Daihui Peng

Dissociated large-scale functional connectivity networks of the precuneus in medication-naïve first-episode depression

An imbalance in neural activity within large-scale networks appears to be an important pathophysiological aspect of depression. Yet, there is little consensus regarding the abnormality within the default mode network (DMN) in major depressive disorder (MDD). In the present study, 16 first-episode, medication-naïve patients with MDD and 16 matched healthy controls underwent functional magnetic resonance imaging (fMRI) at rest. With the precuneus (a central node of the DMN) as a seed region, functional connectivity (FC) was measured across the entire brain. The association between the FC of the precuneus and overall symptom severity was assessed using the Hamilton Depression Rating Scale. Patients with MDD exhibited a more negative relationship between the precuneus and the non-DMN regions, including the sensory processing regions (fusiform gyrus, postcentral gyrus) and the secondary motor cortex (supplementary motor area and precentral gyrus). Moreover, greater severity of depression was associated with greater anti-correlation between the precuneus and the temporo-parietal junction as well as stronger positive connectivity between the precuneus and the dorsomedial prefrontal cortex. These results indicate that dissociated large-scale networks of the precuneus may contribute to the clinical expression of depression in MDD.

Difference in remission in a Chinese population with anxious versus nonanxious treatment-resistant depression: A report of OPERATION study

BACKGROUND A secondary analysis was conducted to compare treatment outcomes for anxious depression and nonanxious depression in previous published OPERATION trials of a variety of antidepressants and augmentation strategies for patients with treatment-resistant depression (TRD). METHODS A total of 375 patients that met DSM-IV criteria for major depressive disorder (MDD) and the stage 2 TRD criteria (described by Thase & Rush) were enrolled. Anxious depression was defined as MDD with a HRSD-17 anxiety/somatization factor score ≥7. Data were derived from an earlier study, designed to compare efficacy and tolerability of fixed dosage of extended-release venlafaxine, mitazapine, paroxetine, and risperidone, sodium valproate, buspirone, trazodone or thyroid hormone augmenting to paroxetine in those patients. Treatment outcomes were compared between patients with anxious and nonanxious TRD. RESULTS Nearly 70% of participants had anxious depression. Remission rates were significantly lower and ratings of adverse event frequency were significantly greater in patients with anxious TRD than in those with nonanxious TRD. Presence of anxious depression predicted worse outcomes. LIMITATIONS Lack of a placebo control arm prevents us from ruling out placebo effects. The two groups were non-randomly allocated to medications. Only patients with stage 2 TRD were enrolled, which may limit generalizablity to patients without a history of resistance. Comorbid anxiety disorders that might confound the specific treatment effects were not addressed. CONCLUSIONS The findings support and extend the hypothesis that anxious depression is associated with poorer outcomes. It suggests a dimensional assessment of co-occurring anxious features of MDD patients may be clinically feasible for countries like China where difficulties in making comorbidity diagnosis exist.

Significantly decreased mRNA levels of BDNF and MEK1 genes in treatment-resistant depression.

The aim of the current study was to investigate whether the levels of mRNA expression of brain-derived neurotrophin factor (BDNF) and a related gene MEK1 were more obviously decreased in treatment-resistant depression (TRD). In total, 50 patients with major depressive disorder (including 26 with TRD and 24 with treatment-responsive depression) and 48 healthy controls were enrolled. BDNF and MEK1 mRNA levels in blood samples from all patients and controls were measured using reverse transcriptase-PCR. BDNF and MEK1 mRNA levels were significantly reduced in patients with major depressive disorder when compared with healthy controls (BDNF: P<0.01; MEK1: P<0.001), as well as among treatment-resistant depressive patients as compared with treatment-responsive depressive patients (BDNF: P<0.001; MEK1: P<0.01). Our findings support the hypothesis that BDNF and MEK1 mRNA expression levels are more obviously decreased in patients with TRD.

Association of genetic variation in CACNA1C with bipolar disorder in Han Chinese.

