Neurobiology Of Major Depressive Disorder Research Articles

The role of polyunsaturated fatty acids in the neurobiology of major depressive disorder and suicide risk.

Long-chain polyunsaturated fatty acids (LC-PUFAs) are obtained from diet or derived from essential shorter-chain fatty acids, and are crucial for brain development and functioning. Fundamentally, LC-PUFAs' neurobiological effects derive from their physicochemical characteristics, including length and double bond configuration, which differentiate LC-PUFA species and give rise to functional differences between n(omega)-3 and n-6 LC-PUFAs. LC-PUFA imbalances are implicated in psychiatric disorders, including major depression and suicide risk. Dietary intake and genetic variants in enzymes involved in biosynthesis of LC-PUFAs from shorter chain fatty acids influence LC-PUFA status. Domains impacted by LC-PUFAs include 1) cell signaling, 2) inflammation, and 3) bioenergetics. 1) As major constituents of lipid bilayers, LC-PUFAs are determinants of cell membrane properties of viscosity and order, affecting lipid rafts, which play a role in regulation of membrane-bound proteins involved in cell-cell signaling, including monoaminergic receptors and transporters. 2) The n-3:n-6 LC-PUFA balance profoundly influences inflammation. Generally, metabolic products of n-6 LC-PUFAs (eicosanoids) are pro-inflammatory, while those of n-3 LC-PUFAs (docosanoids) participate in the resolution of inflammation. Additionally, n-3 LC-PUFAs suppress microglial activation and the ensuing proinflammatory cascade. 3) N-3 LC-PUFAs in the inner mitochondrial membrane affect oxidative stress, suppressing production of and scavenging reactive oxygen species (ROS), with neuroprotective benefits. Until now, this wealth of knowledge about LC-PUFA biomechanisms has not been adequately tapped to develop translational studies of LC-PUFA clinical effects in humans. Future studies integrating neurobiological mechanisms with clinical outcomes may suggest ways to identify depressed individuals most likely to respond to n-3 LC-PUFA supplementation, and mechanistic research may generate new treatment strategies.

Home-based transcranial direct current stimulation combined with behavioral therapy delivered through smartphone to treat major depressive disorder: a randomized, double-blind placebo-controlled trial

Abstract Major depressive disorder (MDD) is the leading cause of disability worldwide. First-line treatments, antidepressants, and cognitive behavioral therapy (CBT), have significant side effects and limited availability, respectively. Transcranial direct current stimulation (tDCS) has been studied in the last two decades as a therapeutic alternative for MDD. tDCS demonstrates good efficacy, safety and tolerability, both as monotherapy and associated with antidepressants and/or psychotherapy. tDCS is a simple procedure that can be performed at home with remote supervision and can possibly be enhanced by combining it with self-directed CBT modalities via smartphone applications. We will present data from a randomized, double-blind, placebo-controlled clinical trial aiming to evaluate the efficacy, safety, tolerability and usability of home-based tDCS combined with behavioral therapy (BT) delivered through smartphone. The study includes 3 arms: (1) active tDCS + active BT, (2) active tDCS + placebo BT and (3) sham-tDCS + placebo BT. Twenty-one sessions of home-based tDCS + BT will be applied, for 6 weeks, ,in patients between 18-59 years, diagnosed with MDD, without contraindications for tDCS, with a smartphone for personal use and internet access at home. Participants are not asked to washout of antidepressant to enter the study. The active tDCS protocol will include daily tDCS sessions at 2mA, for 30 minutes, with the anode and cathode positioned over the left and right prefrontal cortex, respectively. The Flow (Flow Neuroscience, Malmö, Sweden) tDCS equipment and BT application will be used. The results of this study will contribute to the development of home-based tDCS systems, offering a better understanding of the combined effects of tDCS with potentiating strategies (e.g. BT), known to modulate the functioning of key areas in the neurobiology of MDD, such as the dorsolateral prefrontal cortex. Research Category and Technology and Methods Clinical Research: 9. Transcranial Direct Current Stimulation (tDCS) Keywords: tDCS, Home-based, RCT, Behavioral Therapy

The Role of Beta-Adrenergic Receptors in Depression and Resilience.

