Jun Mu

Left versus right repetitive transcranial magnetic stimulation in treating major depression: a meta-analysis of randomised controlled trials.

Although the majority of randomised controlled trials suggest that major depressive disorder (MDD, major depression) and treatment-resistant depression can be effectively treated by applying either high- (HF) or low-frequency (LF) repetitive transcranial magnetic stimulation (rTMS) to the left and right dorsolateral prefrontal cortex (DLPFC), respectively, it is not clear which rTMS approach is more effective or safer. This systematic review and meta-analysis was conducted on randomised controlled trials on HF and LF rTMS applied to the left and right DLPFC, respectively, for the treatment of MDD. Eight randomised controlled trials composed of 249 patients were selected to compare the effects of LF (≤ 1 Hz) rTMS over the right DLPFC to HF (10-20 Hz) rTMS over the left DLPFC. The therapeutic effects of both approaches were similar (odds ratio (OR) = 1.15; 95% confidence interval = 0.65-2.03). Dropout analysis based on only two studies was insufficient to draw a conclusion on the tolerability of LF rTMS. The pooled examination demonstrated that both rTMS methods were equally effective therapies for MDD. However, considering that LF right-sided rTMS produces fewer side effects and is more protective against seizures, its clinical applicability shows greater promise and should be explored further.

Comparative proteomic analysis of plasma from major depressive patients: identification of proteins associated with lipid metabolism and immunoregulation

Major depressive disorder is a common neuropsychiatric disorder contributing to several socio-economic burdens including disability and suicide. As the underlying pathophysiology of major depressive disorder remains unclear, no objective test is yet available for aiding diagnosis or monitoring disease progression. To contribute to a better understanding of its pathogenesis, a comparative proteomic study was performed to identify proteins differentially expressed in plasma samples obtained from first-onset, treatment-naive depressed patients as compared to healthy controls. Samples from the two groups were immunodepleted of seven high-abundance proteins, labelled with isobaric tags for relative and absolute quantitation and then analysed by multi-dimensional liquid chromatography-tandem mass spectrometry. The proteomic results were further validated by immunoblotting or enzyme-linked immunoadsorbent assays and analysed with the MetaCore database. The results demonstrate that the functions of the altered proteins are primarily involved in lipid metabolism and immunoregulation. These findings suggest that early perturbation of lipid metabolism and immunoregulation may be involved in the pathophysiology of major depressive disorder.

Combined Application of NMR- and GC-MS-Based Metabonomics Yields a Superior Urinary Biomarker Panel for Bipolar Disorder

Bipolar disorder (BD) is a debilitating mental disorder that cannot be diagnosed by objective laboratory-based modalities. Our previous studies have independently used nuclear magnetic resonance (NMR)-based and gas chromatography-mass spectrometry (GC-MS)-based metabonomic methods to characterize the urinary metabolic profiles of BD subjects and healthy controls (HC). However, the combined application of NMR spectroscopy and GC-MS may identify a more comprehensive metabolite panel than any single metabonomic platform alone. Therefore, here we applied a dual platform (NMR spectroscopy and GC-MS) that generated a panel of five metabolite biomarkers for BD-four GC-MS-derived metabolites and one NMR-derived metabolite. This composite biomarker panel could effectively discriminate BD subjects from HC, achieving an area under receiver operating characteristic curve (AUC) values of 0.974 in a training set and 0.964 in a test set. Moreover, the diagnostic performance of this panel was significantly superior to the previous single platform-derived metabolite panels. Thus, the urinary biomarker panel identified here shows promise as an effective diagnostic tool for BD. These findings also demonstrate the complementary nature of NMR spectroscopy and GC-MS for metabonomic analysis, suggesting that the combination of NMR spectroscopy and GC-MS can identify a more comprehensive metabolite panel than applying each platform in isolation.

