Subtype Of Major Depressive Disorder Research Articles

Tissue-specific gene expression of genome-wide significant loci associated with major depressive disorder subtypes

Major depressive disorder (MDD) is a clinically and genetically heterogeneous disorder. To reduce heterogeneity, large-scale genome-wide association studies have recently identified genome-wide significant loci associated with seven MDD subtypes. However, it was unclear in which tissues the genes near those loci are specifically expressed. We investigated whether genes related to specific MDD subtypes would be preferably expressed in a specific tissue. At 14 novel subtype-specific loci related to seven MDD subtypes—(1) non-atypical-like features MDD, (2) early-onset MDD, (3) recurrent MDD, (4) MDD with suicidal thoughts, (5) MDD without suicidal thoughts, (6) MDD with moderate impairment, and (7) postpartum depression, we investigated whether 22 genome-wide significant genetic variant-mapped genes were tissue-specifically expressed in brain, female reproductive, male specific, cardiovascular, gastrointestinal, or urinary tissues in the Genotype-Tissue Expression (GTEx) subjects (n ≤ 948). To confirm the tissue-specific expression in the GTEx, we used independent Human Protein Atlas (HPA) RNA-seq subjects (n ≤ 95). Of 22 genes, nine and five genes were tissue-specifically expressed in brain and female reproductive tissues, respectively (p < 2.27 × 10−3). RTN1, ERBB4, and AMIGO1 related to early-onset MDD, recurrent MDD, or MDD with suicidal thoughts were highly expressed in brain tissues (d = 1.19–2.71), while OAS1, LRRC9, DHRS7, PSMA5, SYPL2, and GULP1 related to non-atypical-like features MDD, early-onset MDD, MDD with suicidal thoughts, or postpartum depression were expressed at low levels in brain tissues (d = −0.17−−1.48). DFNA5, CTBP2, PCNX4, SDCCAG8, and GULP1, which are related to early-onset MDD, MDD with moderate impairment, or postpartum depression, were highly expressed in female reproductive tissues (d = 0.80–2.08). Brain and female reproductive tissue-specific expression was confirmed in the HPA RNA-seq subjects. Our findings suggest that brain and female reproductive tissue-specific expression might contribute to the pathogenesis of MDD subtypes.

Impaired topology and connectivity of grey matter structural networks in major depressive disorder: evidence from a multi-site neuroimaging data-set.

Major depressive disorder (MDD) has been increasingly understood as a disruption of brain connectome. Investigating grey matter structural networks with a large sample size can provide valuable insights into the structural basis of network-level neuropathological underpinnings of MDD. Using a multisite MRI data-set including nearly 2000 individuals, this study aimed to identify robust topology and connectivity abnormalities of grey matter structural network linked to MDD and relevant clinical phenotypes. A total of 955 MDD patients and 1009 healthy controls were included from 23 sites. Individualised structural covariance networks (SCN) were established based on grey matter volume maps. Following data harmonisation, network topological metrics and focal connectivity were examined for group-level comparisons, individual-level classification performance and association with clinical ratings. Various validation strategies were applied to confirm the reliability of findings. Compared with healthy controls, MDD individuals exhibited increased global efficiency, abnormal regional centralities (i.e. thalamus, precentral gyrus, middle cingulate cortex and default mode network) and altered circuit connectivity (i.e. ventral attention network and frontoparietal network). First-episode drug-naive and recurrent patients exhibited different patterns of deficits in network topology and connectivity. In addition, the individual-level classification of topological metrics outperforms that of structural connectivity. The thalamus-insula connectivity was positively associated with the severity of depressive symptoms. Based on this high-powered data-set, we identified reliable patterns of impaired topology and connectivity of individualised SCN in MDD and relevant subtypes, which adds to the current understanding of neuropathology of MDD and might guide future development of diagnostic and therapeutic markers.

