Pathogenesis Of Major Depressive Disorder Research Articles

Neuroimmune Advance in Depressive Disorder.

Major depressive disorder (MDD) or depression is one of the most highly prevalent, chronic, and recurrent disorders, which is associated with a high burden of disease and substantial impairment in social functions. Both immune molecules and cells have been implicated in the pathophysiology and maintenance of MDD. Findings in animals and MDD patients have suggested that both pro- and anti-inflammatory cytokines are activated in the neuroinflammation which contribute to behavioral symptoms and changes in the course of depression. There is a growing body of evidence to support that neuroinflammation is a mediator for the communication among stress response, neuroendocrine, neurotransmission, neurogenesis, and gut microbiota. These communications have been known as risk factors in the pathogenesis of MDD. In the meantime, accumulating evidence has suggested that some interventions targeting the inflammatory processes may play an important role in the treatment of MDD.

The Depression GWAS Risk Allele Predicts Smaller Cerebellar Gray Matter Volume and Reduced <i>SIRT1</i> mRNA Expression in Chinese Population

Major depressive disorder (MDD) is recognized as a primary cause of disability worldwide, and effective management of this illness has been a great challenge. While genetic component is supposed to play pivotal roles in MDD pathogenesis, its genetic and phenotypic heterogeneity has hampered successful discovery of its genetic determinants. In this study, we conducted replication analyses of genetic loci highlighted in a previous Chinese MDD genome-wide association studies (GWAS) in an independent Han Chinese sample (1,824 MDD cases and 3,031 controls), and have confirmed the significant association between MDD and a previous highlighted single nucleotide polymorphism (SNP) rs12415800 near SIRT1. Subsequently, using hypothesis-free whole-brain analysis in two independent Han Chinese imaging samples, we found that individuals carrying the MDD risk allele of rs12415800 exhibited aberrant gray matter volume in the left posterior cerebellar lobe compared with those carrying the non-risk allele. Further, in two independent Han Chinese postmortem brain samples, the MDD risk allele of rs12415800 predicted lower SIRT1 mRNA levels, which was consistent with the reduced expression of this gene in MDD patients compared with healthy subjects. These results provide further evidence for the involvement of SIRT1 in MDD, and suggest that this gene might participate in the illness via affecting the development of cerebellum, a brain region that is potentially underestimated in previous MDD studies. Funding Statement: This work was supported by grants from National Natural Science Foundation of China (81722019 to M.L., 31701133 to X.X., 81825009 to W.Y., 81571313 to W.Y.); Yunnan Applied Basic Research Projects (2018FB051 to X.X.); National Key RD the medical and health science and technology project in Zhejiang (2018KY721 to D.S.Z.); the Major Science and Technology Projects in Ningbo, Zhejiang Province, China (2017C510012); the Medical Science and Technology Project in Ningbo, Zhejiang Province, China (2017A10). Xiao Xiao was also supported by the Chinese Academy of Sciences Western Light Program, and Youth Innovation Promotion Association, CAS. Ming Li was also supported by CAS Pioneer Hundred Talents Program and the 1000 Young Talents Program. Declaration of Interests: The authors have no conflicts of interest to declare. Ethics Approval Statement: All the protocols and methods were approved by the institutional review board of Kunming Institute of Zoology, Chinese Academy of Sciences, and the ethics committees of all participating hospitals and universities. Written informed consents from all participants were obtained prior to the study.

MicroRNAs in Major Depressive Disorder.

Major depressive disorder (MDD) is a severe and chronic psychiatric disorder with a high prevalence in the population. Although our understanding of its pathophysiological mechanisms has significantly increased over the years, available treatments still present several limitations and are not effective to all MDD patients. Epigenetic mechanisms have recently been suggested to play key roles in MDD pathogenesis and treatment, including the effects of small noncoding RNAs known as microRNAs (miRNAs). miRNAs can modulate gene expression posttranscriptionally by interfering with the stability and translation of messenger RNA molecules and are also known to cross-talk with other epigenetic mechanisms. In this review, we will summarize and discuss recent findings of alterations in miRNAs in tissues of patients with MDD and evidence of treatment-induced effects in these molecules.

