Major depressive disorder (MDD) presumably includes heterogeneous subgroups with differing pathologies. To obtain a marker reflecting such a subgroup, we analyzed the cerebrospinal fluid (CSF) levels of fibrinogen, which has been reported to be elevated in the plasma of patients with MDD. Three fibrinogen-related proteins were measured using aptamer-based analyses and CSF samples of 30 patients with MDD and 30 controls. The numbers of patients with an excessively high level (>99 percentile of the controls) was significantly increased (17 to 23%). Measurement reproducibility of these results was confirmed by an ELISA for fibrinogen (Pearson's r = 0.77). In an independent sample set from 36 patients and 30 controls, using the ELISA, results were similar (22%). When these two sample sets were combined, the number of patients with a high fibrinogen level was significantly increased (15/66; odds ratio 8.53; 95% confidence interval 1.9-39.1, p = 0.0011). By using diffusion tensor imaging, we found white matter tracts abnormalities in patients with a high fibrinogen level but not those patients with a normal fibrinogen level, compared with controls. Plasma fibrinogen levels were similar among the diagnostic groups. Our results point to a subgroup of MDD represented by increased CSF fibrinogen and white matter tract abnormalities.

Depression is associated with reduced olfactory function. This relationship is assumed to be based on either a reduced olfactory bulb volume or diminished functioning of higher cortical areas. As previous results are controversial, we aimed to re-evaluate central olfactory processing in depression. We recorded the BOLD signal of 21 patients with Major Depressive Disorder and 21 age and gender matched healthy controls during odor presentation. In addition, we measured the individual olfactory bulb volume, tested odor identification and odor threshold, and asked for hedonic odor perception. In both groups, odor presentation led to a pronounced activation of primary olfactory areas. However, secondary olfactory areas were significantly less activated in depressed individuals. The two groups did not differ in olfactory bulb volume. Our results point towards altered olfactory processing in patients in those regions that relate to sensory integration and attention allocation. Difficulties in cognitive processing could impact olfactory function in depression. We are therefore in favor of a top-down mechanism originating in higher cortical areas explaining parts of the relation between depression and olfaction.

Identifying brain differences and similarities between bipolar disorder (BD) and major depressive disorder (MDD) is necessary for increasing our understanding of the pathophysiology and for developing more effective treatments. However, the features of whole-brain intrinsic functional connectivity underlying BD and MDD have not been directly compared. We collected resting-state fMRI data from 48 BD patients, 48 MDD patients, and 51 healthy subjects. We constructed voxel-wise whole-brain functional networks and computed regional functional connectivity strength (FCS) using graph-theory and further divided the regional FCS into long-range FCS (lFCS) and short-range FCS (sFCS). Relative to the controls, both the BD and MDD patients showed decreased sFCS in the bilateral precuneus. In addition, the BD patients showed increased and the MDD patients showed decreased lFCS and sFCS in the bilateral cerebellum. The BD patients also showed increased lFCS in the right middle temporal gyrus and increased sFCS in the bilateral thalamus compared to either the MDD patients or the controls. These findings suggest that BD and MDD may have some shared as well as a greater number of specific impairments in their functional connectivity patterns, providing new evidence for the pathophysiology of BD and MDD at the large-scale whole brain connectivity level.

Though social functioning is often hampered in Major Depressive Disorder (MDD), we lack a complete and integrated understanding of the underlying neurobiology. Connectional disturbances in the brain's Default Mode Network (DMN) might be an associated factor, as they could relate to suboptimal social processing. DMN connectional integrity, however, has not been explicitly studied in relation to social dysfunctioning in MDD patients. Applying Independent Component Analysis and Dual Regression on resting-state fMRI data, we explored DMN intrinsic functional connectivity in relation to social dysfunctioning (i.e. composite of loneliness, social disability, small social network) among 74 MDD patients (66.2% female, Mean age = 36.9, SD = 11.9). Categorical analyses examined whether DMN connectivity differs between high and low social dysfunctioning MDD groups, dimensional analyses studied linear associations between social dysfunction and DMN connectivity across MDD patients. Threshold-free cluster enhancement (TFCE) with family-wise error (FWE) correction was used for statistical thresholding and multiple comparisons correction (P < 0.05). The analyses cautiously linked greater social dysfunctioning among MDD patients to diminished DMN connectivity, specifically within the rostromedial prefrontal cortex and posterior superior frontal gyrus. These preliminary findings pinpoint DMN connectional alterations as potentially germane to social dysfunction in MDD, and may as such improve our understanding of the underlying neurobiology.