Identifying data-driven subtypes of major depressive disorder with electronic health records

BackgroundEfforts to reduce the heterogeneity of major depressive disorder (MDD) by identifying subtypes have not yet facilitated treatment personalization or investigation of biology, so novel approaches merit consideration. MethodsWe utilized electronic health records drawn from 2 academic medical centers and affiliated health systems in Massachusetts to identify data-driven subtypes of MDD, characterizing sociodemographic features, comorbid diagnoses, and treatment patterns. We applied Latent Dirichlet Allocation (LDA) to summarize diagnostic codes followed by agglomerative clustering to define patient subgroups. ResultsAmong 136,371 patients (95,034 women [70 %]; 41,337 men [30 %]; mean [SD] age, 47.0 [14.0] years), the 15 putative MDD subtypes were characterized by comorbidities and distinct patterns in medication use. There was substantial variation in rates of selective serotonin reuptake inhibitor (SSRI) use (from a low of 62 % to a high of 78 %) and selective norepinephrine reuptake inhibitor (SNRI) use (from 4 % to 21 %). LimitationsElectronic health records lack reliable symptom-level data, so we cannot examine the extent to which subtypes might differ in clinical presentation or symptom dimensions. ConclusionThese data-driven subtypes, drawing on representative clinical cohorts, merit further investigation for their utility in identifying more homogeneous patient populations for basic as well as clinical investigation.

Reduced gray matter volume of the hippocampal tail in melancholic depression: evidence from an MRI study

BackgroundMelancholic depression (MD) is one of the most prevalent and severe subtypes of major depressive disorder (MDD). Previous studies have revealed inconsistent results regarding alterations in grey matter volume (GMV) of the hippocampus and amygdala of MD patients, possibly due to overlooking the complexity of their internal structure. The hippocampus and amygdala consist of multiple and functionally distinct subregions, and these subregions may play different roles in MD. This study aims to investigate the volumetric alterations of each subregion of the hippocampus and amygdala in patients with MD and non-melancholic depression (NMD).MethodsA total of 146 drug-naïve, first-episode MDD patients (72 with MD and 74 with NMD) and 81 gender-, age-, and education-matched healthy controls (HCs) were included in the study. All participants underwent magnetic resonance imaging (MRI) scans. The subregional segmentation of hippocampus and amygdala was performed using the FreeSurfer 6.0 software. The multivariate analysis of covariance (MANCOVA) was used to detect GMV differences of the hippocampal and amygdala subregions between three groups. Partial correlation analysis was conducted to explore the relationship between hippocampus or amygdala subfields and clinical characteristics in the MD group. Age, gender, years of education and intracranial volume (ICV) were included as covariates in both MANCOVA and partial correlation analyses.ResultsPatients with MD exhibited a significantly lower GMV of the right hippocampal tail compared to HCs, which was uncorrelated with clinical characteristics of MD. No significant differences were observed among the three groups in overall and subregional GMV of amygdala.ConclusionsOur findings suggest that specific hippocampal subregions in MD patients are more susceptible to volumetric alterations than the entire hippocampus. The reduced right hippocampal tail may underlie the unique neuropathology of MD. Future longitudinal studies are required to better investigate the associations between reduced right hippocampal tail and the onset and progression of MD.

A genetic risk score to predict treatment nonresponse in psychotic depression

Psychotic depression is a severe and difficult-to-treat subtype of major depressive disorder for which higher rates of treatment-resistant depression were found. Studies have been performed aiming to predict treatment-resistant depression or treatment nonresponse. However, most of these studies excluded patients with psychotic depression. We created a genetic risk score (GRS) based on a large treatment-resistant depression genome-wide association study. We tested whether this GRS was associated with nonresponse, nonremission and the number of prior adequate antidepressant trials in patients with a psychotic depression. Using data from a randomized clinical trial with patients with a psychotic depression (n = 122), we created GRS deciles and calculated positive prediction values (PPV), negative predictive values (NPV) and odds ratios (OR). Nonresponse and nonremission were assessed after 7 weeks of treatment with venlafaxine, imipramine or venlafaxine plus quetiapine. The GRS was negatively correlated with treatment response (r = −0.32, p = 0.0023, n = 88) and remission (r = −0.31, p = 0.0037, n = 88), but was not correlated with the number of prior adequate antidepressant trials. For patients with a GRS in the top 10%, we observed a PPV of 100%, a NPV of 73.7% and an OR of 52.4 (p = 0.00072, n = 88) for nonresponse. For nonremission, a PPV of 100%, a NPV of 51.9% and an OR of 21.3 (p = 0.036, n = 88) was observed for patients with a GRS in the top 10%. Overall, an increased risk for nonresponse and nonremission was seen in patients with GRSs in the top 40%. Our results suggest that a treatment-resistant depression GRS is predictive of treatment nonresponse and nonremission in psychotic depression.

