[Efficacy of psychedelics in psychiatry, a systematic review of the literature]. / Efficacité des psychédéliques en psychiatrie, une revue systématique.

OBJECTIVES: Psychedelics are powerful psychoactive substances. Natural psychedelics have been used for millennia by human civilizations, in particular in Latin America, while synthetic psychedelics were discovered in the 50s, giving rise to a lot of research before they were prohibited. More recently, their therapeutic properties have been studied especially to help patients with psychiatric conditions, psychological distress or substance use disorders. This article is a systematic review of the literature which aims to provide an overview of all studies that assessed the efficacy of psychedelics, i.e. psilocybin, ayahuasca and lysergic acid diethylamide (LSD), on psychiatric diseases and addictions. METHODS: We conducted this literature review following the PRISMA recommendations. MEDLINE, PsycInfo, Web of Science and Scopus were searched from January 1990 to May 2020 with the following keywords "(ayahuasca OR psilocybin OR lysergic acid diethylamide) AND (depression OR anxiety OR major depressive disorder OR bipolar disorder OR anxiety disorder OR substance use disorder OR dependence)". RESULTS: Twenty-five articles met the inclusion criteria. Five articles studied psychedelic efficacy in the treatment of life-threatening diseases related to anxiety and depression: four were randomized controlled crossover trials (three with psilocybin for a total of 92 patients, and one with LSD, n=12), and one was a long-term follow-up study. Eleven articles explored the efficacy of psychedelics in the treatment of major depressive episodes: two were open-labeled trials (one with ayahuasca, n=17, one with psilocybin, n=20), one was a randomized controlled trial using ayahuasca against placebo (n=29), and the others were long-term follow-up studies or assessed more precise dimensions of the depressive disorder, such as suicidality, emotion processing or personality traits. Eight articles studied the efficacy of psychedelics in the treatment of addictions: two were open-labeled studies using psilocybin (one in alcohol use disorder, n=10, and one in tobacco use disorder, n=15), and the others were long-term follow-up studies or retrospective observational descriptive studies on alcohol, tobacco, opioids, cannabis, and psychostimulants. One study explored the efficacy of psilocybin in obsessional-compulsive disorder (n=9). Overall, these studies found a quick and important response after psychedelic administration that lasted for several months, even after a single dose. However most of these studies were descriptive or open-label studies conducted on small size samples. No severe adverse events occurred. CONCLUSIONS: Psychedelics are promising treatments for anxiety, depression and addiction, their efficacy is quick and sustainable, and they are well tolerated. These effects need to be confirmed in larger studies and compared to standard care.

[Validation of a French version of the 16-item Prodromal Questionnaire (fPQ16) in adolescents and young adults seeking help]. / Validation d'une version française du 16-items Prodromal Questionnaire (fPQ16) chez des adolescents et jeunes adultes consultant en psychiatrie.

INTRODUCTION: The duration of untreated psychosis has been largely associated with poor outcomes in psychosis. Actual diagnostic tools may be used by very specialized teams and need sustained evaluation. We present a French version of a self-report questionnaire: the 16-item Prodromal Questionnaire (fPQ16). Our objective was to evaluate its predictive value for an ultra-high-risk state (UHR) or psychosis. The population enrolled was consulting in a young adults and adolescents center in Sainte-Anne hospital, Paris, France. METHODS: PQ16 had first been translated into French and independently back translated and validated by the original authors. Between November 2016 and May 2018, every C'JAAD consulting patient was proposed to fill in the fPQ16. Each patient was next evaluated with the French version of the comprehensive assessment of at-risk mental state (CAARMS), which detects UHR or psychosis. Statistical analysis of fPQ16 concurrent validity was performed using ROC curves. fPQ16 acceptability was studied by four additional questions especially designed for that purpose. RESULTS: One hundred participants were included. Mean age was 19.85years (SD 3.3 y). Fifty-eight percent of patients included were diagnosed with UHR (40%) or psychotic (18%) state after CAARMS evaluation. Mean score at fPQ16 was 5.7 (SD 3.8). Best cut-off score was 4 positive items, with excellent sensibility (91%) and correct specificity (60%). Positive predictive value of fPQ16 was 76%. Area under the curve was 0.85 (P<0.0001). fPQ16 showed good acceptability. DISCUSSION: fPQ16 had good screening performances in our population. Cut-off score was lower than in previous studies, but performances were equal or better. As a well-accepted and short questionnaire, the fPQ16 could be a great screening tool in primary care. A version with 18-items, including two items focused on thought content and disorganization that are missing in PQ16, is under evaluation.

