Peripheral mitochondrial DNA as a neuroinflammatory biomarker for major depressive disorder

In the pathogenesis of major depressive disorder, chronic stress-related neuroinflammation hinders favorable prognosis and antidepressant response. Mitochondrial DNA may be an inflammatory trigger, after its release from stress-induced dysfunctional central nervous system mitochondria into peripheral circulation. This evidence supports the potential use of peripheral mitochondrial DNA as a neuroinflammatory biomarker for the diagnosis and treatment of major depressive disorder. Herein, we critically review the neuroinflammation theory in major depressive disorder, providing compelling evidence that mitochondrial DNA release acts as a critical biological substrate, and that it constitutes the neuroinflammatory disease pathway. After its release, mitochondrial DNA can be carried in the exosomes and transported to extracellular spaces in the central nervous system and peripheral circulation. Detectable exosomes render encaged mitochondrial DNA relatively stable. This mitochondrial DNA in peripheral circulation can thus be directly detected in clinical practice. These characteristics illustrate the potential for mitochondrial DNA to serve as an innovative clinical biomarker and molecular treatment target for major depressive disorder. This review also highlights the future potential value of clinical applications combining mitochondrial DNA with a panel of other biomarkers, to improve diagnostic precision in major depressive disorder.

Vulnerable brain regions in adolescent major depressive disorder:A resting-state functional magnetic resonance imaging activation likelihood estimation meta-analysis

BACKGROUND Adolescent major depressive disorder(MDD)is a significant mental health concern that often leads to recurrent depression in adulthood.Resting-state functional magnetic resonance imaging(rs-fMRI)offers unique insights into the neural mechanisms underlying this condition.However,despite previous research,the specific vulnerable brain regions affected in adolescent MDD patients have not been fully elucidated.AIM To identify consistent vulnerable brain regions in adolescent MDD patients using rs-fMRI and activation likelihood estimation(ALE)meta-analysis.METHODS We performed a comprehensive literature search through July 12,2023,for studies investigating brain functional changes in adolescent MDD patients.We utilized regional homogeneity(ReHo),amplitude of low-frequency fluctuations(ALFF)and fractional ALFF(fALFF)analyses.We compared the regions of aberrant spontaneous neural activity in adolescents with MDD vs healthy controls(HCs)using ALE.RESULTS Ten studies(369 adolescent MDD patients and 313 HCs)were included.Combining the ReHo and ALFF/fALFF data,the results revealed that the activity in the right cuneus and left precuneus was lower in the adolescent MDD patients than in the HCs(voxel size:648 mm3,P<0.05),and no brain region exhibited increased activity.Based on the ALFF data,we found decreased activity in the right cuneus and left precuneus in adolescent MDD patients(voxel size:736 mm3,P<0.05),with no regions exhibiting increased activity.CONCLUSION Through ALE meta-analysis,we consistently identified the right cuneus and left precuneus as vulnerable brain regions in adolescent MDD patients,increasing our understanding of the neuropathology of affected adolescents.

Death-associated protein kinase 1 is associated with cognitive dysfunction in major depressive disorder

We previously showed that death-associated protein kinase 1(DAPK1)expression is increased in hippocampal tissue in a mouse model of major depressive disorde and is related to cognitive dysfunction in Alzheimer's disease.In addition,depression is a risk factor for developing Alzheimer's disease,as well as an early clinical manifestation of Alzheimer's disease.Meanwhile,cognitive dysfunction is a distinctive feature of major depressive disorder.Therefore,DAPK1 may be related to cognitive dysfunction in major depressive disorder.In this study,we established a mouse model of major depressive disorder by housing mice individually and exposing them to chronic,mild,unpredictable stressors.We found that DAPK1 and tau protein levels were increased in the hippocampal CA3 area,and tau was hyperphosphorylated at Thr231,Ser262,and Ser396 in these mice.Furthermore,DAPK1 shifted from axonal expression to overexpression on the cell membrane.Exercise and treatment with the antidepressant drug citalopram decreased DAPK1 expression and tau protein phosphorylation in hippocampal tissue and improved both depressive symptoms and cognitive dysfunction.These results indicate that DAPK1 may be a potential reason and therapeutic target of cognitive dysfunction in major depressive disorder.