Fear of depression recurrence among individuals with remitted depression: a qualitative interview study.

Major Depressive Disorder (MDD) is a prevalent psychiatric condition and the largest contributor to disability worldwide. MDD is highly recurrent, yet little is known about the mechanisms that occur following a Major Depressive Episode (MDE) and underlie recurrence. We explored the concept of fear of depression recurrence (FoDR) and its impact on daily functioning among individuals in remission from MDD. 30 participants (83% female; 37% White; Mage = 27.7, SD = 8.96) underwent semi-structured qualitative interviews. The interviews explored participants' experiences of FoDR including the frequency, severity, content, triggers, and impact of fears and associated coping strategies. We used content analysis to analyze the transcriptions. Most participants (73%) reported having FoDR, with varying frequency, severity, and duration of fears. The triggers and content of participants' fears often mirrored the symptoms (e.g., low mood, anhedonia) and consequences (e.g., job loss, social withdrawal) endured during past MDEs. Some participants reported a minimal impact of FoDR on daily functioning, whereas others reported a positive (e.g., personal growth) or negative (e.g., increased anxiety) influence. Our sample size did not allow for explorations of differences in FoDR across unique MDD subtypes or sociocultural factors. The concept of FoDR may present a window into understanding the unique cognitive and behavioural changes that occur following MDD remission and underlie depression recurrence. Future research should aim to identify underlying individual differences and characteristics of the disorder that may influence the presence and impact of FoDR. Finally, a FoDR measure should be developed so that associations between FoDR and recurrence risk, depressive symptoms, and other indices of functioning can be determined.

Prediction of anxious depression using multimodal neuroimaging and machine learning

Anxious depression is a common subtype of major depressive disorder (MDD) associated with adverse outcomes and severely impaired social function. It is important to clarify the underlying neurobiology of anxious depression to refine the diagnosis and stratify patients for therapy. Here we explored associations between anxiety and brain structure/function in MDD patients. A total of 260 MDD patients and 127 healthy controls underwent three-dimensional T1-weighted structural scanning and resting-state functional magnetic resonance imaging. Demographic data were collected from all participants. Differences in gray matter volume (GMV), (fractional) amplitude of low-frequency fluctuation ((f)ALFF), regional homogeneity (ReHo), and seed point-based functional connectivity were compared between anxious MDD patients, non-anxious MDD patients, and healthy controls. A random forest model was used to predict anxiety in MDD patients using neuroimaging features. Anxious MDD patients showed significant differences in GMV in the left middle temporal gyrus and ReHo in the right superior parietal gyrus and the left precuneus than HCs. Compared with non-anxious MDD patients, patients with anxious MDD showed significantly different GMV in the left inferior temporal gyrus, left superior temporal gyrus, left superior frontal gyrus (orbital part), and left dorsolateral superior frontal gyrus; fALFF in the left middle temporal gyrus; ReHo in the inferior temporal gyrus and the superior frontal gyrus (orbital part); and functional connectivity between the left superior temporal gyrus(temporal pole) and left medial superior frontal gyrus. A diagnostic predictive random forest model built using imaging features and validated by 10-fold cross-validation distinguished anxious from non-anxious MDD with an AUC of 0.802. Patients with anxious depression exhibit dysregulation of brain regions associated with emotion regulation, cognition, and decision-making, and our diagnostic model paves the way for more accurate, objective clinical diagnosis of anxious depression.

The novel subtype of major depressive disorder characterized by somatic symptoms is associated with poor treatment efficacy and prognosis: A data-driven cluster analysis of a prospective cohort in China

BackgroundThere is not yet a valid and evidence-based system to classify patients with MDD into more homogeneous subtypes based on their clinical features. This study aims to identify symptom-based subtypes of MDD and investigate whether the treatment outcomes of those subtypes would be different. MethodThe cohort was established at 12 densely populated cities of China. A total of 1487 patients were enrolled. All participants were 18–65 years old and diagnosed with MDD. Participants were followed up at baseline, weeks 4, 8, and 12, and months 4 and 6. K-means algorithm was used to cluster patients with MDD according to clinical symptoms. The network analysis was adopted to characterize and compare the symptom patterns in the clusters. We also examined the associations between the clusters and the clinical outcomes. ResultsThe optimal number of the clusters was determined to be 2. Each cluster's maximum Jaccard Co-efficient was calculated to be >0.5 (cluster1 = 0.53, cluster 2 = 0.67). The symptom “depressed mood” and some other affective symptoms were the most prominent in cluster 1. Somatic symptoms, such as weight loss and general somatic symptoms, had the greatest expected influence in cluster 2. Compared with the response rates of the patients in the “somatic cluster”, those of the patients in the “affective cluster” were significantly higher (P < 0.05). ConclusionsPatients with MDD might be classified into two symptom-based subtypes featured with affective symptoms or somatic symptoms. The treatment efficacy and prognosis of the subtype featured with somatic symptoms may be worse.

