Depression and anxiety before and at the beginning of the COVID-19 pandemic and incident persistent symptoms: a prospective population-based cohort study.

Many patients affected by COVID-19 suffer from debilitating persistent symptoms whose risk factors remained poorly understood. This prospective study examined the association of depression and anxiety symptoms measured before and at the beginning of the COVID-19 pandemic with the incidence of persistent symptoms. Among 25,114 participants [mean (SD) age, 48.72 years (12.82); 51.1% women] from the SAPRIS and SAPRIS-Sérologie surveys nested in the French CONSTANCES population-based cohort, depression and anxiety symptoms were measured with the Center for Epidemiologic Studies-Depression scale and the 12-item General Health Questionnaire before the pandemic, and with the 9-item Patient Health Questionnaire and the 7-Item Generalized Anxiety Disorder scale at the beginning of the pandemic (i.e., between April 6, 2020 and May 4, 2020). Incident persistent symptoms were self-reported between December 2020 and January 2021. The following variables were also considered: gender, age, educational level, household income, smoking status, BMI, hypertension, diabetes, self-rated health, and SARS-CoV-2 infection according to serology/PCR test results. After a follow-up of seven to ten months, 2329 participants (9.3%) had been infected with SARS-CoV-2 and 4262 (17.0%) reported at least one incident persistent symptom that emerged from March 2020, regardless of SARS-CoV-2 infection. In multi-adjusted logistic regression models, participants in the highest (versus the lowest) quartile of depressive or anxiety symptom levels before or at the beginning of the pandemic were more likely to have at least one incident persistent symptom (versus none) at follow-up [OR (95%CI) ranging from 2.10 (1.89-2.32) to 3.01 (2.68-3.37)], with dose-response relationships (p for linear trend <0.001). Overall, these associations were significantly stronger in non-infected versus infected participants, except for depressive symptoms at the beginning of the pandemic. Depressive symptoms at the beginning of the pandemic were the strongest predictor of incident persistent symptoms in both infected and non-infected participants [OR (95%CI): 2.88 (2.01-4.14) and 3.03 (2.69-3.42), respectively]. In exploratory analyses, similar associations were found for each symptom taken separately in different models. Depression and anxiety symptoms should be tested as a potential target for preventive interventions against persistent symptoms after an infection with SARS-CoV-2.

Association of fluvoxamine with mortality and symptom resolution among inpatients with COVID-19 in Uganda: a prospective interventional open-label cohort study.

Prior research suggests that fluvoxamine, a selective serotonin reuptake inhibitor (SSRI) used for the treatment of obsessive-compulsive disorder and major depressive disorder, could be repurposed against COVID-19. We undertook a prospective interventional open-label cohort study to evaluate the efficacy and tolerability of fluvoxamine among inpatients with laboratory-confirmed COVID-19 in Uganda. The main outcome was all-cause mortality. Secondary outcomes were hospital discharge and complete symptom resolution. We included 316 patients, of whom 94 received fluvoxamine in addition to standard care [median age, 60 years (IQR = 37.0); women, 52.2%]. Fluvoxamine use was significantly associated with reduced mortality [AHR = 0.32; 95% CI = 0.19-0.53; p < 0.001, NNT = 4.46] and with increased complete symptom resolution [AOR = 2.56; 95% CI = 1.53-5.51; p < 0.001, NNT = 4.44]. Sensitivity analyses yielded similar results. These effects did not significantly differ by clinical characteristic, including vaccination status. Among the 161 survivors, fluvoxamine was not significantly associated with time to hospital discharge [AHR 0.81, 95% CI (0.54-1.23), p = 0.32]. There was a trend toward greater side effects with fluvoxamine (7.45% versus 3.15%; SMD = 0.21; χ2 = 3.46, p = 0.06), most of which were light or mild in severity and none of which were serious. One hundred mg of fluvoxamine prescribed twice daily for 10 days was well tolerated and significantly associated with reduced mortality and with increased complete symptom resolution, without a significant increase in time to hospital discharge, among inpatients with COVID-19. Large-scale randomized trials are urgently needed to confirm these findings, especially for low- and middle-income countries, where access to vaccines and approved treatments against COVID-19 is limited.