Norepinephrine is a catecholamine neurotransmitter that has been extensively implicated in the neurobiology of major depressive disorder (MDD). An accumulating body of evidence indicates that investigations into the action of norepinephrine at the synaptic/receptor level hold high potential for a better understanding of MDD neuropathology and introduce possibilities for developing novel treatments for depression. In this review article, we discuss recent advances in depression neuropathology and the effects of antidepressant medications based on preclinical and clinical studies related to beta-adrenergic receptor subtypes. We also highlight a beta-3 adrenergic receptor-involved mechanism that promotes stress resilience, through which antidepressant efficacy is achieved in both rodent models for depression and patients with major depression—an alternative therapeutic strategy that is conceptually different from the typical therapeutic approach in which treatment efficacy is achieved by reversing pathological alterations rather than by enhancing a good mechanism such as natural resilience. Altogether, in this review, we systematically describe the role of beta-adrenergic receptors in depression and stress resilience and provide a new avenue for developing a conceptually innovative treatment for depression.

Pinocembrin ameliorates depressive-like behaviors by regulating P2X7/TRL4 receptors expression in mouse hippocampus.

Mounting evidence indicates that immune dysfunction may contribute to the neurobiology of major depressive disorder (MDD). Toll-like receptor 4 (TLR4) and P2X7 receptor (P2X7R) were recently reckoned pivotally to regulate NOD-like receptor protein 3 (NLRP3) in microglia. Pinocembrin, one of the primary flavonoids from Pinus heartwood and Eucalyptus, has been studied in various animal models of human disease with anti-inflammatory and antioxidant activities. Herein, we investigated the potential antineuroinflammatory effects of pinocembrin on chronic unpredictable mild stress (CUMS)-induced depressive-like behavior. Male C57BL/6J mice were subjected to CUMS for 4 weeks, treatment group was injected with pinocembrin at a dose of 20 mg/kg. After the stress procedure, behavioral tests, including sucrose preference tests (SPTs) and tail suspension tests (TSTs) were performed to evaluate depressive-like phenotype. Subsequently, the expression of cytokines and microglia-related inflammatory biomarkers were assessed. In the study, we found that pinocembrin significantly blocked the declination of SPT percentage and the extension of TST immobility durations in the depression mouse model. Also, we observed that pinocembrin significantly suppressed microglial activation in the hippocampus. Additionally, pinocembrin downregulated hippocampal NLRP3 through P2X7/TLR4 pathway, and also regulated the CUMS-induced imbalance of pro-inflammatory cytokines, including interleukin-1beta, tumor necrosis factor-alpha and interleukin-6. In conclusion, pinocembrin ameliorates CUMS-induced depressive-like behaviors possibly through downregulating P2X7/TLR4 pathway, providing the mechanism of antidepressant treatment.

Neurobiology of Depression: Chronic Stress Alters the Glutamatergic System in the Brain-Focusing on AMPA Receptor.

Major depressive disorder (MDD) is a common neuropsychiatric disorder affecting the mood and mental well-being. Its pathophysiology remains elusive due to the complexity and heterogeneity of this disorder that affects millions of individuals worldwide. Chronic stress is frequently cited as the one of the risk factors for MDD. To date, the conventional monoaminergic theory (serotonin, norepinephrine, and/or dopamine dysregulation) has received the most attention in the treatment of MDD, and all available classes of antidepressants target these monoaminergic systems. However, the contributions of other neurotransmitter systems in MDD have been widely reported. Emerging preclinical and clinical findings reveal that maladaptive glutamatergic neurotransmission might underlie the pathophysiology of MDD, thus revealing its critical role in the neurobiology of MDD and as the therapeutic target. Aiming beyond the monoaminergic hypothesis, studies of the neurobiological mechanisms underlying the stress-induced impairment of AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)-glutamatergic neurotransmission in the brain could provide novel insights for the development of a new generation of antidepressants without the detrimental side effects. Here, the authors reviewed the recent literature focusing on the role of AMPA-glutamatergic neurotransmission in stress-induced maladaptive responses in emotional and mood-associated brain regions, including the hippocampus, amygdala, prefrontal cortex, nucleus accumbens and periaqueductal gray.

