Study of the Serum Copper Levels in Patients with Major Depressive Disorder

Copper may be involved in the pathophysiology of depression. Clinical data on this issue are very limited and not conclusive. The purpose of the study was to determine the copper concentration in the serum of patients with major depressive disorder and to discuss its potential clinical usefulness as a biomarker of the disease. A case–control clinical study included 69 patients with current depressive episode, 45 patients in remission and 50 healthy volunteers. Cu concentration was measured by electrothermal atomic absorption spectrometry (ETAAS). The mean serum copper level in depressed patients was slightly lower (by 11 %; not statistically significant) than in the control group. Furthermore, there was no significant difference in Cu²⁺ concentration between depressive episode and remission, nor between remission and control group. In the remission group were observed significant correlations between copper levels and the average number of relapses over the past years or time of remission. There was no correlation between serum copper and severity of depression, as measured by HDRS and MADRS. The obtained results showed no significant differences between the copper concentration in the blood serum of patients (both with current depressive episode and in remission) and healthy volunteers, as well as the lack of correlations between the copper level in the active stage of the disease and clinical features of the population. Our study is the first conducted on such a large population of patients, so the results may be particularly important and reliable source of knowledge about the potential role of copper in depression.     

Event-Related Potentials in Response to Facial Affect Recognition in Patients with Schizophrenia

Neurophysiology - In the identification of facial expressions related to certain emotions, certain parameters of event-related potentials (ERPs) can be interpreted as the respective indices....     

Poor Clinical Outcomes among Pneumonia Patients with Depressive Disorder

Background

Some studies suggested that psychological stress may be associated with the severity and duration of infectious diseases. In this population-based study, we investigated associations between depressive disorder (DD) and pneumonia outcomes in Taiwan with a large-scale database from the National Health Insurance.

Methods

Our study defined 112,198 patients who were hospitalized with a principal diagnosis of pneumonia. We defined their admission date for treatment of pneumonia as the index date. Subsequently, we selected 2,394 patients with DD within 3 years prior to their index date and 11,970 matched patients without DD. We carried out separate conditional logistic regressions to explore the association of clinical pneumonia treatment outcome (ICU admission, use of mechanical ventilation, acute respiratory failure and in-hospital death) with previously diagnosed DD.

Results

Patients with DD had a significantly higher probability of an intensive care unit admission (18.1% vs. 12.9%; p<0.001), need for mechanical ventilation (21.9% vs. 18.1%; p<0.001) and in-hospital death (10.4% vs. 9.0%; p = 0.025) than patients without DD. The study showed that pneumonia patients with DD were respectively 1.41- (95% CI: 1.25∼1.59, p<0.001), 1.28- (95% CI: 1.14∼1.43, p<0.001), and 1.17- times (95% CI: 1.01∼1.36, p = 0.039) greater odds of being admitted to the ICU, need for mechanical ventilation, and in-hospital death than patients without DD after adjusting for monthly income, urbanization level, geographic region and Charlson Comorbidity Index score.

Conclusions

In conclusion, we found that pneumonia patients with DD were associated with poor treatment outcomes compared to patients without DD.     

Insular and Hippocampal Gray Matter Volume Reductions in Patients with Major Depressive Disorder

Background

Major depressive disorder is a serious psychiatric illness with a highly variable and heterogeneous clinical course. Due to the lack of consistent data from previous studies, the study of morphometric changes in major depressive disorder is still a major point of research requiring additional studies. The aim of the study presented here was to characterize and quantify regional gray matter abnormalities in a large sample of clinically well-characterized patients with major depressive disorder.

Methods

For this study one-hundred thirty two patients with major depressive disorder and 132 age- and gender-matched healthy control participants were included, 35 with their first episode and 97 with recurrent depression. To analyse gray matter abnormalities, voxel-based morphometry (VBM8) was employed on T1 weighted MRI data. We performed whole-brain analyses as well as a region-of-interest approach on the hippocampal formation, anterior cingulate cortex and amygdala, correlating the number of depressive episodes.

