Impact of vortioxetine on depressive symptoms moderated by symptoms of anxiety in persons with post-COVID-19 condition: A secondary analysis.

OBJECTIVE: Recovery from a COVID-19 infection can lead to post-COVID-19 condition (PCC), which causes a multitude of debilitating symptoms that negatively affect an individual's health-related quality of life, including depressive and anxiety symptoms. We aim to examine the mediatory effects of anxiety on depressive symptoms in persons with PCC receiving vortioxetine. METHODS: We performed a post-hoc analysis of a randomized, double-blinded, placebo-controlled clinical trial investigating vortioxetine treatment on cognitive functioning in persons with PCC. Anxiety and depressive symptoms were measured by the 7-Item Generalized Anxiety Disorder (GAD-7) Scale and the 16-Item Quick Inventory of Depressive Symptomatology (QIDS-SR-16), respectively. RESULTS: Based on data of 147 participants, GAD-7 scores were significantly positively associated with QIDS-SR-16 scores (ß=0.038, 95 % CI [0.029,0.047], p < 0.001). After adjusting for covariates, a significant group (χ2=176.786, p < 0.001), time (χ2=8.914, p = 0.003), and treatment x time x GAD-7 score interaction (χ2=236.483, p < 0.001) effect was observed. Vortioxetine-treated participants had a significant difference in overall change in depressive symptoms (mean difference=-3.15, SEM=0.642, 95 % CI [-4.40,-1.89], p < 0.001). CONCLUSION: Anxiety symptoms were significantly associated with depressive symptoms in persons with PCC. Antidepressant efficacy on ameliorating depressive symptoms is dependent on improving anxiety symptoms, underscoring significant implications in improving treatment efficacy and patient quality of life.

Comparative Efficacy of Omega-3 Fatty Acid with Other Interventions for Depression in Children and Adolescents: A Systematic Review and Network Meta-Analysis.

Background: The administration of omega-3 polyunsaturated fatty acid supplements is recommended as an adjuvant therapy for adults diagnosed with major depressive disorder. The evaluation of replicated data in combination treatment with omega-3 has been extensively conducted in adults over the past decade. However, the generalizability of these findings to pediatric groups is still uncertain. The objectives of this evaluation were twofold: (1) to evaluate the effectiveness of omega-3 and associated combination therapies in reducing the severity of depressive symptoms, and (2) to include remission rates (i.e., reduction of more than 50% in depression symptoms) as a measure of therapeutic efficacy. Methods: We conducted a literature search on PubMed/EMBASE from inception to October 2023. Data analyses were conducted using Stata (version 17.0). Results: We identified a total of 3168 articles. After eligibility screening of identified studies, nine studies (n = 561 participants) were included in our analysis herein. Pairwise comparisons revealed no significant improvement in depression symptoms for any intervention versus placebo. However, a clustered ranking plot identified omega-3 plus inositol as the most effective treatment for pediatric depression (77.3% efficacy). Omega-3 paired with psychoeducational psychotherapy significantly lowered the remission rate compared to placebo (standardized mean difference = 0.44, 95% confidence interval: 0.00-0.87, p = 0.048), resulting in a 91.5% remission rate, making it the most effective treatment in the study. Conclusions: Taken together, this network meta-analysis presents compelling evidence supporting the antidepressant effects of omega-3 in pediatric groups with depression. Future research should aim to investigate omega-3 as monotherapy for young individuals with depression, as well as investigate the efficacy of omega-3 in comparison to psychosocial interventions for affected individuals.

Relationship between anhedonia and psychosocial functioning in post-COVID-19 condition: a post-hoc analysis.

