Cognitive Impairment In Major Depressive Disorder Research Articles

Childhood Adversity, Cognition, and Response to Cognitive Remediation in Major Depressive Disorder.

Cognitive impairment is experienced by many individuals with major depressive disorder (MDD) and is significantly related to sustained disability. Recent work has begun to explore the relationship between childhood adversity (CA) and cognitive impairment in MDD, but this work is limited by unreliable measures of CA. Furthermore, no previous research has examined whether CA relates to cognitive remediation response. The current study clarifies how CA and clinical characteristics of illness explain cognitive variance. In addition, we investigate whether CA is associated with response to cognitive remediation. Thirty-nine individuals who completed cognitive remediation were rerecruited to complete a retrospective interview on CA. Results showed that CA, repeated depressive episodes, and earlier age at diagnosis were associated with poorer cognition. We did not observe a difference in treatment response based on CA. Findings suggest that CA is an important variable to consider when examining the expression of depressive illness and areas for intervention.

Cognitive dysfunction and neurometabolic alternations in major depressive disorder with gastrointestinal symptoms

BackgroundBrain biochemical abnormalities have been associated with major depressive disorder (MDD) and cognitive impairments. However, the cognitive performance and neurometabolic alterations of MDD patients accompanied by gastrointestinal (GI) symptoms remain to be elucidated. We aimed to reveal the features and correlation between cognitive impairments and brain biochemical abnormalities of depressed patients with GI symptoms. MethodsFifty MDD patients with GI symptoms (GI group), 46 patients without GI symptoms (NGI group) and 50 demographically matched healthy controls (HCs) underwent Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) assessments. In addition, proton magnetic resonance spectroscopy (1H-MRS) was used to obtain ratios of N-acetyl aspartate to creatine (NAA/Cr) and choline-containing compounds to creatine (Cho/Cr) in the thalamus, putamen and anterior cingulate cortex (ACC). Finally, association analysis was conducted to investigate the relationships of these measurements. ResultsCompared to HCs, participants in both the GI and NGI groups had significantly reduced performance in the six MCCB cognitive domains (all p < 0.05), except for reasoning and problem solving. Higher Cho/Cr ratios in the right thalamus (p < 0.05) and lower NAA/Cr ratios in the left putamen (p < 0.05) were found in the NGI group than in the GI group. The severity of GI symptoms was negatively correlated with Cho/Cr ratios in the right ACC (r = −0.288, p = 0.037). In addition, the T-scores of visual learning were negatively correlated with NAA/Cr ratios in the right ACC (r = −0.443, p = 0.001) and right thalamus (r = −0.335, p = 0.015). ConclusionOur findings suggest that MDD patients with GI symptoms may exhibit greater neurometabolic alternations than those without GI symptoms, while both show similar cognitive dysfunction. In addition, neurometabolic alterations in the ACC and thalamus may underlie the neural basis of GI symptoms and cognitive impairment in MDD.

Cognitive factor structure and measurement invariance between healthy controls and patients with major depressive disorder

Cognitive impairments are crucial in functional outcomes of major depressive disorder (MDD). The effectiveness of currently available treatment methods for cognitive deficits is suboptimal. A cognitive test battery is often applied to evaluate cognition with multiple interrelated and difficult-to-interpret outcomes. Generating cognitive factor scores after the confirmation of a common cognitive structure and measurement invariance between healthy controls (HCs) and patients may aid in understanding cognition further. This methodology has been applied for several neuropsychiatric disorders, but not for MDD. Therefore, we conducted a series of exploratory factor analyses (EFA), confirmatory factor analyses (CFA), and multiple groups CFA (MGCFA) for a cognitive test battery in HCs and patients with MDD. The initial EFA of 106 HCs yielded a three-factor model—comprising attention, memory, and executive function. The CFA confirmed the initial model in other 94 HCs with revisions, which reasonably fit the cognitive data of 54 patients with MDD. MGCFA supported the measurement invariance of the determined model between HCs and patients with MDD. The associations of cognitive factor scores with age or education and the effect sizes of group differences in cognitive factor scores externally validated the determined model. In conclusion, this is the first study to demonstrate the measurement invariance of a cognitive model between HCs and patients with MDD using MGCFA. The measurement invariance substantiated valid group comparisons of factor scores and their relationships with other markers. The current results may be applicable for the development of improved treatment strategies for cognitive impairments in MDD.

Brain function mediates the association between low vitamin D and neurocognitive status in female patients with major depressive disorder.

