Function In Major Depressive Disorder Research Articles

A bayesian approach to examining default mode network functional connectivity and cognitive performance in major depressive disorder

To reconcile the inconsistency of the association between the resting-state functional connectivity (RSFC) and cognitive performance in healthy and depressed groups due to high variance of both measures, we proposed a Bayesian spatio-temporal model to precisely and accurately estimate the RSFC in depressed and nondepressed participants. This model was employed to estimate spatially-adjusted functional connectivity (saFC) in the extended default mode network (DMN) that was hypothesized to correlate with cognitive performance in both depressed and nondepressed. Multiple linear regression models were used to study the relationship between DMN saFC and cognitive performance scores measured in the following four cognitive domains while adjusting for age, sex, and education. In ROI pairs including the posterior cingulate (PCC) and anterior cingulate (ACC) cortex regions, the relationship between connectivity and cognition was found only with the Bayesian approach. Moreover, only the Bayesian approach was able to detect a significant diagnostic difference in the association in ROI pairs, including both PCC and ACC regions, due to smaller variance for the saFC estimator. The results confirm that a reliable and precise saFC estimator, based on the Bayesian model, can foster scientific discovery that may not be feasible with the conventional ROI-based FC estimator (denoted as ‘AVG-FC’).

Altered Resting-State Functional Connectivity of Multiple Networks and Disrupted Correlation With Executive Function in Major Depressive Disorder.

Background: Major depressive disorder (MDD) is one of the most common and costly psychiatric disorders. In addition to significant changes in mood, MDD patients face an increased risk of developing cognitive dysfunction. It is important to gain an improved understanding of cognitive impairments and find a biomarker for cognitive impairment diagnosis in MDD.Methods: One hundred MDD patients and 100 normal controls (NCs) completed resting-state fMRI (rs-fMRI) scan, in which 34 MDD patients and 34 NCs had scores in multiple cognitive domains (executive function, verbal fluency, and processing speed). Twenty-seven regions of interest from the default mode network (DMN), central executive network (CEN), salience network (SN), and limbic system (LS) were selected as seeds for functional connectivity (FC) analyses with the voxels in the whole brain. Finally, partial correlations were conducted for cognitive domain scores and FCs with significant differences between the MDD and NC groups.Results: Significant FC differences between groups were identified among the seeds and clusters in the DMN, CEN, LS, visual network, somatomotor network, ventral attention network, and dorsal attention network. In the MDD patients, the magnitude of the Stroop interference effect was positively correlated with the illness duration, and the illness duration was negatively correlated with the FC between the right ventral hippocampal gyrus and the left inferior frontal gyrus. However, the correlation between the Stroop interference effect and the FC of the right anterior prefrontal cortex with the left cerebellum_4_5 was disrupted in these patients.Conclusions: The MDD patients have altered FCs among multiple brain networks and a disrupted correlation between the FC of prefrontal cortex and executive function. The disrupted correlation could present before the symptoms develop and may be the core process in the development of executive function impairment.

Multimodal Abnormalities of Brain Structure and Function in Major Depressive Disorder: A Meta-Analysis of Neuroimaging Studies.

Imaging studies of major depressive disorder have reported structural and functional abnormalities in a variety of spatially diverse brain regions. Quantitative meta-analyses of this literature, however, have failed to find statistically significant between-study spatial convergence, other than transdiagnostic-only effects. In the present study, the authors applied a novel multimodal meta-analytic approach to test the hypothesis that major depression exhibits spatially convergent structural and functional brain abnormalities. This coordinate-based meta-analysis included voxel-based morphometry (VBM) studies and resting-state voxel-based pathophysiology (VBP) studies of blood flow, glucose metabolism, regional homogeneity, and amplitude of low-frequency fluctuations (ALFF) and fractional ALFF (fALFF). Input data were grouped into three primary meta-analytic classes: gray matter atrophy, increased function, and decreased function in patients with major depression relative to healthy control subjects. In secondary meta-analyses, the data were grouped across primary categories, and in tertiary analyses, by medication status and absence of psychiatric comorbidity. Activation likelihood estimation was used for all analyses. A total of 92 publications reporting 152 experiments were identified, collectively representing 2,928 patients with major depressive disorder. The primary analyses detected no convergence across studies. The secondary analyses identified portions of the subgenual cingulate cortex, hippocampus, amygdala, and putamen as demonstrating convergent abnormalities. The tertiary analyses (clinical subtypes) showed improved convergence relative to the secondary analyses. Coordinate-based meta-analysis identified spatially convergent structural (VBM) and functional (VBP) abnormalities in major depression. The findings suggest replicable neuroimaging features associated with major depression, beyond the transdiagnostic effects reported in previous meta-analyses, and support a continued research focus on the subgenual cingulate and other selected regions' role in depression.