BACKGROUND: Post-COVID-19 condition (PCC), also known as "long COVID," is characterized by persistent symptoms, negatively affecting the well-being of individuals with PCC. Anhedonia (i.e. reduced capacity for pleasure) and compromised psychosocial functioning are notable symptoms in those with PCC. We aimed to provide insights to understand the effects of anhedonia and impaired psychosocial functioning of individuals with PCC. METHODS: This post-hoc analysis used data from an 8-week, double-blind, randomized, placebo-controlled trial which evaluated vortioxetine for cognitive deficits in individuals with PCC (Clinicaltrials.gov Identifier: NCT05047952). A total of 147 eligible participants were randomly assigned to receive vortioxetine or matching placebo over eight weeks of double-blind treatment. Our study investigated the relationship between anhedonia, assessed by the Snaith-Hamilton Pleasure Scale (SHAPS), and psychosocial functioning, measured with the Post-COVID Functional Status (PCFS) scale. The analysis was conducted using a generalized linear model, with adjustments for relevant covariates such as age, sex, education, suspected versus confirmed COVID diagnosis, MDD diagnosis, and alcohol consumption. RESULTS: Of the 147 participants, 143 participants had available baseline data for analysis. We observed that baseline PCFS score was statistically significantly positively correlated to baseline SHAPS score (ß = 0.070, p = 0.045, 95% CI). DISCUSSIONS: Our analysis revealed a significant relationship between measures of anhedonia and psychosocial functioning in adults with PCC. Strategies that aim to improve patient-reported outcomes with PCC need to prioritize the prevention and treatment of hedonic disturbances in patients experiencing PCC.

Longitudinal Association between Stressful Life Events and Suicidal Ideation in Adults with Major Depression Disorder: The Mediating Effects of Insomnia Symptoms.

Stressful life events (SLEs) and suicidal ideation (SI) are prevalent in persons with major depression disorder (MDD). Less is known about the underlying role of insomnia symptoms in the association between SLEs and SI. This three-wave prospective cohort study sought to investigate the longitudinal association among SLEs, insomnia symptoms, and SI in persons with MDD. The study population included 511 persons with MDD (mean [SD] age, 28.7 [6.7] years; 67.1% were females). Generalized estimated equations (GEEs) were utilized to explore prospective association among exposure of SLEs, insomnia symptoms, and SI. Additionally, a structural equation model (SEM) was employed to estimate the longitudinal mediating effect of insomnia symptoms in the relationship between SLEs and SI. Our study demonstrated that cumulative SLEs were determined to be longitudinally associated with SI in persons with MDD. We further observed that the association between SLEs and SI was significantly mediated by insomnia symptoms. Clinicians assessing persons with MDD, especially those with the history of SLE, could carefully evaluate and promptly treat insomnia symptoms as part of personalized assessment of their depressive illness, thereby achieving early prevention and intervention for suicidal behaviors in persons with MDD.

Association between fatigue and depressive symptoms in persons with post-COVID-19 condition: a post hoc analysis.

OBJECTIVE: Post-COVID-19 Condition (PCC) is a prevalent, persistent and debilitating phenomenon occurring three or more months after resolution of acute COVID-19 infection. Fatigue and depressive symptoms are commonly reported in PCC. We aimed to further characterize PCC by assessing the relationship between fatigue and depressive symptom severity in adults with PCC. METHODS: A post hoc analysis was conducted on data retrieved from a randomized, double-blinded, placebo-controlled study evaluating vortioxetine for cognitive deficits in persons with PCC. We sought to determine the relationship between baseline fatigue [i.e. Fatigue Severity Scale (FSS) total score] and baseline depressive symptom severity [i.e. 16-item Quick Inventory of Depressive Symptomatology (QIDS-SR-16) total score] in adults with PCC. RESULTS: The statistical analysis included baseline data from 142 participants. After adjusting for age, sex, education, employment status, history of major depressive disorder (MDD) diagnosis, self-reported physical activity, history of documented acute SARS-CoV-2 infection and body mass index (BMI), baseline FSS was significantly correlated with baseline QIDS-SR-16 (ß = 0.825, p = .001). CONCLUSION: In our sample, baseline measures of fatigue and depressive symptoms are correlated in persons living with PCC. Individuals presenting with PCC and fatigue should be screened for the presence and severity of depressive symptoms. Guideline-concordant care should be prescribed for individuals experiencing clinically significant depressive symptoms. Fatigue and depressive symptom severity scores were not pre-specified as primary objectives of the study. Multiple confounding factors (i.e. disturbance in sleep, anthropometrics and cognitive impairment) were not collected nor adjusted for in the analysis herein. TRIAL REGISTRATION: Unrestricted Research Grant from H. Lundbeck A/S, Copenhagen, Denmark. ClinicalTrials.gov Identifier: NCT05047952.

The association between ketamine and esketamine and suicidality: reports to the Food And Drug Administration Adverse Event Reporting System (FAERS).