Vitamin D is engaged in various neural processes, with low vitamin D linked to depression and cognitive dysfunction. There are gender differences in depression and vitamin D level. However, the relationship between depression, gender, vitamin D, cognition, and brain function has yet to be determined. One hundred and twenty-two patients with major depressive disorder (MDD) and 119 healthy controls underwent resting-state functional MRI and fractional amplitude of low-frequency fluctuations (fALFF) was calculated to assess brain function. Serum concentration of vitamin D (SCVD) and cognition (i.e. prospective memory and sustained attention) were also measured. We found a significant group-by-gender interaction effect on SCVD whereby MDD patients showed a reduction in SCVD relative to controls in females but not males. Concurrently, there was a female-specific association of SCVD with cognition and MDD-related fALFF alterations in widespread brain regions. Remarkably, MDD- and SCVD-related fALFF changes mediated the relation between SCVD and cognition in females. Apart from providing insights into the neural mechanisms by which low vitamin D contributes to cognitive impairment in MDD in a gender-dependent manner, these findings might have clinical implications for assignment of female patients with MDD and cognitive dysfunction to adjuvant vitamin D supplementation therapy, which may ultimately advance a precision approach to personalized antidepressant choice.

Cognitive Dysfunction in Mood Disorder: Similarities and Differences Between Depression Subtypes

Cognitive dysfunction is common in depression. Depression is heterogeneous conditions that comprise biologically diverse subtypes. This manuscript reviewed the similarities and differences in cognitive function between major depressive disorder (MDD) and bipolar disorder (BD). Relatively few studies have compared the cognitive function in BD and MDD; furthermore, the differences might exist between BD types I and II. The neurobiological background of cognitive impairment in MDD and BD involves structural and functional disturbances in neural circuits, as well as disturbances in the connectivity of cognitive networks. Several clinical factors such as symptom severity, onset age, premorbid IQ, psychotic features, and illness course may influence cognitive dysfunction in depression. To understand the differences between the cognitive dysfunctions of MDD and BD, the aforementioned features should be controlled. Setting a standard of evaluating cognitive functions in various mood disorders will be a critical step for future studies. [ Psychiatr Ann . 2022;52(3):100–104.]

A Multi-Center Study for the Development of the Taiwan Cognition Questionnaire (TCQ) in Major Depressive Disorder.

Cognitive dysfunction is associated with functional impairment of patients with Major Depressive Disorder (MDD). The goals were to explore the associated factors of cognitive impairment in MDD and to develop and validate a brief and culture-relevant questionnaire, the Taiwan Cognition Questionnaire (TCQ), among patients with MDD. This was a cross-sectional, multi-center observational study of MDD patients in Taiwan. Participants of Group 1 from 10 centers contributed to the validation of the TCQ by their response and sociodemographics. The participants of Group 2 from one center received an objective cognitive assessment for clarification of the relationship between the TCQ score and its associated factors. In Group 1, 493 participants were recruited. As for Group 2, an extra 100 participants were recruited. The global Cronbach’s alpha for the TCQ was 0.908. According to the coordinates of the ROC curve, 9/10 was the ideal cut-off point. With the criteria, the sensitivity/specificity of the TCQ was 0.610/0.689. The TCQ score was positively associated with a history of being admitted to acute psychiatric care and the severity of depression and negatively associated with objective cognitive measures. The TCQ provides a reliable, valid, and convenient measure of subjective cognitive dysfunction in patients with MDD.

Olfactory Dysfunction: Its Association With Subjective Cognitive Impairment in Patients With Major Depression.

Olfactory disorders may be observed together with cognitive impairment in patients with major depressive disorder (MDD). This study compared olfactory performances between patients with MDD and healthy controls and investigated the relationship between olfactory performance and subjective cognitive impairment in these patients. This study included 52 patients diagnosed with MDD and 46 healthy controls. The participants were evaluated in terms of their olfactory capacities (threshold, discrimination, and identification), subjective cognitive impairment, and depression. Although the olfactory threshold (OT) and olfactory discrimination scores were lower in patients with MDD compared with those in the control group, their olfactory identification scores did not differ significantly. OT was negatively correlated with subjective cognitive impairment and may serve as a determinant for subjective cognitive changes. Consequently, patients with MDD had lower olfactory performances compared with healthy controls. Finally, OT may be a component of subjective cognitive impairment in MDD.

Anomalous functional connectivity within the default-mode network in treatment-naive patients possessing first-episode major depressive disorder.

