Study Of Relationship Among 5-HT_1AR Gene C(-1019)G Polymorphism, Brain Structure MRI And Clinical Response In The Treatment Of Major Depressive Disorder With Fluoxetine

ObjectiveTo explore the relationship between the 5-HT_1Areceptor genetic polymorphism and the onset and therapeutic effect of fluoxetine for major depressive disorder (MDD);To explore the change of cerebral gray matter density and white matter integrity in unmedicated patients with a first episode of major depressive disorder;To explore the relationship between the change of cerebral gray matter density and the therapeutic effect of fluoxetine for MDD;To explore the pathophysiologic mechanism of MDD in molecular biology and cerebral structure level;To supply some evidence for the diagnosis and treatment of MDD.MethodsPART ONE:The case-control study was used to analyze the relationship between MDD patients(n=142)and normal controls(n=154)using the polymerase chain reaction and restriction fragment length polymorphisms(PCR-RFLP)technique,and evaluate the symptom groups of cases applying the Hamilton Rating Scale for Depression(HAMD).One polymorphism site,which is 5-HT_1Areceptor C(-1019)G gene polymorphisms,is concluded in this association study.We also analyze the relationship between 5-HT_1Areceptor C(-1019)G gene polymorphisms and the therapeutic effect of MDD.PART TWO:Voxel-based morphometry(VBM)in conjunction with statistical parametric mapping was applied to the magnetic resonance imaging(MRI)of MDD patients(n=15)and normal controls(n=15).We compared the difference of gray matter density between the patients before fluoxetine treatment and controls,and between the patients before and after fluoxetine treatment.PART THREE:Diffusion tensor imaging was employed to examine the white matter integrity in MDD patients(n=15)and normal controls(n=15).The fractional anisotropy(FA)of MDD patients before fluoxetine treatment and normal controls was compared.Results1.There are significant difference in C(-1019)G gene genotypes and alleles distribution between case group and control group,G allele of case group is higher than that of control group(P＜0.05).2.The HAMD factors of different genotypes are significant difference in case group(P=0.01),which in C/C genotype is higher than C/G genotype(P=0.024)and G/G genotype(P=0.008).3.There are no significant difference in fluoxetine response among different genotypes and alleles distribution(P=0.761).4.Compared with controls,MDD patients had significantly(P＜0.01)lower gray matter density in the frontal lobe(the bilateral superior frontal gyrus,the right anterior central gyras,the bilateral paracentral gyrus,the left interior frontal gyrus),the parietal lobe(the right paracentral gyrus,the left precuneus),the anterior cingutate,the cerebellum(the bilateral posterior lobe)and the right thalamus.5.Compared with MDD patients before fluoxetine treatment,MDD patients after fluoxetine treatment have significantly(P＜0.01)higher gray matter density in the frontal lobe(the bilateral middle frontal gyrus,the bilateral inferior frontal gyrus),the cerebellum(the bilateral anterior lobe)and the cingulate.6.Compared with controls,FA showed significantly(P＜0.01)decrease in some brain regions of MDD patients,including the frontal lobe(the bilateral middle frontal gyrus,the bilateral inferior frontal gyrus),the temporal lobe(the right inferior temporal gyrus,the left fusiform gyrus),the parietal lobe(the bilateral posterior central gyrus,the bilateral inferior parietal lobule,the left precuneus),the bilateral posterior cingulate,the right parahippocampal gyrus,the callosum.Conclusion1.There may be relationship between 5-HT_1AR C(-1019)G genetic polymorphism and MDD.Our result suggests that G allele may be the risk factor of MDD,and C/C genotype maybe the protective factor.2.There may be relationship between 5-HT_1AR C(-1019)G genetic polymorphism and the severity of MDD.The patients with C/C genotype may be more severity than the other genotypes.3.There is no relationship between 5-HT_1AR C(-1019)G genetic polymorphism and fluoxetine response.4.The gray matter was lost in some brain regions of MDD patients compared with normal control,the white matter integrity was also reduced in some brain regions of MDD patients compared with normal control,especially in the frontal lobe.5.The gray matter density in the frontal lobe,the cerebellum and the cingulate was increased after fluoxetine treatment,which means fluoxetine may improve the brain structure of above regions.6.Some brain regions of MDD patients including the limbic lobe and the parietal lobe show reduced gray matter density and reduced white matter integrity,which indicates the onset of MDD may be the result of several brain regions' involvement.7.The reduced white matter integrity in the callosum of MDD patients indicates that MDD shows the impairment of cerebral hemisphere connectivity.