Revealing the metabonomic variation of EC using 1H-NMR spectroscopy and its association with the clinicopathological characteristics

In this study, (1)H NMR-based metabonomics has been applied to investigate esophageal cancer metabolic signatures in plasma and urine, purpose of assessing the diagnostic potential of this approach and gaining novel insights into esophageal cancer metabolism and systemic effects. Plasma and urine samples from esophageal cancer patients (n = 108) and a control healthy group (n = 40) were analyzed by Nuclear Magnetic Resonance (NMR) spectroscopy (600 MHz), and their spectral profiles subjected to Orthogonal Projections to Latent Structures (OPLS-DA) for multivariate statistics. Potential metabolic biomarkers were identified using data base comparisons used for examining the significance of metabolites. Compared to healthy controls, esophageal cancer plasma had higher levels of dimethylamine, α-glucose, β-glucose, citric acid, together with lower levels of Leucine, alanine, isoleucine, valine, glycoprotein, lactate, acetone, acetate, choline, isobutyrate, unsaturated lipid, VLDL, LDL, 1-methylhistidine; Compared to healthy controls, esophageal cancer urine had higher levels of Mannitol, glutamate, γ-propalanine, phenylalanine, acetate, allantoin, pyruvate, tyrosine, β-glucose and guinolinate, together with lower levels of N-acetylcysteine, valine, dihydrothymine, hippurate, methylguanidine, 1-methylnicotin- amide and Citric acid; Very good discrimination between cancer and control groups was achieved by multivariate modeling of plasma and urinary profiles. (1)H NMR-based metabolite profiling analysis was shown to be an effective approach to differentiating between patients with EC and healthy subjects. Good sensitivity and selectivity were shown by using the metabolite markers discovered to predict the classification of samples from the healthy control group and the patients with the disease. Plasma and urine metabolic profiling may have potential for early diagnosis of EC and may enhance our understanding of its mechanisms.     

Peripheral metabolic abnormalities of lipids and amino acids implicated in increased risk of suicidal behavior in major depressive disorder

Suicide is the most serious consequence of major depressive disorder (MDD), yet a vast majority of MDD patients never attempt nor commit suicide. This discrepancy suggests a predisposition to suicidal behavior independent of MDD. However, the molecular basis of this predisposition remains largely unknown, hampering development of specific and targeted treatment of MDD patients at risk for suicide. A proton nuclear magnetic resonance (¹H NMR)-based metabonomic approach was used to capture metabolic perturbations related to suicide predisposition in the context of MDD. ¹H NMR spectra of plasma sampled from drug-naïve depressed suicide attempters (n = 21), non-attempters (n = 35), and healthy controls (n = 35) were recorded and analyzed through a multivariate statistical approach. Multivariate statistical analysis demonstrated that the depressed suicide attempter group was significantly distinguishable from the depressed non-attempter group and controls group. Several key metabolites, including lipids (low-density lipoprotein, very low-density lipoprotein, cholesterol and unsaturated lipid), lipid metabolism-related molecules (glucose, pyruvate and lactate) and amino acids (alanine, glycine and taurine) responsible for discriminating depressed suicide attempters from the nonattempters and controls were identified. This study is the first to indicate that peripheral perturbations in lipid and amino acid metabolism may be implicated in the predisposition to suicide in MDD patients.     

Identification and Validation of Urinary Metabolite Biomarkers for Major Depressive Disorder

