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Original Article |

Folate, Vitamin B12, Homocysteine, and the MTHFR 677C→T Polymorphism in Anxiety and Depression:  The Hordaland Homocysteine Study FREE

Ingvar Bjelland, MD; Grethe S. Tell, PhD, MPH; Stein Emil Vollset, MD, DrPH; Helga Refsum, MD; Per Magne Ueland, MD
[+] Author Affiliations

From the Department of Public Health and Primary Health Care (Drs Bjelland, Tell, and Vollset), Locus for Homocysteine and Related Vitamins (Drs Bjelland, Tell, Vollset, and Ueland), and Department of Pharmacology (Drs Refsum and Ueland), University of Bergen, Bergen, Norway.


Arch Gen Psychiatry. 2003;60(6):618-626. doi:10.1001/archpsyc.60.6.618.
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Background  An association between depression and folate status has been demonstrated in clinical studies, whereas data are sparse on the relationship between depression and other components of 1-carbon metabolism such as vitamin B12, homocysteine, and the methylenetetrahydrofolate reductase 677C→T polymorphism. The relationship between anxiety and these components is less well known. This study examined the associations between folate, total homocysteine, vitamin B12, and the methylenetetrahydrofolate reductase 677C→T polymorphism, and anxiety and depression in a large population-based study.

Methods  Anxiety and depression, measured by the Hospital Anxiety and Depression Scale, were assessed in 5948 subjects aged 46 to 49 years (mean, 47.4 years) and 70 to 74 years (mean, 71.9 years) from the Hordaland Homocysteine Study cohort. By means of logistic regression models, anxiety and depression scores were examined in relation to the factors listed above.

Results  Overall, hyperhomocysteinemia (plasma total homocysteine level ≥15.0 µmol/L [≥2.02 mg/dL]) (odds ratio, 1.90; 95% confidence interval, 1.11-3.25) and T/T methylenetetrahydrofolate reductase genotype (odds ratio, 1.69; 95% confidence interval, 1.09-2.62), but not low plasma folate or vitamin B12 levels, were significantly related to depression without comorbid anxiety disorder. Plasma folate level was inversely associated with depression only in the subgroup of middle-aged women. None of the investigated parameters showed a significant relationship to anxiety.

Conclusion  Our results provide further evidence of a role of impaired 1-carbon metabolism in depression.

Figures in this Article

HOMOCYSTEINE and the vitamins involved in 1-carbon metabolism, folate and vitamin B12, have been associated with a diversity of diseases, including cardiovascular disease,1,2 malignancies,3 Alzheimer disease, impaired cognitive functioning,4,5 and birth defects and pregnancy complications.6,7 Several studies have investigated the 677C→T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene as a risk factor for these conditions, as the C-to-T transition causes reduced enzyme activity, and elevated plasma total homocysteine (tHcy) levels under conditions of impaired folate status.8

Both anxiety and depression are common symptoms or disorders with a major impact on public health.9,10 Although a possible role of nutritional factors in the pathogenesis of neuropsychiatric disorders has long been debated,11,12 clinical studies have shown an inverse relationship between folate status and depression.13 Such a relationship has been inferred from studies showing increased frequency of folate deficiency among depressed patients1418;more severe1821 and prolonged22 depressive episodes and weaker treatment response to antidepressants in patients with low folate status14,18,2125;and enhanced antidepressant response with folic acid supplementation.2629

Investigations on a possible role of vitamin B12 status in neuropsychiatric disorders have been motivated by the central nervous system damage caused by overt or subtle vitamin B12 deficiency.30,31 Data regarding the association between vitamin B12 status and depression are scarce.14,18,3234

While some studies have demonstrated a positive relationship between depression and plasma tHcy levels35 or the MTHFR 677C→T polymorphism,36 such relationships have not been confirmed in other studies.14,32,34,37

Folate, vitamin B12, and homocysteine are involved in processes important for central nervous system function (Figure 1). Folate metabolism is linked to biopterin-dependent neurotransmitter synthesis38 and S-adenosylmethionine–dependent methylation of biogenic amines and phospholipids in the central nervous system.39 Homocysteine, or its metabolites such as homocysteic acid, may have a direct excitotoxic effect on the N-methyl-D-aspartate glutamate receptors, or may inhibit the methylation processes in the central nervous system.39 This biochemical knowledge adds to the clinical data cited already, suggesting a possible role of 1-carbon metabolism in mental disorders, particularly in depression and dementia.40 However, despite the extensive comorbidity between depression and anxiety,4143 we have found no more than 3 studies33,44,45 addressing the possibility of impaired 1-carbon metabolism in anxiety disorders. Only one study suggests such an association, namely, between low vitamin B12 levels and anxiety.33

Place holder to copy figure label and caption
Figure 1.

