unipolar depression, vitamin B12, and folate


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Taylor MJ, Carney S, Geddes J, Goodwin G.
Folate for depressive disorders.
Cochrane Database Syst Rev. 2003;(2):CD003390.
"BACKGROUND: There are a number of effective interventions for the treatment of depression. It is possible that the efficacy of these treatments will be improved further by the use of adjunctive therapies such as folate. OBJECTIVES: 1. To determine the effectiveness of folate in the treatment of depression 2. To determine the adverse effects and acceptability of treatment with folate. SEARCH STRATEGY: The Cochrane Controlled Trials Register (CCTR), and the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR) incorporating results of group searches of EMBASE, MEDLINE, LILACS, CINAHL, PSYNDEX and PsycLIT were searched. Reference lists of relevant papers and major textbooks of affective disorder were checked. Experts in the field and pharmaceutical companies were contacted regarding unpublished material. SELECTION CRITERIA: All randomised controlled trials that compared treatment with folic acid or 5'-methyltetrahydrofolic acid to an alternative treatment, whether another antidepressant medication or placebo, for patients with a diagnosis of depressive disorder (diagnosed according to explicit criteria). DATA COLLECTION AND ANALYSIS: Data were independently extracted from the original reports by two reviewers. Statistical analysis was conducted using Review Manager version 4.1. MAIN RESULTS: Three trials involving 247 people were included. Two studies involving 151 people assessed the use of folate in addition to other treatment, and found that adding folate reduced Hamilton Depression Rating Scale scores on average by a further 2.65 points (95% confidence interval 0.38 to 4.93). Fewer patients treated with folate experienced a reduction in their HDRS score of less than 50% at ten weeks (relative risk (RR) 0.47, 95% CI 0.24 to 0.92) The number needed to treat with folate for one additional person to experience a 50% reduction on this scale was 5 (95% confidence interval 4 to 33). One study involving 96 people assessed the use of folate instead of the antidepressant trazodone and did not find a significant benefit from the use of folate. The trials identified did not find evidence of any problems with the acceptability or safety of folate. REVIEWER'S CONCLUSIONS: The limited available evidence suggests folate may have a potential role as a supplement to other treatment for depression. It is currently unclear if this is the case both for people with normal folate levels, and for those with folate deficiency." [Abstract]

Fava M, Borus JS, Alpert JE, Nierenberg AA, Rosenbaum JF, Bottiglieri T.
Folate, vitamin B12, and homocysteine in major depressive disorder.
Am J Psychiatry. 1997 Mar;154(3):426-8.
"OBJECTIVE: The authors examined the relationships between levels of three metabolites (folate, vitamin B12, and homocysteine) and both depressive subtype and response to fluoxetine treatment in depressed patients. METHOD: Fluoxetine, 20 mg/day for 8 weeks, was given to 213 outpatients with major depressive disorder. At baseline, depressive subtypes were assessed, and a blood sample was collected from each patient. Serum metabolite levels were assayed. Response to treatment was determined by percentage change in score on the 17-item Hamilton Depression Rating Scale. RESULTS: Subjects with low folate levels were more likely to have melancholic depression and were significantly less likely to respond to fluoxetine. Homocysteine and B12 levels were not associated with depressive subtype or treatment response. CONCLUSIONS: Overall, the results are consistent with findings linking low folate levels to poorer response to antidepressant treatment. Folate levels might be considered in the evaluation of depressed patients who do not respond to antidepressant treatment." [Abstract]

Hintikka J, Tolmunen T, Tanskanen A, Viinamaki H.
High vitamin B12 level and good treatment outcome may be associated in major depressive disorder.
BMC Psychiatry. 2003 Dec 2;3(1):17.
"BACKGROUND: Despite of an increasing body of research the associations between vitamin B12 and folate levels and the treatment outcome in depressive disorders are still unsolved. We therefore conducted this naturalistic prospective follow-up study. Our aim was to determine whether there were any associations between the vitamin B12 and folate level and the six-month treatment outcome in patients with major depressive disorder. Because vitamin B12 and folate deficiency may result in changes in haematological indices, including mean corpuscular volume, red blood cell count and hematocrit, we also examined whether these indices were associated with the treatment outcome. METHODS: Haematological indices, erythrocyte folate and serum vitamin B12 levels were determined in 115 outpatients with DSM-III-R major depressive disorder at baseline and serum vitamin B12 level again on six-month follow-up. The 17-item Hamilton Depression Rating Scale was also compiled, respectively. In the statistical analysis we used chi-squared test, Pearson's correlation coefficient, the Student's t-test, analysis of variance (ANOVA), and univariate and multivariate linear regression analysis. RESULTS: Higher vitamin B12 levels significantly associated with a better outcome. The association between the folate level and treatment outcome was weak and probably not independent. No relationship was found between haematological indices and the six-month outcome. CONCLUSION: The vitamin B12 level and the probability of recovery from major depression may be positively associated. Nevertheless, further studies are suggested to confirm this finding." [Full Text]

Botez MI, Young SN, Bachevalier J, Gauthier S.
Effect of folic acid and vitamin B12 deficiencies on 5-hydroxyindoleacetic acid in human cerebrospinal fluid.
Ann Neurol. 1982 Nov;12(5):479-84.
"Indoles were measured in cerebrospinal fluid (CSF) from control patients, from patients suffering from folate deficiency, and from patients with vitamin B12 deficiency. The folate-deficient patients were classified according to whether they exhibited a neuropsychiatric syndrome, consisting of organic mental changes, polyneuropathy, and depression, which responded to folate administration. CSF 5-hydroxyindoleacetic acid was low in the vitamin B12-deficient patients and in those folate-deficient patients whose symptoms were not related to folate deficiency. CSF 5-hydroxyindoleacetic acid returned to normal with folate treatment in the patients exhibiting folate-responsive neuropsychiatric signs. The data indicate a close association between folate-responsive neuropsychiatric symptoms and changes in 5-hydroxytryptamine metabolism in the central nervous system." [Abstract]

Bottiglieri T, Hyland K, Laundy M, Godfrey P, Carney MW, Toone BK, Reynolds EH.
Folate deficiency, biopterin and monoamine metabolism in depression.
Psychol Med. 1992 Nov;22(4):871-6.
"Seven (21%) of 34 patients with a severe DSM-III diagnosis of major depression had red-cell folate levels below 150 ng/ml. This subgroup with folate deficiency had significantly lower CSF 5-hydroxyindoleacetic acid (5HIAA) compared to neurological controls. For all depressed patients red-cell folate was significantly correlated with CSF 5HIAA and homovanillic acid (HVA). CSF tetrahydrobiopterin (BH4) was significantly correlated with CSF 5HIAA and HVA and red-cell folate. Our observations provide further evidence of the links between folate, biopterin and monoamine metabolism in depression." [Abstract]

Surtees R, Heales S, Bowron A.
Association of cerebrospinal fluid deficiency of 5-methyltetrahydrofolate, but not S-adenosylmethionine, with reduced concentrations of the acid metabolites of 5-hydroxytryptamine and dopamine.
Clin Sci (Lond). 1994 Jun;86(6):697-702.
"1. Folate deficiency, or inborn errors of folate metabolism, cause reduced turnover of 5-hydroxytryptamine (serotonin), and perhaps dopamine, in the central nervous system. The mechanism by which this occurs are not known. One possibility is that this is mediated by deficiency of the methyl-donor S-adenosylmethionine. 2. To test this in humans, we have measured cerebrospinal fluid concentrations of 5-hydroxyindoleacetic acid and homovanillic acid, metabolites of 5-hydroxytryptamine and dopamine, respectively, in children with inborn errors of the methyl-transfer pathway. These children are naturally deficient in 5-methyltetrahydrofolate, S-adenosylmethionine or both before treatment, and replete with S-adenosylmethionine, but not necessarily with 5-methyltetrahydrofolate, during treatment. 3. Children with subnormal cerebrospinal fluid concentrations of 5-methyltetrahydrofolate had significantly reduced concentrations of 5-hydroxyindoleacetic acid and homovanillic acid. Children with subnormal cerebrospinal fluid concentrations of S-adenosylmethionine did not have significantly reduced concentrations of these metabolites. 4. We conclude that the mechanism by which deficiency of 5-methyltetrahydrofolate causes reduced 5-hydroxytryptamine and dopamine turnover is unlikely to be mediated by S-adenosylmethionine." [Abstract]