INTRODUCTION: Replicated evidence indicates that ketamine and esketamine reduce measures of suicidality in persons with treatment-resistant depression (TRD). It remains uncertain whether individuals experience worsening of preexisting suicidality with either agent. RESEARCH DESIGN AND METHODS: The Food and Drug Administration Adverse Event Reporting System (FAERS) database was searched from 1970 and 2019 to 30 September 2023 for reports of suicidal ideation, depression suicidal, suicidal behavior, suicidal attempt, and completed suicide in association with ketamine and esketamine exposure, respectively. We present reporting odds ratios (ROR) significance was determined when the lower limit of the 95% confidence interval (CI) exceeded 1.0. Lithium was used as the control agent. RESULTS: Observed a higher ROR for suicidal ideation (ROR 7.58, 95% CI 6.34-9.07) and depression suicidal (ROR 14.19, 95% CI 1.80-112.07) with esketamine. Significantly lower RORs were observed for suicide attempt with ketamine (ROR 0.15, 95% CI 0.11-0.21) and esketamine (ROR 0.57, 95% CI 0.48-0.67). CONCLUSIONS: Mixed RORs across aspects of suicidality were observed with ketamine and esketamine. Limitations of the FAERS database prevent any determination of causal effects new onset suicidality to either agent. The lower RORs for suicide attempt with ketamine and esketamine is noted but cannot be interpreted as a direct therapeutic effect.

Effect of RANKL on Lower Depressive Symptoms In Hemodialysis Patients.

Depression and osteoporosis are common diseases in dialysis patients. In addition, patients with osteoporosis are more susceptible to depression. Contrary to previous anti-osteoporosis agents, denosumab and romosozumab could be used in dialysis patients and have similar action mechanisms for blocking RANKL. RANKL causes bone resorption after binding RANKL, but binding with OPG leads to suppress of bone resorption. In recent mice study, inhibition of RANKL with denosumab improved depressive-like phenotype. Besides, it was found that OPG was associated with depression. Therefore, this study aimed to investigate the association of depressive symptoms with RANKL and OPG in hemodialysis patients. We conducted a cross-sectional study with a total of 172 hemodialysis patients. The participants were measured for plasma RANKL, OPG, MMP-2, and MMP-9 levels. Logistic regression analysis was performed to evaluate the effect of RANKL and OPG on the presence of depressive symptoms. The depressive symptoms were observed in 90 (52.3%) subjects. RANKL tertile 3 had negative association with BDI score (ß - 4.527, 95% CI - 8.310 to - 0.743) in univariate analysis, and this association persisted even after multivariate adjustments (ß - 5.603, 95% CI - 9.715 to -1.491) in linear regression. In logistic regression between RANKL tertiles and depressive symptoms, RANKL tertile 3 had significantly lower unadjusted OR (0.40, 95% CI 0.19-0.86), and multivariate-adjusted OR (0.31, 95% CI 0.12-0.82) for depressive symptoms. OPG was not significantly associated with depressive symptoms. Higher plasma RANKL concentrations were significantly associated with lower depressive symptoms in HD patients.Trial registration WHO registry, No. KCT0003281, date: January 12, 2017.

Comparing suicide completion rates in bipolar I versus bipolar II disorder: A systematic review and meta-analysis.

BACKGROUND: Bipolar disorder (BD) has a high disease burden and the highest mortality risk in BD comes from suicide. Bipolar disorder type II (BD-II) has been described as a milder form of bipolar disorder; however, extant literature is inconsistent with this description and instead describe illness burden and notably suicidality comparable to persons with bipolar I disorder (BD-I). Towards quantifying the hazard of BD-II, herein we aim via systematic review and meta-analysis to evaluate the rates of completed suicide in BD-I and BD-II. METHOD: We conducted a literature search on PubMed, OVID (Embase, Medline) and PsychINFO databases from inception to June 30th, 2023, according to PRISMA guidelines. Articles were selected based on the predetermined eligibility criteria. A meta-analysis was performed, comparing the risk of completed suicide between individuals diagnosed with BD-I to BD-II. RESULTS: Four out of eight studies reported higher suicide completion rates in persons living with BD-II when compared to persons living with BD-I; however, two of the studies reported non-significance. Two studies reported significantly higher suicide completion rates for BD-I than BD-II. The pooled odds ratio of BD-II suicide rates to BD-I was 1.00 [95 % CI = 0.75, 1.34]. LIMITATIONS: The overarching limitation is the small number of studies and heterogeneity of studies that report on suicide completion in BD-I and BD-II. CONCLUSION: Our study underscores the severity of BD-II, with a risk for suicide not dissimilar from BD-I. The greater propensity to depression, comorbidity and rapid-cycling course reported in BD-II are contributing factors to the significant mortality hazard in BD-II.