Excess mortality and its causes among older adults with schizophrenia versus those with bipolar disorder and major depressive disorder: a 5-year prospective multicenter study.

Excess mortality observed in people with schizophrenia may persist in later life. The specific causes of increased mortality observed in older adults with schizophrenia and the potential influence of psychotropic medications remain partly unknown. We compared 5-year mortality and its causes of older adults with schizophrenia to bipolar disorder (BD) or major depressive disorder (MDD). We used a 5-year prospective cohort, including 564 older inpatients and outpatients with schizophrenia, BD or MDD (mean age: 67.9 years, SD = 7.2 years). Causes of death were cardiovascular disorder (CVD) mortality, non-CVD disease-related mortality (e.g., infections), suicide, and unintentional injury. The primary analysis was a multivariable logistic model with inverse probability weighting (IPW) to reduce the effects of confounders, including sociodemographic factors, duration and severity of the disorder, and psychiatric and non-psychiatric comorbidity. Five-year all-cause mortality among older participants with schizophrenia and with BD or MDD were 29.4% (n = 89) and 18.4% (n = 45), respectively. Following adjustments, schizophrenia compared to MDD or BD was significantly associated with increased all-cause mortality (AOR = 1.35; 95%CI = 1.04-1.76; p = 0.024) and cardiovascular mortality (AOR = 1.50; 95%CI = 1.13-1.99; p = 0.005). These associations were significantly reduced among patients taking antidepressants [interaction odds ratio (IOR) = 0.42; 95%CI = 0.22-0.79; p = 0.008 and IOR = 0.39: 95%CI = 0.16-0.94; p = 0.035, respectively]. Schizophrenia was associated with higher mortality compared to BD or MDD. Cardiovascular diseases explained most of this excess mortality. Exploratory analyses suggested that psychotropic medications did not influence this excess mortality, except for antidepressants, which were associated with significantly reduced between-group difference in all-cause and cardiovascular mortality.

Toward a generalized developmental model of psychopathological liabilities and psychiatric disorders.

BACKGROUND: Most psychiatric disorders are associated with several risk factors, but a few underlying psychopathological dimensions account for the common co-occurrence of disorders. If these underlying psychopathological dimensions mediate associations of the risk factors with psychiatric disorders, it would support a trans-diagnostic orientation to etiological research and treatment development. METHOD: An analysis was performed of the 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions III (NESARC-III), a US nationally representative sample of non-institutionalized civilian adults, focusing on respondents who were aged ⩾21 (n = 34 712). Structural equation modeling was used to identify the psychopathological dimensions underlying psychiatric disorders; to examine associations between risk factors, psychopathological dimensions and individual disorders; and to test whether associations of risk factors occurring earlier in life were mediated by risk factors occurring later in life. RESULTS: A bifactor model of 13 axis I disorders provided a good fit (CFI = 0.987, TLI = 0.982, and RMSEA = 0.011) including an overall psychopathology factor as measured by all 13 disorders and 2 specific factors, one for externalizing disorders and one for fear-related disorders. A substantial proportion of the total effects of the risk factors occurring early in life were indirectly mediated through factors occurring later in life. All risk factors showed a significant total effect on the general psychopathology, externalizing and fear-related factors. Only 23 of 325 direct associations of risk factors with psychiatric disorders achieved statistical significance. CONCLUSION: Most risk factors for psychiatric disorders are mediated through broad psychopathological dimensions. The central role of these dimensions supports trans-diagnostic etiological and intervention research.

The acid sphingomyelinase/ceramide system in COVID-19.

