Preoperative ketamine administration for prevention of postoperative neurocognitive disorders after major orthopedic surgery in elderly patients: A multicenter randomized blinded placebo-controlled trial.

BACKGROUND: Preventive anesthetic impact on the high rates of postoperative neurocognitive disorders in elderly patients is debated. The Prevention of postOperative Cognitive dysfunction by Ketamine (POCK) study aimed to assess the effect of ketamine on this condition. METHODS: This is a multicenter, randomized, double-blind, interventional study. Patients ≥60 years undergoing major orthopedic surgery were randomly assigned in a 1:1 ratio to receive preoperative ketamine 0.5 mg/kg as an intravenous bolus (n = 152) or placebo (n = 149) in random blocks stratified according to the study site, preoperative cognitive status and age. The primary outcome was the proportion of objective delayed neurocognitive recovery (dNR) defined as a decline of one or more neuropsychological assessment standard deviations on postoperative day 7. Secondary outcomes included a three-month incidence of objective postoperative neurocognitive disorder (POND), as well as delirium, anxiety, and symptoms of depression seven days and three months after surgery. RESULTS: Among 301 patients included, 292 (97%) completed the trial. Objective dNR occurred in 50 (38.8%) patients in the ketamine group and 54 (40.9%) patients in the placebo group (OR [95% CI] 0.92 [0.56;1.51], p = 0.73) on postoperative day 7. Incidence of objective POND three months after surgery did not differ significantly between the two groups nor did incidence of delirium, anxiety, apathy, and fatigue. Symptoms of depression were less frequent in the ketamine group three months after surgery (OR [95%CI] 0.34 [0.13-0.86]). CONCLUSIONS: A single preoperative bolus of intravenous ketamine does not prevent the occurrence of dNR or POND in elderly patients scheduled for major orthopedic surgery. (Clinicaltrials.gov NCT02892916.).

An immune signature of postoperative cognitive decline in elderly patients.

Postoperative cognitive decline (POCD) is the predominant complication affecting elderly patients following major surgery, yet its prediction and prevention remain challenging. Understanding biological processes underlying the pathogenesis of POCD is essential for identifying mechanistic biomarkers to advance diagnostics and therapeutics. This longitudinal study involving 26 elderly patients undergoing orthopedic surgery aimed to characterize the impact of peripheral immune cell responses to surgical trauma on POCD. Trajectory analyses of single-cell mass cytometry data highlighted early JAK/STAT signaling exacerbation and diminished MyD88 signaling post-surgery in patients who developed POCD. Further analyses integrating single-cell and plasma proteomic data collected before surgery with clinical variables yielded a sparse predictive model that accurately identified patients who would develop POCD (AUC = 0.80). The resulting POCD immune signature included one plasma protein and ten immune cell features, offering a concise list of biomarker candidates for developing point-of-care prognostic tests to personalize perioperative management of at-risk patients. The code and the data are documented and available at https://github.com/gregbellan/POCD . Teaser: Modeling immune cell responses and plasma proteomic data predicts postoperative cognitive decline.

Opinions of French psychiatrists on the regulatory status of cannabis: Results from the "PsyCan - Encéphale" national online survey.

OBJECTIVE: To explore the opinions of French psychiatrists toward the legalization of medical or recreational use of cannabis in France. METHODS: Psycan was an anonymous Internet survey conducted between September 28, 2021 and March 29, 2022, among subscribers of the Encéphale Online community, i.e., approximately 4000 French psychiatrists. Participants were asked to complete a structured questionnaire, collecting their socio-demographic features, clinical experience, opinions toward cannabis legalization, and perceived impact of cannabis derivatives for psychiatric disorders. Logistic regression models were used to identify factors associated with being for or against cannabis legalization. RESULTS: In total, 413 psychiatrists answered the survey, of whom 253 (61.3%) declared being in favour of recreational cannabis, and 349 (84.4%) of medical cannabis. Being in favour of legalization of recreational cannabis was negatively associated with being female (odd ratio [OR]=0.61; 95% confidence interval [CI]=0.41-0.93), and with the frequency of meeting patients with cannabis use disorder (OR=0.60; 95%CI=0.43-0.83). Most respondents were concerned about the development of psychotic disorders. The most frequent pro-legalization arguments were improved prevention, better control of product content, and better protection of youth, respectively. Arguments against legalization were increased societal damages, increased impact on health, including mental health. CONCLUSIONS: A majority of French psychiatrists were in favour of the marketing of medical cannabis, and, to a lesser extent, the legalization of recreational cannabis. For recreational cannabis, the proportion of pro-legalization psychiatrists was slightly more elevated than that found in the French general population.

