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Highlights • Chlorpromazine, an FDA-approved drug, inhibits clathrin-mediated endocytosis • CPZ acts as an antiviral against SARS-CoV-1 and MERS-CoV • We evidenced antiviral activity of CPZ against SARS-CoV-2 in monkey and human cells • Because of CPZ high distribution in lungs, CPZ IC50 may translate in clinical routine • CPZ brain distribution could be of high interest for neurological forms of COVID-19, Introduction Urgent action is needed to fight the ongoing COVID-19 pandemic by reducing the number of infected people along with the infection contagiousness and severity. Chlorpromazine (CPZ), the prototype of typical antipsychotics from the phenothiazine group, is known to inhibit clathrin-mediated endocytosis and acts as an antiviral, in particular against SARS-CoV-1 and MERS-CoV. The aim of this in vitro study was to test CPZ against a SARS-CoV-2 isolate in monkey and human cells. Material and methods Monkey VeroE6 cells and human alveolar basal epithelial A549-ACE2 cells were infected with SARS-CoV-2 in presence of different concentrations of CPZ. Supernatants were harvested at day 2 and analysed by RT-qPCR for the presence of SARS-CoV-2 RNA. Cell viability was assessed on non-infected cells. Results We evidenced an antiviral activity of CPZ against SARS-CoV-2 in monkey VeroE6 cells with an IC50 of 8.2 µM, a CC50 of 13.5µM and a SI of 1.65. In human A549-ACE2 cells, CPZ was also associated with an anti-SARS-CoV-2 activity, with an IC50 of 11.3 µM, a CC50 of 23.1 µM and a SI of 2.04. Discussion Even though the measured SI are low, such IC50 measured in vitro may translate to CPZ dosage used in clinical routine because of CPZ high biodistribution in lungs and in saliva. Also, CPZ brain distribution could be of high interest for treating or preventing the neurological and psychiatric forms of COVID-19. Conclusions These preclinical findings support clinical investigation of the repurposing of CPZ, a largely used drug with mild side effects, in COVID-19 treatment.

International audience; ObjectivesThe ongoing COVID-19 pandemic has caused approximately 2,350,000 infections worldwide and killed more than 160,000 individuals. In Sainte-Anne Hospital (GHU PARIS Psychiatrie & Neuroscience, Paris, France) we have observed a lower incidence of symptomatic forms of COVID-19 among patients than among our clinical staff. This observation led us to hypothesize that psychotropic drugs could have a prophylactic action against SARS-CoV-2 and protect patients from the symptomatic and virulent forms of this infection, since several of these psychotropic drugs have documented antiviral properties. Chlorpromazine (CPZ), a phenothiazine derivative, is also known for its antiviral activity via the inhibition of clathrin-mediated endocytosis. Recentin vitro studies have reported that CPZ exhibits anti-MERS-CoV and anti-SARS-CoV-1 activity.MethodsIn this context, the ReCoVery study aims to repurpose CPZ, a molecule with an excellent tolerance profile and a very high biodistribution in the saliva, lungs and brain. We hypothesize that CPZ could reduce the unfavorable course of COVID-19 infection among patients requiring respiratory support without the need for ICU care, and that it could also reduce the contagiousness of SARS-CoV-2. For this purpose, we plan a pilot, multicenter, randomized, single blind, controlled, phase III therapeutic trial (standard treatment vs. CPZ + standard treatment).ConclusionThis repurposing of CPZ for its anti-SARS-CoV-2 activity could offer an alternative, rapid strategy to alleviate infection severity. This repurposing strategy also avoids numerous developmental and experimental steps, and could save precious time to rapidly establish an anti-COVID-19 therapy with well-known, limited and easily managed side effects.; ObjectifsLa pandémie mondiale actuelle de COVID-19 a touché environ 2 350 000 personnes et fait plus de 160 000 morts. Nous avons observé dans le GHU PARIS Psychiatrie & Neurosciences (site Sainte-Anne, Paris, France) une incidence moins importante de formes symptomatiques de COVID-19 chez les patients que dans notre personnel soignant. Notre hypothèse est que les traitements psychotropes pourraient avoir une action prophylactique sur le SARS-CoV-2. Cette hypothèse est cohérente avec les propriétés antivirales connues de plusieurs psychotropes au premier rang desquels la chlorpromazine (CPZ). En plus de ses effets antipsychotiques classiques, plusieurs études in vitro ont également démontré une activité antivirale de cette phénothiazine via l’inhibition de l’endocytose dépendante des clathrines. Récemment, des études ont révélé un effet anti-MERS-CoV et anti-SARS-CoV-1 de la CPZ.MéthodesDans ce contexte, l’étude reCoVery, basée sur le repositionnement de la CPZ – molécule avec un excellent profil de tolérance et une biodistribution très élevée dans la salive, les poumons et le cerveau – vise à tester l’hypothèse que la CPZ pourrait diminuer l’évolution défavorable de l’infection COVID-19 chez des patients oxygénorequérants sans nécessité de soins en réanimation mais aussi réduire la contagiosité du SARS-CoV-2. Nous allons réaliser pour cela un essai thérapeutique pilote de phase III multicentrique, randomisé, contrôlé (traitement standard vs CPZ + traitement standard) et en simple insu.ConclusionLe repositionnement de la CPZ comme antiviral anti-SARS-CoV-2 offre une stratégie alternative et rapide pour atténuer la propagation du virus ainsi que la gravité et la létalité du COVID-19.