Acid sphingomyelinase (ASM) cleaves sphingomyelin into the highly lipophilic ceramide, which forms large gel-like rafts/platforms in the plasma membrane. We showed that SARS-CoV-2 uses these platforms for cell entry. Lowering the amount of ceramide or ceramide blockade due to inhibitors of ASM, genetic downregulation of ASM, anti-ceramide antibodies or degradation by neutral ceramidase protected against infection with SARS-CoV-2. The addition of ceramide restored infection with SARS-CoV-2. Many clinically approved medications functionally inhibit ASM and are called FIASMAs (functional inhibitors of acid sphingomyelinase). The FIASMA fluvoxamine showed beneficial effects on COVID-19 in a randomized prospective study and a prospective open-label real-world study. Retrospective and observational studies showed favorable effects of FIASMA antidepressants including fluoxetine, and the FIASMA hydroxyzine on the course of COVID-19. The ASM/ceramide system provides a framework for a better understanding of the infection of cells by SARS-CoV-2 and the clinical, antiviral, and anti-inflammatory effects of functional inhibitors of ASM. This framework also supports the development of new drugs or the repurposing of "old" drugs against COVID-19.

Psychiatric symptoms and mortality in older adults with major psychiatric disorders: results from a multicenter study.

Prior research suggests that certain psychiatric symptoms could be associated with increased risk of death. However, it remains unclear whether this association could rely on all or specific symptoms. In this report, we used data from a multicenter 5-year prospective study (N = 641) of older adults with an ICD-10 diagnosis of schizophrenia, bipolar disorder or major depressive disorder, recruited from French community psychiatric departments. We used a latent variable approach to disentangle the effects shared by all psychiatric symptoms (i.e., general psychopathology factor) and those specific to individual psychiatric symptoms, while adjusting for sociodemographic and clinical factors. Psychiatric symptoms were assessed face-to-face by psychiatrists trained to semi-structured interviews using the Brief Psychiatric Rating Scale (BPRS). Among older adults with major psychiatric disorders, we found that all psychiatric symptoms were associated with increased mortality, and that their effect on the 5-year mortality were exerted mostly through a general psychopathology dimension (ß = 0.13, SE = 0.05, p < 0.05). No BPRS item or lower order factor had a significant effect on mortality beyond and above the effect of the general psychopathology factor. Greater number of medical conditions, older age, male sex, and being hospitalized or institutionalized at baseline were significantly associated with this risk beyond the effect of the general psychopathology factor. Since psychiatric symptoms may affect mortality mainly through a general psychopathology dimension, biological and psychological mechanisms underlying this dimension should be considered as promising targets for interventions to decrease excess mortality of older individuals with psychiatric disorders.

Impact of lithium on mortality among older adults with major psychiatric disorders: A 5-year prospective multicenter study.

OBJECTIVE: Prior studies report conflicting results about the association between lithium use and all-cause mortality. In addition, data are scarce on this association among older adults with psychiatric disorders. In this report, we sought to examine the associations of lithium use with all-cause mortality and specific causes of death (i.e., due to cardiovascular disorder, non-cardiovascular disease, accident, or suicide) among older adults with psychiatric disorders during a 5-year follow-up period. METHODS: In this observational epidemiological study, we used data from 561 patients belonging to a Cohort of individuals with Schizophrenia or Affective disorders aged 55-years or more (CSA). Patients taking lithium at baseline were first compared to patients not taking lithium, and then to patients taking (i) antiepileptics and (ii) atypical antipsychotics in sensitivity analyses. Analyses were adjusted for socio-demographic (e.g., age, gender), clinical characteristics (e.g., psychiatric diagnosis, cognitive functioning), and other psychotropic medications (e.g. benzodiazepines). RESULTS: There was no significant association between lithium use and all-cause mortality [AOR=1.12; 95%CI=0.45-2.79; p=0.810] or disease-related mortality [AOR=1.37; 95%CI=0.51-3.65; p=0.530]. None of the 44 patients taking lithium died from suicide, whereas 4.0% (N=16) of patients not receiving lithium did. CONCLUSION: These findings suggest that lithium may not be associated with all-cause or disease-related mortality and might be associated with reduced risk of suicide in this population. They argue against the underuse of lithium as compared with antiepileptics and atypical antipsychotics among older adults with mood disorders.

Acculturation and Disparities in Telemedicine Readiness: A National Study.

