| Background With the development of global economic level,anxiety and depression as common mood diseases,the number of affected people is increasing day by day,and there is a gender difference in the prevalence,which is higher in women than in men.Several cross-sectional surveys showed that serum and erythrocyte folate levels were significantly lower in patients with anxiety and depression.However,because the current clinical studies have mixed sample size,methodology,and quality levels,so that the relationship between folate levels and anxiety and depression cannot be accurately judged.Meta-analysis,as an important way in evidence-based medicine to seek the best evidence,can provide ideas for the determination of the relationship between folate levels and anxiety and depression.In addition,this study intends to explore the potential etiology of anxiety and depression from the perspective of folate deficiency,to provide a theoretical basis for the health education of folate supplementation,and to provide ideas for the etiology exploration of clinical anxiety and depression.Objective This study aims to clarify the association of folate levels with anxiety and depression through meta-analysis of relevant studies of folate with anxiety and depression.An animal model of chronic folate deficiency was constructed by feeding a folate deficient diet for a long time,aiming to explore whether chronic folate deficiency could lead to anxiety-and depression-like behaviors in mice,and to observe whether there is gender differences in the effects of chronic folate deficiency on anxiety-and depression-like behaviors in mice and its possible internal mechanismMethods1.Pub Med,Cochrane Library,Web of Science,CNKI,Wanfang and VIP databases were searched.The time limit was from the databases establishment to December 31,2020.The quality of the included cross-sectional studies was evaluated according to the quality assessment scale for cross-sectional studies of the American agency for healthcare research and quality(AHRQ)and the quality of the included case-control studies and cohort studies was evaluated according to the Newcastle Ottawa scale(NOS)tool recommended by Cochrane.Rev Man 5.3 software was used for meta analysis.2.Ten week old ICR male and female mice were randomly divided into control group and chronic folate deficiency group,respectively.Both female and male control groups were fed a control diet,and both chronic folate deficiency groups were fed a folate deficient diet.All mice were fed until 38 weeks of age and observed daily for eating,drinking,and locomotor behaviors,which were well documented,and body weights were weighed and recorded at 8 am every monday.At 38 weeks of age,mice were observed to develop abnormal behaviors such as stereotypic behavior and markedly reduced activity.Open field test(OFT)and elevated plus-maze(EPM)were used to determin anxiety-like behavior of mice,and sucrose preference and forced swimming were used to determin depression-like behavior of mice.After behavioral tests,all mice were weighed,hearts were bled after anesthesia,and serum samples were prepared by centrifugation in the following morning.Serum folate,homocysteine,estradiol,and testosterone were measured.The mice brains were harvested after anesthesia and Western Blotting was used to detect the protein expression of ERβ,PI3K,P-Akt,Akt and BDNF.Results1.A total of 39 studies involving 33543 participants were included in the meta-analysis(7225 in the depression group,311 in anxiety and depression comorbid group and26007 in the control group).The results of this meta-analysis showed that the levels of folate in the depression group were significantly lower than that of control group[SMD=-0.27,95%CI(-0.29,-0.24),P<0.00001],and the overall heterogeneity was higher(I~2=99%,P<0.00001)by using a random effect model.After sensitivity analysis,excluding high bias risk literature,we found that folate levels in patients with comorbid anxiety and depression were significantly lower than that in patients without comorbid anxiety and depression[SMD=-0.64,95%CI(-1.04,-0.24),P=0.002],and the overall heterogeneity was higher(I~2=65%,P=0.09)by using a random effect model,too.Age subgroup analysis showed that folate levels in the depression group were significantly lower than in the control group,no matter in childhood/adolescence,adulthood or old age[SMD=-0.14,95%CI(-0.25,-0.03),P=0.01;SMD=-1.13,95%CI(-1.54,-0.73),P<0.00001;SMD=-0.41,95%CI(-0.67,-0.14),P=0.002].Perinatal depressed patients also had significantly lower folate levels than non depressed perinatal participants[SMD=-0.19,95%CI(-0.30,-0.09),P=0.002].In the subgroup analysis based on gender,the folate levels in the female depression group were significantly lower than that in the control group[SMD=-0.63,95%CI(-1.20,-0.07),P=0.03],while there was no significant difference in folate levels in the male groups[SMD=-0.22,95%CI(-0.55,0.11),P=0.19].Patients with depression had significantly lower folate levels than control participants regardless of folate source and type of study design.Both sensitivity analysis and funnel plot showed that the results were reliable and robust.2.(1)Chronic folate deficiency significantly reduced serum folate levels and increased serum total homocysteine levels in both female and male mice,indicating successful construction of a mouse model of chronic folate deficiency.(2)Chronic folate deficiency significantly reduced body weight gain in male mice without statistically significant differences to females.(3)Chronic folate deficiency significantly caused a significant decrease in the testosterone/body weight ratio and serum testosterone hormone levels in male mice without affecting their serum estradiol levels,and in addition,chronic folate deficiency caused a decrease in serum estradiol levels in female mice without affecting the ovarian/body weight ratio in female mice.(4)In the OFT,female mice with chronic folate deficiency exhibited a reduction in the time spent in center area,and the time in the outer area was increased,indicating that chronic folate deficiency induced the reduction of the self exploration behavior and increment of the anxiety like behavior of female mice.Compared with female mice with chronic folate deficiency,the total movement distance of male mice with chronic folate deficiency was significantly shortened,and the number of entering the center area was reduced,indicating that chronic folate deficiency reduced the locomotor activity of males.(5)In the EPM,the movement distance of male mice with chronic folate deficiency in the open arms was significantly shorter than that of female mice with chronic folate deficiency,also indicating that chronic folate deficiency reduced the locomotor activity of males.(6)In the sucrose preference test,the female mice with chronic folate deficiency showed a significant decrease in sucrose preference,which was lower than that of male mice with chronic folate deficiency.This suggested that chronic folate deficiency induce severe depression-like behavior in female mice.(7)In the forced swim test,the female mice with chronic folate deficiency exhibited a significant increase in immobility time in water,whereas no significant difference was observed between the two male groups,indicating that chronic folate deficiency induced depression-like behavior in female mice,while it has no effect on males.(8)Chronic folate deficiency induced a decrease in the protein expression levels of the ERβ/PI3K/Akt pathway in the brain of female mice and a concomitant decrease in the protein levels of BDNF in both female and male mice brain.Conclusions1.Patients with depression and comorbid anxiety and depression had significantly lower folate levels and gender differences were found in depressed patients,and the significant decrease in folate levels occurred only in female depressed patients.However,due to the high heterogeneity of the results of this analysis,there is still high heterogeneity through subgroup analysis,so the conclusion needs to be cautious,and more relevant studies need to be included in the future to further explore the source of heterogeneity.In addition,the vast majority of literatures included in this study were cross-sectional studies,which could not clarify the causality of low folate levels and anxiety and depression,and more large prospective cohort studies are needed in the future to clarify above causality.2.Chronic folate deficiency can cause anxiety-and depression-like behaviors in female mice,but not on the behavior of male mice.This gender differences may be related to the down-regulation of ERβ/PI3K/Akt pathway proteins and BDNF protein expression in the female mice brain. |
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