Early Stage Of Major Depressive Disorder Research Articles

The longitudinal change pattern of cognitive subtypes in medication-free patients with major depressive disorder: a cluster analysis

This study aimed to investigate whether there are different cognitive subtypes in patients with major depressive disorder (MDD) and the change pattern of cognitive clusters across the course of MDD. A battery of comprehensive cognitive tests was used to assess the executive function, processing speed, attention, and memory of 153 medication-free patients and 142 healthy controls (HCs). After 6 months of treatment with antidepressants, 87 patients completed cognitive tests again. K-means cluster analysis was performed to determine the cognitive subtypes. A preserved cognition cluster and an impaired cognition cluster were identified in the acute episode phase and the 6-month follow-up phase. 80.5% of the patients remained in their original subgroup after 6 months of treatment. The impaired cognition cluster during the 6-month follow-up period could be predicted by impaired cognition during the episode phase, disease state (remission or non-remission), current illness duration, and education level. This study supporting the heterogeneity of cognitive performance across the course of disease in patients with MDD using cluster analysis. It was found that cognitive impairment during depressive episodes was predictive of poorer cognitive performance even after treatment with antidepressants. Therefore, interventions targeting cognitive function from the early stages of MDD is essential.

Altered brain network in first-episode, drug-naive patients with major depressive disorder

BackgroundResting-state functional magnetic resonance imaging has been widely used for the assessment of brain functional network, yet with inconsistent results. The present study aimed to investigate intranetwork and internetwork connectivity differences between patients with major depressive disorder (MDD) and healthy controls at the integrity, network and edge levels of 8 well-defined resting state networks. MethodsThirty patients with MDD and sixty-three healthy control subjects were recruited in this study. ResultsCompared with healthy controls, patients with MDD showed increased node degree in the right amygdala and putamen, increased connectivity strength in the deep gray matter network (DGN) and increased functional connectivity in intranetwork and internetwork. Meanwhile, MDD showed decreased connectivity strength in visual network-DGN pair. LimitationsThe sample size was small, and all patients in this study were of Asian ethnicity, especially Han individuals. ConclusionsThese findings demonstrate that MDD cases and healthy controls may have divergent intranetwork and internetwork connectivity at an early stage without confounding influence of medication. These differences may underlie cognitive and behavioral alterations in patients with MDD. And these differences may help with the discrimination of patients and healthy people at an early stage of MDD. More studies in the future are warranted to assist in the diagnosis of this burdensome disease.

Prospective study on microstructure in medication-naïve adolescents with first-episode major depressive disorder

Background: Major depressive disorder (MDD) is one of the most prevalent mental disorders during adolescence, and early diagnosis and treatment are important. We aimed to characterize the microstructure of the brain in medication-naïve adolescents with first-episode MDD. Methods: Patients with MDD (N = 31) and healthy controls (N = 27) participated in this study and severity of depressive symptoms, duration of untreated depressive episode, demographic data, and diffuse tensor imaging data were collected. A comparative analysis of patients and healthy controls was performed, and the effect of medication on the brain`s integrity was investigated through comparison before and after 3 months of treatment in the patient group. Tract-based spatial statistics was used for diffusion tensor image analysis. Results: In the patient group, functional anisotropy (FA) values were significantly higher at the genu of the corpus callosum, body of the corpus callosum, and right anterior corona radiata than in healthy controls. After 3 months of treatment, FA values were significantly decreased in the left anterior limb of the internal capsule, left posterior limb of the internal capsule, and left superior longitudinal fasciculus. Limitations: The sample size is relatively small and 3-month treatment period was relatively short. Conclusion: FA values of patients with MDD were increased compared to healthy controls and decreased after treatment. These results suggested that pharmacological treatments in the early stages of MDD might restore the brain`s integrity.

Interleukin-1 family and serotonin transporter in first-episode, drug-naive major depressive disorder: A pilot study