Prevalence and impact of patient suicide in psychiatrists: Results from a national French web-based survey.

BACKGROUND: Patient suicide (PS) is known to be a frequent and challenging occupational hazard for mental health professionals. No study previously explored the prevalence and impact of PS in a large sample of French psychiatrists. METHOD: A national web-based survey was performed between September and December 2019 to assess (a) the prevalence of the exposure to PS, (b) the emotional, traumatic and professional impacts of PS, and (c) the perceived support in the aftermath of PS in French psychiatrists. Participants were contacted through email to answer the online 62-item questionnaire, including a measure of traumatic impact through the Impact of Event Scale-Revised. Emotional and professional impacts and perceived support were assessed through dedicated items. RESULTS: A total of 764 psychiatrists fully completed the survey. Of them, 87.3% reported an exposure to PS and 13.7% reported PTSD symptoms afterward. Guilt, sadness and shock were the most frequent emotions. Among the exposed psychiatrists, 15.1% have temporarily considered changing their career path. The most emotionally distressing PS occurred during their ten first years of practice or during residency. A total of 37.1% of respondents felt unsupported and 50.4% reported that no team meeting had been organized in the aftermath. The feeling of responsibility for the death was strongly associated with negative impacts. CONCLUSION: Our results entail considerations to prevent negative mental health outcomes in psychiatrists after PS. Notably, our results advocate for the implementation of educational programs during psychiatric residency and postvention programs in healthcare settings to effectively help psychiatrists in dealing with PS.

Psychotropics and COVID-19: An analysis of safety and prophylaxis.

The use of psychotropics during the COVID-19 pandemic has raised two questions, in order of importance: first, what changes should be made to pharmacological treatments prescribed to mental health patients? Secondly, are there any positive side effects of these substances against SARS-CoV-2? Our aim was to analyze usage safety of psychotropics during COVID-19; therefore, herein, we have studied: (i) the risk of symptomatic complications of COVID-19 associated with the use of these drugs, notably central nervous system activity depression, QTc interval enlargement and infectious and thromboembolic complications; (ii) the risk of mistaking the iatrogenic impact of psychotropics with COVID-19 symptoms, causing diagnostic error. Moreover, we provided a summary of the different information available today for these risks, categorized by mental health disorder, for the following: schizophrenia, bipolar disorder, anxiety disorder, ADHD, sleep disorders and suicidal risk. The matter of psychoactive substance use during the pandemic is also analyzed in this paper, and guideline websites and publications for psychotropic treatments in the context of COVID-19 are referenced during the text, so that changes on those guidelines and eventual interaction between psychotropics and COVID-19 treatment medication can be reported and studied. Finally, we also provide a literature review of the latest known antiviral properties of psychotropics against SARS-CoV-2 as complementary information.

Combined ACL reconstruction and opening wedge high tibial osteotomy at 10-year follow-up: excellent laxity control but uncertain return to high level sport.

PURPOSE: The purpose of this study was to report the long-term outcomes of a continuous series of patients who underwent simultaneous anterior cruciate ligament (ACL) reconstruction and opening wedge high tibial osteotomy (HTO) for varus-related early medial tibio-femoral osteoarthritis. It was hypothesized that this combined surgery sustainably allowed return to sport with efficient clinical and radiological results. METHODS: From 1995 to 2015, all combined ACL reconstruction (bone-patellar tendon-bone graft) and opening wedge HTO for anterior laxity and early medial arthritis were included. Clinical evaluation at final follow-up used Tegner activity score, Lysholm score, subjective and objective IKDC scores. Radiologic evaluation consisted in full-length, standing, hip-to-ankle X-rays, monopodal weight-bearing X-rays and skyline views. AP laxity assessment used Telos™ at 150 N load. Student's t test was performed for matched parametric data, Wilcoxon for nonparametric variables and Friedman test was used to compare small cohorts, with p < 0.05. RESULTS: 35 Patients (36 knees) were reviewed with a mean follow-up of 10 ± 5.2 years. The mean age at surgery was 39 ± 9. At final follow-up 28 patients (80%) returned to sport (IKDC ≥ B): 11 patients (31%) returned to sport at the same level and 6 (17%) to competitive sports. Mean subjective IKDC and Lysholm scores were 71.8 ± 14.9 and 82 ± 14.1, respectively. The mean decrease of the Tegner activity level from preinjury state to follow-up was 0.8 (p < 0.01). Mean side-to-side difference in anterior tibial translation was 5.1 ± 3.8 mm. Three patients were considered as failures. The mean preoperative mechanical axis was 4.2° ± 2.6° varus and 0.8° ± 2.7° valgus at follow-up. Osteoarthritis progression for medial, lateral, and femoro-patellar compartments was recorded for 12 (33%, p < 0.05), 6 (17%, p < 0.001), and 8 (22%, p < 0.05) knees, respectively. No femoro-tibial osteoarthritis progression was observed in 22 knees (61%). CONCLUSIONS: Combined ACL reconstruction and opening wedge HTO allowed sustainable stabilization of the knee at 10-year follow-up. However, return to sport at the same level was possible just for one-third of patients, with femoro-tibial osteoarthritis progression in 39% of cases. LEVEL OF EVIDENCE: III.