Study Design and Rationale for the Mood and Methylation Study: A Platform for Multi-Omics Investigation of Depression in Twins.

Major depression is a complex disorder with no single, direct causal mechanism. Morbidity has been linked to genetic processes, developmental history, and unique environmental exposures. Epigenetic mechanisms, especially DNA methylation, are also likely important factors in the pathogenesis of major depressive disorder (MDD). A community-based twin sample has many advantages for epigenetic studies, given the shared genetic and developmental histories of same-sex twin pairs. This article describes the rationale and study design for the Mood and Methylation Study in which 133 twin pairs (101 monozygotic and 32 dizygotic), both discordant and concordant for lifetime history of MDD, were evaluated on a large number of variables related to MDD. The twins also provided blood samples for an epigenome-wide association study of differentially methylated regions (DMR) relevant to MDD. Although MDD is typically considered a disorder of the central nervous system, it is unfeasible to obtain a large sample of brain tissues. However, epigenetic variation is not limited to the affected tissue but can also be detected in peripheral blood leukocytes. Thus, this study focused on monocytes for the major analyses. Additional plans for the study include gene expression analysis from the same set of twins using RNA-seq and validation of significant DMRs in postmortem brain tissues from a separate sample. Moreover, sufficient samples have been collected to perform future 'multi-omic' analyses, including metabolome, microbiome, and transcriptome. Our long-term goal is to understand how epigenomic and other 'omic' factors can be manipulated for diagnostic, preventive, and therapeutic purposes for MDD and its related conditions.

Gender differences of plasma glial cell line-derived neurotrophic factor levels in patients with major depressive disorder

Objective To investigate gender differences of plasma glial cell line-derived neurotrophic factor (GDNF) levels in patients with major depressive disorder (MDD). Methods MDD subjects (male 20, female 36) and healthy controls (HCs) (male 35, female 45) were divided into four groups by gender. Plasma levels of GDNF were measured and compared in different gender groups. The clinical symptom severity of MDD patients was evaluated by 17-item Hamilton Depression Scale (HAMD-17) and Hamilton Anxiety Scale (HAMA-17). Results (1)The plasma GDNF level in male patients with major depressive disorder((1.55±0.43)pg/ml) was significantly lower than that in healthy controls((1.86±0.50)pg/ml, F=4.64, P=0.036). There was no significant difference in GDNF level between female depression patients((1.62±0.46)pg/ml)) and female healthy control((1.64±0.48)pg/ml, F=0.18, P=0.672). In HCs, the GDNF level of male was significantly higher than that of female((1.86±0.50)pg/ml, (1.64±0.48)pg/ml, F=2.04, P=0.045). There was no significant difference in GDNF level between male and female patients(P>0.05). (2) GDNF level in male patients with major depressive disorder was negatively correlated with HAMA score(r=-0.388, P=0.034). Conclusion The expression of GDNF is affected by sex factors, which may be related to the different pathogenesis of MDD. Key words: Major depressive disorder; Glial cell line-derived neurotrophic factor; Gender

Evaluation of Prioritization Methods of Extrinsic Apoptotic Signaling Pathway Genes for Retrieval of the New Candidates Associated with Major Depressive Disorder

Major depressive disorder (MDD) is an important problem in psychophysical health and well-being of society in Russia and worldwide. In the present work, the role of apoptosis in the associative gene network of MDD was studied. The methods of prioritization were analyzed and candidate genes for further research were predicted. The quality of prioritization methods and their combinations was tested, and the most effective methods were selected. Prioritization was carried out for genes of the extrinsic apoptotic signaling pathway considering their role in the structure of the associative genetic network of MDD, since the external pathway of apoptosis is important for drug development. The methods of the ANDSystem, a computer system for reconstruction of gene networks on the basis of automatic data retrieval from scientific publications, were considered and used for gene prioritization. As a result of prioritization, some candidate genes were suggested for the further experimental study of their role in MDD pathogenesis, including CAV1, FYN, JAK2, PTEN, RAF1, RELA and SRC.