Our previous work implied that interleukin 6 (IL6) may be a biological marker for major depressive disorder (MDD). In this study, we performed a comprehensive genetic study to determine the association between the gene encoding IL6 (IL6) and MDD in Han Chinese. There were 50 drug-naïve MDD patients and 50 healthy controls undergoing an mRNA expression study. A sample of 772 patients with MDD and 759 healthy controls were used for genetic analysis. Next, we performed an eQTL analysis to identify whether risk SNP(s) is associated with IL6 expression in brain. Our results showed that patients with MDD have higher levels of IL6 than healthy controls (P = 0.008). The SNP rs1800797 has a significant association with MDD (P = 0.01) in a dominant model. The eQTL analysis showed a marginally significant association between the rs1800797 and IL6 expression in the frontal cortex (P = 0.087). Our preliminary findings are suggestive of an association between rs1800797 and the risk of MDD. Further investigations are required to evaluate this association in larger samples to increase statistical power, and to examine the correlation between rs1800797 and IL6 methylation patterns.

Depression is clinically characterized by obvious changes in decision making that cause distress and impairment. Though several studies suggest impairments in depressed individuals in single tasks, there has been no systematic investigation of decision making in depression across tasks. We compare participants diagnosed with Major Depressive Disorder (MDD) (n = 64) to healthy controls (n = 64) using a comprehensive battery of nine value-based decision-making tasks which yield ten distinct measures. MDD participants performed worse on punishment (d = -0.54) and reward learning tasks (d = 0.38), expressed more pessimistic predictions regarding winning money in the study (d = -0.47) and were less willing to wait in a persistence task (d = -0.39). Performance on learning, expectation, and persistence tasks each loaded on unique dimensions in a factor analysis and punishment learning and future expectations each accounted for unique variance in predicting depressed status. Decision-making performance alone could predict depressed status out-of-sample with 72% accuracy. The findings are limited to MDD patients ranging between moderate to severe depression and the effects of medication could not be accounted for due to the cross sectional nature of the study design. These results confirm hints from single task studies that depression has the strongest effects on reinforcement learning and expectations about the future. Our results highlight the decision processes that are impacted in major depression, and whose further study could lead to a more detailed computational understanding of distinct facets of this heterogeneous disorder.

Major depressive disorder is associated with aberrant topological organizations of brain networks. However, whether this aberrance is shown in broader frequency bands or in a specific frequency band remains unknown. Fifty patients and fifty gender, age and education matched normal controls underwent resting state functional magnetic resonance imaging. Frequency dependent topological measures based on graph theory were calculated from wavelet decomposed resting state functional brain signals. In the specific frequency band of 0.03-0.06 Hz, the clustering coefficient and the global efficiency were reduced while the characteristic path length was increased. Furthermore, patients showed aberrant nodal centralities in the default mode network, executive network and occipital network. Network based statistical analysis revealed system-wise topological alterations in these networks. The finding provides the first systematic evidence that depression is associated with frequency specific global and local topological disruptions and highlights the importance of frequency information in investigating major depressive disorders.