Telemedicine provided older adults the ability to safely seek care during the coronavirus disease (COVID-19) pandemic. This study aimed to evaluate the potential impact of acculturation factors in telemedicine uptake between ethnic groups. As part of the National Health and Aging Trends Study 2018 survey, 303 participants (≥65 years) were interviewed. We assessed the impact of acculturation on telemedicine readiness by race and ethnicity. Compared to the white non-Hispanic immigrant population, Hispanic and Asian/Pacific Islander (API) populations had significantly lower telemedicine readiness and uptake. Limited English proficiency or older age at the time of migration was associated with telemedicine unreadiness and uptake in the Hispanic and API populations. Our findings suggested that acculturation factors play a substantial role in telemedicine uptake among older adult immigrants in the United States. Therefore, acculturation factors should be considered when promoting and adopting telemedicine technologies in older adults.

Inhibition of acid sphingomyelinase by ambroxol prevents SARS-CoV-2 entry into epithelial cells.

The acid sphingomyelinase/ceramide system has been shown to be important for cellular infection with at least some viruses, for instance, rhinovirus or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Functional inhibition of the acid sphingomyelinase using tricyclic antidepressants prevented infection of epithelial cells, for instance with SARS-CoV-2. The structure of ambroxol, that is, trans-4-[(2,4-dibromanilin-6-yl)-methyamino]-cyclohexanol, a mucolytic drug applied by inhalation, suggests that the drug might inhibit the acid sphingomyelinase and thereby infection with SARS-CoV-2. To test this, we used vesicular stomatitis virus pseudoviral particles presenting SARS-CoV-2 spike protein on their surface (pp-VSV-SARS-CoV-2 spike), a bona fide system for mimicking SARS-CoV-2 entry into cells. Viral uptake and formation of ceramide localization were determined by fluorescence microscopy, activity of the acid sphingomyelinase by consumption of [14C]sphingomyelin and ceramide was quantified by a kinase method. We found that entry of pp-VSV-SARS-CoV-2 spike required activation of acid sphingomyelinase and release of ceramide, events that were all prevented by pretreatment with ambroxol. We also obtained nasal epithelial cells from human volunteers prior to and after inhalation of ambroxol. Inhalation of ambroxol reduced acid sphingomyelinase activity in nasal epithelial cells and prevented pp-VSV-SARS-CoV-2 spike-induced acid sphingomyelinase activation, ceramide release, and entry of pp-VSV-SARS-CoV-2 spike ex vivo. The addition of purified acid sphingomyelinase or C16 ceramide restored entry of pp-VSV-SARS-CoV-2 spike into ambroxol-treated epithelial cells. We propose that ambroxol might be suitable for clinical studies to prevent coronavirus disease 2019.

Psychiatric disorders and risk for multiple adverse outcomes: a national prospective study.

Most psychiatric disorders, when examined individually, are associated with a broad range of adverse outcomes. However, psychiatric disorders often co-occur and their co-occurrence is well explained by a limited number of transdiagnostic factors. Yet it remains unclear whether the risk of these adverse outcomes is due to specific psychiatric disorders, specific dimensions of psychopathology (i.e., internalizing and externalizing dimensions), a general psychopathology factor, or a combination of these explanations. In a large nationally representative prospective survey, the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), we used structural equation modeling to examine the shared and specific effects of common Axis I and Axis II disorders on the risk of ten adverse outcomes (unemployment; financial crisis; low income; poorer general health; worse mental and physical health; legal problems; divorce; problems with a neighbor, friend, or relative; and violence) in the general adult population. Effects of psychiatric disorders were exerted mostly through a general psychopathology factor representing the shared effect across all disorders, independent of sociodemographic characteristics and the presence of the adverse outcomes at baseline. Violence and legal problems were further associated with the externalizing factor, but there were no independent associations of the internalizing factor or any individual psychiatric disorders with any of the adverse outcomes. Our findings reveal that associations between psychiatric disorders and adverse outcomes occur through broad psychological dimensions. Understanding the biological and psychological mechanisms underlying these dimensions should yield key intervention targets to decrease the individual suffering and societal burden associated with common psychiatric disorders.

