Temporal trends in disparities in COVID-19 seropositivity among Canadian blood donors.

BACKGROUND: In Canada's largest COVID-19 serological study, SARS-CoV-2 antibodies in blood donors have been monitored since 2020. No study has analysed changes in the association between anti-N seropositivity (a marker of recent infection) and geographic and sociodemographic characteristics over the pandemic. METHODS: Using Bayesian multi-level models with spatial effects at the census division level, we analysed changes in correlates of SARS-CoV-2 anti-N seropositivity across three periods in which different variants predominated (pre-Delta, Delta and Omicron). We analysed disparities by geographic area, individual traits (age, sex, race) and neighbourhood factors (urbanicity, material deprivation and social deprivation). Data were from 420 319 blood donations across four regions (Ontario, British Columbia [BC], the Prairies and the Atlantic region) from December 2020 to November 2022. RESULTS: Seropositivity was higher for racialized minorities, males and individuals in more materially deprived neighbourhoods in the pre-Delta and Delta waves. These subgroup differences dissipated in the Omicron wave as large swaths of the population became infected. Across all waves, seropositivity was higher in younger individuals and those with lower neighbourhood social deprivation. Rural residents had high seropositivity in the Prairies, but not other regions. Compared to generalized linear models, multi-level models with spatial effects had better fit and lower error when predicting SARS-CoV-2 anti-N seropositivity by geographic region. CONCLUSIONS: Correlates of recent COVID-19 infection have evolved over the pandemic. Many disparities lessened during the Omicron wave, but public health intervention may be warranted to address persistently higher burden among young people and those with less social deprivation.

Cognitive improvement in patients with major depressive disorder after personalised multi domain training in the CERT-D study.

The CERT-D program offers a new treatment approach addressing disturbed cognitive and psychosocial functioning in major depressive disorder (MDD). The current analysis of a randomised controlled trial (RCT) comprises two objectives: Firstly, evaluating the program's efficacy of a personalised versus standard treatment and secondly, assessing the treatment's persistence longitudinally. Participants (N = 112) were randomised into a personalised or standard treatment group. Both groups received 8 weeks of cognitive training, followed by a three-month follow-up without additional training. The type of personalised training was determined by pre-treatment impairments in the domains of cognition, emotion-processing and social-cognition. Standard training addressed all three domains equivalent. Performance in these domains was assessed repeatedly during RCT and follow-up. Treatment comparisons during the RCT-period showed benefits of personalised versus standard treatment in certain aspects of social-cognition. Conversely, no benefits in the remaining domains were found, contradicting a general advantage of personalisation. Exploratory follow-up analysis on persistence of the program's effects indicated sustained intervention outcomes across the entire sample. A subsequent comparison of clinical outcomes between personalised versus standard treatment over a three-month follow-up period showed similar results. First evidence suggests that existing therapies for MDD could benefit from an adjunct administration of the CERT-D program.

Longitudinal early epigenomic signatures inform molecular paths of therapy response and remission in depressed patients.

Introduction: The etiology of major depressive disorder (MDD) involves the interaction between genes and environment, including treatment. Early molecular signatures for treatment response and remission are relevant in a context of personalized medicine and stratification and reduce the time-to-decision. Therefore, we focused the analyses on patients that responded or remitted following a cognitive intervention of 8 weeks. Methods: We used data from a randomized controlled trial (RCT) with MDD patients (N = 112) receiving a cognitive intervention. At baseline and 8 weeks, blood for DNA methylation (Illumina Infinium MethylationEPIC 850k BeadChip) was collected, as well as MADRS. First, responders (N = 24; MADRS-reduction of at least 50%) were compared with non-responders (N = 60). Then, we performed longitudinal within-individual analyses, for response (N = 21) and for remission (N = 18; MADRS smaller or equal to 9 and higher than 9 at baseline), respectively, as well as patients with no change in MADRS over time. At 8 weeks the sample comprised 84 individuals; 73 patients had DNA methylation for both time-points. The RnBeads package (R) was used for data cleaning, quality control, and differential DNA-methylation (limma). The within-individual paired longitudinal analysis was performed using Welch's t-test. Subsequently gene-ontology (GO) pathway analyses were performed. Results: No CpG was genome-wide significant CpG (p < 5 × 10-8). The most significant CpG in the differential methylation analysis comparing response versus non-response was in the IQSEC1 gene (cg01601845; p = 1.53 × 10-6), linked to neurotransmission. The most significant GO-terms were linked to telomeres. The longitudinal response analysis returned 67 GO pathways with a p < 0.05. Two of the three most significant pathways were linked to sodium transport. The analysis for remission returned 46 GO terms with a p-value smaller than 0.05 with pathways linked to phosphatase regulation and synaptic functioning. The analysis with stable patients returned mainly GO-terms linked to basic cellular processes. Discussion: Our result suggest that DNA methylation can be suitable to capture early signs of treatment response and remission following a cognitive intervention in depression. Despite not being genome-wide significant, the CpG locations and GO-terms returned by our analysis comparing patients with and without cognitive impairment, are in line with prior knowledge on pathways and genes relevant for depression treatment and cognition. Our analysis provides new hypotheses for the understanding of how treatment for depression can act through DNA methylation and induce response and remission.

