Disparities in COVID-19 infection, hospitalisation and death in people with schizophrenia, bipolar disorder, and major depressive disorder: a cohort study of the UK Biobank.

People with severe mental illness (SMI; including schizophrenia/psychosis, bipolar disorder (BD), major depressive disorder (MDD)) experience large disparities in physical health. Emerging evidence suggests this group experiences higher risks of infection and death from COVID-19, although the full extent of these disparities are not yet established. We investigated COVID-19 related infection, hospitalisation and mortality among people with SMI in the UK Biobank (UKB) cohort study. Overall, 447,296 participants from UKB (schizophrenia/psychosis = 1925, BD = 1483 and MDD = 41,448, non-SMI = 402,440) were linked with healthcare and death records. Multivariable logistic regression analysis was used to examine differences in COVID-19 outcomes by diagnosis, controlling for sociodemographic factors and comorbidities. In unadjusted analyses, higher odds of COVID-19 mortality were seen among people with schizophrenia/psychosis (odds ratio [OR] 4.84, 95% confidence interval [CI] 3.00-7.34), BD (OR 3.76, 95% CI 2.00-6.35), and MDD (OR 1.99, 95% CI 1.69-2.33) compared to people with no SMI. Higher odds of infection and hospitalisation were also seen across all SMI groups, particularly among people with schizophrenia/psychosis (OR 1.61, 95% CI 1.32-1.96; OR 3.47, 95% CI 2.47-4.72) and BD (OR 1.48, 95% CI 1.16-1.85; OR 3.31, 95% CI 2.22-4.73). In fully adjusted models, mortality and hospitalisation odds remained significantly higher among all SMI groups, though infection odds remained significantly higher only for MDD. People with schizophrenia/psychosis, BD and MDD have higher risks of COVID-19 infection, hospitalisation and mortality. Only a proportion of these disparities were accounted for by pre-existing demographic characteristics or comorbidities. Vaccination and preventive measures should be prioritised in these particularly vulnerable groups.

Trial Sequential Analysis and Updated Meta-Analysis of Fluvoxamine on Clinical Deterioration in Adult Patients with Symptomatic COVID-19 Infection

Preliminary meta-analyses suggested that fluvoxamine was effective in treating COVID-19 infection. However, the reliability of this evidence has not yet been examined. MEDLINE, CENTRAL, EMBASE, PsycINFO, and ClinicalTrials.gov were searched to identify any randomized controlled trials (RCTs) from the inception of the databases to 5 February 2023. We used trial sequential analysis (TSA) to examine the reliability of the current existing evidence on the benefits of fluvoxamine on COVID-19 infection. The primary outcome was clinical deterioration, as defined in the original study (reported as odds ratio (OR), with 95% confidence intervals), and the secondary outcome was hospitalization. In the TSA, we used the relative risk reduction thresholds of 10, 20, and 30%. The updated meta-analysis of the five RCTs showed that fluvoxamine was not associated with lower odds of clinical deterioration when compared with a placebo (OR: 0.81;0.59–1.11). The effect of fluvoxamine lay within the futility boundary (i.e., lack of effect) when using a 30% relative risk reduction threshold. The effect estimates lay between the superiority and futility boundary using the 10% and 20% threshold, and the required size of information was not reached for these two thresholds. The effect of fluvoxamine on the odds of hospitalization was not statistically significant (0.76;0.56–1.03). In conclusion, there is no reliable evidence that fluvoxamine, when compared to a placebo, reduces the relative risk of clinical deterioration among adult patients with COVID-19 infection by 30%, and a relative risk reduction of 20% or 10% is still uncertain. The role of fluvoxamine as a COVID-19 treatment cannot be justified.

Trial Sequential Analysis and Updated Meta-Analysis of Fluvoxamine on Clinical Deterioration in Adult Patients with Symptomatic COVID-19 Infection.

