used to estimate the odds of patients requiring as-needed medications (midazolam, lorazepam, diazepam, clonazepam, alprazolam, haloperidol, chlorpromazine, quetiapine, risperidone, aripiprazole, olanzapine, and ziprasidone) based on time period, controlling for clinical and demographic variables (age, sex, race, length of stay, and restraint use). Results: Among the 1,636 patients in the study, average age was 14.0 years (IQR 8.1 to 17.2) and 57.9% were female. Overall, 68.6% were White, 13.6% were Black, and 2.4% were Asian. Among all races, 5.7% identified as Hispanic. Percent of pediatric patients receiving psychiatry and/or psychology consults was higher on average during the pandemic months (71.2% during steady-state pandemic compared to 47.9% pre-pandemic). Across all participants, 2.1% required restraints, 34.4% used psychotropics, and 42.6% used benzodiazepines. During the pandemic, admissions became proportionally more female (64.1% during steady-state pandemic vs. 55.3% pre-pandemic) and older (average age 14.8 years during steady-state pandemic vs. 13.4 years pre-pandemic). During steady-state pandemic, children admitted had 5.70 times higher odds of requiring restraints and 1.78 times higher odds of using psychotropics, compared to children admitted pre-pandemic. Length of stay decreased during the pandemic, and was associated with psychotropic use, benzodiazepine use, male sex, and younger age. Conclusion: A higher proportion of pediatric admissions during the COVID-19 pandemic required psychiatry and/or psychology consults. Additionally, these patients were of higher psychiatric acuity, based on increased use of as-needed medications and restraints. These findings highlight the dramatic changes experienced by individual patients and their healthcare teams during the pandemic.

Conversion of Stuporous Catatonia to Excited Catatonia from Lorazepam Challenge

Background: Catatonia, a motor dysregulation syndrome with behavioral components, has undergone many conceptual changes since its inception as a syndrome by Kahlbaum in 1874. Prevalence of catatonia in consultation-liaison services is approximately 5.5 percent in patients aged 65 and older.1 Stuporous catatonia is most common, but catatonia may present in excited or malignant subtypes. Together, the subtypes have over 40 documented signs and symptoms, making catatonia difficult to diagnose and appropriately treat.2 Catatonia involves hyperactivation of the orbitofrontal cortex (OFC) and ventromedial prefrontal cortex. GABA, NMDA, and dopamine have been implicated. GABA-A agonism by benzodiazepines improve catatonia by normalizing OFC activity.3 Case: A 66-year-old male with schizophrenia was admitted to a medical unit for failure to thrive after not eating for three days. He had not taken his medications for 2 weeks including chlorpromazine, quetiapine, oxcarbazepine, and clonazepam. Upon psychiatric consult, the patient exhibited staring, grimacing, echopraxia, and negativism. He was diagnosed with stuporous catatonia. 30 minutes after lorazepam challenge (2 milligram intravenous lorazepam), the patient was moving, conversing, and eating. After second dose of lorazepam, the patient became difficult to redirect, displaying stereotypy, verbigeration, and hitting. Additional doses of lorazepam were unsuccessful in breaking excited catatonia. History revealed previous catatonic episodes, including nine months prior when the patient was admitted to a gero-psychiatric unit. He initially presented in stuporous state, normalized with lorazepam, then transitioned to excited state. He received 16 milligrams of lorazepam in 24 hours without successful termination of excited catatonia. Lorazepam in combination with carbamazepine, clozapine, or valproic acid was unsuccessful. Catatonia was successfully treated with 10 sessions of electroconvulsive therapy (ECT) with lorazepam, clozapine, and valproic acid. Maintenance ECT was not continued because of the COVID pandemic, and the patient was admitted to a state facility after regression. Discussion: Catatonia is often encountered on consultation-liaison services in general hospital settings. We observed conversion of stuporous catatonia to excited catatonia after administration of lorazepam. This treatment-resistant catatonia ultimately required ECT. No reported cases of stuporous catatonia transitioning to excited catatonia were found on thorough literature review. Recognition of this conversion may be difficult and may require development of a catatonia scale that clearly identifies the presenting subtype. This is a challenge;clinical signs are not mutually exclusive among subtypes. This patient’s clinical course may provide insight into the identification of treatment-resistant catatonia, and accurate identification is necessary to allow for timely escalation of treatment. References: 1. Solmi M, et al. Prevalence of catatonia and its moderators in clinical samples: Results from a meta-analysis and meta-regression analysis. Schizophrenia Bulletin. 2017;44(5):1133–50. 2. Fink M, Taylor MA. The catatonia syndrome. Archives of General Psychiatry. 009;66(11):1173. 3. Ellul P, Choucha W. Neurobiological approach of Catatonia and Treatment Perspectives. Frontiers in Psychiatry. 2015;6.

