Targets For Major Depressive Disorder Research Articles

Effect of Antidepressant Treatment on 5-HT4 Receptor Binding and Associations With Clinical Outcomes and Verbal Memory in Major Depressive Disorder

BackgroundBrain serotonin 4 receptor (5-HT4R) levels are lower in untreated patients with major depressive disorder (MDD) and are linked to verbal memory. Here, we investigated the relationship between 5-HT4R levels, clinical outcomes, and cognitive function in patients with MDD who initiated selective serotonin reuptake inhibitor drug treatment. MethodsNinety patients with moderate to severe depression underwent molecular brain imaging to measure 5-HT4R binding prior to antidepressant treatment with escitalopram. Pretreatment 5-HT4R binding was assessed for its ability to predict treatment outcome at weeks 4, 8, or 12. In 40 patients who were rescanned 8 weeks posttreatment, change in cerebral 5-HT4R binding was correlated with change in verbal memory and with change in depressive symptoms, as evaluated by the 6-item Hamilton Depression Rating Scale. ResultsAfter 8 weeks of serotonergic intervention, neostriatal 5-HT4R binding was reduced by 9%. Global change in 5-HT4R binding from baseline was associated with verbal memory outcomes, but not with overall clinical depressive symptom outcomes. Pretreatment 5-HT4R binding did not predict clinical recovery status at week 8 and was not associated with change in the 6-item Hamilton Depression Rating Scale scores. ConclusionsIn patients with moderate to severe MDD, treatment with selective serotonin reuptake inhibitors downregulated neostriatal 5-HT4R levels, which is consistent with the notion that the drugs increase cerebral extracellular serotonin. The less global brain 5-HT4R levels were downregulated after selective serotonin reuptake inhibitors, the more verbal memory improved, highlighting the potential importance of 5-HT4R as a treatment target in MDD. The findings offer insights into mechanisms that underlie antidepressant effects and point to new directions for precision medicine treatments for MDD.

Enhanced neuronal survival and BDNF elevation via long-term co-activation of galanin 2 (GALR2) and neuropeptide Y1 receptors (NPY1R): potential therapeutic targets for major depressive disorder

ABSTRACT Background Major Depressive Disorder (MDD) is a prevalent and debilitating condition, necessitating novel therapeutic strategies due to the limited efficacy and adverse effects of current treatments. We explored how galanin receptor 2 (GALR2) and Neuropeptide Y1 Receptor (NPYY1R) agonists, working together, can boost brain cell growth and increase antidepressant-like effects in rats. This suggests new ways to treat Major Depressive Disorder (MDD). Research Design and Methods In a controlled laboratory setting, adult naive Sprague-Dawley rats were administered directly into the brain’s ventricles, a method known as intracerebroventricular (ICV) administration, with GALR2 agonist (M1145), NPYY1R agonist, both, or in combination with a GALR2 antagonist (M871). Main outcome measures included long-term neuronal survival, differentiation, and behavioral. Results Co-administration of M1145 and NPYY1R agonist significantly enhanced neuronal survival and maturation in the ventral dentate gyrus, with a notable increase in Brain-Derived Neurotrophic Factor (BDNF) expression. This neurogenic effect was associated with an antidepressant-like effect, an outcome partially reversed by M871. Conclusions GALR2 and NPYY1R agonists jointly promote hippocampal neurogenesis and exert antidepressant-like effects in rats without adverse outcomes, highlighting their therapeutic potential for MDD. The study’s reliance on an animal model and intracerebroventricular delivery warrants further clinical exploration to confirm these promising results.

Regulation of depressive-like behaviours by palmitoylation: Role of AKAP150 in the basolateral amygdala.