[Sensorimotor aspects and manual dexterity in autism spectrum disorders: A literature review]. / Aspects sensorimoteurs et motricité manuelle dans les troubles du spectre autistique : une revue de la littérature.

OBJECTIVES: Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by difficulties in communication and social interactions as well as by restricted and repetitive patterns of behavior and interests. They are frequently associated with motor signs. However, literature concerning these motor anomalies remains scarce when it comes to the adult population. Among motor aspects, those concerning manual motor skills warrant a particular attention as their alteration often persists through adulthood with a major impact on functioning and quality of life. The purpose of this article was to systematically review and analyze the literature on sensorimotor aspects and manual motor impairments in ASD. METHODS: We have searched the Medline database using the Pubmed search engine and retaining all articles published since the year 2000 with either their title, abstract or key-words containing the root autis* and any combination of the following terms: hand, manual, finger, dexterity, prehension, grip or grasp. Reference lists where also reviewed. After irrelevant articles were excluded, 33 studies were retained for this work. RESULTS: The basic motor anomaly in autism seems to be a deficit in sensorimotor integration. The central nervous system of individuals with ASD seems unable to efficiently extract sensory information and integrate it correctly into a motor plan and execution. This type of online correction aims to save time on the initial ballistic phase of a movement. Thus, its alteration results in generalized slowness and motor clumsiness that require retroactive feedback corrections. Moreover, difficulties in integrating external sensory information to correctly adapt movement to environmental requirements could explain stereotyped and inflexible behaviors characteristic of autism. The same sensorimotor alterations are found in both gross and fine manual dexterity tasks. They seem to persist significantly though adolescence and into adulthood. To explain these anomalies, the underlying neuroanatomical and neurofunctional substratum might be a hypoconnectivity within cortico-cerebellar tracts. However, several other cerebral structures are also implicated. A delay in the maturational processes of these structures appears to be the common determinant of motor signs found in ASD but also in neurodevelopmental disorders as a whole. CONCLUSIONS: Current works tackling motor aspects in autism comprise several limitations preventing homogenization of their findings. Firstly, characterization of the extremely diverse clinical forms of ASD does not always rely on the same clinical criteria or tools. Furthermore, the motor tasks and the clinical assessments used are not always the same across publications complicating comparison. Moreover, sample sizes are almost always small and only a few studies have addressed motor impairments in adults with ASD. Furthermore, only two studies examine the dynamic longitudinal evolution of motor aspects from childhood to adult age. Finally, despite a recent effort of a consistent number of publications converging towards the hypothesis of a deficit in sensorimotor integration, a common pathophysiological model explaining these deficits in ASD is lacking. A more precise description of these motor signs and further comprehension of the neurological mechanisms underpinning them would allow more tailored managements directed towards subgroups with more homogenous neurodevelopmental profiles.

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.

[Informations on psychotropics and their adaptations for patients suffering from mental disorders in France during the SARS-CoV-2 epidemic]. / Informations relatives aux psychotropes et à leurs adaptations éventuelles pour les patients souffrant de troubles psychiques en France pendant l'épidémie à SARS-CoV-2.

