unipolar depression, vitamin B12, and folate

unipolar depression, vitamin B12, and folate

(Updated 4-26-04)

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 Psy**** 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 Experts in the field and pharmaceutical companies were contacted regarding unpublished material.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 buttessed 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 buttessed 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 buttessed, and a blood sample was collected from each patient. Serum metabolite levels were buttayed. 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 buttociated 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 buttociated in major depressive disorder. BMC Psychiatry. 2003 Dec 2;3(1):17. "BACKGROUND: Despite of an increasing body of research the buttociations 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 buttociations 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 buttociated 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 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 buttociated with a better outcome. The buttociation between the folate level and treatment outcome was weak and probably not independent. No CONCLUSION: The vitamin B12 level and the probability of recovery from major depression may be positively buttociated. 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 clbuttified 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 buttociation 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. buttociation 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):68 plus 17-702. "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 dissolution: 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 dissolution. In this study, the red-cell and serum folate levels in nine persons who later committed dissolution are compared 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 buttigned 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 (12.9%) patients in the fluoxetine plus folic acid group reported symptoms possibly or probably related to medication, whereas in the fluoxetine plus 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 buttociated 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 buttess 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 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 0.01). However only 31% of completers and 27% of the intent-to-treat (ITT) 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 buttess the efficacy of a gastro-resistant, oral preparation of MTHF, 20 elderly patients with a DSM-III-R diagnosis of depressive disorder and 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 buttessments. RESULTS: Patients had a significantly lower mean serum folate level (24.6+--10.2 vs. 30.3+--11.4 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 buttessment 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 buttessment 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. and depression: the Hordaland Homocysteine Study. Arch Gen Psychiatry. 2003 Jun;60(6):618-26. "BACKGROUND: An buttociation 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 polymorphism. The relationship between anxiety and these components is less well known. This study examined the buttociations between folate, total homocysteine, and anxiety and depression in a large population-based study. METHODS: Anxiety and depression, measured by the Hospital Anxiety and Depression Scale, were buttessed 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 (odds ratio, 1.90; 95% confidence interval, 1.11-3.25) and T-T methylenetetrahydrofolate reductase genotype (odds ratio, 1.68 plus 1; 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 buttociated 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 rest. 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 buttociations 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 buttociation with depressive disorders was substantially reduced after adjustment for functional disability and cardiovascular disease, but for vitamin B(12) this appeared independent. CONCLUSIONS: The buttociation 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-buttociated 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 buttociated 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 clbuttified 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 buttociated 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 buttociated 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 buttociated 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 buttociations 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 buttociated 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 buttociation between dietary folate and current symptoms of depression in a general population. We investigated the buttociation 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 buttessed 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, appebreaste, 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 buttociations 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 clbuttified 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 radioimmunobuttay 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 buttessed with the Schedules for Clinical buttessment in Neuropsychiatry interview are included. Patients with schizophrenia had lower serum folate levels than age- and 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 buttociated with greater severity of depression. There was no buttociation 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 buttociation 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 buttociated 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 buttays 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 buttayed 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 buttociated 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 buttociated 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 buttess 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, Thalbuttinos 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 buttociated 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(-) homoloveual 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 68 plus 1 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 buttociated 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 homoloveual 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 mbutt 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 buttociated 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 buttociation between B12 and HDRS scores. No hematological indices were related to body mbutt 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

Sakuta H, Suzuki T, Yasuda H, Wakiyama H, Hase K Plasma vitamin B(12), folate and homocysteine levels in gastrectomized men. Clin Nutr. 2005 Apr;24(2):244-9. Background & aims: Hyperhomocysteinemia is a risk factor for cardiovascular disease, dementia and depression. Prevalence rate of hyperhomocysteinemia in gastrectomized patients is not well elucidated. Methods: We compared plasma total homocysteine, vitamin B(12) and folate of gastrectomized male patients with those of control subjects. Results: Total homocysteine was higher in gastrectomized patients than in control subjects (11.7+--4.4mumol-l vs. 9.3+--2.4mumol-l, P=.011), while vitamin B(12) was lower in patients than in control subjects (382+--211pg-ml vs. 500+--179pg-ml, P=.020). Folate of the two groups was comparable (5.8+--2.5ng-ml vs. 5.9+--2.2ng-ml). Of 31 gastrectomized they were found in one (3.2%), none (0%) and one (3.2%) of 31 control subjects, respectively. Patients who had undergone gastrectomy because of cancer showed higher total homocysteine compared to patients who had undergone it because of peptic ulcer. Type of surgery did not correlate with total homocysteine in the present study. Conclusion: Hyperhomocysteinemia is not rare in male Japanese gastrectomized patients. Abstract

