Burnout Mediates the Association Between Workaholism and Substance Use: Findings from a French National Company.

To examine the mediation effect of burnout on the association between workaholism and tobacco and alcohol use. A total of 2199 workers from the French national electricity company fulfilled an online questionnaire. Smoking status, alcohol use disorder based on the Alcohol Use Disorders Identification Test-Consumption and workaholism based on the Work Addiction Risk Test were used as binary variables. Burnout was assessed as a continuous variable with the Copenhagen Burn-Out Inventory. Mediation analyses tested the direct effect of the associations between workaholism and each substance use, as well as the indirect effect passing through burnout, while adjusting for sociodemographic factors (gender, age, occupational grade and marital life), work stress using the effort-reward imbalance and overcommitment. When testing the mediation effect of burnout on the relation between workaholism and smoking, there was a significant direct effect of workaholism on smoking (Estimated effect of 0.27 [95% CI 0.01; 0.54]) and a significant indirect effect passing through burnout (Estimated effect of 0.09 [95% CI 0.02; 0.15]). When testing the mediation effect of burnout on the relation between workaholism and alcohol use, the direct effect of workaholism on alcohol use was not significant (Estimated effect of 0.21 [95% CI - 0.01; 0.44]) while the indirect effect passing through burnout was significant (Estimated effect of 0.10 [95% CI 0.04; 0.17]). Information and prevention regarding substance use should be reinforced among workers exposed to workaholism, especially if their workaholism led to a high level of burnout. Preventing the emergence of burnout among workaholics might have some benefits on their tobacco and alcohol use.

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.

Antipsychotic use and 28-day mortality in patients hospitalized with COVID-19: A multicenter observational retrospective study.

Prior research has yielded conflicting results about the potential influence of antipsychotics in patients with COVID-19. In this multicenter retrospective study, we examined the association of antipsychotic use at admission with 28-day all-cause mortality in a sample of 59,021 adult patients hospitalized with COVID-19 from January 2020 to November 2021. In a 1:1 ratio matched analytic sample (N=1,454) accounting for age, sex, hospital, hospitalization period, the Elixhauser Comorbidity Index, other psychotropic medications, medications prescribed according to compassionate use or as part of a clinical trial, current diagnoses of psychiatric disorders, and clinical and biological markers of COVID-19 severity, antipsychotic use was not associated with 28-day mortality [23.5% (N=727) versus 18.6% (N=727); OR=1.16; 95%CI=0.89-1.51; p=0.280]. This association remained non-significant in exploratory analyses across all classes of antipsychotics and individual molecules, except for typical antipsychotics and loxapine, which were significantly linked to increased 28-day mortality, associations likely due to residual indication bias. Contrariwise, antipsychotics prescribed at daily doses higher than 200 mg of chlorpromazine-equivalents might be associated with reduced 28-day mortality when compared to patients not taking antipsychotics in the matched analytic sample [10.4% (N=154) versus 18.6% (N=727); AOR=0.56; 95%CI=0.31-0.96; p=0.040]. These results suggest that antipsychotic use, when prescribed at usual doses, are not be associated with 28-day mortality in patients hospitalized with COVID-19.

Medications Modulating the Acid Sphingomyelinase/Ceramide System and 28-Day Mortality among Patients with SARS-CoV-2: An Observational Study.

Prior evidence indicates the potential central role of the acid sphingomyelinase (ASM)/ceramide system in the infection of cells with SARS-CoV-2. We conducted a multicenter retrospective observational study including 72,105 adult patients with laboratory-confirmed SARS-CoV-2 infection who were admitted to 36 AP-HP (Assistance Publique-Hôpitaux de Paris) hospitals from 2 May 2020 to 31 August 2022. We examined the association between the ongoing use of medications functionally inhibiting acid sphingomyelinase (FIASMA), which reduces the infection of cells with SARS-CoV-2 in vitro, upon hospital admission with 28-day all-cause mortality in a 1:1 ratio matched analytic sample based on clinical characteristics, disease severity and other medications (N = 9714). The univariate Cox regression model of the matched analytic sample showed that FIASMA medication use at admission was associated with significantly lower risks of 28-day mortality (HR = 0.80; 95% CI = 0.72-0.88; p < 0.001). In this multicenter observational study, the use of FIASMA medications was significantly and substantially associated with reduced 28-day mortality among adult patients hospitalized with COVID-19. These findings support the continuation of these medications during the treatment of SARS-CoV-2 infections. Randomized clinical trials (RCTs) are needed to confirm these results, starting with the molecules with the greatest effect size in the study, e.g., fluoxetine, escitalopram, and amlodipine.