Abnormalities of neuroinflammatory process and serotonergic system have been reported in major depressive disorder (MDD). However, most previous studies were performed in recurrent MDD and only a few studies explored the interaction of the two systems. This study examined both systems concurrently and their clinical relevance in first-episode drug-naive MDD. Thirty-four MDD patients and 34 age and gender matched healthy controls (HC) were recruited. Plasma concentrations of the cytokines of interleukin-1 (IL-1) family, including IL-1α, IL-1β, IL-1 receptor antagonist (IL-1Ra) and IL-1 receptor type 2 (IL-1R2) were measured using enzyme-linked immune-sorbent assays. The serotonin transporter (SERT) availability in midbrain, thalamus, caudate, and putamen was examined by single-photon emission computed tomography with 123I-ADAM. There were significantly lower concentrations of pro-inflammatory IL-1β and its inhibitor, IL-1R2 in MDD than HC. The SERT availability was at the same level between groups. A negative association between IL-1Ra concentration and the SERT availability in midbrain was observed in MDD but not in HC. Both IL-1β concentration and the SERT availability in caudate negatively correlated with depression severity and the effect of IL-1β was not moderated or mediated by the SERT. In conclusion, this study demonstrated the involvement of IL-1 family in the early stage of MDD, especially for IL-1β. SERT was not the main central target of altered IL-1β and these two systems might contribute to MDD by different mechanisms. The pathophysiology might be varied between early and recurrent MDD and tuning treatment strategies at different clinical stages might be needed.

Brain structural network alterations related to serum cortisol levels in drug-na\xefve, first-episode major depressive disorder patients: a source-based morphometric study

Higher cortisol levels due to a hyperactive hypothalamic–pituitary–adrenal axis have been reported in patients with major depressive disorder (MDD). Increased cortisol levels change both the brain morphology and function in MDD patients. The multivariate source-based morphometry (SBM) technique has been applied to investigate neuroanatomical changes in some neuropsychiatric diseases, but not MDD. We aimed to examine the alterations in gray matter (GM) networks and their relationship with serum cortisol levels in first-episode, drug-naïve MDD patients using SBM. Forty-two patients with MDD and 39 controls were recruited via interviews. Morning serum cortisol levels were measured, and high-resolution T1-weighted imaging followed by SBM analysis was performed in all participants. The patients had significantly higher serum cortisol levels than the controls. We found two GM sources, which were significantly different between patients with MDD and controls (prefrontal network, p < .01; insula-temporal network, p < .01). Serum cortisol levels showed a statistically significant negative correlation with the loading coefficients of the prefrontal network (r = − 0.354, p = 0.02). In conclusion, increased serum cortisol levels were associated with reductions in the prefrontal network in the early stage of MDD, and SBM may be a useful approach for analyzing structural MRI data.

Sex-Specific Differences in Severity of Depressive Symptoms, Heart Rate Variability, and Neurocognitive Profiles of Depressed Young Adults: Exploring Characteristics for Mild Depression.

Mild depressive symptoms (MDS) reflect vulnerability to major depression that does not meet the criteria for a major depressive disorder (MDD). Previous research indicates that it is difficult to identify MDS in young adults, and they exhibit diverse aspects of depressive symptoms caused by clinical depression, which can lead to poor academic performance, relationship difficulties, and even suicide. Additionally, many young adults remain unaware of their depressive symptoms during the early stages of MDD. Thus, the present study investigated clinical, neurocognitive, and physiological characteristics of young adults with various symptoms of depression and explored sex-specific differences. A total of 113 students aged 18–35 (MDD: n = 32; MDS: n =37; control [CON]: n = 44) participated in the study. Self-report clinical measures, short-term cardiac activity measured by finger sensors, and neurocognitive data were collected. Pearson's correlations, two-way analysis of variance (ANOVA), principal component analysis, and exploratory structural equation modeling were conducted for the statistical analyses. Furthermore, the measurement invariance of the latent factor model was tested, and fit indices were compared according to sex. The results revealed that male students showed greater sympatho-vagal activity than female students. Additionally, male MDS students tended to exhibit decreased performance levels in neurocognitive function tasks compared with MDD and CON males, whereas female MDS students showed distinct characteristics compared to MDD and CON females on self-report measures of anxiety. Correlation analyses identified a positive association between the level of anger perception and latency in the executive function test among both males and females. Additionally, the use of a structured model revealed significant sex-specific differences in factor estimates. The present results suggest that recognizing the early signs of MDS that account for sex-specific differences in both subjective and objective measures may improve the diagnosis and monitoring of young adults with MDS.

Abnormal functional connectivity strength in first-episode, drug-naïve adult patients with major depressive disorder