Wolfersdorf M, Keller F, Maier V, Froscher W, Kaschka WP.
Red-cell and serum folate levels in depressed inpatients who commit violent suicide: a comparison with control groups.
Pharmacopsychiatry. 1995 May;28(3):77-9.
"There has been some discussion in the recent literature regarding the possible relationship between peripheral levels of folate and serotonin deficiency in the CNS. At the same time, such a serotonin deficiency has been implicated in the biology of suicidal behavior. Thus, decreased peripheral folate levels may be expected in patients who commit violent suicide. In this study, the red-cell and serum folate levels in nine persons who later committed suicide are compared with those in age- and sex-matched control groups. A one-way analysis of variance showed no significant difference between the groups." [Abstract]

Young SN.
The use of diet and dietary components in the study of factors controlling affect in humans: a review.
J Psychiatry Neurosci 1993 Nov;18(5):235-44
"Although one of the first biological treatments of a major psychiatric disorder was the dietary treatment of pellagra, the use of diet and dietary components in the study of psychopathology has not aroused much interest. This article reviews three areas in which the dietary approach has provided interesting information. The tryptophan depletion strategy uses a mixture of amino acids devoid of tryptophan to lower brain tryptophan in order to study the symptoms that can be elicited. One effect of tryptophan depletion is a lowering of mood, the magnitude of which seems to depend on the baseline state of the subject. Therefore, recovered depressed patients often undergo an acute relapse, while normal subjects show more moderate changes of mood. Totally euthymic subjects show no lowering of mood, but subjects with high normal depression scale scores or subjects with a family history of depression show a moderate lowering of mood. These data indicate that low serotonin levels alone cannot cause depression. However, serotonin does have a direct effect on mood, and low levels of serotonin contribute to the etiology of depression in some depressed patients. Folic acid deficiency causes a lowering of brain serotonin in rats, and of cerebrospinal fluid 5-hydroxyindoleacetic acid in humans. There is a high incidence of folate deficiency in depression, and there are indications in the literature that some depressed patients who are folate deficient respond to folate administration. Folate deficiency is known to lower levels of S-adenosylmethionine, and S-adenosylmethionine is an antidepressant that raises brain serotonin levels. These data suggest that low levels of serotonin in some depressed patients may be a secondary consequence of low levels of S-adenosylmethionine. They also suggest that the dietary intake and psychopharmacological action of methionine, the precursor of S-adenosylmethionine, should be studied in patients with depression. Normal meals have definite effects on mood and performance in humans. The composition of the meal, in terms of protein and carbohydrate content, can influence these behaviors. Because protein and carbohydrate meals can influence brain serotonin in rats, these effects in humans have usually been interpreted in terms of altered serotonin functioning. However, the current balance of evidence is against the involvement of serotonin in the acute effects of protein and carbohydrate meals in humans. The underlying mechanisms involved are unknown, but there are a variety of possibilities." [Abstract]

Coppen A, Bailey J.
Enhancement of the antidepressant action of fluoxetine by folic acid: a randomised, placebo controlled trial.
J Affect Disord. 2000 Nov;60(2):121-30.
"BACKGROUND: A consistent finding in major depression has been a low plasma and red cell folate which has also been linked to poor response to antidepressants. The present investigation was designed to investigate whether the co-administration of folic acid would enhance the antidepressant action of fluoxetine. METHODS: 127 patients were randomly assigned to receive either 500 microg folic acid or an identical looking placebo in addition to 20 mg fluoxetine daily. All patients met the DSM-III-R criteria for major depression and had a baseline Hamilton Rating Scale (17 item version) score for depression of 20 or more. Baseline and 10-week estimations of plasma folate and homocysteine were carried out. RESULTS: Patients receiving folate showed a significant increase in plasma folate.This was less in men than in women. Plasma homocysteine was significantly decreased in women by 20.6%, but there was no significant change in men. Overall there was a significantly greater improvement in the fluoxetine plus folic acid group. This was confined to women where the mean Hamilton Rating Scale score on completion was 6.8 (S.D. 4. 1) in the fluoxetine plus folate group, as compared to 11.7 (S.D. 6. 7) in the fluoxetine plus placebo group (P<0.001).A percentage of 93. 9 of women, who received the folic acid supplement, showed a good response (>50% reduction in score) as compared to 61.1% of women who received placebo supplement (P<0.005). Eight (12.9%) patients in the fluoxetine plus folic acid group reported symptoms possibly or probably related to medication, whereas in the fluoxetine plus placebo group 19 (29.7%) patients reported such symptoms (P<0.05). LIMITATIONS AND CONCLUSIONS: Folic acid is a simple method of greatly improving the antidepressant action of fluoxetine and probably other antidepressants. Folic acid should be given in doses sufficient to decrease plasma homocysteine. Men require a higher dose of folic acid to achieve this than women, but more work is required to ascertain the optimum dose of folic acid." [Abstract]

Alpert JE, Mischoulon D, Rubenstein GE, Bottonari K, Nierenberg AA, Fava M.
Folinic acid (Leucovorin) as an adjunctive treatment for SSRI-refractory depression.
Ann Clin Psychiatry. 2002 Mar;14(1):33-8.
"Low folate is associated with poorer response to selective serotonin reuptake inhibitors (SSRIs) in major depressive disorder (MDD). Folate supplementation in MDD has been studied in other settings with promising results. The objective of this study was to assess the efficacy of methylfolate as an adjunctive treatment among adults with MDD and inadequate response to an SSRI. Twenty-two adults (59% female; mean age 45.2 +/- 11.0 years) with DSM-IV MDD, partial or nonresponse to an SSRI after at least 4 weeks of treatment, and a 17-item Hamilton Depression Rating Scale (HAM-D-17) score > or = 12 were enrolled in this 8-week prospective open trial. Exclusion criteria included current use of anticonvulsants or psychotropics other than an SSRI, or B12 deficiency. Leucovorin (folinic acid), which is metabolized to methylfolate, was added to SSRIs at 15-30 mg/day. Folate levels rose from 28 +/- 19 ng/mL to 301 +/- 203 ng/mL (p < 0.001). HAM-D-17 scores among the 16 completers decreased from 19.1 +/- 3.9 to 12.8 +/- 7.0 (p < 0.01). However only 31% of completers and 27% of the intent-to-treat (ITT) sample achieved response (> or = 50% reduction in HAM-D-17 scores), and only 19% of completers and 18% of the ITT sample achieved remission (HAM-D-17 < or = 7). Leucovorin appears to be modestly effective as an adjunct among SSRI-refractory depressed individuals with normal folate levels. The application of leucovorin as an adjunct in the setting of refractory depression deserves further study." [Abstract]

Procter A.
Enhancement of recovery from psychiatric illness by methylfolate.
Br J Psychiatry. 1991 Aug;159:271-2.
"41 (33%) of 123 patients with acute psychiatric disorders (DSM III diagnosis of major depression or schizophrenia) had borderline or definite folate deficiency (red-cell folate below 200 micrograms/l) and took part in a double-blind, placebo-controlled trial of methylfolate, 15 mg daily, for 6 months in addition to standard psychotropic treatment. Among both depressed and schizophrenic patients methylfolate significantly improved clinical and social recovery. The differences in outcome scores between methylfolate and placebo groups became greater with time. These findings add to the evidence implicating disturbances of methylation in the nervous system in the biology of some forms of mental illness." [Abstract]

Godfrey PS, Toone BK, Carney MW, Flynn TG, Bottiglieri T, Laundy M, Chanarin I, Reynolds EH.
Enhancement of recovery from psychiatric illness by methylfolate.
Lancet. 1990 Aug 18;336(8712):392-5.
"41 (33%) of 123 patients with acute psychiatric disorders (DSM III diagnosis of major depression or schizophrenia) had borderline or definite folate deficiency (red-cell folate below 200 micrograms/l) and took part in a double-blind, placebo-controlled trial of methylfolate, 15 mg daily, for 6 months in addition to standard psychotropic treatment. Among both depressed and schizophrenic patients methylfolate significantly improved clinical and social recovery. The differences in outcome scores between methylfolate and placebo groups became greater with time. These findings add to the evidence implicating disturbances of methylation in the nervous system in the biology of some forms of mental illness." [Abstract]

Wesson VA, Levitt AJ, Joffe RT.
Change in folate status with antidepressant treatment.
Psychiatry Res. 1994 Sep;53(3):313-22.
"Ninety-nine consecutive unmedicated outpatients with a major depressive illness had blood drawn for measurement of serum folate (SF), red cell folate (RCF), and vitamin B12 within 24 hours of completion of ratings of severity of depression at the beginning and ending of a 5-week trial of desmethylimipramine (mean dose = 149.2 mg/day, range = 75-225 mg). As compared with nonresponders, responders had a significantly higher mean SF at baseline (nonresponders = 13.8 nmol/l; responders = 17.7 nmol/l) and RCF showed a significant inverse correlation with severity of depression and a significant positive correlation with age of onset of illness. At week 5, change in severity of depression was significantly correlated with change in RCF, and significantly more responders than nonresponders had an increase in RCF. The possible role of folate status in the regulation of mood and response to treatment is discussed." [Abstract]