Personality disorder and functioning in major depressive disorder: a nested study within a randomized controlled trial.

Objective:This study aimed to determine if personality disorder (PD) predicted functional outcomes in patients with major depressive disorder (MDD).Methods:Data (n=71) from a double-blind, randomized, placebo-controlled 12-week trial assessing the efficacy of 200 mg/day adjunctive minocycline for MDD were examined. PD was measured using the Standardized Assessment of Personality Abbreviated Scale. Outcome measures included Clinical Global Impression – Improvement (CGI-I), Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), Social and Occupational Functioning Scale (SOFAS), and Range of Impaired Functioning (RIFT). Analysis of covariance was used to examine the impact of PD (dichotomized factor [≥ 3] or continuous measure) on the outcome measures-treatment group correlation.Results:PD was identified in 69% of the sample. After adjusting for age, sex, and baseline scores for each of the outcome measures, there was no significant difference between participants with and without PD on week 12 scores for any of the outcome measures (all p > 0.14).Conclusion:In this secondary analysis of a primary efficacy study, PD was a common comorbidity among those with MDD, but was not a significant predictor of functional outcomes. This study adds to the limited literature on PD in randomized controlled trials for MDD.Clinical trial registration:ACTRN12612000283875.

The relationship between sleep efficiency and clinical symptoms is mediated by brain function in major depressive disorder

BackgroundSleep disturbance is a common and key symptom that affects most of patients with major depressive disorder (MDD). However, neural substrates underlying sleep disturbance and their clinical relevance in depression remain unclear. MethodsNinety-six MDD patients underwent resting-state functional MRI. Fractional amplitude of low-frequency fluctuation (fALFF) and resting-state functional connectivity (rsFC) were used to measure brain function. Overnight polysomnography was performed to objectively measure sleep efficiency (SE), which was used to classify patients into normal sleep efficiency (NSE) and low sleep efficiency (LSE) groups. Between-group differences in fALFF and rsFC were examined using two-sample t-tests. Moreover, correlation and mediation analyses were conducted to test for potential associations between SE, brain functional changes, and clinical variables. ResultsLSE group showed decreased fALFF in right cuneus, thalamus, and middle temporal gyrus compared to NSE group. MDD patients with low SE also exhibited lower rsFC of right cuneus to right lateral temporal cortex, which was associated with more severe depression and anxiety symptoms. More importantly, mediation analyses revealed that the relationships between SE and severity of depression and anxiety symptoms were significantly mediated by the altered rsFC. In addition, these low SE-related brain functional alterations were not affected by antidepressant medication and were independent of structural changes. LimitationsThe lack of healthy controls because of “first-night effect”. ConclusionThese findings not only may expand existing knowledge about neuropathology of sleep disturbance in depression, but also may inform real-world clinical practice by improving depression and anxiety symptoms through sleep regulation.