Major depressive disorder (MDD) is a widespread and debilitating mental disorder. However, there are no biomarkers available to aid in the diagnosis of this disorder. In this study, a nuclear magnetic resonance spectroscopy–based metabonomic approach was employed to profile urine samples from 82 first-episode drug-naïve depressed subjects and 82 healthy controls (the training set) in order to identify urinary metabolite biomarkers for MDD. Then, 44 unselected depressed subjects and 52 healthy controls (the test set) were used to independently validate the diagnostic generalizability of these biomarkers. A panel of five urinary metabolite biomarkers—malonate, formate, N-methylnicotinamide, m-hydroxyphenylacetate, and alanine—was identified. This panel was capable of distinguishing depressed subjects from healthy controls with an area under the receiver operating characteristic curve (AUC) of 0.81 in the training set. Moreover, this panel could classify blinded samples from the test set with an AUC of 0.89. These findings demonstrate that this urinary metabolite biomarker panel can aid in the future development of a urine-based diagnostic test for MDD.Major depressive disorder (MDD)¹ is a debilitating mental disorder affecting up to 15% of the general population and accounting for 12.3% of the global burden of disease (1, 2). Currently, the diagnosis of MDD still relies on the subjective identification of symptom clusters rather than empirical laboratory tests. The current diagnostic modality results in a considerable error rate (3), as the clinical presentation of MDD is highly heterogeneous and the current symptom-based method is not capable of adequately characterizing this heterogeneity (4). An approach that can be used to circumvent these limitations is to identify disease biomarkers to support objective diagnostic laboratory tests for MDD.Metabonomics, which can measure the small molecules in given biosamples such as plasma and urine without bias (5), has been extensively used to characterize the metabolic changes of diseases and thus facilitate the identification of novel disease-specific signatures as putative biomarkers (6–10). Nuclear magnetic resonance (NMR) spectroscopy–based metabonomic approaches characterized by sensitive, high-throughput molecular screening have been employed previously in identifying novel biomarkers for a variety of neuropsychiatric disorders, including stroke, bipolar disorder, and schizophrenia (11–13).Specifically with regard to MDD, several animal studies have already characterized the metabolic changes in the blood and urine (14–19). These studies provide valuable clues as to the pathophysiological mechanism of MDD. However, no study has been designed with the aim of diagnosing this disease. Recently, using an NMR-based metabonomic approach, this research group identified a unique plasma metabolic signature that enables the discrimination of MDD from healthy controls with both high sensitivity and specificity (20). These findings motivated further study on urinary diagnostic metabolite biomarkers for MDD, which would be more valuable from a clinical applicability standpoint, as urine can be more non-invasively collected. Moreover, previous studies have also demonstrated the feasibility of identifying diagnostic metabolite biomarkers of psychiatric disorders in the urine. For example, using an NMR-based metabonomics approach, Yap et al. (21) identified a unique urinary metabolite signature that clearly discriminated autism patients from healthy controls. As systemic metabolic disturbances have been observed in the urine of a depressed animal model, it is likely that diagnostic metabolite markers for MDD can be detected in human urine.Therefore, in this study, NMR spectroscopy combined with multivariate pattern recognition techniques were used to profile 82 first-episode drug-naïve MDD subjects and 82 healthy controls (the training set) in order to identify potential metabolite biomarkers for MDD. Furthermore, 44 unselected MDD subjects and 52 healthy controls (the test set) were employed to independently validate the diagnostic performance of these urinary metabolite biomarkers.     

Posttraumatic Stress Disorder Increases Sensitivity to Long Term Losses among Patients with Major Depressive Disorder

Background

Decisions under risk and with outcomes that are delayed in time are ubiquitous in real life and can have a significant impact on the health and wealth of the decision-maker. Despite its potential relevance for real-world choices, the degree of aberrant risky and intertemporal decision-making in patients suffering from major depressive disorder (MDD) and posttraumatic stress disorder (PTSD) has received little attention to date.

Method

We used a case-control design to compare decision-making in healthy control subjects (N=16) versus untreated depressed subjects in a current major depressive episode (N=20). In order to examine how major depressive disorder (MDD) may impact decision-making, subjects made decisions over (1) risky outcomes and (2) delayed outcomes in the domain of gains and losses using choice paradigms from neuroeconomics. In a pre-planned analysis, depressed subjects were subdivided into those with primary PTSD along with comorbid MDD (MDD+PTSD) versus those with primary MDD without PTSD (MDD-only). Choice behavior was modeled via a standard econometric model of intertemporal choice, a quasi-hyperbolic temporal discounting function, which was estimated for each subject group separately.

