Impact of elevated body mass index (BMI) on cognitive functioning and inflammation in persons with post-COVID-19 condition: a secondary analysis.

BACKGROUND: Individuals who have recovered from the acute stage of SARS-CoV-2 infection may be at risk of developing post-COVID-19 condition (PCC), characterised by a spectrum of persisting, non-specific, and functionally impairing symptoms across multiple organ systems. Obesity has been implicated as a risk factor for PCC, mediated by chronic systemic inflammation. The foregoing has also been separately reported to mediate cognitive dysfunction in PCC. METHODS: This is a post-hoc analysis of a randomised, double-blinded, placebo-controlled clinical trial evaluating vortioxetine treatment for cognitive impairments in persons with PCC who received vortioxetine or placebo for eight weeks. This analysis comprises baseline data, examining the impact of BMI on cognitive functioning measured by the Digit Symbol Substitution Test (DSST) and Trails Making Tests (TMT)-A/B, as well as inflammation, via serum c-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). RESULTS: Complete data from 70 participants were statistically analysed and adjusted for age and sex. BMI was negatively correlated with performance on the DSST (ß = -0.003, p = 0.047), TMT-A (ß = -0.006, p = 0.025), and TMT-B (ß = -0.006, p = 0.002). BMI was positively correlated with serum CRP (unstandardized ß = 0.193, standardized ß = 0.612, p < 0.001) and ESR (ß = 0.039, p < 0.001) levels. CONCLUSION: We observed a significant negative correlation between BMI and cognitive functioning, and a significant positive correlation between BMI and inflammation in persons with PCC, suggesting a bidirectional interplay between BMI, PCC, and cognitive function; individuals with an elevated BMI may be at a greater risk of developing PCC and/or presenting with greater cognitive deficits mediated by chronic systemic inflammation.

Impact of Baseline Anxiety on Well-being in People with Post-COVID-19 Condition: A Secondary Analysis.

BACKGROUND: Post-COVID-19 condition (PCC) is associated with a host of psychopathological conditions including prominent anxiety symptoms. However, it is not known what effect anxious symptoms have on measures of well-being in individuals living with PCC. This study aims to evaluate anxiety's association with measures of well-being in people with PCC. METHODS: This is a post hoc analysis utilizing data from a placebo-controlled, randomized, double-blind clinical trial assessing the effect of vortioxetine on cognitive impairment in individuals with PCC (NCT05047952). Baseline data with respect to anxiety and well-being were collected using the Generalized Anxiety Disorder Scale, 7-Item (GAD-7), and the World Health Organization (WHO) Well-Being Index, 5-Item (WHO-5), respectively. A generalized linear model (GLM) analysis on baseline GAD-7 and WHO-5 scores was conducted with age, sex, employment status, education level, previous major depressive disorder (MDD) diagnosis, and confirmed COVID-19 cases as covariates. RESULTS: Data was analyzed in a sample of 144 participants (N = 144). After controlling for the aforementioned covariates, the results found that GAD-7 and WHO-5 scores had a significant negative correlation (ß = -0.053, p = <0.001), signifying that increased anxiety had adverse effects on the overall well-being of individuals with PCC. CONCLUSION: Herein, we observed a clinically meaningful level of anxiety in individuals with PCC. We also identified a robust correlation between anxiety in PCC and measures of general well-being. Our results require replication, providing the impetus for recommending screening and targeting anxious symptoms as a tactic to improve general well-being and outcomes in individuals with PCC.

Assessing the Effects of Metabolic Disruption, Body Mass Index and Inflammation on Depressive Symptoms in Post-COVID-19 Condition: A Randomized Controlled Trial on Vortioxetine.