Components of 1-carbon metabolism and central nervous system (CNS) functions. SAM indicates S-adenosylmethionine; Hcy, homocysteine; Met, methionine; B12, vitamin B12; MS, methionine synthetase; 5mTHF, 5-methyl-tetrahydrofolate; 5,10mTHF, 5,10-methylene-tetrahydrofolate; THF, tetrahydrofolate; and MTHFR, methylenetetrahydrofolate reductase.

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The present study is part of the Hordaland Health Study, which included self-administered questionnaires of anxiety and depression according to the Hospital Anxiety and Depression Scale (HADS),46 determination of tHcy and related vitamins, and C677T MTHFR genotyping in approximately 6000 middle-aged and elderly subjects. The aim of the current study was to examine whether key components of the 1-carbon metabolism were associated with anxiety disorders and/or depression in this large population.

STUDY POPULATION

The Hordaland Health Study 1997-1999 was conducted from 1997 to 1999 as a collaboration between the National Health Screening Service, the University of Bergen (Bergen, Norway), and local health services. A subsample of the study included 2291 men and 2558 women aged 46 to 49 years (mean, 47.4 years) and 1868 men and 2470 women aged 70 to 74 years (mean, 71.9 years) who had participated in the Hordaland Homocysteine Studies in 1992 to 1993.47 The younger age group was originally a part of the ordinary national cardiovascular risk survey program, while the older group was included to examine age effects. Participation rate was 77% of those invited. At attendance, the subjects underwent a brief physical examination (height, weight, blood pressure), and a blood sample was drawn and stored at −20°C until the biochemical analyses were performed 1 to 3 years later. A self-administered questionnaire providing information on demographic, socioeconomic, and psychosocial parameters; health behaviors; subjective health; present or former diseases; and use of medication was delivered. Among those who participated, 5948 individuals(84%) returned questionnaires with valid ratings of anxiety and depression.

The study protocol was approved by the Regional Committee for Medical Research Ethics and the Norwegian Data Inspectorate.

ASSESSMENT OF ANXIETY AND DEPRESSION

The HADS is a self-administered questionnaire consisting of 14 items, 7 for anxiety (HADS-A subscale) and 7 for depression (HADS-D subscale).46 To avoid making individuals feel that they are being tested for mental disorders, symptoms of severe psychopathology are not included. The HADS-A contains items mainly related to restlessness and worry, and 1 item reflecting panic attacks. The HADS-D focuses mainly on the reduced pleasure response aspect (anhedonia) of depression, but also psychomotor retardation and impaired mood.

The HADS-A and HADS-D are intercorrelated, most often in the range of 0.50 to 0.60.48 Hence, to identify more homogeneous groups with anxiety disorders or depressions, restrictions were put on the other subscale when cases were defined. Thus, anxiety disorder was defined as a HADS-A score of 8 or more restricted to a HADS-D score less than 8 to avoid comorbid disorders. Accordingly, depression was defined as a HADS-D score of 8 or more restricted to a HADS-A score less than 8. Analyses were also carried out on comorbid cases, which were defined as subjects with both subscale scores of 8 or more. To enhance the specificity of anxiety disorder and depression, analyses were carried out on cases defined to HADS-A and HADS-D scores of 11 or more, using the same restrictions as mentioned in this paragraph.

BIOCHEMICAL AND GENETIC MEASUREMENTS

Plasma tHcy was analyzed by high-performance liquid chromatography and fluorescence detection.49 Serum folate was determined by a Lactobacillus casei microbiologic assay50 and serum vitamin B12 by a Lactobacillus leichmannii microbiologic assay.51 Both the folate and vitamin B12 assays were adapted to a microtiter plate format and carried out by a robotic workstation (Micro-lab AT plus 2; Hamilton Bonaduz AG, Bonaduz, Switzerland). The MTHFR C677T genotyping was performed by a real-time polymerase chain reaction as described elsewhere.52