BACKGROUND A growing body of evidence highlights the existence of shared genetic susceptibility to both major depressive disorder (MDD) and bipolar disorder (BD), suggesting some potential genetic overlap between the disorders. Genome-wide association studies have identified consistent association of single nucleotide polymorphisms of the α-1 C subunit of the L-type voltage-gated calcium channel gene (CACNA1C) with MDD and BD, suggesting CACNA1C as a promising candidate gene for susceptibility to mood disorders. In the present study, we tested the association of CACNA1C with MDD and BD in Han Chinese. METHODS We genotyped three potentially functional polymorphisms in 635 MDD patients, 286 BD patients and 730 normal, control patients. RESULTS The genotype frequencies of SNP rs1051375 showed statistically significant differences between the BD and control groups (P=0.005). At the allele level, the difference of G allele frequency of rs1051375 between BD patients and control subjects was also significant (P=0.011; OR=1.30, 95% CI: 1.06-1.58). We found that GG genotype of rs1051375 carriers had a lower age at onset than those with the AG or AA genotype, and the mean±standard deviation ages at onset of GG, AG and AA carriers were 24.04±4.22, 25.76±4.75 and 25.78±4.33 years, respectively. Neither genotype nor allele frequencies of the three polymorphisms were found to be significantly different between the MDD patients and control subjects. LIMITATIONS The relative small sample size in BD group should be considered a limitation of this study. CONCLUSIONS Our initial findings support a potential association of CACNA1C as a genetic risk factor for BD susceptibility.

Influence of BCL2 gene in major depression susceptibility and antidepressant treatment outcome

BACKGROUND Our recent work indicated that low-expression of the anti-apoptotic protein B-cell/lymphoma 2 (Bcl-2) mRNA was observed among untreated major depressive disorder (MDD) patients, and the subsequent altered level of Bcl-2 was found to be close to the antidepressant treatment outcome. The primary aim of this present study was to examine whether a particular gene, encoding Bcl-2 (BCL2) confers risk to MDD, and likewise to investigate whether this gene acts as an indicator of antidepressant treatment outcome. METHODS We enrolled 178 treatment-resistant depression (TRD) and 612 non-treatment-resistant depression (NTRD) patients as well as 725 healthy controls. In total, three selected tagging SNPs (tagSNPs) of BCL2 (rs2279115, rs1801018 and rs1564483) were genotyped to test for possible association. Using TaqMan relative quantitative real-time polymerase chain reaction (PCR), we analyzed leukocytic expression of BCL2 mRNA in 47 healthy subjects. RESULTS Of the three SNPs, we observed no significant differences in genotype and allele frequencies between the MDD and control groups as well as between the TRD and NTRD groups. However, we found a significant association between the rs2279115C allele and TRD in males (corrected P=0.048) but not in females. Further real-time quantitative PCR analysis in healthy subjects revealed that the rs2279115 polymorphism significantly influenced BCL2 mRNA expression (P=0.03). LIMITATIONS This is a preliminary investigation with relatively small sample size and cross-sectional design. CONCLUSIONS These initial findings strengthen the hypothesis that BCL2 may play an important role in mediating the outcome of antidepressant treatment, a result that may further be confirmed by future genetic studies from large-scale populations that can overcome the limited sample size of this preliminary finding.

Alterations in effective connectivity anchored on the insula in major depressive disorder

Recent work has identified disruption of several brain networks involving limbic and cortical regions that contribute to the generation of diverse symptoms of major depressive disorder (MDD). Of particular interest are the networks anchored on the right anterior insula, which binds the cortical and limbic regions to enable key functions that integrate bottom-up and top-down information in emotional and cognitive processing. Emotional appraisal has been linked to a presumed hierarchy of processing, from sensory percepts to affective states. But it is unclear whether the network level dysfunction seen in depression relates to a breakdown of this presumed hierarchical processing system from sensory to higher cognitive regions, mediated by core limbic regions (e.g. insula). In 16 patients with current MDD, and 16 healthy controls, we investigated differences in directional influences between anterior insula and the rest of the brain using resting-state functional magnetic resonance imaging (fMRI) and Granger-causal analysis (GCA), using anterior insula as a seed region. Results showed a failure of reciprocal influence between insula and higher frontal regions (dorsomedial prefrontal cortex) in addition to a weakening of influences from sensory regions (pulvinar and visual cortex) to the insula. This suggests dysfunction of both sensory and putative self-processing regulatory loops centered around the insula in MDD. For the first time, we demonstrate a network-level processing defect extending from sensory to frontal regions through insula in depression. Within limitations of inferences drawn from GCA of resting fMRI, we offer a novel framework to advance targeted network modulation approaches to treat depression.

Decreased serum fibroblast growth factor - 2 levels in pre- and post-treatment patients with major depressive disorder.