The association between ketamine and esketamine with alcohol and substance misuse: Reports to the Food and Drug Administration adverse event reporting system (FAERS).

INTRODUCTION: Ketamine and esketamine have been proven to be effective in treating adults with treatment resistant depression (TRD). Preliminary evidence indicates that, when combined with behavioral and psychological interventions, both agents may offer benefits for individuals with substance use disorder (SUD) and alcohol use disorder (AUD). Notwithstanding, concerns have been raised as to whether either or both agents are associated with abuse and/or gateway activity. METHODS: Herein, we evaluate disproportionate reporting expressed as reporting odds ratios (ROR) for esketamine and ketamine. The outcomes of interest include alcohol problem, alcoholism, alcohol abuse, substance dependence, SUD, substance abuse, drug dependence, drug use disorder and drug abuse as codified by the Medical Dictionary for Regulatory Activities (MedDRA) within the FAERS. The IC025 values were significant for ketamine in cases of alcohol abuse (0.28), substance dependence (1.88), substance use disorder (0.996), substance abuse (0.61), drug dependence (0.56), drug use disorder (1.17) and drug abuse (1.22). Additionally, oxycontin showed significant IC025 values for substance dependence (0.067), substance use disorder (0.094), substance abuse (0.035), and drug dependence (0.27). RESULTS: We observed significant increases in the reporting odds ratios (RORs) for ketamine with respect to various outcomes: alcohol abuse (ROR 2.84, 95 % CI 1.53-5.28; p = 0.0010), substance dependence (ROR 18.72, 95 % CI 8.49-41.30; p ≤ 0.0001), SUD (ROR 11.40, 95 % CI 4.24-30.65; p ≤ 0.0001), substance abuse (ROR 2.29, 95 % CI 1.73-3.04; p ≤ 0.0001), drug dependence (ROR 1.99, 95 % CI 1.64-2.42; p ≤ 0.0001), drug use disorder (ROR 4.50, 2.94-6.88; p ≤ 0.0001) and drug abuse (ROR 3.72, 3.36-4.12; p ≤ 0.0001). For esketamine, we observed that the ROR was significantly reduced for substance abuse (ROR 0.37, 95 % CI 0.22-0.63; p = 0.0003), drug dependence (ROR 0.13, 95 % CI 0.076-0.23; p ≤ 0.0001) and drug abuse (ROR 0.048, 95 % CI 0.030-0.078; p ≤ 0.0001). To our knowledge, this is the first report of spontaneous adverse events related to these outcomes of interest in the FAERS. CONCLUSION: Mixed RORs were observed across aspects of SUD and AUD for both ketamine and esketamine. Due to limitations in the FAERS, establishing causal links between new onset alcohol and substance misuse with either agent remains inconclusive. Possible beneficial effects on measures of SUD and AUD were observed. It is currently unclear, but possible, whether both agents have differential ameliorative effects across dimensions of SUD and AUD, which is a focus of ongoing research.

The role of KCNQ channel activators in management of major depressive disorder.

Depression, a complex disorder with significant treatment challenges, necessitates innovative therapeutic approaches to address its multifaceted nature and enhance treatment outcomes. The modulation of KCNQ potassium (K+) channels, pivotal regulators of neuronal excitability and neurotransmitter release, is a promising innovative therapeutic target in psychiatry. Widely expressed across various tissues, including the nervous and cardiovascular systems, KCNQ channels play a crucial role in modulating membrane potential and regulating neuronal activity. Recent preclinical evidence suggests that KCNQ channels, particularly KCNQ3, contribute to the regulation of neuronal excitability within the reward circuitry, offering a potential target for alleviating depressive symptoms, notably anhedonia. Studies using animal models demonstrate that interventions targeting KCNQ channels can restore dopaminergic firing balance and mitigate depressive symptoms. Human studies investigating the effects of KCNQ channel activators, such as ezogabine, have shown promising results in alleviating depressive symptoms and anhedonia. The aforementioned observations underscore the therapeutic potential of KCNQ channel modulation in depression management and highlight the need and justification for phase 2 and phase 3 dose-finding studies as well as studies prespecifying symptomatic targets in depression including anhedonia.