Major depressive disorder is correlated with the mitochondrial ND1 T3394C mutation in two Han Chinese families:Two case reports

BACKGROUND Major depressive disorder(MDD)is the most frequent reason of disabled people in the world,as reported by the World Health Organization.However,the diagnosis of MDD is mainly based on clinical symptoms.CASE SUMMARY The clinical,genetic,and molecular characteristics of two Chinese families with MDD are described in this study.There were variable ages of onset and severity in depression among the families.Both Chinese families had a very low prevalence of MDD.The mitochondrial genomes of these pedigrees were sequenced and indicated a homoplasmic T3394C(Y30H)mutation,with the polymorphism located at a highly conserved tyrosine at position 30 of ND1.The analysis also revealed unique sets of mitochondrial DNA(mtDNA)polymorphisms originating from haplogroups M9a3 and M9a.CONCLUSION This finding of the T3394C mutation in two unrelated depressed patients provides strong evidence that this mutation may have a part in the etiology of MDD.However,In these two Chinese families having the T3394C mutation,no functional mt DNA mutation was observed.Therefore,T3394C mutations are related with MDD,and the phenotypic manifestation of these mutations may be affected by changes in nuclear genes or environmental factors.

Identification and characterization of noncoding RNAs-associated competing endogenous RNA networks in major depressive disorder

BACKGROUND Major depressive disorder(MDD)is a common and serious mental illness.Many novel genes in MDD have been characterized by high-throughput methods such as microarrays or sequencing.Recently,noncoding RNAs(ncRNAs)were suggested to be involved in the complicated environmental-genetic regulatory network of MDD occurrence;however,the interplay among RNA species,including protein-coding RNAs and ncRNAs,in MDD remains unclear.AIM To investigate the RNA expression datasets downloaded from a public database and construct a network based on differentially expressed long noncoding RNA(lncRNAs),microRNAs(miRNAs),and mRNAs between MDD and controls.METHODS Gene expression data were searched in NCBI Gene Expression Omnibus using the search term“major depressive disorder.”Six array datasets from humans were related to the search term:GSE19738,GSE32280,GSE38206,GSE52790,GSE76826,and GSE81152.These datasets were processed for initial assessment and subjected to quality control and differential expression analysis.Differentially expressed lncRNAs,miRNAs,and mRNAs were determined,Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed,and protein-protein interaction network was generated.The results were analyzed for their association with MDD.RESULTS After analysis,3 miRNAs,12 lncRNAs,and 33 mRNAs were identified in the competing endogenous RNA network.Two of these miRNAs were earlier shown to be involved in psychiatric disorders,and differentially expressed mRNAs were found to be highly enriched in pathways related to neurogenesis and neuroplasticity as per Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses.The expression of hub gene fatty acid 2-hydroxylase was enriched,and the encoded protein was found to be involved in myelin formation,indicating that neurological development and signal transduction are involved in MDD pathogenesis.CONCLUSION The present study presents candidate nc RNAs involved in the neurogenesis and neuroplasticity pathways related to MDD.

Kynurenine pathway of tryptophan metabolism in pathophysiology and therapy of major depressive disorder

Serotonin deficiency in major depressive disorder(MDD)has formed the basis of antidepressant drug development and was originally attributed to induction of the major tryptophan(Trp)-degrading enzyme,liver Trp 2,3-dioxygenase(TDO),by cortisol,leading to decreased Trp availability to the brain for serotonin synthesis.Subsequently,the serotonin deficiency was proposed to involve induction of the extrahepatic Trp-degrading enzyme indoleamine 2,3-dioxygenase(IDO)by proinflammatory cytokines,with inflammation being the underlying cause.Recent evidence,however,challenges this latter concept,as not all MDD patients are immune-activated and,when present,inflammation is mild and/or transient.A wide range of antidepressant drugs inhibit the activity of liver TDO and bind specifically to the enzyme,but not to IDO.IDO induction is not a major event in MDD,but,when it occurs,its metabolic consequences may be masked and overridden by upregulation of kynurenine monooxygenase(KMO),the gateway to production of modulators of immune and neuronal functions.KMO appears to be activated in MDD by certain proinflammatory cytokines and antidepressants with anti-inflammatory properties may block this activation.We demonstrate the ability of the antidepressant ketamine to dock(bind)to KMO.The pathophysiology of MDD may be underpinned by both the serotonin deficiency and glutamatergic activation mediated respectively by TDO induction and N-methyl-D-aspartate receptor activation.Inhibition of TDO and KMO should be the focus of MDD pharmacotherapy.