Management of COVID-19-A Review

Coronavirus disease-2019 (COVID-19) has gained much popularity not only in the Wuhan city of China but internationally also;in January 2020, the corona rapidly spread to many countries like the USA, Italy, Russia, India, Singapore, Pakistan, Thailand, Canada, Australia, England, and so on through passengers traveling to other countries. Corona patients can be cured with synthetic drugs, traditional herbal medicines (THM), use of Vitamin D and the quarantine approach. Different allopathic medicines, herbal extracts, and vitamin D have been observed to be useful in the treatment of novel coronavirus, like Remdesivir, hydroxychloroquine, Teicoplanin, Lopinavir+ Ritonavir, Ribavirin + corticosteroids, Glycyrrhizin, Sanguisorbae radix, Acanthopanacis cortex, Sophorae radix, etc. Various antiviral drugs are used to treat COVID-19, alone or in combination with other medications like Interferon-α, Lopinavir + Ritonavir, Arbidol, corticosteroids, etc., and some herbal extracts;also quarantine approach and Vitamin D are used that not only cure the infection but also boost up our immunity. For this review article, different papers were searched on Google Scholar, Scopus, WHO’s website, PubMed, clinicaltrials.gov and other relevant scientific research websites. In this review article, we have discussed the current strategies that are being used to treat COVID-19. Along with allopathic drugs, some herbal extracts can also be used to treat this novel coronavirus, like Glycyrrhizin, Sanguisorbae radix, Acanthopanacis cortex, Sophorae radix, etc. and even vitamin D.

Drug Repurposing: A Potentially Emerging Discipline

Drug repurposing is the remodeling of already existing drugs to reduce the time frame, costs, and efforts in developing a new novel drug. This strategy has secured significant momentum in the previous decade. It overcomes the snags and pitfalls in the traditional means of drug discovery. This core research strategy has now become the sole approach to containing many deadly diseases that have no cure in the present. In astound, for pandemics like COVID-19 that is spreading like a wildfire worldwide, large-scale research programs and trials have been carried out to identify and modify existing drugs to counter the novel virus. Thus, this technology of drug repurposing offers a new lease of life, and greatly promotes the progress of the medicine, health, and pharma sectors. The purpose of this study is to understand the current status of drug repurposing in the field of virology, bacteriology, mycology, and oncology for clinical translatability.

Chlorpromazine, a Clinically Approved Drug, Inhibits SARS-CoV-2 Nucleocapsid-Mediated Induction of IL-6 in Human Monocytes.

The COVID-19 pandemic, caused by the rapidly spreading SARS-CoV-2 virus, led to the unprecedented mobilization of scientists, resulting in the rapid development of vaccines and potential pharmaceuticals. Although COVID-19 symptoms are moderately severe in most people, in some cases the disease can result in pneumonia and acute respiratory failure as well as can be fatal. The severe course of COVID-19 is associated with a hyperinflammatory state called a cytokine storm. One of the key cytokines creating a proinflammatory environment is IL-6, which is secreted mainly by monocytes and macrophages. Therefore, this cytokine has become a target for some therapies that inhibit its biological action; however, these therapies are expensive, and their availability is limited in poorer countries. Thus, new cheaper drugs that can overcome the severe infections of COVID-19 are needed. Here, we show that chlorpromazine inhibits the expression and secretion of IL-6 by monocytes activated by SARS-CoV-2 virus nucleocapsid protein and affects the activity of NF-κB and MEK/ERK signaling. Our results, including others, indicate that chlorpromazine, which has been used for several decades as a neuroleptic, exerts antiviral and immunomodulatory activity, is safe and inexpensive, and might be a desirable drug to support the therapy of patients with COVID-19.

