[The next psychoactive drugs: From imipramine to ketamine]. / Psychotropes du futur : de l'imipramine à la kétamine.

Since the 1950s, the therapeutic arsenal against depression has grown considerably. From the discovery of monoamine oxidase inhibitors (MAOI) to the antidepressant effect of ketamine, these pharmacological breakthroughs made the history of psychiatry. They also guided the research about the pathophysiology of depression, one of the most devasting diseases, which affects between 10 and 20 % of general population. In this article, we offer a short historical review of the various therapeutic options developed over the past century and the consequences of these innovations. We then review the most recent one, ketamine (and its enantiomer S, esketamine). Ketamine's effects are spectacular both in terms of their very short onset time, and because they are observed even in treatment-resistant depression. Just as MAOIs and tricyclic antidepressants allowed the "monoaminergic hypothesis of depression" to emerge, to unravel the mechanisms of ketamine's antidepressant effects should allow the understanding of the role of glutamatergic system, or that of neuro-inflammation, in the neurobiology of depression. Ketamine might also help to refine our understanding of the cognitive pathophysiology of depression, or even to deeply transform the clinical representations about what depression is.

Repurposing chlorpromazine to treat COVID-19: The reCoVery study.

OBJECTIVES: The 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. METHODS: In 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). CONCLUSION: This 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.

[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.

[Use of botulinum toxin A in pelvic floor dysfunctions in the elderly: A review]. / Intérêt de la toxine botulinique A dans le traitement des troubles pelvi-périnéaux de la personne âgée.

INTRODUCTION: The present article is the final report of a multi-disciplinary meeting supported by the GRAPPPA (group for research applied to pelvic floor dysfunctions in the elderly). The objective was to conduct a comprehensive review on the role of botulinum toxin A (BonTA) in the treatment of pelvic floor dysfunctions in the elderly. METHODS: The present article, written as a comprehensive review of the literature, combines data issued from the scientific literature with expert's opinions. Review of the literature was performed using the online bibliographic database MedLine (National Library of Medicine). Regarding intra-detrusor BonTA injections, only articles focusing on elderly patients (>65 yo) were included. Regarding other localizations, given the limited number of data, all articles reporting outcomes of BonTA were included, regardless of studies population age. In case of missing or insufficient data, expert's opinions were formulated. RESULTS: Although, available data are lacking in this specific population, it appears that BonTA could be used in the non-fraily elderly patients to treat overactive bladder or even neurogenic detrusor overactivity, with a success rate comparable to younger population at 3 months (88.9% vs. 91.2%), 6 months (49.4% vs. 52.1%) and 12 months (23.1% vs. 22.3%), as well as a significant decrease in number of voids per day (11.4 vs. 5.29 P<0.001) and in the number of pads per day (4.0 vs. 1.3, P<0.01). Furthermore, BonTA is likely to be offered in the future as a treatment of fecal incontinence and obstructed defecation syndrome symptoms. Concerning bladder outlet obstruction/voiding dysfunction symptoms, intra-urethral sphincter BonTA should not be recommended. CONCLUSION: BonTA injections are of interest in the management of various pelvic floor dysfunctions in the elderly, and its various applications should be better evaluated in this specific population in order to further determine its safety and efficacy.

[Cardiovascular adverse effects of antimuscarinics used in the treatment of overactive bladder in the elderly : A review]. / Effets cardio-vasculaires des traitements anticholinergiques à visée vésicale chez la personne âgée : une revue.

AIM: The aim of this study was to review the evidence regarding the cardiovascular effects of urinary anticholinergic drugs in the elderly. METHODS: A literature review was conducted in October 2017 using the Medline/Pubmed database limiting the search to works in English or French. RESULTS: In total, 602 articles between March 1964 and October 2017 have been reported, 60 studies were analyzed, 19 were prospective trials. Geriatric population has a high prevalence of cardiovascular diseases (24.4% of heart diseases on 65-74years and 36.9% on ≥75years). More than 20% of the geriatric population has overactive bladder history and 41.43% of them use of antimuscarinic drugs. Evaluating the cardiovascular adverse effects of antimusarinics in the geriatric population is not easy because of exclusion of high-risk patients in trials. However, serious cardiovascular adverse effects were reported like atrial fibrillation, atrioventricular block or torsade de pointe. Further studies are needed especially in the "real life" in order to precise the exact prevalence of such cardiovascular alterations. CONCLUSION: Without conclusive evidence, potential cardiovascular adverse effects of anticholinergic agents used in overactive bladder must lead to a cautious prescription.

[Pathophysiology of detrusor underactivity in the elderly]. / Physiopathologie de l'hypoactivité détrusorienne de la personne âgée.