Association study of six candidate genes with major depressive disorder in the North-Western population of Pakistan.

People around the world are currently affected by Major Depressive Disorder (MDD). Despite its many aspects, symptoms, manifestations and impacts, efforts have been made to identify the root causes of the disorder. In particular, genetic studies have concentrated on identifying candidate genes for MDD and exploring associations between these genes and some specific group of individuals. The aim of this research was to find out the association between single nucleotide polymorphisms in 6 candidate genes linked to the neurobiology of major depressive disorder in the North-Western population of Pakistan. We performed a case-control analysis, with 400 MDD and 232 controls. A trained psychiatrist or clinical psychologists evaluated the patients. Six polymorphisms were genotyped and tested for allele and genotype association with MDD. There were no statistical variations between MDD patients and healthy controls for genotypic and allelic distribution of all the polymorphisms observed. Thus, our analysis does not support the major role of these polymorphisms in contributing to MDD susceptibility, although it does not preclude minor impact. The statistically significant correlation between six polymorphisms and major depressive disorder in the studied population was not observed. There are inconsistencies in investigations around the world. Future research, including GWAS and association analysis on larger scale should be addressed for further validation and replication of the present findings.

Functional Contribution of the Medial Prefrontal Circuitry in Major Depressive Disorder and Stress-Induced Depressive-Like Behaviors.

Despite decades of research on the neurobiology of major depressive disorder (MDD), the mechanisms underlying its expression remain unknown. The medial prefrontal cortex (mPFC), a hub region involved in emotional processing and stress response elaboration, is highly impacted in MDD patients and animal models of chronic stress. Recent advances showed alterations in the morphology and activity of mPFC neurons along with profound changes in their transcriptional programs. Studies at the circuitry level highlighted the relevance of deciphering the contributions of the distinct prefrontal circuits in the elaboration of adapted and maladapted behavioral responses in the context of chronic stress. Interestingly, MDD presents a sexual dimorphism, a feature recognized in the molecular field but understudied on the circuit level. This review examines the recent literature and summarizes the contribution of the mPFC circuitry in the expression of MDD in males and females along with the morphological and functional alterations that change the activity of these neuronal circuits in human MDD and animal models of depressive-like behaviors.

The Role of Neurotrophic Factors in Pathophysiology of Major Depressive Disorder.

According to the neurotrophic hypothesis of major depressive disorder (MDD), impairment in growth factor signaling might be associated with the pathology of this illness. Current evidence demonstrates that impaired neuroplasticity induced by alterations of neurotrophic growth factors and related signaling pathways may be underlying to the pathophysiology of MDD. Brain-derived neurotrophic factor (BDNF) is the most studied neurotrophic factor involved in the neurobiology of MDD. Nevertheless, developing evidence has implicated other neurotrophic factors, including neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), nerve growth factor (NGF), vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF), glial cell-derived neurotrophic factor (GDNF), and fibroblast growth factor (FGF) in the MDD pathophysiology. Here, we summarize the current literature on the involvement of neurotrophic factors and related signaling pathways in the pathophysiology of MDD.

Indices of cortical plasticity after therapeutic sleep deprivation in patients with major depressive disorder

BackgroundTherapeutic sleep deprivation (SD) presents a unique paradigm to study the neurobiology of major depressive disorder (MDD). However, the rapid antidepressant mechanism, which differs from today's slow first-line treatments, is not sufficiently understood. We recently integrated two prominent hypotheses of MDD and sleep, the synaptic plasticity hypothesis of MDD and the synaptic homeostasis hypothesis of sleep-wake regulation, into a synaptic plasticity model of therapeutic SD in MDD. Here, we further tested this model positing that homeostatically elevating net synaptic strength through therapeutic SD shifts the initially deficient inducibility of associative synaptic long-term potentiation (LTP)-like plasticity in patients with MDD into a more favorable window of associative plasticity. MethodsWe used paired associative stimulation (PAS), a transcranial magnetic stimulation protocol (TMS), to quantify cortical LTP-like plasticity after one night of therapeutic sleep deprivation in 28 patients with MDD. ResultsWe demonstrate a significantly different inducibility of associative plasticity in clinical responders to therapeutic SD (> 50% improvement on the 6-item Hamilton-Rating-Scale for Depression, n=13) compared to non-responders (n=15), which was driven by a long-term depression (LTD)-like response in SD-non-responders. Indices of global net synaptic strength (wake EEG theta activity, intracortical inhibition and BDNF serum levels) were increased after SD in both groups, with responders showing a generally lower intracortical inhibition than non-responders. LimitationsRepetitive assessments prior to and after treatment would be needed to further determine potential mechanisms. ConclusionAfter a night of therapeutic SD, clinical responders show a significantly higher inducibility of associative LTP-like plasticity than non-responders.