INTRODUCTION: To date, there are no therapeutics that have gained regulatory approval by the United States Food and Drug Administration (FDA) for the treatment of post-COVID-19 condition (PCC), a debilitating condition characterized by cognitive impairment and mood symptoms. Additionally, persistent inflammation, metabolic dysfunction, and risks associated with an elevated body mass index (BMI) have been observed. Herein, we aimed to assess the efficacy of vortioxetine in improving depressive symptoms among individuals with PCC,  as modulated by inflammation, metabolic dysfunction, and BMI. METHODS: In this post-hoc analysis, we present preliminary data obtained from an 8-week randomized, double-blind, placebo-controlled trial. Participants included  adults aged 18 years and older residing in Canada who were experiencing symptoms of World Health Organization (WHO)-defined PCC. Recruitment began November 2021 and ended January 2023. Of the 200 participants enrolled, 147 were randomized (1:1) to receive vortioxetine (5-20 mg, n = 73) or placebo (n = 74) for daily treatment under double-blind conditions. The primary outcome measure was the change from baseline to endpoint in the 16-Item Quick Inventory of Depressive Symptomatology Self-Report Questionnaire (QIDS-SR-16). RESULTS: Our findings revealed significant effects for time (χ2 = 9.601, p = 0.002), treatment (χ2 = 9.135, p = 0.003), and the treatment × time × CRP × TG-HDL × BMI interaction (χ2 = 26.092, p < 0.001) on PCC-related depressive symptoms in the adjusted model. Moreover, the between-group analysis showed a significant improvement with vortioxetine at endpoint as compared to placebo (mean difference = - 5.41, SEM = 1.335, p < 0.001). CONCLUSION: Overall, vortioxetine significantly improved depressive symptoms among participants with PCC in the adjusted model. Notably, individuals with baseline markers of increased inflammation, metabolic disruption, and elevated BMI exhibited a more pronounced antidepressant effect at endpoint. TRIAL REGISTRATION NUMBER: NCT05047952 (ClinicalTrials.gov).

Impact of vortioxetine on psychosocial functioning moderated by symptoms of fatigue in post-COVID-19 condition: a secondary analysis.

INTRODUCTION: Fatigue is a prominent symptom in post-COVID condition (PCC) sequelae, termed "long COVID." Herein, we aim to ascertain the effect of fatigue on psychosocial function in persons living with PCC. METHODS: This post hoc analysis evaluated the effects of vortioxetine on measures of fatigue as assessed by the Fatigue Severity Scale (FSS) in psychosocial function as measured by the Sheehan Disability Scale (SDS) in persons with PCC. We also evaluated the change in FSS on psychosocial functioning as measured by the Sheehan Disability Scale (SDS). This post hoc analysis obtained data from a recently published placebo-controlled study evaluating vortioxetine's effect on objective cognitive functions in persons living with PCC. RESULTS: One hundred forty-four participants meeting World Health Organization (WHO) criteria for PCC were included in this analysis. At the end of 8 weeks of vortioxetine treatment, significant improvement of all domains was observed for psychosocial functioning. There was a significant between-group difference at treatment endpoint in the family, social, and work SDS subcategories (p < 0.001). There was a statistically significant interaction effect between the treatment condition time point and FSS effect on the SDS social (χ2 = 10.640, p = 0.014) and work (χ2 = 9.342, p = 0.025) categories but a statistically insignificant effect on the family categories ((χ2 = 5.201, p = 0.158)). DISCUSSION: This post hoc analysis suggests that vortioxetine treatment significantly improves psychosocial function in persons with PCC. Our results also indicate that the improvement in psychosocial function was significantly mediated by improvement in measures of fatigue. Our results provide empirical support for recommendations to identify therapeutics for fatigue in persons living with PCC with a broader aim to improve psychosocial function in this common and severely impaired population.

Impacts of metabolic disruption, body mass index and inflammation on cognitive function in post-COVID-19 condition: a randomized controlled trial on vortioxetine.