Guaraldi GP, Fava M, Mazzi F, la Greca P.
An open trial of methyltetrahydrofolate in elderly depressed patients.
Ann Clin Psychiatry. 1993 Jun;5(2):101-5.
"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 clinically relevant changes in the routine laboratory tests during the study, and no adverse events considered to be definitely drug-related were reported." [Abstract]

Lee S, Wing YK, Fong S.
A controlled study of folate levels in Chinese inpatients with major depression in Hong Kong.
J Affect Disord. 1998 Apr;49(1):73-7.
"BACKGROUND: Although Western and, in particular, British studies have revealed a substantial rate of hypofolatemia in patients with depression, few such studies have been conducted in Asian populations. METHODS: A group of 117 newly admitted inpatients with DSM-III-R major depression and 72 healthy controls underwent blood investigations and psychometric assessments. RESULTS: Patients had a significantly lower mean serum folate level (24.6+/-10.2 vs. 30.3+/-11.4 nmol/l, P < 0.001) but a higher mean erythrocyte folate level (801.8+/-284.6 nmol/l vs. 699.5+/-248.7 nmol/l, P < 0.01) than control subjects. No patient or control subjects had low folate, while only four patients (3.4%) and six control subjects (8.3%) had low erythrocyte folate. Folate levels were not related to patients' age, duration of illness, Hamilton Depression Rating Scale, Beck Depression Inventory and Global Assessment Scale scores, and prior psychotropic drug usage. Both patients and control subjects revealed a high intake of green vegetables. CONCLUSION: Patients' lower serum folate level was likely to be secondary to their depression but, being well in the normal range, should not have aggravated their depressive symptoms. Culturally patterned health beliefs and dietary practices can influence the connection between folate status and depression in different societies. LIMITATIONS: Patients were not drug-free, while the lack of detailed dietary analysis and longitudinal data on folate level and psychiatric outcome tempered the above conclusion. CLINICAL RELEVANCE: Since normofolatemia is normative in Hong Kong, the routine screening of folate levels in Chinese depressive patients is not indicated. However, a double-blind, placebo-controlled trial may be useful for finding out whether Chinese patients will still benefit from folate pharmacotherapy." [Abstract]

Wilkinson AM, Anderson DN, Abou-Saleh MT, Wesson M, Blair JA, Farrar G, Leeming RJ.
5-Methyltetrahydrofolate level in the serum of depressed subjects and its relationship to the outcome of ECT.
J Affect Disord. 1994 Nov;32(3):163-8.
"Serum 5-MeTHF levels are reported in 26 subjects, before and after completing a course of ECT, and compared to 21 healthy volunteers. 5-MeTHF levels of depressed subjects were significantly lower than controls before and after ECT. There was no difference in 5-MeTHF levels between ECT responders and non-responders but folate deficiency was related to severity of depression before ECT. Serum 5-MeTHF was not related to treatment response and values remained markedly low even after a good response to treatment." [Abstract]

Mischoulon D, Burger JK, Spillmann MK, Worthington JJ, Fava M, Alpert JE.
Anemia and macrocytosis in the prediction of serum folate and vitamin B12 status, and treatment outcome in major depression.
J Psychosom Res. 2000 Sep;49(3):183-7.
"BACKGROUND: Folate and B12 deficiencies may result in macrocytic anemia, and are common in major depression; hypofolatemia may result in poorer antidepressant response. We wished to determine whether anemia or macrocytosis predict hypofolatemia, low B12, or refractoriness to antidepressants. METHODS: After obtaining serum folate, B12, and hematological indices, 213 depressed adults were treated with fluoxetine 20 mg/day. Amelioration of depressive symptoms was measured. RESULTS: Neither macrocytosis nor anemia predicted low serum folate/B12, or antidepressant refractoriness. Among 39 patients with hypofolatemia, none had macrocytosis; 28% had low HCT; 41% had low RBC. Among 25 patients with low B12, none had macrocytosis; 24% had low HCT; 28% had low RBC. Among non-responders, 3% had macrocytosis; 24% had low HCT; 25% had low RBC. CONCLUSION: Anemia and macrocytosis should not be used to predict folate or B12 deficiencies, or refractoriness to antidepressants. Measurement of folate and B12 should be considered when evaluating treatment refractoriness." [Abstract]

Gultepe M, Ozcan O, Avsar K, Cetin M, Ozdemir AS, Gok M.
Urine methylmalonic acid measurements for the assessment of cobalamin deficiency related to neuropsychiatric disorders.
Clin Biochem. 2003 Jun;36(4):275-82.
"BACKGROUND: Detection of cobalamin deficiency is clinically important for a better understanding of neuropsychiatric diseases, and why the deficiency occurs more frequently than previously anticipated. However, serum cobalamin measurements have a limited ability to diagnose a deficiency state. OBJECTIVE: To evaluate functional cobalamin status in neuropsychiatric patients using an appropriate photometric urine methylmalonic acid (MMA) determination method that could be easily adapted to all routine clinical laboratories. METHODS: We modified the old photometric method used for determining urinary MMA concentrations. MMA measurements were made in first morning urine samples with normalizing by creatinine concentrations. The serum cobalamin, total homocysteine (tHcy), folate, red cell folate, and urinary MMA concentrations taken from 17 psychosis, 28 depression, 16 dementia patients and 47 healthy people were analyzed using the ROC, correlation and multiple regression analysis.RESULTS: The modified method was found to have better recovery (96-103%) and CV% values than the old method. Mean +/- SDs of uMMA and cobalamin concentrations were 11.49 +/- 4.93 mmol/mol creatinine, and 231 +/- 151 pg/mL in psychosis and depression group, and 6.04 +/- 1.93 mmol/mol creatinine and 308 +/- 140 pg/mL in control group, respectively. Those in the dementia group were 11.53 +/- 4.0 mmol/mol creatinine and 231 +/- 84 pg/mL, and in the control group 6.05 +/- 1.94 mmol/mol creatinine and 364 +/- 188 pg/mL. There was a good correlation between urinary MMA and serum Vitamin B(12) determinations for all groups at a confidence level (p) of 99%. The correlation between urinary MMA and red cell folate was also significant at p = 95% for depression, psychosis and control groups, and p = 99% for dementia group. In the ROC analyses, area under the curve values for uMMA, B12 and tHcy were 0.842, 0.796 and 0.728, respectively. CONCLUSIONS: A sensitive and easy photometric method has been presented. When cobalamin deficiency is suspected in neuropsychiatric patients, photometric urinary MMA determination analysis can be the first diagnostic test used. If the urinary MMA concentration is above the reference value, serum cobalamin levels can be determined for further diagnosis." [Abstract]

Bjelland I, Tell GS, Vollset SE, Refsum H, Ueland PM.
Folate, vitamin B12, homocysteine, and the MTHFR 677C->T polymorphism in anxiety and depression: the Hordaland Homocysteine Study.
Arch Gen Psychiatry. 2003 Jun;60(6):618-26.
"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 > or =15.0 micro mol/L [> or =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." [Abstract]

Mattson MP, Shea TB.
Folate and homocysteine metabolism in neural plasticity and neurodegenerative disorders.
Trends Neurosci. 2003 Mar;26(3):137-46.
"Folate is a cofactor in one-carbon metabolism, during which it promotes the remethylation of homocysteine -- a cytotoxic sulfur-containing amino acid that can induce DNA strand breakage, oxidative stress and apoptosis. Dietary folate is required for normal development of the nervous system, playing important roles regulating neurogenesis and programmed cell death. Recent epidemiological and experimental studies have linked folate deficiency and resultant increased homocysteine levels with several neurodegenerative conditions, including stroke, Alzheimer's disease and Parkinson's disease. Moreover, genetic and clinical data suggest roles for folate and homocysteine in the pathogenesis of psychiatric disorders. A better understanding of the roles of folate and homocysteine in neuronal homeostasis throughout life is revealing novel approaches for preventing and treating neurological disorders." [Abstract]

Tiemeier H, van Tuijl HR, Hofman A, Meijer J, Kiliaan AJ, Breteler MM.
Vitamin B12, folate, and homocysteine in depression: the Rotterdam Study.
Am J Psychiatry. 2002 Dec;159(12):2099-101.
"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 randomly 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." [Abstract]

