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.

Trust in sources of information on COVID-19 at the beginning of the pandemic's first wave and incident persistent symptoms in the population-based CONSTANCES cohort: A prospective study.

OBJECTIVE: To examine the association between trust in different sources of information on COVID-19 at the beginning of the pandemic and the burden of incident persistent symptoms. METHODS: This prospective study used data from the SAPRIS and SAPRIS-Sérologie surveys nested in the French CONSTANCES population-based cohort. Trust in different information sources was measured between April 6 and May 4, 2020. Persistent symptoms that emerged afterwards were self-reported between December 2020 and January 2021. The associated psychological burden was measured with the somatic symptom disorder B criteria scale (SSD-12). The analyses were adjusted for gender, age, education, income, self-rated health, SARS-CoV-2 serology tests, and self-reported COVID-19. RESULTS: Among 20,985 participants [mean age (SD), 49.0 years (12.7); 50.2% women], those with higher trust in government/journalists at baseline had fewer incident persistent symptoms at follow-up (estimate (SE) for one IQR increase: -0.21 (0.03), p < 0.001). Participants with higher trust in government/journalists and medical doctors/scientists were less likely to have ≥1 symptom (odds ratio (95% confidence interval) for one IQR increase: 0.87 (0.82-0.91) and 0.91 (0.85-0.98), respectively). Among 3372 participants (16.1%) who reported ≥1 symptom, higher trust in government/journalists and medical doctors/scientists predicted lower SSD-12 scores (-0.39 (0.17), p = 0.02 and - 0.85 (0.24), p < 0.001, respectively), whereas higher trust in social media predicted higher scores in those with lower trust in government/journalists (0.90 (0.34), p = 0.008). These associations did not depend upon surrogate markers of infection with SARS-CoV-2. CONCLUSIONS: Trust in information sources on COVID-19 may be associated with incident persistent symptoms and associated psychological burden, regardless of 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.

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.

Prevalence of Medical Contraindications to Nirmatrelvir/Ritonavir in a Cohort of Hospitalized and Nonhospitalized Patients With COVID-19.

This analysis describes the prevalence of contraindications to nirmatrelvir/ritonavir among 66 007 patients with coronavirus disease 2019 in a large health care system. A possible contradiction was present in 9830 patients (14.8%), with the prevalence of contraindications increasing with higher acuity of illness.

Association between antidepressant use and ED or hospital visits in outpatients with SARS-CoV-2.

Antidepressants have previously been associated with better outcomes in patients hospitalized with COVID-19, but their effect on clinical deterioration among ambulatory patients has not been fully explored. The objective of this study was to assess whether antidepressant exposure was associated with reduced emergency department (ED) or hospital visits among ambulatory patients with SARS-CoV-2 infection. This retrospective cohort study included adult patients (N = 25 034) with a positive SARS-CoV-2 test performed in a non-hospital setting. Logistic regression analyses tested associations between home use of antidepressant medications and a composite outcome of ED visitation or hospital admission within 30 days. Secondary exposures included individual antidepressants and antidepressants with functional inhibition of acid sphingomyelinase (FIASMA) activity. Patients with antidepressant exposure were less likely to experience the primary composite outcome compared to patients without antidepressant exposure (adjusted odds ratio [aOR] 0.89, 95% CI 0.79-0.99, p = 0.04). This association was only observed with daily doses of at least 20 mg fluoxetine-equivalent (aOR 0.87, 95% CI 0.77-0.99, p = 0.04), but not with daily doses lower than 20 mg fluoxetine-equivalent (aOR 0.94, 95% CI 0.80-1.11, p = 0.48). In exploratory secondary analyses, the outcome incidence was also reduced with exposure to selective serotonin reuptake inhibitors (aOR 0.87, 95% CI 0.75-0.99, p = 0.04), bupropion (aOR 0.70, 95% CI 0.55-0.90, p = 0.005), and FIASMA antidepressant drugs (aOR 0.87, 95% CI 0.77-0.99, p = 0.03). Antidepressant exposure was associated with a reduced incidence of emergency department visitation or hospital admission among SARS-CoV-2 positive patients, in a dose-dependent manner. These data support the FIASMA model of antidepressants' effects against COVID-19.

Prevalence of medical contraindications to nirmatrelvir/ritonavir in a cohort of hospitalized and non-hospitalized patients with COVID-19

This analysis describes the prevalence of contraindications to nirmatrelvir/ritonavir among 66,007 patients with COVID-19 in a large health care system. A possible contradiction was present in 9,830 patients (14.8%), with the prevalence of contraindications increasing with higher acuity of illness.

Learning-to-augment incorporated noise-robust deep CNN for detection of COVID-19 in noisy X-ray images.

