title: B vitamins to enhance treatment response to antidepressants in middle-aged and older adults: results from the B-VITAGE randomised, double-blind, placebo-controlled trial. Longitudinal association of vitamin B-6, folate, and vitamin B-12 with depressive symptoms among older adults over time. Predictive value of folate, vitamin B12 and homocysteine levels in late-life depression. Serum Vitamin B12, C and Folate Concentrations in the New Mexico Elder Health Survey: Correlations with Cognitive and Affective Functions Vitamin B12, folate, and homocysteine in depression: the Rotterdam Study. L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials. Prediction of Treatment Response in Geriatric Depression From Baseline Folate Level: Interaction With an SSRI or a Tricyclic Antidepressant Plasma pterins and folate in late life depression: The Rotterdam Study An open trial of methyltetrahydrofolate in elderly depressed patients. Brief communication. Vitamin B1, B2, and B6 augmentation of tricyclic antidepressant treatment in geriatric depression with cognitive dysfunction. Serum folate, vitamin B12, and homocysteine in major depressive disorder, Part 1: predictors of clinical response in fluoxetine-resistant depression. Folate Augmentation of Treatment--Evaluation for Depression (FolATED): randomised trial and economic evaluation.
abstract: BACKGROUND Depression is common and the efficacy of antidepressants is suboptimal . High plasma homocysteine has been consistently associated with depression , and treatment with certain B vitamins demonstrably reduces its concentration . AIMS To determine whether vitamins B6 , B12 and folic acid enhance response to antidepressant treatment  over 52 weeks . METHOD R and omised , double-blind , placebo-controlled trial of citalopram ( 20 - 40 g ) together with 0.5 mg of vitamin B12 , 2 mg of folic acid and 25 mg of vitamin B6 for 52 weeks ( Australian and New Zeal and Clinical Trials Registry : 12609000256279 ) . Participants were community-dwelling adults aged 50 years or over with DSM-IV-TR major depression . We measured severity of symptoms with the Montgomery-Åsberg Depression Rating Scale ( MADRS ) . The primary outcome was remission of the depressive episode after 12 , 26 and 52 weeks . Secondary outcomes included reduction of MADRS scores over time and relapse of major depression after recovery by week 12 . Results In total , 153 people were r and omised ( 76 placebo , 77 vitamins ) .  Remission of symptoms was achieved by 78.1 and 79.4 % of participants treated with placebo and vitamins by week 12 ( P = 0.840 ) , by 76.5 and 85.3 % at week 26 and 75.8 and 85.5 % at week 52 ( effect of intervention over 52 weeks : odds ratio ( OR ) = 2.49 , 95 % CI 1.12 - 5.51 ) . Group differences in MADRS scores over time were not significant ( P = 0.739 ) . The risk of subsequent relapse among those who had achieved remission of symptoms at week 12 was lower in the vitamins than placebo group ( OR = 0.33 , 95 % CI 0.12 - 0.94 ) . CONCLUSIONS B vitamins did not increase the 12-week efficacy of antidepressant treatment , but enhanced and sustained antidepressant response over 1 year . Replication of these findings would m and ate that treatment guidelines adopt the adjunctive use of B vitamins as a safe and inexpensive strategy to manage major depression in middle-aged and older adults BACKGROUND B-vitamin deficiencies have been associated with depression ; however , there is very little prospect i ve evidence from population -based studies of older adults . OBJECTIVE We examined whether dietary intakes of vitamins B-6 , folate , or vitamin B-12 were predictive of depressive symptoms over an average of 7.2 y in a community-based population of older adults . DESIGN The study sample consisted of 3503 adults from the Chicago Health and Aging project , an ongoing , population -based , biracial ( 59 % African American ) study in adults aged > or = 65 y.  Dietary assessment was made by food-frequency question naire . Incident depression was measured by the presence of > or = 4 depressive symptoms from the 10-item version of the Center for Epidemiologic Studies Depression scale . RESULTS The logistic regression models , which used generalized estimating equations , showed that higher total intakes , which included supplementation , of vitamins B-6 and B-12 were associated with a decreased likelihood of incident depression for up to 12 y of follow-up , after adjustment for age , sex , race , education , income , and antidepressant medication use . For example , each 10 additional milligrams of vitamin B-6 and 10 additional micrograms of vitamin B-12 were associated with 2 % lower odds of depressive symptoms per year . There was no association between depressive symptoms and food intakes of these vitamins or folate . These associations remained after adjustment for smoking , alcohol use , widowhood , caregiving status , cognitive function , physical disability , and medical conditions . CONCLUSION Our results support the hypotheses that high total intakes of vitamins B-6 and B-12 are protective of depressive symptoms over time in community-residing older adults BACKGROUND The role of folate , vitamin B(12 ) and homocysteine levels in depression is not clear . AIMS To investigate cross-sectional and prospect i ve associations between folate , B(12 ) and homocysteine levels and late-life depression . METHOD A total of 732 Korean people aged 65 years or over were evaluated at baseline . Of the 631 persons who were not depressed , 521 ( 83 % ) were followed over a period of 2 - 3 years and incident depression was ascertained with the Geriatric Mental State schedule .  