TNF-α Level & The Genetic Polymorphisms And Change Of Microstructure Of White Matter In First Episode Major Depressive Disorder

Background: Major Depression Disorder(MDD)is one of the common severe mental disorders.Compelling evidence suggests that there may be a relationship between peripheral inflammatory system and MDD.Because of the heterogeneity of MDD,interaction between genes and gene-environmental interactions,most of the results from genetic studies about MDD could not be replicated among different samples.By finding endophenotypes,the heterogeneity problem about MDD could be resolved.Neuroimaging alternation found by functional magnetic resonance imaging(f MRI)maybe one of the endophenotypes.We recuit first episode depressive patients,study on TNF-α level & its genotypes,and the microchange in white matter,to explore the exact regions where cytokines take effect,to enrichen the theories about TNF-α’s role in the mechanism of first episode MDD,and to provide new perspective to the diagnosis and treatment of depression.Objective:(1)To measure the serum level of TNF-α before and after exposure to antidepressants during a 12-week treatment protocol for major depressive disorder,and to determine the immune state of MDD by serum level of TNF-α,and whether the level of TNF-α was correlated with clinical variables.(2)To examine whether the TNF-α-308G/A-1031 T/C-863C/A polymorphism confer susceptibility to MDD,and to explore the effect of gene polymorphism on cytokine secretion by comparing cytokine levels and symptom levels in patients of different genotypes.(3)To investigate the white matter intergrity of patients with different prognosis with Tract-Based Spatial Statistics(TBSS)within DTI parameter maps.and detect the effects of TNF-α genotype on treatment response and white matter integrity.Methods:(1)The subjects were 178 patients who met the DSM-IV diagnostic criteria for major depressive disorder and 175 healthy control subjects.The patients had been diagnosed as having melancholic,atypical and anxious subtypes according to it’s clinical traits.All patients were treated with escitalopram or mitrazapine randomly.The psychopathological status of each MDD patient was assessed using the HAMD,HAMA and CGI before and 12-week after the start of antidepressants administration.For all subjects,TNF-α level was estimated using commercial ELISA kits according to the manufacturer’s instructions.(2)The subjects were 247 patients who met the DSM-IV diagnostic criteria for MDD and 214 healthy control subjects.The patients were received medication and clinical assessment as in the former part.Amplication of the target sites in the TNF-α gene-308-1031 and-863 were carried out by SNap Shot.The allelic and genotypic types were determined by restriction fragment length polymorphism.(3)Diffusion tensor imaging(DTI)was applied to explore the difference in fractional anisotropy(FA)values,between the MDD group(n=128)and healthy control group(n=128)and correlation analysis between the the FA values and clinical straits& genotypes of TNF-α.Results: 1.Serum TNF-α level in the MDD group was significantly higher than those in the control group(P<0.05). 2.Serum TNF-α level of the melancholic MDD were significantly higher before treatment than those without obvious such kind of symptoms(P<0.05).3.There was significantly correlation between the levels of TNF-α and the severity of lowly motivated symptom clusters evaluated by the HAMD,and also significantly correlation between the difference of serum TNF-α level before and after treatment and the decreased HAMD.4.Serum cytokine level of the subjects with AA and G/A genotypes were significantly higher than those of the subjects with GG genotype in the TNF-α gene-308 target site.and also-1031 target site of(CC+CT)vs TT;significantly difference in the reaction to antidepressants among different genotypes.None such findings were detected in the-863 target site C/A.5.In MDD patients,the HAMD score was negatively correlated with the FA value in many white matter fibers like: the posterior cingulate,superior longitudinal fasciculus,corpus callosum from DTI analysis.The main effect of rs1800629 genotypes were found in left cingulum fasciculus of MDD with treatment response,left uncinate fasciculus showed a genotype×treatment response interaction.Conclusions: 1.The proinflammatory cytokine,tumor necrosis factor alpha play a critical role in the development of depressive disorders and the mechanism of antidepressant treatment.2.The morphisms of TNF-alpha genotype-308 G→A and-1031T→C are related to the reaction to antidepressants of MDD patients.3.It showed that the white matter microstructure abnormalities in posterior cingulate,superior longitudinal fasciculus,corpus callosum in first-episode MDD patients,suggesting that the abnormalities of brain white matter may be present early in the course of MDD.4.TNF-α may play an important role in treatment response and the neuroimaging changes in MDD,the morphisms of-308 genotype have effects on not only the treatment reaction of MDD,but also its neuroimaging change in microstructure of white matter.