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.

Multimodal abnormalities of brain structures in adolescents and young adults with major depressive disorder:An activation likelihood estimation meta-analysis

BACKGROUND Major depressive disorder(MDD)in adolescents and young adults contributes significantly to global morbidity,with inconsistent findings on brain structural changes from structural magnetic resonance imaging studies.Activation likeli-hood estimation(ALE)offers a method to synthesize these diverse findings and identify consistent brain anomalies.METHODS We performed a comprehensive literature search in PubMed,Web of Science,Embase,and Chinese National Knowledge Infrastructure databases for neuroi-maging studies on MDD among adolescents and young adults published up to November 19,2023.Two independent researchers performed the study selection,quality assessment,and data extraction.The ALE technique was employed to synthesize findings on localized brain function anomalies in MDD patients,which was supplemented by sensitivity analyses.RESULTS Twenty-two studies comprising fourteen diffusion tensor imaging(DTI)studies and eight voxel-based morphome-try(VBM)studies,and involving 451 MDD patients and 465 healthy controls(HCs)for DTI and 664 MDD patients and 946 HCs for VBM,were included.DTI-based ALE demonstrated significant reductions in fractional anisotropy(FA)values in the right caudate head,right insula,and right lentiform nucleus putamen in adolescents and young adults with MDD compared to HCs,with no regions exhibiting increased FA values.VBM-based ALE did not demonstrate significant alterations in gray matter volume.Sensitivity analyses highlighted consistent findings in the right caudate head(11 of 14 analyses),right insula(10 of 14 analyses),and right lentiform nucleus putamen(11 of 14 analyses).CONCLUSION Structural alterations in the right caudate head,right insula,and right lentiform nucleus putamen in young MDD patients may contribute to its recurrent nature,offering insights for targeted therapies.

Resting-state functional magnetic resonance imaging and support vector machines for the diagnosis of major depressive disorder in adolescents

BACKGROUND Research has found that the amygdala plays a significant role in underlying pathology of major depressive disorder(MDD).However,few studies have explored machine learning-assisted diagnostic biomarkers based on amygdala functional connectivity(FC).AIM To investigate the analysis of neuroimaging biomarkers as a streamlined approach for the diagnosis of MDD in adolescents.METHODS Forty-four adolescents diagnosed with MDD and 43 healthy controls were enrolled in the study.Using resting-state functional magnetic resonance imaging,the FC was compared between the adolescents with MDD and the healthy controls,with the bilateral amygdala serving as the seed point,followed by statistical analysis of the results.The support vector machine(SVM)method was then applied to classify functional connections in various brain regions and to evaluate the neurophysiological characteristics associated with MDD.RESULTS Compared to the controls and using the bilateral amygdala as the region of interest,patients with MDD showed significantly lower FC values in the left inferior temporal gyrus,bilateral calcarine,right lingual gyrus,and left superior occipital gyrus.However,there was an increase in the FC value in Vermis-10.The SVM analysis revealed that the reduction in the FC value in the right lingual gyrus could effectively differentiate patients with MDD from healthy controls,achieving a diagnostic accuracy of 83.91%,sensitivity of 79.55%,specificity of 88.37%,and an area under the curve of 67.65%.CONCLUSION The results showed that an abnormal FC value in the right lingual gyrus was effective as a neuroimaging biomarker to distinguish patients with MDD from healthy controls.