Serum folate , serum vitamin B(12 ) and plasma homocysteine levels were assayed at both baseline and follow-up . RESULTS Lower levels of folate and vitamin B(12 ) and higher homocysteine levels at baseline were associated with a higher risk of incident depression at follow-up . Incident depression was associated with a decline in vitamin B(12 ) and an increase in homocysteine levels over the follow-up period . CONCLUSIONS Lower folate , lower vitamin B(12 ) and raised homocysteine levels may be risk factors for late-life depression Objectives : 1 ) To compare serum vitamin B12 , C and folate concentrations in a r and omly selected sample of elderly ( age 65 years or older ) male and female Hispanics and nonHispanic whites ( NHW ) and 2 ) to examine associations between serum B12 , C and folate concentrations compared to measures of cognitive and affective ( depression ) functions . Methods : Equal numbers of male and female Hispanics and NHW were r and omly sample d from the Health Care Financing Administration ( Medicare ) registrant list for Bernalillo County , New Mexico , and asked to volunteer for a paid home interview followed by a paid comprehensive interview/examination covering health and health-related issues . In addition to serum determinations of B12 , C and folate , associations were examined between these vitamins and measures of cognitive and affective functions . Results : Males and Hispanics had lower serum vitamin B12 , C and folate concentrations than females and NHW respectively . Participants taking a multivitamin supplement ( MVI ) had higher serum vitamin concentrations than those not taking MVI . There were significant associations between serum folate concentrations and measures of cognitive function , not seen with B12 or C , nor between any of the vitamins and affective function . Conclusions : Hispanics , even after adjustments for gender , age , vitamin supplementation , vitamin content of dietary foods , education and household income , had lower serum concentrations of B12 , C and folate than NHW . The most significant associations observed were those between serum folate and various measures of cognitive function , even after adjusting for presence of depression OBJECTIVE The associations of vitamin B(12 ) , folate , and homocysteine with depression were examined in a population -based study . METHOD The authors screened 3,884 elderly people for depressive symptoms . Subjects with positive screening results had psychiatric workups .  Folate , vitamin B(12 ) , and homocysteine blood levels  were compared in 278 persons with depressive symptoms , including 112 with depressive disorders , and 416 r and omly selected reference subjects . Adjustments were made for age , gender , cardiovascular disease , and functional disability . RESULTS Hyperhomocysteinemia , vitamin B(12 ) deficiency , and to a lesser extent , folate deficiency were all related to depressive disorders . For folate deficiency and hyperhomocysteinemia , the association with depressive disorders was substantially reduced after adjustment for functional disability and cardiovascular disease , but for vitamin B(12 ) this appeared independent . CONCLUSIONS The association of vitamin B(12 ) and folate with depressive disorders may have different underlying mechanisms . Vitamin B(12 ) may be causally related to depression , whereas the relation with folate is due to physical comorbidity OBJECTIVE The authors conducted two multicenter sequential parallel comparison design trials to investigate the effect of L-methylfolate augmentation in the treatment of major depressive disorder in patients who had a partial response or no response to selective serotonin reuptake inhibitors ( SSRIs ) .  METHOD In the first trial , 148 out patients with SSRI-resistant major depressive disorder were enrolled in a 60-day study divided into two 30-day periods . Patients were r and omly assigned , in a 2:3:3 ratio , to receive L-methylfolate for 60 days ( 7.5 mg/day for 30 days followed by 15 mg/day for 30 days ) , placebo for 30 days followed by L-methylfolate ( 7.5 mg/day ) for 30 days , or placebo for 60 days . SSRI dosages were kept constant throughout the study . In the second trial , with 75 patients , the design was identical to the first , except that the l-methylfolate dosage was 15 mg/day during both 30-day periods . RESULTS In the first trial , no significant difference was observed in outcomes between the treatment groups . In the second trial , adjunctive L-methylfolate at 15 mg/day showed significantly greater efficacy compared with continued SSRI therapy plus placebo on both primary outcome measures ( response rate and degree of change in depression symptom score ) and two secondary outcome measures of symptom severity . The number needed to treat for response was approximately six in favor of adjunctive