Deep convolutional neural networks (CNNs) are used for the detection of COVID-19 in X-ray images. The detection performance of deep CNNs may be reduced by noisy X-ray images. To improve the robustness of a deep CNN against impulse noise, we propose a novel CNN approach using adaptive convolution, with the aim to ameliorate COVID-19 detection in noisy X-ray images without requiring any preprocessing for noise removal. This approach includes an impulse noise-map layer, an adaptive resizing layer, and an adaptive convolution layer to the conventional CNN framework. We also used a learning-to-augment strategy using noisy X-ray images to improve the generalization of a deep CNN. We have collected a dataset of 2093 chest X-ray images including COVID-19 (452 images), non-COVID pneumonia (621 images), and healthy ones (1020 images). The architecture of pre-trained networks such as SqueezeNet, GoogleNet, MobileNetv2, ResNet18, ResNet50, ShuffleNet, and EfficientNetb0 has been modified to increase their robustness to impulse noise. Validation on the noisy X-ray images using the proposed noise-robust layers and learning-to-augment strategy-incorporated ResNet50 showed 2% better classification accuracy compared with state-of-the-art method.

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.

Telemedicine Readiness Across Medical Conditions in a US National Representative Sample of Older Adults.

Telemedicine has provided older adults the ability to seek care remotely during the coronavirus disease (COVID-19) pandemic. However, it is unclear how diverse medical conditions play a role in telemedicine uptake. A total of 3379 participants (≥65 years) were interviewed in 2018 as part of the National Health and Aging Trends Study. We assessed telemedicine readiness across multiple medical conditions. Most chronic medical conditions and mood symptoms were significantly associated with telemedicine unreadiness, for physical or technical reasons or both, while cancer, hypertension, and arthritis were significantly associated with telemedicine readiness. Our findings suggest that multiple medical conditions play a substantial role in telemedicine uptake among older adults in the US. Therefore, comorbidities should be taken into consideration when promoting and adopting telemedicine technologies among older adults.

Association of Self-reported COVID-19 Infection and SARS-CoV-2 Serology Test Results With Persistent Physical Symptoms Among French Adults During the COVID-19 Pandemic.

Importance: After an infection by SARS-CoV-2, many patients present with persistent physical symptoms that may impair their quality of life. Beliefs regarding the causes of these symptoms may influence their perception and promote maladaptive health behaviors. Objective: To examine the associations of self-reported COVID-19 infection and SARS-CoV-2 serology test results with persistent physical symptoms (eg, fatigue, breathlessness, or impaired attention) in the general population during the COVID-19 pandemic. Design, Setting, and Participants: Participants in this cross-sectional analysis were 26 823 individuals from the French population-based CONSTANCES cohort, included between 2012 and 2019, who took part in the nested SAPRIS and SAPRIS-SERO surveys. Between May and November 2020, an enzyme-linked immunosorbent assay was used to detect anti-SARS-CoV-2 antibodies. Between December 2020 and January 2021, the participants reported whether they believed they had experienced COVID-19 infection and had physical symptoms during the previous 4 weeks that had persisted for at least 8 weeks. Participants who reported having an initial COVID-19 infection only after completing the serology test were excluded. Main Outcomes and Measures: Logistic regressions for each persistent symptom as the outcome were computed in models including both self-reported COVID-19 infection and serology test results and adjusting for age, sex, income, and educational level. Results: Of 35 852 volunteers invited to participate in the study, 26 823 (74.8%) with complete data were included in the present study (mean [SD] age, 49.4 [12.9] years; 13 731 women [51.2%]). Self-reported infection was positively associated with persistent physical symptoms, with odds ratios ranging from 1.39 (95% CI, 1.03-1.86) to 16.37 (95% CI, 10.21-26.24) except for hearing impairment (odds ratio, 1.45; 95% CI, 0.82-2.55) and sleep problems (odds ratio, 1.14; 95% CI, 0.89-1.46). A serology test result positive for SARS-COV-2 was positively associated only with persistent anosmia (odds ratio, 2.72; 95% CI, 1.66-4.46), even when restricting the analyses to participants who attributed their symptoms to COVID-19 infection. Further adjusting for self-rated health or depressive symptoms yielded similar results. There was no significant interaction between belief and serology test results. Conclusions and Relevance: The findings of this cross-sectional analysis of a large, population-based French cohort suggest that persistent physical symptoms after COVID-19 infection may be associated more with the belief in having been infected with SARS-CoV-2 than with having laboratory-confirmed COVID-19 infection. Further research in this area should consider underlying mechanisms that may not be specific to the SARS-CoV-2 virus. A medical evaluation of these patients may be needed to prevent symptoms due to another disease being erroneously attributed to "long COVID."

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.