Peer bullying victimization in adolescence is associated with substance use: cross-sectional findings from French high school students.

The relationships between peer bullying victimization in adolescence and substance use have been poorly studied. Thus, we examined the associations between peer bullying victimization and tobacco, alcohol and cannabis use in 496 French high school students. Peer bullying victimization was measured with a 17-item standardized assessment and analyzed as quartiles. Tobacco, alcohol, and cannabis use were assessed with the Hooked on Nicotine Checklist (HONC), the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) and the Cannabis Abuse Screening Test (CAST), respectively. Total scores at the HONC (0 to 10), AUDIT-C (0 to 12), and CAST (0 to 24) were used as dependent variables in generalized linear models, adjusting for sex, age, prepared graduation, last school marks and friends outside high school. Compared to the first quartile (i.e., the least bullied students), those from the second, third and fourth quartiles had significant increase of the AUDIT-C (B = 0.78 [95%CI 0.17-1.40] with p = 0.013; B = 0.86 [95%CI 0.26;1.46] with p = 0.005 and B = 1.00 [95%CI 0.38;1.62] with p = 0.002, respectively), with dose-dependent relationships (B = 0.33 ([95%CI 0.13; 0.52] with p = 0.001). Those from the fourth quartile had a significant increase of the CAST (B = 2.13[95%CI 1.25;3.01], p < 0.001). When examining the role of peer bullying victimization on the number of substances used, there were significant increased odds for students from the third and fourth quartiles, with dose-dependent relationships (OR = 1.24 [95% CI 1.07;1.44], p = 0.005). These findings encourage paying a particular attention to substance use in students who report being bullied. Consequently, information and prevention using standardized screening tools should be proposed. Conversely, substance use could be an indicator of peer bullying victimization and should thus be explored.

Comorbidity patterns and mortality among hospitalized patients with psychiatric disorders and COVID-19

Objectives: To examine the association between psychiatric and non-psychiatric comorbidity and 28-day mortality among patients with psychiatric disorders and COVID-19. Methods: Multicenter observational retrospective cohort study of adult patients with psychiatric disorders hospitalized with laboratory-confirmed COVID-19 at 36 Greater Paris university hospitals (January 2020-May 2021) (n=3,768). First, we searched for different subgroups of patients according to their psychiatric and non-psychiatric comorbidities through cluster analysis. Next, we compared 28-day all-cause mortality rates across the identified clusters, while taking into account sex, age, and the number of medical conditions. Results: We found five clusters of patients with distinct psychiatric and non-psychiatric comorbidity patterns. Twenty-eight-day mortality in the cluster of patients with mood disorders was significantly lower than in other clusters. There were no significant differences in mortality across other clusters. Conclusion: All psychiatric and non-psychiatric conditions may be associated with increased mortality in patients with psychiatric disorders and COVID-19. The lower risk of death among patients with mood disorders might be in line with the potential beneficial effect of certain antidepressants in COVID-19, but requires further research. These findings may help identify at-risk patients with psychiatric disorders who should benefit from vaccine booster prioritization and other prevention measures.

[Depression in older adults. What are the differences in clinical practice?] / Dépression du sujet âgé. Quelles différences de prise en charge en pratique ?

BACKGROUND: Management of depression in the elderly is a growing public health issue in France. The objective of this study was to compare practitioners' perception of depression severity (i.e., intensity and suicidal risk) and clinical practice (i.e., clinical assessment and medication choice) in elderly versus younger adult patients with major depression. MATERIALS AND METHOD: The method consisted of an online questionnaire completed by general practitioners and psychiatrists. Respondents'answers to a fictive case of a patient with major depression were randomized according to the patient's age, if the patient'age was either 40 or 70 years old. We assessed the perceived intensity of the depression, the perceived suicidal risk, the prescription of biological tests and cerebral imaging, and of antidepressive or other psychotropic medications. 102 completed forms were included. Data indicate that there were no significant differences in terms of perceived depression intensity and suicidal risk according to the patients'age. The prescription of biological tests was systematic in both groups, but a significant difference was observed in terms of prescription of brain imaging (71% of respondents for the 70-year-old patient versus 43% for the 40-year-old patient, p < 0.005), use of tetracyclic antidepressant (33% if aged 70 years versus 2% if aged 40 years, p < 0.001) and other psychotropic non-antidepressant medications (69% if aged 70 years versus 85% if aged 40 years, p < 0.05). This study did not show any significant difference in the perception of depression according to age. However, it highlights differences in terms of practical care according to age. These results suggest a partial gap between clinical practice and guidelines for the management of major depression in older adults, reflecting the need to favor the dissemination of guidelines and strengthen research for this population.