Immune gene co-expression signatures implicated in occurence and persistence of cognitive dysfunction in depression.

Cognitive dysfunction contributes significantly to the burden caused by Major Depressive Disorder (MDD). Yet, while compelling evidence suggests that different biological processes play a part in both MDD aetiology and the development of cognitive decline more generally, we only begin to understand the molecular underpinnings of depression-related cognitive impairment. Developments in psychometric assessments, molecular high-throughput methods and systems biology derived analysis strategies advance this endeavour. Here, we aim to identify gene expression signatures associated with cognitive dysfunction and cognitive improvement following therapy using RNA sequencing to analyze the whole blood-derived transcriptome of altogether 101 MDD patients who enrolled in the CERT-D study. The mRNA(Nova)Seq based transcriptome was analyzed from whole blood taken at baseline assessment, and patients' cognitive performance was measured twice at baseline and following eight weeks of therapy by means of the THINC integrated tool. Thirty-six patients showed comparatively low cognitive performance at baseline assessment, and 32 patients showed comparatively strong cognitive improvement following therapy. Differential gene expression analysis was performed using limma to a significance threshold of 0.05 and a logFC cutoff of |1.2|. Although we observed some indications for expression differences related to low cognitive performance and cognitive therapy response, signals did not withstand adjustment for multiple testing. Applying WGCNA, we retrieved altogether 25 modules of co-expressed genes and we used a combination of correlational and linear analyses to identify modules related to baseline cognitive performance and cognitive improvement following therapy. Three immune modules reflected distinct but interrelated immune processes (the yellow module: neutrophil-mediated immunity, the darkorange module: interferon signaling, the tan module: platelet activation), and higher expression of the yellow (r = -0.21, p < .05), the dark orange (r = 0.2, p < .05), and the tan (r = -0.23, p < .05) module correlated significantly negatively with patients' cognitive baseline performance. Patients' cognitive baseline performance was a significant predictor of the darkorange module (b = -0.039, p < .05) and the tan module's expression (b = 0.02, p < .05) and was close to becoming a significant predictor of the yellow module's expression (b = -0.02, p = .05). Furthermore, patients characterized by comparatively low cognitive performance at baseline showed significantly higher expression of the tan module when compared to all other patients F(1,97) = 4.32, p < .05, η= 0.04. Following eight weeks of treatment, we observed altogether significant improvement in patients' cognitive performance (b = 0.30, p < .001), and patients with comparatively high cognitive gain showed noticeably lower, but not significantly lower F(1,98) = 3.76, p = .058, expression of a dark turquoise module, which reflects complement and B-cell-associated immune processes. Noteworthy, the relation between cognitive performance and module expression remained observable after controlling for symptom severity and BMI, which partly accounted for variance in module expression. As such, our findings provide further evidence for the involvement of immune processes in MDD related cognitive dysfunction and they suggest that different immune processes contribute to the development and long-term persistence of cognitive dysfunction in the context of depression.

Epigenetic modification related to cognitive changes during a cognitive training intervention in depression.