The 2019-20 coronavirus pandemic (SARS-CoV-2; severe acute respiratory syndrome coronavirus 2) has dramatic consequences on populations in terms of morbidity and mortality and in social terms, the general confinement of almost half of the world's population being a situation unprecedented in history, which is difficult today to measure the impact at the individual and collective levels. More specifically, it affects people with various risk factors, which are more frequent in patients suffering from psychiatric disorders. Psychiatrists need to know: (i) how to identify, the risks associated with the prescription of psychotropic drugs and which can prove to be counterproductive in their association with COVID-19 (coronavirus disease 2019), (ii) how to assess in terms of benefit/risk ratio, the implication of any hasty and brutal modification on psychotropic drugs that can induce confusion for a differential diagnosis with the evolution of COVID-19. We carried out a review of the literature aimed at assessing the specific benefit/risk ratio of psychotropic treatments in patients suffering from COVID-19. Clinically, symptoms suggestive of COVID-19 (fever, cough, dyspnea, digestive signs) can be caused by various psychotropic drugs and require vigilance to avoid false negatives and false positives. In infected patients, psychotropic drugs should be used with caution, especially in the elderly, considering the pulmonary risk. Lithium and Clozapine, which are the reference drugs in bipolar disorder and resistant schizophrenia, warrant specific attention. For these two treatments the possibility of a reduction in the dosage - in case of minimal infectious signs and in a situation, which does not allow rapid control - should ideally be considered taking into account the clinical response (even biological; plasma concentrations) observed in the face of previous dose reductions. Tobacco is well identified for its effects as an inducer of CYP1A2 enzyme. In a COVID+ patient, the consequences of an abrupt cessation of smoking, particularly related with the appearance of respiratory symptoms (cough, dyspnea), must therefore be anticipated for patients receiving psychotropics metabolized by CYP1A2. Plasma concentrations of these drugs are expected to decrease and can be related to an increase risk of relapse. The symptomatic treatments used in COVID-19 have frequent interactions with the most used psychotropics. If there is no curative treatment for infection to SARS-CoV-2, the interactions of the various molecules currently tested with several classes of psychotropic drugs (antidepressants, antipsychotics) are important to consider because of the risk of changes in cardiac conduction. Specific knowledge on COVID-19 remains poor today, but we must recommend rigor in this context in the use of psychotropic drugs, to avoid adding, in patients suffering from psychiatric disorders, potentially vulnerable in the epidemic context, an iatrogenic risk or loss of efficiency.

Ensuring mental health care during the SARS-CoV-2 epidemic in France: A narrative review.

OBJECTIVE: The lack of resources and coordination to face the coronavirus epidemic raises concerns for the health of patients with mental disorders in a country where we still have memories of the dramatic experience of famine in psychiatric hospitals during the Second World War. This article aims to propose guidance to ensure mental health care during the SARS-CoV epidemic in France. METHODS: The authors performed a narrative review identifying relevant results in the scientific and medical literature and in local initiatives in France. RESULTS: We identified four types of major vulnerabilities among patients with mental disorders during this pandemic: (1) medical comorbidities that are more frequently found among patients with mental disorders (cardiovascular and pulmonary pathologies, diabetes, obesity, etc.) which are risk factors for severe covid-19 infection; (2) age (the elderly form the population most vulnerable to the coronavirus); (3) cognitive and behavioural disorders, which can hamper compliance with confinement and hygiene measures and finally and (4) psychosocial vulnerability as a result of stigmatization and/or socio-economic difficulties. Furthermore, the mental health healthcare system is more vulnerable than other healthcare systems. Current government plans are poorly suited to psychiatric establishments in a context of major shortages of organizational, material and human resources. In addition, a certain number of structural aspects make the psychiatric institution particularly vulnerable: many beds have been closed, wards have high densities of patients, mental health community facilities are closed, and medical teams are understaffed and poorly trained to face infectious diseases. There are also major issues when referring patients with acute mental disorders to intensive care units. To maintain the continuity of psychiatric care in this pandemic situation, several directions can be considered, in particular with the creation of "COVID+ units". These units are under the dual supervision of a psychiatrist and an internist/infectious disease specialist; all new entrants are placed in quarantine for 14 days; the nursing staff receives specific training, daily medical check-ups and close psychological support. Family visits are prohibited and replaced by videoconference. At the end of hospitalization, in particular for the population of patients in compulsory ambulatory care situations, specific case-management are organized with the possibility of home visits, in order to support patients when they get back home and to help them cope with the experience of confinement, which is liable to induce recurrences of mental disorders. The total or partial closure of community mental health facilities is particularly disturbing for patients, but a regular follow-up is possible with telemedicine and should include the monitoring of suicide risk and psycho-education strategies; developing support platforms could also be very helpful in this context. Private practice psychiatrists also have a crucial role of information towards their patients on confinement and barrier measures, and also on measures to prevent the psychological risks inherent in confinement: maintenance of regular sleep r, physical exercise, social interactions, stress management and coping strategies, prevention of addictions, etc. They should also be trained to prevent, detect and treat early warning symptoms of post-traumatic stress disorder, because their prevalence was high in the regions of China most affected by the pandemic. DISCUSSION: French mental healthcare is now facing a great and urgent need for reorganization and must also prepare in the coming days and weeks to face an epidemic of emotional disorders due to the confinement of the general population.