Protein palmitoylation is involved in learning and memory, and in emotional disorders. Yet, the underlying mechanisms in these processes remain unclear. Herein, we describe that A-kinase anchoring protein 150 (AKAP150) is essential and sufficient for depressive-like behaviours in mice via a palmitoylation-dependent mechanism. Depressive-like behaviours in mice were induced by chronic restraint stress (CRS) and chronic unpredictable mild stress (CUMS). Palmitoylated proteins in the basolateral amygdala (BLA) were assessed by an acyl-biotin exchange assay. Genetic and pharmacological approaches were used to investigate the role of the DHHC2-mediated AKAP150 palmitoylation signalling pathway in depressive-like behaviours. Electrophysiological recording, western blotting and co-immunoprecipitation were performed to define the mechanistic pathway. Chronic stress successfully induced depressive-like behaviours in mice and enhanced AKAP150 palmitoylation in the BLA, and a palmitoylation inhibitor was enough to reverse these changes. Blocking the AKAP150-PKA interaction with the peptide Ht-31 abolished the CRS-induced AKAP150 palmitoylation signalling pathway. DHHC2 expression and palmitoylation levels were both increased after chronic stress. DHHC2 knockdown prevented CRS-induced depressive-like behaviours, as well as attenuating AKAP150 signalling and synaptic transmission in the BLA in CRS-treated mice. These results delineate that DHHC2 modulates chronic stress-induced depressive-like behaviours and synaptic transmission in the BLA via the AKAP150 palmitoylation signalling pathway, and this pathway may be considered as a promising novel therapeutic target for major depressive disorder.

MicroRNA-451a is a candidate biomarker and therapeutic target for major depressive disorder

BackgroundIncreasing evidence supports the role of microRNAs (miRNAs) in major depressive disorder (MDD), but the pathophysiological mechanism remains elusive.AimsTo explore the mechanism of microRNA-451a (miR-451a) in the pathology and behaviours...

Clinical and preclinical evaluation of miR-144-5p as a key target for major depressive disorder.

Neuronal abnormalities are closely associated with major depressive disorder (MDD). Available evidence suggests a role for microRNAs (miRNAs) in regulating the expression of genes involved in MDD. Hence, miRNAs that can be potential therapeutic targets need to be identified. A mouse model of chronic unpredictable stress (CUS) was used to evaluate the function of miRNAs in MDD. miR-144-5p was screened from the hippocampi of CUS mice based on sequencing results. Adenovirus-associated vectors were used to overexpress or knockdown miR-144-5p in mice. BpV(pic) and LY294002 were used to determine the relationship between miR-144-5p target genes PTEN and TLR4 in neuronal impairment caused by miR-144-5p deficiency. Western blotting, immunofluorescence, ELISA immunosorbent assay, and Golgi staining were used to detect neuronal abnormalities. Serum samples from healthy individuals and patients with MDD were used to detect miR-144-5p levels in the serum and serum exosomes using qRT-PCR. miR-144-5p expression was significantly decreased within the hippocampal dentate gyrus (DG) of CUS mice. Upregulation of miR-144-5p in the DG ameliorated depression-like behavior in CUS mice and attenuated neuronal abnormalities by directly targeting PTEN and TLR4 expression. Furthermore, miR-144-5p knockdown in normal mice led to depression-like behavior via inducing neuronal abnormalities, including abnormal neurogenesis, neuronal apoptosis, altered synaptic plasticity, and neuroinflammation. miR-144-5p deficiency-mediated neuronal impairment was mediated by PI3K/Akt/FoxO1 signaling. Furthermore, miR-144-5p levels were downregulated in the sera of patients with MDD and associated with depressive symptoms. Consistently, serum exosome-derived miR-144-5p levels were decreased in patients with MDD. miR-144-5p plays a vital role in regulating neuronal abnormalities in depression. Our findings provide translational evidence that miR-144-5p is a new potential therapeutic target for MDD.