STATISTICAL ANALYSES

Plasma tHcy level was divided into 4 categories (<9.0 µmol/L[<1.22 mg/dL] [reference], 9.0-11.9 µmol/L [1.22-1.61 mg/dL], 12.0-14.9 µmol/L [1.62-2.01 mg/dL], and ≥15.0 µmol/L [≥2.02 mg/dL]).53 Plasma folate and plasma vitamin B12 levels were similarly divided into 4 categories (plasma folate: <3.80 nmol/L [<1.7 ng/mL], 3.80-4.99 nmol/L [1.7-2.2 ng/mL], 5.00-8.49 nmol/L [2.3-3.7 ng/mL], and ≥8.50 nmol/L [≥3.8 ng/mL] [reference]; plasma vitamin B12: <230.0 pmol/L [<312 pg/mL], 230.0-279.9 pmol/L [312-379 pg/mL], 280.0-414.9 pmol/L [380-562 pg/mL], and ≥415.0 pmol/L [≥563 pg/mL] [reference]). Logistic regression analyses were used to estimate odds ratios (ORs) for being a case, comparing each category with the reference category of the metabolites and the MTHFR polymorphism. The representation of covariates as indicator variables was used to allow for assessment of nonlinear dose-response relationships, while a linear (1 df) representation was used to test for linear trends. Two logistic regression models were used, one with adjustment for age and sex (model 1) and one with additional adjustments for smoking status and educational level (model 2). The effect of other possible confounders, such as coffee consumption, physical exercise, body mass index, and self-reported cardiovascular disease, was examined by adding these one by one to model 2. To evaluate possible effect modification of age and sex, product terms were added separately to the models. Possible effect modification of B-vitamin supplementation and tranquilizer and antidepressant use was evaluated by stratification.

To examine whether use of B-vitamin supplements was associated with anxiety or depression, logistic regression analyses were used to estimate OR for being a case, comparing nonusers with users after adjusting for age, sex, smoking status, and educational level.

The precision of the OR estimates was expressed with 95% confidence intervals (CIs). Generalized additive logistic regression was used to provide a graphic representation of the dose-response relationship between folate, vitamin B12, and tHcy and anxiety or depression. This technique is based on the generalized additive model54 and allowed adjustment for age, sex, smoking status, and educational level.

A 2-sided P<.05 was chosen to indicate statistical significance. The statistical analyses were conducted with the software package SPSS 11.0 (SPSS Inc, Chicago, Ill) and S-Plus 6.0 (Insightful Corp, Seattle, Wash).

CHARACTERISTICS OF THE STUDY POPULATION

Table 1 summarizes some demographic characteristics and blood indexes according to age groups and sex. The prevalences of anxiety disorder and depression; use of psychoactive drugs; distribution of tHcy, vitamin B12, and folate levels; and some lifestyle factors are also presented. The total numbers of subjects with anxiety disorder and depression were 622 (11.5%) and 243 (4.8%), respectively. Anxiety disorder was most prevalent among middle-aged women (15.3%) and depression among older men (7.5%).

Table Graphic Jump LocationTable 1. Characteristics of the Study Population: the Hordaland Homocysteine Studies*

Plasma tHcy level correlated well with plasma folate value and modestly with plasma vitamin B12 level (Spearman coefficient r = −0.40, P<.001, and r = −0.25, P<.001, respectively), and plasma folate and plasma vitamin B12 levels correlated poorly(r = 0.06, P<.001), as has been reported elsewhere.55 In the MTHFR T/T genotype, compared with the C/C and C/T genotypes, the mean value of plasma tHcy was significantly increased (13.66 µmol/L [1.85 mg/dL] vs 10.62 µmol/L [1.44 mg/dL] and 10.98 µmol/L [1.48 mg/dL]; P<.001 and P<.001, respectively) and mean plasma folate significantly decreased (7.49 nmol/L [3.3 ng/mL] vs 8.46 nmol/L [3.7 ng/mL] and 8.15 nmol/L [3.6 ng/mL]; P<.001 and P<.05, respectively), while mean plasma vitamin B12 did not show significant differences between the genotypes (data not shown).

UNIVARIATE ASSOCIATIONS

The proportions of the sample with anxiety disorder or depression according to the increasing concentrations of tHcy, folate, and vitamin B12, and according to MTHFR genotype and some lifestyle factors, are listed in Table 2, stratified by age and sex. The distributions indicated associations with both anxiety disorder and depression for a variety of the variables listed. Plasma tHcy and folate levels and MTHFR genotype all seemed associated with depression, as did educational level, smoking status, coffee consumption, use of antidepressants and tranquilizers, physical exercise, and body mass index. Associations with anxiety disorder were seen for smoking status, use of antidepressants and tranquilizers, and body mass index, but only in some strata within plasma tHcy, folate, and vitamin B12 levels.

Table Graphic Jump LocationTable 2. Relationship of Anxiety Disorder and Depression to Various Characteristics of the Study Population: the Hordaland Homocysteine Studies*
HOMOCYSTEINE

Plasma levels of tHcy were not significantly associated with anxiety disorder (Table 3) but were significantly related to depression (Table 4), as demonstrated by logistic regression models adjusting for age and sex (model 1), or further adjusting for smoking status and educational level (model 2). The association with depression was, however, strongest at high plasma tHcy level (≥15.0 µmol/L [≥2.02 mg/dL]) (OR, 1.90; 95% CI, 1.11-3.25), and test for linear trend was significant only in model 1 (P = .03). Including folate level, vitamin B12 level, or MTHFR genotypes in the analyses did not essentially influence the estimates.