Distinct Expression Pattern of Epigenetic Machinery Genes in Blood Leucocytes and Brain Cortex of Depressive Patients

In major depressive disorder (MDD), altered gene expression in brain cortex and blood leucocytes may be due to aberrant expression of epigenetic machinery coding genes. Here, we explore the expression of these genes both at the central and peripheral levels. Using real-time quantitative PCR technique, we first measured expression levels of genes encoding DNA and histone modifying enzymes in the dorsolateral prefrontal cortex (DLPFC) and cingulate cortex (CC) of MDD patients (n = 24) and healthy controls (n = 12). For each brain structure, transcripts levels were compared between subject groups. In an exploratory analysis, we then compared the candidate gene expressions between a subgroup of MDD patients with psychotic characteristics (n = 13) and the group of healthy subjects (n = 12). Finally, we compared transcript levels of the candidate genes in blood leucocytes between separate samples of MDD patients (n = 17) and healthy controls (n = 16). In brain and blood leucocytes of MDD patients, we identified an overexpression of genes encoding enzymes which transfer repressive transcriptional marks: HDAC4-5-6-8 and DNMT3B in the DLPFC, HDAC2 in the CC and blood leucocytes. In the DLPFC of patients with psychotic characteristics, two genes (KAT2A and UBE2A) were additionally overexpressed suggesting a shift to a more transcriptionally permissive conformation of chromatin. Aberrant activation of epigenetic repressive systems may be involved in MDD pathogenesis both in brain tissue and blood leucocytes.

Altered cellular immune reactivity in traumatized women with and without major depressive disorder

Alterations of the hypothalamic-pituitary-adrenal (HPA) axis such as altered glucocorticoid receptor sensitivity and increased immune reactivity might contribute to the pathogenesis of major depressive disorder (MDD). Exposure to adverse childhood experiences (ACE) precipitates vulnerability to MDD and might be associated with endocrine and immune alterations in the disorder.In order to disentangle the effects of ACE and MDD, we recruited 87 women: n = 23 with MDD and ACE as determined by clinical interview and questionnaires (Structured Clinical Interview for DSM-IV, Early Trauma Inventory, Childhood Trauma Questionnaire), n = 24 with MDD without ACE, n = 21 with ACE but no current or lifetime MDD, and n = 26 healthy women without either MDD or ACE. Glucocorticoid signaling and mitogen-stimulated proliferation were analyzed ex vivo in peripheral blood-derived mononuclear cells. Additionally, mRNA expression of the glucocorticoid and the mineralocorticoid receptor (GR / MR) was assessed.Peripheral GR sensitivity as well as GR and MR expression levels were not significantly different between groups. Women with ACE showed an increased immune response after mitogen stimulation independent of the presence of MDD.Our results provide evidence for a functionally altered ex-vivo immune response in cell cultures from women with a history of ACE. Thus, ACE might contribute to the pathogenesis of MDD through inflammatory pathways.

Major Depressive Disorder and Magnetic Resonance Imaging: A Mini-Review of Recent Progress.

Major depressive disorder (MDD) has been a prominent topic in recent years due to its unknown etiology and pathology, high prevalence rate, and the high cost of treatment. Due to its high resolution for soft tissue, magnetic resonance imaging (MRI) has become an essential noninvasive tool for the evaluation of the brain substrates underlying mental disorders. MRI enables characterization of brain morphology and function in MDD patients. Compared to healthy controls, MDD patients have structural changes in certain brain regions such as the prefrontal cortex, cingulate cortex, precuneus, thalamus, and hippocampus. Abnormal brain functions as indicated by various MRI measurements including region homogeneity, the amplitude of low-frequency fluctuation, functional connectivity, and mean kurtosis may also contribute to the pathogenesis of MDD. This mini-review summarizes recent MRI findings on the neural manifestations of MDD. We discuss the potential of MRI biomarkers that may prove clinically useful for early diagnosis and evaluation of treatment outcomes for depression.