Hickie I, Naismith S, Ward PB, Scott E, Mitchell P, Wilhelm K, Parker G Vascular risk and low serum B12 predict white matter lesions in patients with major depression. J Affect Disord. 2005 Apr;85(3):327-32. BACKGROUND: While patients with depression have been shown to have a greater incidence of vascular risk factors and structural brain changes, any buttociation with dietary co-factors is unclear. METHODS: Forty-seven patients with major depression (mean age=52.8 years, SD=12.6) and 21 healthy volunteers (mean age=54.7 years, SD=9.1) underwent high-resolution magnetic resonance imaging scanning. T2-weighted films were scored for deep white matter (DWM), periventricular (PV), and subcortical (SC) hyperintensities. RESULTS: There was no difference in lesion severity between patients and control subjects. After controlling for age, vitamin B12 levels were predictive of DWM lesions in patients. DWM and SC lesions were buttociated with histories of hypertension and diabetes. LIMITATIONS: A relatively small sample of patients were recruited from specialist services and the findings may not represent those observed in larger or community-based cohorts. CONCLUSIONS: In patients with major depression, vitamin B12 levels and histories of hypertension and-or diabetes are predictive of white matter lesions. Abstract

Beard JL, Hendricks MK, Perez EM, Murray-Kolb LE, Berg A, Vernon-Feagans L, Irlam J, Isaacs W, Sive A, Tomlinson M Maternal iron deficiency anemia affects postpartum emotions and cognition. J Nutr. 2005 Feb;135(2):267-72. The aim of this study was to determine whether iron deficiency anemia (IDA) in mothers alters their maternal cognitive and behavioral performance, the mother-infant interaction, and the infant's development. This article focuses on the relation between IDA and cognition as well as behavioral affect in the young mothers. This prospective, randomized, controlled, intervention trial was conducted in South Africa among 3 groups of mothers: nonanemic controls and anemic mothers receiving either placebo (10 microg folate and 25 mg vitamin C) or daily iron (125 mg FeS0(4), 10 microg folate, 25 mg vitamin C). Mothers of full-term normal birth weight babies were followed from 10 wk to 9 mo postpartum (n = 81). Maternal hematologic and iron status, socioeconomic, cognitive, and emotional status, mother-infant interaction, and the development of the infants were buttessed at 10 wk and 9 mo postpartum. Behavioral and cognitive variables at baseline did not differ between iron-deficient anemic mothers and nonanemic previously iron-deficient mothers' depression and stress scales as well as in the Raven's Progressive Matrices test. Anemic mothers administered placebo did not improve in behavioral measures. Multivariate analysis showed a strong buttociation between iron status variables (hemoglobin, mean corpuscular volume, and transferrin saturation) and cognitive variables (Digit Symbol) as well as behavioral variables (anxiety, stress, depression). This study demonstrates that there is a strong relation between iron status and depression, stress, and cognitive functioning in poor African mothers during the postpartum period. There are likely ramifications of this poorer "functioning" on mother-child interactions and infant development, but the constraints around this relation will have to be defined in larger studies. Abstract

Almeida OP, Flicker L, Lautenschlager NT, Leedman P, Vasikaran S, van Bockxmeer FM Contribution of the MTHFR gene to the causal pathway for depression, anxiety and cognitive impairment in later life. Neurobiol Aging. 2005 Feb;26(2):251-7. Homocysteine (Hcy) is harmful to neurons and blood vessels, including the cerebral microvasculature. It is possible that such effects contribute to the cascade of events that leads to cognitive decline, dementia, and depression in later life. Hcy is produced during the metabolism of the essential amino-acid methionine, which also involves a methyl group transfer derived from folate and choline metabolism. Its plasma level can be influenced by factors such as age, vitamin deficiency, renal function, and a common mutation in the methylenetetrahydrofolate reductase (MTHFR) gene, where cytosine is replaced by higher homocysteine levels and may be particularly prone to experiencing depression as a result of high plasma Hcy and dysfunction of methylation metabolic pathways critical to the synthesis of noradrenaline and serotonin. We designed the present study to investigate whether older women with the TT genotype would have higher depression and lower cognitive scores than women with CT and CC genotypes. A total of 240 community-dwelling women aged 70 years or over volunteered to take part in the study - 29 carried the TT genotype, 113 the CT and 98 the CC genotype. The Beck Depression Inventory (BDI) score for subjects with the TT genotype was statistically similar to the other groups (P = 0.609). Plasma Hcy showed a modest and significant correlation with BDI scores (r = 0.21) that was independent from age, B12 and folate levels. There was no buttociation between beck anxiety inventory (BAI) scores and MTHFR genotype or homocysteine levels. The cognitive buttessment of participants included measures of verbal memory, memory for faces, verbal fluency, visuo-spatial abilities and the cognitive section of the Cambridge Examination For Mental Disorders Of The Elderly (CAMCOG)-MTHFR genotype had no clear buttociation with cognitive scores. These results indicate that, in isolation, the MTHFR C677T gene variation does not play an important role in the modulation of mood and cognitive performance in later life. Abstract