Amygdala functional connectivity in major depression - disentangling markers of pathology, risk and resilience.

Limbic-cortical imbalance is an established model for the neurobiology of major depressive disorder (MDD), but imaging genetics studies have been contradicting regarding potential risk and resilience mechanisms. Here, we re-assessed previously reported limbic-cortical alterations between MDD relatives and controls in combination with a newly acquired sample of MDD patients and controls, to disentangle pathology, risk, and resilience. We analyzed functional magnetic resonance imaging data and negative affectivity (NA) of MDD patients (n = 48), unaffected first-degree relatives of MDD patients (n = 49) and controls (n = 109) who performed a faces matching task. Brain response and task-dependent amygdala functional connectivity (FC) were compared between groups and assessed for associations with NA. Groups did not differ in task-related brain activation but activation in the superior frontal gyrus (SFG) was inversely correlated with NA in patients and controls. Pathology was associated with task-independent decreases of amygdala FC with regions of the default mode network (DMN) and decreased amygdala FC with the medial frontal gyrus during faces matching, potentially reflecting a task-independent DMN predominance and a limbic-cortical disintegration during faces processing in MDD. Risk was associated with task-independent decreases of amygdala-FC with fronto-parietal regions and reduced faces-associated amygdala-fusiform gyrus FC. Resilience corresponded to task-independent increases in amygdala FC with the perigenual anterior cingulate cortex (pgACC) and increased FC between amygdala, pgACC, and SFG during faces matching. Our results encourage a refinement of the limbic-cortical imbalance model of depression. The validity of proposed risk and resilience markers needs to be tested in prospective studies. Further limitations are discussed.

A multivariate neuroimaging biomarker of individual outcome to transcranial magnetic stimulation in depression.

The neurobiology of major depressive disorder (MDD) remains incompletely understood, and many individuals fail to respond to standard treatments. Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (DLPFC) has emerged as a promising antidepressant therapy. However, the heterogeneity of response underscores a pressing need for biomarkers of treatment outcome. We acquired resting state functional magnetic resonance imaging (rsfMRI) data in 47 MDD individuals prior to 5-8 weeks of rTMS treatment targeted using the F3 beam approach and in 29 healthy comparison subjects. The caudate, prefrontal cortex, and thalamus showed significantly lower blood oxygenation level-dependent (BOLD) signal power in MDD individuals at baseline. Critically, individuals who responded best to treatment were associated with lower pre-treatment BOLD power in these regions. Additionally, functional connectivity (FC) in the default mode and affective networks was associated with treatment response. We leveraged these findings to train support vector machines (SVMs) to predict individual treatment responses, based on learned patterns of baseline FC, BOLD signal power and clinical features. Treatment response (responder vs. nonresponder) was predicted with 85-95% accuracy. Reduction in symptoms was predicted to within a mean error of ±16% (r = .68, p < .001). These preliminary findings suggest that therapeutic outcome to DLPFC-rTMS could be predicted at a clinically meaningful level using only a small number of core neurobiological features of MDD, warranting prospective testing to ascertain generalizability. This provides a novel, transparent and physiologically plausible multivariate approach for classification of individual response to what has become the most commonly employed rTMS treatment worldwide. This study utilizes data from a larger clinical study (Australian New Zealand Clinical Trials Registry: Investigating Predictors of Response to Transcranial Magnetic Stimulation for the Treatment of Depression; ACTRN12610001071011; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=336262).

Translational new approaches for investigating mood disorders in rodents and what they may reveal about the underlying neurobiology of major depressive disorder.