Menin Deficiency Leads to Depressive-like Behaviors in Mice by Modulating Astrocyte-Mediated Neuroinflammation

Astrocyte dysfunction and inflammation are associated with the pathogenesis of major depressive disorder (MDD). However, the mechanisms underlying these effects remain largely unknown. Here, we found that multiple endocrine neoplasia type 1 (Men1; protein: menin) expression is attenuated in the brain of mice exposed to CUMS (chronic unpredictable mild stress) or lipopolysaccharide. Astrocyte-specific reduction of Men1 (GcKO) led to depressive-like behaviors in mice. We observed enhanced NF-κB activation and IL-1β production with menin deficiency in astrocytes, where depressive-like behaviors in GcKO mice were restored by NF-κB inhibitor or IL-1β receptor antagonist. Importantly, we identified a SNP, rs375804228, in human MEN1, where G503D substitution is associated with a higher risk of MDD onset. G503D substitution abolished menin-p65 interactions, thereby enhancing NF-κB activation and IL-1β production. Our results reveal a distinct astroglial role for menin in regulating neuroinflammation in depression, indicating that menin may be an attractive therapeutic target in MDD.

Basic fibroblast growth factor increased glucocorticoid receptors in cortical neurons through MAP kinase pathway

Prolonged and intense stress chronically increases blood concentration of glucocorticoids, which in turn causes downregulation of glucocorticoid receptor (GR) in the central nervous system (CNS). This process has been suggested to be involved in the pathogenesis of major depressive disorder (MDD). Here, we found that basic fibroblast growth factor (bFGF) increased the expression of GR in the rat cerebral cortex and cultured cortical neurons and restored the reduced GR expression caused by glucocorticoid exposure. Among intracellular signaling pathways stimulated by bFGF, extracellular signal–regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway was responsible for the upregulation of GR. The bFGF-induced GR was functional as a transcription factor to enhance transcription of a target gene. Because high stress augments bFGF levels in the brain, it is likely that bFGF plays a compensating role for reduced GR expression after stress and thus should be studied as a therapeutic target for the treatment of MDD.

Dl-3-n-Butylphthalide improves lipopolysaccharide-induced depressive-like behavior in rats: involvement of Nrf2 and NF-κB pathways.

Dl-3-n-Butylphthalide (NBP), a small molecule compound extracted from the seeds of Apium graveolens, possesses a large range of biological effects. Here, we attempted to explore the therapeutic effects of NBP on lipopolysaccharide (LPS)-induced major depressive disorder (MDD) and gain further insight into the underlying mechanisms of the antidepressant effects of NBP. We evaluated the effect of NBP against LPS-induced behavioral changes in rats. We also examined the inflammation, oxidative stress, and apoptosis markers and analyzed the Nrf2 and NF-κB pathways in the hippocampus of rats following repeated peripheral immune challenge by LPS for 2weeks (500μg/kg every other day). Our results indicated that repeated LPS administration induced the rats to a depressive-like state and activated inflammatory response, oxidative stress, and apoptosis reactions in the hippocampus. NBP treatment attenuated the LPS-induced abnormal behavior and ameliorated pathogenic processes in rats with MDD. NBP reduced the inflammatory response with inhibited expression of pro-inflammatory cytokines including IL-1β and IL-6 and downregulated the NF-κB signal pathway. Concurrent with the anti-inflammation action, NBP reduced LPS-induced oxidative reactions in the hippocampus and enhanced Nrf2-targeted signals, as evidenced by increased transcription of antioxidant enzymes and decreased malondialdehyde (MDA) production. In addition, NBP inhibited LPS-induced neuronal apoptosis in the rat brain, as evidenced by decreased apoptosis marker Caspase-3 production and TUNEL assay. These results provide more insight into pathogenesis of MDD and firstly demonstrated the potential antidepressant actions of NBP.

Treatment of Major Depressive Disorder in Pediatric Populations.