Comorbidity Patterns and Mortality Among Hospitalized Patients with Psychiatric Disorders and COVID-19.

OBJECTIVE: To examine the association between psychiatric and non-psychiatric comorbidity and 28-day mortality among patients with psychiatric disorders and COVID-19. METHODS: We performed a multicenter observational retrospective cohort study of adult patients with psychiatric disorders hospitalized with laboratory-confirmed COVID-19 at 36 Greater Paris University hospitals (January 2020-May 2021) (N=3,768). First, we searched for different subgroups of patients according to their psychiatric and non-psychiatric comorbidities through cluster analysis. Next, we compared 28-day all-cause mortality rates across the identified clusters, while taking into account sex, age, and the number of medical conditions. RESULTS: We found 5 clusters of patients with distinct psychiatric and non-psychiatric comorbidity patterns. Twenty-eight-day mortality in the cluster of patients with mood disorders was significantly lower than in other clusters. There were no significant differences in mortality across other clusters. CONCLUSIONS: All psychiatric and non-psychiatric conditions may be associated with increased mortality in patients with psychiatric disorders and COVID-19. The lower risk of death among patients with mood disorders might be in line with the potential beneficial effect of certain antidepressants in COVID-19, but requires further research. These findings help identify at-risk patients with psychiatric disorders who should benefit from vaccine booster prioritization and other prevention measures.

Magnesium in the treatment of alcohol withdrawal syndrome: a multicenter randomized controlled trial.

OBJECTIVE: Alcohol withdrawal syndrome (AWS) is a frequent and potentially life-threatening condition experienced in alcohol use disorder. Since hypomagnesemia is involved in AWS's severity, we conducted a multicenter double-blind randomized placebo-controlled trial to examine the efficacy of oral magnesium supplementation as an adjuvant therapy of AWS. MATERIAL AND METHODS: Inpatients were recruited in six different centers if they had a baseline score higher than eight on the Revised Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar). The experimental treatment was magnesium lactate dehydrate, administrated three times per day providing a total of 426.6 mg per day and up to 15 days. The primary endpoint was the significant between-group difference of the CIWA-Ar total score change from baseline to 3 days later. The treatment group and baseline score were introduced as covariables in an analysis of covariance. RESULTS: A total of 98 inpatients were included {71.4% of men; mean age of 49.1 years [standard deviation (SD): 10.3]}. In the intention-to-treat population, the mean reduction of the CIWA-Ar score in the experimental group between baseline and 3 days later was 10.1 (SD: 5.2), whereas it was 9.2 (SD: 3.9) in the control group. The absolute difference of the adjusted mean in the experimental group compared with the control group was -0.69 (SD: 0.72), which did not correspond to a significant between-group difference (P = 0.34). Per-protocol analysis and sensitivity analyses also supported this result. Supplementary analyses found no significant difference regarding benzodiazepine consumption, magnesium blood concentration, and satisfaction to care. CONCLUSIONS: The present study does not support the rationale of systematic oral magnesium supplementation in patients with AWS.

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.

Using filled prescription sequences to rank antidepressants: A nationwide replication study.