Table Graphic Jump LocationTable 3. Odds Ratios for Having Anxiety Disorder at Different Levels of tHcy, Folate, Vitamin B12, and MTHFR Polymorphism in Model 1 (Adjusted for Age and Sex) and Model 2 (Adjusted for Age, Sex, Smoking Status, and Educational Level): the Hordaland Homocysteine Studies
Table Graphic Jump LocationTable 4. Odds Ratios for Having Depression at Different Levels of tHcy, Folate, Vitamin B12, and MTHFR Polymorphism in Model 1 (Adjusted for Age and Sex) and Model 2 (Adjusted for Age, Sex, Smoking Status, and Educational Level): the Hordaland Homocysteine Studies

Figure 2 shows a graphic representation of the relationship between tHcy and the vitamins, and anxiety disorder and depression. A dose-response relationship was seen only between tHcy level and depression.

Place holder to copy figure label and caption
Figure 2.

Dose-response relationships between plasma total homocysteine (tHcy), folate, and vitamin B12 levels and anxiety disorder and depression. The curves were constructed by using generalized additive regression analyses adjusting for age, sex, smoking status, and educational level. The shaded areas indicate 95% pointwise confidence intervals. To convert tHcy levels to milligrams per deciliter, divide by 7.397; folate to nanograms per milliliter, divide by 2.266; and vitamin B12 to picograms per milliliter, divide by 0.738.

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FOLATE AND VITAMIN B12

Neither folate nor vitamin B12 was significantly related to anxiety disorder or depression. These results were obtained by logistic regression also after adjustments (models 1 and 2, Table 3 and Table 4) and were supported by generalized additive logistic regression (Figure 2). However, the dose-response curves obtained by the latter approach suggested a weak negative relationship between folate and depression but not anxiety disorder, and the curve for the vitamin B12 and depression relationship was actually U-shaped (Figure 2).

The estimates did not change markedly when analyses were performed separately for the 4 age and sex strata, except for middle-aged women. In this subgroup, ORs (95% CIs) were 3.41 (1.02-11.42) and 3.08 (0.97-9.72) (model 1) and 3.15(0.94-10.60) and 3.05 (0.96-9.65) (model 2) for the 2 lower folate categories, respectively. The P for trend was .02 in both models.

THE MTHFR 677C→T POLYMORPHISM

Depression but not anxiety disorder was related to the C677T MTHFR genotype. The OR (95% CI) for depression by logistic regression was 1.69 (1.09-2.62) for the T/T genotype (using C/C as reference) in model 2 (Table 4). This estimate was essentially the same when carried out in the 4 age and sex strata (data not shown).

Including coffee consumption, physical exercise, body mass index, or self-reported cardiovascular disease in the logistic regression analyses did not significantly influence the estimates. We observed no effect modification by age or sex or by use of B vitamins, tranquilizers, or antidepressants.

There were no significant associations between levels of plasma folate, vitamin B12, or tHcy or MTHFR 677C→T polymorphism and comorbid anxiety disorder and depression. Nonusers of B-vitamin supplements were not more prone to anxiety or depression than users.

ESTIMATES IN SUBGROUPS WITH HIGHER HADS SCORES

Elevating the cutoff for both anxiety disorder and depression to HADS-A score of 11 or more and HADS-D score of 11 or more, respectively, resulted in only minor changes in the estimates. The relationship with tHcy was weaker for anxiety disorder and stronger for depression; neither of them was significant. The OR for anxiety disorder and depression associated with folate or vitamin B12 was unchanged, except for the relationship between vitamin B12 and depression, which became significant at the lower vitamin B12 level with an OR (95% CI) of 2.33 (1.05-5.21) in model 1 and 2.39 (1.07-5.36) in model 2. Significant effects of MTHFR T/T genotype were not obtained for anxiety disorder, but they were for depression. The OR (95% CI) increased to 2.65 (1.16-6.08) in model 1 and 2.75 (1.20-6.32) in model 2.

We investigated the association between anxiety disorders and depression and key components of the 1-carbon metabolism in a cohort of 5948 subjects. The strongest relationship was observed between the T/T MTHFR genotype and depression, and the association was present for both cutoff levels of depression. Associations were observed between tHcy and depression, lowest level of vitamin B12 (<230.0 pmol/L [<312 pg/mL]) and depression with high cutoff (HADS-D score ≥11), and in middle aged women, between depression and folate. Only a weak relationship or no relationship was seen between anxiety disorder and tHcy, folate, or vitamin B12 level or MTHFR genotype.

