Zuowei Wang

Blood-Based Gene Expression Profiles Models for Classification of Subsyndromal Symptomatic Depression and Major Depressive Disorder

Subsyndromal symptomatic depression (SSD) is a subtype of subthreshold depressive and also lead to significant psychosocial functional impairment as same as major depressive disorder (MDD). Several studies have suggested that SSD is a transitory phenomena in the depression spectrum and is thus considered a subtype of depression. However, the pathophysioloy of depression remain largely obscure and studies on SSD are limited. The present study compared the expression profile and made the classification with the leukocytes by using whole-genome cRNA microarrays among drug-free first-episode subjects with SSD, MDD, and matched controls (8 subjects in each group). Support vector machines (SVMs) were utilized for training and testing on candidate signature expression profiles from signature selection step. Firstly, we identified 63 differentially expressed SSD signatures in contrast to control (P< = 5.0E-4) and 30 differentially expressed MDD signatures in contrast to control, respectively. Then, 123 gene signatures were identified with significantly differential expression level between SSD and MDD. Secondly, in order to conduct priority selection for biomarkers for SSD and MDD together, we selected top gene signatures from each group of pair-wise comparison results, and merged the signatures together to generate better profiles used for clearly classify SSD and MDD sets in the same time. In details, we tried different combination of signatures from the three pair-wise compartmental results and finally determined 48 gene expression signatures with 100% accuracy. Our finding suggested that SSD and MDD did not exhibit the same expressed genome signature with peripheral blood leukocyte, and blood cell–derived RNA of these 48 gene models may have significant value for performing diagnostic functions and classifying SSD, MDD, and healthy controls.

The role of BDNF, NTRK2 gene and their interaction in development of treatment-resistant depression: Data from multicenter, prospective, longitudinal clinic practice

BACKGROUND Although genetic variants may play a key role in development of treatment-resistant depression (TRD), relevant research is scarce. METHODS To examine whether the polymorphisms of BDNF (rs6265) and NTRK2 (rs1387923, rs2769605 and rs1565445) genes confer risk for TRD in major depressive disorder (MDD), a total of 948 MDD patients were recruited in a 12-week, multicenter, prospective longitudinal study. RESULTS Our study showed a significant allelic association between rs1565445 and TRD with an excess of the T allele in the TRD group, compared to non-TRD group (OR = 1.43, 95%CI: 1.16-1.76, p = 0.0008); while patients with genotype C/C and T/C in rs1565445 were less likely to develop TRD than those carrying T/T (OR = 0.52, 95%CI: 0.33-0.82; OR = 0.72, 95%CI: 0.54-0.97, respectively; p = 0.005). Haplotype T-T (rs1565445 and rs1387923) had 1.41-fold increased risk of TRD (p = 0.0014). Furthermore, significant four-locus (rs1387923-rs1565445-rs2769605-rs6265) gene-gene interactions were detected by the Multifactor-dimensionality reduction (MDR) method. DISCUSSION These results suggest that the interactions of BDNF (rs6265) with NTRK2 (rs1387923, rs2769605 and rs1565445) gene polymorphisms likely play an essential role in the development of TRD in Han Chinese MDD patients.

Brain-derived neurotrophic factor levels and bipolar disorder in patients in their first depressive episode: 3-Year prospective longitudinal study

BACKGROUND Early identification of patients with bipolar disorder during their first depressive episode is beneficial to the outcome of the disorder and treatment, but traditionally this has been a great challenge to clinicians. Recently, brain-derived neurotrophic factor (BDNF) has been suggested to be involved in the pathophysiology of bipolar disorder and major depressive disorder (MDD), but it is not clear whether BDNF levels can be used to predict bipolar disorder among patients in their first major depressive episode. AIMS To explore whether BDNF levels can differentiate between MDD and bipolar disorder in the first depressive episode. METHOD A total of 203 patients with a first major depressive episode as well as 167 healthy controls were recruited. After 3 years of bi-annual follow-up, 164 patients with a major depressive episode completed the study, and of these, 21 were identified as having bipolar disorder and 143 patients were diagnosed as having MDD. BDNF gene expression and plasma levels at baseline were compared among the bipolar disorder, MDD and healthy control groups. Logistic regression and decision tree methods were applied to determine the best model for predicting bipolar disorder at the first depressive episode. RESULTS At baseline, patients in the bipolar disorder and MDD groups showed lower BDNF mRNA levels (P<0.001 and P = 0.02 respectively) and plasma levels (P = 0.002 and P = 0.01 respectively) compared with healthy controls. Similarly, BDNF levels in the bipolar disorder group were lower than those in the MDD group. These results showed that the best model for predicting bipolar disorder during a first depressive episode was a combination of BDNF mRNA levels with plasma BDNF levels (receiver operating characteristics (ROC) = 0.80, logistic regression; ROC = 0.84, decision tree). CONCLUSIONS Our findings suggest that BDNF levels may serve as a potential differential diagnostic biomarker for bipolar disorder in a patients first depressive episode.