A Review on Schizophrenia: Outline and Treatment

Schizophrenia is a debilitating, genetic brain condition caused by anomalies that appear early in infancy and interrupt normal brain development. It has a lifetime risk of 1% and affects people of all ages, with around 10% dying by suicide. COVID-19 may raise the risk of mortality and morbidity in people with schizophrenia. Although antipsychotic medications of the first, second, and third generations are the most commonly prescribed treatments for schizophrenia, they are linked to major side effects such as tardive dyskinesia, oxidative stress, and EPS. Ayurvedic herbal medications and some dietary supplements score well in this category since they can be taken for a long time without causing major adverse effects and have antioxidant properties. Low potency first generation antipsychotics, sedating antihistamines, and benzodiazepines, as well as inhalable antipsychotics, oral and short acting injectable olanzapine, and ziprasidone, as well as low potency first generation antipsychotics, sedating antihistamines, and benzodiazepines, should be avoided or closely monitored for patients with COVID-19. Mentally ill patients with COVID-19 should be segregated if at all possible, and employees should be adequately protected.

Computational drug repurposing against SARS-CoV-2 reveals plasma membrane cholesterol depletion as key factor of antiviral drug activity

Comparing SARS-CoV-2 infection-induced gene expression signatures to drug treatment-induced gene expression signatures is a promising bioinformatic tool to repurpose existing drugs against SARS-CoV-2. The general hypothesis of signature-based drug repurposing is that drugs with inverse similarity to a disease signature can reverse disease phenotype and thus be effective against it. However, in the case of viral infection diseases, like SARS-CoV-2, infected cells also activate adaptive, antiviral pathways, so that the relationship between effective drug and disease signature can be more ambiguous. To address this question, we analysed gene expression data from in vitro SARS-CoV-2 infected cell lines, and gene expression signatures of drugs showing anti-SARS-CoV-2 activity. Our extensive functional genomic analysis showed that both infection and treatment with in vitro effective drugs leads to activation of antiviral pathways like NFkB and JAK-STAT. Based on the similarity—and not inverse similarity—between drug and infection-induced gene expression signatures, we were able to predict the in vitro antiviral activity of drugs. We also identified SREBF1/2, key regulators of lipid metabolising enzymes, as the most activated transcription factors by several in vitro effective antiviral drugs. Using a fluorescently labeled cholesterol sensor, we showed that these drugs decrease the cholesterol levels of plasma-membrane. Supplementing drug-treated cells with cholesterol reversed the in vitro antiviral effect, suggesting the depleting plasma-membrane cholesterol plays a key role in virus inhibitory mechanism. Our results can help to more effectively repurpose approved drugs against SARS-CoV-2, and also highlights key mechanisms behind their antiviral effect.

A comparative study of long acting injectable antipsychotic agents and oral agents during covid-19 pandemic: Quality of life, adherence and shortage of supply