Although the cross-sectional designof this study allows association between parameters to be assessed, causality cannot be determined. Because anxiety disorders and depression may influence dietary habits, it is conceivable that these disorders may alter homocysteine and B-vitamin status through dietary changes. Among the parameters studied, only MTHFR genotype is a nonmodifiable trait.

Published studies on folate status and depression, most of which are case-control studies, demonstrate stronger relationships56 than documented in the present study. Such case-control studies are more prone to selection bias than a population-based cross-sectional study. Although the primary participation rate of the present study was relatively high (77%), it might have been affected by mental disorders themselves, since persons with anxiety disorders and depression might be less likely to participate in the study.

The plasma levels of folate in the frozen samples were lower than would be expected in a fresh sample, in contrast to the plasma levels of vitamin B12 and tHcy. Others have found similar deviations of plasma folate levels in frozen samples.57 Nevertheless, plasma folate level was correlated with tHcy level (Spearman coefficient r = −0.40, P<.001), as reported elsewhere.55

Serum (or plasma) folate level has been considered a less reliable measure of folate status than red blood cell folate content.58 Hence, if red blood cell folate level had been measured, one would expect a stronger association with depression compared with our findings. However, because of substantial intermethod variation, red blood cell folate level has its shortcomings as a measure of folate deficiency as well.59

The HADS is a dimensional rating scale, and categorical diagnoses have to be based on research-proved cutoff levels. Optimal cutoff levels for anxiety disorders and depressive disorders are at scores of 8 or more for both subscales, resulting in sensitivities and specificities of approximately 0.80 for both HADS-A and HADS-D.48 Higher specificity is usually obtained by raising the cutoff level, which was demonstrated by the increased OR for depression in the MTHFR polymorphism, tHcy level, and vitamin B12 level.

The observed association between the MTHFR T/T genotype and depression is in accordance with results from one case-control study,36 while another case-control study did not confirm such an association.37 These somewhat inconsistent results of smaller studies could be explained by low statistical power due to the limited number of cases (n = 71 and 32, respectively), combined with the low frequency (10%) of MTHFR T/T homozygosity.8

We found that depression was related to tHcy, folate, and vitamin B12 levels, but the associations were weak and/or present only in certain subgroups. This contrasts somewhat with the findings in clinical studies of impaired folate status in depressed patients,56 and one report on the high frequency of elevated tHcy levels in depression.18 The relatively weak associations found in the present work could be explained by better folate status and less severe depression of the subjects recruited from a general population as compared with hospitalized depressed patients.

Some antidepressant effect by folic acid supplementation has been reported in randomized clinical trials.2629 The largest (n = 127) of these trials26 showed, however, a significant beneficial effect only in women. The lack of significant results in men could be due to the small sample size or an insufficient dosage. In contrast, in our study, use of vitamin B supplements was not associated with a lower prevalence of depression. Notably, most of the B-vitamin supplements in Norway at the time of recruitment did not contain folic acid, or only in relatively low doses of 100 µg.

Associations between folate, vitamin B12, and tHcy levels or the MTHFR 677C→T polymorphism and anxiety disorders have seldom been reported so far; this may be due to reporting or publication bias of negative findings. We found only a weak, nonsignificant relationship between plasma tHcy level and anxiety disorder, and no associations between any of the index variables and comorbid depression and anxiety disorder. Hence, our data suggest that impaired 1-carbon metabolism is related to the subgroup of depression without comorbid anxiety disorder. One possible explanation is that they have a different cause. Further subgrouping to obtain more specific categories, eg, unipolar vs bipolar depression and lifetime or recurrent depression, was not possible when HADS was used in this cross-sectional design. Such analyses of subgroups should be carried out in future studies.

In summary, results from this large population-based study suggest a role of impaired 1-carbon metabolism in depression without comorbid anxiety disorder. This conclusion is supported by increased risk among subjects with the MTHFR T/T genotype, which has an effect on folate distribution and thereby tHcy level. The observation that the T/T genotype confers increased risk suggests that altered B-vitamin status may be a risk factor for, rather than the result of, depression. However, our results are preliminary and there is a need for prospective studies. Furthermore, a dose-response relationship between B vitamins, metabolic markers, and clearly defined subgroups of depression should be investigated. More adequately sized double-blind randomized trials are warranted as well.

Corresponding author: Ingvar Bjelland, MD, Department of Public Health and Primary Health Care, University of Bergen, Armauer Hansen Building, Haukeland Hospital, N-5021 Bergen, Norway (e-mail: ingvar.bjelland@uib.no).