Association between dual orexin receptor antagonists (DORAs) and suicidality: reports to the United States Food and Drug Administration Adverse Event Reporting System (FAERS).

BACKGROUND: Package inserts for the FDA-approved dual orexin receptor antagonists (DORAs) suvorexant, lemborexant and daridorexant state that suicide risk should be monitored. It remains unknown whether suicidality is attributed to DORAs. We aim to evaluate suicidality associated with DORAs reported to the FDA Adverse Event Reporting System (FAERS). METHODS: The reporting odds ratio (ROR) was determined with trazodone as the control. Significant disproportionate reporting was determined when 95% confidence intervals (CIs) did not encompass 1.0. We used information components (ICs) to calculate the lower limit of the 95% CI (IC025). IC was significantly increased when the IC025 ≥0. RESULTS: Suvorexant (0.025 ROR), lemborexant (0.019 ROR) and daridorexant (0.002 ROR) were significantly associated with lower odds of reported completed suicides compared to trazodone (p < 0.05). There was no significantly increased RORs for the DORAs regarding suicidal ideation, depression suicidal, suicidal behavior and suicide attempts. Nonsignificant associations between all parameters of suicidality were observed for each DORA using IC025. CONCLUSION: We did not find a significant association between any parameter of suicidality captured in the FAERS for each DORA. All persons treated for insomnia pharmacologically/non-pharmacologically should be evaluated for emergence/worsening of any suicidality aspect.

Risk of VMAT2 inhibitors on suicidality and parkinsonism: report utilizing the United States Food and Drug Administration adverse event reporting system.

Prescription of vesicular monoamine transporter 2 (VMAT2) inhibitors, valbenazine, deutetrabenazine, and tetrabenazine, is becoming increasingly common in persons treated with antipsychotics. Reported suicidality and parkinsonism are safety concerns with VMAT2 inhibitors. Herein, we aim to evaluate the aforementioned safety outcomes using the FDA Adverse Event Reporting System. Reporting odds ratios (RORs) and lower limits of 95% confidence intervals of information components (IC025) were calculated to quantify VMAT2 inhibitor-associated adverse events. Acetaminophen was the reference agent. Suicidal ideation was significantly associated with VMAT2 inhibitors, with RORs ranging from 2.38 to 10.67 and IC025 ranging from 0.73 to 2.39. Increased odds of suicidal behavior was observed with tetrabenazine (ROR 3.011, IC025 0.0087), but not deutetrabenazine or valbenazine. Decreased odds of suicide attempts and completed suicide were observed with VMAT2 inhibitors, with RORs ranging from 0.011 to 0.10 (all IC025 < 0). Increased odds of parkinsonism were reported for all VMAT2 inhibitors, with RORs and IC025 ranging from 19.49 to 25.37 and 1.66 to 2.93, respectively. The mixed results with VMAT2 inhibitor-associated suicidality and parkinsonism do not establish causal relationships. The parameters of suicidality may be explained by underlying psychiatric disorders.

Number needed to treat (NNT) for ketamine and esketamine in adults with treatment-resistant depression: A systematic review and meta-analysis.

BACKGROUND: Ketamine has been established as efficacious in adults living with Treatment-resistant Depression (TRD). Toward providing a quantifiable estimate of the clinical meaningfulness of the therapeutic benefit of ketamine, herein, we conduct a systematic review that aims to report the Number Needed to Treat (NNT) and the Number Needed to Harm (NNH). METHODS: This systematic review searched Embase, Medline/Pubmed, PsycINFO and ClinicalTrials.gov from inception up to October 15th 2023, for placebo-controlled, Randomized Controlled Trials (RCTs) assessing racemic ketamine or esketamine therapy for unipolar TRD. We calculated NNT and NNH for ketamine treatments over various time points. RESULTS: A total of 21 studies with 2042 participants were included. Racemic ketamine treatments had pooled NNTs for response of 7 at 4 h, 3 from one day to one week and 9 for studies at four weeks. Esketamine treatment was found to have a similar efficacy with an NNT of 2 at one day and 11 at four weeks. NNH values indicated low risk for ketamine treatments. LIMITATIONS: Limitations in the data used include the possibility of functional unblinding and selective reporting bias. Moreover, the meta-analysis may have been limited in its precision by including low threshold definitions of treatment resistance (≥ 1 failed antidepressant) and low-dose ketamine treatments. CONCLUSION: Herein, we determined that the NNT for ketamine treatment in adults living with TRD across different intervals of observation was <10. We conclude that the NNTs observed herein are highly clinically meaningful in this difficult to treat disorder.