BACKGROUND: DNA methylation as a biomarker is well suited to investigate dynamic processes, such as symptom improvement. For this study we focus on epigenomic state or trait markers as early signatures of cognitive improvement in individuals receiving a cognitive intervention. We performed a first epigenome-wide association study (EWAS) on patients with cognitive dysfunction in depression comparing those with vs without cognitive dysfunction and those cognitively improving vs non-improving following a cognitive intervention. METHOD: Data from a randomized controlled trial (RCT) were used for this analysis, where cognitive function of 112 patients randomly assigned to a personalized cognitive intervention was compared to standard cognitive treatment. Cognition was measured for this study using the four cognitive tasks from the THINC-it battery. We compared individuals with cognitive impairment with individuals without cognitive impairment at baseline and after a cognitive intervention of 8 weeks. Blood for DNA methylation analysis (Illumina Infinium MethylationEPIC 850 k BeadChip) was collected at baseline and 8 weeks into the treatment. For the baseline analysis, after quality control, the final sample comprised 90 individuals, and analyses at week 8 were performed on 84 individuals. Data cleaning, quality control, and differential methylation analysis of DNA methylation data was performed using the RnBeads package (R). Analyses were corrected for gender, age, depression score (MADRS), reported years of education, height and weight, as well as surrogate variables estimated by the pipeline used. The within-individual paired longitudinal analysis was performed using Welch's t-test. RESULTS: Analyses at baseline and at week 8 did not show any genome-wide significant CpGs (p < 5 × 10-8) comparing patients with and without cognitive impairment. The most significant result in the baseline analysis comparing the groups with and without cognitive impairment at baseline is located in an open Sea region with predominantly regulatory qualities (cg10962945; 6.61 × 10-7). The most significant CpG at 8 weeks was also located in open sea, though in exon 13 of the NTRK2-gene, linked to the BDNF pathway (cg13620631, 5.56 × 10-7). Finally, a within-individual paired longitudinal analysis with only patients that show improved cognitive function over time was performed, showing 65 CpGs that overlapped between the 1% most significant of this analysis and the 1% most significant CpGs from the cross-sectional analysis at 8 weeks. CONCLUSION: Our result suggest that DNA methylation can be suitable to capture early signs of treatment response of a cognitive intervention in depression. In our layered approach we could capture dynamics that can help differentiate between biological trait and state markers of cognitive function in depression. Despite not being genome-wide significant, the CpG locations returned by our analysis comparing patients with and without cognitive impairment, are in line with prior knowledge on pathways and genes relevant for depression treatment and cognition.

Psychological training to improve psychosocial function in patients with major depressive disorder: A randomised clinical trial.

Cognitive and emotional remediation training for depression (CERT-D): a randomised controlled trial to improve cognitive, emotional and functional outcomes in depression The aim of the current study was to evaluate an experimental treatment designed to improve psychosocial function in patients with Major Depressive Disorder (MDD) by reinforcing cognitive, emotional, and social-cognitive abilities. Participants (N = 112) with current or lifetime MDD were recruited to participate in a randomised, blinded, controlled trial. Exclusion criteria included diagnosis of a substance abuse disorder, bipolar disorder organic, eating disorders, or illness which affect cognitive function. The treatment involved repeated cognitive training designed to improve cognitive, emotional, and social-cognitive abilities. In training sessions, the principles of cognitive training were applied across cognitive, emotional, and social domains, with participants completing repeated mental exercises. Exercises included critically analysing interpretations of social interactions (e.g., body language), exploring emotional reactions to stimuli, and completing game-like cognitive training tasks. Training sessions placed great emphasis on the application of trained cognitive, emotional, and social cognitive skills to psychosocial outcomes. Outcomes demonstrated significant improvement in psychosocial function, symptom severity, self-reported cognition, and social-cognition. Our findings demonstrate the efficacy of multi-domain cognitive training to improve psychosocial functioning in individuals with MDD. We suggest that the present treatment could be deployed at a lower cost and with minimal training in comparison to established psychological therapies.

The association of cognitive deficits with mental and physical Quality of Life in Major Depressive Disorder.