Functional connectivity analysis of the depression connectome provides potential markers and targets for transcranial magnetic stimulation

BackgroundDespite efforts to improve targeting accuracy of the dorsolateral prefrontal cortex (DLPFC) as a repetitive transcranial magnetic stimulation (rTMS) target for Major Depressive Disorder (MDD), the heterogeneity in clinical response remains unexplained. ObjectiveWe sought to compare the patterns of functional connectivity from the DLPFC treatment site in patients with MDD who were TMS responders to those who were TMS non-responders. MethodsBaseline anatomical T1 magnetic resonance imaging (MRI), resting-state functional MRI, and diffusion weighted imaging scans were obtained from 37 participants before they underwent a course of rTMS to left Brodmann area 46. A novel machine learning method was utilized to identify brain regions associated with each item of the Beck's Depression Inventory II (BDI-II), and for 26 participants who underwent rTMS treatment over the left Brodmann area 46, identify regions differentiating rTMS responders and non-responders. ResultsNine parcels of the Human Connectome Project Multimodal Parcellation Atlas matched to at least three items of the Beck's Depression Inventory II (BDI-II) as predictors of response to rTMS, with many in the temporal, parietal and cingulate cortices. Additionally, pre-treatment mapping for 17 items of the BDI-II demonstrated significant variability in symptom to parcel mapping. When parcels associated with symptom presence and symptom resolution were compared, 15 parcels were uniquely associated with resolution (potential targets), and 12 parcels were associated with both symptom presence and resolution (blockers or biomarkers). ConclusionsMachine learning approaches show promise for the development of pathoanatomical diagnosis and treatment algorithms for MDD. Prospective studies are required to facilitate clinical translation.

NLRP3 Inflammasome: From Pathophysiology to Therapeutic Target in Major Depressive Disorder

Major depressive disorder (MDD) is a highly prevalent psychiatric disorder, whose pathophysiology has been linked to the neuroinflammatory process. The increased activity of the Nod-like receptor pyrin containing protein 3 (NLRP3) inflammasome, an intracellular multiprotein complex, is intrinsically implicated in neuroinflammation by promoting the maturation and release of proinflammatory cytokines such as interleukin (IL)-1β and IL-18. Interestingly, individuals suffering from MDD have higher expression of NLRP3 inflammasome components and proinflammatory cytokines when compared to healthy individuals. In part, intense activation of the inflammasome may be related to autophagic impairment. Noteworthy, some conventional antidepressants induce autophagy, resulting in less activation of the NLRP3 inflammasome. In addition, the fast-acting antidepressant ketamine, some bioactive compounds and physical exercise have also been shown to have anti-inflammatory properties via inflammasome inhibition. Therefore, it is suggested that modulation of inflammasome-driven pathways may have an antidepressant effect. Here, we review the role of the NLRP3 inflammasome in the pathogenesis of MDD, highlighting that pathways related to its priming and activation are potential therapeutic targets for the treatment of MDD.

Evaluating cognitive disturbances as treatment target and predictor of antidepressant action in major depressive disorder: A NeuroPharm study

Cognitive disturbances in major depressive disorder (MDD) constitute a critical treatment target and hold promise as an early predictor of antidepressant treatment response; yet their clinical relevance is not fully established. Therefore, we here investigate if (1) cognitive performance improves over the course of antidepressant treatment and (2) cognitive performance at baseline is predictive of antidepressant treatment response. In the NeuroPharm study (clinical trial id: NCT02869035), 92 antidepressant-free patients with a moderate to severe depressive episode were assessed with a comprehensive cognitive test battery including both cold (emotion-independent) and hot (emotion-dependent) tasks. Patients were tested before and after 12 weeks of standard antidepressant treatment with escitalopram in flexible doses of 10–20 mg. Performance improved across most cognitive domains over the course of antidepressant treatment. Notably, these improvements were independent of improvement in mood symptoms, emphasizing that cognitive disturbances are a distinct symptom and therefore treatment target in MDD. Results did not suggest that performance on any single cognitive measure at baseline was associated with later clinical response to antidepressant treatment. However, a small cluster of patients (N = 28) with globally disturbed cognition at baseline exhibited poorer clinical response after 8 but not 12 weeks of antidepressant treatment, suggesting that severe cognitive disturbances may delay treatment response. Thus, while pretreatment cognitive performance on individual tests may not be useful as clinical markers of treatment response, profiles capturing performance across different cognitive domains may be useful for stratification of patients with MDD and could be helpful in future intervention trials.