Major depressive disorder (MDD) is a severe illness that afflicts about 16.6% of people over their lifetime. MDD is highly correlated with suicidality, and often first presents in adolescence. Unfortunately, many pediatric patients suffering from MDD go undiagnosed, and current evidence-based treatment options in the U.S. are limited to psychotherapy and two selective serotonin reuptake inhibitors approved by the United States Food and Drug Administration. Molecular mechanisms have been shown to play a role in MDD pathogenesis, progression, and response to medication, yet few studies have explored the role of these pathways in pediatric MDD. In this review, we outline the gravity and importance of MDD in pediatric patients, some challenges in diagnosis and treatment, current treatments available for pediatric patients, and research to investigate differences between pediatric and adult MDD. We hope that this review will provide an outline of the current understanding and treatment of MDD in pediatric patients, and provide thoughtful insights for future work that could advance our understanding of MDD in pediatric populations, and also identify new therapeutic strategies.

Therapeutic role of long non-coding RNA TCONS_00019174 in depressive disorders is dependent on Wnt/β-catenin signaling pathway.

Chronic stress is one of the major causes that lead to major depressive disorder, which is a prevalent mood disorder worldwide. Many patients with major depressive disorder do not benefit from available medication due to the complex etiology of the condition. Recently, long non-coding RNAs, molecular switches of downstream genes expression, have been reported to be involved in the pathogenesis of major depressive disorder. The long non-coding RNA TCONS_00019174 has been implicated in major depressive disorder risk and antidepressant effects, However, the effect of long non-coding RNA TCONS_00019174 on antidepressant responses has not been investigated. This study is designed to determine whether altered expression of long non-coding RNA TCONS_00019174 contributes to depression-like behaviors associated with chronic stress. We found that mice exposed to chronic ultra-mild stress displayed apparent depression-like behaviors and decreased expression of long non-coding RNA TCONS_00019174 in hippocampus. Both changed behaviors and long non-coding RNA TCONS_00019174 expression level were rescued by chronic treatment with imipramine. Viral-mediated long non-coding RNA TCONS_00019174 over expression in hippocampal neurons improved the behaviors of mice exposed to chronic ultra-mild stress. Further, it was found long non-coding RNA TCONS_00019174 over expression upregulated phosphorylated-GSK3β (p-GSK3β) protein and β-catenin in the hippocampus. These findings suggest that long non-coding RNA TCONS_00019174 exerts antidepressant-like effect in mice by activating a Wnt/β-catenin pathway, and that long non-coding RNA may serve as a potential therapeutic target for major depressive disorder in clinical application.

S140. Altered brain activation in major depressive disorder during heat pain stimuli: An fMRI study

WHO predicts that major depressive disorder (MDD) will become the largest disease burden in the world by 2030. Studies have shown that about two-thirds of patients with MDD have painful somatic symptoms. The pathogenesis of MDD combined with pain is yet fully understood. The brain mechanism is the hotspot of current research. The brain activation areas were observed in patients with MDD (with pain or not) in our study, using the technology of contact heat stimulation combined with fMRI (CHS-fMRI). The purpose of this study is to explore the brain network related to pain in MDD, and further to provide useful information for the early diagnosis and treatment of MDD associated with pain. We recruited 42 untreated patients (meeting with the DSM-5 diagnostic criteria for MDD), who were assigned into two groups: pain group (MDDP group, 22 cases) and no pain group (MDDNP group, 20 cases), and 22 healthy volunteers were recruited as control group(HC group). Before the experiment, all subjects have completed the test of visual analogue scale (VAS) and the Mc-Gill pain questionnaire-2 (SF-MPQ-2). During the acquisition of fMRI, the right dorsal forearm received CHS in 51 degree. Finally, VAS was used to score the heat pain stimulation for each subject, as well as the quantitative sensory test (QST) of the contact heat stimulus site was performed. These activated brain areas in MDD group with statistical significance (P < 0.05) included bilateral cerebellum,vermis,right frontal cortex, right middle temporal gyrus, right thalamus, middle cingulate gyrus, and bilateral semioval center. These decreased activated brain areas in MDD group with statistical significance (P < 0.05) included bilateral hippocampus, bilateral amygdale, bilateral putamen, bilateral thalamus, bilateral insula, bilateral inferior frontal gyrus, right superior frontal gyrus, bilateral temporal lobe, and right calcarine. These activated brain areas in HC group with statistical significance (P < 0.05) included bilateral cerebellum, vermis, bilateral inferior frontal gyrus, right middle frontal gyrus, bilateral temporal lobe, bilateral inferior parietal lobule, left lingual gyrus, and left cuneus gyrus. These decreased activated brain areas in HC group with statistical significance (P < 0.05) included bilateral hippocampus, bilateral parahippocampal gyrus, bilateral middle temporal gyrus, bilateral amygdala, bilateral thalamus, bilateral putamen, bilateral insula, bilateral lingual gyrus, and right calcarine. The application of technology of CHS-fMRI is an ideal method for studying the network related to pain. There are abnormal activation of frontal-limbic region in MDDP group compared with MDDNP and HC group. Moreover, their activated area and activated intensity of activated brain regions are different. The network related to pain may change in MDD, which is worthy of further study.