Submitted for publication September 17, 2002; final revision received January 8, 2003; accepted January 9, 2003.

This study was supported by the Norwegian Research Council, Oslo. Dr Bjelland has research grants from H. Lundbeck Ltd (Norway), Lysaker, and Upjohn Ltd (Norway), Oslo.

We thank Alv A. Dahl, MD, PhD, for his advice and encouragement in writing and revising the drafts of this article.

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Tiemeier  HVan Tuijl  HRHofman  AMeijer  JKiliaan  AJBreteler  MM Vitamin B12, folate, and homocysteine in depression: the Rotterdam Study. Am J Psychiatry. 2002;1592099- 2101
Link to Article
Bottiglieri  TLaundy  MCrellin  RToone  BKCarney  MWReynolds  EH Homocysteine, folate, methylation, and monoamine metabolism in depression. J Neurol Neurosurg Psychiatry. 2000;69228- 232
Link to Article
Arinami  TYamada  NYamakawa-Kobayashi  KHamaguchi  HToru  M Methylenetetrahydrofolate reductase variant and schizophrenia/depression. Am J Med Genet. 1997;74526- 528
Link to Article
Kunugi  HFukuda  RHattori  MKato  TTatsumi  MSakai  THirose  TNanko  S C677T polymorphism in methylenetetrahydrofolate reductase gene and psychoses. Mol Psychiatry. 1998;3435- 437
Link to Article
van Praag  HM Depression. Lancet. 1982;21259- 1283
Link to Article
Bottiglieri  THyland  KReynolds  EH The clinical potential of ademetionine (S-adenosylmethionine) in neurological disorders. Drugs. 1994;48137- 152
Link to Article
Reynolds  EH Folic acid, ageing, depression, and dementia. BMJ. 2002;3241512- 1515
Link to Article
Kessler  RCNelson  CBMcGonagle  KALiu  JSwartz  MBlazer  DG Comorbidity of DSM-III-R major depressive disorder in the general population: results from the US National Comorbidity Survey. Br J Psychiatry Suppl. 1996;3017- 30
Mezzich  JEAhn  CWFabrega  HJPilkonis  PA Patterns of psychiatric comorbidity in a large population presenting for care. Maser  JDCloninger  CRedsComorbidity of Mood and Anxiety Disorders. Washington, DC American Psychiatric Press1990;189- 204
Sartorius  NUstun  TBLecrubier  YWittchen  HU Depression comorbid with anxiety: results from the WHO study on psychological disorders in primary health care. Br J Psychiatry Suppl. 1996;3038- 43
Edeh  JToone  BK Antiepileptic therapy, folate deficiency, and psychiatric morbidity: a general practice survey. Epilepsia. 1985;26434- 440
Link to Article
Hermesh  HWeizman  AShahar  AMunitz  H Vitamin B12 and folic acid serum levels in obsessive compulsive disorder. Acta Psychiatr Scand. 1988;788- 10
Link to Article
Zigmond  ASSnaith  RP The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983;67361- 370
Link to Article
Ueland  PMNygard  OVollset  SERefsum  H The Hordaland Homocysteine Studies. Lipids. 2001;36supplS33- S39
Link to Article
Bjelland  IDahl  AAHaug  TTNeckelmann  D The validity of the Hospital Anxiety and Depression Scale: an updated literature review. J Psychosom Res. 2002;5269- 77
Link to Article
Fiskerstrand  TRefsum  HKvalheim  GUeland  PM Homocysteine and other thiols in plasma and urine: automated determination and sample stability. Clin Chem. 1993;39263- 271
Molloy  AMScott  JM Microbiological assay for serum, plasma, and red cell folate using cryopreserved, microtiter plate method. Methods Enzymol. 1997;28143- 53
Kelleher  BPBroin  SD Microbiological assay for vitamin B12 performed in 96-well microtitre plates. J Clin Pathol. 1991;44592- 595
Link to Article
Ulvik  AUeland  PM Single nucleotide polymorphism (SNP) genotyping in unprocessed whole blood and serum by real-time PCR: application to SNPs affecting homocysteine and folate metabolism. Clin Chem. 2001;472050- 2053
Vollset  SERefsum  HTverdal  ANygard  ONordrehaug  JETell  GSUeland  PM Plasma total homocysteine and cardiovascular and noncardiovascular mortality: the Hordaland Homocysteine Study. Am J Clin Nutr. 2001;74130- 136
Hastie  TTibshirani  R Generalized Additive Models.  London, England Chapman & Hall1990;
Guttormsen  ABUeland  PMNesthus  INygard  OSchneede  JVollset  SERefsum  H Determinants and vitamin responsiveness of intermediate hyperhomocysteinemia(≥40 micromol/liter): the Hordaland Homocysteine Study. J Clin Invest. 1996;982174- 2183
Link to Article
Alpert  JEMischoulon  DNierenberg  AAFava  M Nutrition and depression: focus on folate. Nutrition. 2000;16544- 546
Link to Article
Ocke  MCSchrijver  JObermann-de Boer  GLBloemberg  BPHaenen  GRKromhout  D Stability of blood (pro)vitamins during four years of storage at −20 degrees C: consequences for epidemiologic research. J Clin Epidemiol. 1995;481077- 1085
Link to Article
Zittoun  JZittoun  R Modern clinical testing strategies in cobalamin and folate deficiency. Semin Hematol. 1999;3635- 46
Gunter  EWBowman  BACaudill  SPTwite  DBAdams  MJSampson  EJ Results of an international round robin for serum and whole-blood folate. Clin Chem. 1996;421689- 1694