AIM: The aim of this study was to review the evidence regarding the pathophysiology of detrusor underactivity in the elderly. METHODS: A literature review was conducted in July 2016 using the Medline/Pubmed database limiting the search to works in English or French. RESULTS: The prevalence of detrusor underactivity has been reported to range from 8% to 48% depending on the definition used and the age of the population studied. Current data suggest that aging may itself be a causative factor of detrusor underactivity through myogenic dysfunctions (ultrastructural degeneration of the detrusor muscle) and neurogenic dysfunctions (by degeneration of efferent but mostly afferent innervation mechanisms). Beyond these inherently age-related mechanisms, many comorbidities whose prevalence increase with age (diabetes, bladder outlet obstruction, estrogen deficiency, atherosclerosis, etc.) may be implicated in the development of detrusor underactivity in the elderly. The role played by detrusor overactivity in the appearance of detrusor underactivity must be considered separately as both seem to be the expression of the same condition of the lower urinary tract responding to different stages and secondary to numerous etiopathogenic factors which modulate its progression and clinical expressions. CONCLUSION: Pathophysiology of detrusor underactivity remains poorly understood but seems to imply myogenic and neurogenic factors which are favored, besides the aging per se, by various and numerous comorbidities which prevalence increase with age (diabetes, bladder outlet obstruction…).

[Impact on cognitive function of anticholinergic drugs used for the treatment of overactive bladder in the elderly]. / Traitement anticholinergique de l'hyperactivité vésicale de la personne âgée et ses impacts sur la cognition. Revue de la littérature.

OBJECTIVES: Describe the central nervous system (CNS) adverse effects of anticholinergic drugs used for the treatment of overactive bladder (OAB) in the elderly. PATIENTS AND METHODS: Relevant data from the literature were identified primarily through a Medline search of articles published through December 2013. The search terms included overactive bladder, central nervous system, elderly, anticholinergic, and antimuscarinic. Articles were chosen for inclusion based on their pertinence to the focus on treatment of OAB in the elderly. RESULTS: Several anticholinergic drugs are available for the treatment of OAB, including oxybutinin, tolterodine, trospium chloride, solifenacine, fesoterodine. Among the agents reviewed, penetration of the blood-brain barrier (as predicted by lipophilicity, polarity, and molecular size and structure) is highest for oxybutinin, lower for tolterodine, solifenacine, and darifenacine, and lowest for fesoterodine and trospium chloride. Unwanted CNS adverse effects depend in part on patient specific variability in pharmacokinetic parameters, blood-brain barrier permeability, degree of cholinergic neuronal degeneration, total anticholinergic drug burden and patient's baseline cognitive status. The spectrum of anticholinergic CNS adverse effects ranges from drowsiness to hallucinations, severe cognitive impairment, and coma. Among the different anticholinergic agents, oxybutinin has been associated with cognitive impairment and trospium chloride and fesoterodine have shown favorable CNS tolerability. CONCLUSIONS: Anticholinergic drugs improve significatively overactive bladder symptoms in older adults. However, potential CNS adverse effects of anticholinergic agents used in OAB must lead to a full evaluation before and during the treatment in order to evaluate benefice, risks and central side effects in this frail population.

[Guidelines concerning urinary incontinence in elderly: construction and validation of GRAPPPA algorithm]. / Recommandations concernant l'incontinence urinaire de la personne âgée : construction et validation de l'algorithme décisionnel GRAPPPA.

OBJECTIVES: Provide guidelines presented as an algorithm for practical evaluation and first line therapy of urinary incontinence in elderly. PATIENTS AND METHODS: Guidelines using formalized consensus guidelines method. These guidelines have been validated by a group of 40 experts quoting proposals, subsequently reviewed by an independent group of multidisciplinary experts (urologist, general practitioner, neurologist, gynecologist, geriatrist, specialist in physical medicine and rehabilitation). RESULTS: By means of 3 rounds of interrogation of the expert panel, GRAPPPA algorithm was constructed. This algorithm take in account both evaluation and first line therapeutic options in the different type of incontinences observed in this population (urge, stress and mixed incontinence). Initial evaluation consists to track down urinary retention (and subsequently fecal stool impaction, use of anticholinergic or morphinic drugs), urinary tract infection and cognitive impairment. Haematuria, bladder-pelvic pain, history of radiotherapy or recent pelvic surgery, lead to refer the patient to a specialized unit. First line therapy is in all the cases pelvic floor training, use of local oestrogenotherapy and dietetic measures. In urge incontinence, anticholinergic drugs may be used. CONCLUSIONS: Implementation of this algorithm may promote best practice in management of urinary incontinence in elderly.

Ultrasonic depolymerization of an exopolysaccharide produced by a bacterium isolated from a deep-sea hydrothermal vent polychaete annelid.

Low frequency ultrasound was used to depolymerize a high-molecular-weight exopolysaccharide (EPS) produced by a deep-sea hydrothermal bacterium Alteromonas macleodii subsp. fijiensis biovar deepsane. The influence of several parameters was examined including the duration of ultrasonic irradiation, EPS concentration, reaction temperature and volume of the sonicated solution. With the aim of optimizing the depolymerization, the native EPS was simultaneously treated with hydrogen peroxide and ultrasound. This study identified the sonication conditions that produce low-molecular-weight derivatives from the native EPS (>10(6)Da) with good reproducibility.