BackgroundThe pathogenesis of major depressive disorder (MDD) is complicated and equivocal. Previous studies have found an incidence of abnormal changes of neural networks, with plentiful evidence pointing the finger of suspicion firmly at the default mode network (DMN) and cortico-limbic networks. The aim of the present study was to use the approach of functional connectivity strength (FCS) to directly investigate the features of spontaneous brain activity in the case of first-episode, drug-naïve adult patients with MDD at rest. MethodsResting-state functional magnetic resonance imaging (MRI) scans were performed on 23 first-episode drug-naïve major depressive disorder (MDD) patients and 20 healthy controls (HCs). In this study, using graph-theory approaches(FCS), we computed the characteristics of brain connectivity. Simultaneously, we used a series of validated test procedures to evaluate the patients' cognitive function. Subsequently, the results were compared with the peak of FCS value and a correlation analysis was conducted. ResultsCompared with the HCs group, MDD patients showed significantly decreased FCS in bilateral posterior cingulate cortex (PCC)/precuneus and bilateral prefrontal cortex(PFC) and increased FCS in right posterior central gyrus, left thalamus and left temporal lobe. These brain regions belongs to the default-mode network and cortico-limbic networks. Finally, the correlation analyses showed the negative correlation of the FCS values in the left posterior cingulate cortex (PCC)/precuneus and Hamilton Anxiety Rating Scale (HAMA, r = −0.472, p = .023), Stroop Color Word Test-A(SCWT-A, r = −0.451, p = .031), Stroop Color Word Test-B(SCWT-B, r = −0.588, p = .003).Meanwhile, there was negative correlation between the FCS values in the left thalamus and SCWT-A(r = −0.473, p = .023), SCWT-B(r = −0.465, p = .025), SCWTC(r = −0.524, p = .010).In addition, the FCS values in the right PCC has negative correlation with Montgomery Asberg Depression Rating Scale (MADRS) (r = −0.433, p = .039). ConclusionsDMN is an important node of MDD. FCS within the default mode network and cortico-limbic networks in patients with major depressive disorder has been changed in the early stage of MDD. FCS can provide favourable and additional evidence in the investigation of brain pathophysiology and therapy in depression.

Aberrant brain regional homogeneity in first-episode drug-naïve patients with major depressive disorder: A voxel-wise meta-analysis

BackgroundResting-state functional magnetic resonance imaging studies have reported aberrant brain regional homogeneity (ReHo) in patients with major depressive disorder (MDD). However, the findings across studies were confounded by medication status and different depressive episodes. MethodsA systematic literature search of the PubMed, Embase, and Web of Science databases was conducted. We conducted a quantitative voxel-wise meta-analysis of ReHo studies, using the Seed-based d Mapping approach, in first-episode drug-naïve patients with MDD. ResultsWe identified 10 studies with 12 datasets suitable for inclusion, consisting of 402 first-episode drug-naïve patients with MDD and 330 healthy controls. The most consistent and robust findings were that patients with MDD relative to healthy controls exhibited increased ReHo in the left hippocampus and decreased ReHo in the left orbitofrontal cortex. LimitationsThe patient samples included in our meta-analysis were all Chinese, thus limiting the applicability of the present findings to other populations. ConclusionsReHo alterations in these brain regions are likely to reflect the core disease-related functional abnormalities, which are implicated in emotional dysregulation and cognitive impairment that are seen in the early stage of MDD. These findings contribute to a better understanding of the neurobiological underpinnings of MDD, and the left hippocampus and orbitofrontal cortex could serve as specific regions of interest for further investigations.

Relationship between interleukin (IL)-6 and brain morphology in drug-na\xefve, first-episode major depressive disorder using surface-based morphometry

There is a growing body of evidence to support the involvement of proinflammatory cytokines in the pathophysiology of depression; however, no previous studies have examined the relationship between cytokines and the brain morphology of patients with major depressive disorder (MDD). We therefore evaluated the relationship between serum cytokine levels and cortical thinning during the first depressive episode in drug-naïve patients with MDD. We measured the serum cytokine levels (IL-1β, IL-6, IFN-γ, and TNFα), and whole-brain cortical thickness and hippocampal subfield volumes on brain magnetic resonance imaging (MRI) using surface-based morphometry in 40 patients with MDD and 47 healthy volunteers (controls). Only the serum IL-6 level was significantly higher in patients with MDD than in controls. The prefrontal cortex (PFC) thickness was significantly reduced in patients with MDD, and showed a significant inverse correlation with the serum IL-6 level. Although high serum IL-6 levels were correlated with reduced left subiculum and right CA1, CA3, CA4, GC-DG, subiculum, and whole hippocampus volumes, the presence or absence of MDD had no effect on the volume of any hippocampal subfields. Our results suggest that IL-6 may play a key role in the morphological changes in the PFC during the early stage of MDD.

Abnormal dynamic functional connectivity of amygdalar subregions in untreated patients with first-episode major depressive disorder.

