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.

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.

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 of 14.6 days (SD=17.9), death occurred in 326/857 (38.0%) patients with a diagnosis of psychiatric disorder versus 1,276/14,311 (8.9%) in patients without such a diagnosis (OR=6.27; 95%CI=5.40-7.28; p<0.01). 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 (AOR=3.27; 95%CI=2.78-3.85; p<0.01). However, additional adjustments for obesity and number of medical conditions resulted in a non-significant association (AOR=1.02; 95%CI=0.84-1.23; p=0.86). Exploratory analyses following the same adjustments suggest 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, but not by the underlying psychiatric disease.

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.

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.

Association between FIASMA psychotropic medications and reduced risk of intubation or death in individuals with psychiatric disorders hospitalized for severe COVID-19: an observational multicenter study.

The acid sphingomyelinase (ASM)/ceramide system may provide a useful framework for better understanding SARS-CoV-2 infection and the repurposing of psychotropic medications functionally inhibiting the acid sphingomyelinase/ceramide system (named FIASMA psychotropic medications) against COVID-19. We examined the potential usefulness of FIASMA psychotropic medications in patients with psychiatric disorders hospitalized for severe COVID-19, in an observational multicenter study conducted at Greater Paris University hospitals. Of 545 adult inpatients, 164 (30.1%) received a FIASMA psychotropic medication upon hospital admission for COVID-19. We compared the composite endpoint of intubation or death between patients who received a psychotropic FIASMA medication at baseline and those who did not in time-to-event analyses adjusted for sociodemographic characteristics, psychiatric and other medical comorbidity, and other medications. FIASMA psychotropic medication use at baseline was significantly associated with reduced risk of intubation or death in both crude (HR = 0.42; 95%CI = 0.31-0.57; p < 0.01) and primary inverse probability weighting (IPW) (HR = 0.50; 95%CI = 0.37-0.67; p < 0.01) analyses. This association was not specific to one FIASMA psychotropic class or medication. Patients taking a FIASMA antidepressant at baseline had a significantly reduced risk of intubation or death compared with those taking a non-FIASMA antidepressant at baseline in both crude (HR = 0.57; 95%CI = 0.38-0.86; p < 0.01) and primary IPW (HR = 0.57; 95%CI = 0.37-0.87; p < 0.01) analyses. These associations remained significant in multiple sensitivity analyses. Our results show the potential importance of the ASM/ceramide system framework in COVID-19 and support the continuation of FIASMA psychotropic medications in these patients and the need of large- scale clinical trials evaluating FIASMA medications, and particularly FIASMA antidepressants, against COVID-19.

Hydroxyzine Use and Mortality in Patients Hospitalized for COVID-19: A Multicenter Observational Study.

(1) Background: Based on its antiviral activity, anti-inflammatory properties, and functional inhibition effects on the acid sphingomyelinase/ceramide system (FIASMA), we sought to examine the potential usefulness of the H1 antihistamine hydroxyzine in patients hospitalized for COVID-19. (2) Methods: In a multicenter observational study, we included 15,103 adults hospitalized for COVID-19, of which 164 (1.1%) received hydroxyzine within the first 48 h of hospitalization, administered orally at a median daily dose of 25.0 mg (SD = 29.5). We compared mortality rates between patients who received hydroxyzine at hospital admission and those who did not, using a multivariable logistic regression model adjusting for patients' characteristics, medical conditions, and use of other medications. (3) Results: This analysis showed a significant association between hydroxyzine use and reduced mortality (AOR, 0.51; 95%CI, 0.29-0.88, p = 0.016). This association was similar in multiple sensitivity analyses. (4) Conclusions: In this retrospective observational multicenter study, the use of the FIASMA hydroxyzine was associated with reduced mortality in patients hospitalized for COVID-19. Double-blind placebo-controlled randomized clinical trials of hydroxyzine for COVID-19 are needed to confirm these results, as are studies to examine the potential usefulness of this medication for outpatients and as post-exposure prophylaxis for individuals at high risk for severe COVID-19.

Association Between FIASMAs and Reduced Risk of Intubation or Death in Individuals Hospitalized for Severe COVID-19: An Observational Multicenter Study.