Results

Compared to healthy control persons, patients showed a strong gray-matter reduction in the right anterior insula. In addition, region-of-interest analyses revealed significant gray-matter reductions in the hippocampal formation. The observed alterations were more severe in patients with recurrent depressive episodes than in patients with a first episode. The number of depressive episodes was negatively correlated with gray-matter volume in the right hippocampus and right amygdala.

Conclusions

The anterior insula gray matter structure appears to be strongly affected in major depressive disorder and might play an important role in the neurobiology of depression. The hippocampal and amygdala volume loss cumulating with the number of episodes might be explained either by repeated neurotoxic stress or alternatively by higher relapse rates in patients showing hippocampal atrophy.     

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.     

Interhemispheric Functional Connectivity and Its Relationships with Clinical Characteristics in Major Depressive Disorder: A Resting State fMRI Study

Background

Abnormalities in large-scale, structural and functional brain connectivity have been increasingly reported in patients with major depressive disorder (MDD). However, MDD-related alterations in functional interaction between the cerebral hemispheres are still not well understood. Resting state fMRI, which reveals spontaneous neural fluctuations in blood oxygen level dependent signals, provides a means to detect interhemispheric functional coherence. We examined the resting state functional connectivity (RSFC) between the two hemispheres and its relationships with clinical characteristics in MDD patients using a recently proposed measurement named “voxel-mirrored homotopic connectivity (VMHC)”.

Methodology/Principal Findings

We compared the interhemispheric RSFC, computed using the VMHC approach, of seventeen first-episode drug-naive patients with MDD and seventeen healthy controls. Compared to the controls, MDD patients showed significant VMHC decreases in the medial orbitofrontal gyrus, parahippocampal gyrus, fusiform gyrus, and occipital regions including the middle occipital gyrus and cuneus. In MDD patients, a negative correlation was found between VMHC of the fusiform gyrus and illness duration. Moreover, there were several regions whose VMHC showed significant negative correlations with the severity of cognitive disturbance, including the prefrontal regions, such as middle and inferior frontal gyri, and two regions in the cereballar crus.

Conclusions/Significance

These findings suggest that the functional coordination between homotopic brain regions is impaired in MDD patients, thereby providing new evidence supporting the interhemispheric connectivity deficits of MDD. The significant correlations between the VMHC and clinical characteristics in MDD patients suggest potential clinical implication of VMHC measures for MDD. Interhemispheric RSFC may serve as a useful screening method for evaluating MDD where neural connectivity is implicated in the pathophysiology.     

Genetic Association of Butyrylcholinesterase with Major Depressive Disorder

Biochemical Genetics - Major depressive disorder (MDD) is characterized as clinical depression, which primarily affects the mood and behaviour of an individual. In the present study...     

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.     

Identification of Differential MicroRNAs in Cerebrospinal Fluid and Serum of Patients with Major Depressive Disorder

Major depression is a debilitating disease. To date, the development of biomarkers of major depressive disorder (MDD) remains a challenge. Recently, alterations in the expression of microRNAs (miRNAs) from post-mortem brain tissue and peripheral blood have been linked to MDD. The goals of this study were to detect the differential miRNAs in cerebrospinal fluid (CSF) and serum of MDD patients. First, the relative expression levels of 179 miRNAs (relative high levels in serum) were analyzed by miRNA PCR Panel in the CSF of MDD patients. Then, the differentially altered miRNAs from CSF were further assessed by qRT-PCR in the serum of the same patients. Finally, the serum differentially altered miRNAs were further validated by qRT-PCR in the serum of another MDD patients. The CSF-results indicated that 11 miRNAs in MDD patients were significantly higher than these in control subjects, and 5 miRNAs were significantly lower than these in control subjects. The serum-results from the same patients showed that 3 miRNAs (miR-221-3p, miR-34a-5p, and let-7d-3p) of the 11 miRNAs were significantly higher than these in control subjects, and 1 miRNA (miR-451a) of 5 miRNAs was significantly lower than these in control subjects. The up-regulation of miR-221-3p, miR-34a-5p, let-7d-3p and down-regulation of miR-451a was further validated in another 32 MDD patients. ROC analysis showed that the area under curve of let-7d-3p, miR-34a-5p, miR-221-3p and miR-451a was 0.94, 0.98, 0.97 and 0.94, with specificity of 90.48%, 95.24%, 90.48% and 90.48%, and sensitivity of 93.75%, 96.88%, 90.63% and 84.85%, respectively. In addition, target gene prediction found that the altered miRNAs are involved in affecting some important genes and pathway related to MDD. Our results suggested that differentially altered miRNAs in CSF might be involved in MDD, and serum miR-221-3p, miR-34a-5p, let-7d-3p, and miR-451a might be able to serve as biomarkers for MDD.     