Brain-derived neurotrophic factor association with amygdala response in major depressive disorder

BackgroundBrain-derived neurotrophic factor (BDNF) has an essential role in synaptic plasticity and neurogenesis. BDNF mediates amygdala-dependent learning for both aversive and appetitive emotional memories. The expression of BDNF in limbic regions is posited to contribute the development of depression, and amygdala responsivity is a potential marker of depressive state. MethodsThe present study examined the relationship between platelet BDNF levels and amygdala volume and function in major depressive disorder (MDD). Participants were 23 MDD (mean age 38.9 years) and 23 healthy controls (mean age 38.8 years). All participants were recruited from the community. MDD participants were in a current depressive episode of moderate severity and medication-free. Amygdala responses were acquired during a functional MRI task of implicit emotional processing with sad facial expressions. ResultsSignificant correlation was observed between platelet BDNF levels and left amygdala responses, but no significant correlations were found with right amygdala responses or with amygdala volumes. LimitationsInteractions with neuroprotective as well as neurotoxic metabolites in the kyneurenine pathway were not examined. ConclusionsRelationship between BDNF levels and amygdala responsivity to emotionally salient stimuli in MDD could reflect the importance of BDNF in amygdala-dependent learning with clinical implications for potential pathways for treatment.

An integrated meta-analysis of peripheral blood metabolites and biological functions in major depressive disorder

Major depressive disorder (MDD) is a serious mental illness, characterized by high morbidity, which has increased in recent decades. However, the molecular mechanisms underlying MDD remain unclear. Previous studies have identified altered metabolic profiles in peripheral tissues associated with MDD. Using curated metabolic characterization data from a large sample of MDD patients, we meta-analyzed the results of metabolites in peripheral blood. Pathway and network analyses were then performed to elucidate the biological themes within these altered metabolites. We identified 23 differentially expressed metabolites between MDD patients and controls from 46 studies. MDD patients were characterized by higher levels of asymmetric dimethylarginine, tyramine, 2-hydroxybutyric acid, phosphatidylcholine (32:1), and taurochenodesoxycholic acid and lower levels of l-acetylcarnitine, creatinine, l-asparagine, l-glutamine, linoleic acid, pyruvic acid, palmitoleic acid, l-serine, oleic acid, myo-inositol, dodecanoic acid, l-methionine, hypoxanthine, palmitic acid, l-tryptophan, kynurenic acid, taurine, and 25-hydroxyvitamin D compared with controls. l-tryptophan and kynurenic acid were consistently downregulated in MDD patients, regardless of antidepressant exposure. Depression rating scores were negatively associated with decreased levels of l-tryptophan. Pathway and network analyses revealed altered amino acid metabolism and lipid metabolism, especially for the tryptophan–kynurenine pathway and fatty acid metabolism, in the peripheral system of MDD patients. Taken together, our integrated results revealed that metabolic changes in the peripheral blood were associated with MDD, particularly decreased l-tryptophan and kynurenic acid levels, and alterations in the tryptophan–kynurenine and fatty acid metabolism pathways. Our findings may facilitate biomarker development and the elucidation of the molecular mechanisms that underly MDD.

Kappa Opioid Receptor Antagonists as Potential Therapeutics for Stress-Related Disorders.

Exposure to stressful stimuli activates kappa opioid receptor (KOR) signaling, a process known to produce aversion and dysphoria in humans and other species. This endogenous opioid system is dysregulated in stress-related disorders, specifically in major depressive disorder (MDD). These findings serve as the foundation for a growing interest in the therapeutic potential of KOR antagonists as novel antidepressants. In this review, data supporting the hypothesis of dysregulated KOR function in MDD are considered. The clinical data demonstrating the therapeutic efficacy and safety of selective and mixed opioid antagonists are then presented. Finally, the preclinical evidence illustrating the induction of behaviors relevant to the endophenotypes of MDD and KOR antagonist activity in stress-naïve and stress-exposed animals is evaluated. Overall, this review highlights the emergent literature supporting the pursuit of KOR antagonists as novel therapeutics for MDD and other stress-related disorders.

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.