Reduced haemodynamic response in the frontotemporal cortices of patients with major depressive disorder (MDD) has been demonstrated using functional near-infrared spectroscopy (fNIRS). Most notably, changes in cortical oxy-haemoglobin during a Japanese phonetic fluency task can differentiate psychiatric patients from healthy controls (HC). However, this paradigm has not been validated in the English language. Therefore, the present work aimed to distinguish patients with MDD from HCs, using haemodynamic response measured during an English letter fluency task. One hundred and five HCs and 105 patients with MDD took part in this study. NIRS signals during the verbal fluency task (VFT) was acquired using a 52-channel system, and changes in oxy-haemoglobin in the frontal and temporal regions were quantified. Depression severity, psychosocial functioning, pharmacotherapy and psychiatric history were noted. Patients with MDD had smaller changes in oxy-haemoglobin in the frontal and temporal cortices than HCs. In both regions of interest, oxy-haemoglobin was not associated with any of the clinical variables studied. 75.2% and 76.5% of patients with MDD were correctly classified using frontal and temporal region oxy-haemoglobin, respectively. Haemodynamic response measured by fNIRS during an English letter fluency task is a promising biomarker for MDD.

Major depressive disorder (MDD) is a chronic illness wherein relapses contribute to significant patient morbidity and mortality. Near-term prediction of relapses in MDD patients has the potential to improve outcomes by helping implement a 'predict and preempt' paradigm in clinical care. In this study, we developed a novel personalized (N-of-1) encoder-decoder anomaly detection-based framework of combining anomalies in multivariate actigraphy features (passive) as triggers to utilize an active concurrent self-reported symptomatology questionnaire (core symptoms of depression and anxiety) to predict near-term relapse in MDD. The framework was evaluated on two independent longitudinal observational trials, characterized by regular bimonthly (every other month) in-person clinical assessments, weekly self-reported symptom assessments, and continuous activity monitoring data with two different wearable sensors for ≥ 1 year or until the first relapse episode. This combined passive-active relapse prediction framework achieved a balanced accuracy of ≥ 71%, false alarm rate of ≤ 2.3 alarm/patient/year with a median relapse detection time of 2-3 weeks in advance of clinical onset in both studies. The study results suggest that the proposed personalized N-of-1 prediction framework is generalizable and can help predict a majority of MDD relapses in an actionable time frame with relatively low patient and provider burden.

Abnormal reward-related responses in the nucleus accumbens (NAcc) have been reported for major depressive disorder (MDD) patients. However, variability exists in the reported results, which could be due to heterogeneity in neuropathology of depression. To parse the heterogeneity of MDD we investigated variation of NAcc responses to gain and loss anticipations using fMRI. We found NAcc responses to monetary gain and loss were significantly variable across subjects in both MDD and healthy control (HC) groups. The variations were seen as a hyperactive response subtype that showed elevated activation to the anticipation of both gain and loss, an intermediate response with greater activation to gain than loss, and a suppressed-activity with reduced activation to both gain and loss compared to a non-monetary condition. While these response variability were seen in both MDD and HC subjects, specific symptoms were significantly associated with the right NAcc variation in MDD. Both the hyper- and suppressed-activity subtypes of MDD patients had severe suicidal ideation and anhedonia symptoms. The intermediate subjects had less severity in these symptoms. These results suggest that differing propensities in reward responsiveness in the NAcc may affect the development of specific symptoms in MDD.

The aim of our study is to examine the levels of routine biochemical markers in patients with major depressive disorder (MDD), and combine multiple biochemical parameters to assess the discriminative power for patients with MDD. We used the Hamilton Depression (HAMD) score to evaluate the severity of depressive symptoms in 228 patients with MDD. The phase of depression severity was between moderate and severe in MDD patients. There were significant differences between MDD patients and healthy controls in alanine transaminase (ALT), urea nitrogen (UN), lactate dehydrogenase (LDH), uric acid (UA), total protein (TP), total bile acid (TBA), creatinine (Cr), total bilirubin (Tbil), direct bilirubin (Dbil) and indirect bilirubin (Ibil), high density lipoprotein-cholesterol (HDL-C), fasting blood-glucose (FBG) and fructosamine (SF). Multivariate analysis showed that UN, FBG, HDL-C, SF, TP, Cr and Tbil remained independently association with MDD. Further, a logit equation was established to identify patients with MDD. The composite markers exhibited an area under the curve of 0.810 with cut-off values of 0.410. Our results suggest the associations between UN, FBG, HDL-C, TP, Cr, Tbil, SF and MDD, use of these routine biochemical markers in combination may contribute to improve the complete management for patients with MDD.