BACKGROUND: Post-COVID-19 Condition (PCC), as defined by the World Health Organization (WHO), currently lacks any regulatory-approved treatments and is characterized by persistent and debilitating cognitive impairment and mood symptoms. Additionally, metabolic dysfunction, chronic inflammation and the associated risks of elevated body mass index (BMI) have been reported. In this study, we aim to investigate the efficacy of vortioxetine in improving cognitive deficits in individuals with PCC, accounting for the interaction of metabolic dysfunction, elevated inflammation and BMI. METHODS: This is a post-hoc analysis of an 8-week randomized, double-blind, placebo-controlled trial that was conducted among adults aged 18 years and older living in Canada who were experiencing WHO-defined PCC symptoms. The recruitment of participants began in November 2021 and concluded in January 2023. A total of 200 individuals were enrolled, where 147 were randomized in a 1:1 ratio to receive either vortioxetine (5-20 mg, n = 73) or placebo (n = 74) for daily treatment under double-blind conditions. The primary outcome measure was the change in the Digit Symbol Substitution Test (DSST) score from baseline to endpoint. RESULTS: Our findings showed significant effects for time (χ2 = 7.771, p = 0.005), treatment (χ2 = 7.583, p = 0.006) and the treatment x time x CRP x TG-HDL x BMI interaction (χ2 = 11.967, p = 0.018) on cognitive function. Moreover, the between-group analysis showed a significant improvement with vortioxetine at endpoint (mean difference = 0.621, SEM = 0.313, p = 0.047). CONCLUSION: Overall, vortioxetine demonstrated significant improvements in cognitive deficits among individuals with baseline markers of metabolic dysfunction, elevated inflammation and higher BMI at endpoint as compared to placebo. TRIAL REGISTRATION: NCT05047952 (ClinicalTrials.gov; Registration Date: September 17, 2021).

Vortioxetine for the treatment of post-COVID-19 condition: a randomized controlled trial.

Hitherto no therapeutic has received regulatory approval for the treatment of post-COVID-19 condition (PCC). Cognitive deficits, mood symptoms and significant reduction in health-related quality of life (HRQoL) are highly replicated and debilitating aspects of PCC. We sought to determine the impact of vortioxetine on the foregoing symptoms and HRQoL in persons living with PCC. An 8-week randomized, double-blind, placebo-controlled study of adults ≥ 18 years of age residing in Canada and who are experiencing symptoms of World Health Organization (WHO)-defined PCC, with a history of confirmed SARS-CoV-2 infection, was conducted. Recruitment began November 2021 and ended January 2023. Of the 200 participants enrolled (487 invited: 121 ineligible and 59 eligible but declined participation; 307 cleared pre-screening stage), a total of 149 participants were randomized (1:1) to receive either vortioxetine (5-20 mg, n = 75) or placebo (n = 74) daily for 8 weeks of double-blind treatment (i.e. end point). The primary outcome was the change from baseline-to-end point in the Digit Symbol Substitution Test. Secondary outcomes included the effect on depressive symptoms and HRQoL, as measured by changes from baseline-to-end point on the Quick Inventory of Depressive Symptomatology 16-item and WHO Wellbeing Scale 5-item, respectively. A total of 68 (90.7%) participants randomized to vortioxetine and 73 (98.6%) participants randomized to placebo completed all 8 weeks. Between-group analysis did not show a significant difference in the overall change in cognitive function [P = 0.361, 95% confidence interval (CI) (-0.179, 0.492)]. However, in the fully adjusted model, a significant treatment × time interaction was observed in favour of vortioxetine treatment with baseline c-reactive protein (CRP) as a moderator (P = 0.012). In addition, a significant improvement in Digit Symbol Substitution Test scores were observed in vortioxetine versus placebo treated participants in those whose baseline CRP was above the mean (P = 0.045). Moreover, significant improvement was obtained in measures of depressive symptoms [P < 0.001, 95% CI (-4.378, -2.323)] and HRQoL [P < 0.001, 95% CI (2.297, 4.647)] in vortioxetine-treated participants and between the treatment groups [depressive symptoms: P = 0.026, 95% CI (-2.847, -0.185); HRQoL: P = 0.004, 95% CI (0.774, 3.938)]. Although vortioxetine did not improve cognitive function in the unadjusted model, when adjusting for CRP, a significant pro-cognitive effect was observed; antidepressant effects and improvement in HRQoL in this debilitating disorder were also noted.