Preliminary meta-analyses suggested that fluvoxamine was effective in treating COVID-19 infection. However, the reliability of this evidence has not yet been examined. MEDLINE, CENTRAL, EMBASE, PsycINFO, and ClinicalTrials.gov were searched to identify any randomized controlled trials (RCTs) from the inception of the databases to 5 February 2023. We used trial sequential analysis (TSA) to examine the reliability of the current existing evidence on the benefits of fluvoxamine on COVID-19 infection. The primary outcome was clinical deterioration, as defined in the original study (reported as odds ratio (OR), with 95% confidence intervals), and the secondary outcome was hospitalization. In the TSA, we used the relative risk reduction thresholds of 10, 20, and 30%. The updated meta-analysis of the five RCTs showed that fluvoxamine was not associated with lower odds of clinical deterioration when compared with a placebo (OR: 0.81; 0.59-1.11). The effect of fluvoxamine lay within the futility boundary (i.e., lack of effect) when using a 30% relative risk reduction threshold. The effect estimates lay between the superiority and futility boundary using the 10% and 20% threshold, and the required size of information was not reached for these two thresholds. The effect of fluvoxamine on the odds of hospitalization was not statistically significant (0.76; 0.56-1.03). In conclusion, there is no reliable evidence that fluvoxamine, when compared to a placebo, reduces the relative risk of clinical deterioration among adult patients with COVID-19 infection by 30%, and a relative risk reduction of 20% or 10% is still uncertain. The role of fluvoxamine as a COVID-19 treatment cannot be justified.

Heightened COVID-19 Mortality in People With Severe Mental Illness Persists After Vaccination: A Cohort Study of Greater Manchester Residents.

BACKGROUND AND HYPOTHESIS: Previous studies show that people with severe mental illness (SMI) are at higher risk of COVID-19 mortality, however limited evidence exists regarding risk postvaccination. We investigated COVID-19 mortality among people with schizophrenia and other SMIs before, during and after the UK vaccine roll-out. STUDY DESIGN: Using the Greater Manchester (GM) Care Record to access routinely collected health data linked with death records, we plotted COVID-19 mortality rates over time in GM residents with schizophrenia/psychosis, bipolar disorder (BD), and/or recurrent major depressive disorder (MDD) from February 2020 to September 2021. Multivariable logistic regression was used to compare mortality risk (risk ratios; RRs) between people with SMI (N = 193 435) and age-sex matched controls (N = 773 734), adjusted for sociodemographic factors, preexisting comorbidities, and vaccination status. STUDY RESULTS: Mortality risks were significantly higher among people with SMI compared with matched controls, particularly among people with schizophrenia/psychosis (RR 3.18, CI 2.94-3.44) and/or BD (RR 2.69, CI 2.16-3.34). In adjusted models, the relative risk of COVID-19 mortality decreased, though remained significantly higher than matched controls for people with schizophrenia (RR 1.61, CI 1.45-1.79) and BD (RR 1.92, CI 1.47-2.50), but not recurrent MDD (RR 1.08, CI 0.99-1.17). People with SMI continued to show higher mortality rate ratios relative to controls throughout 2021, during vaccination roll-out. CONCLUSIONS: People with SMI, notably schizophrenia and BD, were at greater risk of COVID-19 mortality compared to matched controls. Despite population vaccination efforts that have prioritized people with SMI, disparities still remain in COVID-19 mortality for people with SMI.

A large-scale meta-analytic atlas of mental health problems prevalence during the COVID-19 early pandemic.

The COVID-19 pandemic and related restrictions can impact mental health. To quantify the mental health burden of COVID-19 pandemic, we conducted a systematic review and meta-analysis, searching World Health Organization COVID-19/PsycInfo/PubMed databases (09/29/2020), including observational studies reporting on mental health outcomes in any population affected by COVID-19. Primary outcomes were the prevalence of anxiety, depression, stress, sleep problems, posttraumatic symptoms. Sensitivity analyses were conducted on severe mental health problems, in high-quality studies, and in representative samples. Subgroup analyses were conducted stratified by age, sex, country income level, and COVID-19 infection status. One-hundred-seventy-three studies from February to July 2020 were included (n = 502,261, median sample = 948, age = 34.4 years, females = 63%). Ninety-one percent were cross-sectional studies, and 18.5%/57.2% were of high/moderate quality. The highest prevalence emerged for posttraumatic symptoms in COVID-19 infected people (94%), followed by behavioral problems in those with prior mental disorders (77%), fear in healthcare workers (71%), anxiety in caregivers/family members of people with COVID-19 (42%), general health/social contact/passive coping style in the general population (38%), depression in those with prior somatic disorders (37%), and fear in other-than-healthcare workers (29%). Females and people with COVID-19 infection had higher rates of almost all outcomes; college students/young adults of anxiety, depression, sleep problems, suicidal ideation; adults of fear and posttraumatic symptoms. Anxiety, depression, and posttraumatic symptoms were more prevalent in low-/middle-income countries, sleep problems in high-income countries. The COVID-19 pandemic adversely impacts mental health in a unique manner across population subgroups. Our results inform tailored preventive strategies and interventions to mitigate current, future, and transgenerational adverse mental health of the COVID-19 pandemic.