Accumulating evidence supports the concept of the amygdala as a complex of structurally and functionally heterogeneous nuclei rather than as a single homogeneous structure. However, changes in resting-state functional connectivity in amygdalar subregions have not been investigated in major depressive disorder (MDD). Here, we explored whether amygdalar subregions - including the laterobasal, centromedial (CM) and superficial (SF) areas - exhibited distinct disruption patterns for different dynamic functional connectivity (dFC) properties, and whether these different properties were correlated with clinical information in patients with MDD. Thirty untreated patients with first-episode MDD and 62 matched controls were included. We assessed between-group differences in the mean strength of dFC in each amygdalar subregion in the whole brain using general linear model analysis. The patients with MDD showed decreased strength in positive dFC between the left CM/SF and brainstem and between the left SF and left thalamus; they showed decreased strength in negative dFC between the left CM and right superior frontal gyrus (p < 0.05, family-wise error-corrected). We found significant positive correlations between age at onset and the mean positive strength of dFC in the left CM/brainstem in patients with MDD. The definitions of amygdalar subregions were based on a cytoarchitectonic delineation, and the temporal resolution of the fMRI was slow (repetition time = 2 s). These findings confirm the distinct dynamic functional pathway of amygdalar subregions in MDD and suggest that the limbic-cortical-striato-pallido-thalamic circuitry plays a crucial role in the early stages of MDD.

Alternations of White Matter Structural Networks in First Episode Untreated Major Depressive Disorder with Short Duration.

It is crucial to explore the pathogenesis of major depressive disorder (MDD) at the early stage for the better diagnostic and treatment strategies. It was suggested that MDD might be involving in functional or structural alternations at the brain network level. However, at the onset of MDD, whether the whole brain white matter (WM) alterations at network level are already evident still remains unclear. In the present study, diffusion MRI scanning was adopt to depict the unique WM structural network topology across the entire brain at the early stage of MDD. Twenty-one first episode, short duration (<1 year) and drug-naïve depression patients, and 25 healthy control (HC) subjects were recruited. To construct the WM structural network, atlas-based brain regions were used for nodes, and the value of multiplying fiber number by the mean fractional anisotropy along the fiber bundles connected a pair of brain regions were used for edges. The structural network was analyzed by graph theoretic and network-based statistic methods. Pearson partial correlation analysis was also performed to evaluate their correlation with the clinical variables. Compared with HCs, the MDD patients had a significant decrease in the small-worldness (σ). Meanwhile, the MDD patients presented a significantly decreased subnetwork, which mainly involved in the frontal–subcortical and limbic regions. Our results suggested that the abnormal structural network of the orbitofrontal cortex and thalamus, involving the imbalance with the limbic system, might be a key pathology in early stage drug-naive depression. And the structural network analysis might be potential in early detection and diagnosis of MDD.

The volumetric and shape changes of the putamen and thalamus in first episode, untreated major depressive disorder.

Previous MRI studies confirmed abnormalities in the limbic-cortical-striatal-pallidal-thalamic (LCSPT) network or limbic-cortico-striatal-thalamic-cortical (LCSTC) circuits in patients with major depressive disorder (MDD), but few studies have investigated the subcortical structural abnormalities. Therefore, we sought to determine whether focal subcortical grey matter (GM) changes might be present in MDD at an early stage. We recruited 30 first episode, untreated patients with major depressive disorder (MDD) and 26 healthy control subjects. Voxel-based morphometry was used to evaluate cortical grey matter changes, and automated volumetric and shape analyses were used to assess volume and shape changes of the subcortical GM structures, respectively. In addition, probabilistic tractography methods were used to demonstrate the relationship between the subcortical and the cortical GM. Compared to healthy controls, MDD patients had significant volume reductions in the bilateral putamen and left thalamus (FWE-corrected, p < 0.05). Meanwhile, the vertex-based shape analysis showed regionally contracted areas on the dorsolateral and ventromedial aspects of the bilateral putamen, and on the dorsal and ventral aspects of left thalamus in MDD patients (FWE-corrected, p < 0.05). Additionally, a negative correlation was found between local atrophy in the dorsal aspects of the left thalamus and clinical variables representing severity. Furthermore, probabilistic tractography demonstrated that the area of shape deformation of the bilateral putamen and left thalamus have connections with the frontal and temporal lobes, which were found to be related to major depression. Our results suggested that structural abnormalities in the putamen and thalamus might be present in the early stages of MDD, which support the role of subcortical structure in the pathophysiology of MDD. Meanwhile, the present study showed that these subcortical structural abnormalities might be the potential trait markers of MDD.

RELATIONSHIP BETWEEN THE CORTICAL THICKNESS AND SERUM CORTISOL LEVELS IN DRUG-NAÏVE, FIRST-EPISODE PATIENTS WITH MAJOR DEPRESSIVE DISORDER: A SURFACE-BASED MORPHOMETRIC STUDY.