Wolters M, Strohle A, Hahn A.
[Age-associated changes in the metabolism of vitamin B(12) and folic acid: Prevalence, aetiopathogenesis and pathophysiological consequences]
Z Gerontol Geriatr. 2004 Apr;37(2):109-35.
"The increasing number of older people is characteristic for most industrialised nations and implicates the known psychosocial and economic consequences. Therefore, an optimal nutrient supply that promotes continuing mental and physical well-being is particularly important. In this respect, vitamin B(12) and folic acid play a major role, since deficiency of both vitamins is associated with the pathogenesis of different diseases such as declining neurocognitive function and atherosclerotic lesions. Vitamin B(12) and folic acid act as coenzymes and show a close molecular interaction on the basis of the homocysteine metabolism. In addition to the serum concentrations of the vitamins, the metabolites homocysteine and methylmalonic acid are sensitive markers of cobalamin and folate status. Depending on the used marker, 3-60% of the elderly are classified as vitamin B(12) deficient and about 29% as folate deficient. Predominantly, this high prevalence of poor cobalamin status is caused by the increasing prevalence of atrophic gastritis type B, which occurs with a frequency of approximately 20-50% in elderly subjects. Atrophic gastritis results in declining gastric acid and pepsinogen secretion, and hence decreasing intestinal digestion and absorption of both B vitamins. This is the reason why an insufficient vitamin B(12) status in the elderly is rarely due to low dietary intake. In contrast, folic acid intake among elderly subjects is generally well below the recommended dietary reference values.Even moderately increased homocysteine levels or poor folate and vitamin B(12) status are associated with vascular disease and neurocognitive disorders. Results of a meta-analysis of prospective studies revealed that a 25% lower homocysteine level (about 3 micromol/L) was associated with an 11% lower ischemic heart disease risk and 19% lower stroke risk. It is still discussed, whether hyperhomocysteinemia is causally related to vascular disease or whether it is a consequence of atherosclerosis. Estimated risk reduction is based on cohort studies, not on clinical trials. Homocysteine initiates different proatherogenetic mechanisms such as the formation of reactive oxygen species and an enhanced fibrin synthesis. Supplementation of folic acid (0.5-5 mg/d) reduces the homocysteine concentration by 25%. Additional vitamin B(12) (0.5 mg/d) induces further reduction by 7%. In secondary prevention, supplementation already led to clinical improvements (reduction of restenosis rate and plaques).Depression, dementia, and mental impairment are often associated with folate and vitamin B(12) deficiency. The biochemical reason of this finding may be the importance of folic acid and vitamin B(12) for the transmethylation of neuroactive substances (myelin, neurotransmitters) which is impaired in vitamin deficiency ("hypomethylation hypothesis").In recent years, there is increasing evidence for a role of folic acid in cancer prevention. As a molecular mechanism of a preventive effect of folic acid the hypomethylation of certain DNA sections in folate deficiency has been suggested. Since folate and vitamin B(12) intake and status are mostly insufficient in elderly subjects, a supplementation can generally be recommended." [Abstract]

Morris MS, Fava M, Jacques PF, Selhub J, Rosenberg IH.
Depression and folate status in the US Population.
Psychother Psychosom. 2003 Mar-Apr;72(2):80-7.
"BACKGROUND: Folate deficiency and low folate status have been linked in clinic studies to depression, persistent depressive symptoms, and poor antidepressant response. These relationships have not been demonstrated in general populations. This study examined associations between depression and folate status indicators in an ethnically diverse general US population sample aged 15-39 years. METHODS: Healthy subjects whose red blood cell (RBC) folate concentrations had been measured were determined to have no depression (n = 2,526), major depression (n = 301), or dysthymia (n = 121) using a diagnostic interview schedule. Serum concentrations of folate and total homocysteine (tHcy) were also measured. RESULTS: After adjustment for sociodemographic factors, serum vitamin B(12) concentration, alcohol consumption over the past year and current status as to overweight and use of vitamin/mineral supplements, cigarettes and illegal drugs, subjects who met criteria for a lifetime diagnosis of major depression had folate concentrations in serum and RBCs that were lower than those of subjects who had never been depressed. Subjects who met criteria for dysthymia alone had lower RBC folate concentrations than never-depressed subjects, but the serum folate concentrations of the two groups were comparable. Serum tHcy concentration was not related to lifetime depression diagnoses. Low folate status was found to be most characteristic of recently recovered subjects, and a large proportion of such subjects were folate deficient. CONCLUSIONS: Low folate status was detectable in depressed members of the general US population. Folate supplementation may be indicated during the year following a depressive episode." [Abstract]

Tolmunen, Tommi, Voutilainen, Sari, Hintikka, Jukka, Rissanen, Tiina, Tanskanen, Antti, Viinamaki, Heimo, Kaplan, George A., Salonen, Jukka T.
Dietary Folate and Depressive Symptoms Are Associated in Middle-Aged Finnish Men
J. Nutr. 2003 133: 3233-3236
"Several cross-sectional studies have focused on the low blood folate levels of depressed patients. However, no published studies have examined the association between dietary folate and current symptoms of depression in a general population. We investigated the association between dietary folate, cobalamin, pyridoxine and riboflavin and current symptoms of depression in a cross-sectional general population study. We recruited 2682 men aged between 42 and 60 y from eastern Finland. Those who had a previous history of psychiatric disorder were excluded (n = 146, 5.6% of the cohort). Depressive symptoms were assessed with the 18-item Human Population Laboratory Depression Scale. Those who scored 5 or more at baseline were considered to have elevated depressive symptoms (n = 228, 9.3% of the cohort). The participants were grouped into thirds according to their dietary folate intake. Those in the lowest third of energy-adjusted folate intake had a higher risk of being depressed [odds ratio (OR) 1.67, 95% CI = 1.19-2.35, P = 0.003] than those in the highest folate intake third. This increased risk remained significant after adjustment for smoking habits, alcohol consumption, appetite, BMI, marital status, education, adulthood socioeconomic status and total fat consumption (OR = 1.46, 95% CI = 1.01-2.12, P = 0.044). There were no associations between the intake of cobalamin, pyridoxine or riboflavin, and depression. These results indicate that nutrition may have a role in the prevention of depression." [Abstract]

Carney MW, Chary TK, Laundy M, Bottiglieri T, Chanarin I, Reynolds EH, Toone B.
Red cell folate concentrations in psychiatric patients.
J Affect Disord. 1990 Jul;19(3):207-13.
"Red cell folate and vitamin B12 estimations were performed on 243 successively admitted in-patients at a District General Hospital Psychiatric Unit and 42 out-patients (29 attending a lithium clinic). Patients were classified into five diagnostic groups. The mean ages of the manic and schizophrenic patients were lower than of the depressed or euthymic patients but age was not correlated with red cell folate or serum B12 levels in any group. There were 89 (31%) patients with red cell folate below 200 ng/ml and 35 (12%) with concentrations below 150 ng/ml. Significantly more of these low-folate patients were in-patients than out-patients. The mean red cell folate in the depressed patients was significantly lower than in the euthymic, manic and schizophrenic groups. Alcoholics had a similar mean red cell folate to depressed patients which was not quite significantly lower than the other groups. The mean serum B12 level in the alcoholics was, however, significantly raised. There were no significant differences in red cell folate or serum B12 between lithium-treated and untreated euthymic patients. The highest proportions of values below 200 ng/ml and 150 ng/ml were found in depressed and alcoholic patients. Endogenous depressives had the highest percentage of values below 150 ng/ml (folate-deficient) of all psychiatric groups and alcoholic patients." [Abstract]

Wolfersdorf M, Konig F.
[Serum folic acid and vitamin B12 in depressed inpatients. A study of serum folic acid with radioimmunoassay in 121 depressed inpatients]
Psychiatr Prax. 1995 Jul;22(4):162-4.
"According to the newer literature on folate deficiencies in depressive patients serum folate and vitamin B12 levels were studied (RIA) in 121 consecutively admitted depressive inpatients (47 male, 74 female depressives; age 17-86 years, mean age 48 years, diagnostic by ICD-9 300.4, 296.1) during the first (1-3) days of admission (normal volumes folate 3-17 ng/ml, vitamin B12 200-900 pg/ml). Only in two patients serum folate below 3 ng/ml were found, low vitamin B12 levels (below 200 pg/ml) showed 14 patients. This result is in contrast to other authors who found folate deficiencies in 10-50% of psychiatric patients." [Abstract]