Subtypes of major depressive disorders and objectively measured physical activity and sedentary behaviors in the community

BackgroundLack of physical activity (PA) and high sedentary behavior (SB) may enhance mental health problems, including depression, and are associated with increased mortality. Aside from a large body of research on major depressive disorder (MDD) assessed as an entity and either PA or SB, few studies have examined associations among subtypes of MDD and both PA and SB simultaneously derived from wrist-worn accelerometers. Accordingly, our aim was to explore the associations among MDD subtypes (atypical, melancholic, combined atypical-melancholic and unspecified) and four actigraphy-derived behaviors combining the levels of PA and SB. MethodsThe sample stemmed from CoLaus|PsyCoLaus, a population-based cohort study, consisting of 2375 participants (55.1% women; mean age: 62.4 years) who wore an accelorometer for 14 days after a physical exam and subsequently completed a semi-structured psychiatric interview. Activity behaviors were defined according to the combination of the levels of moderate-to-vigorous intensity PA and SB. Associations of remitted MDD subtypes, current MDD and physical inactivity behaviors were assessed using multinomial logistic regression, adjusted for socio-demographic characteristics, a history of anxiety, alcohol and drug use disorders and cardiovascular risk factors. ResultsIn the fully adjusted model, participants with the remitted combined atypical-melancholic subtype had a higher risk of being more physically inactive. ConclusionsOur findings suggest that low PA and high SB are not restricted to the duration of depressive episodes in people with atypical and melancholic episodes. The lack of PA and high SB in this group of depressive patients exposes them to an additional long-term cardiovascular risk and measures to increase PA may be particularly fruitful in this MDD subgroup.

Effects of Anxious Depression on Antidepressant Treatment Response.

Anxious depression represents a subtype of major depressive disorder and is associated with increased suicidality, severity, chronicity and lower treatment response. Only a few studies have investigated the differences between anxious depressed (aMDD) and non-anxious depressed (naMDD) patients regarding treatment dosage, serum-concentration and drug-specific treatment response. In our naturalistic and prospective study, we investigated whether the effectiveness of therapy including antidepressants (SSRI, SNRI, NaSSA, tricyclics and combinations) in aMDD patients differs significantly from that in naMDD patients. In a sample of 346 patients, we calculated the anxiety somatization factor (ASF) and defined treatment response as a reduction (≥50%) in the Hamilton Depression Rating Scale (HDRS)-21 score after 7 weeks of pharmacological treatment. We did not observe an association between therapy response and the baseline ASF-scores, or differences in therapy outcomes between aMDD and naMDD patients. However, non-responders had higher ASF-scores, and at week 7 aMDD patients displayed a worse therapy outcome than naMDD patients. In subgroup analyses for different antidepressant drugs, venlafaxine-treated aMDD patients showed a significantly worse outcome at week 7. Future prospective, randomized-controlled studies should address the question of a worse therapy outcome in aMDD patients for different psychopharmaceuticals individually.

Uncovering the Neural Correlates of Anhedonia Subtypes in Major Depressive Disorder: Implications for Intervention Strategies.