Esketamine-induced post-traumatic stress disorder flashbacks during treatment-resistant depression indication: is it just a side effect?

Background: Posttraumatic stress disorder (PTSD) is a severe and frequent affection that is highly comorbid to major depressive disorder. Comorbid PTSD and depression are usually treatment-resistant, with a high risk of functional impairment and suicide. Esketamine nasal spray is a recent validated treatment for treatment-resistant depression (TRD), but its efficacy on comorbid TRD-PTSD remains insufficiently documented. In particular, flashbacks can occur during esketamine administration and their influence on clinical outcomes is unknown. Objectives: Our main objective was to describe esketamine-induced traumatic flashbacks and their impact on clinical trajectories within a sample of patients with comorbid TRD-PTSD. Methods: We retrospectively collected clinical data of patients receiving esketamine nasal spray for TRD with comorbid PTSD who experienced at least one flashback of their trauma during esketamine sessions across 11 psychiatric departments. Results: Between February 2020 and March 2023, 22 adult patients with TRD met inclusion criteria. In sixteen patients (72.7%) flashbacks disappeared as the sessions progressed. In six patients (27.3%), esketamine treatment was stopped because of persistent flashbacks. When esketamine was continued, clinical response was observed both for depression and PTSD (depression response rate: 45.5% and remission rate: 22.7%; PTSD response rate: 45.5% and remission: 18.2%). Limitations: The retrospective design of the study and the absence of a comparator group are the main limitations of our study. Conclusions: Our results suggest that the occurrence of esketamine-induced traumatic flashbacks does not hinder clinical response. On the contrary, when managed appropriately and combined with targeted psychotherapy, it could even contribute to positive outcomes.

Pharmacogenetic Guidelines for Psychotropic Drugs: Optimizing Prescriptions in Clinical Practice.

The modalities for prescribing a psychotropic (dose and choice of molecule) are currently unsatisfactory, which can lead to a lack of efficacy of the treatment associated with prolonged exposure of the patient to the symptoms of his or her illness and the side effects of the molecule. In order to improve the quality of treatment prescription, a part of the current biomedical research is dedicated to the development of pharmacogenetic tools for individualized prescription. In this guideline, we will present the genes of interest with level 1 clinical recommendations according to PharmGKB for the two major families of psychotropics: antipsychotics and antidepressants. For antipsychotics, there are CYP2D6 and CYP3A4, and for antidepressants, CYP2B6, CYP2D6, and CYP2C19. The study will focus on describing the role of each gene, presenting the variants that cause functional changes, and discussing the implications for prescriptions in clinical practice.

Early effects predict trajectories of response to esketamine in treatment-resistant depression.

BACKGROUND: The efficacy of esketamine in treatment-resistant depression (TRD) has been confirmed. However, its administration is expensive and restrictive, with limited knowledge on how long the treatment should be continued. Predicting the treatment outcome would benefit patients and alleviate the global treatment cost. We aimed to define distinct trajectories of treatment response and assess their predictability. METHODS: In this longitudinal study, two independent samples of patients with unipolar or bipolar TRD were treated with esketamine in real-world settings. Depression severity was assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS) before each esketamine administration. Latent class analyses were used to define trajectories of response. RESULTS: In the original sample (N = 50), we identified two classes whose trajectories depicted response and non-response, respectively. The model was validated in the confirmatory sample (N = 55). Class membership was influenced by a few baseline characteristics such as concomitant benzodiazepine medication, number of depressive episodes or polarity. On the other hand, after only two esketamine administrations, the MADRS score predicted the 90-day trajectory of response with an accuracy of 80 %. LIMITATIONS: This observational study is not placebo-controlled. Therefore, its results and their generalizability need to be confirmed in experimental settings. CONCLUSIONS: After the first administrations of esketamine, the MADRS score has a good capacity to predict the most plausible trajectory of response. While thresholds and their predictive values need to be confirmed, this finding suggests that clinicians could base on MADRS scores their decision to discontinue treatment because of poor remaining chances of treatment response.