Depressive symptoms are negatively associated with hair N-arachidonoylethanolamine (anandamide) levels: A cross-lagged panel analysis of four annual assessment waves examining hair endocannabinoids and cortisol

BackgroundThe endocannabinoid system (ECS) is increasingly being recognized as key regulatory system coupled with the glucocorticoid system implicated in the pathophysiology of major depressive disorder (MDD). However, prior studies examining the ECS in MDD have been inconclusive, of small sample size or of cross-sectional nature limiting interpretation of causal inferences or time-dependent effects. MethodsIn a prospective community-based cohort study including 128 individuals (women: 108), depressive symptoms (PHQ-9) as well as hair cortisol and endocannabinoids were measured annually over four years (T1-T4). Cortisol, N-arachidonoylethanolamine (AEA), and 2-arachidonoyl-sn-glycerol/1-arachidonoyl-sn-glycerol (2-AG/1-AG) were extracted from 3 cm hair segments reflecting cumulative concentrations of the last three months prior sampling. ResultsCross-sectional group comparisons at baseline revealed reduced AEA and cortisol levels in the group with a positive MDD screening compared to individuals with low depressive symptomatology (both p < .05). Cross-lagged panel models showed that AEA levels at T2 were negatively associated with depressive symptoms at T3 (p < .05). Also, depressive symptoms at T3 were negatively associated with AEA levels at T4 (p < .01). The direction of association was reversed for 2-AG/1-AG, as 2-AG/1-AG levels at T1 were positively associated with depressive symptoms at T2 (p < .01). ConclusionsWhile cross-sectional analyses suggest higher depressive symptomatology to be associated with reduced AEA and cortisol release, longitudinal analyses reveal that primarily AEA levels are negatively associated with depressive symptoms. These longitudinal associations elucidate time-dependent relationships between depressive symptomatology and the ECS and further highlight AEA as potential treatment target in MDD.

Mapping Inter-individual Functional Connectivity Variability in TMS Targets for Major Depressive Disorder.

Transcranial magnetic stimulation (TMS) is an emerging alternative to existing treatments for major depressive disorder (MDD). The effects of TMS on both brain physiology and therapeutic outcomes are known to be highly variable from subject to subject, however. Proposed reasons for this variability include individual differences in neurophysiology, in cortical geometry, and in brain connectivity. Standard approaches to TMS target site definition tend to focus on coordinates or landmarks within the individual brain regions implicated in MDD, such as the dorsolateral prefrontal cortex (dlPFC) and orbitofrontal cortex (OFC). Additionally considering the network connectivity of these sites (i.e., the wider set of brain regions that may be mono- or poly-synaptically activated by TMS stimulation) has the potential to improve subject-specificity of TMS targeting and, in turn, improve treatment outcomes. In this study, we looked at the functional connectivity (FC) of dlPFC and OFC TMS targets, based on induced electrical field (E-field) maps, estimated using the SimNIBS library. We hypothesized that individual differences in spontaneous functional brain dynamics would contribute more to downstream network engagement than individual differences in cortical geometry (i.e., E-field variability). We generated individualized E-field maps on the cortical surface for 121 subjects (67 female) from the Human Connectome Project database using tetrahedral head models generated from T1- and T2-weighted MR images. F3 and Fp1 electrode positions were used to target the left dlPFC and left OFC, respectively. We analyzed inter-subject variability in the shape and location of these TMS target E-field patterns, their FC, and the major functional networks to which they belong. Our results revealed the key differences in TMS target FC between the dlPFC and OFC, and also how this connectivity varies across subjects. Three major functional networks were targeted across the dlPFC and OFC: the ventral attention, fronto-parietal and default-mode networks in the dlPFC, and the fronto-parietal and default mode networks in the OFC. Inter-subject variability in cortical geometry and in FC was high. Our analyses showed that the use of normative neuroimaging reference data (group-average or representative FC and subject E-field) allows prediction of which networks are targeted, but fails to accurately quantify the relative loading of TMS targeting on each of the principal networks. Our results characterize the FC patterns of canonical therapeutic TMS targets, and the key dimensions of their variability across subjects. The high inter-individual variability in cortical geometry and FC, leading to high variability in distributions of targeted brain networks, may account for the high levels of variability in physiological and therapeutic TMS outcomes. These insights should, we hope, prove useful as part of the broader effort by the psychiatry, neurology, and neuroimaging communities to help improve and refine TMS therapy, through a better understanding of the technology and its neurophysiological effects.