[Ensuring mental health care during the SARS-CoV-2 epidemic in France: A narrative review]. / Assurer les soins aux patients souffrant de troubles psychiques en France pendant l'épidémie à SARS-CoV-2.

OBJECTIVE: The lack of ressources and coordination to face the epidemic of coronavirus raises concerns for the health of patients with mental disorders in a country where we keep in memory the dramatic experience of famine in psychiatric hospitals during the Second World War. This article aims at proposing guidance to ensure mental health care during the SARS-CoV epidemy in France. METHODS: Authors performed a narrative review identifying relevant results in the scientific and medical literature and local initiatives in France. RESULTS: We identified four types of major vulnerabilities in patients suffering from mental disorders during this pandemic: (1) medical comorbidities that are more frequently found in patients suffering from mental disorders (cardiovascular and pulmonary pathologies, diabetes, obesity, etc.) which represent risk factors for severe infections with Covid-19; (2) age (the elderly constituting the population most vulnerable to coronavirus); (3) cognitive and behavioral troubles which can hamper compliance with confinement and hygiene measures and finally and (4) psychosocial vulnerability due to stigmatization and/or socio-economic difficulties. Furthermore, the mental health healthcare system is more vulnerable than other healthcare systems. Current government plans are poorly adapted to psychiatric establishments in a context of major shortage of organizational, material and human resources. In addition, a certain number of structural aspects make the psychiatric institution particularly vulnerable: many beds are closed, wards have a high density of patients, mental health community facilities are closed, medical teams are understaffed and poorly trained to face infectious diseases. We could also face major issues in referring patients with acute mental disorders to intensive care units. To maintain continuity of psychiatric care in this pandemic situation, several directions can be considered, in particular with the creation of Covid+ units. These units are under the dual supervision of a psychiatrist and of an internist/infectious disease specialist; all new entrants should be placed in quarantine for 14 days; the nurse staff should benefit from specific training, from daily medical check-ups and from close psychological support. Family visits would be prohibited and replaced by videoconference. At the end of hospitalization, in particular for the population of patients in compulsory ambulatory care situations, specific case-management should be organized with the possibility of home visits, in order to support them when they get back home and to help them to cope with the experience of confinement, which is at risk to induce recurrences of mental disorders. The total or partial closure of mental health community facilities is particularly disturbing for patients but a regular follow-up is possible with telemedicine and should include the monitoring of the suicide risk and psychoeducation strategies; developing support platforms could also be very helpful in this context. Private psychiatrists have also a crucial role of information with their patients on confinement and barrier measures, but also on measures to prevent the psychological risks inherent to confinement: maintenance of sleep regularity, physical exercise, social interactions, stress management and coping strategies, prevention of addictions, etc. They should also be trained to prevent, detect and treat early warning symptoms of post-traumatic stress disorder, because their prevalence was high in the regions of China most affected by the pandemic. DISCUSSION: French mental healthcare is now in a great and urgent need for reorganization and must also prepare in the coming days and weeks to face an epidemic of emotional disorders due to the containment of the general population.

[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.

Increased valgus laxity in flexion with greater tibial resection depth following total knee arthroplasty.