Venlafaxine inhibits the upregulation of plasma tumor necrosis factor-alpha (TNF-α) in the Chinese patients with major depressive disorder: A prospective longitudinal study

Although tumor necrosis factor-alpha (TNF-α) has been recognized to be involved in the pathogenesis of major depressive disorder (MDD) for a long time, only few studies so far investigated the effects of antidepressant, venlafaxine on TNF-α and the results are inconsistent. Moreover, the association between plasma TNF-α levels and suicide accompanied with MDD is entirely unknown. To elucidate these relationships, in the present study, 64 first-episode drug-naïve MDD patients and 64 matched healthy controls were recruited. Total 61 MDD patients received 8-week venlafaxine treatment and they were divided into responders and non-responders according to the reduction rate of HRSD-17. Prior to venlafaxine treatment, both responders and non-responders shared a similar plasma TNF-α (p=0.33), which was significantly decreased following venlafaxine treatment (p<0.001, p=0.03, respectively). Compared to non-responders, the responder group had a greater reduction in TNF-α (p=0.01), which was associated with the greater reduction rate of HRSD-17 (B=1.02, p=0.01). In addition, the plasma TNF-α levels were equally higher in both suicidal and non-suicidal MDD patients (p=0.84) compared to the healthy controls on admission (p=0.001, p=0.03, respectively). Together, our data suggest that MDD per se rather than suicide is associated with the elevated plasma TNF-α, which can be inhibited with venlfaxine monotherapy. The extent of TNF-α reduction may be associated with the efficiency of venlafaxine.

Neurotrophic Tyrosine Kinase Receptor Type 2 (NTRK2) Gene Associated with Treatment Response to Mood Stabilizers in Patients with Bipolar I Disorder

There is increasing evidence supporting the relationship between bipolar disorder (BP) and neurotrophin. The present study investigated the relationship between neurotrophic tyrosine kinase receptor type 2 (NTRK2) gene polymorphisms and bipolar I disorder (BP I) susceptibility and treatment response to mood stabilizers (lithium or valproate). Two-hundred eighty-four patients who met the DSM-IV criteria for BP I and 295 matched healthy controls were enrolled into this study. TaqMan® SNP genotyping assays were applied to genotype three NTRK2 gene polymorphisms (rs2769605, rs1565445, rs1387923). Our study showed a significant allelic association between NTRK2 gene polymorphism rs2769605 and treatment response to mood stabilizers in BP I patients (t = −2.53, P = 0.01). However, no significant association between NTRK2 gene polymorphisms and BP I susceptibility was observed after correcting for multiple comparisons. The results suggest that the NTRK2 gene polymorphism likely plays an essential role in treatment response to mood stabilizers in Han Chinese BP I patients.

IL-23 and TGF-β1 levels as potential predictive biomarkers in treatment of bipolar I disorder with acute manic episode.