Mechanism of Zuojin Pill in the treatment of anxiety disorder and Major depressive disorder based on network pharmacology and molecular docking validation

Background:Zuojin Pill(ZJP)is a classic Chinese herbal prescription with good efficacy in the treatment of Anxiety disorder(AD)and Major depressive disorder(MDD).Nevertheless,the potential mechanisms of ZJP remain unclear.Based on network pharmacology and molecular docking methods,this study aims to elucidate the possible mechanism of ZJP in the treatment of AD and MDD.Methods:The components and targets of Rhizoma Coptidis and Fructus Evodiae were collected from TCMSP,ETCM,HERB,SWISSADME and STITCH databases.The disease targets related to MDD and AD were collected from DISGENET,GENECARDS and OMIM databases.Protein-protein interaction network was constructed by STRING database,GO and KEGG enrichment analysis was performed by METASCAPE database,and“drugs-components-targets network”was constructed by Cytoscape software.Molecular docking verification was performed by Sailvina2.0 software.Results:ZJP may act on AKT1,IL6,TNF and other targets through caffeine,isorhamnetin,berberine and other components,regulating the Inflammatory mediator regulation of TRP channels,Serotonergic synapse,Dopaminergic synapse,PI3K/AKT signaling pathway,and other pathways.The results of molecular docking showed that berberine had the best binding activity with the core target.Conclusion:ZJP can exert anti-anxiety and anti-depression effects through multiple components,multiple targets and multiple pathways.

Meteorological factors, ambient air pollution, and daily hospital admissions for depressive disorder in Harbin: A time-series study

BACKGROUND The literature has discussed the relationship between environmental factors and depressive disorders;however,the results are inconsistent in different studies and regions,as are the interaction effects between environmental factors.We hypo-thesized that meteorological factors and ambient air pollution individually affect and interact to affect depressive disorder morbidity.AIM To investigate the effects of meteorological factors and air pollution on depressive disorders,including their lagged effects and interactions.METHODS The samples were obtained from a class 3 hospital in Harbin,China.Daily hos-pital admission data for depressive disorders from January 1,2015 to December 31,2022 were obtained.Meteorological and air pollution data were also collected during the same period.Generalized additive models with quasi-Poisson regre-ssion were used for time-series modeling to measure the non-linear and delayed effects of environmental factors.We further incorporated each pair of environ-mental factors into a bivariate response surface model to examine the interaction effects on hospital admissions for depressive disorders.RESULTS Data for 2922 d were included in the study,with no missing values.The total number of depressive admissions was 83905.Medium to high correlations existed between environmental factors.Air temperature(AT)and wind speed(WS)significantly affected the number of admissions for depression.An extremely low temperature(-29.0℃)at lag 0 caused a 53%[relative risk(RR)=1.53,95%confidence interval(CI):1.23-1.89]increase in daily hospital admissions relative to the median temperature.Extremely low WSs(0.4 m/s)at lag 7 increased the number of admissions by 58%(RR=1.58,95%CI:1.07-2.31).In contrast,atmospheric pressure and relative humidity had smaller effects.Among the six air pollutants considered in the time-series model,nitrogen dioxide(NO_(2))was the only pollutant that showed significant effects over non-cumulative,cumulative,immediate,and lagged conditions.The cumulative effect of NO_(2) at lag 7 was 0.47%(RR=1.0047,95%CI:1.0024-1.0071).Interaction effects were found between AT and the five air pollutants,atmospheric temperature and the four air pollutants,WS and sulfur dioxide.CONCLUSION Meteorological factors and the air pollutant NO_(2) affect daily hospital admissions for depressive disorders,and interactions exist between meteorological factors and ambient air pollution.