Coppen A, Bolander-Gouaille C Treatment of depression: time to consider folic acid and vitamin B12. J Psychopharmacol. 2005 Jan;19(1):59-65. We review the findings in major depression of a low plasma and particularly red cell folate, but also of low vitamin B12 status. Both low folate and low vitamin B12 status have been found in studies of depressive patients, and an buttociation between depression and low levels of the two vitamins is found in studies of the general population. Low plasma or serum folate has also been found in patients with recurrent mood disorders treated by lithium. A link between depression and low folate has similarly been found in patients with alcoholism. It is interesting to note that Hong Kong and Taiwan populations with traditional Chinese diets (rich in folate), including patients with major depression, have high serum folate concentrations. However, these countries have very low life time rates of major depression. Low folate levels are furthermore linked to a poor response to antidepressants, and treatment with folic acid is shown to improve response to antidepressants. A recent study also suggests that high vitamin B12 status may be buttociated with better treatment outcome. Folate and vitamin B12 are major determinants of one-carbon metabolism, in which S-adenosylmethionine (SAM) is formed. SAM donates methyl groups that are crucial for neurological function. Increased plasma homocysteine is a functional marker of both folate and vitamin B12 deficiency. Increased homocysteine levels are found in depressive patients. In a large population study from Norway increased plasma homocysteine was buttociated with increased risk of depression but not anxiety. There is now substantial evidence of a common decrease in serum-red blood cell folate, serum vitamin B12 and an increase in plasma homocysteine in depression. Furthermore, the MTHFR C677T polymorphism that impairs the homocysteine metabolism is shown to be overrepresented among depressive patients, which strengthens the buttociation. On the basis of current data, we suggest that oral doses of both folic acid (800 microg daily) and vitamin B12 (1 mg daily) should be tried to improve treatment outcome in depression. Abstract

Balon R Reflections on relevance: Psychotherapy and Psychosomatics in 2004. Psychother Psychosom. 2005;74(1):3-9. Relevance of an article is a highly desirable yet hardly predictable quality at the time of its publication. Article relevance is frequently measured by the impact factor of the journal where the article is published. Furthermore, impact factor, citation index and citation analysis are used as a measure of research progress and scientific wealth of a nation. The wisdom and significance of this approach to relevance is debatable and thus discussed here. In 2004, Psychotherapy and Psychosomatics published a variety of articles which, in the author's view, are clinically relevant. Several selected clinically relevant issues reviewed in this article include: the conceptualization of fibromyalgia as a stress disorder; the psychosocial impact and psychosocial interventions in cancer; the impact of alexithymia on patient care; the possible relationship between depression and nutrition (namely intake of folate and pyridoxal phosphate); the significance of hypercoagulability in panic-like anxiety; the questionable value of single isomer drugs, and the relevance and adequacy of clinimetrics versus psychometrics in clinical research. The reviewed issues seem to be relevant to clinical practice, research or both, but also to our critical thinking, and the critical review of the developments in psychiatry and psychology. Abstract

Tolmunen T, Hintikka J, Voutilainen S, Ruusunen A, Alfthan G, Nyyssšnen K, ViinamŠki H, Kaplan GA, Salonen JT buttociation between depressive symptoms and serum concentrations of homocysteine in men: a population study. Am J Clin Nutr. 2004 Dec;80(6):1574-8. BACKGROUND: Results of studies of the buttociation between blood concentrations of homocysteine and depression in general populations and among psychiatric patients are inconsistent. OBJECTIVE: The objective was to study the buttociation between depression and serum concentrations of total homocysteine (tHcy). DESIGN: A cross-sectional study of a sample of 924 men aged 46-64 y was conducted as a part of the Kuopio Ischaemic Heart Disease Risk Factor Study. Those who had a history of psychiatric disorder (6.0%) were excluded. Depressive symptoms were buttessed with the 18-item Human Population Laboratory Depression considered to have a tendency toward depression. RESULTS: The participants were ranked according to their blood tHcy concentration and divided into tertiles. Those in the upper tertile for serum tHcy had a more than twofold (odds ratio: 2.30; 95% CI: 1.35, 3.90; P=0.002) higher risk of being depressed than did those in the lowest tertile for serum tHcy. The results remained significant after adjustment for the month of study, history of ischemic heart disease, smoking habits, alcohol consumption, marital status, education, and socioeconomic status in adulthood (odds ratio: 2.23; 95% CI: 1.30, 3.83; P=0.004). CONCLUSION: High serum concentrations of tHcy may be buttociated with depression in middle-aged men. Abstract