DNA Methylation as a Therapeutic and Diagnostic Target in Major Depressive Disorder

DNA Methylation as a Therapeutic and Diagnostic Target in Major Depressive Disorder

Antidepressant Treatment-Induced State-Dependent Reconfiguration of Emotion Regulation Networks in Major Depressive Disorder.

Deficits in emotion regulation are the main clinical features, common risk factors, and treatment-related targets for major depressive disorder (MDD). The neural bases of emotion regulation are moving beyond specific functions and emphasizing instead the integrative functions of spatially distributed brain areas that work together as large-scale brain networks, but it is still unclear whether the dynamic interactions among these emotion networks would be the target of clinical intervention for MDD. Data were collected from 70 MDD patients and 43 sex- and age-matched healthy controls. The dynamic functional connectivity (dFC) between emotion regions was estimated via a sliding-window method based on resting-state functional magnetic resonance imaging (R-fMRI). A k-means clustering method was applied to classify all time windows across all participants into several dFC states reflecting recurring functional interaction patterns among emotion regions over time. The results showed that four dFC states were identified in the emotion networks. Their alterations of state-related occurrence proportion were found in MDD and subsequently normalized following 12-week antidepressant treatment. Baseline strong dFC could predict the reduction rate of Hamilton Depression Rating Scale (HAMD) scores. These findings highlighted the state-dependent reconfiguration of emotion regulation networks in MDD patients owing to antidepressant treatment.

Promoter Hypomethylation of miR-124 Gene Is Associated With Major Depressive Disorder

Based on our previous studies and other evidence, miR-124 is an important biomarker and therapeutic target for major depressive disorder (MDD). The aim of this study was to clarify the role of miR-124 methylation in MDD and antidepressant effects from the perspective of epigenetics. MethylTarget™ was used to detect methylation levels of the three miR-124 precursor genes (MIR124-1, MIR124-2, and MIR124-3) in 33 pre- and post-treatment MDD patients and 33 healthy controls. A total of 11 cytosine-phosphate-guanine (CpG) islands in the three miR-124 precursor genes, including 222 CpG sites, were detected. All CpG islands were hypomethylated in MDD patients when compared to healthy controls and seven CpG regions were still identified with a statistically significant difference after Bonferroni correction. In addition, 137 of 222 CpG sites were found a statistical difference between MDD patients and controls, and 40 CpG sites were still statistically significant after Bonferroni correction. After performing the LASSO regression model, seven biomarkers with differential methylation among 40 CpG sites were identified. Mean methylation score was lower in MDD patients (z = −5.84, p = 5.16E-9). The AUC value reached 0.917 (95% CI: 0.854–0.981) to discriminate MDD and controls. No changes in methylation of the three miR-124 precursor genes were found in MDD patients following antidepressant treatment. The methylation of miR-124 could be a promising diagnostic biomarker for MDD.

Identification of key genes and crucial pathways for major depressive disorder using peripheral blood samples and chronic unpredictable mild stress rat models.