Sleep complaints are associated with increased suicide risk independently of psychiatric disorders: results from a national 3-year prospective study.

Prior research suggests that sleep disturbances are associated with increased risk of suicide. However, sleep disturbances are associated with a wide range of psychiatric disorders, and it is unknown whether this association is independent of psychopathology. In a large nationally representative prospective survey, the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), we used structural equation modeling to examine the shared and specific effects of three sleep complaints (i.e., trouble falling asleep, early morning awakening, and hypersomnia) on the 3-year occurrence of attempting suicide. Because psychiatric disorders increase the risk of suicide attempt almost exclusively through a general psychopathology factor representing their shared effect, covariates included that factor, prior history of suicide attempt, and a wide range of sociodemographic and clinical characteristics. The 3-year prevalence rate of suicide attempt was 0.6% (n = 241). Compared with participants who did not attempt suicide between the two waves, those who did reported significantly more frequently having trouble falling asleep (44.6% vs. 16.6%), early morning awakening (38.9% vs. 12.7%), and hypersomnia (35.0% vs. 10.7%). Following adjustments, effects of sleep complaints on this risk were significant and exerted almost exclusively through a general sleep complaints factor representing the shared effect across all sleep complaints. There were no residual associations of any individual sleep complaint with attempting suicide above that association. Sleep complaints are associated with an increased risk of attempting suicide independently of psychopathology, and should be included in suicide risk assessments as these symptoms may provide targets for reducing the risks of suicidal behaviors.

Association between antidepressant use and reduced risk of intubation or death in hospitalized patients with COVID-19: results from an observational study.

A prior meta-analysis showed that antidepressant use in major depressive disorder was associated with reduced plasma levels of several pro-inflammatory mediators, which have been associated with severe COVID-19. Recent studies also suggest that several antidepressants may inhibit acid sphingomyelinase activity, which may prevent the infection of epithelial cells with SARS-CoV-2, and that the SSRI fluoxetine may exert in-vitro antiviral effects on SARS-CoV-2. We examined the potential usefulness of antidepressant use in patients hospitalized for COVID-19 in an observational multicenter retrospective cohort study conducted at AP-HP Greater Paris University hospitals. Of 7230 adults hospitalized for COVID-19, 345 patients (4.8%) received an antidepressant within 48 h of hospital admission. The primary endpoint was a composite of intubation or death. We compared this endpoint between patients who received antidepressants and those who did not in time-to-event analyses adjusted for patient characteristics, clinical and biological markers of disease severity, and other psychotropic medications. The primary analysis was a multivariable Cox model with inverse probability weighting. This analysis showed a significant association between antidepressant use and reduced risk of intubation or death (HR, 0.56; 95% CI, 0.43-0.73, p < 0.001). This association remained significant in multiple sensitivity analyses. Exploratory analyses suggest that this association was also significant for SSRI and non-SSRI antidepressants, and for fluoxetine, paroxetine, escitalopram, venlafaxine, and mirtazapine (all p < 0.05). These results suggest that antidepressant use could be associated with lower risk of death or intubation in patients hospitalized for COVID-19. Double-blind controlled randomized clinical trials of antidepressant medications for COVID-19 are needed.

Metabolic syndrome and risk of death in older adults with major psychiatric disorders: Results from a 5-year prospective multicenter study.