BACKGROUND: Patients with Major Depressive Disorder experience significantly reduced subjective Quality of Life (QOL), including impaired social and emotional functioning and greater fatigue and physical pain. Mounting evidence suggests that cognitive dysfunction (e.g., deficits in memory, executive function) contributes independently to the onset of reduced QOL, however the domain-specific nature of this relationship has not been investigated. The present study examined the relationship between specific cognitive domains (e.g., attention, spatial cognition) and specific deficits in mental and physical QOL in subjects with lifetime MDD, as well as acutely depressed, remitted and healthy participants. METHODS: Data were obtained (N = 387) from the Cognitive Function and Mood Study (COFAMS), a cross-sectional study of emotional, functional and cognitive status in individuals with mood disorders. Participants' (acutely depressed n = 93, remitted n = 170, and healthy control n = 124) QOL was assessed with the 36-Item Short Form Health Survey (SF-36) and cognitive functioning was evaluated with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), the Colorado Assessment Tests (CATs) and the Psychology Experiment Building Language (PEBL). RESULTS: Analyses revealed that poor immediate and delayed memory were associated with reduced mental QOL in individuals with lifetime MDD, acutely depressed, and healthy controls. In contrast, cognitive functioning was not associated with mental QOL in remitted patients. No cognitive domains were significantly related to physical QOL in any participant group. CONCLUSIONS: The result suggests that deficits in immediate and delayed memory may contribute to reduced mental QOL in acute MDD, whereas cognition does not appear to play a role in physical QOL. Memory should be considered important cognitive treatment targets for MDD patients suffering specifically from reduced mental QOL.

The Direct and Indirect Relationship Between Social Cognition and Psychosocial Dysfunction in Major Depressive Disorder.

Background: Recent evidence suggests that depressed patients experience social cognitive deficits (e.g., poor affect recognition). However, very little is known regarding the contribution of social cognitive deficits to psychosocial dysfunction (e.g., occupational functioning). In particular, the mechanistic roles of depression severity and cognitive deficits (e.g., memory) in this domain have not been explored. The current study evaluated the extent to which mood symptoms and cognitive deficits provide a mechanistic explanation for the relationship between social cognitive and psychosocial deficits in major depressive disorder (MDD). Methods: Data were obtained from 111 participants with MDD (75 Female, mean age = 35, 84% Caucasian, 12% Asian, 4% Other) in the Cognitive Function and Mood Study (CoFaM-S), a cross-sectional study of mood, social cognition, cognition, and psychosocial functioning in mood disorders. Social cognitive abilities were assessed using the Social Perception subtest of the Wechsler Adult Intelligence Scale, and psychosocial dysfunction was clinically evaluated with the Functioning Assessment Short Test (FAST). Results: Cognitive deficits and mood symptoms did not significantly mediate relationships between social cognitive ability and psychosocial dysfunction. The exception was executive function, which mediated an indirect relationship between meaning interpretation (i.e., theory of mind) and self-perceived cognitive dysfunction. Conclusion: The results suggest that the relationship between social cognitive deficits and psychosocial dysfunction is not mechanistically explained by mood symptoms or nonsocial cognition. Development of treatment strategies targeting social cognitive deficits in patients with MDD is warranted.

Contemporary methods of improving cognitive dysfunction in clinical depression.

INTRODUCTION: Cognitive dysfunction is prevalent in patients with major depressive disorder (MDD), with deficits observed across several domains (e.g., executive function, memory, attention). While depression alone is disabling, patients with cognitive deficits typically experience greater functional impairments, poorer clinical recovery, and reduced quality of life. Consequently, it is imperative to elucidate recent advances in our understanding of the treatment of cognitive dysfunction in MDD. Areas covered: This review spans psychological, physical, and pharmacological treatment approaches for cognitive dysfunction in depression. Where possible, the authors summarise where treatments have demonstrated efficacy in improving specific cognitive domains (e.g., attention), and highlight the differential mechanisms which underpin cognitive improvement. In addition, the roles of adjunctive cognitive treatments (e.g., exercise), and the possible side effects and drawbacks of specific treatments are explored. Expert opinion: Psychological treatments typically confer cognitive improvement alongside functional and/or clinical recovery; however, the efficacy of cognitive training and cognitive behavioral therapy to longitudinal cognitive improvement remains to be established. Recently developed pharmacological agents may improve cognition by reducing low-grade inflammation and promoting neurogenesis; however, the pro-cognitive effects of typical antidepressants are limited. Integrated approaches which emphasize cognitive recovery alongside clinical and functional improvement may be key to advancing patient outcomes.