Saffron (Crocus sativus L.) and major depressive disorder:a meta-analysis of randomized clinical trials

Due to safety concerns and side effects of many antidepressant medications, herbal psychopharmacology research has increased, and herbal remedies are becoming increasingly popular as alternatives to prescribed medications for the treatment of major depressive disorder （MDD）. Of these, accumulating trials reveal positive effects of the spice saffron （Crocus sativus L.） for the treatment of depression. A comprehensive and statistical review of the clinical trials examining the effects of saffron for treatment of MDD is warranted. OBJECTIVE： The purpose of this study was to conduct a meta-analysis of published randomized controlled trials examining the effects of saffron supplementation on symptoms of depression among participants with MDD. SEARCH STRATEGY： We conducted electronic and non-electronic searches to identify all relevant randomized, double-blind controlled trials. Reference lists of all retrieved articles were searched for relevant studies. INCLUSION CRITERIA： The criteria for study selection included the following： （1） adults （aged 18 and older） with symptoms of depression, （2） randomized controlled trial, （3） effects of saffron supplementation on depressive symptoms examined, and （4） study had either a placebo control or antidepressant comparison group. DATA EXTRACTION AND ANALYSIS： Using random effects modeling procedures, we calculated weighted mean effect sizes separately for the saffron supplementation vs placebo control groups, and for the saffron supplementation vs antidepressant groups. The methodological quality of all studies was assessed using the Jadad score. The computer software Comprehensive Meta- analysis 2 was used to analyze the data. RESULTS： Based on our pre-specified criteria, five randomized controlled trials （n = 2 placebo controlled trials, n = 3 antidepressant controlled trials） were included in our review. A large effect size was found for saffron supplementation vs placebo control in treating depressive symptoms （M ES = 1.62, P 〈 0.001）, revealing that saffron supplementation significantly reduced depression symptoms compared to the placebo control. A null effect size was evidenced between saffron supplementation and the antidepressant groups （M ES = -0.15） indicating that both treatments were similarly effective in reducing depression symptoms. The mean Jadad score was 5 indicating high quality of trials. CONCLUSION： Findings from clinical trials conducted to date indicate that saffron supplementation can improve symptoms of depression in adults with MDD. Larger clinical trials, conducted by research teams outside of Iran, with long-term follow-ups are needed before firm conclusions can be made regarding saffron＇s efficacy and safety for treating depressive symptoms.

Metabolomic and structural brain connectomic evidence validating traditional Chinese medicine diagnostic classification of major depressive disorder

OBJECTIVE Major depressive disorder(MDD) is a highly heterogeneous mental illness.Further classification may help characterize its heterogeneity.The purpose of this study was to examine metabolomic and brain connectomic associations with traditional Chinese medicine(TCM) diagnostic classification of MDD.METHODS Fifty unmedicated depressed patients were classified into Liver Qi Stagnation(LQS,n=30) and Heart and Spleen Deficiency(HSD,n=20) subtypes according to TCM diagnosis.Healthy volunteers(n=28) were included as controls.Gas chromatography-mass spectrometry(GC-MS) and diffusion tensor imaging were used to detect serum and urinary metabolomic profiles and whole-brain white matter connectivity,respectively.RESULTS In metabolomic analysis,28 metabolites were identified for good separations between TCM subtypes and healthy controls in serum and urine samples.While both TCM subtypes had similar profiles in proteinogenic branched-chain amino acids and energy metabolism-related metabolites that were differentiated from healthy controls,the LQS subtype additionally differed from healthy controls in multiple amino acid metabolites that are involved in the biosynthesis of monoamine and amino acid neurotransmitters.Several metabolites are differentially associated with the two subtypes.In connectomic analysis,The LQS subtype showed significant differences in multiple network metrics of the angular gyrus,middle occipital gyrus,calcarine sulcus,and Heschl′ s gyrus when compared to the other two groups.The HSD subtype had markedly greater regional connectivity of the insula,parahippocampal gyrus,and posterior cingulate gyrus than the other two groups,and microstructural abnormalities of the frontal medial orbital gyrus and middle temporal pole.The insular betweenness centrality was strongly inversely correlated with the severity of depression and dichotomized the two subtypes at the optimal cutoff value with acceptable sensitivity and specificity.CONCLUSION The LQS subtype may represent an MDD subpopulation mainly characterized by abnormalities in the biosynthesis of monoamine and amino acid neurotransmitters,closer associations with stress-related pathophysiology,and aberrant connectivity of the audiovisual perception-related temporal-occipital network,whereas the HSD subtype is more closely associated with hyperconnectivity and microstructural abnormalities of the limbicparalimbic network.Certain metabolomic and connectomic variables are potential biomarkers for TCM diagnostic subtypes which is perhaps an alternative classification for depressive disorders.