Common variants on 6q16.2, 12q24.31 and 16p13.3 are associated with major depressive disorder

Accumulating evidence suggests that genetic factors have a role in major depressive disorder (MDD). However, only limited MDD risk loci have been identified so far. Here we perform a meta-analysis (a total of 90,150 MDD cases and 246,603 controls) through combing three genome-wide association studies of MDD, including 23andMe (cases were self-reported with a clinical diagnosis or treatment of depression), CONVERGE (cases were diagnosed using the Composite International Diagnostic Interview) and PGC (cases were diagnosed using direct structured diagnostic interview (by trained interviewers) or clinician-administered DSM-IV checklists). Genetic variants from two previously unreported loci (rs10457592 on 6q16.2 and rs2004910 on 12q24.31) showed significant associations with MDD (P < 5 × 10-8) in a total of 336,753 subjects. SNPs (a total of 171) with a P < 1 × 10-7 in the meta-analysis were further replicated in an independent sample (GS:SFHS, 2,659 MDD cases (diagnosed with DSM-IV) and 17,237 controls) and one additional risk locus (rs3785234 on 16p13.3, P = 1.57 × 10-8) was identified in the combined samples (a total of 92,809 cases and 263,840 controls). Risk variants on the identified risk loci were associated with gene expression in human brain tissues and mRNA expression analysis showed that FBXL4 and RSRC1 were significantly upregulated in brains of MDD cases compared with controls, suggesting that genetic variants may confer risk of MDD through regulating the expression of these two genes. Our study identified three novel risk loci (6q16.2, 12q24.31, and 16p13.3) for MDD and suggested that FBXL4 and RSRC1 may play a role in MDD. Further functional characterization of the identified risk genes may provide new insights for MDD pathogenesis.

Microglia Polarization and Endoplasmic Reticulum Stress in Chronic Social Defeat Stress Induced Depression Mouse.

Inflammation recently has been considered to be participated in the pathogenesis of major depressive disorder (MDD). However, the detailed mechanism of inflammation in depression has not been completely understood yet. In the present study, depression mice model was established by chronic social defeat stress (CSDS) method and confirmed by behavior examinations including forced swimming test and sucrose preference test. The decrease of spine density and postsynaptic density protein 95 (PSD95) in hippocampus further verified the depression model. Then, the microglia polarization state and endoplasmic reticulum (ER) stress were investigated. At transcriptional level, M1 marker (inducible nitric oxide synthase (iNOS), CD16, CD86, CXCL10) in CSDS mice was higher than that in control group while there was no difference in M2 marker (Arginase and CD206) between two groups. And it was observed in the hippocampus of CSDS induced depression mice that increased activated microglia was merged with iNOS instead of arginase by immunofluorescence staining. Furthermore, the M1 marker Interleukin (IL)-1β and tumor necrosis factor (TNF)-α were increased in depression mice while the M1 marker IL-6 and M2 marker IL-10 remained unchanged. The expression of ER stress signaling factors, including protein kinase RNA-like ER kinase (PERK), Phosphorylated α-subunit of eukaryotic translation initiation factor 2(p-eIF2α), C/EBP homologous protein (CHOP), and X-box binding protein 1(XBP1) were significantly higher in CSDS-induced depression mice than in control mice. In all, our results suggest that M1 polarization and ER stress play a vital role in MDD pathogenesis.