Sleep disturbances and psychomotor retardation in the prediction of cognitive impairments in patients with major depressive disorder

BACKGROUND Symptoms of depression and comorbid anxiety are known risk factors for cognitive impairment in major depressive disorder(MDD).Understanding their relationships is crucial for developing targeted interventions to mitigate cognitive impairments in MDD patients.We expect that the severity of sleep disturbances and other depressive symptoms will be positively correlated with the degree of cognitive impairments.We also hypothesize that anxiety symptoms,especially psychic anxiety,is a key factor in predicting cognitive performance in MDD patients and may indirectly contribute to cognitive impairment by affecting sleep disturbances and other potential factors.AIM To determine which dimension of the depressive and anxiety symptoms predicts cognitive impairment during a depressive episode.METHODS A comprehensive neurocognitive test battery assessed executive function,attention,processing speed,and memory in 162 medication-free MDD patients and 142 matched healthy controls.The 24-item Hamilton Depression Rating Scale was used to assess depressive symptoms,and the 14-item Hamilton Anxiety Scale was used to assess anxiety symptoms.Linear regression analyses and mediation analyses were conducted to evaluate the impact of depressive and anxiety symptoms,as well as their interactions,on cognitive impairments.RESULTS Among the depressive symptoms,sleep disturbances were associated with poorer executive function(P=0.004),lower processing speed(P=0.047),and memory impairments(P<0.001),and psychomotor retardation(PR)was associated with lower processing speed in patients with MDD(P=0.019).Notably,PR was found to mediate the impact of sleep disturbances on the processing speed.Regarding anxiety symptoms,psychic anxiety,rather than somatic anxiety,was associated with cognitive impairments in all aspects.Sleep disturbances mediated the effect of psychic anxiety on executive function[β=-0.013,BC CI(-0.027,-0.001)]and memory[β=-0.149,BC CI(-0.237,-0.063)],while PR mediated its effect on processing speed(β=-0.023,BC CI(-0.045,-0.004)].CONCLUSION Sleep disturbances may be a key predictor of poorer executive function,lower processing speed,and memory loss,while PR is crucial for lower processing speed during a depressive episode.Psychic anxiety contributes to all aspects of cognitive impairments,mediated by sleep disturbances and PR.

Major depressive disorder is associated with mitochondrial ND6 T14502C mutation in two Han Chinese families

BACKGROUND Globally,the World Health Organization ranks major depressive disorder(MDD)as the leading cause of disability.However,MDD molecular etiology is still poorly understood.AIM To explore the possible association between mitochondrial ND6 T14502C mutation and MDD.METHODS Clinical data were collected from two pedigrees,and detailed mitochondrial genomes were obtained for the two proband members.The assessment of the resulting variants included an evaluation of their evolutionary conservation,allelic frequencies,as well as their structural and functional consequences.Detailed mitochondrial whole genome analysis,phylogenetic,and haplotype analysis were performed on the probands.RESULTS Herein,we reported the clinical,genetic,and molecular profiling of two Chinese families afflicted with MDD.These Chinese families exhibited not only a range of onset and severity ages in their depression but also extremely low penetrances to MDD.Sequence analyses of mitochondrial genomes from these pedigrees have resulted in the identification of a homoplasmic T14502C(I58V)mutation.The polymorphism is located at a highly conserved isoleucine at position 58 of ND6 and distinct mitochondrial DNA(mtDNA)polymorphisms originating from haplogroups M10 and H2.CONCLUSION Identifying the T14502C mutation in two individuals with no genetic relation who exhibit symptoms of depression provides compelling evidence that this mutation may be implicated in MDD development.Nonetheless,the two Chinese pedigrees that carried the T14502C mutation did not exhibit any functionally significant mutations in their mtDNA.Therefore,the phenotypic expression of the T14502C mutation related to MDD may be influenced by the nuclear modifier gene(s)or environmental factors.

Repetitive transcranial magnetic stimulation enhanced by neuronavigation in the treatment of depressive disorder and schizophrenia

This editorial assesses the advancements in neuronavigation enhanced repetitive transcranial magnetic stimulation for depressive disorder and schizophrenia treatment.Conventional repetitive transcranial magnetic stimulation faces challenges due to the intricacies of brain anatomy and patient variability.Neuronavigation offers innovative solutions by integrating neuroimaging with three-dimensional localization to pinpoint brain regions and refine therapeutic targeting.This systematic review of recent literature underscores the enhanced efficacy of neuronavigation in improving treatment outcomes for these disorders.This editorial highlights the pivotal role of neuronavigation in advancing psychiatric care.