Background: Long-acting injectable antipsychotics improved markedly patient adherence to psychotropic agents during the past decade. They were used mainly for long-term treatment of schizophrenia. However their role in short term or intermittent use or their effect on quality of life was not elucidated clearly. Objectives: To assess the impact of Long Acting Antipsychotic agents on quality of life of schizophrenic patients. Methods: This is a retrospective cohort study of psychiatric patients who were taking LAIs and/or oral antipsychotic drugs at Mohammad Said Kamal Hospital for Mental Illness in Bethlehem and Mental Health Clinic of The Ministry of Health in Hebron city during the period of September 2019 to March 2020. Results: Fifty one patients were included in this study, 74% males, age 50.69 ± 11.14 years old. Average duration of psychiatric disease was 17.78 ± 11.4 years. It was found that 9.6% patients were on oral dosage form (category I), 80.4% were on LAI and oral antipsychotics (category II), and 10% were on LAIs (Category III). Chi square test showed a significant difference between the 3-categories and GAF score (functionality), p=0.003. However, there was insignificant difference between the three categories and CGI-S(severity of symptoms) scores, p=0.170. When it comes to side effects, there was a significant difference among the three categories and DIEPSS, p=0.049. Kruskal–Wallis Test showed a significant difference between patients in the three categories and number of all drugs, p=0.007. There was also a significant difference between CGI-S-normal group and CGI-S-severe symptoms group and overall number of drugs used, p=0.02. Mann-Whitney test showed a significant difference between number of all drugs used and the use of trihexphenidyl, p=0.001. Also there was a significant difference between number of antipsychotic drugs alone and thrihexphenidyl use, p=0.001. Patients were prescribed LAIs for the following reasons: non-adherence (47%), no reason at all (27.4%), patient dissatisfaction (13.7%), adherence and patient dissatisfaction (5.8%), side effects, convenience (ease of use), and availability of drug, (1.9%), for each. Conclusion: Improvement in functionality of schizophrenic patients goes along with use of LAIs either alone or in combination. LAIs improved adherence and minimizes polypharmacy.

The Effectiveness of Chlorpromazine to Decrease the Level of Tumor Necrosis Factor-Alpha Serum in Schizophrenic Patients with Coronavirus Disease 2019

BACKGROUND: The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus-2. The COVID-19 pandemic has also had an impact on mental health, including those with schizophrenia (SCH). There were 131 inpatient schizophrenic patients who were confirmed positive for COVID-19 at Dadi Makassar Hospital, South Sulawesi, Indonesia, but all of these patients did not experience any clinical symptoms of COVID-19. Chlorpromazine as an antipsychotic also has antiviral and anti-inflammatory effects in schizophrenic patients with COVID-19, and the schizophrenic neuroinflammatory is very likely to occur in patients with COVID-19 infection. AIM: The researchers tried to examine the effectiveness of chlorpromazine on serum TNF-values in schizophrenic patients with COVID-19. METHODS: This research is a nested case–control study. The study was conducted on schizophrenic patients with mild and asymptomatic cases of COVID-19 at Dadi Mental Hospital with a sample of 40 patients compared to 42 schizophrenic patients who were not COVID-19. Study subjects received chlorpromazine 100 mg/day for 4 weeks. Serum tumor necrosis factor-alpha (TNF-α) concentrations were measured by enzyme-linked immunosorbent assays when COVID-19 was first confirmed and after 4 weeks. Positive and negative syndrome scale (PANSS) and clinical global impression SCH (CGI-SCH) examinations were also performed to measure the clinical symptoms of SCH. RESULTS: The comparison of baseline TNF-serum levels that increased in the schizophrenic group with COVID-19 was 9.33 pg/ml higher, compared to the schizophrenic group without COVID-19. The decrease in TNF-levels in the schizophrenic group with COVID-19 of 7.96 pg/ml (p < 0.001) indicated an improvement in TNF-serum levels at week 4. Meanwhile, there was no significant decrease in serum TNF-levels in the non-COVID-19 schizophrenic group (p > 0.05). CONCLUSION: The serum TNF-value of schizophrenic patients with COVID-19 is higher than schizophrenic patients without COVID-19. Coadministration of chlorpromazine, antipsychotics, and COVID-19 therapy reduces serum TNF-values in schizophrenic patients with COVID-19. The administration of chlorpromazine and antipsychotic in therapeutic doses reduced the total PANSS and CGI-SCH values. © 2021 Andi Jayalangkara Tanra, Ahmad Andi Sameggu, Rinvil Renaldi, Burhanuddin Bahar, Saidah Syamsuddin, Muhammad Ilyas, Sonny T. Lisal.