Major depressive disorder (MDD) represents a serious public health concern, negatively affecting individuals' quality of life and making a substantial contribution to the global burden of disease. Anhedonia is a core symptom of MDD and is associated with poor treatment outcomes. Variability in anhedonia components within MDD has been observed, suggesting heterogeneity in psychopathology across subgroups. However, little is known about anhedonia subgroups in MDD and their underlying neural correlates across subgroups. To address this question, we employed a hierarchical cluster analysis based on Temporal Experience of Pleasure Scale subscales in 60 first-episode, drug-naive MDD patients and 32 healthy controls. Then we conducted a connectome-wide association study and whole-brain voxel-wise functional analyses for identified subgroups. There were three main findings: (1) three subgroups with different anhedonia profiles were identified using a data mining approach; (2) several parts of the reward network (especially pallidum and dorsal striatum) were associated with anticipatory and consummatory pleasure; (3) different patterns of within- and between-network connectivity contributed to the disparities of anhedonia profiles across three MDD subgroups. Here, we show that anhedonia in MDD is not uniform and can be categorized into distinct subgroups, and our research contributes to the understanding of neural underpinnings, offering potential treatment directions. This work emphasizes the need for tailored approaches in the complex landscape of MDD. The identification of homogeneous, stable, and neurobiologically valid MDD subtypes could significantly enhance our comprehension and management of this multifaceted condition.

Increased brain nucleus accumbens functional connectivity in melancholic depression

BackgroundMelancholic depression, marked by typical symptoms of anhedonia, is regarded as a homogeneous subtype of major depressive disorder (MDD). However, little attention was paid to underlying mechanisms of melancholic depression. This study aims to examine functional connectivity of the reward circuit associated with anhedonia symptoms in melancholic depression. MethodsFifty-nine patients with first-episode drug- naive MDD, including 31 melancholic patients and 28 non-melancholic patients, were recruited and underwent resting-state functional magnetic resonance imaging (rs-fMRI). Thirty-two healthy volunteers were recruited as controls. Bilateral nucleus accumbens (NAc) were selected as seed points to form functional NAc network. Then support vector machine (SVM) was used to distinguish melancholic patients from non-melancholic patients. ResultsRelative to non-melancholic patients, melancholic patients displayed increased functional connectivity (FC) between bilateral NAc and right middle frontal gyrus (MFG) and between right NAc and left cerebellum lobule VIII. Compared to healthy controls, melancholic patients showed increased FC between right NAc and right lingual gyrus and between left NAc and left postcentral gyrus; non-melancholic patients had increased FC between bilateral NAc and right lingual gyrus. No significant correlations were observed between altered FC and clinical variables in melancholic patients. SVM results showed that FC between left NAc and right MFG could accurately distinguish melancholic patients from non-melancholic patients. ConclusionMelancholic depression exhibited different patterns of functional connectivity of the reward circuit relative to non-melancholic patients. This study highlights the significance of the reward circuit in the neuropathology of melancholic depression.

Altered fractional amplitude of low-frequency fluctuations in the superior temporal gyrus: a resting-state fMRI study in anxious depression

BackgroundAnxious depression, which is a common subtype of major depressive disorder, has distinct clinical features from nonanxious depression. However, little is known about the neurobiological characteristics of anxious depression. In this study, we explored resting-state regional brain activity changes between anxious depression and nonanxious depression.MethodResting-state functional magnetic resonance (rs-fMRI) imaging data were collected from 60 patients with anxious depression, 38 patients with nonanxious depression, and 60 matched healthy controls (HCs). One-way analysis of variance was performed to compare the whole-brain fractional amplitude of low-frequency fluctuation (fALFF) in the three groups. The correlation between the fALFF values and the clinical measures was examined.ResultsCompared with those of HCs, the fALFF values in the left superior temporal gyrus (STG) in patients with anxious depression were significantly increased, while the fALFF values in the left middle temporal gyrus (MTG), left STG, and right STG in patients with nonanxious depression were significantly increased. Patients with anxious depression showed reduced fALFF values in the right STG compared with patients with nonanxious depression (p < 0.001, corrected). Within the anxious depression group, fALFF value in the right STG was positively correlated with the cognitive disturbance score (r = 0.36, p = 0.005 corrected).ConclusionThe bilateral STG and left MTG, which are related to the default mode network, appear to be key brain regions in nonanxious depression, while the right STG plays an essential role in the neuropathological mechanism of anxious depression.

A multicenter, randomized controlled study on the efficacy of agomelatine in ameliorating anhedonia, reduced motivation, and circadian rhythm disruptions in patients with major depressive disorder (MDD).