Abnormal activation of the occipital lobes during emotion picture processing in major depressive disorder patients

A large number of studies have demonstrated that depression patients have cognitive dysfunction. With recently developed brain functional imaging, studies have focused on changes in brain function to investigate cognitive changes. However, there is still controversy regarding abnormalities in brain functions or correlation between cognitive impairment and brain function changes. Thus, it is important to design an emotion-related task for research into brain function changes. We selected positive, neutral, and negative pictures from the International Affective Picture System. Patients with major depressive disorder were asked to judge emotion pictures. In addition, functional MRI was performed to synchronously record behavior data and imaging data. Results showed that the total correct rate for recognizing pictures was lower in patients compared with normal controls. Moreover, the consistency for recognizing pictures for depressed patients was worse than normal controls, and they frequently recognized positive pictures as negative pictures. The consistency for recognizing pictures was negatively correlated with the Hamilton Depression Rating Scale. Functional MRI suggested that the activation of some areas in the frontal lobe, temporal lobe, parietal lobe, limbic lobe, and cerebellum was enhanced, but that the activation of some areas in the frontal lobe, parietal lobe and occipital lobe was weakened while the patients were watching positive and neutral pictures compared with normal controls. The activation of some areas in the frontal lobe temporal lobe, parietal lobe, and limbic lobe was enhanced, but the activation of some areas in the occipital lobe were weakened while the patients were watching the negative pictures compared with normal controls. These findings indicate that patients with major depressive disorder have negative cognitive disorder and extensive brain dysfunction. Thus, reduced activation of the occipital lobe may be an initiating factor for cognitive disorder in depressed patients.

The norepinephrine transporter gene is associated with the retardation symptoms of major depressive disorder in the Han Chinese population

The norepinephrine transporter plays an important role in the pathophysiology and pharmacological treatment of major depressive disorder. Consequently, the norepinephrine transporter gene is an attractive candidate in major depressive disorder research. In the present study, we evaluated the depression symptoms of subjects with major depressive disorder, who were all from the North of China and of Hart Chinese origin, using the Hamilton Depression Scale. We examined the relationship between two single nucleotide polymorphisms in the norepinephrine transporter, rs2242446 and rs5569, and the retardation symptoms of major depressive disorder using quantitative trait testing with the UNPHASED program, rs5569 was associated with depressed mood, and the GG genotype may be a risk factor for this; rs2242446 was associated with work and interest, and the TT genotype may be a risk factor for loss of interest. Our findings suggest that rs2242446 and rs5569 in the norepinephrine transporter gene are associated with the retardation symptoms of depression in the Hart Chinese population.