BackgroundAccurate diagnosis of major depressive disorder (MDD) remains difficult, and one of the key challenges in diagnosing MDD is the lack of reliable diagnostic biomarkers. The objective of this study was to explore gene networks and identify potential biomarkers for MDD.MethodsIn the present study, we performed a comprehensive analysis of the mRNA expression profiles using blood samples of four patients with MDD and four controls by RNA sequencing. Differentially expressed genes (DEGs) were screened, and functional and pathway enrichment analyses were performed using the Database for Annotation, Visualization, and Integrated Discovery. All DEGs were inputted to the STRING database to build a PPI network, and the top 10 hub genes were screened using the cytoHubba plugin of the Cytoscape software. The relative expression of 10 key genes was identified by quantitative real-time polymerase chain reaction (qRT-PCR) of blood samples from 50 MDD patients and 50 controls. Plasma levels of SQSTM1 and TNFα were measured using an enzyme-linked immunosorbent assay in blood samples of 44 MDD patients and 44 controls. A sucrose preference test was used to evaluate depression-like behavior in chronic unpredictable mild stress (CUMS) model rats. Immunofluorescence assay and western blotting were performed to study the expression of proteins in the brain samples of CUMS model ratsResultsWe identified 247 DEGs that were closely associated with MDD. Gene ontology analyses suggested that the DEGs were mainly enriched in negative regulation of transcription by RNA polymerase II promoter, cytoplasm, and protein binding. Moreover, Kyoto Encyclopedia of Genes and Genomes pathway analysis suggested that the DEGs were significantly enriched in the MAPK signaling pathway. Ten hub genes were screened through the PPI network, and qRT-PCR assay revealed that one and six genes were downregulated and upregulated, respectively; however, SMARCA2, PPP3CB, and RAB5C were not detected. Pathway enrichment analysis for the 10 genes showed that the mTOR signaling pathway was also enriched. A strong positive correlation was observed between SQSTM1 and TNFα protein levels in patients with MDD. LC3 II and SQSTM1 protein levels were increased in the CUMS rat model; however, p-mTOR protein levels were decreased. The sucrose preference values decreased in the CUMS rat model.ConclusionsWe identified 247 DEGs and constructed an MDD-specific network; thereafter, 10 hub genes were selected for further analysis. Our results provide novel insights into the pathogenesis of MDD. Moreover, SQSTM1, which is related to autophagy and inflammatory reactions, may play a key role in MDD. SQSTM1 may be used as a promising therapeutic target in MDD; additionally, more molecular mechanisms have been suggested that should be focused on in future in vivo and in vitro studies.

P2X7 Receptor as a Potential Target for Major Depressive Disorder

Major depressive disorder (MDD) is a common mental disorder. Although the genetic, biochemical, and psychological factors have been related to the development of MDD, it is generally believed that a series of pathological changes in the brain caused by chronic stress is the main cause of MDD. However, the specific mechanisms underlying chronic stress-induced MDD are largely undermined. Recent investigations have found that increased pro-inflammatory cytokines and changes in the inflammatory pathway in the microglia cells in the brain are the potential pathophysiological mechanism of MDD. P2X7 receptor (P2X7R) and its mediated signaling pathway play a key role in microglia activation. The present review aimed to present and discuss the accumulating data on the role of P2X7R in MDD. Firstly, we summarized the research progress in the correlation between P2X7R and MDD. Subsequently, we presented the P2X7R mediated microglia activation in MDD and the role of P2X7R in increased blood-brain barrier (BBB) permeability caused by chronic stress. Lastly, we also discussed the potential mechanism underlying-P2X7R expression changes after chronic stress. In conclusion, P2X7R is a key molecule regulating the activation of microglia. Chronic stress activates microglia in the hippocampus by secreting interleukin- 1β (IL-1β) and other inflammatory cytokines, and increasing the BBB permeability, thus promoting the occurrence and development of MDD, which indicated that P2X7R might be a promising therapeutic target for MDD.