Suicidal risk and executive functions in major depressive disorder: a study protocol

BackgroundSuicide is a serious public health concern. Depression is the main gateway to suicidal behavior. The already established relationship between depression and suicidal risk should now focus on the investigation of more specific factors: recent studies have suggested an association between vulnerability to suicidal behavior and neurocognitive alterations, a nuclear symptom of depression. This project aims to identify alterations in the Executive Functions (EF) of patients suffering a first depressive episode that might constitute a risk factor for suicidal ideation, suicidal attempts and suicide, to allow for more adequate suicide prevention.MethodsProspective longitudinal design involving two groups (first depressive episodes with and without alterations in their EF) and four repeated measures (0, 6, 12 and 24 months). The estimated minimum sample size is 216 subjects. The variables and measurement instruments will include socio-demographic variables, clinical variables (age of illness onset, family and personal antecedents, psychopathological and medical comorbidity, suicidal ideation, suicide attempts and completed suicides, severity of depression, including melancholic or atypical, remission of the depressive episode), and neuropsychological variables (EF and decision-making processes evaluated through the Cambridge Neuropsychological Test Automated Battery (CANTAB)).DiscussionFirst and foremost, the identification of clinical and neuropsychological risk factors associated with suicidal behavior will open the possibility to prevent such behavior in patients with a first depressive episode in the context of clinical practice. Secondly, interventions aimed at cognitive impairment (in particular: EF) derived from the study may be incorporated into strategies for the prevention of suicidal behavior. Finally, impaired neurocognitive function (even in early stages) could become an identifiable endophenotype or “marker” in clinical and neurobiological studies about suicidal behavior in depressive patients.

Impact of adrenal hormones, reproductive aging, and major depression on memory circuitry decline in early midlife

Dehydroepiandrosterone-sulfate (DHEAS) is an adrenal androgen that is, in part, aromatized to estradiol. It continues to be produced after menopause and provides estrogenicity after depletion of ovarian hormones. Estradiol depletion contributes to memory circuitry changes over menopause, including changes in hippocampal (HIPP) and dorsolateral- and ventrolateral-prefrontal cortex (DLPFC; VLPFC) function. Further, major depressive disorder (MDD) patients have, in general, lower levels of estradiol and lower DHEAS than healthy controls, thus potentially a higher risk of adverse menopausal outcomes. We investigated whether higher DHEAS levels after menopause is associated with better memory circuitry function, especially in women with MDD. 212 adults (ages 45–55, 50% women) underwent clinical and fMRI testing. Participants performed a working memory (WM) N-back task and an episodic memory verbal encoding (VE) task during fMRI scanning. DHEAS levels were significantly associated with memory circuitry function, specifically in MDD postmenopausal women. On the WM task, lower DHEAS levels were associated with increased HIPP activity. On the VE task, lower DHEAS levels were associated with decreased activity in the HIPP and VLPFC. In contrast, there was no association between DHEAS levels and memory circuitry function in MDD pre/perimenopausal women, men, and non-MDD participants regardless of sex and reproductive status. In fact, MDD postmenopausal women with higher levels of DHEAS were similar to MDD pre/perimenopausal women and men. Thus, memory circuitry deficits associated with MDD and a lower ability of the adrenal gland to produce DHEAS after menopause may contribute to a lower ability to maintain intact memory function with age.

Music therapy on non linear assessment of cardiac autonomic function in patients with major depressive disorder

Background :Non linear measure of heart rate variability (HRV) is an emerging method to detect changes in cardiac autonomic nerve function in major depressive disorder (MDD).
 Objective: To observe the effect of music therapy on non linear measures of HRV in newly diagnosed MDD patients.
 Methods: This prospective interventional study was done in the Department of Physiology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Shahbag, Dhaka in 2018 on 60 newly diagnosed MDD patients aged 20-40 years, both male and female. They were further subdivided into 30 patients with only antidepressant medication (Mirtazapine) and 30 patients received music therapy with Raga kafi (Rabindrasangeet) along with the same medication for 3 months. Age, sex and BMI matched healthy control were also enrolled. HRV non linear parameters were recorded by Power Lab 8/35. For statistical analysis paired sample ‘t’ test and independent sample ‘t’ test were done.
 Result: SD1, SD2 and SD1/SD2 were found significantly lower in MDD patients compared to healthy control at baseline. After 3 months of music therapy, significant increment of these parameters occurred with trend of improvement in cardiac autonomic nerve function (CANF) in these patients.
 Conclusion: This study concluded that music therapy can improve CANF by increasing parasympathetic and reducing sympathetic activity in MDD patients.
 J Bangladesh Soc Physiol. 2019, June; 14(1): 7-13

Lower resting cardiac autonomic balance in young adults with current major depression.