To evaluate the clinical efficacy and safety of Agomelatine in improving symptoms in patients with major depressive disorder (MDD), providing more scientific evidence for the treatment of depression, and offering more effective therapeutic options for patients. A total of 180 MDD patients in acute phase from 10 psychiatric hospitals of Grade three in Zhejiang Province were enrolled in this 12-week study with the competitive and consecutive pattern, and they were randomized into two different groups treated with flexible-dosage antidepressants of selective serotonin reuptake inhibitors (SSRI) or agomelatine, respectively. The subjects were evaluated with psychological scales of HAMD-17, HAMA, SHAPS for anhedonia, MFI-20 for fatigue, PQSI for sleep quality and MEQ for disturbances in chronobiologic rhythms at baseline, 2, 4, 8 and 12-weekend points, and TESS was used for side-effect. The results were analyzed with repeated measurement analysis of variance. The two groups each had 90 participants, and there were no significant differences at baseline. The scores of various assessment scales showed statistically significant time main effects during the visits (P < 0.01). The Agomelatine group demonstrated faster efficacy within 2weeks, with better improvement in SHAPS, MEQ, and PSQI compared to the SSRIs group. However, the remission rate at 12weeks was lower in the Agomelatine group than in the SSRIs group (63.3% and 72.2%), but the difference between the groups was not statistically significant. The Agomelatine group had fewer adverse reactions (14.4% and 16.7%), but there was a slightly higher incidence of liver function impairment (6.7% and 4.4%), with no statistically significant difference between the groups. Agomelatine, as a novel antidepressant, shows certain advantages in improving depression and anxiety symptoms and is comparable to SSRIs in terms of safety. However, its long-term efficacy and safety on MDD or other depressive subtypes still require further observation and research.

49 A Preliminary Neurocognitive Profile Characterization of Treatment Resistant Depression

Objective:Major Depressive Disorder (MDD) subtypes have been shown to differentially impact psychiatric symptom presentation, clinical features, and functional abilities. While there is extensive research regarding MDD subtypes and clinical characteristics, there has been limited information regarding the relationship between MDD subtypes and neurocognitive functioning. In particular, the neurocognitive impact of the subtype of treatment resistant depression (TRD), defined as MDD that is unresponsive to treatment, is unknown. The aim of this preliminary study was to address this gap by characterizing the neurocognitive profile of TRD. We characterized the performance of older adults with TRD on measures across multiple neurocognitive domains, and explored whether performance varied based on age and education.Participants and Methods:Data utilized were drawn from a broader NIMH-funded, randomized, controlled study conducted at the University of New Mexico that investigated the clinical and cognitive outcomes of varying pulse amplitudes during acute electroconvulsive therapy (ECT) in adults with MDD. Participants in the study were age 50+ with a diagnosis of MDD, and further delineated by subtype as TRD. For this analysis, we utilized demographic and baseline neurocognitive data collected prior to start of treatment for those diagnosed with MDD, recurrent, severe (TRD). Neurocognitive measures included the Delis Kaplan Executive Function System (D-KEFS) Verbal Fluency and Color-Word Interference Subtests, Hopkins Verbal Learning Test-Revised (HVLT-R), and the Wechsler Adult Intelligence Scale 4th Edition (WAIS-IV) Digit Spans. Demographic-adjusted scaled scores were computed, and descriptive statistics were used to characterize the demographic and neurocognitive features of the sample. Multiple Analysis of Variance (MANOVA) was used to investigate difference in performance across neurocognitive measures based on level of education, with age as a covariate.Results:The sample (n = 42) had a mean age of 65 (SD=8), education level between12 and 14 years, 66.6% were female and 93% were Caucasian. DKEFS Verbal Fluency Category Switching Total Switching Accuracy fell in the Average range (Mean SS=9.5, SD=3.1), and Color Word Inhibition Total Completion Time fell in the Average range (Mean SS=8.5, SD=3.3). HVLT-R Total Recall Correct fell in the Mildly Impaired range (Mean T=35.5, SD=9.9) and Delayed Recall Correct fell in the Mildly to Moderately Impaired range (Mean T=32.9, SD=11.0). WAIS-IV Digit Span fell in the Average range (Mean SS=9.5, SD=2.2). Results indicated that age did not adjust outcomes on the neurocognitive variables, Wilks's λ=0.63, F(6, 23)=2.13, p=0.08. We found no evidence for significant effect of level of education on neurocognitive functioning when controlling for the covariate of age, Wilks's λ=-0.16, F(36, 103.7)=1.47, p=0.07.Conclusions:To our knowledge, this is one of two studies to examine neurocognitive functioning in patients with TRD. The analysis indicated generally intact performance in the neurocognitive domains of executive function (inclusive of verbal fluency, cognitive flexibility, and inhibition), auditory attention and working memory, and Impaired performance on indices of verbal learning and memory. Age did not impact performance on neurocognitive measures, and there was no significant effect for level of education. Further research is warranted to confirm these findings and further explicate the neurocognitive profile of TRD.