Impact of Elevated Body Mass Index (BMI) on Hedonic Tone in Persons with Post-COVID-19 Condition: A Secondary Analysis.

INTRODUCTION: The post-COVID-19 condition (PCC) is characterized by persistent, distressing symptoms following an acute COVID-19 infection. These symptoms encompass various domains, including hedonic tone, which is critical for overall well-being. Furthermore, obesity is both a risk factor for COVID-19 and PCC and associated with impaired hedonic tone. This study aims to investigate whether elevated body mass index (BMI) is associated with hedonic tone in persons with PCC. METHODS: We perform a post hoc analysis of a randomized, double-blind, placebo-controlled clinical trial investigating the impact of vortioxetine on cognitive impairment in persons with PCC. Statistical analysis of baseline data using a generalized linear model was undertaken to determine the relationship of BMI to hedonic tone measured by Snaith-Hamilton Pleasure Scale (SHAPS) scores. The model was adjusted for covariates including age, sex, race, suspected versus confirmed COVID-19 cases, alcohol amount consumed per week, and annual household income. RESULTS: The baseline data of 147 participants were available for analysis. BMI had a statistically significant positive association with baseline SHAPS total scores (ß = 0.003, 95% CI [6.251E-5, 0.006], p = 0.045), indicating elevated BMI is associated with deficits in self-reported reward system functioning. CONCLUSION: Higher BMI is associated with greater deficits in hedonic tone in persons with PCC, which may impact reward functioning processes such as reward prediction and processing. The mediatory effect of BMI on reward function underscores the need to investigate the neurobiologic interactions to elucidate preventative and therapeutic interventions for persons with PCC. Therapeutic development targeting debilitating features of PCC (e.g., motivation, cognitive dysfunction) could consider stratification on the basis of baseline BMI. TRIAL REGISTRATION NUMBER: NCT05047952.

Dextromethorphan-Bupropion for the Treatment of Depression: A Systematic Review of Efficacy and Safety in Clinical Trials.

BACKGROUND: A significant proportion of adults with major depressive disorder (MDD) do not respond to treatments which are currently used in clinical practice such as first-generation monoamine-based antidepressants. OBJECTIVES: The objective of this systematic review was to assess the efficacy, safety, and mechanisms of action of AXS-05, a combination of the NMDA-receptor antagonist dextromethorphan with bupropion, in adults with MDD. METHODS: We searched PubMed, Embase, Google Scholar, and ClinicalTrials.gov for current studies reporting on efficacy and/or safety of AXS-05 in patients with MDD. The search terms included: "AXS-05" OR "dextromethorphan and bupropion" AND "depression". Studies from database inception to January 2023 were evaluated. Risk of bias was assessed using the Cochrane Risk of Bias tool. RESULTS: The search yielded 54 studies of which 5 were included. All studies had low risk of bias. Depression severity, measured with the Montgomery-Åsberg Depression Rating Scale (MADRS) significantly decreased as early as 1-week post-treatment from baseline when compared to a placebo-controlled group (LS mean difference 2.2; 95% CI 0.6-3.9; p = 0.007) and at 2 weeks compared to an active control group (LS mean difference 4.7; 95% CI 0.6-8.8; p = 0.024). Treatment efficacy could be maintained for up to 12 months with mean MADRS score reduction of 23 points from baseline. Clinical remission and response rates also improved at week 1 and were maintained for 12 months. The treatment was well-tolerated, with some transient adverse events reported. CONCLUSION: Current evidence suggests that the combination of dextromethorphan and bupropion is a well-tolerated, rapid-acting treatment option for adults with MDD. Initial success with AXS-05 supports the mechanistic role of glutamatergeric and sigma 1 signaling in the pathophysiology of MDD.