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.

Association between 5-HTR1A gene C-1019G polymorphism and antidepressant response in patients with major depressive disorder:A meta-analysis

BACKGROUND Major depressive disorder(MDD)is a substantial global health concern,and its treatment is complicated by the variability in individual response to antide-pressants.AIM To consolidate research and clarify the impact of genetic variation on MDD treatment outcomes.METHODS Adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines,a systematic search across PubMed,EMBASE,Web of Science,and the Cochrane Library was conducted without date restrictions,utilizing key terms related to MDD,serotonin 1A receptor polymorphism(5-HTR1A),C-1019G polymorphism,and antidepressant response.Studies meeting inclusion criteria were thoroughly screened,and quality assessed using the Newcastle-Ottawa Scale.Statistical analyses,includingχ2 and I²values,were used to evaluate heterogeneity and fixed-effect or random-effect models were applied accordingly.RESULTS The initial search yielded 1216 articles,with 11 studies meeting criteria for inclusion.Analysis of various genetic models showed no significant association between the 5-HTR1A C-1019G polymorphism and antidepressant efficacy.The heterogeneity was low to moderate,and no publication bias was detected through funnel plot symmetry and Egger's and Begg's tests.CONCLUSION This meta-analysis does not support a significant association between the 5-HTR1A C-1019G polymorphism and the efficacy of antidepressant treatment in MDD.The findings call for further research with larger cohorts to substantiate these results and enhance the understanding of antidepressant pharmacogenetics.

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.

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.

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.

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.

Association between estrogen receptor β gene Rsa1 polymorphism and depressive disorder in peri-menopausal and menopausal women

Objective: To investigate estrogen receptor β (ERβ) gene Rsa1 polymorphism and concentration of estrogen, FSH and LH in serum in peri-menopausal and menopausal women with depressive disorder. Methods: Seventy-four peri-menopausal and menopausal women with depressive disorder met ICD-10 and CCMD-3 assessment criteria for depressive disorder were recruited. ERβ gene Rsa1 polymorphism was analyzed with PCR-RFLP. Serum levels of estrogen, FSH and LH were measured by magnetism-ELISA. Results: The respective frequency of ERβ gene Rsa1 polymorphism was no significant difference between women with depressive disorder and the healthy women (χ 2=1.106,P>0.05). The serum level of estrogen was lower in women with depressive disorder than in the healthy women (P<0.05). No difference was found for FSH and LH between two groups. Conclusion: ERβ gene Rsa1 polymorphism may be not associated with depressive disorder in the peri-menopausal and menopausal women. The serum level of estrogen is associated with depressive disorder in the peri-menopausal and menopausal women.

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.

Predicting South Korea adolescents vulnerable to depressive disorder using Bayesian nomogram:A community-based crosssectional study

BACKGROUND Although South Korea has developed and carried out evidence-based interventions and prevention programs to prevent depressive disorder in adolescents,the number of adolescents with depressive disorder has increased every year for the past 10 years.AIM To develop a nomogram based on a naïve Bayesian algorithm by using epidemiological data on adolescents in South Korea and present baseline data for screening depressive disorder in adolescents.METHODS Epidemiological data from 2438 subjects who completed a brief symptom inventory questionnaire were used to develop a model based on a Bayesian nomogram for predicting depressive disorder in adolescents.RESULTS Physical symptoms,aggression,social withdrawal,attention,satisfaction with school life,mean sleeping hours,and conversation time with parents were influential factors on depressive disorder in adolescents.Among them,physical symptoms were the most influential.CONCLUSION Active intervention by periodically checking the emotional state of adolescents and offering individual counseling and in-depth psychological examinations when necessary are required to mitigate depressive disorder in adolescents.

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.

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.

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.

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.