L-methylfolate at 15 mg/day . L-Methylfolate was well tolerated , with rates of adverse events no different from those reported with placebo . CONCLUSIONS Adjunctive L-methylfolate at 15 mg/day may constitute an effective , safe , and relatively well tolerated treatment strategy for patients with major depressive disorder who have a partial response or no response to SSRIs Depressed geriatric patients have lower levels of folate ( FOL ) than controls . Also , FOL supplement can reduce depressive morbidity . One hypothesis consistent with this is that FOL deficiency causes a lowering of CNS serotonin that contributes to depression . The present report is from one site of a multicenter study that compared an SSRI ( sertraline ) with a nonspecific tricyclic antidepressant ( nortriptyline ) in geriatric depressed patients . We added measures of FOL at baseline and outcome for 22 depressed patients older than 60 years . Both treatments were effective . At baseline , FOL levels were within the normal range . Higher FOL levels at baseline predicted greater improvement . Further study of FOL interaction with SSRI is warranted . For the group treated with the SSRI , baseline FOL level was a more efficient predictor of improvement , especially for results on a self-rating depression scale ( POMS ) Tetrahydrobiopterin is a cofactor in the synthesis of monoamine neurotransmitters . High neopterin levels generally signal increased immune activation . Both pterins have been investigated in several small clinical studies of depressed patients with conflicting results . Therefore , we examined the relation of plasma biopterin and neopterin with depression in a population -based study . We also studied the association of pterins with folates in depressed persons as this vitamin is required for pterin bio synthesis . We screened 3884 adults aged 60 years and over for depressive symptoms . Screen positive subjects had a psychiatric interview to diagnose DSM-IV disorder .  Plasma pterins and serum folate  were determined in all persons with depressive symptoms ( n=238 ) and r and omly selected non-depressed persons ( n=357 ) . We found no association between the concentration of biopterin or neopterin with depressive symptoms or depressive disorders . However , in depressed persons the relation between pterins and folates was different than in the non-depressed , i.e. neopterin concentrations increased with folate levels in persons with depressive symptoms ( 0.09 per log(nmol/l folate ) ; 95 % CI=0.01 , 0.18 , P=0.03 ) , but not in non-depressed persons ( -0.07 per log(nmol/l folate ) ; 95 % CI=-0.17 , 0.03 , P=0.18 ) . The interaction between depressive symptoms , folate and neopterin was significant ( P=0.03 ) . The study suggests that the relation between folate and pterins is altered in the depressed elderly 5-methyltetrahydrofolate ( MTHF ) is a naturally occurring substance involved in the synthesis of s-adenosyl-l-methionine ( SAMe ) , a major source of methyl groups in the brain . To assess the efficacy of a gastro-resistant , oral preparation of MTHF , 20 elderly patients with a DSM-III-R diagnosis of depressive disorder and a HAM-D-21 score > or = 18 underwent 6-weeks of open-label treatment with 50 mg per day of oral MTHF . Of these 20 patients , 16 completed at least 4 weeks of treatment and showed a markedly significant improvement in their depressive symptoms at endpoint , with 81 % of them being considered responders . There were no clinical ly relevant changes in the routine laboratory tests during the study , and no adverse events considered to be definitely drug-related were reported This was a 4-week r and omized placebo-controlled double-blind study to assess augmentation of open tricyclic antidepressant treatment with 10 mg each of vitamins B1 , B2 , and B6 in 14 geriatric in patients with depression . The active vitamin group demonstrated significantly better B2 and B6 status on enzyme activity coefficients and trends toward greater improvement in scores on ratings of depression and congnitive function , as well as in serum nortriptyline levels compared with placebo-treated subjects ( Ss ) . Without specific supplementation , B12 levels increased in Ss receiving B1/B2/B6 and decreased in placebo Ss . These findings offer preliminary support for further investigation of B complex vitamin augmentation in the treatment of geriatric depression OBJECTIVE In the present study , we assessed the relationship between serum folate , vitamin B12 , and homocysteine levels and clinical response in patients with major depressive disorder ( MDD ) who had previously failed to respond to open treatment with fluoxetine 20 mg/day and were enrolled in a 4-week , double-blind trial of either ( 1 ) fluoxetine dose increase , ( 2 ) lithium augmentation of fluoxetine , or ( 3 ) desipramine augmentation of fluoxetine . METHOD Fifty-five out patients ( mean + /- SD age = 41.7 + /- 10.6 years ; 50.9 % women ) with MDD as assessed with the Structured Clinical Interview for DSM-III-R who were enrolled in the double-blind trial had  serum folate , vitamin B12 , and homocysteine measurements completed at baseline ( prior to fluoxetine treatment initiation ) . Folate levels were classified as either low ( < or = 2.5 