Mood disorders represent one of society's most costly and challenging health burdens. The drug treatments used today were initially discovered serendipitously in the 1950s. Animal models were then developed based on the ability of these drugs to alter specific behaviours. These models have played a major role in the development of the second generation of antidepressants. However, their use has been heavily criticized, particularly in relation to whether they recapitulate similar underlying biology to the psychiatric disorder they are proposed to represent. This article considers our work in the field of affective bias and the development of a translational research programme to try to develop and validate better animal models. We discuss whether the new data that have arisen from these studies support an alternative perspective on the underlying neurobiological processes that lead to major depressive disorder (MDD). Specifically, this article will consider whether a neuropsychological mechanism involving affective biases plays a causal role in the development of MDD and its associated emotional and behavioural symptoms. These animal studies also raise the possibility that neuropsychological mechanisms involving affective biases are a precursor to, rather than a consequence of, the neurotrophic changes linked to MDD.This article is part of a discussion meeting issue ‘Of mice and mental health: facilitating dialogue between basic and clinical neuroscientists’.

Translational Shifts in Preclinical Models of Depression: Implications for Biomarkers for Improved Treatments.

Understanding the neurobiology of major depressive disorder (MDD) remains one of the major challenges in neuroscience. The disease is heterogeneous in nature, and patients present with a varied symptom profile. Studies seeking to identify biomarkers for MDD diagnosis and treatment have not yet found any one candidate which achieves sufficient sensitivity and specificity. In this article, we consider whether neuropsychological impairments, specifically affective biases, could provide a behavioural biomarker. Affective biases are observed when emotional states influence cognitive function. These biases have been shown to influence a number of different cognitive domains with some specific deficits observed in MDD. It has also been possible to use these neuropsychological tests to inform the development of translational tasks for non-human species. The results from studies in rodents suggest that quantification of affective biases is feasible and may provide a reliable method to predict antidepressant efficacy as well as pro-depressant risk. Animal studies suggest that affective state-induced biases in learning and memory operate over a different time course to biases influencing decision-making. The implications for these differences in terms of task validity and future ideas relating to affective biases and MDD are discussed. We also describe our most recent studies which have shown that depression-like phenotypes share a common deficit in reward-related learning and memory which we refer to as a reward-induced positive bias. This deficit is dissociable from more typical measures of hedonic behaviour and motivation for reward and may represent an important and distinct form of reward deficit linked to MDD.

Anhedonia correlates with abnormal functional connectivity of the superior temporal gyrus and the caudate nucleus in patients with first-episode drug-naive major depressive disorder

BackgroundRecent empirical findings have suggested that imbalanced neural networks may underlie the pathophysiology of major depressive disorder (MDD). However, the contribution of the superior temporal gyrus (STG) and the caudate nucleus to its pathophysiology remains unclear. MethodsFunctional magnetic resonance imaging (MRI) date were acquired from 40 patients with first-episode drug-naive MDD and 36 matched healthy controls during wakeful rest. We used whole-brain voxel-wise statistical maps to quantify within-group resting state functional connectivity (RSFC) and between-group differences of bilateral caudate and STG seeds. ResultsCompared with healthy controls, first-episode MDD patients were found to have reduced connectivity between the ventral caudate and several brain regions including the superior frontal gyrus (SFG), the superior parietal lobule (SPL) and the middle temporal gyrus (MTG), as well as increased connectivity with the cuneus. We also found increased connectivity between the left STG and the precuneus, the angular gyrus and the cuneus. Moreover, we found that increased anhedonia severity was correlated with the magnitude of ventral caudate functional connectivity with the cuneus and the MTG in MDD patients. LimitationsDue to our small sample size, we did not correct the statistical threshold in the correlation analyses between clinical variables and connectivity abnormalities. ConclusionsThe present study suggests that anhedonia is mainly associated with altered ventral caudate-cortical connectivity and highlights the importance of the ventral caudate in the neurobiology of MDD.

Endothelial nitric oxide synthase in rat brain is downregulated by sub-chronic antidepressant treatment.