OBJECTIVES: No study has explored the association of individual components of metabolic syndrome with mortality in older patients with psychiatric disorders. In this report, we examined whether metabolic syndrome or any of its components predicted mortality in a cohort of older adults with psychiatric disorders. METHODS: We used data from a multicenter 5-year prospective cohort, including 634 in- and out-patients with schizophrenia, bipolar or major depressive disorder. Metabolic syndrome was assessed at baseline following NCEP-ATPIII criteria. Cause of death was categorized as cardiovascular disorder (CVD) mortality, non-CVD disease-related mortality (e.g., infections), suicide and accident. RESULTS: 122 participants (44.0%) were diagnosed with metabolic syndrome at baseline. In the full sample, there was no significant association between metabolic syndrome or any of its components with all-cause, CVD and non-CVD mortality. However, for the subpopulation of older adults with major depressive disorder, metabolic syndrome was significantly associated with increased all-cause and disease-related mortality after adjustment for age, sex and smoking status (p = 0.032 and p = 0.036, respectively). There was a significant interaction between metabolic syndrome and psychiatric diagnoses indicating that in participants with major depressive disorder, metabolic syndrome had a significantly greater effect on all-cause mortality (p = 0.025) and on disease-related mortality (p = 0.008) than in participants with either bipolar disorder or schizophrenia. CONCLUSIONS: Our findings do not support an association between metabolic syndrome and increased mortality in older patients with major psychiatric disorders. Several explanations are discussed, including a survival bias, a lack of sensitivity of the used cut-offs and a ceiling effect of metabolic syndrome on mortality in this very high-risk population. The latter hypothesis could also explain the significant association between metabolic syndrome and mortality in the depressive subgroup, where a ceiling effect is yet to be reached, given the less marked premature mortality in depressive patients compared to those with bipolar disorder or schizophrenia.

Retirement age does not modify the association of prior working conditions with self-rated health and mortality in retirees: results from a prospective study of retired French workers.

OBJECTIVE: It is unclear whether retirement age can modify the association of working conditions with health and mortality in retirees who are no longer exposed to these conditions. METHODS: The present study investigated this issue in a cohort of 13,378 French workers in whom self-rated health and mortality were measured over 15 years after statutory retirement. The analyses were also performed in homogenous clusters of workers differentiated on the basis of working conditions, social position, birth and retirement years. RESULTS: Bad working conditions before retirement, which were assessed using a global score combining 25 different occupational exposures, were associated with higher rates of suboptimum self-rated health and mortality in retirees after adjusting for retirement age, social position, demographics and health status before retirement. These rates were also substantially higher in the cluster of workers characterized by bad working conditions in comparison to other clusters. In contrast, retirement age was not associated with self-rated health or mortality after adjusting for working conditions, social position, demographics and health status before retirement. Likewise, no association of retirement age with self-rated health or mortality was found in any cluster of workers and no interactions were observed with any of these clusters. CONCLUSION: These results suggest that bad working conditions before retirement have long-term detrimental effects on health and mortality in retirees and that retirement age does not modulate these effects. Improving work environment rather than modifying retirement age should be prioritized to promote health and reduce mortality not only in workers but also in retirees.

Healthcare use for major depressive disorders among middle-aged and older adults in the community.

PURPOSE: There is a substantial gap between people having a mental disorder and those treated for this disorder. Studies that assessed the influence of age on healthcare use for major depressive disorder (MDD) have provided inconsistent results. We aimed to assess healthcare use in terms of treatment-seeking and psychotropic medication use in four age groups of 45- to 85-year-old community dwellers meeting criteria for MDD. METHODS: Data stemmed from CoLaus|PsyCoLaus, a population-based prospective cohort study. Diagnostic information on mental disorders, utilization of professional healthcare and psychotropic drugs was elicited using a semi-structured interview. Associations between age groups and healthcare use were established using logistic regression models with serial adjustments for socio-demographic and depression characteristics as well as comorbid mental disorders and cardio-metabolic features. RESULTS: Compared to participants of the youngest age group (ages 45 to 54 years), (1) those older than 75 years were less likely to use healthcare from psychiatrists or psychologists (OR: 0.4 [95% CI 0.17-0.96]), although the frequency of using any professional health care did not vary across age groups; (2) those older than 55 years used any psychotropic medication more frequently; and (3) those aged 55-64 years used antidepressants more frequently (OR: 1.61 [95% CI 1.07-2.44]), whereas those aged 65-74 years used anxiolytics more frequently (OR: 2.30 [95% CI 1.15-4.58]). CONCLUSION: Age is a complex biological and social factor that influences healthcare use.