ng/mL ) or normal . Vitamin B12 levels were classified as either low ( < or = 200 pg/mL ) or normal . Homocysteine levels were classified as either elevated ( > or = 13.2 micromol/L ) or normal . With the use of a logistic regression , we then assessed the relationship between ( 1 ) low or normal folate levels , ( 2 ) normal or low B12 levels , and ( 3 ) elevated or normal homocysteine levels and clinical response to double-blind treatment . The study was conducted from November 1992 to January 1999 . RESULTS Low serum folate levels ( chi2=3.626 , p = .04 ) , but not elevated homocysteine ( p > .05 ) or low vitamin B12 levels ( p > .05 ) , were associated with poorer response to treatment . The response rates for patients with ( N = 14 ) and without ( N = 38 ) low folate levels were 7.1 % versus 44.7 % , respectively . CONCLUSION Low serum folate levels were found to be associated with further treatment resistance among patients with fluoxetine-resistant MDD BACKGROUND Folate deficiency is associated with depression . Despite the biological plausibility of a causal link , the evidence that adding folate enhances antidepressant treatment is weak . OBJECTIVES ( 1 ) Estimate the clinical effectiveness and cost-effectiveness of folic acid as adjunct to antidepressant medication ( ADM ) . ( 2 ) Explore whether baseline folate and homocysteine predict response to treatment . ( 3 ) Investigate whether response to treatment depends on genetic polymorphisms related to folate metabolism . DESIGN FolATED ( Folate Augmentation of Treatment - Evaluation for Depression ) was a double-blind and placebo-controlled , but otherwise pragmatic , r and omised trial including cost-utility analysis . To yield 80 % power of detecting st and ardised difference on the Beck Depression Inventory version 2 ( BDI-II ) of 0.3 between groups ( a ' small ' effect ) ,  FolATED trialists sought to analyse 358 participants . To allow for an estimated loss of 21 % of participants over three time points , we planned to r and omise 453 . SETTING S Clinical - Three centres in Wales - North East Wales , North West Wales and Swansea . Trial management - North Wales Organisation for R and omised Trials in Health in Bangor University . Biochemical analysis - University Hospital of Wales , Cardiff . Genetic analysis - University of Liverpool . PARTICIPANTS Four hundred and seventy-five adult patients presenting to primary or secondary care with confirmed moderate to severe depression for which they were taking or about to start ADM , and able to consent and complete assessment s , but not ( 1 ) folate deficient , vitamin B12 deficient , or taking folic acid or anticonvulsants ; ( 2 ) misusing drugs or alcohol , or suffering from psychosis , bipolar disorder , malignancy or other unstable or terminal illness ; ( 3 ) ( planning to become ) pregnant ; or ( 4 ) participating in other clinical research . INTERVENTIONS Once a day for 12 weeks experimental participants added 5 mg of folic acid to their ADM , and control participants added an indistinguishable placebo . All participants followed pragmatic management plans initiated by a trial psychiatrist and maintained by their general medical practitioners . MAIN OUTCOME MEASURES Assessed at baseline , and 4 , 12 and 25 weeks thereafter , and analysed by ' area under curve ' ( main ) ; by analysis of covariance at each time point ( secondary ) ; and by multi-level repeated measures ( sensitivity analysis ): Mental health - BDI-II ( primary ) , Clinical Global Impression ( CGI ) , Montgomery-Åsberg Depression Rating Scale ( MADRS ) , UKU side effects scale , and Mini International Neuropsychiatric Interview ( MINI ) suicidality subscale ; General health - UK 12-item Short Form Health Survey ( SF-12 ) , European Quality of Life scale - 5 Dimensions ( EQ-5D ) ; Biochemistry - serum folate , B12 , homocysteine ; Adherence - Morisky Question naire ; Economics - re source use . RESULTS Folic acid did not significantly improve any of these measures . For example it gained a mean of just 2.9 quality -adjusted life-days [ 95 % confidence interval ( CI ) from -12.7 to 7.0 days ] and saved a mean of just £ 48 ( 95 % CI from -£292 to £ 389 ) . In contrast it significantly reduced mental health scores on the SF-12 by 3.0 % ( 95 % CI from -5.2 % to -0.8 % ) . CONCLUSIONS The FolATED trial generated no evidence that folic acid was clinical ly effective or cost-effective in augmenting ADM . This negative finding is consistent with improving underst and ing of the one-carbon folate pathway suggesting that methylfolate is a better c and i date for augmenting ADM . Hence the findings of FolATED undermine treatment guidelines that advocate folic acid for treating depression , and suggest future trials of methylfolate to augment ADM . TRIAL REGISTRATION Current Controlled Trials IS RCT N37558856 . FUNDING This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol . 18 , No. 48 . See the HTA programme website for further project information
target: Conclusion : Low folate and B12 serum levels seem to be associated with  depression in the aged .
background: Objectives : To systematic ally review and meta-analyse existing evidence on the association between folate/B12 , and depression among the aged people .