Cues of social rejection and affiliation represent proximal risk and protective factors in the onset and maintenance of depression. Such cues are thought to activate an evolutionarily primed neuro-cognitive alarm system, alerting the agent to the benefits of inclusion or the risk of social exclusion within social hierarchies focused on ensuring continued access to resources. In tandem, autobiographical memory is thought to be over-general and negatively biased in Major Depressive Disorder (MDD) which can contribute to maintenance and relapse. How memories of social rejection and affiliation are experienced and processed in MDD remains unexplored. Eighteen participants with recurrent and chronic MDD and 18 never-depressed controls listened to and vividly revisited autobiographical social experiences in an ecologically valid script-driven imagery paradigm using naturalistic memory narratives in an fMRI paradigm. Memories of Social Inclusion and Social Rejection broadly activated a common network of regions including the bilateral insula, thalamus and pre/postcentral gyrus across both groups. However, having a diagnosis of MDD was associated with an increased activation of the right middle frontal gyrus irrespective of memory type. Changes in positive affect were associated with activity in the dorsal ACC in the MDD group and in the insular cortex of the Control group. Our findings add to the evidence for complex representations for both positive and negative social signals in MDD and suggest neural sensitivity in MDD towards any socially salient information as opposed to selective sensitivity towards negative social experiences.

Not all patients with major depressive disorder respond to adequate pharmacological therapy. Psychoradiological studies have reported that antidepressant responders and nonresponders show different alterations in brain grey matter, but the findings are inconsistent. The present study reports a meta-analysis of voxel-based morphometric studies of patients with major depressive disorder, both antidepressant responders and nonresponders, using the anisotropic effect size version of Seed-based D Mapping to identify brain regions correlated to clinical response. A systematic search was conducted up to June 2016 to identify studies focussing on antidepressant response. In responders across 9 datasets grey matter volume (GMV) was significantly higher in the left inferior frontal gyrus and insula, while GMV was significantly lower in the bilateral anterior cingulate cortex (ACC) and the right superior frontal gyrus (SFG). In nonresponders across 5 datasets GMV was significantly lower in the bilateral ACC, median cingulate cortex (MCC) and right SFG. Conjunction analysis confirmed significant differences in the bilateral ACC and right SFG, where GMV was significantly lower in nonresponders but higher in responders. The current study adds to psychoradiology, an evolving subspecialty of radiology mainly for psychiatry and clinical psychology.

Attention deficit/hyperactivity disorder (ADHD) demonstrates a high level of comorbidity with major depressive disorder (MDD). One possible contributor to this is that the two disorders show high genetic correlation. However, the specific regions of the genome that may be responsible for this overlap are unclear. To identify variants associated with both ADHD and MDD, we performed a meta-analysis of GWAS of ADHD and MDD. All genome wide significant (p < 5 × 10-8) SNPs in the meta-analysis that were also strongly associated (p < 5 × 10-4) independently with each disorder were followed up. These putatively pleiotropic SNPs were tested for additional associations across a broad range of phenotypes. Fourteen linkage disequilibrium-independent SNPs were associated with each disorder separately (p < 5 × 10-4) and in the cross-disorder meta-analysis (p < 5 × 10-8). Nine of these SNPs had not been highlighted previously in either individual GWAS. Evidence supported nine of the fourteen SNPs acting as eQTL and two as brain eQTL. Index SNPs and their genomic regions demonstrated associations with other mental health phenotypes. Through conducting meta-analysis on ADHD and MDD only, our results build upon the previously observed genetic correlation between ADHD and MDD and reveal novel genomic regions that may be implicated in this overlap.