P.0707 Suicide attempt and depression after COVID-19 vaccination: a case report

The coronavirus disease 2019 (COVID-19) pandemic is having a profound effect on all aspects of society, including mental and physical health [1]. Vaccines to prevent SARS-CoV-2 infection are considered to be the most promising approach for the pandemic and are being vigorously pursued [2]. Since the outbreak began, researchers around the world have been trying to develop vaccines for COVID-19, with more than 198 vaccines currently in preclinical or clinical development phase [3]. Inactivated SARS-CoV-2 vaccine (CoronaVac) is one of the vaccine that has been in use in Turkey. It has been on the market a while now and some adverse effects are defined but many others are waiting to be discovered. This article reports a case of prolonged fatigue, depression, loss of functionality and suicide attempt after the CoronaVac vaccination. The reported patient was 72 years old female and had no background of any psychiatric disorder. The patient was admitted to the emergency service after a suicide attempt by drug overdose. After the patient's observation was completed in the emergency service, psychiatric evaluation was performed. The patient had depressive mood, loss of joy, anhedonia, fatigue, psychomotor retardation, feeling of worthlessness and recurrent suicidal thoughts nearly everyday for a two months period. She received the first dose of CoronaVac vaccination on the 24th of February in 2021. After the first injection she developed nausea, vomiting, dizziness, fatigue and hypertension. A complete examination has been made in another hospital and any organic pathology has not been detected. Because of this symptoms, she was scared to get the second dose of vaccine. Fatigue, and other depressive symptoms increased and got worsened and she made superficial cuts with kitchen knife on the dorsal faces of both her ankles and wrists five days prior to suicide attempt. She took unknown amount of chlorpromazine that expired in 1970 to commit suicide. The patient was admitted to psychiatry clinic and after a treatment process with venlafaxine she discharged with her own will and depressive symptoms were in remission. The psychiatric background has been evaluated for the causes of depression such as recent stressor, trauma, loss of family members, life style changes or anxiety about the pandemic but any specific cause could not be found. In addition during this time the patient was not infected by COVID-19 virus. In previous studies the most common side effects caused by the CoronaVac were mild pain and redness at the injection site and slight fatigue [4]. But this study observed the participants only for 28 days, so prolonged side effects that may be caused by the CoronaVac has not been reported yet. Our patient is the first case reported that developed a fully depressive episode after CoronaVac vaccination. It may guide clinicians in establishing a linkage between prolonged fatigue and depressive symptoms in vaccinated patients. No conflict of interest

Drugs that offer the potential to reduce hospitalization and mortality from SARS-CoV-2 infection: The possible role of the sigma-1 receptor and autophagy.

Introduction: Despite the availability of new vaccines for SARS-CoV-2, there has been slow uptake and problems with supply in some parts of the world. Hence, there is still a necessity for drugs that can prevent hospitalization of patients and reduce the strain on health care systems. Drugs with sigma affinity potentially provide protection against the most severe symptoms of SARS-COV-2 and could prevent mortality via interactions with the sigma-1 receptor.Areas covered: This review examines the role of the sigma-1 receptor and autophagy in SARS-CoV-2 infections and how they may be linked. The authors reveal how sigma ligands may reduce the symptoms, complications, and deaths resulting from SARS-CoV-2 and offer insights on those patient cohorts that may benefit most from these drugs.Expert opinion: Drugs with sigma affinity potentially offer protection against the most severe symptoms of SARS-CoV-2 via interactions with the sigma-1 receptor. Agonists of the sigma-1 receptor may provide protection of the mitochondria, activate mitophagy to remove damaged and leaking mitochondria, prevent ER stress, manage calcium ion transport, and induce autophagy to prevent cell death in response to infection.

[Repurposing of chlorpromazine in COVID-19 treatment: the reCoVery study]. / Repositionnement de la chlorpromazine dans le traitement du COVID-19 : étude reCoVery.