Metabolomics in Schizophrenia and Major Depressive Disorder

Defining pathophenotype, a systems level consequence of a disease genotype, together with environmental and stochastic influences, is an arduous task in psychiatry. It is also an appealing goal, given growing need for appreciation of brain disorders biological complexity, aspiration for diagnostic tests development and ambition to identify novel drug targets. Here, we focus on the Schizophrenia and Major Depressive Disorder and highlight recent advances in metabolomics research. As a systems biology tool, metabolomics holds a promise to take part in elucidating interactions between genes and environment, in complex behavioral traits and psychopathology risk translational research.     

The Efficacy of Neurofeedback in Patients with Major Depressive Disorder: An Open Labeled Prospective Study

The purpose of this study was to evaluate the effect of neurofeedback on depressive symptoms and electrophysiological disturbances in patients with major depressive disorder. We recruited participants suffering from depression to evaluate efficacy of left prefrontal beta with alpha/theta training. An 8-week, prospective, open-label study was undertaken. Twenty participants were recruited. The treatment protocol was twice or three times a week training of beta at F3 with alpha/theta at Pz for 8 weeks. When every visit, patients were received beta training for 30 min, and then alpha/theta training for 30 min. Baseline, 4 and 8 week scores of; the Hamilton rating scale for Depression (HAM-D), the Hamilton rating scale for Anxiety (HAM-A), the Beck Depression Inventory (BDI)-II, the Beck Anxiety Inventory (BAI), Clinical global impression-severity (CGI-S), and pre- and post-treatment resting state EEGs were compared. Interhemispheric alpha power asymmetry (A score) was computed for homologous sites F3–F4. Pre- and post-training clinical assessments revealed significant improvements in HAM–D, HAM-A, BDI, and CGI-S scores. Cumulative response rates by HAM-D were 35.0 and 75.0 % at 4 and 8 weeks, respectively, corresponding cumulative remission rates by HAM-D were 15.0 and 55.0 %, respectively. No significant differences were found between pre- and post-treatment A score. Neurofeedback treatment could improve depressive symptoms significantly. In addition, anxiety symptoms and clinical illness severity decreased significantly after neurofeedback treatment. Despite its several limitations, such as, small sample size and lack of a control group, this study suggested neurofeedback has significant effects in patients with major depressive disorder.     

Smoking and Major Depressive Disorder in Chinese Women

Objective

To investigate the risk factors that contribute to smoking in female patients with major depressive disorder (MDD) and the clinical features in depressed smokers.

Methods

We examined the smoking status and clinical features in 6120 Han Chinese women with MDD (DSM-IV) between 30 and 60 years of age across China. Logistic regression was used to determine the association between clinical features of MDD and smoking status and between risk factors for MDD and smoking status.

Results

Among the recurrent MDD patients there were 216(3.6%) current smokers, 117 (2.0%) former smokers and 333(5.6%) lifetime smokers. Lifetime smokers had a slightly more severe illness, characterized by more episodes, longer duration, more comorbid illness (panic and phobias), with more DSM-IV A criteria and reported more symptoms of fatigue and suicidal ideation or attempts than never smokers. Some known risk factors for MDD were also differentially represented among smokers compared to non-smokers. Smokers reported more stressful life events, were more likely to report childhood sexual abuse, had higher levels of neuroticism and an increased rate of familial MDD. Only neuroticism was significantly related to nicotine dependence.