Meta-Analyses of Genome-Wide Association Studies for Postpartum Depression.

Postpartum depression (PPD) is a common subtype of major depressive disorder (MDD) that is more heritable, yet is understudied in psychiatric genetics. The authors conducted meta-analyses of genome-wide association studies (GWASs) to investigate the genetic architecture of PPD. Meta-analyses were conducted on 18 cohorts of European ancestry (17,339 PPD cases and 53,426 controls), one cohort of East Asian ancestry (975 cases and 3,780 controls), and one cohort of African ancestry (456 cases and 1,255 controls), totaling 18,770 PPD cases and 58,461 controls. Post-GWAS analyses included 1) single-nucleotide polymorphism (SNP)-based heritability ([Formula: see text]), 2) genetic correlations between PPD and other phenotypes, and 3) enrichment of the PPD GWAS findings in 27 human tissues and 265 cell types from the mouse central and peripheral nervous system. No SNP achieved genome-wide significance in the European or the trans-ancestry meta-analyses. The [Formula: see text] of PPD was 0.14 (SE=0.02). Significant genetic correlations were estimated for PPD with MDD, bipolar disorder, anxiety disorders, posttraumatic stress disorder, insomnia, age at menarche, and polycystic ovary syndrome. Cell-type enrichment analyses implicate inhibitory neurons in the thalamus and cholinergic neurons within septal nuclei of the hypothalamus, a pattern that differs from MDD. While more samples are needed to reach genome-wide levels of significance, the results presented confirm PPD as a polygenic and heritable phenotype. There is also evidence that despite a high correlation with MDD, PPD may have unique genetic components. Cell enrichment results suggest GABAergic neurons, which converge on a common mechanism with the only medication approved by the U.S. Food and Drug Administration for PPD (brexanolone).

Identification of a diagnostic model and molecular subtypes of major depressive disorder based on endoplasmic reticulum stress-related genes.

Major depressive disorder (MDD) negatively affects patients' behaviours and daily lives. Due to the high heterogeneity and complex pathological features of MDD, its diagnosis remains challenging. Evidence suggests that endoplasmic reticulum stress (ERS) is involved in the pathogenesis of MDD; however, relevant diagnostic markers have not been well studied. This study aimed to screen for ERS genes with potential diagnostic value in MDD. Gene expression data on MDD samples were downloaded from the GEO database, and ERS-related genes were obtained from the GeneCards and MSigDB databases. Differentially expressed genes (DEGs) in MDD patients and healthy subjects were identified and then integrated with ERS genes. ERS diagnostic model and nomogram were developed based on biomarkers screened using the LASSO method. The diagnostic performance of this model was evaluated. ERS-associated subtypes were identified. CIBERSORT and GSEA were used to explore the differences between the different subtypes. Finally, WGCNA was performed to identify hub genes related to the subtypes. A diagnostic model was developed based on seven ERS genes: KCNE1, PDIA4, STAU1, TMED4, MGST1, RCN1, and SHC1. The validation analysis showed that this model had a good diagnostic performance. KCNE1 expression was positively correlated with M0 macrophages and negatively correlated with resting CD4+ memory T cells. Two subtypes (SubA and SubB) were identified, and these two subtypes showed different ER score. The SubB group showed higher immune infiltration than the SubA group. Finally, NCF4, NCF2, CSF3R, and FPR2 were identified as hub genes associated with ERS molecular subtypes. Our current study provides novel diagnostic biomarkers for MDD from an ERS perspective, and these findings further facilitate the use of precision medicine in MDD.

Specificity of affective dynamics of bipolar and major depressive disorder.