Herran A, Garcia-Unzueta MT, Amado JA, Lopez-Cordovilla JJ, Diez-Manrique JF, Vazquez-Barquero JL.
Folate levels in psychiatric outpatients.
Psychiatry Clin Neurosci. 1999 Aug;53(4):531-3.
"This study examines folate in psychiatric outpatients. Fifty-three outpatients with schizophrenia and 24 outpatients with depressive disorder assessed with the Schedules for Clinical Assessment in Neuropsychiatry interview are included. Patients with schizophrenia had lower serum folate levels than age- and sex-matched controls, while red cell folate levels did not differ. Serum folate levels showed a negative correlation with the Clinical Global Impression, disorganized dimension, and total Positive and Negative Syndrome Scale score. Patients with depressive disorder had lower serum folate levels than healthy controls, but showed no differences in red cell folate levels. Only two patients with schizophrenia had red cell folate levels below the normal range." [Abstract]

Abou-Saleh MT, Coppen A.
Serum and red blood cell folate in depression.
Acta Psychiatr Scand. 1989 Jul;80(1):78-82.
"Serum folate concentrations were estimated in patients with major depressive disorders, lithium-treated patients, detoxified alcoholic patients and normal controls. Red blood cell (RBC) folate concentrations were also estimated in subgroups of patients with major depressive disorder and normal controls. Results showed significantly lower serum and RBC folate concentrations in patients with major depressive disorder than in normal controls. Lower serum folate concentrations were associated with greater severity of depression. There was no association between serum and RBC folate concentrations and endogenicity of depression or the presence of weight loss." [Abstract]

Levitt AJ, Joffe RT.
Folate, B12, and life course of depressive illness.
Biol Psychiatry. 1989 Apr 1;25(7):867-72.
"Forty-four consecutive, unmedicated outpatients with a major depressive disorder were evaluated to determine the relationships in life course, severity of depressive illness, and serum folate and B12 levels. Duration of current episode was significantly inversely correlated with folate levels. Age at onset of illness was significantly correlated with B12. In a subgroup of recurrent depressives, current age and age at onset of depressive illness were positively correlated with folate. The findings are discussed in light of the current hypotheses regarding the association of folate and mood." [Abstract]

Alpert M, Silva RR, Pouget ER.
Prediction of treatment response in geriatric depression from baseline folate level: interaction with an SSRI or a tricyclic antidepressant.
J Clin Psychopharmacol. 2003 Jun;23(3):309-13.
"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)." [Abstract]

Bell IR, Edman JS, Morrow FD, Marby DW, Mirages S, Perrone G, Kayne HL, Cole JO.
B complex vitamin patterns in geriatric and young adult inpatients with major depression.
J Am Geriatr Soc. 1991 Mar;39(3):252-7.
"This study compared the B complex vitamin status at time of admission of 20 geriatric and 16 young adult non-alcoholic inpatients with major depression. Twenty-eight percent of all subjects were deficient in B2 (riboflavin), B6 (pyridoxine), and/or B12 (cobalamin), but none in B1 (thiamine) or folate. The geriatric sample had significantly higher serum folate levels. Psychotic depressives had lower B12 than did non-psychotic depressives. Poorer blood vitamin status was not associated with higher scores on the Hamilton Depression Rating Scale or lower scores on the Mini-Mental State Examination in either age group. The data support the hypothesis that poorer status in certain B vitamins is present in major depression, but blood measures may not reflect central nervous system vitamin function or severity of affective syndromes as measured by the assays and scales in the present study." [Abstract]

Penninx BW, Guralnik JM, Ferrucci L, Fried LP, Allen RH, Stabler SP.
Vitamin B(12) deficiency and depression in physically disabled older women: epidemiologic evidence from the Women's Health and Aging Study.
Am J Psychiatry. 2000 May;157(5):715-21.
"OBJECTIVE: It has been hypothesized that adequate concentrations of vitamin B(12) and folate are essential to maintain the integrity of the neurological systems involved in mood regulation, but epidemiologic evidence for such a link in the general population is unavailable. This study examined whether community-dwelling older women with metabolically significant vitamin B(12) or folate deficiency are particularly prone to depression. METHOD: Serum levels of vitamin B(12), folate, methylmalonic acid, and total homocysteine were assayed in 700 disabled, nondemented women aged 65 years and over living in the community. Depressive symptoms were measured by means of the Geriatric Depression Scale and categorized as no depression, mild depression, and severe depression. RESULTS: Serum homocysteine levels, serum folate levels, and the prevalences of folate deficiency and anemia were not associated with depression status. The depressed subjects, especially those with severe depression, had a significantly higher serum methylmalonic acid level and a nonsignificantly lower serum vitamin B(12) level than the nondepressed subjects. Metabolically significant vitamin B(12) deficiency was present in 14.9% of the 478 nondepressed subjects, 17. 0% of the 100 mildly depressed subjects, and 27.0% of the 122 severely depressed women. After adjustment for sociodemographic characteristics and health status, the subjects with vitamin B(12) deficiency were 2.05 times as likely to be severely depressed as were nondeficient subjects. CONCLUSIONS: In community-dwelling older women, metabolically significant vitamin B(12)deficiency is associated with a twofold risk of severe depression." [Abstract]

Bell IR, Edman JS, Miller J, Hebben N, Linn RT, Ray D, Kayne HL.
Relationship of normal serum vitamin B12 and folate levels to cognitive test performance in subtypes of geriatric major depression.
J Geriatr Psychiatry Neurol. 1990 Apr-Jun;3(2):98-105.
"This retrospective study evaluated the relationships between normal serum vitamin B12 and folate levels and neuropsychologic measures in a sample of 60 geriatric inpatients with psychotic depression, nonpsychotic depression, bipolar disorder, and dementia--all consecutively referred for cognitive testing. The psychotic depression subgroup demonstrated numerous significant positive correlations between B12 and cognitive subtests not seen in other diagnostic subgroups, especially those of IQ, and verbal and visual memory. Metabolic factors including vitamin B12 may play specific roles in the cognitive dysfunctions of different geropsychiatric disorders." [Abstract]

Bell IR, Edman JS, Marby DW, Satlin A, Dreier T, Liptzin B, Cole JO.
Vitamin B12 and folate status in acute geropsychiatric inpatients: affective and cognitive characteristics of a vitamin nondeficient population.
Biol Psychiatry. 1990 Jan 15;27(2):125-37.
"This chart review study examined the serum vitamin B12 and folate status of 102 geriatric patients newly admitted to a private psychiatric hospital. Only 3.7% were B12 deficient and 1.3% were folate deficient; 4% were anemic. Nevertheless, those with below-median values of both vitamins had significantly lower Mini-Mental State scores than patients higher in one or both vitamins. Patients with "organic psychosis" with a negative family history for psychiatric disorder had significantly lower B12 levels than those with a positive family history. In major depression, folate levels correlated negatively with age at onset of psychiatric illness and length of hospitalization. These data suggest that (1) biochemically interrelated vitamins such as B12 and folate may exert both a separate and a concomitant influence on affect and cognition; (2) poorer vitamin status may contribute to certain geropsychiatric disorders that begin at a later age and lack a familial predisposition." [Abstract]

Bell IR, Edman JS, Morrow FD, Marby DW, Perrone G, Kayne HL, Greenwald M, Cole JO.
Brief communication. Vitamin B1, B2, and B6 augmentation of tricyclic antidepressant treatment in geriatric depression with cognitive dysfunction.
J Am Coll Nutr. 1992 Apr;11(2):159-63.
"This was a 4-week randomized 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 inpatients 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." [Abstract]

Rouillon F, Thalassinos M, Miller HD, Lemperiere T.
Folates and post partum depression.
J Affect Disord. 1992 Aug;25(4):235-41.
"Hypofolatemia can cause psychiatric disturbances of a depressive nature. Pregnancy and delivery are often associated with hypofolatemia. This study was conducted to determine if hypofolatemia at day 3 post partum is a risk factor for baby blues or post partum depression. To study this hypothesis, 131 post partum women were followed prospectively for the 3 months immediately following delivery. 19% were found to have 'baby blues', as defined by a score greater than 20 on Pitt's scale (Pitt, 1968, J. Psychiatry 114, 1325-1335) and 12% had post partum depression as defined by a score greater than 7 on QD2A scale (Pichot et al., 1984, Rev. Psycholog. App. 34, 229-250, 323-340), within the three months post partum. No relationship was observed between the serum or erythrocyte folate levels on the third day following delivery and the maternal post partum depression scores. A statistically significant correlation between post partum depression and previous psychiatric disturbance was, however, observed." [Abstract]