Background and Objective:Previous studies have shown that the default-mode network (DMN) has a substantial role in patients with major depressive disorder (MDD). However, there is a shortage of information regarding variations in the functional connectivity (FC) of the DMN of treatment-naive patients with first-episode MDD. The present study aims to explore the FC of the DMN in such patients.Methods:The study population consisted of 33 patients and 35 controls, paired regarding age, gender, education level, and health condition. Depression severity was assessed through the Hamilton Depression Scale (HAM-D), and subjects underwent evaluation during the resting-state through functional magnetic resonance imaging (rs-fMRI). To assess the result, we used FC and ICA. We used Spearman's correlation test to detect potential correlations between anomalous FC and severity of HAM-D scores.Results:We have found a decreased FC in the left medial orbitofrontal gyrus (MOFG) and right marginal gyrus (SMG) in depressive patients compared to controls. There was a negative correlation between abnormal FC in the right SMG and HAM-D scores. We have not found any increase in FC of the DMN in treatment-naive, first-episode of MDD patients.Conclusions:Our study provided evidence of a negative correlation between abnormal FC in the DMN and severity of depression symptoms measured by HAM-D in treatment-naive MDD patients. This finding could shed some light on the relevance of DMN for understanding the pathophysiology of cognitive impairment in MDD.

The Effects of Bilateral Theta-burst Stimulation on Executive Functions and Affective Symptoms in Major Depressive Disorder

Major depressive disorder (MDD) is characterized by severe affective as well as cognitive symptoms. Moreover, cognitive impairment in MDD can persist after the remission of affective symptoms. Theta-burst stimulation (TBS) is a promising tool to manage the affective symptoms of major depressive disorder (MDD); however, its cognition-enhancing effects are sparsely investigated. Here, we aimed to examine whether the administration of bilateral TBS has pro-cognitive effects in MDD. Ten daily sessions of neuronavigated active or sham TBS were delivered bilaterally over the dorsolateral prefrontal cortex to patients with MDD. The n-back task and the attention network task were administered to assess working memory and attention, respectively. Affective symptoms were measured using the 21-item Hamilton Depression Rating Scale. We observed moderate evidence that the depressive symptoms of patients receiving active TBS improved compared to participants in the sham stimulation. No effects of TBS on attention and working memory were detected, supported by a moderate-to-strong level of evidence. The effects of TBS on psychomotor processing speed should be further investigated. Bilateral TBS has a substantial antidepressive effect with no immediate adverse effects on executive functions.

Linking peripheral IL-6, IL-1β and hypocretin-1 with cognitive impairment from major depression

BackgroundCognitive impairment has long challenged the patients with major depressive disorder (MDD), hypocretins and inflammation have recently been implicated in cognitive function. However, limited studies have compressively assessed their associations with cognitive impairment in MDD. MethodsA total of 100 MDD patients and 100 healthy controls (HC) were recruited for this study. They were tested with HAMD, HAMA, and MCCB scales. The plasma level of selected inflammatory factors (IL-1β, IL-6, and TNF-α) and hypocretin-1 were determined using enzyme-linked immunosorbent assay (ELISA). Correlation analysis was performed to explore the relationship between the plasma level of the factors and clinical performances. ResultsPatients with MDD showed cognitive impairment in each MCCB subdomain except working memory compared with HC. The levels of IL-6, IL-1β and hypocretin-1 in MDD patients were higher than HC. Besides, IL-1β levels was negatively correlated with overall cognitive function in the combined group. Hypocretin-1 was positively correlated with socially cognitive impairment in MDD patients. A negative correlation between plasma hypocretin-1 levels and HAMA scales was also observed in MDD patients. LimitationThe study was cross-sectional, thereby limiting causal inference, and had a relatively small sample size. There are no subcategories for MDD based on characteristics. ConclusionIL-1β, IL-6 and Hypocretin-1 were reported as potential factors involved in MDD pathology. Hypocretin-1 could contribute to the biological mechanisms of anxiety relief. Hypocretin-1, therefore, may be important in exploring the pathological mechanisms of social cognitive impairment in MDD patients. Conclusively, this study provides new insights for exploring cognitive impairment in depression.

Procognitive Effects of Antidepressants and Other Therapeutic Agents in Major Depressive Disorder: A Systematic Review.