OBJECTIVES: The ongoing COVID-19 pandemic comprises a total of more than 2,350,000 cases and 160,000 deaths. The interest in anti-coronavirus drug development has been limited so far and effective methods to prevent or treat coronavirus infections in humans are still lacking. Urgent action is needed to fight this fatal coronavirus infection by reducing the number of infected people along with the infection contagiousness and severity. Since the beginning of the COVID-19 outbreak several weeks ago, we observe in GHU PARIS Psychiatrie & Neurosciences (Sainte-Anne hospital, Paris, France) a lower prevalence of symptomatic and severe forms of COVID-19 infections in psychiatric patients (∼4%) compared to health care professionals (∼14%). Similar observations have been noted in other psychiatric units in France and abroad. Our hypothesis is that psychiatric patients could be protected from severe forms of COVID-19 by their psychotropic treatments. Chlorpromazine (CPZ) is a phenothiazine derivative widely used in clinical routine in the treatment of acute and chronic psychoses. This first antipsychotic medication has been discovered in 1952 by Jean Delay and Pierre Deniker at Sainte-Anne hospital. In addition, to its antipsychotic effects, several in vitro studies have also demonstrated a CPZ antiviral activity via the inhibition of clathrin-mediated endocytosis. Recently, independent studies revealed that CPZ is an anti-MERS-CoV and an anti-SARS-CoV-1 drug. In comparison to other antiviral drugs, the main advantages of CPZ lie in its biodistribution: (i) preclinical and clinical studies have reported a high CPZ concentration in the lungs (20-200 times higher than in plasma), which is critical because of the respiratory tropism of SARS-CoV-2; (ii) CPZ is highly concentrated in saliva (30-100 times higher than in plasma) and could therefore reduce the contagiousness of COVID-19; (iii) CPZ can cross the blood-brain barrier and could therefore prevent the neurological forms of COVID-19. METHODS: Our hypothesis is that CPZ could decrease the unfavorable evolution of COVID-19 infection in oxygen-requiring patients without the need for intensive care, but also reduce the contagiousness of SARS-CoV-2. At this end, we designed a pilot, phase III, multicenter, single blind, randomized controlled clinical trial. Efficacy of CPZ will be assessed according to clinical, biological and radiological criteria. The main objective is to demonstrate a shorter time to response (TTR) to treatment in the CPZ+standard-of-care (CPZ+SOC) group, compared to the SOC group. Response to treatment is defined by a reduction of at least one level of severity on the WHO-Ordinal Scale for Clinical Improvement (WHO-OSCI). The secondary objectives are to demonstrate in the CPZ+SOC group, compared to the SOC group: (A) superior clinical improvement; (B) a greater decrease in the biological markers of viral attack by SARS-CoV-2 (PCR, viral load); (C) a greater decrease in inflammatory markers (e.g. CRP and lymphopenia); (D) a greater decrease in parenchymal involvement (chest CT) on the seventh day post-randomization; (E) to define the optimal dosage of CPZ and its tolerance; (F) to evaluate the biological parameters of response to treatment, in particular the involvement of inflammatory cytokines. Patient recruitment along with the main and secondary objectives are in line with WHO 2020 COVID-19 guidelines. CONCLUSION: This repositioning of CPZ as an anti-SARS-CoV-2 drug offers an alternative and rapid strategy to alleviate the virus propagation and the infection severity and lethality. This CPZ repositioning strategy also avoids numerous developmental and experimental steps and can save precious time to rapidly establish an anti-COVID-19 therapy with well-known, limited and easy to manage side effects. Indeed, CPZ is an FDA-approved drug with an excellent tolerance profile, prescribed for around 70 years in psychiatry but also in clinical routine in nausea and vomiting of pregnancy, in advanced cancer and also to treat headaches in various neurological conditions. The broad spectrum of CPZ treatment - including antipsychotic, anxiolytic, antiemetic, antiviral, immunomodulatory effects along with inhibition of clathrin-mediated endocytosis and modulation of blood-brain barrier - is in line with the historical French commercial name for CPZ, i.e. LARGACTIL, chosen as a reference to its "LARGe ACTion" properties. The discovery of those CPZ properties, as for many other molecules in psychiatry, is both the result of serendipity and careful clinical observations. Using this approach, the field of mental illness could provide innovative therapeutic approaches to fight SARS-CoV-2.