Conclusions

Although depressed women smokers experience more severe illness, smoking rates remain low in MDD patients. Family history of MDD and environmental factors contribute to lifetime smoking in Chinese women, consistent with the hypothesis that the association of smoking and depression may be caused by common underlying factors.     

Influence of the CYP2D6 Isoenzyme in Patients Treated with Venlafaxine for Major Depressive Disorder: Clinical and Economic Consequences

Background

Antidepressant drugs are the mainstay of drug therapy for sustained remission of symptoms. However, the clinical results are not encouraging. This lack of response could be due, among other causes, to factors that alter the metabolism of the antidepressant drug. Objective: to evaluate the impact of concomitant administration of CYP2D6 inhibitors or substrates on the efficacy, tolerability and costs of patients treated with venlafaxine for major depressive disorder in clinical practice.

Methods

We designed an observational study using the medical records of outpatients. Subjects aged ≥18 years who started taking venlafaxine during 2008–2010 were included. Three study groups were considered: no combinations (reference), venlafaxine-substrate, and venlafaxine-inhibitor. The follow-up period was 12 months. The main variables were: demographic data, comorbidity, remission (Hamilton <7), response to treatment, adverse events and costs. The statistical analysis included logistic regression models and ANCOVA, with p values <0.05 considered significant.

Results

A total of 1,115 subjects were recruited. The mean age was 61.7 years and 75.1% were female. Approximately 33.3% (95% CI: 30.5 to 36.1) were receiving some kind of drug combination (venlafaxine-substrate: 23.0%, and venlafaxine-inhibitor: 10.3%). Compared with the venlafaxine-substrate and venlafaxine-inhibitor groups, patients not taking concomitant drugs had a better response to therapy (49.1% vs. 39.9% and 34.3%, p<0.01), greater remission of symptoms (59.9% vs. 50.2% and 43.8%, p<0.001), fewer adverse events (1.9% vs. 7.0% and 6.1%, p<0.05) and a lower mean adjusted cost (€2,881.7 vs. €4,963.3 and €7,389.1, p<0.001), respectively. All cost components showed these differences.

Conclusions

The patients treated with venlafaxine alone showed a better response to anti-depressant treatment, greater remission of symptoms, a lower incidence of adverse events and lower healthcare costs.     

Copy Number Variation in Subjects with Major Depressive Disorder Who Attempted Suicide

Background

Suicide is one of the top ten leading causes of death in North America and represents a major public health burden, partcularly for people with Major Depressive disorder (MD). Many studies have suggested that suicidal behavior runs in families, however, identification of genomic loci that drive this efffect remain to be identified.

Methodology/Principal Findings

Using subjects collected as part of STAR*D, we genotyped 189 subjects with MD with history of a suicide attempt and 1073 subjects with Major Depressive disorder that had never attempted suicide. Copy Number Variants (CNVs) were called in Birdsuite and analyzed in PLINK. We found a set of CNVs present in the suicide attempter group that were not present in in the non-attempter group including in SNTG2 and MACROD2 – two brain expressed genes previously linked to psychopathology; however, these results failed to reach genome-wide signifigance.

Conclusions

These data suggest potential CNVs to be investigated further in relation to suicide attempts in MD using large sample sizes.     