Research on cardiac autonomic function in major depressive disorder (MDD) has predominantly examined cardiac vagal control and adopted a model of reciprocal autonomic balance. A proposed bivariate autonomic continuum uses cardiac autonomic balance (CAB) and cardiac autonomic regulation (CAR) models, derived from normalized values of respiratory sinus arrhythmia and pre-ejection period, to more adequately index patterns of autonomic control. The purpose of this study was to assess resting levels of CAB and CAR among young adults with and without a current diagnosis of major depression. One hundred forty-two young adults (n=65 MDD, n=77 healthy controls; 20.8±2.6 years) completed a structured diagnostic interview, cardiovascular assessment, and a maximal aerobic fitness test. The findings revealed that CAB, but not CAR, significantly predicted current MDD status (OR=0.70, 95% CI [0.53, 0.93]), an effect that remained after controlling for aerobic fitness and body mass index. Although CAB was found to be a significant predictor of current MDD status among a sample of young adults, there remained substantial variation in autonomic control that was not captured by the traditional model of reciprocal autonomic balance.

Regional default mode network connectivity in major depressive disorder: modulation by acute intravenous citalopram

The relationship between altered default mode network (DMN) connectivity and abnormal serotonin function in major depressive disorder (MDD) has not been investigated. Using intravenous citalopram and resting-state fMRI, we investigated DMN intra-network connectivity and serotonin function in 77 healthy controls and patients with MDD. There were no significant main effects of MDD or citalopram on DMN intra-network connectivity; however, significant interactions indicated that group differences under saline were modified by citalopram. In MDD patients during saline infusion, in contrast with controls, the DMN (i) did not include the precuneus that was instead part of an anti-correlated network but (ii) did include amygdala that was part of the anti-correlated network in controls. Citalopram infusion in MDD patients restored the pattern seen in controls under saline. In healthy controls, citalopram infusion disengaged the precuneus from the DMN and engaged the amygdala, partially reproducing the abnormalities seen under saline in MDD. In exploratory analyses within the MDD group, greater rumination self-ratings were associated with greater intra-network connectivity of the anterior cingulate cortex with the DMN. We hypothesise that, in MDD, disengagement of the precuneus from the DMN relates to overgeneral memory bias in rumination. The opposite effect, with greater engagement of the amygdala in the DMN, reflects the negative valence of rumination. Reversal of these abnormalities by citalopram suggests that they may be related to impaired serotonin function. That citalopram engaged the amygdala in the DMN in controls may relate to the paradoxical effects on aversive processing seen with acute SSRIs in healthy subjects.

A systematic review of the impact of social cognitive deficits on psychosocial functioning in major depressive disorder and opportunities for therapeutic intervention

Social cognition is the ability to identify, perceive and interpret socially relevant information from the external world. It is an important adaptive trait, but is frequently affected in major depressive disorder by a mood-congruent interpretive bias. The present review examined the existing body of literature to determine (i) the impact social cognitive deficits in depression have on psychosocial functioning; and (ii) the utility of psychotropic, psychological and procedural interventions employed to target these deficits. A total of 107 studies met inclusion criteria for review. Social cognitive performance was found to adversely impact depressed patients’ psychosocial functioning across the key domains of general cognitive functioning and quality of life. Secondly, many current therapies were found to have a normalising effect on the social cognitive abilities of subjects with major depressive disorder, both at a neural and functional level. In particular, certain anti-depressant medications corrected facial affect recognition deficits, while several psychotherapeutic approaches improved impairments in theory of mind and negative interpretive bias.