Results

Under conditions of potential gain, depressed subjects demonstrated greater discounting for gains across all time frames compared to controls. In the realm of losses, both subgroups of depressed subjects discounted more steeply than controls for short time frames. However, for delayed losses ranging from >1-10 years, MDD+PTSD subjects showed shallower discounting rates relative to MDD-only subjects, who continued to discount future losses steeply. Risk attitudes did not contribute to differences in intertemporal choice.

Conclusions

Depressed patients make choices that minimize current pain and maximize current reward, despite severe later consequences or lost opportunities. Anxiety associated with PTSD may serve as a partially protective factor in decision-making about long-term potential losses compared to MDD patients without PTSD.     

Autistic-Like Traits in Adult Patients with Mood Disorders and Schizophrenia

Autism spectrum disorder often co-occurs with other psychiatric disorders. Although a high prevalence of autistic-like traits/symptoms has been identified in the pediatric psychiatric population of normal intelligence, there are no reports from adult psychiatric population. This study examined whether there is a greater prevalence of autistic-like traits/symptoms in patients with adult-onset psychiatric disorders such as major depressive disorder (MDD), bipolar disorder, or schizophrenia, and whether such an association is independent of symptom severity. The subjects were 290 adults of normal intelligence between 25 and 59 years of age (MDD, n=125; bipolar disorder, n=56; schizophrenia, n=44; healthy controls, n=65). Autistic-like traits/symptoms were measured using the Social Responsiveness Scale for Adults. Symptom severity was measured using the Positive and Negative Symptoms Scale, the Hamilton Depression Rating Scale, and/or the Young Mania Rating Scale. Almost half of the clinical subjects, except those with remitted MDD, exhibited autistic-like traits/symptoms at levels typical for sub-threshold or threshold autism spectrum disorder. Furthermore, the proportion of psychiatric patients that demonstrated high autistic-like traits/symptoms was significantly greater than that of healthy controls, and not different between that of remitted or unremitted subjects with bipolar disorder or schizophrenia. On the other hand, remitted subjects with MDD did not differ from healthy controls with regard to the prevalence or degree of high autistic-like traits/symptoms. A substantial proportion of adults with bipolar disorder and schizophrenia showed high autistic-like traits/symptoms independent of symptom severity, suggesting a shared pathophysiology among autism spectrum disorder and these psychiatric disorders. Conversely, autistic-like traits among subjects with MDD were associated with the depressive symptom severity. These findings suggest the importance of evaluating autistic-like traits/symptoms underlying adult-onset psychiatric disorders for the best-suited treatment. Further studies with a prospective design and larger samples are needed.     

基于内在功能连接推定抑郁症脑网络效率的改变

本文研究了在保留最大化内在功能连接条件下抑郁症患者脑网络效率的改变,并探索了改变的拓扑效率和抑郁症病理学之间的关系.为此,我们收集了20例抑郁症患者和20例在年龄、性别和教育水平相匹配的健康被试的静息态功能磁共振图像数据.图论分析显示,与健康对照组比较,抑郁症患者的节点效率减少在左海马旁回、右杏仁核,左颞横回和左颞极(颞中回)减少.减少的节点效率表明,在抑郁症患者脑网络中这些区域传送信息到其他区域的能力减弱.此外,发现局部效率降低在左内侧额上回、左眶部额上回、右回直肌、左杏仁核、右顶上回、左丘脑和左颞极(颞中回).并且发现左内侧额上回、左杏仁核、左丘脑与PHQ-9得分呈负相关.降低的局部效率表明抑郁症患者脑网络中这些区域的局部网络信息传送能力受到抑制.这些结果进一步确认在抑郁症患者中涉及情感信息处理的前额-丘脑-边缘区域被破坏.我们的发现为抑郁症病人的辅助诊断提供了新的潜在生物学标记物.     