Mapping Inter-Individual Functional Connectivity Variability in TMS Targets for Major Depressive Disorder

Mapping Inter-Individual Functional Connectivity Variability in TMS Targets for Major Depressive Disorder

The kappa opioid receptor antagonist aticaprant reverses behavioral effects from unpredictable chronic mild stress in male mice.

Major depressive disorder is a leading cause of disability worldwide and is likely precipitated by chronic stress. Although many antidepressants are currently available, these drugs require weeks to months of daily administration before reduction of symptoms occurs and many patients remain treatment-resistant despite several courses of treatment. There is a pressing need for new treatments for stress-related disorders. Kappa opioid receptors (KORs) are a promising new therapeutic target for major depressive disorder and anhedonia because acute KOR blockade prevents many effects of stress in rodents. The following study assessed whether repeated treatment with the selective KOR antagonist aticaprant (also known as JNJ-67953964, and previously LY-2456302 and CERC-501) was effective in reversing behaviors in rodents following exposure to unpredictable chronic mild stress (UCMS). Adult male C57BL/6J mice were exposed to 4 weeks of UCMS. After 3 weeks of stress, aticaprant (10 mg/kg) was administered daily for 11 treatments. Behavioral assessments included the sucrose preference test, nesting, forced swim test, hot plate test, light-dark test, and social interaction test. Aticaprant significantly reversed stress-induced deficits produced by UCMS on the SPT, nesting, FST, and hot plate test. The effects of aticaprant persisted through a stress and treatment recovery period. Aticaprant was not effective at reversing behavioral effects caused by stress in the light-dark and social interaction tests. The results support further study of the role of KORs in regulating circuits related to reward, self-care, and cognition when they are disrupted by chronic stress. They are also consistent with the clinical development of aticaprant as a therapeutic for stress-related disorders targeted at anhedonia, such as depression and post-traumatic stress disorder.

Clinical Efficacy and Biological Regulations of ω–3 PUFA-Derived Endocannabinoids in Major Depressive Disorder

Background: Endocannabinoids (ECs) are one type of bioactive endogenous neuroinflammatory mediator derived from polyunsaturated fatty acids (PUFAs), which may regulate the emotional processes. Here, we assessed the effect of ω–3 PUFAs on EC levels, which may be the novel targets for the ω–3 PUFAs’ antidepressive effects. Methods: We conducted a 12-week double-blind, nonplacebo, randomized controlled trial. Eighty-eight major depressive disorder (MDD) participants were randomly assigned to receive eicosapentaenoic acid (EPA, 3.0 g/day), docosahexaenoic acid (DHA, 1.4 g/day), or a combination of EPA (1.5 g/d) and DHA (0.7 g/day). Eighty-five participants completed the trial, and their clinical remission and plasma PUFA-derived EC levels (pmol/mL) were measured. Results: The cumulative rates of clinical remission were significantly higher in the EPA and EPA + DHA groups than the DHA group (51.85 and 53.84 vs. 34.37%; p =0.027 and p =0.024, respectively). EPA and EPA + DHA treatments increased the eicosapentaenoylethanolamide (EPEA) levels compared to DHA treatment (0.33 ± 0.18 and 0.35 ± 0.24 vs. 0.08 ± 0.12; p =0.002 and p =0.001, respectively), while EPA + DHA treatment increased the docosahexaenoylethanolamide levels more than EPA treatment (1.34 ± 2.09 vs. 0.01 ± 1.79; p =0.006). Plasma EPEA levels were positively correlated with rates of clinical remission (hazard ratio: 1.60, 95% confidence interval: 1.08–2.39). Conclusions: Treatments enriched with EPA increased plasma EPEA levels, which was positively associated with clinical remission. This finding may suggest that levels of plasma EPEA play a potential novel endogenous therapeutic target in MDD.

Ketamine exerts a protective role in a cell-based model of major depressive disorder via the inhibition of apoptosis and inflammation and activation of the Krebs cycle.