Case Report: Zolpidem's paradoxical restorative action: A case report of functional brain imaging.

Zolpidem is a sedative drug that has been shown to induce a paradoxical effect, restoring brain function in wide range of neurological disorders. The underlying functional mechanism of the effect of zolpidem in the brain in clinical improvement is still poorly understood. Thus, we aimed to investigate rest brain function to study zolpidem-induced symptom improvement in a patient who developed postoperative pediatric cerebellar mutism syndrome, a postoperative complication characterized by delayed onset transient mutism/reduced speech that can occur after medulloblastoma resection. The patient experienced clinical recovery after a single dose of zolpidem. Brain function was investigated using arterial spin labeling MRI and resting-state functional MRI. Imaging was performed at three time-points: preoperative, postoperative during symptoms, and after zolpidem intake when the symptoms regressed. Whole brain rest cerebral blood flow (CBF) and resting state functional connectivity using Pearson coefficient correlations between pairs of regions of interest were investigated two-by-two at the different time points. A comparison between postoperative and preoperative images showed a significant decrease in rest CBF in the left supplementary motor area, Broca's area, and the left striatum and a decrease in functional connectivity within the dentato-thalamo-cortical and cortico-striato-pallido-thalamo-cortical loops. Post-zolpidem images showed increased CBF in the left striatum and increased functional connectivity within the disrupted loops relative to postoperative images. Thus, we observed functional changes within the broader speech network and thalamo-subcortical interactions associated with the paradoxical effect of zolpidem in promoting clinical recovery. This should encourage further functional investigations in the brain to better understand the mechanism of zolpidem in neurological recovery.

Job Strain, Burnout, and Suicidal Ideation in Tenured University Hospital Faculty Staff in France in 2021.

Importance: The ability to attract and retain university hospital faculty staff is in jeopardy because of the high levels of mental symptoms in this professional group. Objective: To examine the prevalence and determinants of symptoms of severe burnout, job strain, and suicidal ideation in tenured associate and full professors in university hospitals. Design, Setting, and Participants: This nationwide cross-sectional study offered online surveys to 5332 tenured university hospital faculty members in France from October 25, 2021, to December 20, 2021. Exposures: Burnout and job strain. Main Outcomes and Measures: Participants completed the 22-item Maslach Burnout Inventory and a 12-item job strain assessment tool, reported suicidal ideation, and used visual analog scales to evaluate unidimensional parameters. The primary outcome was presence of severe burnout symptoms. Factors associated with mental health symptoms were identified by multivariable logistic regression. Results: Completed questionnaires were returned by 2390 of 5332 faculty members (response rate, 45%; range, 43%-46%). Tenured associate professors were a median of 40 (IQR, 37-45) years old with a sex ratio of 1:1, whereas tenured full professors were a median of 53 (IQR, 46-60) years old with a sex ratio of 1:5. Of 2390 respondents, 952 (40%) reported symptoms of severe burnout. Symptoms of job strain (296 professors [12%]) and suicidal ideation (343 professors [14%]) were also reported. Compared with full professors, significantly more associate professors reported feeling overwhelmed at work (496 [73%] vs 972 [57%]; P < .001), considering resignation (365 [54%] vs 834 [49%]; P = .004), or considering a career change (277 [41%] vs 496 [29%]; P < .001). Factors independently associated with less burnout were a longer time being a professor (adjusted odds ratio [aOR], 0.97; 95% CI, 0.96-0.98 per year of age), sleeping well (aOR, 0.88; 95% CI, 0.83-0.92), feeling valued by colleagues (aOR, 0.91; 95% CI, 0.86-0.95 per visual analog scale point) or the public (aOR, 0.92; 95% CI, 0.88-0.96 per visual analog scale point), and accepting more tasks (aOR, 0.82; 95% CI, 0.72-0.93). Factors independently associated with more burnout were having a nonclinical position (OR, 2.48; 95% CI, 1.96-3.16), reporting work encroachment on private life (OR, 1.17; 95% CI, 1.10-1.25), feeling the need to constantly put on a brave face (OR, 1.82; 95% CI, 1.32-2.52), considering a career change (OR, 1.53; 95% CI, 1.22-1.92), and having experienced harassment (OR, 1.52; 95% CI, 1.22-1.88). Conclusions and Relevance: These findings suggest that the psychological burden on tenured university hospital faculty staff in France is considerable. Hospital administrators and health care authorities should urgently develop strategies for burden prevention and alleviation and for attraction of the next generation.