Surface Vulnerability of Cerebral Cortex to Major Depressive Disorder

Major depressive disorder (MDD) is accompanied by atypical brain structure. This study first presents the alterations in the cortical surface of patients with MDD using multidimensional structural patterns that reflect different neurodevelopment. Sixteen first-episode, untreated patients with MDD and 16 matched healthy controls underwent a magnetic resonance imaging (MRI) scan. The cortical maps of thickness, surface area, and gyrification were examined using the surface-based morphometry (SBM) approach. Increase of cortical thickness was observed in the right posterior cingulate region and the parietal cortex involving the bilateral inferior, left superior parietal and right paracentral regions, while decreased thickness was noted in the parietal cortex including bilateral pars opercularis and left precentral region, as well as the left rostral-middle frontal regions in patients with MDD. Likewise, increased or decreased surface area was found in five sub-regions of the cingulate gyrus, parietal and frontal cortices (e.g., bilateral inferior parietal and superior frontal regions). In addition, MDD patients exhibited a significant hypergyrification in the right precentral and supramarginal region. This integrated structural assessment of cortical surface suggests that MDD patients have cortical alterations of the frontal, parietal and cingulate regions, indicating a vulnerability to MDD during earlier neurodevelopmental process.     

Further Evidence of Emotional Allodynia in Unmedicated Young Adults with Major Depressive Disorder

Background

Recent evidence suggests that sensitivity to the emotional sequela of experimental thermal pain(measured by emotional unpleasantness) is heightened in individuals with major depressive disorder(MDD), a phenomenon we termed “emotional allodynia”. The aim of this study was to examine whether acute happy and sad mood induction alters emotional allodynia in MDD. We hypothesized that emotional allodynia will be a robust characteristic of individuals with MDD compared to healthy controls. Thus, it would remain following acute mood induction, independent of valence.

Methods

Twenty-one subjects with current MDD and 21 well-matched healthy subjects(HC) received graded brief temperature stimuli following happy and sad mood inductions procedures(MIP). All subjects rated the intensity and affect(pleasantness/unpleasantness) of each stimulus. Sensory(pain intensity) and affective(pain unpleasantness) thresholds were determined by methods of constant stimuli.

Results

The MIPs reliably induced happy and sad mood and the resulting induced mood and subjective arousal were not different between the groups at the time of temperature stimulation. Compared to HC, MDD individuals demonstrated emotional allodynia. We found significantly decreased affective pain thresholds whereby significantly lower temperatures became unpleasant in the MDD compared to the HC group. This was not observed for the sensory pain thresholds. Within the MDD, the affective pain thresholds were significantly lower than the corresponding pain intensity thresholds, whereby non-painful temperatures were already unpleasant for the MDD irrespective of the induced mood. This was not observed for the HC groups where the affective and pain intensity thresholds were comparable.

Conclusions

These findings suggest that emotional allodynia may be a chronic characteristic of current MDD. Future studies should determine if emotional allodynia persists after psychological or pharmacological interventions. Finally, longitudinal work should examine whether emotional allodynia is a result of or vulnerability for depression and the role it plays in the increased susceptibility for pain complaints in this disorder.     

Increased Amygdala Response to Shame in Remitted Major Depressive Disorder

Proneness to self-blaming moral emotions such as shame and guilt is increased in major depressive disorder (MDD), and may play an important role in vulnerability even after symptoms have subsided. Social psychologists have argued that shame-proneness is relevant for depression vulnerability and is distinct from guilt. Shame depends on the imagined critical perception of others, whereas guilt results from one’s own judgement. The neuroanatomy of shame in MDD is unknown. Using fMRI, we compared 21 participants with MDD remitted from symptoms with no current co-morbid axis-I disorders, and 18 control participants with no personal or family history of MDD. The MDD group exhibited higher activation of the right amygdala and posterior insula for shame relative to guilt (SPM8). This neural difference was observed despite equal levels of rated negative emotional valence and frequencies of induced shame and guilt experience across groups. These same results were found in the medication-free MDD subgroup (N = 15). Increased amygdala and posterior insula activations, known to be related to sensory perception of emotional stimuli, distinguish shame from guilt responses in remitted MDD. People with MDD thus exhibit changes in the neural response to shame after symptoms have subsided. This supports the hypothesis that shame and guilt play at least partly distinct roles in vulnerability to MDD. Shame-induction may be a more sensitive probe of residual amygdala hypersensitivity in MDD compared with facial emotion-evoked responses previously found to normalize on remission.

Whoever blushes confesses guilt, true innocence never feels shame.

JJ Rousseau