Brain functional changes in facial expression recognition in patients with major depressive disorder before and after antidepressant treatment A functional magnetic resonance imaging study

Functional magnetic resonance imaging was used during emotion recognition to identify changes in functional brain activation in 21 first-episode, treatment-naive major depressive disorder patients before and after antidepressant treatment. Following escitalopram oxalate treatment, patients exhibited decreased activation in bilateral precentral gyrus, bilateral middle frontal gyrus, left middle temporal gyrus, bilateral postcentral gyrus, left cingulate and right parahippocampal gyrus, and increased activation in right superior frontal gyrus, bilateral superior parietal Iobule and left occipital gyrus during sad facial expression recognition. After antidepressant treatment, patients also exhibited decreased activation in the bilateral middle frontal gyrus, bilateral cingulate and right parahippocampal gyrus, and increased activation in the right inferior frontal gyrus, left fusiform gyrus and right precuneus during happy facial expression recognition. Our experimental findings indicate that the limbic-cortical network might be a key target region for antidepressant treatment in major depressive disorder.

Evaluation Efficacy and Safety of Vortioxetine 20 mg/d versus Placebo for Treatment Major Depressive Disorder: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Major depressive disorder, a common debilitating illness, is one of the leading causes of disability and disease worldwide. Different drugs for the treatment of patients with major depression can be used. Vortioxetine for the treatment of major depressive disorder was approved by the Food and Drug Administration (FDA) in 2013. This study aimed to evaluation efficacy and safety Vortioxetine 20 mg/d compared placebo in major depressive disorder. To conduct this study, we searched Pub Med, Cochrane library, Scopus, and Central Register of Controlled Trials. This study by including randomized controlled trials (RCTs) that evaluated this study by including randomized controlled trials (RCTs) that evaluated Vortioxetine 20 mg/d in patients with major depressive disorder. Data analysis was conducted by standard mean different ratios (SMD) with 95% confidence intervals (CIs), P values and odds ratios (ORs) for adverse events with 95% confidence intervals (CIs) and P values;heterogeneity testing and sensitivity analysis was also performed in this study. We found that 4 articles met the inclusion criteria and were finally used for this meta-analysis. Results showed statistical significance in the MADRS (Montgomery-&Aringsberg Depression Rating Scale), SMD = -4.75 with 95% CI [-6.84, -2.65] and P value < 0.00001), for Clinical Global Impression Scale-Improvement (CGI-I) SMD was -4.34 with 95% CI [-6.41, -2.27] and P value < 0.00001, and for Sheehan Disability Scale (SDS) SMD was -2.62 with 95% CI [-3.99, -1.25] and P value < 0.00001. The pooled analysis for safety demonstrated for diarrhea OR = 0.92 with 95% CI [0.46, 1.83] , P value = 0.09, for dry mouth OR = 1.74 with 95% CI [1.07, 2.83] , P value = 0.80, for dizziness OR = 1.62 with 95% CI [0.72, 3.66] , P value = 0.05, for fatigue OR = 1.17 with 95% CI [0.34, 4.08], P value = 0.07, for headache OR = 1.28 with 95% CI [0.91, 1.79], P value = 0.60 and for nausea OR = 4.78 with 95% CI [3.43, 6.67], P value = 0.61. Vortioxetine 20 mg/d versus placebo showed a significant difference for nausea and dry mouth, but no significant differences were observed for the four adverse effects. In several studies of the drug Vortioxetine 20 mg/d, the treatment of major depressive illness has been more effective for evaluating the effectiveness of this drug, which must be more clinical studies of sound.

Nurse-led group cognitive behavioral therapy for major depressive disorder among adults in Japan: A preliminary single-group study

Objectives:The prevalence and burden of disease of depression necessitates effective and accessible treatment options worldwide.Since April 2016,Japanese national health insurance has covered nurseadministered cognitive behavioral therapy(CBT)for mood disorders.However,empirical support for nurse-led CBT for depression in Asian countries,especially in Japan,is still lacking.This preliminary study aimed to examine the feasibility and acceptability of nurse-led group CBT for Japanese patients with depression.Methods:In this single-arm study,we evaluated the effects of a 6-week group CBT,led by trained nurses,on patients with major depression.The primary outcome was the Beck Depression Inventory-Ⅱ(BDI-Ⅱ).Assessments were conducted at the beginning and end of the intervention.Results:Of 25 participants screened,23 were eligible for the study(of these,three dropped out during the trial but were included in the analysis).Nurse-led group CBT led to significant improvements in the severity of depression(BDI-Ⅱ,P<0.001).The mean total BDI-Ⅱscore improved from 23.1(SD=7.56)to 12.4(SD=8.57),and the pre-to post-effect size was large(Cohen's d=1.33).After CBT,45%of the participants were judged to be treatment responders,and 34%met the remission criteria.Conclusions:Our preliminary findings indicate that 6 weeks of nurse-led group CBT produced a favorable treatment outcome for individuals with major depression in a Japanese clinical setting.The results of this study might encourage more Asian nurses to provide CBT as a part of their nursing practice.Further controlled trials that address the limitations of this study are required.