Neurological, Psychiatric, and Psychological Implications of the COVID-19 Pandemic: Protocol for a Large-Scale Umbrella Review of Observational Studies.

The severe acute respiratory syndrome coronavirus 2 disease (SARS-CoV-2) is the most severe manifestation of the coronavirus disease 2019 (COVID-19) pandemic. Accruing evidence indicates that the COVID-19 pandemic may have profound deleterious neurological, psychiatric, and psychological outcomes. The number of systematic reviews (SRs) and meta-analyses (MAs) on this topic has grown exponentially. This protocol aims to synthesize all evidence from SRs and MAs on the associations between the COVID-19 pandemic and neuropsychiatric outcomes. The following electronic databases will be systematically searched from inception up to 15 January 2022: PubMed, Embase, APA PsycINFO, and Cochrane Reviews. An umbrella review (UR) of SRs and MAs of observational studies will be conducted. SRs and/or MAs of observational studies examining any direct or indirect association of COVID-19 with the neuropsychiatric outcomes will be deemed eligible for potential inclusion in this UR. The direct associations include the impact on the (1) prognosis of COVID-19 and (2) neuropsychiatric sequelae after COVID-19 infection. The indirect associations include the influence of the COVID-19 pandemic on the (1) treatments and (2) outcomes of neurological and psychiatric conditions associated with the COVID-19 pandemic.

The growing field of digital psychiatry: current evidence and the future of apps, social media, chatbots, and virtual reality.

As the COVID-19 pandemic has largely increased the utilization of telehealth, mobile mental health technologies - such as smartphone apps, vir-tual reality, chatbots, and social media - have also gained attention. These digital health technologies offer the potential of accessible and scalable interventions that can augment traditional care. In this paper, we provide a comprehensive update on the overall field of digital psychiatry, covering three areas. First, we outline the relevance of recent technological advances to mental health research and care, by detailing how smartphones, social media, artificial intelligence and virtual reality present new opportunities for "digital phenotyping" and remote intervention. Second, we review the current evidence for the use of these new technological approaches across different mental health contexts, covering their emerging efficacy in self-management of psychological well-being and early intervention, along with more nascent research supporting their use in clinical management of long-term psychiatric conditions - including major depression; anxiety, bipolar and psychotic disorders; and eating and substance use disorders - as well as in child and adolescent mental health care. Third, we discuss the most pressing challenges and opportunities towards real-world implementation, using the Integrated Promoting Action on Research Implementation in Health Services (i-PARIHS) framework to explain how the innovations themselves, the recipients of these innovations, and the context surrounding innovations all must be considered to facilitate their adoption and use in mental health care systems. We conclude that the new technological capabilities of smartphones, artificial intelligence, social media and virtual reality are already changing mental health care in unforeseen and exciting ways, each accompanied by an early but promising evidence base. We point out that further efforts towards strengthening implementation are needed, and detail the key issues at the patient, provider and policy levels which must now be addressed for digital health technologies to truly improve mental health research and treatment in the future.

Implications of the COVID-19 pandemic for people with bipolar disorders: A scoping review.

INTRODUCTION: The COVID-19 (coronavirus disease 2019)-related pandemic represents a global source of societal and health burden. Yet, the impact of the pandemic on people with severe mental illness, including bipolar disorder (BD), remains unclear, warranting scoping review on the matter. METHODS: The MEDLINE and EMBASE databases were systematically searched from inception up to April 24, 2021, adopting broad inclusion criteria to assess a variety of clinical and public health themes related to people with a primary diagnosis of BD during the COVID-19 pandemics. The present work complying with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews (PRISMA-ScR) registered in the Open Science Framework (OSF) repository (https://osf.io/7evpx/). RESULTS: Fourteen papers informed the present scoping review. Four major themes were identified: (i) impact of COVID-19-related stressors on BD; (ii) impact of COVID-19 on mental health service utilization among people with BD; (iii) impact of BD on the risk of acquiring SARS-CoV-2 infection; (iv) engagement in preventative behaviors among people with BD. Additional themes warranting further research were nonetheless detected. LIMITATIONS: Further original studies are needed. CONCLUSION: The present study confirmed the high-vulnerability hypothesis concerning people with BD versus the general population, reinforcing the need for further research related to the COVID-19 pandemic. Additional information is warranted to compare the impact of the pandemic period among BD people against pre-pandemic records, the general population, and other severe mental illnesses, namely people with schizophrenia or major depressive disorder, to inform the public health and the delivery of patient-tailored interventions.