Effects of Ketamine on Brain Activity During Emotional Processing: Differential Findings in Depressed Versus Healthy Control Participants

BackgroundIn the search for novel treatments for depression, ketamine has emerged as a unique agent with rapid antidepressant effects. Experimental tasks involving emotional processing can be used during functional magnetic resonance imaging scanning to investigate ketamine’s effects on brain function in major depressive disorder (MDD). This study examined ketamine’s effects on functional magnetic resonance imaging activity during an emotional processing task. MethodsA total of 33 individuals with treatment-resistant MDD and 24 healthy control participants (HCs) took part in this double-blind, placebo-controlled crossover study. Participants received ketamine and placebo infusions 2 weeks apart, and functional magnetic resonance imaging scans were conducted at baseline and 2 days after each infusion. Blood oxygen level–dependent signal was measured during an emotional processing task, and a linear mixed-effects model was used to analyze differences in activation among group, drug, and task-specific factors. ResultsA group-by-drug interaction was observed in several brain regions, including a right frontal cluster extending into the anterior cingulate cortex and insula. Participants with MDD had greater activity than HCs after placebo infusion but showed lower activity after ketamine infusion, which was similar to the activity in HCs after placebo. A group-by-drug-by-task condition interaction was also found, which showed further differences that varied between implicit and explicit emotional conditions. ConclusionsThe main results indicate that ketamine had differential effects on brain activity in participants with MDD versus HCs. The pattern of activation in participants with MDD after ketamine infusion resembled the activation in HCs after placebo infusion, suggesting a normalization of function during emotional processing. The findings contribute to a better understanding of ketamine’s actions in the brain.

SA116 - A NOVEL APPROACH TO COMBINE GWAS, PGRS AND GENE-GENE INTERACTIONS IN PSYCHIATRY

Background Studies in psychiatric genetics have focused almost solely on single-loci and polygenic associations and have not included possible interactions. Nicodemus et al. (2014, JAMA Psychiatry) introduced a novel statistical model that incorporates single marker, polygenic and epistatic components to assess the association between SNPs in the ZNF804A pathway and cognitive performance in psychosis. Two-SNP interaction modelling was conducted to test for epistasis. This resulted in a regression model that contained the polygenic score and two two-SNP interaction terms, where the epistatic component explained more variation in cognition than the polygenic score. This model is still relatively simplistic in modelling the genetic architecture of complex traits; in particular, the epistatic component, as the model only allowed for pairwise interactions between SNPs. We sought to implement a more flexible specification of the epistatic component by the use of non-parametric rule sets via the algorithm C5.0. Methods As a proof-of-principle we simulated multiple phenotypes using SNPs located on chromosome 19 explaining A) 30% polygenic variation B) 30% epistatic variation using 2-SNP models not included in the polygenic set, not in LD and under weak (β=0.09), intermediate (β=0.15) and strong (β=0.24) interaction strength and C) a combination containing both a polygenic and epistatic component. Five hundred replicates were simulated per condition. We applied C5.0 in an effort to detect these epistatic interactions. C5.0 is a non-parametric algorithm to generate decision tree-based rulesets. Because of its decision tree basis C5.0 only allows for the Boolean operator OR but does allow for non-binary predictors. Each possible combination from the top node to bottom node in the tree is a so-called ruleset and can be used as a predictor in a regression model. Results We found C5.0 is highly capable of detecting both epistatic SNPs in 100% of the 500 simulations of the strong interaction, 99.2% of the intermediate interaction and 19.2% of the weak interaction models. For the intermediate and weak interactions C5.0 detected only one of the two epistatic SNPs in 0.8% and 41.2% of the replicates. C5.0 was immune to detecting polygenic additivity at the single SNP level. In the polygenic setting of 30% variation explained by an additive effect, C5.0 detected in 11.4% simulations at least one ruleset with no SNP being included more than 13 times Discussion These results show that C5.0 is able to detect epistasis even in the presence of a phenotype containing strong-single loci and polygenic components. Further work includes creating an R package that embeds these different components through a penalised regression framework to combine all three types of genetic variation (single loci, polygenic components, epistatic components) to better reflect the underlying biology, and to apply this method to cognitive performance in Major Depressive Disorder.

Increased Functional Connectivity Between Medulla and Inferior Parietal Cortex in Medication-Free Major Depressive Disorder.