COVID-19 vaccination for the prevention and treatment of long COVID: A systematic review and meta-analysis.

Empirical evidence addressing the association between SARS-CoV-2 vaccination and long COVID would guide public health priorities and inform personal health decisions. Herein, the co-primary objectives are to determine the differential risk of long COVID in vaccinated versus unvaccinated patients, and the trajectory of long COVID following vaccination. Of 2775 articles identified via systematic search, 17 were included, and 6 were meta-analyzed. Meta-analytic results determined that at least one vaccine dose was associated with a protective effect against long COVID (OR 0.539, 95% CI 0.295-0.987, p = 0.045, N = 257 817). Qualitative analysis revealed that trajectories of pre-existing long COVID following vaccination were mixed, with most patients reporting no changes. The evidence herein supports SARS-CoV-2 vaccination for the prevention of long COVID, and recommends long COVID patients adhere to standard SARS-CoV-2 vaccination schedules.

Changes in insulin resistance following antidepressant treatment mediate response in major depressive disorder.

BACKGROUND: Insulin resistance (IR) is a potential predictor of antidepressant treatment response. AIMS: We assess changes in IR after antidepressant treatment and whether these changes have any effect on treatment response. Also, to see whether changes in IR mediates relationship between C-reactive protein (CRP) and antidepressant efficacy. METHODS: This is a secondary analysis of an 8-week, open-label clinical trial with 95 adults experiencing a major depressive episode. Response to vortioxetine was measured using the Montgomery-Åsberg Depression Rating Scale (MADRS). Generalized estimating equation models were utilized for this intent-to-treat analysis. RESULTS: When adjusted for age, sex, and body mass index, there was a significant increase in IR following treatment in the overall sample (p = 0.035). This finding was detected in treatment non-responders (p = 0.019), whereas it was not observed in responders (p = 0.329). Mediation analysis revealed that change in IR during treatment was responsible for change in MADRS as well as the relationship between baseline CRP and treatment response. CONCLUSIONS: Exacerbation of IR during antidepressant treatment mediated non-response. Conversely in treatment responders IR reduced. Like previous studies, baseline CRP moderated treatment response. This relationship was also mediated by changes in IR. These findings further elucidate the role of IR in terms of antidepressant response as well as potentially explain inflammation's relationship with the latter.

An App-Based Digit Symbol Substitution Test for Assessment of Cognitive Deficits in Adults With Major Depressive Disorder: Evaluation Study.

BACKGROUND: Cognitive dysfunction is an impairing core symptom of depression. Among adults with major depressive disorder (MDD) treated with antidepressants, residual cognitive symptoms interfere with patient-reported outcomes. The foregoing characterization of cognitive symptoms provides the rationale for screening and assessing the severity of cognitive symptoms at point of care. However, clinical neurocognitive assessments are time-consuming and difficult, and they require specialist expertise to interpret them. A smartphone-delivered neurocognitive test may offer an effective and accessible tool that can be readily implemented into a measurement-based care framework. OBJECTIVE: We aimed to evaluate the use of a smartphone-delivered app-based version of the established Cognition Kit Digit Symbol Substitution Test (DSST) neurocognitive assessment compared to a traditional paper-and-pencil version. METHODS: Convergent validity and test-retest reliability of the 2 versions were evaluated. Patient satisfaction with the app was also assessed. RESULTS: Assessments made using the app-based Cognition Kit DSST were highly correlated with the standard paper-and-pencil version of the test, both at the baseline visit (r=0.69, df=27; P<.001) and at the end-of-study visit (r=0.82, df=27; P<.001), and they were positively evaluated by 30 patients as being user-friendly, easy to navigate, and preferable over the paper-and-pencil version of the DSST. However, although the app-based Cognition Kit DSST was validated in patients with MDD, it still needs to be evaluated in healthy controls. CONCLUSIONS: App-based DSST may facilitate a more personalized, convenient, and cost-effective method of cognitive assessment, helping to guide measurement-based care and psychotherapeutic and pharmacologic treatment options for patients with MDD. TRIAL REGISTRATION: ClinicalTrials.gov NCT03999567; https://tinyurl.com/2p8pnyv7.