PURPOSE: Soft tissue balancing is of central importance to outcome following total knee arthroplasty (TKA). However, there are lack of data analysing the effect of tibial bone cut thickness on valgus laxity. A cadaveric study was undertaken to assess the biomechanical consequences of tibial resection depth on through range knee joint valgus stability. We aimed to establish a maximum tibial resection depth, beyond which medial collateral ligament balancing becomes challenging, and a constrained implant should be considered. METHODS: Eleven cadaveric specimens were included for analysis. The biomechanical effects of increasing tibial resection were studied, with bone cuts made at 6, 10, 14, 18 and 24 mm from the lateral tibial articular surface. A computer navigation system was used to perform the tibial resection and to measure the valgus laxity resulting from a torque of 10 Nm. Measurements were taken in four knee positions: 0° or extension, 30°, 60° and 90° of flexion. Intra-observer reliability was assessed. A minimum sample size of eight cadavers was necessary. Statistical analysis was performed using a nonparametric Spearman's ranking correlation matrix at the different stages: in extension, at 30°, 60° and 90° of knee flexion. Significance was set at p < 0.05. RESULTS: There was no macroscopic injury to the dMCL or sMCL in any of the specimens during tibial resection. There was no significant correlation found between the degree of valgus laxity and the thickness of the tibial cut with the knee in extension. There was a statistically significant correlation between valgus laxity and the thickness of the tibial cut in all other knee flexion positions: 30° (p < 0.0001), 60° (p < 0.001) and 90° (p < 0.0001). We identified greater than 5° of valgus laxity, at 90° of knee flexion, after a tibial resection of 14 mm. CONCLUSION: Increased tibial resection depth is associated with significantly greater valgus laxity when tested in positions from 30° to 90° of flexion, despite stability in extension. Greater than 5° of laxity was identified with a tibial resection of 14 mm. When a tibial bone cut of 14 mm or greater is necessary, as may occur with severe preoperative coronal plane deformity, it is recommended to consider the use of a constrained knee prosthesis.

Maternal and fetal genetic contribution to gestational weight gain.

BACKGROUND: Clinical recommendations to limit gestational weight gain (GWG) imply high GWG is causally related to adverse outcomes in mother or offspring, but GWG is the sum of several inter-related complex phenotypes (maternal fat deposition and vascular expansion, placenta, amniotic fluid and fetal growth). Understanding the genetic contribution to GWG could help clarify the potential effect of its different components on maternal and offspring health. Here we explore the genetic contribution to total, early and late GWG. PARTICIPANTS AND METHODS: A genome-wide association study was used to identify maternal and fetal variants contributing to GWG in up to 10 543 mothers and 16 317 offspring of European origin, with replication in 10 660 mothers and 7561 offspring. Additional analyses determined the proportion of variability in GWG from maternal and fetal common genetic variants and the overlap of established genome-wide significant variants for phenotypes relevant to GWG (for example, maternal body mass index (BMI) and glucose, birth weight). RESULTS: Approximately 20% of the variability in GWG was tagged by common maternal genetic variants, and the fetal genome made a surprisingly minor contribution to explain variation in GWG. Variants near the pregnancy-specific beta-1 glycoprotein 5 (PSG5) gene reached genome-wide significance (P=1.71 × 10-8) for total GWG in the offspring genome, but did not replicate. Some established variants associated with increased BMI, fasting glucose and type 2 diabetes were associated with lower early, and higher later GWG. Maternal variants related to higher systolic blood pressure were related to lower late GWG. Established maternal and fetal birth weight variants were largely unrelated to GWG. CONCLUSIONS: We found a modest contribution of maternal common variants to GWG and some overlap of maternal BMI, glucose and type 2 diabetes variants with GWG. These findings suggest that associations between GWG and later offspring/maternal outcomes may be due to the relationship of maternal BMI and diabetes with GWG.

Methylomic changes during conversion to psychosis.

The onset of psychosis is the consequence of complex interactions between genetic vulnerability to psychosis and response to environmental and/or maturational changes. Epigenetics is hypothesized to mediate the interplay between genes and environment leading to the onset of psychosis. We believe we performed the first longitudinal prospective study of genomic DNA methylation during psychotic transition in help-seeking young individuals referred to a specialized outpatient unit for early detection of psychosis and enrolled in a 1-year follow-up. We used Infinium HumanMethylation450 BeadChip array after bisulfite conversion and analyzed longitudinal variations in methylation at 411 947 cytosine-phosphate-guanine (CpG) sites. Conversion to psychosis was associated with specific methylation changes. Changes in DNA methylation were significantly different between converters and non-converters in two regions: one located in 1q21.1 and a cluster of six CpG located in GSTM5 gene promoter. Methylation data were confirmed by pyrosequencing in the same population. The 100 top CpGs associated with conversion to psychosis were subjected to exploratory analyses regarding the related gene networks and their capacity to distinguish between converters and non-converters. Cluster analysis showed that the top CpG sites correctly distinguished between converters and non-converters. In this first study of methylation during conversion to psychosis, we found that alterations preferentially occurred in gene promoters and pathways relevant for psychosis, including oxidative stress regulation, axon guidance and inflammatory pathways. Although independent replications are warranted to reach definitive conclusions, these results already support that longitudinal variations in DNA methylation may reflect the biological mechanisms that precipitate some prodromal individuals into full-blown psychosis, under the influence of environmental factors and maturational processes at adolescence.