Ranking antidepressants according to their acceptability (i.e., a combination of both efficacy and tolerability) in the general population may help choosing the best first-line medication. This study aimed to replicate the results of a proof-of-concept study ranking anti-depressants according to the proportion of filled prescription sequences consistent with a continuation of the first treatment versus those consistent with a change. We used a nationwide cohort from the French national health data system (SNDS) to support the use of this method as a widely available tool to rank antidepressant treatments in real life settings. About 1.2 million people were identified as new antidepressant users in the SNDS in 2011. The outcome was clinical acceptability as measured by the continuation/failure ratio over the six-month period following the introduction of the first-line treatment. Continuation was defined as at least two refills of the same treatment. Failure was defined as a psychiatric hospitalization, death or at least one filled prescription of another antidepressant, an antipsychotic medication, or a mood-stabilizer. Adjusted Odds Ratios (aOR) and 95% Confidence Interval (CI) were computed through multivariable binary logistic regressions. We ranked antidepressant medications according to clinical acceptability. Escitalopram again was the most acceptable option, and the five following antidepressants were the same as in the replication sample of the proof-of-concept study, in order Fluoxetine, Paroxetine, Sertraline, Citalopram and Venlafaxine with aOR (95% CI) for continuation ranging from 0.79 (0.77-0.81) to 0.66 (0.64-0.67). The present study provides evidence that filled prescription sequences is a widely available, robust and reproductible tool to rank antidepressant treatments in real life settings.

Risk of Death in Individuals Hospitalized for COVID-19 With and Without Psychiatric Disorders: An Observational Multicenter Study in France.

Background: Prior research suggests that psychiatric disorders could be linked to increased mortality among patients with COVID-19. However, whether all or specific psychiatric disorders are intrinsic risk factors of death in COVID-19 or whether these associations reflect the greater prevalence of medical risk factors in people with psychiatric disorders has yet to be evaluated. Methods: We performed an observational, multicenter, retrospective cohort study to examine the association between psychiatric disorders and mortality among patients hospitalized for laboratory-confirmed COVID-19 at 36 Greater Paris University hospitals. Results: Of 15,168 adult patients, 857 (5.7%) had an ICD-10 diagnosis of psychiatric disorder. Over a mean follow-up period of 14.6 days (SD = 17.9), 326 of 857 (38.0%) patients with a diagnosis of psychiatric disorder died compared with 1276 of 14,311 (8.9%) patients without such a diagnosis (odds ratio 6.27, 95% CI 5.40-7.28, p < .01). When adjusting for age, sex, hospital, current smoking status, and medications according to compassionate use or as part of a clinical trial, this association remained significant (adjusted odds ratio 3.27, 95% CI 2.78-3.85, p < .01). However, additional adjustments for obesity and number of medical conditions resulted in a nonsignificant association (adjusted odds ratio 1.02, 95% CI 0.84-1.23, p = .86). Exploratory analyses after the same adjustments suggested that a diagnosis of mood disorders was significantly associated with reduced mortality, which might be explained by the use of antidepressants. Conclusions: These findings suggest that the increased risk of COVID-19-related mortality in individuals with psychiatric disorders hospitalized for COVID-19 might be explained by the greater number of medical conditions and the higher prevalence of obesity in this population and not by the underlying psychiatric disease.

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.

Sleep Complaints Among Adults With Major Depressive Episode Are Associated With Increased Risk of Incident Psychiatric Disorders: Results From a Population-Based 3-Year Prospective Study.

Objective: Sleep alterations have been suggested as a cause and consequence of psychiatric disorders. In this context, we evaluated the incidence of psychiatric disorders following sleep complaints in adults with major depressive episode (MDE).Methods: In a large, nationally representative 3-year prospective survey, the National Epidemiologic Survey on Alcohol and Related Conditions conducted in 2001-2002 (Wave 1) and 2004-2005 (Wave 2), we used structural equation modeling to examine shared and specific effects of trouble falling asleep, early morning awakening, and hypersomnia on incidence of common comorbid DSM-IV disorders among patients with MDE. The analyses adjusted for sociodemographic and clinical characteristics, including sedative or tranquilizer use.Results: Among participants with MDE at Wave 1, 3-year incidence rates were dysthymia = 2.9%, general anxiety disorder = 8.2%, panic disorder = 3.4%, social anxiety disorder = 4.0%, specific phobia = 3.0%, alcohol use disorder = 8.1%, nicotine dependence = 6.2%, cannabis use disorder = 2.7%, and other drug use disorder = 4.9%. Participants with 3-year incident psychiatric disorders commonly had trouble falling asleep (67.6% for cannabis use disorder to 76.4% for panic disorder), early morning awakening (43.3% for cannabis use disorder to 55.6% for dysthymia), and hypersomnia (51.3% for nicotine use disorder to 72.1% for social anxiety disorder). The effects of the incident general psychopathology factor, representing mechanisms related to incidence of all psychiatric disorders, were exerted almost exclusively through a factor representing shared effect across all sleep complaints. Sleep complaints were associated with increased risk of incident psychiatric disorders, independent of sociodemographic and clinical characteristics.Conclusions: These findings suggest that sleep complaints should be clinically assessed in all psychiatric disorders, as these prodromal symptoms might constitute transdiagnostic biomarkers and therapeutic targets for prevention.