Baldewicz TT, Goodkin K, Blaney NT, Shor-Posner G, Kumar M, Wilkie FL, Baum MK, Eisdorfer 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 Feb;48(2):177-85.
"OBJECTIVE: An examination of the relationship of plasma cobalamin (vitamin B(12)) level to overall psychological distress, specific mood states, and major depressive disorder was conducted in 159 bereaved men (90 HIV-1(+) and 69 HIV-1(-)). METHODS: The relationship of a continuous measure of cobalamin level to psychological distress was examined, while controlling for HIV-1 serostatus, life stressors, social support, and coping styles. RESULTS: Of this sample, 23.9% were either overtly or marginally cobalamin deficient; however, the deficiency rate was not significantly different by HIV-1 serostatus. Cobalamin level was inversely related to self-reported overall distress level and specifically to depression, anxiety, and confusion subscale scores, as well as to clinically rated depressed and anxious mood. Lower plasma cobalamin levels also were associated with the presence of symptoms consistent with major depressive disorder. CONCLUSION: These findings suggest that cobalamin level may be physiologically related to depressed and anxious mood level, as well as to syndromal depression." [Abstract]

Perkins DO, Stern RA, Golden RN, Murphy C, Naftolowitz D, Evans DL.
Mood disorders in HIV infection: prevalence and risk factors in a nonepicenter of the AIDS epidemic.
Am J Psychiatry. 1994 Feb;151(2):233-6.
"CONCLUSIONS: These findings are in agreement with previous studies of areas with a high prevalence of HIV. However, the proportion of subjects with mood disorders is high compared with general population studies. Both HIV-infected and uninfected homosexual men may be at high risk for major depression, especially if they have a past history of depression. Moreover, in the asymptomatic stage of HIV infection, major depression does not appear to be secondary to HIV central nervous system effects or low vitamin B12 levels." [Abstract]

Gendall KA, Bulik CM, Joyce PR.
Visceral protein and hematological status of women with bulimia nervosa and depressed controls.
Physiol Behav. 1999 Mar;66(1):159-63.
"Serum visceral protein and hematological indices and their behavioral and clinical correlates were determined in women with bulimia nervosa and depressed controls. One hundred and fifty-two women who met DSM-IV criteria for bulimia nervosa and 68 women with DSM-IV major depression completed a structured clinical interview and had blood samples drawn prior to admission to outpatient treatment programs. Albumin and prealbumin concentrations were lower in the depressed women, possibly due to recent weight loss. Elevated transferrin values suggested mild iron deficiency in nearly one-fifth of women with bulimia nervosa. Of women with bulimia nervosa, the 10.7% who had hemoglobin and 5.1% who had vitamin B12 levels below the normal range were not distinguishable on measures of body mass index, binge eating, vomiting, or restriction frequency. The 4.3% with low prealbumin levels experienced significantly more episodes of binge eating and vomiting in the prior fortnight than those with normal values. Frequency of vomiting was also inversely associated with albumin concentration. Hamilton Depression Rating Scale scores were inversely and linearly related to serum vitamin B12. Lower B12 levels in those with alcohol abuse/dependence did not explain the association between B12 and HDRS scores. No hematological indices were related to body mass index, binge eating or restriction frequency, or restriction intensity. In summary, women with bulimia nervosa do not appear to be at greater risk of visceral protein or hematological abnormalities than psychiatric controls. It is suggested that a high frequency of vomiting and alcohol abuse/dependence, increases the risk of subclinical malnutrition in women with bulimia nervosa, and that poor vitamin B12 nutriture may interfere with the functioning of the serotonergic or catecholaminergic systems and contribute to depressive symptoms in bulimia nervosa." [Abstract]


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Recent Unipolar Depression, Vitamin B12, and Folate Research

1) Mischoulon D, Lamon-Fava S, Selhub J, Katz J, Papakostas GI, Iosifescu DV, Yeung AS, Dording CM, Farabaugh AH, Clain AJ, Baer L, Alpert JE, Nierenberg AA, Fava M
Prevalence of MTHFR C677T and MS A2756G polymorphisms in major depressive disorder, and their impact on response to fluoxetine treatment.
CNS Spectr. 2012 Jun;17(2):76-86.
[PubMed Citation] [Order full text from Infotrieve]

2) Singer C
Comprehensive treatment of Huntington disease and other choreic disorders.
Cleve Clin J Med. 2012 Jul;79 Suppl 2:S30-4.
The management of choreic disorders presents significant challenges, including identifying the etiology of the disorder, treating and preventing motor symptoms, and managing a range of other neurologic and behavioral complications. Chorea may occur in several neurodegenerative, genetic, or drug-related conditions, and a thorough diagnostic evaluation is needed to identify the specific underlying causes. Some choreic disorders have specific treatable underlying etiologies, such as vitamin B(12) deficiency or drug-induced dyskinesia. Autoimmune disorders such as Sydenham chorea may be treated with penicillin, corticosteroids, intravenous immunoglobulin, or plasma exchange. Heredodegenerative choreas such as Huntington disease often respond to treatment with tetrabenazine or amantadine. Many other agents may be used nonspecifically for symptom control, including benzodiazepines, neuroleptics, and antiepileptic medications. In addition to motor symptoms, patients with Huntington disease or other choreic disorders often experience increasing depression, bradykinesia, cognitive impairment, aggressive behaviors, and other complications as the disease progresses. Caring for the caregiver is also a significant concern in the long-term treatment of choreic disorders. [PubMed Citation] [Order full text from Infotrieve]

3) Kalita J, Agarwal R, Chandra S, Misra UK
A study of neurobehavioral, clinical psychometric, and P3 changes in vitamin B12 deficiency neurological syndrome.
Nutr Neurosci. 2012 Jul 9;
OBJECTIVE: To evaluate cognitive functions and behavioral changes in the patients with vitamin B12 deficiency neurological syndromes (VBDNS) using detailed clinical psychometric and P3 studies and their response to treatment. METHODS: The patients with VBDNS were included and their detailed medical history was recorded. Neurobehavioral and cognitive functions were evaluated by neuropsychiatry inventory (NPI), forward and backward digit span, mini mental state examination (MMSE), Luria's three-step test, trail making test (TMT), motor speed and precision test (MSPT), Benton's visual retention test (BVRT), clock drawing (CD), category fluency, hospital anxiety and depression (HAD) scale, and cognitive evoked potential using oddball paradigm at baseline and 3 and 6 months following treatment. Complete hemogram, serum chemistry, vitamin B12, homocysteine, and craniospinal magnetic resonance imaging (MRI) were done. RESULTS: Thirty-three patients with VBDNS, whose median age was 43 (12-68) years, five (15.2%) of whom were females were included. Twenty-one patients had neurobehavioral/cognitive decline, 26 myelopathy, and 17 neuropathy. MSPT, TMT, CD, and HAD scores improved significantly at 3 months and category naming and MMSE improved at 6 months compared to baseline. The P3 latency also improved significantly at 3 months. The baseline P3 changes correlated with MMSE, Luria's three-step test, and MSPT. Hemoglobin and mean corpuscular volume also correlated with some of the cognitive tests. CONCLUSION: VBDNS results in frontal-subcortical neurobehavioral and cognitive abnormalities which may be due to cortical and subcortical dysfunction. The reversibility of these changes is suggestive of metabolic alteration in neuronal or myelin function. [PubMed Citation] [Order full text from Infotrieve]

4) Papakostas GI, Cassiello CF, Iovieno N
Folates and s-adenosylmethionine for major depressive disorder.
Can J Psychiatry. 2012 Jul;57(7):406-13.
Interest in nonpharmaceutical supplements for treating major depressive disorder (MDD) has increased signi?cantly, both among patients and among clinicians during the past decades. Despite the large array of antidepressants (ADs) available, many patients continue to experience relatively modest response and remission rates, in addition to a burden of side effects that can hinder treatment compliance and acceptability. In this article, we review the literature on folates and S-adenosylmethionine (SAMe), 2 natural compounds linked in the 1-carbon cycle metabolic pathway, for which substantial evidence supports their involvement in mood disorders. Background information, ef?cacy data, proposed mechanisms of action, and side effects are reviewed. Based on existing data, supplementation with SAMe, as well as with various formulations of folates, appears to be efficacious and well tolerated in reducing depressive symptoms. Compared with other forms of folates, 5-methyltetrahydrofolate (L-methylfolate or 5-MTHF) may represent a preferable treatment option for MDD given its greater bioavailability in patients with a genetic polymorphism, and the lower risk of specific side effects associated with folic acid. Although further randomized controlled trials in this area appear warranted, SAMe and L-methylfolate may represent a useful addition to the AD armamentarium. [PubMed Citation] [Order full text from Infotrieve]