Clinical features and outcomes of COVID-19 patients hospitalized for psychiatric disorders: a French multi-centered prospective observational study.

BACKGROUND: Patients with psychiatric disorders are exposed to high risk of COVID-19 and increased mortality. In this study, we set out to assess the clinical features and outcomes of patients with current psychiatric disorders exposed to COVID-19. METHODS: This multi-center prospective study was conducted in 22 psychiatric wards dedicated to COVID-19 inpatients between 28 February and 30 May 2020. The main outcomes were the number of patients transferred to somatic care units, the number of deaths, and the number of patients developing a confusional state. The risk factors of confusional state and transfer to somatic care units were assessed by a multivariate logistic model. The risk of death was analyzed by a univariate analysis. RESULTS: In total, 350 patients were included in the study. Overall, 24 (7%) were transferred to medicine units, 7 (2%) died, and 51 (15%) patients presented a confusional state. Severe respiratory symptoms predicted the transfer to a medicine unit [odds ratio (OR) 17.1; confidence interval (CI) 4.9-59.3]. Older age, an organic mental disorder, a confusional state, and severe respiratory symptoms predicted mortality in univariate analysis. Age >55 (OR 4.9; CI 2.1-11.4), an affective disorder (OR 4.1; CI 1.6-10.9), and severe respiratory symptoms (OR 4.6; CI 2.2-9.7) predicted a higher risk, whereas smoking (OR 0.3; CI 0.1-0.9) predicted a lower risk of a confusional state. CONCLUSION: COVID-19 patients with severe psychiatric disorders have multiple somatic comorbidities and have a risk of developing a confusional state. These data underline the need for extreme caution given the risks of COVID-19 in patients hospitalized for psychiatric disorders.

Vagus nerve stimulation allows to cease maintenance electroconvulsive therapy in treatment-resistant depression: a retrospective monocentric case series.

Context: The use of vagus nerve stimulation (VNS) to reduce or stop electroconvulsive therapy (ECT) in treatment-resistant depression seems promising. The aim of this study was to investigate the efficacy of VNS on the reduction of ECT sessions and mood stabilization. Methods: We conducted a monocentric retrospective case series of patients who suffered from treatment-resistant depression, treated with ECT and referred to our center for VNS. We investigated the number and the frequency of ECT sessions before and after VNS implantation. Secondary criteria consisted in the Montgomery Åsberg Depression Rating Scale (MADRS) score, number of medical treatments, dosage of the main treatment and length of hospital stays before and after VNS. Additionally, we sent an anonymous survey to psychiatrists and other physicians in our institution to investigate their knowledge and perception of VNS therapy to treat treatment-resistant depression. Results: Seven patients benefited from VNS: six (86%) were female (mean age of 51.7 +/- 16.0 years at surgery), and five (71%) suffered from bipolar depression (three type I and two type II). All patients were followed up at least 2 years post-implantation (range: 27-68 months). Prior to VNS, six patients were treated by maintenance ECT. After VNS, three (43%) patients did not require maintenance ECT anymore, and three (43%) patients required less frequent ECT session with a mean 14.7 +/- 9.8 weeks between sessions after VNS vs. 2.9 +/- 0.8 weeks before VNS. At last follow-up, 4 (57%) patients had stopped ECT. Five (71%) patients implanted with VNS were good responders (50% decrease relative to baseline MADRS). According to the survey, psychiatrists had a significantly better perception and knowledge of ECT, but a worse perception and knowledge of VNS compared to other physicians. Conclusion: VNS is a good option for treatment-resistant depression requiring maintenance ECT dependence. Larger on-going studies will help broaden the implanted patients while strengthening psychiatrists' knowledge on this therapy.

A new ranking index to identify the work-related psychosocial factors most impacting mental health: a cross-sectional study.