Figures

Place holder to copy figure label and caption
Figure 1.

Components of 1-carbon metabolism and central nervous system (CNS) functions. SAM indicates S-adenosylmethionine; Hcy, homocysteine; Met, methionine; B12, vitamin B12; MS, methionine synthetase; 5mTHF, 5-methyl-tetrahydrofolate; 5,10mTHF, 5,10-methylene-tetrahydrofolate; THF, tetrahydrofolate; and MTHFR, methylenetetrahydrofolate reductase.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Dose-response relationships between plasma total homocysteine (tHcy), folate, and vitamin B12 levels and anxiety disorder and depression. The curves were constructed by using generalized additive regression analyses adjusting for age, sex, smoking status, and educational level. The shaded areas indicate 95% pointwise confidence intervals. To convert tHcy levels to milligrams per deciliter, divide by 7.397; folate to nanograms per milliliter, divide by 2.266; and vitamin B12 to picograms per milliliter, divide by 0.738.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Characteristics of the Study Population: the Hordaland Homocysteine Studies*
Table Graphic Jump LocationTable 2. Relationship of Anxiety Disorder and Depression to Various Characteristics of the Study Population: the Hordaland Homocysteine Studies*
Table Graphic Jump LocationTable 3. Odds Ratios for Having Anxiety Disorder at Different Levels of tHcy, Folate, Vitamin B12, and MTHFR Polymorphism in Model 1 (Adjusted for Age and Sex) and Model 2 (Adjusted for Age, Sex, Smoking Status, and Educational Level): the Hordaland Homocysteine Studies
Table Graphic Jump LocationTable 4. Odds Ratios for Having Depression at Different Levels of tHcy, Folate, Vitamin B12, and MTHFR Polymorphism in Model 1 (Adjusted for Age and Sex) and Model 2 (Adjusted for Age, Sex, Smoking Status, and Educational Level): the Hordaland Homocysteine Studies