BACKGROUND Growing evidence suggests that immune dysfunction may be involved in the physiopathology of bipolar disorders, with typical first-line treatment using lithium and quetiapine serving to restore pro-inflammation status. This study aimed to explore the relationship between inflammatory cytokines-especially regulatory factors and the effect of combination treatment-with quetiapine and lithium in manic patients. METHODS 41 patients of bipolar I disorder with manic episode were enrolled and received combination treatment with quetiapine and lithium. Blood sampling and assessments were performed at baseline and after 8-week treatment. YMRS was used to evaluate the severity of manic symptoms at the same time of detecting plasma levels. A control group comprised of 36 age and gender matched healthy volunteers were enrolled, and their blood samples were assessed at the time of enrollment. RESULTS TGF-β1 and IL-23 plasma levels in patients were significantly higher than healthy controls at baseline (P<0.05). When comparing remitted patients with non-remitted patients, initial plasma level TGF-β1 was higher (P=0.029) while IL-23 was lower (P=0.035). The plasma levels of TNF-α, TGF-β1, IL-23 and IL-17 significantly decreased after treatment among the patients who achieved response (P<0.05). LIMITATIONS The relatively small sample size in patients and control groups should be considered as a limitation of the study. CONCLUSIONS The high initial plasma level of TGF-β1 and low initial plasma level of IL-23 indicated better prognosis during combination treatment with quetiapine and lithium in manic patients. The trend of decreasing plasma levels of TNF-α, TGF-β1, IL-23 and IL-17 indicated therapeutic effect.

MiRNA-206 and BDNF genes interacted in bipolar I disorder

BACKGROUND Several lines of evidence have suggested that has-mir-206 (miRNA-206) may regulate brain-derived neurotrophic factor (BDNF) protein synthesis. The primary aim of this study was to determine whether miRNA-206 gene (MIR206) may confer susceptibility to bipolar disorder type I (BD-I) and treatment response to mood stabilizers. Also, we intended to verify the hypothesis that a potential interplay of MIR206 and BDNF may influence the genetic risk for BD-I and treatment response. METHODS The MIR206 rs16882131 and BDNF rs6265 polymorphisms were genotyped in 280 BD-I patients and 288 healthy controls. Treatment response to lithium and valproate was retrospectively determined. RESULTS No association was observed in the individual polymorphism with regards to risk of BD-I and treatment response. Our results showed a significant gene to gene interaction between the MIR206 rs16882131 and BDNF rs6265 polymorphisms that contribute to BD-I susceptibility and treatment response. Further analysis showed a significant interaction between MIR206 and BDNF on treatment score (F3, 138=8.61, P=0.046), and individuals with MIR206 T/T+TC and BDNF A/A genotypes had a significantly lower mean treatment score than those with MIR206 CC and BDNF A/A+A/G as well as those with MIR206 CC and BDNF G/G genotypes (P=0.018 and 0.013, respectively). LIMITATION This is a preliminary investigation with relatively small sample size. CONCLUSION Our findings provide initial evidence of the gene-to-gene interaction of MIR206 and BDNF in regards to the risk for BD-I as well as treatment response to mood stabilizers.

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.

Should an assessment of Axis I comorbidity be included in the initial diagnostic assessment of mood disorders? Role of QIDS-16-SR total score in predicting number of Axis I comorbidity

BACKGROUND Axis I comorbidity in mood disorders was common in epidemiological studies. This study was designed to investigate the prevalence, pattern, and number of Axis I comorbidities and the role of the Quick Inventory of Depression Symptomatology - 16 items-Self-Report (QIDS-16-SR) in predicting the number of comorbidities in major depressive disorder (MDD) or bipolar disorder (BPD). METHODS Baseline data from the first 300 routine clinical outpatients diagnosed with the Mini International Neuropsychiatric Interview Systematic-Treatment-Enhancement - Program for BPD version 5.0.0 were used. Baseline severity was measured with QIDS-16-SR and Clinical Global Impression-Severity (CGI-S). RESULTS Of 113 patients with MDD and 166 with BPD, the prevalence of any current anxiety disorder (AD), substance use disorder (SUD), and attention deficit hyperactivity disorder (ADHD) was 76% versus 74%, 14% versus 29%, and 8% versus 21%, respectively. The most common patterns of current comorbidity were MDD+AD (58.4%) for MDD, and BPD+AD (39.8%) and BPD+AD+SUD (11.4%) for BPD. More than 80% patients with MDD or BPD had ≥ 1 current comorbid disorder. About 20% patients with BPD and 10% with MDD had ≥ 4 other disorders. The number of comorbidities was positively associated with baseline severity and suicidal ideation in both MDD and BPD. A QIDS-16-SR of 10 had a positive predictive value of ≥ 90% in predicting ≥ 1 comorbidity in MDD and BPD. LIMITATIONS The sample was modest and from a tertiary medical center. CONCLUSION A thorough diagnostic assessment for Axis I comorbidity should be included in all patients with mood disorders, especially when a QIDS-16-SR of ≥ 10 points.