Association of major depression and binge eating disorder with weight loss in a clinical setting

Objective: Obesity has been linked to both major depressive disorder (MDD) and binge eating disorder (BED) in clinical and epidemiological studies. The present study compared weight loss among patients with and without MDD and BED who participated in a hospital‐based weight loss program modeled after the Diabetes Prevention Program. Research Methods and Procedures: Of 131 obese patients who enrolled in treatment, 17% were diagnosed with MDD only, 13% were diagnosed with BED only, 17% were diagnosed with both MDD and BED, and 53% lacked either diagnosis in a pretreatment clinical interview. Results: After treatment, patients with MDD only attained 63% of the weight loss that non‐depressed patients attained. Patients with BED only attained 55% of the weight loss that non‐binge eaters attained. The effect of MDD on weight loss was not accounted for by the presence of BED or vice versa. Only 27% of patients with both MDD and BED achieved clinically significant weight loss compared with 67% of patients who had neither disorder. Results were not significantly altered when gender, age, and diabetes status were adjusted. Conclusion: Both MDD and BED were prevalent among this obese clinical population, and each disorder was independently associated with worse outcomes. Research is needed to investigate how to increase the efficacy of behavioral weight loss programs for individuals with MDD and/or BED.     

The effect of mood phases on balance control in bipolar disorder

The aim of this study was to investigate balance control during gait and sit-to-walk in individuals with bipolar disorder and healthy controls by examining the inclination angles between the whole-body center-of-mass (COM) and ankle in the sagittal plane. Twenty-one individuals with bipolar disorder in the euthymic (i.e., asymptomatic; n = 11) and depressed (n = 10) phases and 7 healthy controls (ages between 18 and 45) performed gait and sit-to-walk at self-selected comfortable speed. Mood phases for individuals with bipolar disorder were measured using the Patient Health Questionnaire and Altman Self-Rating Mania Scale. We collected motion data using a 16-camera motion capture technology. We found smaller COM-ankle inclination angles at seat-off during sit-to-walk for the bipolar-depressed group compared to the bipolar-euthymic and healthy groups, indicating poorly controlled balance for the bipolar-depressed group in sit-to-walk. However, we found larger COM-ankle inclination angles at beginning of single stance phase of gait for the bipolar-euthymic group compared to the healthy group, indicating well controlled balance for the bipolar-euthymic group in gait. Our results suggest an association between the depressed phase and balance impairment during daily movements in relatively young adults (ages ≤ 45 years). Our results also suggest that the depressed phase may be as detrimental to balance control as the effect of age-related neuromuscular weakness.     

Low salivary cortisol and elevated depressive affect among rural men in Botswana: reliability and validity of laboratory results

Most research on hypothalamic-pituitary-adrenal axis function under aversive conditions has focused on relatively increased acute episodic, or chronic secretions as an operationalization of "stress." Severe or recurrent stress, perhaps in interaction with individual characteristics, results in chronically decreased HPA function among some persons suffering from posttraumatic stress disorder. Little evidence exists to assess the population distribution of chronic low cortisol in different free-ranging human populations, as a manifestation of past trauma or stress. This study reports findings of chronically depressed ambulatory salivary cortisol among rural-dwelling Batswana men (n=30) compared with men living in Gaborone (n=34), the capital of Botswana, based on repeated ambulatory sampling. Out of 914 saliva samples analyzed by radioimmunoassay, 268 (29.3%) samples (41 urban, 227 rural) were below the minimum detectable dose (相似文献   

Increased Soluble Urokinase-Type Plasminogen Activator Receptor (suPAR) Levels in Plasma of Suicide Attempters

The soluble form of the urokinase receptor, suPAR, has been suggested as a novel biomarker of low-grade inflammation. Activation of the immune system has been proposed to contribute to the development of depression and suicidal behavior. In order to identify depressed and suicidal individuals who could benefit from an anti-inflammatory treatment, a reliable biomarker of low-grade inflammation is vital. This study evaluates plasma suPAR levels as a biomarker of low-grade inflammation in patients with major depressive disorder and in patients who recently attempted suicide. The plasma suPAR and an established biomarker, C reactive protein (CRP) of suicide attempters (n = 54), depressed patients (n = 19) and healthy controls (n = 19) was analyzed with enzyme-linked immunosorbent assays. The biomarker attributes of sensitivity and sensibility were evaluated using ROC curve analysis. Both the depressed patients and suicide attempters had increased plasma suPAR. The levels of suPAR discriminated better between controls and suicide attempters than did CRP. In the future, plasma suPAR might be a superior prognosticator regarding outcome of treatment applying conventional antidepressants in conjunction with anti-inflammatory drugs.     