Bilateral vs. unilateral repetitive transcranial magnetic stimulation in treating major depression: A meta-analysis of randomized controlled trials

Previous studies have demonstrated inconsistent findings regarding the efficacy of bilateral vs. unilateral repetitive transcranial magnetic stimulation (rTMS) in treating major depressive disorder (MDD). Therefore, this meta-analysis was conducted to compare the efficacy of these two rTMS modalities. Data were obtained from seven randomized controlled trials (RCTs) consisting of 509 subjects. Bilateral and unilateral rTMS displayed comparable efficacy in treating MDD with a pooled odds ratios of 1.06 (95% confidence interval (CI)=0.58-1.91) for response rates and 1.05 (95% CI=0.52-2.11) for remission rates. Subgroup analysis found that bilateral rTMS was equally effective in comparison with both left and right unilateral rTMS. No significant differences in drop-out rates were found. No publication bias was detected. In conclusion, the pooled examination demonstrated that bilateral rTMS displays comparable anti-depressant efficacy and acceptability to unilateral rTMS in treating MDD. These findings suggest that simultaneous rTMS of the right and left dorsolateral prefrontal cortices in MDD patients does not provide marginal benefits in terms of efficacy or acceptability. As the number of RCTs included here was limited, further large-scale multi-center RCTs are required to validate our conclusions.

Plasma-based proteomics reveals lipid metabolic and immunoregulatory dysregulation in post-stroke depression

BACKGROUND Post-stroke depression (PSD) is the most common psychiatric complication facing stroke survivors and has been associated with increased distress, physical disability, poor rehabilitation, and suicidal ideation. However, the pathophysiological mechanisms underlying PSD remain unknown, and no objective laboratory-based test is available to aid PSD diagnosis or monitor progression. METHODS Here, an isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative proteomic approach was performed to identify differentially expressed proteins in plasma samples obtained from PSD, stroke, and healthy control subjects. RESULTS The significantly differentiated proteins were primarily involved in lipid metabolism and immunoregulation. Six proteins associated with these processes--apolipoprotein A-IV (ApoA-IV), apolipoprotein C-II (ApoC-II), C-reactive protein (CRP), gelsolin, haptoglobin, and leucine-rich alpha-2-glycoprotein (LRG)--were selected for Western blotting validation. ApoA-IV expression was significantly upregulated in PSD as compared to stroke subjects. ApoC-II, LRG, and CRP expression were significantly downregulated in both PSD and HC subjects relative to stroke subjects. Gelsolin and haptoglobin expression were significantly dysregulated across all three groups with the following expression profiles: gelsolin, healthy control>PSD>stroke subjects; haptoglobin, stroke>PSD>healthy control. CONCLUSIONS Early perturbation of lipid metabolism and immunoregulation may be involved in the pathophysiology of PSD. The combination of increased gelsolin levels accompanied by decreased haptoglobin levels shows promise as a plasma-based diagnostic biomarker panel for detecting increased PSD risk in post-stroke patients.

Increased apoptosis and different regulation of pro-apoptosis protein bax and anti-apoptosis protein bcl-2 in the olfactory bulb of a rat model of depression

Reduced olfactory bulb (OB) volume and olfactory sensitivity have been observed in depressed patients, the exact mechanisms underlying, however, are still unknown. Our previous study found that decreased neurogenesis and pre-synaptic dysfunction in the OB of a rat model of depression may be responsible for the phenomena. Nevertheless, whether the apoptosis would also play a certain role in this process is not clear. In this study, we investigated the apoptosis in the OB of a chronic unpredictable mild stress (CUMS) rat model of depression using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. Simultaneously, the pro-apoptosis protein bax and anti-apoptosis protein bcl-2 were detected by Western blot. The results showed that the number of TUNEL-positive cells increased dramatically in the glomerular layer of the OB of the CUMS rats, accompanied with up-regulated expression of bax protein and down-regulated expression of bcl-2 protein. The findings indicate that increased apoptosis may be attributed to explain at some level for the reduced OB volume and olfactory dysfunction in depressed patients. Moreover, the mitochondria-dependent death pathway might be involved in apoptosis in the OB of the CUMS rats.

Potential clinical utility of plasma amino acid profiling in the detection of major depressive disorder

Plasma amino acids levels were measured in first-onset treatment-naïve depressed patients (n=26) and healthy controls (n=25) using a mass spectrometry-based method. One of the major findings was that a logistic regression model constructed from tryptophan, glutamine and cysteine discriminated depressed subjects from controls with a receiver-operating-characteristic curve integral of 0.90.

Divergent Urinary Metabolic Phenotypes between Major Depressive Disorder and Bipolar Disorder Identified by a Combined GC-MS and NMR Spectroscopic Metabonomic Approach.