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.

Prevalence of Contraindications to Nirmatrelvir-Ritonavir Among Hospitalized Patients With COVID-19 at Risk for Progression to Severe Disease.

This cohort study examines the prevalence of contraindications to nirmatrelvir-ritonavir in patients hospitalized with COVID-19.

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.

Acceptability of Second-Line Antidepressant Medications Using Filled Prescription Sequences in a Nationwide Cohort Study.

Background: Although about half of patients do not respond to a first-line antidepressant medication, there is no consensus on the best second-line option. The aim of this nationwide population-based study was to rank antidepressants according to their relative acceptability (ie, efficacy and tolerability) using filled prescription sequences after failure of first treatment.Methods: About 1.2 million people were identified as new antidepressant users in the French national health data system in 2011. The inclusion criterion was having at least 2 filled prescriptions of a second-line treatment after a filled prescription of a first-line treatment, resulting in 63,726 participants. The outcome was clinical acceptability as measured by the continuation/change ratio for second-line treatment. Continuation sequence was defined as at least 2 refills of the same treatment. Change sequence was defined as at least 1 filled prescription of another antidepressant. Adjusted odds ratios (aORs) were computed through multivariable binary logistic regressions.Results: Intraclass switch had a better acceptability than interclass switch (aOR [95% CI]: 1.23 [1.20-1.28]). According to the first-line treatment, intraclass switch remained more acceptable for selective serotonin reuptake inhibitors only (1.37 [1.31-1.42]). For α2 blockers and tricyclic agents, combination antidepressant therapy was the most acceptable second-line option (1.59 [1.27-2.01] and 2.53 [1.53-4.04], respectively), whereas for serotonin-norepinephrine reuptake inhibitors there was no significant difference between the strategies. For other antidepressants, intraclass switch had lower acceptability than interclass switch (0.70 [0.51-0.95]).Conclusions: Administrative claim databases may help with ranking acceptability of second-line treatments in real world settings and complement randomized controlled trials in informing clinicians about the most acceptable second-line options according to the first-line treatment.

Antidepressant Use and Its Association with 28-Day Mortality in Inpatients with SARS-CoV-2: Support for the FIASMA Model against COVID-19.

To reduce Coronavirus Disease 2019 (COVID-19)-related mortality and morbidity, widely available oral COVID-19 treatments are urgently needed. Certain antidepressants, such as fluvoxamine or fluoxetine, may be beneficial against COVID-19. We included 388,945 adult inpatients who tested positive for SARS-CoV-2 at 36 AP−HP (Assistance Publique−Hôpitaux de Paris) hospitals from 2 May 2020 to 2 November 2021. We compared the prevalence of antidepressant use at admission in a 1:1 ratio matched analytic sample with and without COVID-19 (N = 82,586), and assessed its association with 28-day all-cause mortality in a 1:1 ratio matched analytic sample of COVID-19 inpatients with and without antidepressant use at admission (N = 1482). Antidepressant use was significantly less prevalent in inpatients with COVID-19 than in a matched control group of inpatients without COVID-19 (1.9% versus 4.8%; Odds Ratio (OR) = 0.38; 95%CI = 0.35−0.41, p < 0.001). Antidepressant use was significantly associated with reduced 28-day mortality among COVID-19 inpatients (12.8% versus 21.2%; OR = 0.55; 95%CI = 0.41−0.72, p < 0.001), particularly at daily doses of at least 40 mg fluoxetine equivalents. Antidepressants with high FIASMA (Functional Inhibitors of Acid Sphingomyelinase) activity seem to drive both associations. These treatments may reduce SARS-CoV-2 infections and COVID-19-related mortality in inpatients, and may be appropriate for prophylaxis and/or COVID-19 therapy for outpatients or inpatients.