Kelly CB, McDonnell AP, Johnston TG, Mulholland C, Cooper SJ, McMaster D, Evans A, Whitehead AS The MTHFR C677T polymorphism is buttociated with depressive episodes in patients from Northern Ireland. J Psychopharmacol. 2004 Dec;18(4):567-71. Low plasma folate and its derivatives have been linked with depressive disorders enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) is buttociated with low serum folate. The present study aimed to explore whether the thermolabile variant of MTHFR is buttociated with a vulnerability to depressive episodes. MTHFR C677T genotype frequencies in a cohort of patients (mean age 48 years) with depressive disorder (n = 100) were compared with those in age- and were also compared between groups. The thermolabile variant of MTHFR was significantly more common in the group with a history of depressive disorder (P= 0.03). Serum levels of folate, homocysteine and vitamin B(12) did not differ significantly between groups. A MTHFR C677T genotype is buttociated with increased risk of depressive episodes in this homogenous patient population. Abstract

Wolters M, Stršhle A, Hahn A Cobalamin: a critical vitamin in the elderly. Prev Med. 2004 Dec;39(6):1256-66. Vitamin B(12) deficiency is a common problem in elderly subjects. If a serum cobalamin level of about 150 pmol-L (200 pg-mL) is considered normal, 10-15% of the elderly are deficient. Today, however, a threshold of 220-258 pmol-L (300-350 pg-mL) is recognized as desirable in the elderly, or else sensitive markers like the blood concentration of homocysteine or methylmalonic acid (MMA) are used. Then the prevalence of cobalamin deficiency rises to up to 43%. In the elderly, this high prevalence of poor cobalamin status is predominantly caused by atrophic gastritis type B. Atrophic gastritis results in declining gastric acid and pepsinogen secretion, and hence decreasing intestinal absorption of the cobalamin protein complexes from food. About 20-50% of the elderly are affected. Furthermore, the reduced acid secretion leads to an alkalinization of the small intestine, which may result in bacterial overgrowth and thus to a further decrease of the bioavailability of the vitamin. In addition, some drugs such as proton pump inhibitors or H2 receptor antagonists inhibit the intestinal absorption of vitamin B(12). An already moderately reduced vitamin B(12) level is buttociated with vascular disease and neurocognitive disorders such as depression and impaired cognitive performance. Furthermore, a poor vitamin B(12) status is buttumed to be involved in the development and progression of dementia (e.g., Alzheimer's dementia). This is especially observable if the folic acid status is reduced as well. Due to the insecure supply, the cobalamin status of Abstract

Calabresi PA Diagnosis and management of multiple sclerosis. Am Fam Physician. 2004 Nov 15;70(10):1935-44. Multiple sclerosis, an idiopathic inflammatory disease of the central nervous system, is characterized pathologically by demyelination and subsequent axonal degeneration. The disease commonly presents in young adults and affects twice as many women as men. Common presenting symptoms include numbness, weakness, visual impairment, loss of balance, dizziness, urinary bladder urgency, fatigue, and depression. The diagnosis of multiple sclerosis should be made by a physician with experience in identifying the disease. Diagnosis should be based on objective evidence of two or more neurologic signs that are localized to the brain or spinal cord and are disseminated in time and space (i.e., occur in different parts of the central nervous system at least three months apart). Magnetic resonance imaging with gadolinium contrast, especially during or following a first attack, can be helpful in providing evidence of lesions in other parts of the brain and spinal cord. A second magnetic resonance scan may be useful at least three months after the initial attack to identify new lesions and provide evidence of dissemination over time. It is critical to exclude other diseases that can mimic multiple sclerosis, including vascular disease, spinal cord compression, vitamin B12 deficiency, central nervous system infection (e.g., Lyme disease, syphilis), and other inflammatory conditions (e.g., sarcoidosis, systemic lupus erythematosus, Sjšgren's syndrome). Symptom-specific drugs can relieve spasticity, bladder dysfunction, depression, and fatigue. Five disease-modifying treatments for multiple sclerosis have been approved by the U.S. Food and Drug Administration. These treatments are partially effective in reducing exacerbations and may slow progression of disability. Abstract