Bipolar disorder (BD) is a complex debilitating mental disorder that is often misdiagnosed as major depressive disorder (MDD). Therefore, a large percentage of BD subjects are incorrectly treated with antidepressants in clinical practice. To address this challenge, objective laboratory-based tests are needed to discriminate BD from MDD patients. Here, a combined gas chromatography-mass spectrometry (GC-MS)-based and nuclear magnetic resonance (NMR) spectroscopic-based metabonomic approach was performed to profile urine samples from 76 MDD and 43 BD subjects (training set) to identify the differential metabolites. Samples from 126 healthy controls were included as metabolic controls. A candidate biomarker panel was identified by further analyzing these differential metabolites. A testing set of, 50 MDD and 28 BD subjects was then used to independently validate the diagnostic efficacy of the identified panel using an area under the receiver operating characteristic curve (AUC). A total of 20 differential metabolites responsible for the discrimination between MDD and BD subjects were identified. A panel consisting of six candidate urinary metabolite biomarkers (propionate, formate, (R*,S*)2,3-dihydroxybutanoic acid, 2,4-dihydroxypyrimidine, phenylalanine, and β-alanine) was identified. This panel could distinguish BD from MDD subjects with an AUC of 0.913 and 0.896 in the training and testing sets, respectively. These results reveal divergent urinary metabolic phenotypes between MDD and BD. The identified urinary biomarkers can aid in the future development of an objective laboratory-based diagnostic test for distinguishing BD from MDD patients.

Elevated host lipid metabolism revealed by iTRAQ-based quantitative proteomic analysis of cerebrospinal fluid of tuberculous meningitis patients.

PURPOSE Tuberculous meningitis (TBM) remains to be one of the most deadly infectious diseases. The pathogen interacts with the host immune system, the process of which is largely unknown. Various cellular processes of Mycobacterium tuberculosis (MTB) centers around lipid metabolism. To determine the lipid metabolism related proteins, a quantitative proteomic study was performed here to identify differential proteins in the cerebrospinal fluid (CSF) obtained from TBM patients (n = 12) and healthy controls (n = 12). METHODS CSF samples were desalted, concentrated, labelled with isobaric tags for relative and absolute quantitation (iTRAQ™), and analyzed by multi-dimensional liquid chromatography-tandem mass spectrometry (LC-MS/MS). Gene ontology and proteomic phenotyping analysis of the differential proteins were conducted using Database for Annotation, Visualization, and Integrated Discovery (DAVID) Bioinformatics Resources. ApoE and ApoB were selected for validation by ELISA. RESULTS Proteomic phenotyping of the 4 differential proteins was invloved in the lipid metabolism. ELISA showed significantly increased ApoB levels in TBM subjects compared to healthy controls. Area under the receiver operating characteristic curve analysis demonstrated ApoB levels could distinguish TBM subjects from healthy controls and viral meningitis subjects with 89.3% sensitivity and 92% specificity. CONCLUSIONS CSF lipid metabolism disregulation, especially elevated expression of ApoB, gives insights into the pathogenesis of TBM. Further evaluation of these findings in larger studies including anti-tuberculosis medicated and unmedicated patient cohorts with other center nervous system infectious diseases is required for successful clinical translation.

Differential co-expression and regulation analyses reveal different mechanisms underlying major depressive disorder and subsyndromal symptomatic depression.

BackgroundRecent depression research has revealed a growing awareness of how to best classify depression into depressive subtypes. Appropriately subtyping depression can lead to identification of subtypes that are more responsive to current pharmacological treatment and aid in separating out depressed patients in which current antidepressants are not particularly effective.Differential co-expression analysis (DCEA) and differential regulation analysis (DRA) were applied to compare the transcriptomic profiles of peripheral blood lymphocytes from patients with two depressive subtypes: major depressive disorder (MDD) and subsyndromal symptomatic depression (SSD).ResultsSix differentially regulated genes (DRGs) (FOSL1, SRF, JUN, TFAP4, SOX9, and HLF) and 16 transcription factor-to-target differentially co-expressed gene links or pairs (TF2target DCLs) appear to be the key differential factors in MDD; in contrast, one DRG (PATZ1) and eight TF2target DCLs appear to be the key differential factors in SSD. There was no overlap between the MDD target genes and SSD target genes. Venlafaxine (Efexor™, Effexor™) appears to have a significant effect on the gene expression profile of MDD patients but no significant effect on the gene expression profile of SSD patients.ConclusionDCEA and DRA revealed no apparent similarities between the differential regulatory processes underlying MDD and SSD. This bioinformatic analysis may provide novel insights that can support future antidepressant R&D efforts.