Although an association between major depressive disorder (MDD) and suicide exists, most depressed patients never attempt suicide. An improved understanding of the factors contributing to suicidal risk in MDD can provide direction for suicide predictor development. In MDD suicide attempters (MDD-SA), MDD non-attempters (MDD-NA), and healthy controls (HC) (n = 12 each group), complementary plasma proteomics identified 45 differential proteins mapped to coagulation and inflammation, 25 of which underwent Western blotting. In another cohort including antidepressant-treated patients (n = 49 each group), seven additional extrinsic pathway proteins were selected for ELISA. Two inflammatory proteins and eight coagulatory proteins demonstrated alterations in MDD-SA relative to MDD-NA and HC. Applying a relative mass-action ratio, MDD-SA subjects displayed a higher relative prothrombinase activity than MDD-NA subjects, while healthy controls displayed higher relative prothrombinase activity than both MDD-SA and MDD-NA subjects. Consistent with our human findings, we found that heparin treatment significantly increased forced swimming test (FST) immobility time in rodents. MDD, independent of suicidality, is associated with a proinflammatory state accompanied by a hypothrombotic state. Suicidal behavior in MDD is associated with a more pronounced proinflammatory and prothrombotic phenotype accompanied by extrinsic pathway activation, revealing an extrinsic pathway biomarker that can be applied in predicting and monitoring suicidal risk.

The objective of this study was to assess the benefits and potential risks associated with different physical exercise modalities for managing symptoms in adults with major depressive disorder who were not receiving second-generation antidepressants or cognitive behavioral therapy. A systematic review and meta-analysis of randomized controlled trials (RCTs) were conducted. The search included multiple databases: Medline, Cochrane Central Register of Controlled Trials (CENTRAL), Embase, PsycInfo, Web of Science, Clinical Trials repository, gray literature, and manual search. No language restrictions were applied. Eligible studies involved RCTs of adults with major depressive disorder who were not on antidepressants or receiving psychological therapy, comparing various exercise modalities with second-generation antidepressants or cognitive behavioral therapy, body-mind exercise, or no exercise interventions. Nine RCTs involving 678 adults were analyzed. The pooled results indicated a small clinical effect favoring exercise in reducing depressive symptoms, although the difference was not statistically significant (SMD = 0.27, 95% CI [- 0.58, 0.04], P = 0.09). Subgroup analyses suggested that intervention duration, frequency, intensity, supervision, age, overweight/obesity status, and diagnosis of depression could influence treatment outcomes. A sensitivity analysis was conducted for studies with controls without exercise interventions and a low risk of bias in the domains related to the randomization process and deviations from the intended interventions. The results showed that there are no statistically significant differences when interventions are compared with medication and body-mind exercise (p = 0.12, I2 = 78%). Furthermore, the analysis showed a moderate effect size favoring exercise, but no statistically significant difference between groups (p = 0.05), with high heterogeneity (I2 = 85%). The evidence quality was generally low to very low, and methodological limitations compromised the certainty of the findings. Adverse events associated with exercise were manageable. The study emphasizes the need for well-designed RCTs to provide clearer insights into the potential benefits of exercise in managing major depressive disorder symptoms. Caution is warranted in interpreting these results due to the limitations of the included studies.Systematic review registration: PROSPERO CRD42022356741.

Long interspersed nuclear element-1 (LINE-1 or L1) is a type of retrotransposons comprising 17% of the human and mouse genome, and has been found to be associated with several types of neurological disorders. Previous post-mortem brain studies reveal increased L1 copy number in the prefrontal cortex from schizophrenia patients. However, whether L1 retrotransposition occurs similarly in major depressive disorder (MDD) is unknown. Here, L1 copy number was measured by quantitative PCR analysis in peripheral blood of MDD patients (n = 105) and healthy controls (n = 105). The results showed that L1 copy number was increased in MDD patients possibly due to its hypomethylation. Furthermore, L1 copy number in peripheral blood and five brain regions (prefrontal cortex, hippocampus, amygdala, nucleus accumbens and paraventricular hypothalamic nucleus) was measured in the chronic unpredictable mild stress (CUMS) model of depression in mice. Intriguingly, increased L1 copy number in blood and the decreased L1 copy number in the prefrontal cortex were observed in stressed mice, while no change was found in other brain regions. Our results suggest that the changes of L1 may be associated with the pathophysiology of MDD, but the biological mechanism behind dysfunction of L1 retrotransposition in MDD remains to be further investigated.