5) Moorthy D, Peter I, Scott TM, Parnell LD, Lai CQ, Crott JW, Ordovás JM, Selhub J, Griffith J, Rosenberg IH, Tucker KL, Troen AM
Status of Vitamins B-12 and B-6 but Not of Folate, Homocysteine, and the Methylenetetrahydrofolate Reductase C677T Polymorphism Are Associated with Impaired Cognition and Depression in Adults.
J Nutr. 2012 Aug;142(8):1554-60.
The C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene differs in frequency in various ethnic groups that have differing prevalence of age-related cognitive impairments. We used a series of neuro-psychological tests to examine the association of the MTHFR C677T polymorphism with cognition and depression and also to assess whether genotype modifies the association of folate and homocysteine with these outcomes. This study analyzed pooled cross-sectional data from 2 ethnically diverse cohorts of community-living adults: the Boston Puerto Rican Health Study (n = 939) and the Nutrition, Aging, and Memory in Elders study (n = 1017). Individuals in both cohorts underwent anthropometric and laboratory measurements and dietary and health assessments using validated questionnaires between the years 2003 and 2007. Cognitive outcomes included measures of global cognition [Mini-Mental Status Exam (MMSE)], depression (Center for Epidemiological Studies Depression Scale), and 3 factor scores for the domains of attention, executive function, and memory that were derived from a detailed set of neuropsychological tests. Low plasma vitamin B-12 concentrations were associated with poorer MMSE scores and higher depression scores, and low vitamin B-6 concentrations were associated with lower MMSE and worse attention and executive function in the multivariate analysis. In contrast, MTHFR genotype, folate, and homocysteine were not associated with cognition or depression in either ethnicity-pooled or stratified analysis. The current study did not find evidence of an association between the MTHFR C677T TT genotype and impaired cognition or depression in a population with adequate folate status and a high prevalence of cognitive impairment and depression. [PubMed Citation] [Order full text from Infotrieve]

6) Nanri A, Hayabuchi H, Ohta M, Sato M, Mishima N, Mizoue T
Serum Folate and Depressive Symptoms Among Japanese Men and Women: A Cross-Sectional and Prospective Study.
Psychiatry Res. 2012 Jun 6;
Although several studies have reported an association between blood folate concentrations and depressive symptoms, few studies have prospectively examined the association. This study aimed to investigate the cross-sectional and prospective associations between serum folate concentrations and depressive symptoms among Japanese. We analysed data among 545 subjects who participated in a health survey at the time of periodic check-up in 2009 for a cross-sectional association and among 272 subjects without depressive symptoms at baseline (in 2006) who responded to both baseline (2006) and follow-up (2009) surveys for prospective association. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression (CES-D) scale. In a cross-sectional analysis, serum folate concentrations were significantly associated with a decreased prevalence of depressive symptoms (CES-D scale of ?16). Moreover, serum folate concentrations at baseline were significantly inversely associated with depressive symptoms after 3 years; the multivariate-adjusted odds ratios (95% confidence intervals) of depressive symptoms for the lowest through highest tertile categories of serum folate concentrations were 1.00 (reference), 0.66 (0.29-1.52) and 0.40 (0.16-0.99) (P for trend=0.047). Our findings suggest that a higher serum folate may be associated with decreased risk of depressive symptoms in Japanese. [PubMed Citation] [Order full text from Infotrieve]

7) van de Rest O, van Hooijdonk LW, Doets E, Schiepers OJ, Eilander A, de Groot LC
B Vitamins and n-3 Fatty Acids for Brain Development and Function: Review of Human Studies.
Ann Nutr Metab. 2012;60(4):272-92.
Background: Nutrition is one of many factors that affect brain development and functioning, and in recent years the role of certain nutrients has been investigated. B vitamins and n-3 polyunsaturated fatty acids (PUFA) are two of the most promising and widely studied nutritional factors. Methods: In this review, we provide an overview of human studies published before August 2011 on how vitamin B(6), folate, vitamin B(12) and n-3 PUFA may affect the brain, their nutrient status and the existing evidence for an association between these nutrients and brain development, brain functioning and depression during different stages of the life cycle. Results: No recommendation can be given regarding a role of B vitamins, either because the number of studies on B vitamins is too limited (pregnant and lactating women and children) or the studies are not consistent (adults and elderly). For n-3 PUFA, observational evidence may be suggestive of a beneficial effect; however, this has not yet been sufficiently replicated in randomized controlled trials (RCTs). Conclusions: We found that the existing evidence from observational studies as well as RCTs is generally too limited and contradictory to draw firm conclusions. More research is needed, particularly a combination of good-quality long-term prospective studies and well-designed RCTs. [PubMed Citation] [Order full text from Infotrieve]

8) Liu Y, Murphy SK, Murtha AP, Fuemmeler BF, Schildkraut J, Huang Z, Overcash F, Kurtzberg J, Jirtle R, Iversen ES, Forman MR, Hoyo C
Depression in pregnancy, infant birth weight and DNA methylation of imprint regulatory elements.
Epigenetics. 2012 Jul 1;7(7):735-46.
Depressed mood in pregnancy has been linked to low birth weight (LBW, < 2,500 g), a risk factor for adult-onset chronic diseases in offspring. We examined maternal depressed mood in relation to birth weight and evaluated the role of DNA methylation at regulatory sequences of imprinted genes in this association. We measured depressed mood among 922 pregnant women using the CES-D scale and obtained birth weight data from hospital records. Using bisulfite pyrosequencing of cord blood DNA from 508 infants, we measured methylation at differentially methylated regions (DMRs) regulating imprinted genes IGF2/H19, DLK1/MEG3, MEST, PEG3, PEG10/SGCE, NNAT and PLAGL1. Multiple regression models were used to examine the relationship between depressed mood, birth weight and DMR methylation levels. Depressed mood was associated with a more that 3-fold higher risk of LBW, after adjusting for delivery mode, parity, education, cigarette smoking, folic acid use and preterm birth. The association may be more pronounced in offspring of black women and female infants. Compared with infants of women without depressed mood, infants born to women with severe depressed mood had a 2.4% higher methylation at the MEG3 DMR. Whereas LBW infants had 1.6% lower methylation at the IGF2 DMR, high birth weight (> 4,500 g) infants had 5.9% higher methylation at the PLAGL1 DMR compared with normal birth weight infants. Our findings confirm that severe maternal depressed mood in pregnancy is associated with LBW, and that MEG3 and IGF2 plasticity may play important roles. [PubMed Citation] [Order full text from Infotrieve]

9) Loutfy MR, Margolese S, Money DM, Gysler M, Hamilton S, Yudin MH
Canadian HIV pregnancy planning guidelines.
J Obstet Gynaecol Can. 2012 Jun;34(6):575-90.
[PubMed Citation] [Order full text from Infotrieve]

10) Lan WH, Yang AC, Hwang JP, Hong CJ, Liou YJ, Yeh HL, Liu ME, Tsai SJ
Association of MTHFR C677T polymorphism with loneliness but not depression in cognitively normal elderly males.
Neurosci Lett. 2012 Jul 11;521(1):88-91.
Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is involved in folate and homocysteine metabolism, and has been associated with geriatric disorders, including dementia and late-life depression. The present work aimed to investigate the effect of MTHFR C677T polymorphism on the presence of depression and loneliness in cognitively normal male subjects. A total of 323 cognitively normal male subjects were included in this study (mean age=80.6; SD=5.3). Depression was assessed by the Geriatric Depression Scale-Short Form (GDS-SF) and loneliness by UCLA loneliness scales. Analysis of variance (ANOVA) was used to test the between MTHFR genotype difference in depression and loneliness. Multiple regression was used to test the effect of MTHFR polymorphism on the loneliness, controlling for age, education, cognitive function, and depression. ANOVA showed a significant between-genotype difference in loneliness scores (P=0.015), and post hoc comparisons showed that subjects with C/C genotype had significantly higher loneliness ratings, compared to those with C/T or T/T genotype. Regression analysis indicated that the effect of MTHFR polymorphism on loneliness was independent of age, education, cognitive function, and depression. Our findings suggest that MTHFR C677T polymorphism may be linked more to loneliness than depression in the cognitively normal elderly males, and may be implicated in the pathophysiology of late-life depression in relation to MTHFR genes. [PubMed Citation] [Order full text from Infotrieve]

