| PrefaceMajor depressive disorder(MDD)is a heterogenous disease involving genetic and environmental factors.Although there is evidence for the implication of genetic factors in the etiology of MDD,the disease-causing genes remain to be identified.There is increasing evidence from clinical and pharmacological studies that disturbances in serotonergic(5-HT)neuronal function are involved in the pathophysiology of depression.Postmortem studies have suggested that the number of 5-HTR2A receptors is higher in the frontal cortex.Recent experiments have shown that 5-HTR2A may mediate the antidepressant effects seen in putative animal models of anxiety and depression.Moreover,positron emission tomography studies in depressed human subjects evaluating the effect of antidepressant drugs on central 5-HTR2A receptors have also shown a decrease in their density after treatment.One study suggests that a polymorphism in the 5-HTR2A gene is primarily associated with suicidal thoughts in patients with severe depression.The chronic administration of tricyclic or monoamine oxidase inhibitors results in downregulation of 5-HTR2A,and selective serotonin reuptake inhibitors(SSRIs)have also been associated with a decreased responsiveness of 5-HT2.Some studies have suggested that SSRIs induce downregulation of 5-HTR2A.The above reports support the 5-HTR2A gene as a candidate gene influencing the clinical response to antidepressant treatment.There is no consistency about the association between 5-HTR2A and etiology of depression domestic and international, but also the lack of the relation ship between 5-HTR2A-1438A/G gene polymorphism and the effect of antidepressant.The purpose of this study was to determine the relationship between the -1438A/G polymorphism in the 5-HTR2A gene and the response to fluoxetine in a Chinese population with major depressive disorder.MethodsThe case-control study was used to analyze the relationship between MDD patients(n=149)and normal controls(n=152)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-HTR2A - 1438A/G gene polymorphisms,is concluded in this association study.We also analyze the relationship between 5-HTR2A -1438A/G gene polymorphisms and the therapeutic effect of MDD.ResultsFluoxetine was administered for 6 weeks to the 132 patients who completed this study.We found significant differences in genotype,allele,and carrier distribution between the normal group and MDD patients(genotypes:x~2=6.913,df=2,P=0.032; alleles:x~2=7.080,df=1,P=0.008;OR=1.552,95%CI=1.122-2.146;allele carriers: x~2=4.939,df=1,P=0.026;OR=1.924,95%CI=1.074-3.446).The frequency of the -1438A allele was much higher in MDD patients than in the normal group(allele carriers:x~2=4.939,df=1,P=0.026;OR=1.924,95%CI=1.074-3.446).There were also significant differences in response to fluoxetine according to the -1438A/G variation of 5-HTR2A in MDD patients.The group of remitters carried a higher frequency of the GG allele than of the AA and AG alleles.More of nonremitters carried the A allele than were without it(genotype:)x~2=6.587,P=0.037;allele carrier:x~2=6.536,P= 0.011;OR=0.273,95%CI=0.097-0.772).The response to fluoxetine differed with the -1438A/G polymorphism genotype and allele carriers.The G/G genotype appeared to be associated with a better response to fluoxetine.ConclusionThese results suggest that the A allele of the -1438A/G polymorphism in the 5-HTR2A gene is associated with MDD,and that patients with G/G have a better response to citalopram treatment than patients with A/A or A/G.
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