Metabolic effects of light deprivation in the prefrontal cortex of rats with depression-like behavior: In vivo proton magnetic resonance spectroscopy at 7T

Recent evidence suggests that the glutamate system plays an important role in the pathogenesis of major depressive disorder (MDD). The aim of this study was to investigate the effects of light deprivation (LD) in the prefrontal cortex (PFC) of animals with depression-like behavior, targeting the glutamate system, using in vivo proton magnetic resonance spectroscopy (1H MRS). Male Sprague-Dawley rats were housed in constant darkness for six weeks (n = 12; LD group), while controls (n = 8) were housed under normal light cycles. The animals were assessed with forced swim tests. Point-resolved spectroscopy was used to quantify metabolite levels in the PFC. To substantiate the validity of the use of in vivo1H MRS in this study, the spectra obtained in the in vivo1H MRS, parametrically matched spectral simulation, and in vitro experiments were analyzed. The results of the spectral analyses showed that the quantification of glutamate and glutamine was not significantly affected by spectral overlaps. Thus, these results suggested that in vivo1H MRS can be used to reliably investigate the glutamate system. The results of the forced swim test showed LD-induced behavioral despairs in the animals. The levels of glutamate, myo-inositol, phosphocreatine, and total creatine were found significantly (p < 0.010) increased in the PFC of the LD animals compared with the controls. These results suggested that the LD-induced metabolic changes were consistent with the previous findings in patients with MDD and that short-echo-time in vivo1H MRS can be used to effectively measure depression-induced alterations in glutamate systems.

Neuroimaging genomic studies in major depressive disorder: A systematic review.

Genetic-neuroimaging studies could identify new potential endophenotypes of major depressive disorder (MDD). Morphological and functional alterations may be attributable to genetic factors that regulate neurogenesis and neurodegeneration. Given that the association between gene polymorphisms and brain morphology or function has varied across studies, this systematic review aims at evaluating and summarizing all available genetic-neuroimaging studies. Twenty-eight gene variants were evaluated in 64 studies by structural or functional magnetic resonance imaging. Significant genetic-neuroimaging associations were found in monoaminergic genes, BDNF genes, glutamatergic genes, HPA axis genes, and the other common genes, which were consistent with common hypotheses of the pathogenesis of MDD.

Type and Timing of Negative Life Events Are Associated with Adolescent Depression

Previous studies have demonstrated an association between negative life events (NLEs) in childhood and resilience/posttraumatic growth (PTG) with regard to the pathogenesis of major depressive disorder. We hypothesized that the type and timing of NLEs interact to influence mental health in the general youth population. Therefore, the present study aimed to examine the effects of NLE timing and intensity on current depressive symptoms, and to determine the direct and indirect effects of NLEs/resilience on PTG and depression among non-clinical adolescents. Data were collected from 1,038 high-school students across seven high schools in Fukui, Japan, during their freshman and sophomore years (648 boys and 390 girls, mean age = 15.71, SD = 0.524). Respondents completed a set of questionnaires designed to evaluate the type and timing of NLEs, depressive and traumatic symptoms, and PTG. Cluster analysis was used to divide participants into three groups based on outcomes: “cluster 1” (n = 631), for whom depressive scores were significantly lower than other two subgroups (p < 0.05, for both); “cluster 2” (n = 52), for whom levels of current and past perceived stress associated with NLEs were significantly higher than those of the other two subgroups (p < 0.05, for both); “cluster 3” (n = 374), for whom perceived stress at the time of NLE was significantly higher than that of participants in the cluster 1 (p < 0.05) group, but not the cluster 2 group. Our findings indicated that exposure to NLEs at a younger age resulted in stronger negative outcomes and that NLE timing and intensity were associated with PTG and current symptoms of depression. Furthermore, path analysis demonstrated that associations between perceived stress at the time of NLEs were direct and indirect predictors of current depression via PTG and that posttraumatic stress symptom and PTG mediate the association between NLEs/trait-resiliency and current depression. In conclusion, our findings suggest that event intensity, NLE timing, and gender may play a role in emotional vulnerability during adolescence.