The cytokine storms of COVID-19, H1N1 influenza, CRS and MAS compared. Can one sized treatment fit all?

An analysis of published data appertaining to the cytokine storms of COVID-19, H1N1 influenza, cytokine release syndrome (CRS), and macrophage activation syndrome (MAS) reveals many common immunological and biochemical abnormalities. These include evidence of a hyperactive coagulation system with elevated D-dimer and ferritin levels, disseminated intravascular coagulopathy (DIC) and microthrombi coupled with an activated and highly permeable vascular endothelium. Common immune abnormalities include progressive hypercytokinemia with elevated levels of TNF-α, interleukin (IL)-6, and IL-1ß, proinflammatory chemokines, activated macrophages and increased levels of nuclear factor kappa beta (NFκB). Inflammasome activation and release of damage associated molecular patterns (DAMPs) is common to COVID-19, H1N1, and MAS but does not appear to be a feature of CRS. Elevated levels of IL-18 are detected in patients with COVID-19 and MAS but have not been reported in patients with H1N1 influenza and CRS. Elevated interferon-γ is common to H1N1, MAS, and CRS but levels of this molecule appear to be depressed in patients with COVID-19. CD4+ T, CD8+ and NK lymphocytes are involved in the pathophysiology of CRS, MAS, and possibly H1N1 but are reduced in number and dysfunctional in COVID-19. Additional elements underpinning the pathophysiology of cytokine storms include Inflammasome activity and DAMPs. Treatment with anakinra may theoretically offer an avenue to positively manipulate the range of biochemical and immune abnormalities reported in COVID-19 and thought to underpin the pathophysiology of cytokine storms beyond those manipulated via the use of, canakinumab, Jak inhibitors or tocilizumab. Thus, despite the relative success of tocilizumab in reducing mortality in COVID-19 patients already on dexamethasone and promising results with Baricitinib, the combination of anakinra in combination with dexamethasone offers the theoretical prospect of further improvements in patient survival. However, there is currently an absence of trial of evidence in favour or contravening this proposition. Accordingly, a large well powered blinded prospective randomised controlled trial (RCT) to test this hypothesis is recommended.

The Impact of COVID-19 on Psychiatric Emergency and Inpatient Services in the First Month of the Pandemic in a Large Urban Mental Health Hospital in Ontario, Canada.

The World Health Organization characterized COVID-19 (coronavirus disease 2019) as a pandemic on March 11, 2020 (WHO). Within a couple of days, all Canadian provinces announced the implementation of social distancing measures. We evaluated the immediate effect of COVID-19 on psychiatric emergency and inpatient services in Canada's largest psychiatric hospital in the first month of the pandemic. We extracted data from the electronic medical records of the Center for Addiction and Mental Health in Toronto, Canada. We compared emergency department visits, inpatient occupancy rates, and length of stay in March 2019 and March 2020, and during the first and second half of March 2020. There was a decrease in the number of emergency department visits and inpatient occupancy rates in March 2020 compared to March 2019. There was also a significant decrease in the number of emergency department visits and inpatient occupancy rates in the second half of March 2020 compared to the first half. Our findings suggest that the pandemic was followed by a rapid decrease in the usage of psychiatric emergency and inpatient services in a large mental health hospital. Future studies will need to assess whether this decrease will be followed by a return to baseline or an increase in need for these services.

Can endolysosomal deacidification and inhibition of autophagy prevent severe COVID-19?