Social jetlag and depression status: Results obtained from the Netherlands Study of Depression and Anxiety

Social jetlag, the misalignment between the internal clock and the socially required timing of activities, is highly prevalent, especially in people with an evening chronotype and is hypothesized to be related to the link between the evening chronotype and major depressive disorder. Although social jetlag has been linked to depressive symptoms in non-clinical samples, it has never been studied in patients with major depressive disorder (MDD). This study is aimed to study social jetlag in patients with major depressive disorder and healthy controls, and to further examine the link between social jetlag and depressive symptomatology. Patients with a diagnosis of MDD (n = 1084) and healthy controls (n = 385), assessed in a clinical interview, were selected from the Netherlands Study of Depression and Anxiety. Social jetlag was derived from the Munich Chronotype Questionnaire, by calculating the absolute difference between the midsleep on free days and midsleep on work days. Depression severity was measured with the Inventory of Depressive Symptomatology. It was found that patients with MDD did not show more social jetlag compared to healthy controls, neither in a model without medication use (β = 0.06, 95% CI: ?0.03–0.15, p = 0.17) nor in a model where medication use is accounted for. There was no direct association between the amount of social jetlag and depressive symptoms, neither in the full sample, nor in the patient group or the healthy control group. This first study on social jetlag in a clinical sample showed no differences in social jetlag between patients with MDD and healthy controls.     

When does depression become a disorder? Using recurrence rates to evaluate the validity of proposed changes in major depression diagnostic thresholds

High community prevalence estimates of DSM‐defined major depressive disorder (MDD) have led to proposals to raise MDD's diagnostic threshold to more validly distinguish pathology from normal‐range distress. However, such proposals lack empirical validation. We used MDD recurrence rates in the longitudinal 2‐wave Epidemiologic Catchment Area Study to test the predictive validity of three proposals to narrow MDD diagnosis: a) excluding “uncomplicated” episodes (i.e., episodes that last no longer than 2 months and do not include suicidal ideation, psychotic ideation, psychomotor retardation, or feelings of worthlessness); b) excluding mild episodes (i.e., episodes with only five to six symptoms); and c) excluding nonmelancholic episodes. For each proposal, we used lifetime MDD diagnoses at wave 1 to distinguish the group proposed for exclusion, other MDD, and those with no MDD history. We then compared these groups’ 1‐year MDD rates at wave 2. A proposal was considered strongly supported if at wave 2 the excluded group's MDD rate was not only significantly lower than the rate for other MDD but also not significantly greater than the no‐MDD‐history group. Results indicated that all three excluded groups had significantly lower recurrence rates than other MDD (uncomplicated vs. complicated, 3.4% vs. 14.6%; mild vs. severe, 9.6% vs. 20.7%; nonmelancholic vs. melancholic, 10.6% vs. 19.2%, respectively). However, only uncomplicated MDD's recurrence rate was also not significantly greater than the MDD occurrence rate for the no‐MDD‐history group (3.4% vs. 1.7%, respectively). This low recurrence rate resulted from an interaction between uncomplicated duration and symptom criteria. Multiple‐episode uncomplicated MDD did not entail significantly elevated recurrence over single‐episode cases (3.7% vs. 3.0%, respectively). Uncomplicated MDD's general‐distress symptoms, transient duration, and lack of elevated recurrence suggest it may generally represent nonpathologic intense sadness that should be addressed in treatment guidelines and considered for exclusion from MDD diagnosis to increase the validity of the MDD/normal sadness boundary.     