OBJECTIVES: In modern professional life, mental health prevention and promotion have become a major challenge for decision-makers. Devising appropriate actions requires better understanding the role played by each work-related psychosocial factor (WPSF). The objective of this study was to present a relevant tool to hierarchise WPSFs that jointly takes into account their importance (impact on mental health) and their prevalence (the proportion of the population exposed to WPSF). DESIGN: A cross-sectional study was conducted in March 2018 among 3200 French workers which are representative of the French working population. SETTING: France. PARTICIPANTS: Individuals aged 18-80 years who declared currently having a job (even a part-time job) whatever their occupation or status (employee or self-employed) were eligible. We excluded students, unemployed individuals, housewives/husbands and retired people. The mental health level was assessed using the General Health Questionnaire-28 and 44 items were gathered from theoretical models of WPSFs. We assessed two distinct multivariate methods for calculating WPSF importance: (1) weifila (weighted first last) method in a linear regression context and (2) random forests in a non-linear context. Both methods were adjusted on individual, health and job characteristics. RESULTS: The WPSF rankings obtained with the two methods to calculate importance are strongly consistent with each other (correlation coefficient=0.88). We highlighted nine WPSFs that are ranked high by both methods. In particular, irrespective of the chosen method, lack of communication, lack of social and hierarchy support and personal-professional life imbalance, emotional demands at work and dissatisfaction with the compensation received came out as top-ranking WPSFs. CONCLUSIONS: A total of nine WPSFs were identified as key for decision-making. The easy-to-use tools we propose can help decision-makers identify priority WPSFs and design effective strategies to promote mental health in the workplace.

Peripheral proteomic changes after electroconvulsive seizures in a rodent model of non-response to chronic fluoxetine.

Major depressive disorder (MDD) is the psychiatric disorder with the highest prevalence in the world. Pharmacological antidepressant treatment (AD), such as selective serotonin reuptake inhibitors [SSRI, i.e., fluoxetine (Flx)] is the first line of treatment for MDD. Despite its efficacy, lack of AD response occurs in numerous patients characterizing Difficult-to-treat Depression. ElectroConvulsive Therapy (ECT) is a highly effective treatment inducing rapid improvement in depressive symptoms and high remission rates of ∼50-63% in patients with pharmaco-resistant depression. Nevertheless, the need to develop reliable treatment response predictors to guide personalized AD strategies and supplement clinical observation is becoming a pressing clinical objective. Here, we propose to establish a proteomic peripheral biomarkers signature of ECT response in an anxio/depressive animal model of non-response to AD. Using an emotionality score based on the analysis complementary behavioral tests of anxiety/depression (Elevated Plus Maze, Novelty Suppressed Feeding, Splash Test), we showed that a 4-week corticosterone treatment (35 µg/ml, Cort model) in C57BL/6JRj male mice induced an anxiety/depressive-like behavior. A 28-day chronic fluoxetine treatment (Flx, 18 mg/kg/day) reduced corticosterone-induced increase in emotional behavior. A 50% decrease in emotionality score threshold before and after Flx, was used to separate Flx-responding mice (Flx-R, n = 18), or Flx non-responder mice (Flx-NR, n = 7). Then, Flx-NR mice received seven sessions of electroconvulsive seizure (ECS, equivalent to ECT in humans) and blood was collected before and after ECS treatment. Chronic ECS normalized the elevated emotionality observed in Flx-NR mice. Then, proteins were extracted from peripheral blood mononuclear cells (PBMCs) and isolated for proteomic analysis using a high-resolution MS Orbitrap. Data are available via ProteomeXchange with identifier PXD037392. The proteomic analysis revealed a signature of 33 peripheral proteins associated with response to ECS (7 down and 26 upregulated). These proteins were previously associated with mental disorders and involved in regulating pathways which participate to the depressive disorder etiology.

Elevated Effort Cost Identified by Computational Modeling as a Distinctive Feature Explaining Multiple Behaviors in Patients With Depression.

BACKGROUND: Motivational deficit is a core clinical manifestation of depression and a strong predictor of treatment failure. However, the underlying mechanisms, which cannot be accessed through conventional questionnaire-based scoring, remain largely unknown. According to decision theory, apathy could result either from biased subjective estimates (of action costs or outcomes) or from dysfunctional processes (in making decisions or allocating resources). METHODS: Here, we combined a series of behavioral tasks with computational modeling to elucidate the motivational deficits of 35 patients with unipolar or bipolar depression under various treatments compared with 35 matched healthy control subjects. RESULTS: The most striking feature, which was observed independent of medication across preference tasks (likeability ratings and binary decisions), performance tasks (physical and mental effort exertion), and instrumental learning tasks (updating choices to maximize outcomes), was an elevated sensitivity to effort cost. By contrast, sensitivity to action outcomes (reward and punishment) and task-specific processes were relatively spared. CONCLUSIONS: These results highlight effort cost as a critical dimension that might explain multiple behavioral changes in patients with depression. More generally, they validate a test battery for computational phenotyping of motivational states, which could orientate toward specific medication or rehabilitation therapy, and thereby help pave the way for more personalized medicine in psychiatry.