The possibility is examined that immunomodulatory pharmacotherapy may be clinically useful in managing the pandemic coronavirus disease 2019 (COVID-19), known to result from infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a positive-sense single-stranded RNA virus. The dominant route of cell entry of the coronavirus is via phagocytosis, with ensconcement in endosomes thereafter proceeding via the endosomal pathway, involving transfer from early (EEs) to late endosomes (LEs) and ultimately into lysosomes via endolysosomal fusion. EE to LE transportation is a rate-limiting step for coronaviruses. Hence inhibition or dysregulation of endosomal trafficking could potentially inhibit SARS-CoV-2 replication. Furthermore, the acidic luminal pH of the endolysosomal system is critical for the activity of numerous pH-sensitive hydrolytic enzymes. Golgi sub-compartments and Golgi-derived secretory vesicles also depend on being mildly acidic for optimal function and structure. Activation of endosomal toll-like receptors by viral RNA can upregulate inflammatory mediators and contribute to a systemic inflammatory cytokine storm, associated with a worsened clinical outcome in COVID-19. Such endosomal toll-like receptors could be inhibited by the use of pharmacological agents which increase endosomal pH, thereby reducing the activity of acid-dependent endosomal proteases required for their activity and/or assembly, leading to suppression of antigen-presenting cell activity, decreased autoantibody secretion, decreased nuclear factor-kappa B activity and decreased pro-inflammatory cytokine production. It is also noteworthy that SARS-CoV-2 inhibits autophagy, predisposing infected cells to apoptosis. It is therefore also suggested that further pharmacological inhibition of autophagy might encourage the apoptotic clearance of SARS-CoV-2-infected cells.

Prevalence and Psychosocial Correlates of Mental Health Outcomes Among Chinese College Students During the Coronavirus Disease (COVID-19) Pandemic.

OBJECTIVES: To investigate the prevalence and risk factors for poor mental health of Chinese university students during the Corona Virus Disease 2019 (COVID-19) pandemic. METHOD: Chinese nation-wide on-line cross-sectional survey on university students, collected between February 12th and 17th, 2020. Primary outcome was prevalence of clinically-relevant posttraumatic stress disorder symptoms. Secondary outcomes on poor mental health included prevalence of clinically-relevant anxiety and depressive symptoms, while posttraumatic growth was considered as indicator of effective coping reaction. RESULTS: Of 2,500 invited Chinese university students, 2,038 completed the survey. Prevalence of clinically-relevant PTSD, anxiety, and depressive symptoms, and post traumatic growth (PTG) was 30.8, 15.5, 23.3, and 66.9% respectively. Older age, knowing people who had been isolated, more ACEs, higher level of anxious attachment, and lower level of resilience all predicted primary outcome (all p < 0.01). CONCLUSIONS: A significant proportion of young adults exhibit clinically relevant posttraumatic stress disorder (PTSD), anxious or depressive symptoms, but a larger portion of individuals showed to effectively cope with COVID-19 pandemic. Interventions promoting resilience should be provided, even remotely, to those subjects with specific risk factors to develop poor mental health during COVID-19 or other pandemics with social isolation.

The pathophysiology of SARS-CoV-2: A suggested model and therapeutic approach.

In this paper, a model is proposed of the pathophysiological processes of COVID-19 starting from the infection of human type II alveolar epithelial cells (pneumocytes) by SARS-CoV-2 and culminating in the development of ARDS. The innate immune response to infection of type II alveolar epithelial cells leads both to their death by apoptosis and pyroptosis and to alveolar macrophage activation. Activated macrophages secrete proinflammatory cytokines and chemokines and tend to polarise into the inflammatory M1 phenotype. These changes are associated with activation of vascular endothelial cells and thence the recruitment of highly toxic neutrophils and inflammatory activated platelets into the alveolar space. Activated vascular endothelial cells become a source of proinflammatory cytokines and reactive oxygen species (ROS) and contribute to the development of coagulopathy, systemic sepsis, a cytokine storm and ARDS. Pulmonary activated platelets are also an important source of proinflammatory cytokines and ROS, as well as exacerbating pulmonary neutrophil-mediated inflammatory responses and contributing to systemic sepsis by binding to neutrophils to form platelet-neutrophil complexes (PNCs). PNC formation increases neutrophil recruitment, activation priming and extraversion of these immune cells into inflamed pulmonary tissue, thereby contributing to ARDS. Sequestered PNCs cause the development of a procoagulant and proinflammatory environment. The contribution to ARDS of increased extracellular histone levels, circulating mitochondrial DNA, the chromatin protein HMGB1, decreased neutrophil apoptosis, impaired macrophage efferocytosis, the cytokine storm, the toll-like receptor radical cycle, pyroptosis, necroinflammation, lymphopenia and a high Th17 to regulatory T lymphocyte ratio are detailed.