To review the efficacy of antidepressants and other therapeutic agents for the treatment of cognitive impairment in adults with major depressive disorder (MDD). We conducted a database search of MEDLINE, PsycINFO, and Embase through Ovid on May 7, 2019. The year of publication was not restricted. The search terms "Major Depressive Disorder," "depress*," "cognit*," and "therapeutics" were used. The studies included in this review were clinical trials of antidepressants and other therapeutic agents in MDD populations. Participants were aged between 18 and 65 years and had a DSM-III, -IV, or -5 diagnosis of MDD. In total, 2,045 research papers were screened, 53 full-text articles were assessed, and 26 articles were eligible to be included in this systematic review. The data and quality of research papers were assessed and screened by 2 independent reviewers. Discrepancies were resolved through a third reviewer. Overall, studies demonstrated that tricyclic antidepressants do not have procognitive effects, while vortioxetine and bupropion have demonstrated procognitive effects in MDD populations relative to selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors. Several non-antidepressant agents, such as modafinil, amphetamines, and erythropoietin, have also demonstrated significant positive effects on cognition in depression. Present-day antidepressants and other agents have demonstrated procognitive effects in MDD, but the findings between various agents are mixed. Further research looking at objective measures of cognitive performance would be helpful to obtain more definitive results regarding the efficacy of therapeutics for cognitive impairment in MDD.

Vortioxetine for Cognitive Enhancement in Major Depression: From Animal Models to Clinical Research.

Objectives: Vortioxetine has already shown its efficacy in the acute and long-term treatment of major depressive disorder (MDD) and its potential interest in the prevention of relapse. The aim of this study was to review the current status of knowledge regarding its cognitive effects. Methods: We conducted a review of key data obtained from preclinical behavioral models and clinical trials in MDD focusing on vortioxetine-induced cognitive changes. Results: In animals, acute and chronic administration of vortioxetine improves performance on objective measures that cover a broad range of cognitive domains. In human, vortioxetine appears to be a useful treatment option in MDD patients with cognitive dysfunction. Conclusion: Vortioxetine constitutes a promising treatment for treatment of cognitive impairment in MDD, but its place in the therapeutic armamentarium still needs to be determined.

Evening preference and poor sleep independently affect attentional-executive functions in patients with depression

Cognitive impairments are well documented in major depressive disorder (MDD), however, they cannot be fully explained by depressive symptom severity. We investigated how diurnal preference and sleep quality affect cognitive function in MDD. In 34 inpatients with current MDD and 29 healthy controls (HC), we obtained diurnal preference (Morningness-Eveningness Questionnaire, MEQ) and subjective sleep quality (Pittsburgh Sleep Quality Index, PSQI). Further, current mood and neuropsychological performance (Trail Making Test, TMT, part A and B) were assessed in the evening and in the following morning. Patients with MDD performed worse than HC on the TMT-B (particularly requiring executive function), but not on the TMT-A (assessing foremost visuomotor processing speed). In general, participants with evening preference (MEQ-score median split) performed poorer on the TMT than participants with morning preference. Subgroup analyses within MDD confirmed the negative effect of evening preference on the TMT. In addition, patients with severely impaired sleep quality (PSQI > 10) performed cognitively worse than patients with normal to moderately impaired sleep quality (PSQI ≤ 10). The results were largely independent of current mood state. Our findings suggest that evening preference and severely impaired sleep quality independently contribute to cognitive impairment in MDD.

Recognition and Treatment of Cognitive Dysfunction in Major Depressive Disorder.

Major Depressive Disorder (MDD) is a prevalent, chronic, disabling, and multidimensional mental disorder. Cognitive dysfunction represents a core diagnostic and symptomatic criterion of MDD, and is a principal determinant of functional non-recovery. Cognitive impairment has been observed to persist despite remission of mood symptoms, suggesting dissociability of mood and cognitive symptoms in MDD. Recurrent impairments in several domains including, but not limited to, executive function, learning and memory, processing speed, and attention and concentration, are associated with poor psychosocial and occupational outcomes. Attempts to restore premorbid functioning in individuals with MDD requires regular screenings and assessment of objective and subjective measures of cognition by clinicians. Easily accessible and cost-effective tools such as the THINC-integrated tool (THINC-it) are suitable for use in a busy clinical environment and appear to be promising for routine usage in clinical settings. However, antidepressant treatments targeting specific cognitive domains in MDD have been insufficiently studied. While select antidepressants, e.g., vortioxetine, have been demonstrated to have direct and independent pro-cognitive effects in adults with MDD, research on additional agents remains nascent. A comprehensive clinical approach to cognitive impairments in MDD is required. The current narrative review aims to delineate the importance and relevance of cognitive dysfunction as a symptomatic target for prevention and treatment in the phenomenology of MDD.