Nitric oxide (NO) is a neurotransmitter that may be related to major depressive disorder (MDD) because the selective neuronal NO synthase (NOS) inhibitor, 7-nitroindazole, induces a dose-dependent antidepressant-like effect. NO modulates major neurotransmitters involved in the neurobiology of MDD, such as norepinephrine, serotonin, dopamine, and glutamate. In this study, we investigated the effects of antidepressants as NO modulators in acute and sub-chronic treatments. Rats were injected with the SSRI paroxetine (PAR, 10mg/kg), the SNRI milnacipran (MIL, 30mg/kg), or the NaSSA mirtazapine (MIR, 10mg/kg) for acute (1h) or sub-chronic (3weeks) treatment prior to analysis of nine brain regions (frontal cortex, temporal cortex, striatum, thalamus, hippocampus, midbrain, pons, cerebellum, and olfactory bulb). The mRNA expression levels of three NOS subtypes (neuronal: nNOS, inducible: iNOS, and endothelial: eNOS) were analyzed using real-time PCR with Taqman probes. Acute MIR treatment significantly increased nNOS mRNA expression in the hippocampus, midbrain, cerebellum and olfactory bulb, and iNOS mRNA expression in the frontal cortex and midbrain. Acute PAR and MIR treatments significantly increased eNOS mRNA expression in most brain regions. Conversely, sub-chronic treatment with all types of antidepressants resulted in significant decreases of eNOS mRNA expression in most brain regions. Sub-chronic treatment with the three types of antidepressants consistently decreased eNOS mRNA expression levels in the rat brain. These effects may be associated with the involvement of the NO system in the mechanism of action of antidepressants.

Neuroprogression and Immune Activation in Major Depressive Disorder.

Traditionally, the neurobiology of major depressive disorder (MDD) has been largely considered from the perspective of the state of major depressive episodes (MDE) versus being in remission, but the current accumulation of disease markers, largely acquired cross-sectionally, is strongly suggestive of neuroprogressive aspects of MDD. This chapter focuses on the changes in disease markers involved in the reorganization of the nervous system in MDD, including the translocator protein (TSPO; an index of microglial activation), glial fibrillary acidic protein (GFAP; an index of astroglial activation), [11C]harmine (a marker of monoamine oxidase A; MAO-A), and several other indices (metabotropic glutamate receptor 5 [mGluR5], excitatory amino acid transporters, and magnetic resonance imaging spectroscopy measurements) of glutamate dysregulation. These are markers of processes involved in immune activation, oxidative stress, and chronic glucocorticoid exposure. Positron emission tomography studies of the TSPO distribution volume, a marker of microglial activation, provide strong evidence for microglial activation throughout the gray matter of the brain during MDE of MDD. In postmortem studies, GFAP reductions in the orbitofrontal cortex, anterior cingulate cortex, and hippocampus indicate a deficit in reactive astroglia. Elevated MAO-A levels are present throughout the gray matter of the brain, including affect-modulating brain regions, starting in high-risk states for MDE such as the early postpartum period, perimenopause, heavy cigarette smoking, heavy alcohol intake, and prior to MDE recurrence. Evidence is accumulating for glutamate dysregulation, with some findings of reduced glutamate transporter density in the orbitofrontal cortex, and decreased mGluR5 density. Collectively, these changes suggest an imbalance in the immune system with increased microglial activation and decreased astroglial activation, continued elevations of the MAO-A level, and, likely, the development of extracellular glutamate dysregulation. Many of these imbalances involve processes implicated in increased oxidative stress, apoptosis, and neurodegeneration. Future studies are required to assess potential therapeutics targeting these processes to ameliorate progression of MDD.

Gene expression alterations in the medial prefrontal cortex and blood cells in a mouse model of depression during menopause.