Social cognitive abilities predict psychosocial dysfunction in major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is associated with social cognitive deficits (e.g., poor affect recognition and impaired theory of mind). However, the contribution of social cognitive issues to psychosocial dysfunction in MDD (e.g., occupational functioning and interpersonal relationships) has not been investigated. The current study evaluated the relationship between specific social cognitive domains (e.g., prosody interpretation) and psychosocial dysfunction in subjects with lifetime MDD, as well as currently depressed, remitted, and healthy controls (HCs) subjects. METHOD: Data were obtained from 213 participants in the Cognitive Function and mood study (CoFaMS), a cross-sectional study of mood, social cognition, cold cognition, and psychosocial functioning in mood disorders. Participants' (current MDD n = 42, remitted MDD n = 69, and HCs n = 102) social cognitive abilities were assessed using the Social Perception subtest of the Wechsler Adult Intelligence Scale, and psychosocial dysfunction was clinically evaluated with the Functioning Assessment Short Test (FAST). RESULTS: The results indicated that prosody interpretation, but not facial affect or meaning interpretation, was associated with psychosocial dysfunction in subjects with lifetime MDD, as well as remitted MDD subjects relative to HCs. In contrast, social cognition was not associated with functioning in participants with current MDD or in HCs. CONCLUSIONS: These results suggest that the relationship between social cognition and psychosocial functioning differs between the acute and remitted stage of illness in MDD, and that prosody interpretation should be considered a treatment target in patients with residual psychosocial issues.

Cognitive Deficits in the THINC-Integrated Tool (THINC-it) Are Associated With Psychosocial Dysfunction in Patients With Major Depressive Disorder.

OBJECTIVE: To evaluate the extent to which cognitive measures in the recently developed THINC-integrated tool (THINC-it) are associated with global and domain specific psychosocial disability in patients with current and remitted major depressive disorder (MDD). METHODS: Cross-sectional data (N = 127) were obtained from participants with current (n = 105) or remitted (n = 22) MDD who completed the THINC-it between July 2014 and June 2018. Major depressive disorder was diagnostically assessed with DSM-IV and DSM-5 criteria. The THINC-it includes 4 objective cognitive tests: the Spotter (ie, Choice Reaction Time), Symbol Check (ie, n-back), CodeBreaker (ie, Digit Symbol Substitution), and Trails (ie, Trail Making Test part B), as well as a measure of self-perceived cognitive deficits, the Perceived Deficits Questionnaire for Depression-5-item (PDQ-5-D). Psychosocial dysfunction was assessed with the Functioning Assessment Short Test. RESULTS: The whole group analysis (ie, lifetime MDD) indicated that poor objective cognitive performance on the CodeBreaker (ß = 0.346, P = .002) and Trails tasks (ß = 0.232, P = .017) and greater self-reported cognitive deficits on the PDQ-5-D (ß = 0.596, P < .001) were associated with more severe global psychosocial disability. In addition, performance on the CodeBreaker and Trails tasks showed dissociable relationships with specific psychosocial deficits (eg, occupational functioning, daily autonomy). The relationship between cognitive and psychosocial deficits was stronger in participants with current compared to remitted MDD. CONCLUSIONS: Cognitive deficits identified by the THINC-it are associated with global and specific psychosocial deficits, highlighting the clinical value and utility of the THINC-it as a cognitive screening instrument in patients with MDD.

Executive Function and Spatial Cognition Mediate Psychosocial Dysfunction in Major Depressive Disorder.

Background: Cognitive and psychosocial dysfunction are prevalent and disabling features of Major Depressive Disorder (MDD). Emerging evidence suggests that poor cognitive functioning mediates the negative effect of MDD on psychosocial function. However, there is a lack of research examining the domain-specific nature of this relationship. The current study evaluated whether the relationship between MDD and specific psychosocial subdomains (e.g., autonomy, occupational functioning) was mediated by domain-specific cognitive deficits. Methods: Data from 155 participants was obtained from the Cognitive Function and Mood Study (CoFaMS), a cross-sectional analysis of mood, cognition, social cognition, and functioning in individuals with MDD. Cognitive functioning was assessed (Current MDD n = 45, Healthy n = 110), with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), the Colorado Assessment Tests (CATs), and the Psychology Experiment Building Language (PEBL). Psychosocial functioning was clinically evaluated with the Functioning Assessment Short Test (FAST). Results: The results indicated that spatial cognition and executive functioning partially mediated the negative effect of MDD on overall psychosocial functioning, autonomy, and subjective cognition. In contrast, spatial and executive domains showed divergent mediation patterns on interpersonal relationships and leisure time. Conclusions: The findings suggest that executive and spatial cognition play an important role in the pathology of overall psychosocial functioning, and specific functional issues in MDD. Treatments targeting psychosocial recovery in MDD may be improved by emphasizing executive and spatial cognitive remediation.