The Potential Biomarker Panels for Identification of Major Depressive Disorder (MDD) Patients with and without Early Life Stress (ELS) by Metabonomic Analysis

Objective

The lack of the disease biomarker to support objective laboratory tests still constitutes a bottleneck in the clinical diagnosis and evaluation of major depressive disorder (MDD) and its subtypes. We used metabonomic techniques to screen the diagnostic biomarker panels from the plasma of MDD patients with and without early life stress (ELS) experience.

Methods

Plasma samples were collected from 25 healthy adults and 46 patients with MDD, including 23 patients with ELS and 23 patients without ELS. Furthermore, gas chromatography/mass spectrometry (GC/MS) coupled with multivariate statistical analysis was used to identify the differences in global plasma metabolites among the 3 groups.

Results

The distinctive metabolic profiles exist either between healthy subjects and MDD patients or between the MDD patients with ELS experience (ELS/MDD patients) and the MDD patients without it (non-ELS/MDD patients), and some diagnostic panels of feature metabolites'' combination have higher predictive potential than the diagnostic panels of differential metabolites.

Conclusions

These findings in this study have high potential of being used as novel laboratory diagnostic tool for MDD patients and it with ELS or not in clinical application.     

Prediction of Depression in Individuals at High Familial Risk of Mood Disorders Using Functional Magnetic Resonance Imaging

Objective

Bipolar disorder is a highly heritable condition. First-degree relatives of affected individuals have a more than a ten-fold increased risk of developing bipolar disorder (BD), and a three-fold risk of developing major depressive disorder (MDD) than the general population. It is unclear however whether differences in brain activation reported in BD and MDD are present before the onset of illness.

Methods

We studied 98 young unaffected individuals at high familial risk of BD and 58 healthy controls using functional Magnetic Resonance Imaging (fMRI) scans and a task involving executive and language processing. Twenty of the high-risk subjects subsequently developed MDD after the baseline fMRI scan.

Results

At baseline the high-risk subjects who later developed MDD demonstrated relatively increased activation in the insula cortex, compared to controls and high risk subjects who remained well. In the healthy controls and high-risk group who remained well, this region demonstrated reduced engagement with increasing task difficulty. The high risk subjects who subsequently developed MDD did not demonstrate this normal disengagement. Activation in this region correlated positively with measures of cyclothymia and neuroticism at baseline, but not with measures of depression.

Conclusions

These results suggest that increased activation of the insula can differentiate individuals at high-risk of bipolar disorder who later develop MDD from healthy controls and those at familial risk who remain well. These findings offer the potential of future risk stratification in individuals at risk of mood disorder for familial reasons.     

Is There a Valence-Specific Pattern in Emotional Conflict in Major Depressive Disorder? An Exploratory Psychological Study

Objective

Patients with major depressive disorder (MDD) clinically exhibit a deficit in positive emotional processing and are often distracted by especially negative emotional stimuli. Such emotional-cognitive interference in turn hampers the cognitive abilities of patients in their ongoing task. While the psychological correlates of such emotional conflict have been well identified in healthy subjects, possible alterations of emotional conflict in depressed patients remain to be investigated. We conducted an exploratory psychological study to investigate emotional conflict in MDD. We also distinguished depression-related stimuli from negative stimuli in order to check whether the depression-related distractors will induce enhanced conflict in MDD.

Methods

A typical word-face Stroop paradigm was adopted. In order to account for valence-specificities in MDD, we included positive and general negative as well as depression-related words in the study.

Results

MDD patients demonstrated a specific pattern of emotional conflict clearly distinguishable from the healthy control group. In MDD, the positive distractor words did not significantly interrupt the processing of the negative target faces, while they did in healthy subjects. On the other hand, the depression-related distractor words induced significant emotional conflict to the positive target faces in MDD patients but not in the healthy control group.

Conclusion

Our findings demonstrated for the first time an altered valence-specific pattern in emotional conflict in MDD patients. The study sheds a novel and specific light on the affective mechanisms underlying the abnormal emotional-cognitive interference in MDD. Such emotional conflict bears important clinical relevance since it may trigger the widespread cognitive dysfunctions frequently observed in MDD. The present findings may have important clinical implications in both prediction and psychotherapy of MDD.     