Effects of anhedonia on health-related quality of life and functional outcomes in major depressive disorder: A systematic review and meta-analysis.

BACKGROUND: Major depressive disorder (MDD) is a heterogeneous group of mood disorders. A prominent symptom domain is anhedonia narrowly defined as a loss of interest and ability to experience pleasure. Anhedonia is associated with depressive symptom severity, MDD prognosis, and suicidality. We perform a systematic review and meta-analysis of extant literature investigating the effects of anhedonia on health-related quality of life (HRQoL) and functional outcomes in persons with MDD. METHODS: A literature search was conducted on PubMed, OVID databases, and SCOPUS for published articles from inception to November 2023, reporting on anhedonia and patient-reported outcomes in persons with MDD. The reported correlation coefficients between anhedonia and self-reported measures of both HRQoL and functional outcomes were pooled using a random effects model. RESULTS: We identified 20 studies that investigated anhedonia with HRQoL and/or functional outcomes in MDD. Anhedonia as measured by the Snaith-Hamilton Pleasure Scale (SHAPS) scores had a statistically significant correlation with patient-reported HRQoL (r = -0.41 [95 % CI = -0.60, -0.18]) and functional impairment (r = 0.39 [95 % CI = 0.22, 0.54]). LIMITATIONS: These preliminary results primarily investigate correlations with consummatory anhedonia and do not distinguish differences in anticipatory anhedonia, reward valuation or reward learning; therefore, these results require replication. CONCLUSIONS: Persons with MDD experiencing symptoms of anhedonia are more likely to have worse prognosis including physical, psychological, and social functioning deficits. Anhedonia serves as an important predictor and target for future therapeutic and preventative tools in persons with MDD.

Effects of cannabidiol and Δ9-tetrahydrocannabinol on cytochrome P450 enzymes: a systematic review.

Due to legal, political, and cultural changes, the use of cannabis has rapidly increased in recent years. Research has demonstrated that the cannabinoids cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) inhibit and induce cytochrome P450 (CYP450) enzymes. The objective of this review is to evaluate the effect of CBD and THC on the activity of CYP450 enzymes and the implications for drug-drug interactions (DDIs) with psychotropic agents that are CYP substrates. A systematic search was conducted using PubMed, Scopus, Scientific Electronic Library Online (SciELO) and PsychINFO. Search terms included 'cannabidiol', 'tetrahydrocannabinol', and 'cytochrome P450'. A total of seven studies evaluating the interaction of THC and CBD with CYP450 enzymes and psychotropic drugs were included. Both preclinical and clinical studies were included. Results from the included studies indicate that both CBD and THC inhibit several CYP450 enzymes including, but not limited to, CYP1A2, CYP3C19, and CYP2B6. While there are a few known CYP450 enzymes that are induced by THC and CBD, the induction of CYP450 enzymes is an understudied area of research and lacks clinical data. The inhibitory effects observed by CBD and THC on CYP450 enzymes vary in magnitude and may decrease the metabolism of psychotropic agents, cause changes in plasma levels of psychotropic medications, and increase adverse effects. Our findings clearly present interactions between THC and CBD and several CYP450 enzymes, providing clinicians evidence of a high risk of DDIs for patients who consume both cannabis and psychotropic medication. However, more clinical research is necessary before results are applied to clinical settings.

Subjective and Objective Measures of Cognitive Function are Correlated in Persons with Post-COVID-19 Condition: A Secondary Analysis of a Randomized Controlled Trial.