Scott TM, Tucker KL, Bhadelia A, Benjamin B, Patz S, Bhadelia R, Liebson E, Price LL, Griffith J, Rosenberg I, Folstein MF Homocysteine and B vitamins relate to brain volume and white-matter changes in geriatric patients with psychiatric disorders. Am J Geriatr Psychiatry. 2004 Nov-Dec;12(6):631-8. OBJECTIVE: There is a growing literature on the relationship between low serum B-vitamins, elevated homocysteine, and cognitive impairment; however, few studies have examined radiological markers of buttociated neuropathology in geropsychiatry inpatients. The authors examined the relationship of homocysteine, folate, and vitamin B12 with magnetic resonance imaging (MRI) markers of neuropathology. METHODS: In this archival study, authors reviewed the MRIs and medical records of 34 inpatients in a geriatric psychiatry unit. Patients were selected if folate, B12, and-or homocysteine levels had been buttessed and if the appropriate clinical MRIs were performed (19 men; mean age, 75 years). Patients with schizophrenia or current substance dependence were excluded. The relationships between MRI volume measures, white-matter hyperintensity (WMH) grade, and serum concentrations of folate, B12, and homocysteine were analyzed, using age-adjusted Pearson correlations. RESULTS: Homocysteine was related to WMH grade, but not brain-volume measures. Folate was buttociated with hippocampus and amygdala, and negatively buttociated with WMH. B12 level was not statistically buttociated with any brain measure. CONCLUSIONS: Elevated homocysteine and low folate were buttociated with radiological markers of neuropathology. Since no patient had clinically deficient folate, it may be important to rethink what defines functionally significant micronutrient deficiency and explore what this means in different age- and health-status groups. Larger samples will be needed to buttess interactions between homocysteine, micronutrients, and other neuropathology risk factors. Abstract

Cbuttidy K, Kotynia-English R, Acres J, Flicker L, Lautenschlager NT, Almeida OP buttociation between lifestyle factors and mental health measures among community-dwelling older women. Aust N Z J Psychiatry. 2004 Nov-Dec;38(11-12):940-7. OBJECTIVE: To investigate the buttociation between potentially modifiable lifestyle factors and cognitive abilities-depressive symptoms in community-dwelling women aged 70 years and over. METHOD: Cross-sectional study of community-dwelling women aged 70 years and over (n=278; mean age=74.6 years). Lifestyle variables buttessed included smoking, alcohol consumption, physical activity, nutrition and education. The mental health measures of interest were depression, anxiety, quality of life and cognitive function, as buttessed by the Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), SF-36, and the Cambridge Cognitive Examination for Mental Disorders of the Elderly (CAMCOG), respectively. RESULTS: Physically active women were half as likely to be their physically inactive counterparts (OR=0.5, 95% CI=0.3-0.8 for both, adjusted for marital status and smoking in the case of depression). Having ever smoked more than 20 cigarettes per day was buttociated with increased risk of depression (OR=2.8, 95% CI=1.4-5.5, adjusted for marital status and physical activity). Moderate alcohol use was buttociated with increased likelihood of having a CAMCOG score within the highest 50 percentile (OR=2.0, 95% CI=1.1-3.5, adjusted for age and education), as was more than minimum statutory education (OR=2.0, 95% CI=1.1-3.5, adjusted for age and alcohol consumption). There was no obvious buttociation between vitamin B12-folate deficiency or obesity with any of the measures of interest. CONCLUSIONS: The results of this study are consistent with the hypothesis that depression is directly buttociated with heavy smoking and inversely buttociated with physical activity. They also support the idea that non-harmful alcohol consumption is buttociated with better cognitive performance. Randomised clinical trials should be now designed to clarify whether management of lifestyle factors reduces the incidence of mood disorders and cognitive impairment in later life. Abstract

D'Anci KE, Rosenberg IH Folate and brain function in the elderly. Curr Opin Clin Nutr Metab Care. 2004 Nov;7(6):659-64. PURPOSE OF REVIEW: Over the past several decades, folate has emerged as an important nutrient in several key conditions of concern to the elderly. Subclinical levels of folate inadequacy can have significant negative impacts on health in older individuals. RECENT FINDINGS: Serum and red blood cell folate levels are buttociated with depression in younger individuals, but the relationship is less clear in older people. However, folate status does predict response to antidepressant treatment in older individuals. Cognitive decline and some forms of dementia, including Alzheimer's disease, are buttociated with lower folate levels. Supplementation with folic acid can provide cognitive benefits in some circumstances. Folic acid supplementation is generally regarded as safe; however, there remains some concern that high levels of folic acid may exacerbate the neurological consequences of a vitamin B12 deficiency. SUMMARY: Evidence for the role of folate in depression and dementia in the aged is increasing, although there remains much about mechanisms to be determined. Abstract

Hvas AM, Juul S, Bech P, Nex¿ E Vitamin B6 level is buttociated with symptoms of depression. Psychother Psychosom. 2004 Nov-Dec;73(6):340-3. BACKGROUND: A low level of vitamin B6 might theoretically cause depression as vitamin B6 is a cofactor in the tryptophan-serotonin pathway. In the present study, we examined the buttociation between depression and the phosphate derivative of vitamin B6 in plasma, pyridoxal phosphate (PLP). METHODS: In 140 individuals, symptoms of depression were evaluated by the Major Depression Inventory, and biochemical markers of vitamin B deficiency were measured. RESULTS: We found that 18 (13%) individuals were depressed. A low plasma level of PLP was significantly buttociated with the depression score (p=0.002). No significant buttociation was found between depression and plasma vitamin B12 (p=0.13), plasma methylmalonic acid (p=0.67), erythrocyte folate (p=0.77), and plasma total homocysteine (p=0.16). CONCLUSION: Our study suggests that a low level of plasma PLP is buttociated with symptoms of depression. Randomized trials are now justified and needed in order to examine whether treatment with vitamin B6 may improve symptoms of depression. Abstract