Cross-sectional relationship between kynurenine pathway metabolites and cognitive function in major depressive disorder

ObjectiveCognitive impairment is common among patients with major depressive disorder (MDD), but its pathological mechanism is complex and not fully understood. Evidence suggests that the kynurenine (KYN) pathway may be implicated in the pathophysiology of depression, but few studies have explored the association between the KYN pathway and cognitive impairment in MDD. Our aim was to examine the relationship between cognitive impairment and KYN pathway metabolites in patients with MDD. MethodsA total of 146 patients with MDD according to DSM-V and 72 healthy controls (HCs) were enrolled, and the severity of depressive symptoms using the 17-item Hamilton Depression Rating Scale (HAMD-17) and cognitive performance including speed of processing, working memory, visual learning and verbal learning were assessed. Blood samples were collected, and serum concentrations of tryptophan (TRP), kynurenine (KYN) and kynurenic acid (KYNA) were measured by liquid chromatography-tandem mass spectrometry. ResultsIn females with MDD, there was a significant negative association between the KYN level and verbal learning (B=-0.039, adjusted p = 0.018), and the KYN/TRP ratio was negatively correlated with speed of processing (B=-470.086, adjusted p = 0.029), verbal learning (B=-544.251, adjusted p = 0.002) and visual learning (B=-513.777, adjusted p = 0.004). Those associations were not present in male individuals with MDD or in HCs, except for a significant negative correlation between the KYNA/KYN ratio and category fluency (B=−0.373, adjusted p = 0.039) in female HCs. ConclusionOur results suggest that learning function and speed of processing in female MDD were associated with KYN serum level and the KYN/TRP ratio, potentially implicating the KYN pathway in the pathological mechanism of cognitive function in female MDD.

Cerebral blood flow modulations during cognitive control in major depressive disorder

BackgroundThis study investigated cerebral blood flow modulations during proactive and reactive cognitive control in major depressive disorder (MDD). Proactive control refers to preparatory processes during anticipation of a behaviorally relevant event; reactive control is activated after such an event to ensure goal attainment. MethodsUsing functional transcranial Doppler sonography, blood flow velocities in the middle cerebral arteries of both hemispheres were recorded in 40 MDD patients and 40 healthy controls during a precued Stroop task. The font color of color words, which appeared 5 s after an acoustic warning signal, had to be indicated while ignoring word meaning. ResultsPatients, as compared to controls, exhibited smaller bilateral blood flow increases during task preparation and larger increases after color word presentation. Response time was longer in patients irrespective of the match or mismatch between font color and word meaning. The blood flow increase after word presentation correlated positively with response time. LimitationsPotential effects of psychotropic medication on cognition and cerebral blood flow could not be controlled. ConclusionsThe study revealed evidence of reduced cortical activity during proactive and elevated activity that occurs during reactive control in MDD. Deficient implementation of proactive control in MDD may lead to increased reliance on reactive control. The association between the blood flow increase after color word presentation and poorer performance indicates that deficient response preparation cannot be compensated for by reactive strategies. The findings are clinically relevant, as they may contribute to our understanding of the mechanisms relevant to cognitive impairments in MDD.

Pharmacological Treatment of Cognitive Symptoms in Major Depressive Disorder.

Cognitive dysfunction is a core transdiagnostic domain of Major Depressive Disorder (MDD) and is a principal determinant of functional recovery. However, it has been insufficiently targeted within the current therapeutic framework for MDD. To highlight these unmet cognitive needs in MDD. An article search was conducted using PubMed from inception to November 2016: Major Depressive Disorder (and/or variant) was cross-referenced with the following terms: antidepressants, augmentation, cognition, cognitive deficits, cognitive dysfunction, functional outcomes, mechanism of action, and treatment. Articles informed by observational studies, clinical trials, and review articles relevant to the discussion of cognition and cognitive impairment in MDD were included for review. Additional terms and citations previously not identified in the initial search were obtained from a manual review of article reference lists. Cognitive deficits in MDD are replicable, non-specific, and clinically significant. Abnormalities in the domains of learning/memory, executive function, attention, concentration, and processing speed are consistently reported. Only two antidepressants (i.e., duloxetine and vortioxetine) have established procognitive effects utilizing rigorous methodology in MDD. Most antidepressants improve cognitive function(s), but the extent to which they directly exert pro-cognitive effects is not yet understood. Cognitive dysfunction in MDD is a principal determinant of patient-reported outcomes (e.g., psychosocial function). Healthcare providers are encouraged to screen for cognitive dysfunction in MDD and familiarize themselves with the efficacy profiles of antidepressants on disparate cognitive domains.