[Switching and stopping antidepressants]. / Recommandations pour switcher et arrêter les antidépresseurs.

Major depressive disorder (MDD) is a common, typically recurrent, sometimes chronic and very disabling disorder, with a lifetime prevalence of 20%. Moreover, antidepressant treatments may be partially effective. Studies have found that up to 60% of patients with MDD do not fully respond to the first antidepressant prescribed. Thus, switching antidepressants is a common strategy for antidepressant non-responders. When switching between antidepressants, an appropriate switching strategy should be used, depending on the characteristics of the first and the second antidepressant and patient's background. Patients should be informed that antidepressants can cause discontinuation symptoms if stopped abruptly after prolonged used. Relapse and exacerbation of depression can also occur during a switch. Thus, all antidepressant switches must be carried out cautiously and under close observation. This article summarizes the recommendations for an optimal antidepressant switch.

[Switching from antipsychotics to aripiprazole and risk of agitation]. / Relais d'un antipsychotique par l'aripiprazole et risque d'agitation.

The exact modalities of switching between two antipsychotics are rarely studied despite the high frequency of this issue in clinical practice. In this context, description of clinical cases may be enlightening. We report on three new cases of agitation after replacing a dopaminergic antagonist with aripiprazole. A literature review indicated no other predictive clinical feature associated with a higher risk of agitation than therapeutic history. In fact, patients who previously received a greater dose of antipsychotic are more at risk to present paradoxical agitation when switching to aripiprazole. This has led to the hypothesis of dopaminergic hypersensitivity: dopaminergic antagonists could increase the number of receptors to be activated by a partial agonist-like aripiprazole. In one of the cases described here, the patient had received aripiprazole two years previously without any particular side effects. The reintroduction of aripiprazole after a treatment by risperidone was followed by agitation. Other pharmacological hypotheses to explain this agitation involve cholinergic and histaminergic rebounds as well. The frequency of these paradoxical reactions is probably underreported, and psychiatrists should be more attentive to them. During the replacement, aripiprazole should be prescribed at the maximal posology from the start, and the previous antipsychotic should be maintained and slowly decreased in no fewer than four weeks.

[Consequences of the monoaminergic systems cross-talk in the antidepressant activity]. / Conséquences de l'inter-relation des systèmes monoaminergiques dans l'activité antidépressive.

Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed antidepressant treatment for treat major depressive disorders. Despite their effectiveness, only 30% of SSRI-treated patients reach remission of depressive symptoms. SSRIs by inhibiting the serotonin transporter present some limits with residual symptoms. Increasing not only serotonin but also norepinephrine and dopamine levels in limbic areas seems to improve remission. Anatomical relationships across serotoninergic, dopaminergic and noradrenergic systems suggest tight reciprocal regulations among them. This review attempts to present, from acute to chronic administration the consequences of SSRI administration on monoaminergic neurotransmission. The serotonin neurons located in the raphe nucleus (RN) are connected to the locus coeruleus (locus coeruleus), the key structure of norepinephrine synthesis, through GABAergic-inhibiting interneurons. Activation of the 5-HT2A receptors expressed on GABAergic interneurons following SERT-inhibition induces an increase in serotonin leading to inhibitory effect on NE release. Similarly, the serotonin neurons exert negative regulation on dopaminergic neurons from the ventral tegmental area (VTA) through a GABAergic interneuron. These interneurons express the 5-HT2C and 5-HT3 receptors inducing an inhibitory effect of 5-HT on DA release. Positive reciprocal connections are also observed through direct projections from the locus coeruleus to the RN and from the VTA to the RN through α1 and D2 receptors respectively, both stimulating the serotoninergic activity. Acute SSRI treatment induces only a slight increase in 5-HT levels in limbic areas due to the activation of presynaptic 5-HT1A and 5-HT1B autoreceptors counteracting the effects of the transporter blockade. No change in NE levels and a small decrease in the dopaminergic neurotransmission is also observed. These weak changes in monoamine in the limbic areas after acute SSRI treatment seems to be one of key point involved in the onset of action. Following desensitization of the 5-HT1A and 5-HT1B autoreceptors, chronic SSRI treatment induces a large increase in the 5-HT neurotransmission. Changes in 5-HT levels at the limbic areas results in a decrease in NE transmission and an increase in DA transmission through an increase in the post-synaptic D2 receptors sensitivity and not from a change in DA levels, which is mainly due to a desensitization of the 5-HT2A receptor. The observed decrease of NE neurotransmission could explain some limits of the SSRI therapy and the interest to activate NE system for producing more robust effects. On the other hand, the D2 sensitization, especially in the nucleus accumbens, stimulates the motivation behavior as well as remission of anhedonia considering the major role of DA release in this structure. Finally, we need to take into account the key role of each monoaminergic neurotransmission to reach remission. Targeting only one system will limit the therapeutic effectiveness. Clinical evidences, including the STAR*D studies, confirmed this by an increase of the remission rate following the mobilization of several monoaminergic transmissions. However, these combinations cannot constitute first line of treatment considering the observed increase of side effects. Such an approach should be adapted to each patient in regard to its particular symptoms as well as clinical history. The next generation of antidepressant therapy will need to take into consideration the interconnections and the interrelation between the monoaminergic systems.