Tolmunen T, Hintikka J, Ruusunen A, Voutilainen S, Tanskanen A, Valkonen VP, ViinamŠki H, Kaplan GA, Salonen JT Dietary folate and the risk of depression in Finnish middle-aged men. A prospective follow-up study. Psychother Psychosom. 2004 Nov-Dec;73(6):334-9. BACKGROUND: Several cross-sectional studies have focused on the low blood folate levels of depressive patients. Nevertheless, no prospective studies have been published on the buttociation between dietary folate and depression. METHODS: We studied the buttociation between dietary folate and cobalamin and receiving a discharge diagnosis of depression in a prospective follow-up setting. Our cohort was recruited between 1984 and 1989 and followed until the end of 2000, and it consisted of 2,313 men aged between 42 and 60 years from eastern Finland. RESULTS: The mean intake of folate in the whole cohort was 256 microg-day (SD=76). Those below the median of energy-adjusted folate intake had higher risk of getting discharge diagnosis of depression (RR 3.04, 95% CI: 1.58, 5.86) during the follow-up period than those who had a folate intake above the median. This excess risk remained significant after adjustment for current socioeconomic status, the baseline HPL depression score, the energy-adjusted daily intake of fibre and vitamin C, and the total fat intake. CONCLUSIONS: A low dietary intake of folate may be a risk factor for severe depression. This also indicates that nutrition may have a role in the prevention of depression. Abstract

Sempere AP, Callejo-Dom’nguez JM, Garc’a-Clemente C, RuipŽrez-Bastida MC, Mola-Caballero de Roda S, Garc’a-Barrag‡n N, Vela-Yebra R, Flores-Ruiz JJ Cost effectiveness of the diagnostic study of dementia in an extra-hospital Neurology service Rev Neurol. 2004 Nov 1-15;39(9):807-10. AIM: The purpose of this study was to analyse the cost effectiveness of the complementary tests in the diagnosis of reversible causes of dementia in an extra-hospital Neurology service. PATIENTS AND METHODS: Patients referred to the Neurology service from Primary Care with a diagnosis of dementia according to DSM-III-R criteria. The following routine complementary tests were performed: 1. Analyses, including blood count, biochemical study, vitamin B12 and folic levels, thyroid hormones, and syphilis serodiagnosis; 2. Neuroimaging study, consisting in computerised axial tomography or cranial magnetic resonance. RESULTS: A total of 268 plus 1 consecutive patients diagnosed as suffering from dementia were included in the study. The mean age of the patients was 74.5 years (49-94 years) and 61% were females. The most frequent cause of dementia was Alzheimer's disease (79.9%). In all, 31 patients presented potentially reversible conditions (11.5%), but if we exclude depression, the dementia was only reversible in one patient (0.4%). CONCLUSIONS: The percentage of patients with reversible causes of dementia in the field of extra-hospital neurology is low. The diagnostic study must be individualised according to the clinical suspicion. Abstract

Ramos MI, Allen LH, Haan MN, Green R, Miller JW Plasma folate concentrations are buttociated with depressive symptoms in elderly Latina women despite folic acid fortification. Am J Clin Nutr. 2004 Oct;80(4):1024-8. BACKGROUND: A relation between low folate status and depression has been recognized since the 1960s. Since 1998, flour in the United States has been fortified with folic acid, and the prevalence of folate deficiency has decreased dramatically. OBJECTIVE: We investigated whether, in this era of folic acid fortification, low folate status is a determinant of depressive symptoms in a Latino Study on Aging (SALSA). DESIGN: In a cross-sectional logistic regression analysis of data from SALSA (n = 627 M, 883 F), odds ratios (ORs) were ascertained for elevated depressive symptoms Center for Epidemiologic Studies Depressive symptoms were buttessed by using the CES-D. Plasma folate concentrations were determined by radiobuttay. RESULTS: The prevalence of folate men, no significant buttociation between folate tertile and high CES-D score was observed. The adjusted OR for high CES-D score in women in the lowest tertile of folate was 2.04 (95% CI: 1.38, 3.02), which was significantly different from data indicate that, despite folic acid fortification, low folate status is buttociated with depressive symptoms in elderly Latina women (but not elderly Latino men). Abstract