AimsThe prevalence of major depressive disorder (MDD) is higher in women than in men, and this may be due to the decline in estrogen levels that occurs during the menopausal transition. We studied the biological alterations in the medial prefrontal cortex (mPFC), which is a region that is highly implicated in the neurobiology of MDD, and the blood cells (BCs) of ovariectomized (OVX) mice subjected to chronic mild stress (CMS), which represents a mouse model of depression during menopause.Main methodsThe mPFC and the BCs were obtained from the same individuals. Gene expression levels were analyzed by microarray. The data were used for the Ingenuity Pathway Analysis and the Gene Ontology analysis.Key findingsThe gene expression alterations (GEAs) induced by OVX were mainly associated with ribosomal and mitochondrial functions in both the mPFC and the BCs. Rapamycin-insensitive companion of mTOR (RICTOR) was identified as a possible upstream regulator of the OVX-induced GEAs in both tissues. The CMS-induced GEAs were associated with retinoic acid receptor signaling, inflammatory cytokines and post-synaptic density in the mPFC, but not in the BCs.SignificanceOVX and CMS independently affect biological pathways in the mPFC, which is involved in the development of the depression-like phenotype. Because a subset of the OVX-induced GEAs in the mPFC also occurred in the BCs, the GEAs in the BCs might be a useful probe to predict biological pathways in the corresponding brain tissue under specific conditions such as OVX in females.

Decreased long- and short-range functional connectivity at rest in drug-naive major depressive disorder.

Abnormal functional connectivity has been observed in major depressive disorder. Anatomical distance may affect functional connectivity in patients with major depressive disorder. However, whether and how anatomical distance affects functional connectivity at rest remains unclear in drug-naive patients with major depressive disorder. Forty-four patients with major depressive disorder, as well as 44 age-, sex- and education-matched healthy controls, underwent resting-state functional magnetic resonance imaging scanning. Regional functional connectivity strength was calculated for each voxel in the whole brain, which was further divided into short- and long-range functional connectivity strength. The patients showed decreased long-range positive functional connectivity strength in the right inferior parietal lobule, as well as decreased short-range positive functional connectivity strength in the right insula and right superior temporal gyrus relative to those of the controls. No significant correlations existed between abnormal functional connectivity strength and the clinical variables of the patients. The findings revealed that anatomical distance decreases long- and short-range functional connectivity strength in patients with major depressive disorder, which may underlie the neurobiology of major depressive disorder.

Glutamatergic NMDA Receptor as Therapeutic Target for Depression.

Major depressive disorder (MDD) affects approximately 121 million individuals globally and poses a significant burden to the healthcare system. Around 50-60% of patients with MDD respond adequately to existing treatments that are primarily based on a monoaminergic system. However, the neurobiology of MDD has not been fully elucidated; therefore, it is possible that other biochemical alterations are involved. The glutamatergic system and its associated receptors have been implicated in the pathophysiology of MDD. In fact, the N-methyl-d-aspartate (NMDA) receptor, a glutamate receptor, is a binding or modulation site for both classical antidepressants and new fast-acting antidepressants. Thus, this review aims to present evidence describing the effect of antidepressants that modulate NMDA receptors and the mechanisms that contribute to the antidepressant response.

Persistent decrease in alpha current density in fully remitted subjects with major depressive disorder treated with fluoxetine: A prospective electric tomography study

Major depressive disorder (MDD) is recurrent, and its pathophysiology is not fully understood. Studies using electric tomography (ET) have identified abnormalities in the current density (CD) of MDD subjects in regions associated with the neurobiology of MDD, such as the anterior cingulate cortex (ACC) and medial orbitofrontal cortex (mOFC). However, little is known regarding the long-term CD changes in MDD subjects who respond to antidepressants. The aim of this study was to compare CD between healthy and MDD subjects who received 1-year open-label treatment with fluoxetine.Thirty-two-channel electroencephalograms (EEGs) were collected from 70 healthy controls and 74 MDD subjects at baseline (pre-treatment), 1 and 2weeks and 1, 2, 6, 9 and 12months. Variable-resolution ET (VARETA) was used to assess the CD between subject groups at each time point. The MDD group exhibited decreased alpha CD (αCD) in the occipital and parietal cortices, ACC, mOFC, thalamus and caudate nucleus at each time point. The αCD abnormalities persisted in the MDD subjects despite their achieving full remission. The low sub-alpha band was different between the healthy and MDD subjects. Differences in the amount of αCD between sexes and treatment outcomes were observed. Lack of a placebo arm and the loss of depressed patients to follow-up were significant limitations. The persistence of the decrease in αCD might suggest that the underlying pathophysiologic mechanisms of MDD are not corrected despite the asymptomatic state of MDD subjects, which could be significant in understanding the highly recurrent nature of MDD.