Cognitive Impairments in Unipolar Depression: The Impact of Rumination

Background: Major depressive disorder (MDD) is associated with impairments in several cognitive domains. People with depression also tend to focus on and think about their problems (“ruminate”) more than people without depression. Recent studies indicate that depressive rumination is connected to cognitive impairments in MDD. However, there is little scientific understanding of the role of rumination in these deficits. Sampling and Methods: The current study examined the performance of 62 outpatients suffering from unipolar major depression with a low tendency to ruminate versus outpatients with a high tendency to ruminate using a neuropsychological battery covering the 5 cognitive domains: attention, memory, working memory, executive functions and processing speed. Results: The results indicated that high ruminators show a lower performance than low ruminators with regard to processing speed and executive function tasks with low effect sizes. However, these findings were not significant after Bonferroni correction. Hierarchical linear regression revealed that the effect on processing speed could be partially attributed to rumination, but an effect on executive functions was not established. Conclusions: The current study is the first to systematically investigate the impact of rumination on cognitive impairments in MDD, exploring a broad range of cognitive domains. The results partially support the hypothesis that rumination has an impact on single cognitive domains and highlight the necessity for further investigations in order to generalize these findings.

Cognition in major depressive disorder: a 'Systemically Important Functional Index' (SIFI).

Cognitive dysfunction in major depressive disorder (MDD) is common, pervasive across multiple subdomains of cognitive function, and is a principle determinant of health outcomes from patient, provider, and societal perspectives. The overarching aim herein is to provide rationale for the evaluation, measurement, and specific treatment of cognitive function in adults with MDD. Evidence indicates that cognitive dysfunction in MDD is a critical mediator of workplace disability. Systematic evaluation and measurement of cognitive function is warranted. All individuals with MDD should be evaluated for both objective and subjective cognitive dysfunction. Although differences between antidepressants in overall antidepressant efficacy are not consistent, unequivocal differences in improving measures of cognitive function are noted with evidence indicating that vortioxetine has multidomain cognitive benefits, whereas duloxetine has replicated evidence of improving measures of acquisition and recall (i.e. memory). The probability of functional recovery in MDD is likely to increase with interventions that specifically target and improve measures of cognitive function. Clinicians are encouraged to evaluate patients using a validated measure (e.g. the THINC-it tool); prevention of cognitive impairment in MDD is a critical therapeutic priority. Vortioxetine and duloxetine benefit measures of cognitive function in MDD. Preliminary evidence of beneficial effects on cognitive emotional processing are reported with ketamine.

Peripheral blood gene expression analysis implicates B lymphocyte proliferation and ribosomal S26 transcripts in cognitive dysfunction in people with remitted Major Depression

Residual impairments in cognitive domains including attention, memory, executive function, and social perception occur in about 40% of patients with Major Depressive Disorder (MDD) following remission from acute episodes (Conradi et al., 2011), and are associated with reductions in pre-morbid functioning and higher unemployment rates (Baune et al., 2010; Evans et al., 2014). Cognitive impairment in MDD may represent a trait marker, trait-byillness interaction marker, or endophenotype of MDD that is independent of the acute depressive state and particularly active in a subgroup of MDD patients (Hasler et al., 2004; Iverson et al., 2011). We explored the potential molecular underpinnings of such a ‘cognitive’ MDD phenotype in a well-matched pilot sample of remitted MDD patients with poorer versus better performance on cognitive testing. Because the phenotype is likely highly complex, polygenic, and heterogeneous, we performed weighted gene coexpression network analysis (WGCNA), a hypothesis-free systems biology approach that identifies ‘modules’ of co-regulated – and therefore functionally related – genes in transcriptomic datasets. After constructing a gene co-expression network from samples of all patients, we determined whether modules were correlated with poorer versus better cognitive performance. We additionally explored whether modules were also correlated with a continuous measure of cognitive performance in both groups. We utilized whole blood transcriptomic data from remitted MDD patients from the Adelaide Cognitive Function and Mood Study (CoFaMS, HREC RAH protocol no. 111230g) matched for race, gender, age, Hamilton Depression Scale score, presence of psychotic features during any depressive episode, educational status, annual household income, current drugand alcohol use, and