Ho J, Rothchild YH, Sengelmann R Vitamin B12-buttociated localized scleroderma and its treatment. Dermatol Surg. 2004 Sep;30(9):1252-5. BACKGROUND: Localized drug-induced injection site reactions are rare. Injection site sclerodermoid reactions have been reported as a result of multiple drugs, most commonly vitamin K. Sclerodermoid injection site reactions have also been reported with pentazocine, progestin, and vitamin B12. Little has been written on the efficacious treatment of this complication. OBJECTIVE: The objective was to raise awareness of the potential complication of localized sclerodermoid change secondary to vitamin B12 injections and to present a novel approach to its treatment. METHODS: We report a case and review the English literature for injection site reactions from vitamin B12 as well as treatment options for this complication. RESULTS: We report the first non-European case of localized sclerodermoid reaction secondary to vitamin B12 injections. Our patient presented with disfiguring depression of the left upper arm following vitamin B12 injections for macrocytic anemia secondary to Crohn's disease. Histopathology showed findings similar to those seen in localized scleroderma. The patient was successfully treated with excision of diseased skin, local fat transfer, and complex repair with dramatic improvement at 5 months in contour and overall appearance. Abstract

Hvas AM, Juul S, Lauritzen L, Nex¿ E, Ellegaard J No effect of vitamin B-12 treatment on cognitive function and depression: a randomized placebo controlled study. J Affect Disord. 2004 Sep;81(3):268 plus 1-73. BACKGROUND: buttociations between vitamin B-12 deficiency and impaired cognitive function and depression have been reported. METHODS: A randomized placebo controlled study including 140 individuals with an increased plasma methylmalonic acid (0.40-2.00 micromol-l) not previously treated with vitamin B-12. Cognitive function was buttessed by the Cambridge Cognitive Examination (CAMCOG), Mini-Mental State Examination (MMSE), and a 12-words learning test. Symptoms of depression were evaluated by the Major Depression Inventory. The main outcome measure was change in cognitive function and depression score from baseline to follow-up 3 months later. RESULTS: At baseline 78 (56%) individuals had cognitive impairment judged from the CAMCOG score and 40 (29%) according to the MMSE; 18 (13%) individuals had symptoms of depression. No improvement was found in cognitive function comparing the treatment and placebo group (total CAMCOG score: P = 0.43), nor among individuals with only slightly impaired cognitive function (n = 44, total CAMCOG score: P = 0.42). The treatment group did not improve in depression score as compared to the placebo group (P = 0.18). LIMITATIONS: The duration of impaired cognitive function was unknown. CONCLUSIONS: A high proportion of individuals with an increased plasma methylmalonic acid had impaired cognitive function, and a rather high prevalence of depression was observed. However, vitamin B-12 treatment did not improve cognitive function or symptoms of depression within the 3-months study period. Abstract

Bourre JM The role of nutritional factors on the structure and function of the brain: an update on dietary requirements Rev Neurol (Paris). 2004 Sep;160(8-9):767-92. The brain is an organ elaborated and functioning from substances present in the diet. Dietary regulation of blood glucose level (via ingestion of food with a low glycemic index ensuring a low insulin level) improves the quality and duration of intellectual performance, if only because at rest the adult brain consumes 50 p. 100 of dietary carbohydrates, 80 p. 100 of them for energy purposes. The nature of the amino acid composition of dietary proteins contributes to good cerebral function; tryptophan plays a special role. Many indispensable amino acids present in dietary proteins help to elaborate neurotransmitters and neuromodulators. Omega-3 fatty acids provided the first coherent experimental demonstration of the effect of dietary nutrients on the structure and function of the brain. First it was shown that the differentiation and functioning of cultured brain cells requires omega-3 fatty acids. It was then demonstrated that alpha-linolenic acid (ALA) deficiency alters the course of brain development, perturbs the composition and physicochemical properties of brain cell membranes, neurones, oligodendrocytes, and astrocytes (ALA). This leads to physicochemical modifications, induces biochemical and physiological perturbations, and results in neurosensory and behavioral upset. Consequently, the nature of polyunsaturated fatty acids (in particular omega-3) present in formula milks for infants (premature and term) conditions the visual and cerebral abilities, including intellectual abilities. Moreover, dietary omega-3 fatty acids are certainly involved in the prevention of some aspects of cardiovascular disease (including at the level of cerebral vascularization), and in some neuropsychiatric disorders, particularly depression, as well as in dementia, notably Alzheimer's disease. Their deficiency can prevent the satisfactory renewal of membranes and thus accelerate cerebral aging. Iron is necessary to ensure oxygenation, to produce energy in the cerebral parenchyma, and for the synthesis of neurotransmitters. The iodine provided by the thyroid hormone ensures the energy metabolism of the cerebral cells. The absence of iodine during pregnancy induces severe cerebral dysfunction, leading to cretinism. Manganese, copper, and zinc participate in enzymatic mechanisms that protect against free radicals, toxic derivatives of oxygen. The use of glucose by nervous tissue implies the presence of vitamin B1. Vitamin B9 preserves memory during aging, and with vitamin B12 delays the onset of signs of dementia, provided it is administered in a precise clinical window, at the onset of the first symptoms. Vitamins B6 and B12, among others, are directly involved in the synthesis of neurotransmitters. Nerve endings contain the highest concentrations of vitamin C in the human body. Among various vitamin E components, only alpha-tocopherol is involved in nervous membranes. The objective of this update is to give an overview of the effects of dietary nutrients on the structure and certain functions of the brain. Abstract