References

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Godfrey  PSToone  BKCarney  MWFlynn  TGBottiglieri  TLaundy  MChanarin  IReynolds  EH Enhancement of recovery from psychiatric illness by methylfolate. Lancet. 1990;336392- 395
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Allen  RHStabler  SPSavage  DGLindenbaum  J Metabolic abnormalities in cobalamin (vitamin B12) and folate deficiency. FASEB J. 1993;71344- 1353
Lindenbaum  JHealton  EBSavage  DGBrust  JCGarrett  TJPodell  ERMarcell  PDStabler  SPAllen  RH Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med. 1988;3181720- 1728
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Penninx  BWGuralnik  JMFerrucci  LFried  LPAllen  RHStabler  SP Vitamin B12 deficiency and depression in physically disabled older women: epidemiologic evidence from the Women's Health and Aging Study. Am J Psychiatry. 2000;157715- 721
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Baldewicz  TTGoodkin  KBlaney  NTShor-Posner  GKumar  MWilkie  FLBaum  MKEisdorfer  C Cobalamin level is related to self-reported and clinically rated mood and to syndromal depression in bereaved HIV-1+ and HIV-1 homosexual men. J Psychosom Res. 2000;48177- 185
Link to Article
Tiemeier  HVan Tuijl  HRHofman  AMeijer  JKiliaan  AJBreteler  MM Vitamin B12, folate, and homocysteine in depression: the Rotterdam Study. Am J Psychiatry. 2002;1592099- 2101
Link to Article
Bottiglieri  TLaundy  MCrellin  RToone  BKCarney  MWReynolds  EH Homocysteine, folate, methylation, and monoamine metabolism in depression. J Neurol Neurosurg Psychiatry. 2000;69228- 232
Link to Article
Arinami  TYamada  NYamakawa-Kobayashi  KHamaguchi  HToru  M Methylenetetrahydrofolate reductase variant and schizophrenia/depression. Am J Med Genet. 1997;74526- 528
Link to Article
Kunugi  HFukuda  RHattori  MKato  TTatsumi  MSakai  THirose  TNanko  S C677T polymorphism in methylenetetrahydrofolate reductase gene and psychoses. Mol Psychiatry. 1998;3435- 437
Link to Article
van Praag  HM Depression. Lancet. 1982;21259- 1283
Link to Article
Bottiglieri  THyland  KReynolds  EH The clinical potential of ademetionine (S-adenosylmethionine) in neurological disorders. Drugs. 1994;48137- 152
Link to Article
Reynolds  EH Folic acid, ageing, depression, and dementia. BMJ. 2002;3241512- 1515
Link to Article
Kessler  RCNelson  CBMcGonagle  KALiu  JSwartz  MBlazer  DG Comorbidity of DSM-III-R major depressive disorder in the general population: results from the US National Comorbidity Survey. Br J Psychiatry Suppl. 1996;3017- 30
Mezzich  JEAhn  CWFabrega  HJPilkonis  PA Patterns of psychiatric comorbidity in a large population presenting for care. Maser  JDCloninger  CRedsComorbidity of Mood and Anxiety Disorders. Washington, DC American Psychiatric Press1990;189- 204
Sartorius  NUstun  TBLecrubier  YWittchen  HU Depression comorbid with anxiety: results from the WHO study on psychological disorders in primary health care. Br J Psychiatry Suppl. 1996;3038- 43
Edeh  JToone  BK Antiepileptic therapy, folate deficiency, and psychiatric morbidity: a general practice survey. Epilepsia. 1985;26434- 440
Link to Article
Hermesh  HWeizman  AShahar  AMunitz  H Vitamin B12 and folic acid serum levels in obsessive compulsive disorder. Acta Psychiatr Scand. 1988;788- 10
Link to Article
Zigmond  ASSnaith  RP The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983;67361- 370
Link to Article
Ueland  PMNygard  OVollset  SERefsum  H The Hordaland Homocysteine Studies. Lipids. 2001;36supplS33- S39
Link to Article
Bjelland  IDahl  AAHaug  TTNeckelmann  D The validity of the Hospital Anxiety and Depression Scale: an updated literature review. J Psychosom Res. 2002;5269- 77
Link to Article
Fiskerstrand  TRefsum  HKvalheim  GUeland  PM Homocysteine and other thiols in plasma and urine: automated determination and sample stability. Clin Chem. 1993;39263- 271
Molloy  AMScott  JM Microbiological assay for serum, plasma, and red cell folate using cryopreserved, microtiter plate method. Methods Enzymol. 1997;28143- 53
Kelleher  BPBroin  SD Microbiological assay for vitamin B12 performed in 96-well microtitre plates. J Clin Pathol. 1991;44592- 595
Link to Article
Ulvik  AUeland  PM Single nucleotide polymorphism (SNP) genotyping in unprocessed whole blood and serum by real-time PCR: application to SNPs affecting homocysteine and folate metabolism. Clin Chem. 2001;472050- 2053
Vollset  SERefsum  HTverdal  ANygard  ONordrehaug  JETell  GSUeland  PM Plasma total homocysteine and cardiovascular and noncardiovascular mortality: the Hordaland Homocysteine Study. Am J Clin Nutr. 2001;74130- 136
Hastie  TTibshirani  R Generalized Additive Models.  London, England Chapman & Hall1990;
Guttormsen  ABUeland  PMNesthus  INygard  OSchneede  JVollset  SERefsum  H Determinants and vitamin responsiveness of intermediate hyperhomocysteinemia(≥40 micromol/liter): the Hordaland Homocysteine Study. J Clin Invest. 1996;982174- 2183
Link to Article
Alpert  JEMischoulon  DNierenberg  AAFava  M Nutrition and depression: focus on folate. Nutrition. 2000;16544- 546
Link to Article
Ocke  MCSchrijver  JObermann-de Boer  GLBloemberg  BPHaenen  GRKromhout  D Stability of blood (pro)vitamins during four years of storage at −20 degrees C: consequences for epidemiologic research. J Clin Epidemiol. 1995;481077- 1085
Link to Article
Zittoun  JZittoun  R Modern clinical testing strategies in cobalamin and folate deficiency. Semin Hematol. 1999;3635- 46
Gunter  EWBowman  BACaudill  SPTwite  DBAdams  MJSampson  EJ Results of an international round robin for serum and whole-blood folate. Clin Chem. 1996;421689- 1694

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