Mitochondria DNA Change and Oxidative Damage in Clinically Stable Patients with Major Depressive Disorder

BackgroundTo compare alterations of mitochondria DNA (mtDNA) copy number, single nucleotide polymorphisms (SNPs), and oxidative damage of mtDNA in clinically stable patients with major depressive disorder (MDD).MethodsPatients met DSM-IV diagnostic criteria for MDD were recruited from the psychiatric outpatient clinic at Changhua Christian Hospital, Taiwan. They were clinically stable and their medications had not changed for at least the preceding two months. Exclusion criteria were substance-induced psychotic disorder, eating disorder, anxiety disorder or illicit substance abuse. Comparison subjects did not have any major psychiatric disorder and they were medically healthy. Peripheral blood leukocytes were analyzed to compare copy number, SNPs and oxidative damage of mtDNA between the two groups.Results40 MDD patients and 70 comparison subjects were collected. The median age of the subjects was 42 years and 38 years in MDD and comparison groups, respectively. Leukocyte mtDNA copy number of MDD patients was significantly lower than that of the comparison group (p = 0.037). MDD patients had significantly higher mitochondrial oxidative damage than the comparison group (6.44 vs. 3.90, p<0.001). After generalized linear model adjusted for age, sex, smoking, family history, and psychotropic use, mtDNA copy number was still significantly lower in the MDD group (p<0.001). MtDNA oxidative damage was positively correlated with age (p<0.001) and MDD (p<0.001). Antipsychotic use was negatively associated with mtDNA copy number (p = 0.036).LimitationsThe study is cross-sectional with no longitudinal follow up. The cohort is clinically stable and generalizability of our result to other cohort should be considered.ConclusionsOur study suggests that oxidative stress and mitochondria may play a role in the pathophysiology of MDD. More large-scale studies are warranted to assess the interplay between oxidative stress, mitochondria dysfunction and MDD.     

Untargeted Metabolomic Analysis of Human Plasma Indicates Differentially Affected Polyamine and L-Arginine Metabolism in Mild Cognitive Impairment Subjects Converting to Alzheimer’s Disease

This study combined high resolution mass spectrometry (HRMS), advanced chemometrics and pathway enrichment analysis to analyse the blood metabolome of patients attending the memory clinic: cases of mild cognitive impairment (MCI; n = 16), cases of MCI who upon subsequent follow-up developed Alzheimer’s disease (MCI_AD; n = 19), and healthy age-matched controls (Ctrl; n = 37). Plasma was extracted in acetonitrile and applied to an Acquity UPLC HILIC (1.7μm x 2.1 x 100 mm) column coupled to a Xevo G2 QTof mass spectrometer using a previously optimised method. Data comprising 6751 spectral features were used to build an OPLS-DA statistical model capable of accurately distinguishing Ctrl, MCI and MCI_AD. The model accurately distinguished (R2 = 99.1%; Q2 = 97%) those MCI patients who later went on to develop AD. S-plots were used to shortlist ions of interest which were responsible for explaining the maximum amount of variation between patient groups. Metabolite database searching and pathway enrichment analysis indicated disturbances in 22 biochemical pathways, and excitingly it discovered two interlinked areas of metabolism (polyamine metabolism and L-Arginine metabolism) were differentially disrupted in this well-defined clinical cohort. The optimised untargeted HRMS methods described herein not only demonstrate that it is possible to distinguish these pathologies in human blood but also that MCI patients ‘at risk’ from AD could be predicted up to 2 years earlier than conventional clinical diagnosis. Blood-based metabolite profiling of plasma from memory clinic patients is a novel and feasible approach in improving MCI and AD diagnosis and, refining clinical trials through better patient stratification.     