Here, we examine whether the dynamics of the four dimensions of the circumplex model of affect assessed by ecological momentary assessment (EMA) differ among those with bipolar disorder (BD) and major depressive disorder (MDD). Participants aged 11-85years (n=362) reported momentary sad, anxious, active, and energetic dimensional states four times per day for 2weeks. Individuals with lifetime mood disorder subtypes of bipolar-I, bipolar-II, and MDD derived from a semistructured clinical interview were compared to each other and to controls without a lifetime history of psychiatric disorders. Random effects from individual means, inertias, innovation (residual) variances, and cross-lags across the four affective dimensions simultaneously were derived from multivariate dynamic structural equation models. All mood disorder subtypes were associated with higher levels of sad and anxious mood and lower energy than controls. Those with bipolar-I had lower average activation, and lower energy that was independent of activation, compared to MDD or controls. However, increases in activation were more likely to perpetuate in those with bipolar-I. Bipolar-II was characterized by higher lability of sad and anxious mood compared to bipolar-I and controls but not MDD. Compared to BD and controls, those with MDD exhibited cross-augmentation of sadness and anxiety, and sadness blunted energy. Bipolar-I is more strongly characterized by activation and energy than sad and anxious mood. This distinction has potential implications for both specificity of intervention targets and differential pathways underlying these dynamic affective systems. Confirmation of the longer term stability and generalizability of these findings in future studies is necessary.

Mapping Neurophysiological Subtypes of Major Depressive Disorder Using Normative Models of the Functional Connectome

BackgroundMajor depressive disorder (MDD) is a highly heterogeneous disorder that typically emerges in adolescence and can occur throughout adulthood. Studies aimed at quantitatively uncovering the heterogeneity of individual functional connectome abnormalities in MDD and identifying reproducibly distinct neurophysiological MDD subtypes across the lifespan, which could provide promising insights for precise diagnosis and treatment prediction, are still lacking. MethodsLeveraging resting-state functional magnetic resonance imaging data from 1148 patients with MDD and 1079 healthy control participants (ages 11–93), we conducted the largest multisite analysis to date for neurophysiological MDD subtyping. First, we characterized typical lifespan trajectories of functional connectivity strength based on the normative model and quantitatively mapped the heterogeneous individual deviations among patients with MDD. Then, we identified neurobiological MDD subtypes using an unsupervised clustering algorithm and evaluated intersite reproducibility. Finally, we validated the subtype differences in baseline clinical variables and longitudinal treatment predictive capacity. ResultsOur findings indicated great intersubject heterogeneity in the spatial distribution and severity of functional connectome deviations among patients with MDD, which inspired the identification of 2 reproducible neurophysiological subtypes. Subtype 1 showed severe deviations, with positive deviations in the default mode, limbic, and subcortical areas and negative deviations in the sensorimotor and attention areas. Subtype 2 showed a moderate but converse deviation pattern. More importantly, subtype differences were observed in depressive item scores and the predictive ability of baseline deviations for antidepressant treatment outcomes. ConclusionsThese findings shed light on our understanding of different neurobiological mechanisms underlying the clinical heterogeneity of MDD and are essential for developing personalized treatments for this disorder.

Atrophy of bilateral nucleus accumbens in melancholic depression.

Evidence from previous literature suggests that the nucleus accumbens (NAc), hippocampus, and amygdala play critical roles in the reward circuit. Meanwhile, it was also suggested that abnormalities in the reward circuit might be closely associated with the symptom of anhedonia of depression. However, few studies have investigated the structural alterations of the NAc, hippocampus, and amygdala in depression with anhedonia as the main clinical manifestation. Thus, the current study aimed to explore the structural changes of the subcortical regions among melancholic depression (MD) patients, especially in the NAc, hippocampus, and amygdala, to provide a theoretical basis for understanding the pathological mechanisms of MD. Seventy-two MD patients, 74 nonmelancholic depression (NMD) patients, and 81 healthy controls (HCs) matched for sex, age, and years of education were included in the study. All participants underwent T1-weighted MRI scans. Subcortical structure segmentation was performed using the FreeSurfer software. MD and NMD patients had reduced left hippocampal volume compared with HCs. Meanwhile, only MD patients had reduced bilateral NAc volumes. Moreover, correlation analyses showed correlations between left NAc volume and late insomnia and lassitude in MD patients. The reduced hippocampal volume may be related to the pathogenesis of major depressive disorder (MDD), and the reduced volume of the NAc may be the unique neural mechanism of MD. The findings of the current study suggest that future studies should investigate the different pathogenic mechanisms of different subtypes of MDD further to contribute to the development of individualized diagnostic and treatment protocols.