Emerging evidence has documented the abnormalities of primary brain functions in major depressive disorder (MDD). The brainstem has shown to play an important role in regulating basic functions of the human brain, but little is known about its role in MDD, especially the roles of its subregions. To uncover this, the present study adopted resting-state functional magnetic resonance imaging with fine-grained brainstem atlas in 23 medication-free MDD patients and 34 matched healthy controls (HC). The analysis revealed significantly increased functional connectivity of the medulla, one of the brainstem subregions, with the inferior parietal cortex (IPC) in MDD patients. A positive correlation was further identified between the increased medulla-IPC functional connectivity and Hamilton anxiety scores. Functional characterization of the medulla and IPC using a meta-analysis revealed that both regions primarily participated in action execution and inhibition. Our findings suggest that increased medulla-IPC functional connectivity may be related to over-activity or abnormal control of negative emotions in MDD, which provides a new insight for the neurobiology of MDD.

Adjunctive Brexpiprazole and Functioning in Major Depressive Disorder: A Pooled Analysis of Six Randomized Studies Using the Sheehan Disability Scale.

BackgroundPatients with major depressive disorder and inadequate response to antidepressant treatments may experience a prolonged loss of functioning. This post hoc analysis aimed to determine the effect of adjunctive brexpiprazole on functioning in such patients.MethodsA pooled analysis of data from the 6-week, randomized, double-blind treatment phases of 6 studies of adjunctive brexpiprazole (2 and 3 mg/d in fixed-dose studies; 1–3 mg/d in flexible-dose studies) vs placebo in patients with major depressive disorder and inadequate response to antidepressant treatments (NCT01360645, NCT01360632, NCT02196506, NCT01727726, NCT00797966, NCT01052077). Functioning was measured by change in Sheehan Disability Scale score from baseline to week 6.ResultsConsidering Sheehan Disability Scale mean score across all 6 studies (n = 2066 randomized), the least squares mean difference between antidepressant treatments + brexpiprazole and antidepressant treatments + placebo at week 6 was −0.40 (95% CI: −0.56, −0.23; P < .0001). Antidepressant treatments + brexpiprazole showed a greater benefit than antidepressant treatments + placebo on the social life (−0.45; −0.63, −0.27; P < .001) and family life (−0.50; −0.70, −0.31; P < .001) items but not on the work/studies item (−0.16; −0.38, 0.06; P = .16). Pooled analyses of just the (1) fixed-dose, (2) flexible-dose, and (3) Phase 3 studies showed the same pattern of benefits for antidepressant treatments + brexpiprazole.ConclusionsBrexpiprazole, as adjunct to antidepressant treatments, improved functioning in patients with major depressive disorder and inadequate response to antidepressant treatments.

Brain network functional connectivity and cognitive performance in major depressive disorder

BackgroundMajor depressive disorder (MDD) is one of the most prevalent and debilitating psychiatric disorders. Cognitive complaints are commonly reported in MDD and cognitive impairment is a criterion item for MDD diagnosis. As cognitive processes are increasingly understood as the consequences of distributed interactions between brain regions, a network-based approach may provide novel information about the neurobiological basis of cognitive deficits in MDD. Methods51 Depressed (MDD, n = 23) and non-depressed (control, n = 28) adult participants completed neuropsychological testing and resting-state fMRI (rsfMRI). Cognitive domain scores (processing speed, working memory, episodic memory, and executive function) were calculated. Anatomical regions of interests were entered as seeds for functional connectivity analyses in: default mode (DMN), salience, and executive control (ECN) networks. Partial correlations controlling for age and sex were conducted for cognitive domain scores and functional connectivity in clusters with significant differences between groups. ResultsSignificant rsfMRI differences between groups were identified in multiple clusters in the DMN and ECN. Greater positive connectivity within the ECN and between ECN and DMN regions was associated with poorer episodic memory performance in the Non-Depressed group but better performance in the MDD group. Greater connectivity within the DMN was associated with better episodic and working memory performance in the Non-Depressed group but worse performance in the MDD group. ConclusionsThese results provide evidence that cognitive performance in MDD may be associated with aberrant functional connectivity in cognitive networks and suggest patterns of alternate brain function that may support cognitive processes in MDD.