In major depressive disorder (MDD) patients, higher morning cortisol levels due to a hyperactive hypothalamic-pituitary-adrenal (HPA) axis have been reported. The aim of the present study was to evaluate the relationship between cortical thinning and the serum cortisol levels during the first depressive episode in drug-naïve MDD patients using an automated surface-based morphometry (SBM) method. The institutional review board approved this prospective study. MR imaging data were obtained using a 3T scanner by a three-dimensional fast-spoiled gradient recalled acquisition with steady state (3D-FSPGR). Thirty drug-naïve patients with MDD and 41 age- and gender-matched healthy subjects (controls) were enrolled. We then used the SBM method (Freesurfer) to generate cortical thickness maps, and measured the cortical thickness in each subject. Morning blood samples were drawn from all participants for cortisol measurements. We found the serum cortisol levels were significantly higher in the MDD patients than in the controls. The MDD patients manifested significant thinning of the left lateral orbitofrontal cortex compared with the controls. There was a significant negative linear correlation between the thickness of the left lateral orbitofrontal cortex and the serum cortisol levels in the MDD patients. In the early stage of MDD, the thickness of the lateral orbitofrontal cortex was significantly reduced, and also showed a significant inverse correlation with the serum cortisol levels. Since the lateral orbitofrontal cortex contains a high concentration of glucocorticoid receptor, glucocorticoid receptor-mediated signaling transductions could contribute to neurotoxicity, which might occur when there are high cortisol levels in patients with MDD.

Increased cognition connectivity network in major depression disorder: a FMRI study.

ObjectiveEvidence of the brain network involved in cognitive dysfunction has been inconsistent for major depressive disorder (MDD), especially during early stage of MDD. This study seeks to examine abnormal cognition connectivity network (CCN) in MDD within the whole brain.MethodsSixteen patients with MDD and 16 health controls were scanned during resting-state using 3.0 T functional magnetic resonance imaging (fMRI). All patients were first episode without any history of antidepressant treatment. Both the left and right dorsolateral prefrontal cortex (DLPFC) were used as individual seeds to identify CCN by the seed-target correlation analysis. Two sample t test was used to calculate between-group differences in CCN using fisher z-transformed correlation maps.ResultsThe CCN was constructed by bilateral seed DLPFC in two groups separately. Depressed subjects exhibited significantly increased functional connectivity (FC) by left DLPFC in one cluster, overlapping middle frontal gyrus, BA7, BA43, precuneus, BA6, BA40, superior temporal gyrus, BA22, inferior parietal lobule, precentral gyrus, BA4 and cingulate gyrus in left cerebrum. Health controls did not show any cluster with significantly greater FC compared to depressed subjects in left DLPFC network. There was no significant difference of FC in right DLPFC network between depressed subjects and the health controls.ConclusionThere are differences in CCN during early stage of MDD, as identified by increased FCs among part of frontal gyrus, parietal cortex, cingulate cortex, and BA43, BA22, BA4 with left DLPFC. These brain areas might be involved in the underlying mechanisms of cognitive dysfunction in MDD.

Hippocampal N-acetylaspartate and morning cortisol levels in drug-naive, first-episode patients with major depressive disorder: effects of treatment

An excess of glucocorticoids has been associated with hippocampal pathology in major depressive disorder (MDD). However, the relationships between depression, hippocampal structure and function, and cortisol levels are unclear, and the effects of antidepressant treatment on the measures are not well studied. For this study, 26 first-episode, treatment-naive, non-late-life adult depressed patients and 13 healthy controls were enrolled. Subjects underwent proton magnetic resonance spectroscopy ((1)H MRS) to obtain metabolite levels from the bilateral hippocampus. Patients with MDD were treated with serotonergic-noradrenergic reuptake inhibitor duloxetine for 12 weeks. After the 12-week period, all subjects with MDD underwent (1)H MRS again. Morning serum cortisol levels also were measured both before and after antidepressant treatment. Comparison of baseline values indicated that there were no significant differences in any of the metabolite ratios (N-acetyl aspartate/creatine (NAA/Cr) and choline (Cho)/Cr) in the bilateral hippocampus. After treatment, NAA/Cr ratios increased significantly in the right hippocampus compared with pre-treatment values. There was no correlation between morning serum cortisol levels and bilateral hippocampal NAA/Cr or Cho/Cr in patients with MDD. These findings suggest that there are unaltered hippocampal metabolites in the early stage of MDD. Antidepressant treatment may affect hippocampal NAA levels in patients with MDD. In addition, the results do not support cortisol-mediated hippocampal neurotoxicity as the major etiological mechanism.