Antiviral and Anti-Inflammatory Activities of Fluoxetine in a SARS-CoV-2 Infection Mouse Model.

The coronavirus disease 2019 (COVID-19) pandemic continues to cause significant morbidity and mortality worldwide. Since a large portion of the world's population is currently unvaccinated or incompletely vaccinated and has limited access to approved treatments against COVID-19, there is an urgent need to continue research on treatment options, especially those at low cost and which are immediately available to patients, particularly in low- and middle-income countries. Prior in vitro and observational studies have shown that fluoxetine, possibly through its inhibitory effect on the acid sphingomyelinase/ceramide system, could be a promising antiviral and anti-inflammatory treatment against COVID-19. In this report, we evaluated the potential antiviral and anti-inflammatory activities of fluoxetine in a K18-hACE2 mouse model of SARS-CoV-2 infection, and against variants of concern in vitro, i.e., SARS-CoV-2 ancestral strain, Alpha B.1.1.7, Gamma P1, Delta B1.617 and Omicron BA.5. Fluoxetine, administrated after SARS-CoV-2 infection, significantly reduced lung tissue viral titres and expression of several inflammatory markers (i.e., IL-6, TNFα, CCL2 and CXCL10). It also inhibited the replication of all variants of concern in vitro. A modulation of the ceramide system in the lung tissues, as reflected by the increase in the ratio HexCer 16:0/Cer 16:0 in fluoxetine-treated mice, may contribute to explain these effects. Our findings demonstrate the antiviral and anti-inflammatory properties of fluoxetine in a K18-hACE2 mouse model of SARS-CoV-2 infection, and its in vitro antiviral activity against variants of concern, establishing fluoxetine as a very promising candidate for the prevention and treatment of SARS-CoV-2 infection and disease pathogenesis.

Combining multivariate genomic approaches to elucidate the comorbidity between autism spectrum disorder and attention deficit hyperactivity disorder.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are two highly heritable neurodevelopmental disorders. Several lines of evidence point towards the presence of shared genetic factors underlying ASD and ADHD. We conducted genomic analyses of common risk variants (i.e. single nucleotide polymorphisms, SNPs) shared by ASD and ADHD, and those specific to each disorder. METHODS: With the summary data from two GWAS, one on ASD (N = 46,350) and another on ADHD (N = 55,374) individuals, we used genomic structural equation modelling and colocalization analysis to identify SNPs shared by ASD and ADHD and SNPs specific to each disorder. Functional genomic analyses were then conducted on shared and specific common genetic variants. Finally, we performed a bidirectional Mendelian randomization analysis to test whether the shared genetic risk between ASD and ADHD was interpretable in terms of reciprocal relationships between ASD and ADHD. RESULTS: We found that 37.5% of the SNPs associated with ASD (at p < 1e-6) colocalized with ADHD SNPs and that 19.6% of the SNPs associated with ADHD colocalized with ASD SNPs. We identified genes mapped to SNPs that are specific to ASD or ADHD and that are shared by ASD and ADHD, including two novel genes INSM1 and PAX1. Our bidirectional Mendelian randomization analyses indicated that the risk of ASD was associated with an increased risk of ADHD and vice versa. CONCLUSIONS: Using multivariate genomic analyses, the present study uncovers shared and specific genetic variants associated with ASD and ADHD. Further functional investigation of genes mapped to those shared variants may help identify pathophysiological pathways and new targets for treatment.

Dexamethasone use and mortality in hospitalized patients with coronavirus disease 2019: A multicentre retrospective observational study.