Bidirectional relationship between sleep disturbances and affective disorders is increasingly recognised, but its underlying mechanisms are far from clear, and there is a scarcity of studies that report on sleep disturbances in recurrent depressive disorder (RDD) and bipolar affective disorder (BPAD). To address this, we conducted a retrospective study of polysomnographic and clinical records of patients presenting to a tertiary sleep disorders clinic with affective disorders. Sixty-three BPAD patients (32 female; mean age ± S.D.: 41.8 ± 12.4 years) and 126 age- and gender-matched RDD patients (62 female; 41.5 ± 12.8) were studied. Whilst no significant differences were observed in sleep macrostructure parameters between BPAD and RDD patients, major differences were observed in comorbid sleep and physical disorders, both of which were higher in BPAD patients. Two most prevalent sleep disorders, namely obstructive sleep apnoea (OSA) (BPAD 50.8.0% vs RDD 29.3%, P = 0.006) and insomnia (BPAD 34.9% vs RDD 15.0%, P = 0.005) were found to be strongly linked with BPAD. In summary, in our tertiary sleep clinic cohort, no overt differences in the sleep macrostructure between BPAD and RDD patients were demonstrated. However, OSA and insomnia, two most prevalent sleep disorders, were found significantly more prevalent in patients with BPAD, by comparison to RDD patients. Also, BPAD patients presented with significantly more severe OSA, and with higher overall physical co-morbidity. Thus, our findings suggest an unmet/hidden need for earlier diagnosis of those with BPAD.

Major depressive disorder (MDD) is a long-term, recurrent condition that often takes a chronic course. It seems imperative that research should be focused on gaining a better understanding of what predicts recurrent MDD. As a major mediator of the stress response, corticotropin-releasing-hormone receptor 1 (CRHR1) has been demonstrated to be an important contributor to the pathogenesis of MDD. In this study, we show a significant increase in the G-allele (rs242939) of the CRHR1 gene in the recurrent MDD group compared with the control group, and an overrepresentation of G-G-T hyplotype of the CRHR1 gene in recurrent MDD. We also demonstrate the interaction of the CRHR1 gene and negative life events in recurrent MDD. These results suggest that the CRHR1 gene could modify the susceptibility to developing recurrent MDD following negative life events in adulthood.

Previous functional magnetic resonance imaging (fMRI) studies demonstrated an abnormally coordinated network functioning in Major Depression Disorder (MDD) during rest. The main monoamine-producing nuclei within midbrain/brainstem are functionally integrated within these specific networks. Therefore, we aimed to investigate the resting-state functional connectivity (RSFC) of these nuclei in 45 MDD patients and differences between patients receiving two different classes of antidepressant drugs. Patients showed reduced RSFC from the ventral tegmental area (VTA) to dorsal anterior cingulate cortex (dACC) and stronger RSFC to the left amygdala and dorsolateral prefrontal cortex (DLPFC). Patients treated with antidepressants influencing noradrenergic and serotonergic neurotransmission showed different RSFC from locus coeruleus to DLPFC compared to patients treated with antidepressants influencing serotonergic neurotransmission only. In the opposite contrast patients showed stronger RSFC from dorsal raphe to posterior brain regions. Enhanced VTA-RSFC to amygdala as a central region of the salience network may indicate an over-attribution of the affective salience to internally-oriented processes. Significant correlation between decreased VTA-dACC functional connectivity and the BDI-II somatic symptoms indicates an association with diminished volition and behavioral activation in MDD. The observed differences in the FC of the midbrain/brainstem nuclei between two classes of antidepressants suggest differential neural effects of SSRIs and SNRIs.