Effects of mindfulness-based interventions on depressive symptoms in patients with substance use disorders:a systematic review and meta-analysis

Objective:We examined the effects of mindfulness-based interventions(MBIs)on depressive symptoms in patients with substance use disorders(SUDs)and explored the moderating effects of participant,method,and intervention characteristics.Methods:We systematically searched 8 databases from their inception till November 2021.The inclusion criteria were primary studies evaluating MBIs in patients with SUDs with depression measured as an outcome,those including a control group,and those written in English.We used a random-effects model to compute effect sizes(ESs)using Hedges’g,a forest plot,and Q and I2 statistics as measures of heterogeneity;we also examined moderator analyses.Results:Nineteen studies included 1352 participants(age:38.6±7.0 years).Overall,MBIs showed significantly improved depression(g=0.67,95%confidence interval[CI]:0.29,1.05,I2=89%)compared to controls.With regard to moderators,providing MBIs as an individual plus group intervention had a greater effect(g=2.13)on reducing depressive symptoms than providing MBIs as a group intervention(g=0.64)or an individual intervention only(g=0.33,P=0.034).Using concealed allocation tended to reduce depressive symptoms(g=1.22)as compared to not using concealed allocation(g=0.48,P=0.086).No other quality indicators were demonstrated to have a moderating influence on the value of the ES.Conclusions:MBIs improved depressive symptoms in patients with SUDs.MBIs might be used as an adjunctive or alternative to conventional treatment for depressed patients with SUDs.

Efficacy and Safety of Vortioxetine and Duloxetine 60 mg Compared Placebo for the Treatment of Major Depressive Disorder: A Systematic Review and Meta-Analysis

Background: Major depressive disorder is a serious public health problem affecting the lives of millions in the worldwide and leading causes of disability and disease. This study aimed to evaluate the efficacy and safety of Vortioxetine and Duloxetine 60 mg compared to placebo for the treatment of major depressive disorder. Method: We searched the Cochrane library, Pub Med, CRD, Scopus, and Central Register of Controlled Trials to January 2015. We also searched ClinicalTrials.gov, International depressive disorder Conference and the Anxiety Disorders and Depression Conference. We identified that five randomized clinical trials were ultimately included in a Meta analysis. Data analysis was conducted by Standardized Mean Differences (SMD) for Montgomery-&Aring;sberg Depression Rating Scale (MADRS), and Odds Ratio (OR) for adverse events. The SMD and OR reported by 95% CI. Results: Results showed statistical significance in the MADRS for Vortioxetine (SMD = ﹣3.29;95% CI ﹣4.47 to ﹣2.10;I2 = 99.3%) and for Duloxetine 60 mg (SMD = ﹣6.35;95% CI ﹣8.84, ﹣3.87;I2 = 99.3%). Results showed that the Vortioxetine 2.5, 5, 10, 15, 20 mg and overall compared to placebo showed a significance for Nausea and no significance for diarrhea, dry mouth, dizziness, fatigue and headache. Also results of Duloxetine 60 mg showed a significant effect for dry mouth, dizziness, fatigue and nausea. Conclusion: It is necessary to do more studies so as to better assess and much more powerful than the evidence for the use of this drug in the treatment of depression.