How to measure mental pain: a systematic review assessing measures of mental pain.

QUESTION: Although mental pain is present in many mental disorders and is a predictor of suicide, it is rarely investigated in research or treated in care. A valid tool to measure it is a necessary first step towards better understanding, predicting and ultimately relieving this pain. STUDY SELECTION AND ANALYSIS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we performed a systematic review to identify all published standardised measures of mental pain. We used qualitative content analysis to evaluate the similarity of each measure, quantified via Jaccard Index scores ranging from no similarity (0) to full similarity (1). Finally, using the Consensus-based Standards for the selection of health Measurement INstruments (COSMIN) methodology, we evaluated each measure's development (assessing 35 features), its content validity (31 features) and if the latter was rated at least adequate, its other psychometric properties. FINDINGS: We identified 10 self-reported scales of mental pain in 2658 screened studies relying on diverse definitions of this construct. The highest average similarity coefficient for any given measure was 0.24, indicative of weak similarity (individual pairwise coefficients from 0 to 0.5). Little to no information was provided regarding the development and the content validity of all 10 scales. Therefore, their development and content validity were rated 'inadequate' or 'doubtful'. CONCLUSIONS AND CLINICAL IMPLICATIONS: There is not enough evidence of validity to recommend using one measure over others in research or clinical practice. Heterogeneous use of disparate measures across studies limits comparison and combination of their results in meta-analyses. Development by all stakeholders (especially patients) of a consensual patient-reported measure for mental pain is needed. PROSPERO REGISTRATION NUMBER: CRD42021242679.

Efficacy and Safety of Intranasal Esketamine in Patients With Treatment-Resistant Depression and Comorbid Chronic Post-traumatic Stress Disorder: Open-Label Single-Arm Pilot Study.

Introduction: Major depressive disorder (MDD) is more likely to resist to usual treatment when it is associated with post-traumatic stress disorder (PTSD). Capitalizing on the effect of ketamine in both treatment-resistant depression (TRD) and PTSD, we conducted a study in order to assess the efficacy of intranasal (IN) Esketamine in patients having TRD with comorbid PTSD. Materials and Methods: In this open-label, single arm, retrospective pilot study, 11 patients were treated with IN Esketamine (56 or 84 mg) with a longitudinal follow-up of 6 months. IN Esketamine was administered twice weekly during the first month, once weekly during the second month, and then once every 1 or 2 weeks. Patients were assessed with Montgomery-Åsberg Depression Rating Scale (MADRS), Patient Health Questionnaire 9 items, Global Assessment of Functioning (GAF), and Clinical Global Impression-Suicide Scale (CGI-SS). Results: We included 9 women and 2 men (mean age 47.3 ± 11.1 years). The mean (SD) MADRS scores decreased significantly from 38.6 (6.4) at baseline to 18.2 (10.03) after 6 months of IN Esketamine; 7 patients were responders and 3 patients were in remission. The percentage of patients who were moderately to severely suicidal declined from 63.6% at baseline to 27.3% after 1 month of IN Esketamine sessions. No serious adverse reactions were observed. Conclusion: This study reports the outcomes of 11 severely ill patients with comorbid TRD and PTSD after IN Esketamine treatment. Esketamine significantly improved depression symptoms, suggesting that it is likely to be a treatment of choice in this specific population.

Nicotine patches in patients on mechanical ventilation for severe COVID-19: a randomized, double-blind, placebo-controlled, multicentre trial.