AIMS: To examine the association between dexamethasone use and mortality among patients hospitalized for COVID-19. METHODS: We examined the association between dexamethasone use and mortality at AP-HP Greater Paris University hospitals. Study baseline was defined as the date of hospital admission. The primary endpoint was time to death. We compared this endpoint between patients who received dexamethasone and those who did not in time-to-event analyses adjusted for patient characteristics (such as age, sex and comorbidity) and clinical and biological markers of clinical severity of COVID-19, and stratified by the need for respiratory support, i.e. mechanical ventilation or oxygen. The primary analysis was a multivariable Cox regression model. RESULTS: Of 12 217 adult patients hospitalized with a positive COVID-19 reverse transcriptase-polymerase chain reaction test, 171 (1.4%) received dexamethasone orally or by intravenous perfusion during the visit. Among patients who required respiratory support, the end-point occurred in 10/63 (15.9%) patients who received dexamethasone and 298/1129 (26.4%) patients who did not. In this group, there was a significant association between dexamethasone use and reduced mortality in the primary analysis (hazard ratio, 0.46; 95% confidence interval 0.22-0.96, P = .039). Among patients who did not require respiratory support, there was no significant association between dexamethasone use and the endpoint. CONCLUSIONS: In this multicentre observational study, dexamethasone use administered either orally or by intravenous injection at a cumulative dose between 60 mg and 150 mg was associated with reduced mortality among patients with COVID-19 requiring respiratory support.

Late-onset and nonlate-onset schizophrenia: A comparison of clinical characteristics in a multicenter study.

OBJECTIVES: Data are scarce regarding the potential clinical differences between non-late onset schizophrenia (NLOS, i.e., disorder occurring before 40 years of age), late-onset schizophrenia (LOS, occurring between ages 40 and 60 years) and very-late-onset schizophrenia-like psychosis (VLOSLP, occurring after 60 years of age). Furthermore, previous research compared LOS patients with non-age matched NLOS patients. In this study, we sought to examine potential clinical differences between patients of similar age with LOS and NLOS. METHODS/DESIGN: This is a cross-sectional multicentre study that recruited in- and outpatients older adults (aged ≥55 years) with an ICD-10 diagnosis of schizophrenia or schizoaffective disorder with NLOS and LOS. Sociodemographic and clinical characteristics, comorbidity, psychotropic medications, quality of life, functioning, and mental health care utilization were drawn for comparison. RESULTS: Two hundred seventy-two participants (79.8%) had NLOS, 61 (17.9%) LOS, and 8 (2.3%) VLOSLP. LOS was significantly and independently associated with greater severity of emotional withdrawal and lower severity of depression (all p < 0.05). However, the magnitude of these associations was modest, with significant adjusted odds ratios ranging from 0.71 to 1.24, and there were no significant between-group differences in other characteristics. CONCLUSION: In an age-matched multicenter sample of elderly patients with schizophrenia, older adults with LOS were largely similar to older adults with NLOS in terms of clinical characteristics. The few differences observed may be at least partially related to symptom fluctuation with time. Implications of these findings for pharmacological and nonpharmacological management is yet to be determined.

A comprehensive model of predictors of quality of life in older adults with schizophrenia: results from the CSA study.

BACKGROUND: Numerous factors are known to influence quality of life of adults with schizophrenia. However, little is known regarding the potential predictors of quality of life in the increasing population of older adults with schizophrenia. The main objective of the present study was to propose a comprehensive model of quality of life in this specific population. METHODS: Data were derived from the Cohort of individuals with Schizophrenia Aged 55 years or more (CSA) study, a large (N = 353) multicenter sample of older adults with schizophrenia or schizoaffective disorder recruited from French community mental-health teams. We used structural equation modeling to simultaneously examine the effects of six broad groups of clinical factors previously identified as potential predictors of quality of life in this population, including (1) severity of general psychopathology, (2) severity of depression, (3) severity of cognitive impairment, (4) psychotropic medications, (5) general medical conditions and (6) sociodemographic characteristics. RESULTS: General psychopathology symptoms, and in particular negative and depressive symptoms, cognitive impairment, reduced overall functioning and low education were significantly and independently associated with diminished quality of life (all p < 0.05). Greater number of medical conditions and greater number of antipsychotics were also independently and negatively associated with quality of life, although these associations did not reach statistical significance in sensitivity analyses, possibly due to limited statistical power. CONCLUSION: Several domains are implicated in quality of life among older adults with schizophrenia. Interventions targeting these factors may help improve importantly quality of life of this vulnerable population.