Increasing evidence indicates that neurotrophic factor dysfunction might be involved in the pathophysiology and treatment of major depressive disorder (MDD). Fibroblast growth factor (FGF)-2, one of the major neurotrophins, plays an important role in the central nervous system (CNS). The aim of this study was to explore whether the FGF-2 in serum was associated with MDD and to evaluate the effects of antidepressant treatment on serum FGF-2 levels. Serum FGF-2 levels were determined in 28 pre- and post-treatment MDD patients and 30 healthy controls using ELISA. The results of the current study revealed that serum FGF-2 levels in MDD patients were significantly lower than those in healthy controls (p=0.005), and the serum FGF-2 levels decreased significantly but marginally following treatment for 8 weeks (p=0.005). These findings demonstrate that the lower serum FGF-2 levels contribute to the pathophysiology of MDD and that FGF-2 may be used as a peripheral biological marker for MDD.

Altered spontaneous neural activity in first-episode, unmedicated patients with major depressive disorder

Abnormal brain function is presumed to be a pathophysiological aspect of major depressive disorder (MDD). However, the underlying patterns of spontaneous neural activity have been poorly characterized and replicated to date. In this study, we applied a novel approach of fractional amplitude of low-frequency fluctuation (fALFF) to investigate the alteration of spontaneous neural activity in MDD. Sixteen first-episode, unmedicated patients with MDD and 16 healthy controls were recruited and subjected to resting-state fMRI scans to measure the fALFF across the whole brain. Compared with healthy controls, MDD patients exhibited decreased fALFF in the right angular gyrus, left middle temporal gyrus, left superior temporal gyrus, right putamen, right precuneus, and the right superior temporal gyrus. Differences in fALFF between MDD patients and controls indicated that altered spontaneous neural activity was distributed across a number of specific brain regions among MDD patients. These atypical functional regions may help explain some of the neural processes underlying the clinical symptoms accompanying MDD.

Functional −141C Ins/Del polymorphism in the dopamine D2 receptor gene promoter and schizophrenia in a Chinese Han population:

Objective The association between a putative functional promoter polymorphism, −141C insertion/deletion (Ins/Del), in the dopamine receptor D2 gene (DRD2) and schizophrenia was investigated in a Chinese Han population. Methods The polymorphism was studied in unrelated schizophrenia patients and unrelated healthy controls. Linkage relationships were explored in core families of the schizophrenic patients using the transmission disequilibrium test. The Positive and Negative Syndrome Scale was used to evaluate the severity of the disorder. Results The Del allele was significantly less frequently found in patients (13/120; 11%) than in controls (18/100; 18%). In the 32 core families studied, 16 parents were Ins/Del heterozygotes. Parents transmitted the Ins and Del alleles to their children in 10 and six cases, respectively. Data from core families did not demonstrate linkage. Age, age at onset of schizophrenia and sex were not significantly different between carriers of the Ins and Del alleles. The group with the Ins allele had a significantly higher positive symptom score (75.3 ± 23.4 versus 53.9 ± 21.9) and excitement score (83.6 ± 16.8 versus 50.3 ± 24.6) than the Del group. Groups did not differ significantly in negative symptom and general psychopathology scores. Conclusions The DRD2 −141C Ins/Del polymorphism may affect susceptibility to schizophrenia in a Chinese Han population.

Complement factor H and susceptibility to major depressive disorder in Han Chinese

BACKGROUND Accumulating evidence suggests that altered immunity contributes to the development of major depressive disorder (MDD). AIMS To examine whether complement factor H (CFH), a regulator of activation of the alternative pathway of the complement cascade, confers susceptibility to MDD. METHOD Expression analyses were tested in 53 unmedicated people with MDD and 55 healthy controls. A two-stage genetic association analysis was performed in 3323 Han Chinese with or without MDD. Potential associations between CFH single nucleotide polymorphisms and age at MDD onset were evaluated. RESULTS CFH levels were significantly lower in the MDD group at both protein and mRNA levels (P = 0.009 and P = 0.014 respectively). A regulatory variant in the CFH gene, rs1061170, showed statistically significant genotypic and allelic differences between the MDD and control groups (genotypic P = 0.0005, allelic P = 0.0001). Kaplan-Meier survival analysis showed that age at onset of MDD was significantly associated with the C allele of rs1061170 (log rank statistic χ(2) = 6.82, P = 0.009). The C-allele carriers had a younger age at onset of MDD (22.2 years, s.d. = 4.0) than those without the C allele (23.6 years, s.d. = 4.3). CONCLUSIONS CFH is likely to play an important role in the development of MDD. rs1061170 has an important effect on age at onset of MDD in Han Chinese and may therefore be related to early pathogenesis of MDD, although further study is needed.