Escitalopram and neuroendocrine response in healthy first-degree relatives to depressed patients--a randomized placebo-controlled trial

Introduction

The mechanisms by which selective serotonin re-uptake inhibitors (SSRI) act in depressed patients remain unknown. The serotonergic neurotransmitter system and the hypothalamic-pituitary-adrenal (HPA) system may interact. The aim of the AGENDA trial was to investigate whether long-term intervention with SSRI versus placebo affects the cortisol response in the dexamethasone corticotropin-releasing hormone (DEX-CRH) test in healthy first-degree relatives to patients with major depressive disorder (MDD).

Methods

Eighty healthy first-degree relatives to patients with MDD were randomized to escitalopram 10 mg versus matching placebo daily for four weeks. The primary outcome measure was the intervention difference in the change of the total area under the curve (CorAUC_total) for plasma cortisol in the DEX-CRH test at entry to after four weeks of intervention.

Results

Change in CorAUC_total showed no statistically significant difference between the escitalopram and the placebo group, p = 0.47. There were large intra- and inter-individual differences in the results of the DEX-CRH test. There was statistically significant negative correlation between the plasma escitalopram concentration and change in CorAUC_total, rho = −0.41, p = 0.01. Post-hoc analyses showed a statistically significant interaction between age and intervention group and change in log CorAUC_total.

Conclusion

The present trial does not support an effect of escitalopram 10 mg daily compared with placebo on the HPA-axis in healthy first-degree relatives to patients with MDD. Increasing levels of escitalopram tended to decrease the HPA-response in the DEX-CRH test and this effect increased with age.

Trial Registration

ClinicalTrials.gov [{"type":"clinical-trial","attrs":{"text":"NCT00386841","term_id":"NCT00386841"}}NCT00386841     

Effectiveness and specificity of a classroom-based group intervention in children and adolescents exposed to war in Lebanon

The purpose of this study was to examine the effectiveness and specificity of a classroom-based psychosocial intervention after war. All students (n=2500) of six villages in Southern Lebanon designated as most heavily exposed to war received a classroom-based intervention delivered by teachers, consisting of cognitive-behavioural and stress inoculation training strategies. A random sample of treated students (n=101) and a matched control group (n=93) were assessed one month post-war and one year later. Mental disorders and psychosocial stressors were assessed using the Diagnostic Interview for Children and Adolescents - Revised with children and parents. War exposure was measured using the War Events Questionnaire. The prevalence of major depressive disorder (MDD), separation anxiety disorder (SAD) and post-traumatic stress disorder (PTSD) was examined pre-war, one month post-war (pre-intervention), and one year post-war. Specificity of treatment was determined by rating teachers’ therapy diaries. The rates of disorders peaked one month post-war and decreased over one year. There was no significant effect of the intervention on the rates of MDD, SAD or PTSD. Post-war MDD, SAD and PTSD were associated with pre-war SAD and PTSD, family violence parameters, financial problems and witnessing war events. These findings have significant policy and public health implications, given current practices of delivering universal interventions immediately post-war.     

Metabolic signatures of lung cancer in biofluids: NMR-based metabonomics of blood plasma

In this work, the variations in the metabolic profile of blood plasma from lung cancer patients and healthy controls were investigated through NMR-based metabonomics, to assess the potential of this approach for lung cancer screening and diagnosis. PLS-DA modeling of CPMG spectra from plasma, subjected to Monte Carlo Cross Validation, allowed cancer patients to be discriminated from controls with sensitivity and specificity levels of about 90%. Relatively lower HDL and higher VLDL + LDL in the patients' plasma, together with increased lactate and pyruvate and decreased levels of glucose, citrate, formate, acetate, several amino acids (alanine, glutamine, histidine, tyrosine, valine), and methanol, could be detected. These changes were found to be present at initial disease stages and could be related to known cancer biochemical hallmarks, such as enhanced glycolysis, glutaminolysis, and gluconeogenesis, together with suppressed Krebs cycle and reduced lipid catabolism, thus supporting the hypothesis of a systemic metabolic signature for lung cancer. Despite the possible confounding influence of age, smoking habits, and other uncontrolled factors, these results indicate that NMR-based metabonomics of blood plasma can be useful as a screening tool to identify suspicious cases for subsequent, more specific radiological tests, thus contributing to improved disease management.