A Research Domain Criteria (RDoC)-Guided Dashboard to Review Psilocybin Target Domains: A Systematic Review.

BACKGROUND: Preliminary results from randomized controlled studies as well as identified molecular, cellular, and circuit targets of select psychedelics (e.g., psilocybin) suggest that their effects are transdiagnostic. In this review, we exploit the Research Domain Criteria (RDoC) transdiagnostic framework, to synthesize extant literature on psilocybin. OBJECTIVE: We aimed to identify RDoC-based effects of psilocybin and vistas for future mechanistic and interventional research. METHODS: A systematic search in electronic databases (i.e., PubMed, Scopus, PsycINFO, and Web of Science) performed in January and February 2021 identified English articles published between 1990 and 2020 reporting the effects of psilocybin on mental health measures. Data from included articles were retrieved and organized according to the RDoC bio-behavioral matrix and its constituent six main domains, namely: positive valence systems, negative valence systems, cognitive systems, social processes, sensorimotor systems, and arousal and regulatory systems. RESULTS: The preponderance of research with psilocybin has differentially reported beneficial effects on positive valence systems, negative valence system, and social process domains. The data from the included studies support both short-term (23 assessments) and long-term (15 assessments) beneficial effects of psilocybin on the positive valence systems. While 12 of the extracted outcome measures suggest that psilocybin use is associated with increases in the "fear" construct of the negative valence systems domain, 19 findings show no significant effects on this construct, and seven parameters show lowered levels of the "sustained threat" construct in the long term. Thirty-four outcome measures revealed short-term alterations in the social systems' construct namely, "perception and understanding of self," and "social communications" as well as enhancements in "perception and understanding of others" and "affiliation and attachment". The majority of findings related to the cognitive systems' domain reported dyscognitive effects. There have been relatively few studies reporting outcomes of psilocybin on the remaining RDoC domains. Moreover, seven of the included studies suggest the transdiagnostic effects of psilocybin. The dashboard characterization of RDoC outcomes with psilocybin suggests beneficial effects in the measures of reward, threat, and arousal, as well as general social systems. CONCLUSIONS: Psilocybin possesses a multi-domain effectiveness. The field would benefit from highly rigorous proof-of-mechanism research to assess the effects of psilocybin using the RDoC framework. The combined effect of psilocybin with psychosocial interventions with RDoC-based outcomes is a priority therapeutic vista.

Association between selective serotonin reuptake inhibitor and risk of peripheral artery disease in diabetes mellitus: Propensity score matching and landmark analysis.

ABSTRACT: An increasing number of studies have demonstrated the bidirectional hemostatic effect of selective serotonin reuptake inhibitors (SSRIs) on the risk of cerebrovascular and cardiovascular diseases. However, no previous study has focused on the relationship between SSRI and the risk of peripheral artery disease (PAD) in diabetes mellitus (DM). We sought to evaluate the association between SSRIs and the PAD risk in individuals with DM.We conducted a retrospective, population-based cohort study using data from the Longitudinal Health Insurance Database from 1999 to 2010 in Taiwan. A total of 5049 DM patients were included and divided into 2 groups: DM with SSRI users and DM with SSRI non-users. Propensity score matching and 1-year landmark analysis were used for our study design. Stratified Cox proportional hazard regressions were used to analyze the hazard ratio of the PAD risk in certain subgroups.DM with SSRI users did not affect the PAD risk compared to DM with SSRI non-users. These findings were consistent with all sensitivity analyses (i.e., age, sex, SSRI doses, antithrombotic medication use, and medical and psychiatric comorbidities).In this study, we found that there was no significant difference of PAD risk between DM with SSRI users and DM with SSRI non-users. DM with SSRI user did not affect PAD risk across any SSRI dose, age, sex, antithrombotic medications, and multiple comorbidities in the subgroup analysis.