Several medications commonly used for a number of medical conditions share a property of functional inhibition of acid sphingomyelinase (ASM), or FIASMA. Preclinical and clinical evidence suggest that the ASM/ceramide system may be central to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection. We examined the potential usefulness of FIASMA use among patients hospitalized for severe coronavirus disease 2019 (COVID-19) in an observational multicenter study conducted at Greater Paris University hospitals. Of 2,846 adult patients hospitalized for severe COVID-19, 277 (9.7%) were taking an FIASMA medication at the time of their hospital admission. The primary end point was a composite of intubation and/or death. We compared this end point between patients taking vs. not taking an FIASMA medication in time-to-event analyses adjusted for sociodemographic characteristics and medical comorbidities. The primary analysis was a Cox regression model with inverse probability weighting (IPW). Over a mean follow-up of 9.2 days (SD = 12.5), the primary end point occurred in 104 patients (37.5%) receiving an FIASMA medication, and 1,060 patients (41.4%) who did not. Despite being significantly and substantially associated with older age and greater medical severity, FIASMA medication use was significantly associated with reduced likelihood of intubation or death in both crude (hazard ratio (HR) = 0.71, 95% confidence interval (CI) = 0.58-0.87, P < 0.001) and primary IPW (HR = 0.58, 95%CI = 0.46-0.72, P < 0.001) analyses. This association remained significant in multiple sensitivity analyses and was not specific to one particular FIASMA class or medication. These results show the potential importance of the ASM/ceramide system in COVID-19 and support the continuation of FIASMA medications in these patients. Double-blind controlled randomized clinical trials of these medications for COVID-19 are needed.

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.

Observational study of haloperidol in hospitalized patients with COVID-19.

BACKGROUND: Haloperidol, a widely used antipsychotic, has been suggested as potentially useful for patients with COVID-19 on the grounds of its in-vitro antiviral effects against SARS-CoV-2, possibly through sigma-1 receptor antagonist effect. METHODS: We examined the associations of haloperidol use with intubation or death and time to discharge home among adult patients hospitalized for COVID-19 at Assistance Publique-Hôpitaux de Paris (AP-HP) Greater Paris University hospitals. Study baseline was defined as the date of hospital admission. The primary endpoint was a composite of intubation or death and the secondary endpoint was discharge home among survivors in time-to-event analyses. In the primary analyses, we compared these two outcomes between patients receiving and not receiving haloperidol using univariate Cox regression models in matched analytic samples based on patient characteristics and other psychotropic medications. Sensitivity analyses included propensity score analyses with inverse probability weighting and multivariable Cox regression models. RESULTS: Of 15,121 adult inpatients with a positive COVID-19 PT-PCR test, 39 patients (0.03%) received haloperidol within the first 48 hours of admission. Over a mean follow-up of 13.8 days (SD = 17.9), 2,024 patients (13.4%) had a primary end-point event and 10,179 patients (77.6%) were discharged home at the time of study end on May 1st. The primary endpoint occurred in 9 patients (23.1%) who received haloperidol and 2,015 patients (13.4%) who did not. The secondary endpoint of discharge home occurred in 16 patients (61.5%) who received haloperidol and 9,907 patients (85.8%) who did not. There were no significant associations between haloperidol use and the primary (HR, 0.80; 95% CI, 0.39 to 1.62, p = 0.531) and secondary (HR, 1.30; 95% CI, 0.74 to 2.28, p = 0.355) endpoints. Results were similar in multiple sensitivity analyses. CONCLUSION: Findings from this multicenter observational study suggest that haloperidol use prescribed at a mean dose of 4.5 mg per day (SD = 5.2) for a mean duration of 8.4 days (SD = 7.2) may not be associated with risk of intubation or death, or with time to discharge home, among adult patients hospitalized for COVID-19.

Observational Study of Chlorpromazine in Hospitalized Patients with COVID-19.

INTRODUCTION: Chlorpromazine has been suggested as being potentially useful in patients with coronavirus disease 2019 (COVID-19) on the grounds of its potential antiviral and anti-inflammatory effects. OBJECTIVE: The aim of this study was to examine the association between chlorpromazine use and mortality among adult patients hospitalized for COVID-19. METHODS: We conducted an observational, multicenter, retrospective study at Assistance Publique-Hôpitaux de Paris (AP-HP) Greater Paris University hospitals. Study baseline was defined as the date of first prescription of chlorpromazine during hospitalization for COVID-19. The primary endpoint was death. Among patients who had not been hospitalized in intensive care units (ICUs), we compared this endpoint between those who received chlorpromazine and those who did not, in time-to-event analyses adjusted for patient characteristics, clinical markers of disease severity, and other psychotropic medications. The primary analysis used a Cox regression model with inverse probability weighting. Multiple sensitivity analyses were performed. RESULTS: Of the 14,340 adult inpatients hospitalized outside ICUs for COVID-19, 55 patients (0.4%) received chlorpromazine. Over a mean follow-up of 14.3 days (standard deviation [SD] 18.2), death occurred in 13 patients (23.6%) who received chlorpromazine and 1289 patients (9.0%) who did not. In the primary analysis, there was no significant association between chlorpromazine use and mortality (hazard ratio [HR] 2.01, 95% confidence interval [CI] 0.75-5.40; p = 0.163). Sensitivity analyses included a Cox regression in a 1:5 ratio matched analytic sample that showed a similar result (HR 1.67, 95% CI 0.91-3.06; p = 0.100) and a multivariable Cox regression that indicated a significant positive association (HR 3.10, 95% CI 1.31-7.34; p = 0.010). CONCLUSION: Our results suggest that chlorpromazine prescribed at a mean daily dose of 70.8 mg (SD 65.3) was not associated with reduced mortality.

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.