Background: It remains unclear whether subjective and objective measures of cognitive function in Post COVID-19 Condition (PCC) are correlated. The extent of correlation has mechanistic and clinical implications. Methods: This post-hoc analysis of a randomized, double-blind, placebo-controlled clinical trial contains baseline data of subjective and objective measures of cognition in a rigorously characterized cohort living with PCC. Herein, we evaluated the association between subjective and objective condition function, as measured by the Perceived Deficits Questionnaire, 20-item (PDQ-20) and the Digit Symbol Substitution Test (DSST) and Trails Making Test (TMT)-A/B, respectively. Results: A total of 152 participants comprised the baseline sample. Due to missing data, our statistical analyses included 150 for self-reported PDQ-20, 147 individuals for combined DSST-measured cognitive function (composite z-score of the Pen/Paper plus Online CogState Version, N combinedDSST ), 71 for in-person DSST-measured cognitive function (Pen/Paper Version), 70 for TMT-A-measured cognitive function, and 70 for TMT-B-measured cognitive function. After adjusting for age, sex, and education, PDQ-20 was significantly correlated with pen-and-paper DSST (ß = -0.003, p = 0.002) and TMT-B (ß = 0.003, p = 0.008) scores, but not with TMT-A scores (ß = -0.001, p = 0.751). Conclusions: Overall, a statistically significant correlation was observed between subjective and objective cognitive functions. Clinicians providing care for individuals with PCC who have subjective cognitive function complaints may consider taking a measurement-based approach to cognition at the point of care that focuses exclusively on patient-reported measures.

Greater Role of Cognitive Impairment Over Fatigue in Post-COVID-19 Quality of Life: A Post-Hoc Analysis of a Randomized Controlled Trial.

Background: Post COVID-19 Condition (PCC) is a common and debilitating condition with significant reports of fatigue and psychosocial impairment globally. The extent to which cognitive symptoms and fatigue contribute to reduced quality of life in affected individuals remains clear. Methods: This is a post-hoc analysis of a randomized, double-blind, placebo-controlled clinical trial that evaluated the effect of vortioxetine on cognitive function in adults with PCC. The post-hoc analysis herein aimed to determine the overall effect of baseline cognitive function [as measured by the Digit Symbol Substitution Test (DSST)] and baseline fatigue severity [as measured by the Fatigue Severity Scale (FSS)] on baseline health-related quality of life (HRQoL) [as measured by the 5-item World Health Organisation Well-Being Index (WHO-5)]. Results: A total of 200 participants were enrolled in the primary trial. Due to missing baseline data, our statistical analysis included baseline measures of 147 individuals. Our generalized linear model analysis revealed a significant positive correlation between DSST-measured objective cognitive function and self-reported WHO-5-measured HRQoL (ß = 0.069, 95% CI [0.006, 0.131], p = 0.032). In contrast, our analysis revealed a significant negative correlation between FSS and WHO-5 scores (ß = -0.016, 95% CI [-0.021, -0.011], p < 0.001). The beta-coefficient ratio (ß DSST / ß FSS = 0.069 / 0.016) is calculated as 4.313. Conclusions: Overall, we observed that increased cognitive function was associated with increased HRQoL at baseline in adults with PCC. Moreover, we observed that increased severity of fatigue symptoms was associated with decreased HRQoL at baseline in adults with PCC. Furthermore, we observed that an improvement in cognitive function would have a four-fold greater impact on HRQoL than the effect generated by improvement in fatigue.

Spectral signatures of psilocybin, lysergic acid diethylamide (LSD) and ketamine in healthy volunteers and persons with major depressive disorder and treatment-resistant depression: A systematic review.

BACKGROUND: Electrophysiologic measures provide an opportunity to inform mechanistic models and possibly biomarker prediction of response. Serotonergic psychedelics (SPs) (i.e., psilocybin, lysergic acid diethylamide (LSD)) and ketamine represent new investigational and established treatments in mood disorders respectively. There is a need to better characterize the mechanism of action of these agents. METHODS: We conducted a systematic review investigating the spectral signatures of psilocybin, LSD, and ketamine in persons with major depressive disorder (MDD), treatment-resistant depression (TRD), and healthy controls. RESULTS: Ketamine and SPs are associated with increased theta power in persons with depression. Ketamine and SPs are also associated with decreased spectral power in the alpha, beta and delta bands in healthy controls and persons with depression. When administered with SPs, theta power was increased in persons with MDD when administered with SPs. Ketamine is associated with increased gamma band power in both healthy controls and persons with MDD. LIMITATIONS: The studies included in our review were heterogeneous in their patient population, exposure, dosing of treatment and devices used to evaluate EEG and MEG signatures. Our results were extracted entirely from persons who were either healthy volunteers or persons with MDD or TRD. CONCLUSIONS: Extant literature evaluating EEG and MEG spectral signatures indicate that ketamine and SPs have reproducible effects in keeping with disease models of network connectivity. Future research vistas should evaluate whether observed spectral signatures can guide further discovery of therapeutics within the psychedelic and dissociative classes of agents, and its prediction capability in persons treated for depression.

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.

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).