Interactions between social cognition and symptoms of schizophrenia have been investigated, but mostly component by component. Here we tested the assumption that two categories of deficits exist depending on clinical profiles, one corresponding to a defect in social cognition – “under-social cognition” – and one corresponding to excessive attributions leading to social cognitive impairments – “over-social cognition”. To conduct the investigation, we performed a Hierarchical Clustering Analysis using positive and negative symptoms in seventy patients with schizophrenia and we compared the clusters obtained to a group of healthy controls on social cognitive measures. We distinguished two social cognitive profiles based on prevailing symptoms for emotion processes and Theory of Mind. Actually, patients with negative symptoms showed lower performances in emotion recognition task than both those with positive symptoms and controls. Concerning Theory of Mind, patients with positive symptoms had a significant tendency to make over interpretative errors than both patients with negative symptoms and controls. For other processes assessed, further explorations are needed. Actually, concerning social perception and knowledge both patients' groups presented significant impairments compared to controls. Assessment of attribution bias showed that patients in the positive group presented a significant hostility bias and a higher intentionality score compared to healthy controls. These results favor the existence of different categories of impairments depending more on the clinical characteristics of patients than on nosographical categories, but further investigations are now necessary to specify these profiles. It nevertheless showed the importance of assessing symptoms in relationship with cognitive functioning. Keywords: Social cognition, Schizophrenia, Symptoms, Emotion, Theory of mind, Attribution style

Summary The medial frontal cortex has been linked to voluntary action, but an explanation of why decisions to act emerge at particular points in time has been lacking. We show that, in macaques, decisions about whether and when to act are predicted by a set of features defining the animal’s current and past context; for example, respectively, cues indicating the current average rate of reward and recent previous voluntary action decisions. We show that activity in two brain areas—the anterior cingulate cortex and basal forebrain—tracks these contextual factors and mediates their effects on behavior in distinct ways. We use focused transcranial ultrasound to selectively and effectively stimulate deep in the brain, even as deep as the basal forebrain, and demonstrate that alteration of activity in the two areas changes decisions about when to act., Highlights • Likelihood and timing of voluntary action in macaques can be partially predicted • Recent experience and present context influence when voluntary action occurs • A basal forebrain-cingulate circuit mediated effects of these factors on behavior • Stimulation of this circuit by ultrasound changed decisions about when to act, Deciding when to act is crucial for animals’ survival. Khalighinejad et al. used neuroimaging and ultrasound to identify a basal forebrain-cingulate circuit that tracks contextual factors in animals’ environments and mediates their effects on animals’ decisions about when to act.