Major depressive disorder (MDD) is one of the most common psychiatric disorders characterized by major depressive episodes. Although great efforts have been made to develop antidepressant drugs that target the monoaminergic system, these drugs are effective in only approximately 50% of MDD patients. In this study, we established a model of depression in PC12 cells using corticosterone to investigate the effect of ketamine and nuclear factor-κB (NF-κB) on the cell viability, apoptosis, levels of pro-inflammatory cytokines, apoptosis-related molecules, and enzymes of the Krebs cycle. PC12 cells were divided into control (no treatment, NC), ketamine treatment (KT), ketamine treatment with the inhibition of NF-κB (KI), and ketamine treatment with the overexpression of NF-κB (KO) group. Blood serum samples were collected from patients with MDD (n = 10) and healthy controls (n = 10) between 2015 and 2017. Ketamine significantly increased the viability and decreased the apoptosis of PC12 cells in KT and KI vs. NC group, but not in KO group. The levels of anti-apoptotic molecules and Krebs cycle enzymes were significantly increased in KI vs. KT group, while the levels of pro-apoptotic molecules and pro-inflammatory cytokines were decreased in KI vs. KT group. In addition, the levels of pro-inflammatory cytokines in the serum of MDD patients were significantly increased. The antidepressant effect of ketamine was enhanced in KI and reduced in KO group. Our results indicate that ketamine exerts its antidepressant effect via the inhibition of apoptosis and inflammation and the activation of the Krebs cycle in PC12 cells. NF-κB might be a potential therapeutic target in MDD.

SUN-LB082 Sexual Dimorphism of Phosphoethanolamine in HPA-Axis Response to LXR Agonist 25-Hydroxycholesterol: Neuroendocrine Implications for Major Depressive Disorder

Major depression is a chronic illness and a major component of disease burden, with high prevalence in women than in men. Plasma phosphoethanolamine (PEA) levels are significantly decreased in major depressive disorder (MDD) patients compared to healthy controls. Additionally, in the chronic ACTH treatment MDD mouse model, plasma and frontal cortex PEA were significantly decreased compared to vehicle treated controls. However, the reasons behind MDD prevalence in females, the neuroendocrine mechanisms by which PEA changes in vivo, and its role in the pathobiology of MDD is not yet understood. In cells, LXR agonist 25-hydroxycholesterol increased PEA levels: To understand the sexually dimorphic PEA function in the neuroendocrine circuitry of MDD, basal in vivo central and peripheral PEA levels, as well as post 25-hydroxylcholesterol treatment PEA levels in blood plasma, adrenal gland, and brain nuclei implicated in MDD were studied in mice. Both targeted and untargeted metabolomics analysis using capillary electrophoresis-mass spectrometry were applied to measure PEA and various metabolite levels in the respective tissues. Here we report that compared to vehicle control females, vehicle treated male mice had about 50% higher basal plasma PEA levels than females. In the brain areas implicated in MDD, male mice displayed significantly increased basal PEA levels compared to female basal levels by about 3 fold. Specifically, basal PEA levels in males were higher than females in the frontal cortex, striatum, hippocampus, hypothalamus, and the amygdala. Moreover, while acute LXR agonist, 25-hydroxycholesterol decreased plasma PEA levels, chronic LXR agonism significantly increased plasma PEA levels in both male and female mice. Hypothalamic PEA decreased by 20% in females and 80% in males after LXR agonist treatment. Moreover, basal adrenal PEA was 45% significantly higher in females than in males; and 25-hydroxycholesterol significantly increased female adrenal PEA by 35% over basal levels, with no change in males. Metabolomics analysis further revealed significant changes in levels of several metabolites in the plasma, brains, and adrenals of 25-hydroxycholesterol treated mice in a sexually dimorphic manner. These findings underscore the importance of the PEA-LXR system in explaining the sexual dimorphic differential coping strategy of the two sexes to stressful stimuli; and may serve as a novel potential diagnostic and therapeutic target for major depressive disorder. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.