11) Andreeva VA, Galan P, Torrès M, Julia C, Hercberg S, Kesse-Guyot E
Supplementation with B vitamins or n-3 fatty acids and depressive symptoms in cardiovascular disease survivors: ancillary findings from the SUpplementation with FOLate, vitamins B-6 and B-12 and/or OMega-3 fatty acids (SU.FOL.OM3) randomized trial.
Am J Clin Nutr. 2012 Jul;96(1):208-14.
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12) Howland RH
Dietary supplement drug therapies for depression.
J Psychosoc Nurs Ment Health Serv. 2012 Jun;50(6):13-6.
Many dietary supplements are readily accessible and commonly used for the treatment of depression. A dietary supplement is a product intended to supplement the diet but is not intended to treat, diagnose, prevent, or cure disease. The U.S. Food and Drug Administration can take action against dietary supplement manufacturers for products only after they are marketed, mainly if the product is found to be unsafe or if false or misleading claims are made about the product. Few dietary supplement products have been adequately studied for their safety and efficacy. Of the five products reviewed in this article (L-methylfolate, S-adenosyl-L-methionine [SAM-e], omega-3 fatty acids, L-tryptophan, and inositol), only omega-3 fatty acids and SAM-e have sufficient supporting evidence for their efficacy to warrant safe use. [PubMed Citation] [Order full text from Infotrieve]

13) Forsyth AK, Williams PG, Deane FP
Nutrition status of primary care patients with depression and anxiety.
Aust J Prim Health. 2012;18(2):172-6.
The objective of this study was to evaluate the nutrition status of people referred to a nutrition and physical activity program for the management of mental health in general practice. Patients currently being treated for depression and/or anxiety were referred by their GPs to a lifestyle intervention program. The nutrition status was assessed during a comprehensive assessment at the commencement of the program. The lifestyle intervention program, including all assessments, was offered at multiple sites including GP clinics in the Illawarra, and in clinic rooms at the University of Wollongong. Thirty-two men and seventy-seven women completed the assessment. Patients were referred with depression (52%), anxiety (19%) or both (28%). Eighty percent of participants were overweight or obese. All participants completed an assessment that included a diet history, anthropometric measurements and the completion of several questionnaires including the Depression, Anxiety and Stress Scale (DASS). Nutrition status was assessed using mean nutrient intakes and Australian modified Healthy Eating Index scores evaluated against the National Nutrition Survey intakes and DASS scores. Participants met the estimated average requirements for all nutrients except folate (17%), magnesium (78%) and calcium (57%). Intakes were similar to those reported in the National Nutrition Survey. Only magnesium intakes were significantly related to depression (r=-0.26). Australian modified Healthy Eating Index scores were significantly negatively correlated with DASS scores (P<0.01). The associations presented here support the existing body of literature. Nutrition recommendations for patients with depression and anxiety should be based on the Australian Guide to Healthy Eating with particular attention to fruit, vegetables and wholegrains. [PubMed Citation] [Order full text from Infotrieve]

14) Kingston D, Heaman M, Fell D, Chalmers B
Comparison of adolescent, young adult, and adult women's maternity experiences and practices.
Pediatrics. 2012 May;129(5):e1228-37.
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15) Feng L
Oral folic acid and vitamin B-12 supplementation to prevent cognitive decline.
Am J Clin Nutr. 2012 May;95(5):1289-90; author reply 1290.
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16) Miyaki K, Song Y, Htun NC, Tsutsumi A, Hashimoto H, Kawakami N, Takahashi M, Shimazu A, Inoue A, Kurioka S, Shimbo T
Folate intake and depressive symptoms in Japanese workers considering SES and job stress factors: J-HOPE study.
BMC Psychiatry. 2012 Apr 20;12(1):33.
ABSTRACT: BACKGROUND: Recently socioeconomic status (SES) and job stress index received more attention to affect mental health. Folate intake has been implicated to have negative association with depressionHowever, few studies were published for the evidence association together with the consideration of SES and job stress factors. The current study is a part of the Japanese study of Health, Occupation and Psychosocial factors related Equity (J-HOPE study) that focused on the association of social stratification and health and our objective was to clarify the association between folate intake and depressive symptoms in Japanese general workers. METHODS: Subjects were 2266 workers in a Japanese nationwide company. SES and job stress factors were assessed by self-administered questionnaire. Folate intake was estimated by a validated, brief, self-administered diet history questionnaire. Depressive symptoms were measured by Kessler's K6 questionnaire. "Individuals with depressive symptoms" was defined as K69 (in K6 score of 0-24 scoring system). Multiple logistic regression and linear regression model were used to evaluate the association between folate and depressive symptoms. RESULTS: Several SES factors (proportion of management positions, years of continuous employment, and annual household income) and folate intake were found to be significantly lower in the subjects with depressive symptom (SES factors: p<0.001; folate intake: P=0.001). There was an inverse, independent linear association between K6 score and folate intake after adjusting for age, sex, job stress scores (job strains, worksite supports), and SES factors (p=0.010). The impact of folate intake on the prevalence of depressive symptom by a multiple logistic model was (ORs[95% CI]: 0.813 [0.664-0.994]; P =0.044). CONCLUSIONS: Our cross-sectional study suggested an inverse, independent relation of energy-adjusted folate intake with depression score and prevalence of depressive symptoms in Japanese workers, together with the consideration of SES and job stress factors were considered. [PubMed Citation] [Order full text from Infotrieve]

17) Jacka FN, Maes M, Pasco JA, Williams LJ, Berk M
Nutrient intakes and the common mental disorders in women.
J Affect Disord. 2012 Mar 5;
BACKGROUND: There is an increasing recognition of the role of nutrition in depression and anxiety. Magnesium, folate and zinc have all been implicated in depressive illness, however there are few data on these nutrients in anxiety disorders and the data from population-studies are limited. AIMS: In a large, randomly-selected, population-based sample of women, this study aimed to examine the relationship between the dietary intakes of these three micronutrients and clinically determined depressive and anxiety disorders and symptoms. METHODS: Nutrient intakes were determined using a validated food frequency questionnaire. The General Health Questionnaire-12 measured psychological symptoms, and a clinical interview (Structured Clinical Interview for DSM-IV-TR, non-patient edition) assessed current depressive and anxiety disorders. RESULTS: After adjustments for energy intake, each standard deviation increase in the intake of zinc, magnesium and folate was associated with reduced odds ratio (OR) for major depression/dysthymia (zinc: OR=0.52, 95% confidence interval (CI) 0.31 to 0.88; magnesium: OR=0.60, 95% CI 0.37 to 0.96; folate: OR=0.66, 95% CI 0.45 to 0.97). There was also an inverse association between the intake of magnesium and zinc and GHQ-12 scores (zinc: z?=-0.16, 95% CI -0.29 to -0.04; magnesium: -0.14, 95% CI -0.26 to -0.03). These relationships were not confounded by age, socioeconomic status, education or other health behaviours. There was no relationship observed between any nutrient and anxiety disorders. CONCLUSION: These results demonstrate an association between the dietary intakes of magnesium, folate and zinc and depressive illnesses, although reverse causality and/or confounding cannot be ruled out as explanations. [PubMed Citation] [Order full text from Infotrieve]

18) Martin-Du Pan RC, Mercan D
[Effects of folic acid on cerebrovascular and cancer risks].
Rev Med Suisse. 2012 Feb 15;8(328):375-9.
Homocysteine increase is associated with an elevated risk of cerebro-vascular (CV) disease as well as osteoporosis, dementia and depression. However, most secondary prevention trials did not show any CV benefit to decrease homocysteine levels through folate administration, with the possible exception of stroke. Reasons for these failures are analysed. Moreover, folate acid could decrease the risk of colon, breast and prostate cancers mainly in wine drinkers, whereas it increases the growth of preneoplasic cells of the latter cancers. In conclusion, folate acid does not benefit patients for secondary prevention of CV or malignant diseases but it still has to be proven that it could benefit patients for primary prevention. [PubMed Citation] [Order full text from Infotrieve]

19) Bochyńska A, Lipczyńska-Łojkowska W, Gugała-Iwaniuk M, Lechowicz W, Restel M, Graban A, Lipska B, Ryglewicz D
The effect of vitamin B supplementation on homocysteine metabolism and clinical state of patients with chronic epilepsy treated with carbamazepine and valproic acid.
Seizure. 2012 May;21(4):276-81.
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20) Seppälä J, Koponen H, Kautiainen H, Eriksson JG, Kampman O, Männistö S, Mäntyselkä P, Oksa H, Ovaskainen Y, Viikki M, Vanhala M
Association between folate intake and melancholic depressive symptoms. A Finnish population-based study.
J Affect Disord. 2012 May;138(3):473-8.
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