PURPOSE: Epidemiologic studies have documented lower rates of active smokers compared to former or non-smokers in symptomatic patients affected by coronavirus disease 2019 (COVID-19). We assessed the efficacy and safety of nicotine administered by a transdermal patch in critically ill patients with COVID-19 pneumonia. METHODS: In this multicentre, double-blind, placebo-controlled trial conducted in 18 intensive care units in France, we randomly assigned adult patients (non-smokers, non-vapers or who had quit smoking/vaping for at least 12 months) with proven COVID-19 pneumonia receiving invasive mechanical ventilation for up to 72 h to receive transdermal patches containing either nicotine at a daily dose of 14 mg or placebo until 48 h following successful weaning from mechanical ventilation or for a maximum of 30 days, followed by 3-week dose tapering by 3.5 mg per week. Randomization was stratified by centre, non- or former smoker status and Sequential Organ Function Assessment score (< or ≥ 7). The primary outcome was day-28 mortality. Main prespecified secondary outcomes included 60-day mortality, time to successful extubation, days alive and free from mechanical ventilation, renal replacement therapy, vasopressor support or organ failure at day 28. RESULTS: Between November 6th 2020, and April 2nd 2021, 220 patients were randomized from 18 active recruiting centers. After excluding 2 patients who withdrew consent, 218 patients (152 [70%] men) were included in the analysis: 106 patients to the nicotine group and 112 to the placebo group. Day-28 mortality did not differ between the two groups (30 [28%] of 106 patients in the nicotine group vs 31 [28%] of 112 patients in the placebo group; odds ratio 1.03 [95% confidence interval, CI 0.57-1.87]; p = 0.46). The median number of day-28 ventilator-free days was 0 (IQR 0-14) in the nicotine group and 0 (0-13) in the placebo group (with a difference estimate between the medians of 0 [95% CI -3-7]). Adverse events likely related to nicotine were rare (3%) and similar between the two groups. CONCLUSION: In patients having developed severe COVID-19 pneumonia requiring invasive mechanical ventilation, transdermal nicotine did not significantly reduce day-28 mortality. There is no indication to use nicotine in this situation.

Preserved Unconscious Processing in Schizophrenia: The Case of Motivation.

BACKGROUND AND HYPOTHESIS: Motivation deficit is a hallmark of schizophrenia that has a strong impact on their daily life. An alteration of reward processing has been repeatedly highlighted in schizophrenia, but to what extent it involves a deficient amplification of reward representation through conscious processing remains unclear. Indeed, patients with schizophrenia exhibit a disruption of conscious processing, whereas unconscious processing appears to be largely preserved. STUDY DESIGN: To further explore the nature of motivational deficit in schizophrenia and the implication of consciousness disruption in this symptom, we used a masking paradigm testing motivation both under conscious and unconscious conditions in patients with schizophrenia (n = 31) and healthy controls (n = 32). Participants were exposed to conscious or subliminal coin pictures representing money at stake and were subsequently asked to perform an effort-task by squeezing a handgrip as hard as possible to win this reward. STUDY RESULTS: We observed a preserved effect of unconscious monetary rewards on force production in both groups, without any significant difference between them. By contrast, in the conscious condition, patients with schizophrenia were less sensitive to rewards than controls. Our results confirm that unconscious incentives have effects on exerted forces in the general population, and demonstrate that patients with schizophrenia exhibit a dissociation between an impaired conscious motivation and a preserved unconscious motivation. CONCLUSIONS: These findings suggest the existence of several steps in motivational processes that can be differentially affected and might have implication for patient care.

Efficacy of Transcranial Direct-Current Stimulation in Catatonia: A Review and Case Series.

Catatonia is a severe neuropsychiatric syndrome, usually treated by benzodiazepines and electroconvulsive therapy. However, therapeutic alternatives are limited, which is particularly critical in situations of treatment resistance or when electroconvulsive therapy is not available. Transcranial direct-current stimulation (tDCS) is a promising non-invasive neuromodulatory technique that has shown efficacy in other psychiatric conditions. We present the largest case series of tDCS use in catatonia, consisting of eight patients in whom tDCS targeting the left dorsolateral prefrontal cortex and temporoparietal junction was employed. We used a General Linear Mixed Model to isolate the effect of tDCS from other confounding factors such as time (spontaneous evolution) or co-prescriptions. The results indicate that tDCS, in addition to symptomatic pharmacotherapies such as lorazepam, seems to effectively reduce catatonic symptoms. These results corroborate a synthesis of five previous case reports of catatonia treated by tDCS in the literature. However, the specific efficacy of tDCS in catatonia remains to be demonstrated in a randomized controlled trial. The development of therapeutic alternatives in catatonia is of paramount importance.