Targeting TrkB–PSD-95 coupling to mitigate neurological disorders

Tropomyosin receptor kinase B(TrkB)signaling plays a pivotal role in dendritic growth and dendritic spine formation to promote learning and memory.The activity-dependent release of brain-derived neurotrophic factor at synapses binds to pre-or postsynaptic TrkB resulting in the strengthening of synapses,reflected by long-term potentiation.Postsynaptically,the association of postsynaptic density protein-95 with TrkB enhances phospholipase Cγ-Ca^(2+)/calmodulin-dependent protein kinaseⅡand phosphatidylinositol 3-kinase-mechanistic target of rapamycin signaling required for long-term potentiation.In this review,we discuss TrkB-postsynaptic density protein-95 coupling as a promising strategy to magnify brain-derived neurotrophic factor signaling towards the development of novel therapeutics for specific neurological disorders.A reduction of TrkB signaling has been observed in neurodegenerative disorders,such as Alzheimer's disease and Huntington's disease,and enhancement of postsynaptic density protein-95 association with TrkB signaling could mitigate the observed deficiency of neuronal connectivity in schizophrenia and depression.Treatment with brain-derived neurotrophic factor is problematic,due to poor pharmacokinetics,low brain penetration,and side effects resulting from activation of the p75 neurotrophin receptor or the truncated TrkB.T1 isoform.Although TrkB agonists and antibodies that activate TrkB are being intensively investigated,they cannot distinguish the multiple human TrkB splicing isoforms or cell type-specific functions.Targeting TrkB–postsynaptic density protein-95 coupling provides an alternative approach to specifically boost TrkB signaling at localized synaptic sites versus global stimulation that risks many adverse side effects.

Levomilnacipran and vortioxetine:Review of new pharmacotherapies for major depressive disorder

Major depressive disorder(MDD) is a common psychiatric disorder with an estimated lifetime prevalence rate in the range of 13% to 16% in the United States population. Patients with MDD often have symptoms such as depressed mood, loss of interest or pleasure in usual activities, changes in eating or sleeping patterns, fatigue, difficulty concentrating and thoughts of suicide. Although many pharmacotherapy treatment options are available for MDD, antidepressants can oftencause adverse effects that could affect adherence to the medication. Additionally, it is estimated that MDD is unremitting in 15% of patients and 35% can have recurrent episodes. Given the high rate of recurrence and the adverse effects associated with existing medications, new treatment options for depression are needed. Both levomilnacipran and vortioxetine are new antidepressants that were approved by the food and drug administration in 2013 for the treatment of MDD in adults. Levomilnacipran is a serotonin norepinephrine reuptake inhibitor that was effective in several short term studies and sustained efficacy and tolerability was demonstrated in a 48-wk extension study. Vortioxetine is a multi-modal antidepressant and it is thought to work via inhibition of the serotonin(5-HT) transporter, 5-HT3 A, 5-HT7 and 5-HT1 D antagonist, a 5-HT1 B partial agonist, and a 5-HT1 A agonist. Vortioxetine was effective in the treatment of MDD in both short-term trials as well as in the prevention of relapse in a 24-36 wk trial. Sustained efficacy and tolerability was demonstrated in several long-term open-label trials. Further studies comparing levomilnacipran and vortioxetine to other currently available antidepressants are needed to establish its place in therapy.

From Signals to Solutions: Exploring Early Detection of Neuropsychiatric and Neurodevelopment Disorders through Biomarkers

In 2013, the percentage of children ranging from 5 to 17 years who reported being diagnosed with autism surged to 1.2% from 0.1% in 1997 [1]. Alongside this increase in the incidence of autism in children, there were findings of a 21% increase in children who displayed behavioral and conduct problems from 2019 to 2020 [2]. Early detection of neuropsychiatric and neurodevelopmental disorders in children is critical for timely intervention and improved long-term outcomes. With early intervention, there is better aptitude to support healthy development and give proper treatment to attain a better quality of life. This paper explores studies aimed at enhancing the early detection of these disorders through the use of biomarkers with the aim of creating a bridge between the worlds of research and clinical practice. The disorders in this paper specifically discussed are Major Depressive Disorder, Bipolar Disorder, and Autism Spectrum Disorder. With this bridge, we can foster collaborations and encourage further advancement in the field of early detection and intervention.