Screening Depressive Symptoms and Incident Major Depressive Disorder Among Chinese Community Residents Using a Mobile App-Based Integrated Mental Health Care Model: Cohort Study.

BACKGROUND: Depression is associated with significant morbidity and human capital costs globally. Early screening for depressive symptoms and timely depressive disorder case identification and intervention may improve health outcomes and cost-effectiveness among affected individuals. China's public and academic communities have reached a consensus on the need to improve access to early screening, diagnosis, and treatment of depression. OBJECTIVE: This study aims to estimate the screening prevalence and associated factors of subthreshold depressive symptoms among Chinese residents enrolled in the cohort study using a mobile app-based integrated mental health care model and investigate the 12-month incidence rate and related factors of major depressive disorder (MDD) among those with subthreshold depressive symptoms. METHODS: Data were drawn from the Depression Cohort in China (DCC) study. A total of 4243 community residents aged 18 to 64 years living in Nanshan district, Shenzhen city, in Guangdong province, China, were encouraged to participate in the DCC study when visiting the participating primary health care centers, and 4066 (95.83%) residents who met the DCC study criteria were screened for subthreshold depressive symptoms using the Patient Health Questionnaire-9 at baseline. Of the 4066 screened residents, 3168 (77.91%) with subthreshold depressive symptoms were referred to hospitals to receive a psychiatric diagnosis of MDD within 12 months. Sleep duration, anxiety symptoms, well-being, insomnia symptoms, and resilience were also investigated. The diagnosis of MDD was provided by trained psychiatrists using the Mini-International Neuropsychiatric Interview. Univariate and multivariate logistic regression models were performed to explore the potential factors related to subthreshold depressive symptoms at baseline, and Cox proportional hazards models were performed to explore the potential factors related to incident MDD. RESULTS: Anxiety symptoms (adjusted odds ratio [AOR] 1.63, 95% CI 1.42-1.87) and insomnia symptoms (AOR 1.13, 95% CI 1.05-1.22) were associated with an increased risk of subthreshold depressive symptoms, whereas well-being (AOR 0.93, 95% CI 0.87-0.99) was negatively associated with depressive symptoms. During the follow-up period, the 12-month incidence rate of MDD among participants with subthreshold depressive symptoms was 5.97% (189/3168). After incorporating all significant variables from the univariate analyses, the multivariate Cox proportional hazards model reported that a history of comorbidities (adjusted hazard ratio [AHR] 1.49, 95% CI 1.04-2.14) and anxiety symptoms (AHR 1.13, 95% CI 1.09-1.17) were independently associated with an increased risk of incident MDD. The 5-item World Health Organization Well-Being Index was associated with a decreased risk of incident MDD (AHR 0.90, 95% CI 0.86-0.94). CONCLUSIONS: Elevated anxiety symptoms and unfavorable general well-being were significantly associated with subthreshold depressive symptoms and incident MDD among Chinese residents in Shenzhen. Early screening for subthreshold depressive symptoms and related factors may be helpful for identifying populations at high risk of incident MDD.

Registered clinical trials investigating treatment of long COVID: a scoping review and recommendations for research.