The clinical relationship between cognitive impairment and psychosocial functioning in major depressive disorder: A systematic review.

Cognitive deficits are frequently observed in major depressive disorder (MDD), as well as impaired long-term psychosocial functioning. However, the relationship between cognitive deficits and psychosocial functioning in MDD is under-investigated. We aim to systematically review the literature on the relationship between specific cognitive impairments and psychosocial functioning in MDD. We systematically reviewed English-language literature in PubMed, PsychINFO, Scopus and Web of Science using search terms related to psychosocial functioning. Additional studies were identified by searching reference lists. Following our inclusion/exclusion criteria, 28 studies were reviewed. Inclusion criteria included age (> 18), MDD diagnosed by standard tools (e.g., DSM-IV), use of cognitive and psychosocial assessments. Cross-sectional studies indicated that cognitive deficits in domains of executive functioning, attention, memory, and global cognition are associated with psychosocial dysfunction in domains of as quality of life, and social, occupational, and global functioning. The cognition-functioning relationship was also observed in longitudinal studies, showing that only specific cognitive domains affected psychosocial outcomes over the long-term course of illness. Older age and greater MDD symptom severity appear to enhance cognition-psychosocial dysfunction relationship, however little is known regarding the role of a number of other clinical factors (e.g., psychosis, illness duration).

Executive Subdomains Are Differentially Associated With Psychosocial Outcomes in Major Depressive Disorder.

Background: Deficits in executive functioning are frequently associated with poor psychosocial outcomes in Major Depressive Disorder (MDD). However, there is a poor understanding of the domain-specific relationships between executive subdomains (e.g., forward planning, decision making) and specific psychosocial issues (e.g., occupational functioning, social relationships). The current study explored these relationships across currently depressed and remitted MDD patients, as well as a healthy control group. Methods: Data from 142 participants were obtained from the Cognitive Functioning and Mood Study (CoFaM-S), a cross sectional study of mood, cognition, and psychosocial functioning in mood disorders. Participants' [current depression n = 31, remitted depression n = 52, healthy controls (HC) n = 59] executive functioning was evaluated with well-established tests of executive subdomains (i.e., Tower of London, card sorting, Stroop task). The Functioning Assessment Short Test (FAST) was employed to clinically evaluate psychosocial dysfunction. Results: The results indicated that forward planning was most strongly associated with psychosocial issues in the current depression group as compared to HCs, while cognitive updating was primary in the remitted group vs. HC. Conclusions: These findings suggest that executive subdomains are deferentially associated with psychosocial issues across different stages of depressive illness, and that forward planning and cognitive updating should be considered in adjunctive cognitive treatment.

Cognitive dysfunction in major depressive disorder.

PURPOSE OF REVIEW: The principal aim of this review is to highlight recent advances in our understanding of cognitive dysfunction in major depressive disorder (MDD). We review new assessment and treatment approaches, in which cognition and associated psychosocial dysfunction are considered primary outcomes. RECENT FINDINGS: Current work suggests that cognitive dysfunction reduces occupational productivity, and interferes broadly with domains of day-to-day and social functioning. These findings imply that cognitive dysfunction interacts with emotional and social factors relevant to MDD. Recent advances in screening instruments enable standardized detection of cognitive symptoms in MDD. Clinical trials suggest that cognitive symptoms are suitable targets and primary outcomes of psychological and pharmacological treatments. SUMMARY: A growing interest in cognitive dysfunction in MDD has improved our ability to assess and treat MDD. Future research will be strengthened by the use of consistent terminology, standardized cognitive screening, and treatments that target cognitive dysfunction in MDD. Integration of emotional and social treatment strategies may further advance clinical efficacy.