[Early detection of mental health disorders at school: The Fil Harmonie pilot program]. / Détection précoce des troubles psychiques en milieu scolaire : le dispositif Fil Harmonie.

OBJECTIVE: Most psychiatric disorders arise during adolescence, a period of life during which school takes an important place. School in France has an official mission of health education and prevention, and early detection of mental disorders is part of these goals. The aim of this study is to describe an innovative service operating in Paris that helps educational staff to deal with students having psychological or psychiatric symptoms. The Fil Harmonie program was launched in 2011. It consists of a telephone line available to all educational staff working for high schools in Paris. METHODS: When in need of assistance, a member of the educational staff can call the dedicated hotline and expose the situation of their student to a trained psychologist. Over the course of the study, data concerning these phone calls were collected such as: socio-demographic characteristics of the student, the reason behind the call, the caller's professional role within the school, and care pathway information. All data collected during the phone calls were anonymized and computerized. We performed an observational descriptive study based on this data by using mixed methods: we integrated quantitative analysis and qualitative research in order to provide a better understanding of the Fil Harmonie program. RESULTS: Between 18 September 2013 and 12 May 2014, the Fil Harmonie program handled 68 calls from educational staff. Students concerned by the calls were aged between 11 and 22 and the average age was 17.3 years. Over half (52.5%) of the pupils concerned had never seen a mental health professional before the call. In more than 70% of cases, the caller was a school nurse while other professionals such as teachers or headmasters represented only a minority of the callers. Approximately two thirds (67.2%) of students were described by the caller as socially isolated and 48.2% were described as sad or anhedonic. One out of four (26.7%) had repeated a school year at least once, and 55.9% of young people for whom a member of staff contacted Fil Harmonie had been missing class. In 56.7% of cases, there had been no contact with the student's family about the psychological situation. The qualitative analysis particularly highlighted the complexity of the collaboration between the family and the educational staff. CONCLUSION: Schooling is an important opportunity to seize in mental health regarding early detection and access to care. By fostering collaboration between educational professionals and mental health services, Fil Harmonie meets a public health objective of prevention and should contribute to the reduction of care delays thus leading to better treatment outcome. Our study shows that such programs are feasible and answer a real need in our current health care system.

Confidence and psychosis: a neuro-computational account of contingency learning disruption by NMDA blockade.

A state of pathological uncertainty about environmental regularities might represent a key step in the pathway to psychotic illness. Early psychosis can be investigated in healthy volunteers under ketamine, an NMDA receptor antagonist. Here, we explored the effects of ketamine on contingency learning using a placebo-controlled, double-blind, crossover design. During functional magnetic resonance imaging, participants performed an instrumental learning task, in which cue-outcome contingencies were probabilistic and reversed between blocks. Bayesian model comparison indicated that in such an unstable environment, reinforcement learning parameters are downregulated depending on confidence level, an adaptive mechanism that was specifically disrupted by ketamine administration. Drug effects were underpinned by altered neural activity in a fronto-parietal network, which reflected the confidence-based shift to exploitation of learned contingencies. Our findings suggest that an early characteristic of psychosis lies in a persistent doubt that undermines the stabilization of behavioral policy resulting in a failure to exploit regularities in the environment.