BACKGROUND: A considerable proportion of individuals report persistent, debilitating and disparate symptoms despite resolution of acute COVID-19 infection (i.e. long COVID). Numerous registered clinical trials investigating treatment of long COVID are expected to be completed in 2021-2022. The aim of this review is to provide a scope of the candidate treatments for long COVID. A synthesis of ongoing long COVID clinical trials can inform methodologic approaches for future studies and identify key research vistas. METHODS: Scoping searches were conducted on multiple national and international clinical trial registries. Interventional trials testing treatments for long COVID were selected. The search timeline was from database inception to 28 July 2021. RESULTS: This scoping review included 59 clinical trial registration records from 22 countries with a total projected enrolment of 6718. Considerable heterogeneity was exhibited amongst component records with respect to the characterization of long COVID (i.e. name, symptoms- including frequency, intensity, trajectory and duration- mode of ascertainment, and definition of acute phase). In addition, the majority of proposed interventions were non-pharmacological and either targeted multiple long COVID symptoms simultaneously, or focussed on treatment of respiratory/pulmonary sequelae. Multiple interventions targeted inflammation, as well as tissue oxygenation and cellular recovery, and several interventions were repurposed from analogous conditions. CONCLUSIONS: The results of this scoping review investigating ongoing clinical trials testing candidate treatments for long COVID suggest that a greater degree of definitional stringency and homogeneity is needed insofar as the characterization of long COVID and inclusion/exclusion criteria.

Fatigue and cognitive impairment in Post-COVID-19 Syndrome: A systematic review and meta-analysis.

IMPORTANCE: COVID-19 is associated with clinically significant symptoms despite resolution of the acute infection (i.e., post-COVID-19 syndrome). Fatigue and cognitive impairment are amongst the most common and debilitating symptoms of post-COVID-19 syndrome. OBJECTIVE: To quantify the proportion of individuals experiencing fatigue and cognitive impairment 12 or more weeks following COVID-19 diagnosis, and to characterize the inflammatory correlates and functional consequences of post-COVID-19 syndrome. DATA SOURCES: Systematic searches were conducted without language restrictions from database inception to June 8, 2021 on PubMed/MEDLINE, The Cochrane Library, PsycInfo, Embase, Web of Science, Google/Google Scholar, and select reference lists. STUDY SELECTION: Primary research articles which evaluated individuals at least 12 weeks after confirmed COVID-19 diagnosis and specifically reported on fatigue, cognitive impairment, inflammatory parameters, and/or functional outcomes were selected. DATA EXTRACTION & SYNTHESIS: Two reviewers independently extracted published summary data and assessed methodological quality and risk of bias. A meta-analysis of proportions was conducted to pool Freeman-Tukey double arcsine transformed proportions using the random-effects restricted maximum-likelihood model. MAIN OUTCOMES & MEASURES: The co-primary outcomes were the proportions of individuals reporting fatigue and cognitive impairment, respectively, 12 or more weeks following COVID-19 infection. The secondary outcomes were inflammatory correlates and functional consequences associated with post-COVID-19 syndrome. RESULTS: The literature search yielded 10,979 studies, and 81 studies were selected for inclusion. The fatigue meta-analysis comprised 68 studies, the cognitive impairment meta-analysis comprised 43 studies, and 48 studies were included in the narrative synthesis. Meta-analysis revealed that the proportion of individuals experiencing fatigue 12 or more weeks following COVID-19 diagnosis was 0.32 (95% CI, 0.27, 0.37; p < 0.001; n = 25,268; I2 = 99.1%). The proportion of individuals exhibiting cognitive impairment was 0.22 (95% CI, 0.17, 0.28; p < 0.001; n = 13,232; I2 = 98.0). Moreover, narrative synthesis revealed elevations in proinflammatory markers and considerable functional impairment in a subset of individuals. CONCLUSIONS & RELEVANCE: A significant proportion of individuals experience persistent fatigue and/or cognitive impairment following resolution of acute COVID-19. The frequency and debilitating nature of the foregoing symptoms provides the impetus to characterize the underlying neurobiological substrates and how to best treat these phenomena. STUDY REGISTRATION: PROSPERO (CRD42021256965).