The Large Action of Chlorpromazine: Translational and Transdisciplinary Considerations in the Face of COVID-19.

Coronavirus disease 2019 (COVID-19) is a severe acute respiratory syndrome (SARS) in humans that is caused by SARS-associated coronavirus type 2 (SARS-CoV-2). In the context of COVID-19, several aspects of the relations between psychiatry and the pandemic due to the coronavirus have been described. Some drugs used as antiviral medication have neuropsychiatric side effects, and conversely some psychotropic drugs have antiviral properties. Chlorpromazine (CPZ, Largactil®) is a well-established antipsychotic medication that has recently been proposed to have antiviral activity against SARS-CoV-2. This review aims to 1) inform health care professionals and scientists about the history of CPZ use in psychiatry and its potential anti- SARS-CoV-2 activities 2) inform psychiatrists about its potential anti-SARS-CoV-2 activities, and 3) propose a research protocol for investigating the use of CPZ in the treatment of COVID-19 during the potential second wave. The history of CPZ's discovery and development is described in addition to the review of literature from published studies within the discipline of virology related to CPZ. The early stages of infection with coronavirus are critical events in the course of the viral cycle. In particular, viral entry is the first step in the interaction between the virus and the cell that can initiate, maintain, and spread the infection. The possible mechanism of action of CPZ is related to virus cell entry via clathrin-mediated endocytosis. Therefore, CPZ could be useful to treat COVID-19 patients provided that its efficacy is evaluated in adequate and well-conducted clinical trials. Interestingly, clinical trials of very good quality are in progress. However, more information is still needed about the appropriate dosage regimen. In short, CPZ repositioning is defined as a new use beyond the field of psychiatry.

Inhibition of the replication of SARS-CoV-2 in human cells by the FDA-approved drug chlorpromazine.

INTRODUCTION: Urgent action is needed to fight the ongoing coronavirus disease 2019 (COVID-19) pandemic by reducing the number of infected cases, contagiousness and severity. Chlorpromazine (CPZ), an antipsychotic from the phenothiazine group, is known to inhibit clathrin-mediated endocytosis and has antiviral activity against severe acute respiratory syndrome coronavirus-1 (SARS-CoV-1) and Middle East respiratory syndrome coronavirus. The aim of this in-vitro study was to test CPZ against SARS-CoV-2 in monkey and human cells. MATERIALS AND METHODS: Monkey VeroE6 cells and human alveolar basal epithelial A549-ACE2 cells were infected with SARS-CoV-2 in the presence of various concentrations of CPZ. Supernatants were harvested at day 2 and analysed by quantitative reverse transcription polymerase chain reaction (RT-qPCR) for the presence of SARS-CoV-2 RNA. Cell viability was assessed in non-infected cells. RESULTS: CPZ was found to have antiviral activity against SARS-CoV-2 in monkey VeroE6 cells, with a half maximal inhibitory concentration (IC50) of 8.2 µM, half maximal cytotoxic concentration (CC50) of 13.5 µM, and selectivity index (SI) of 1.65. In human A549-ACE2 cells, CPZ was also found to have anti-SARS-CoV-2 activity, with IC50 of 11.3 µM, CC50 of 23.1 µM and SI of 2.04. DISCUSSION: Although the measured SI values are low, the IC50 values measured in vitro may translate to CPZ dosages used in routine clinical practice because of the high biodistribution of CPZ in lungs and saliva. Also, the distribution of CPZ in brain could be of interest for treating or preventing neurological and psychiatric forms of COVID-19. CONCLUSIONS: These preclinical findings support clinical investigation of the repurposing of CPZ, a drug with mild side effects, in the treatment of patients with COVID-19.