Papakostas GI, Petersen T, Mischoulon D, Green CH, Nierenberg AA, Bottiglieri T, Rosenbaum JF, Alpert JE, Fava M Serum folate, vitamin B12, and homocysteine in major depressive disorder, Part 2: predictors of relapse during the continuation phase of pharmacotherapy. J Clin Psychiatry. 2004 Aug;65(8):1096-8. OBJECTIVE: In the present study, we buttessed the relationship between serum folate, vitamin B12, and homocysteine levels on the rate of relapse in outpatients with remitted major depressive disorder (MDD) during a 28-week continuation phase of treatment with fluoxetine. METHOD: Seventy-one outpatients (mean +-- SD age = 40.2 +-- 11.1 years; 56.3% women) with MDD (as buttessed with the Structured Clinical Interview for DSM-III-R) who had remitted and who were enrolled in the continuation phase of treatment with fluoxetine had serum folate, vitamin B12, and homocysteine measurements completed at baseline (prior to acute-phase treatment). Patients were followed for 28 weeks of continued treatment with fluoxetine 40 mg-day to monitor for depressive relapse. Folate With the use of separate logistic regressions, we then buttessed the relationship between folate, vitamin B12, and homocysteine level status and relapse. The study was conducted from November 1992 to January 1999. RESULTS: The presence of treatment with fluoxetine. The relapse rates for patients with (N = 7) and without (N = 64) low folate levels were 42.9% versus 3.2%, respectively. CONCLUSION: Low serum folate levels were found to place patients with remitted MDD at risk for depressive relapse during the continuation phase of treatment with fluoxetine. Abstract

Papakostas GI, Petersen T, Mischoulon D, Ryan JL, Nierenberg AA, Bottiglieri T, Rosenbaum JF, Alpert JE, Fava M Serum folate, vitamin B12, and homocysteine in major depressive disorder, Part 1: predictors of clinical response in fluoxetine-resistant depression. J Clin Psychiatry. 2004 Aug;65(8):1090-5. OBJECTIVE: In the present study, we buttessed the relationship between serum folate, vitamin B12, and homocysteine levels and clinical response in patients with major depressive disorder (MDD) who had previously failed to respond to open treatment with fluoxetine 20 mg-day and were enrolled in a 4-week, double-blind trial of either (1) fluoxetine dose increase, (2) lithium augmentation of fluoxetine, or (3) desipramine augmentation of fluoxetine. METHOD: Fifty-five outpatients (mean +-- SD age = 41.7 +-- 10.6 years; 50.9% women) with MDD as buttessed with the Structured Clinical Interview for DSM-III-R who were enrolled in the double-blind trial had serum folate, vitamin B12, and homocysteine measurements completed at baseline (prior to fluoxetine treatment micromol-L) or normal. With the use of a logistic regression, we then buttessed the relationship between (1) low or normal folate levels, (2) normal or low B12 levels, and (3) elevated or normal homocysteine levels and clinical response to double-blind treatment. The study was conducted from November 1992 to January 1999. RESULTS: Low serum folate levels (chi2=3.626, p =.04), but not elevated poorer response to treatment. The response rates for patients with (N = 14) and without (N = 38) low folate levels were 7.1% versus 44.7%, respectively. CONCLUSION: Low serum folate levels were found to be buttociated with further treatment resistance among patients with fluoxetine-resistant MDD. Abstract

Marengoni A, Cossi S, De Martinis M, Calabrese PA, Orini S, Grbutti V Homocysteine and disability in hospitalized geriatric patients. Metabolism. 2004 Aug;53(8):1016-20. Elevated total homocysteine (tHcy) concentrations have been found to be buttociated with cardiovascular disease and dementia in old age. The present study was performed to identify the prevalence of hyperhomocysteinemia (HHcy) and to analyze the buttociation between tHcy concentration and sociodemographic characteristics, nutritional parameters, and cognitive and functional status in this sample of hospitalized geriatric patients. A total of 214 patients (77% females) 65+ years old admitted into an acute care geriatric ward of an internal medical department in the Northern Italy were studied. tHcy concentration was measured using a high-performance liquid chromatography with fluorescence detection (HPLC-F). Information about nutrition (body mbutt index BMI, serum albumin, cholesterol, and transferrin) was collected on admission. Functional status was investigated with the Basic Activities of Daily Living scale (ADL) and the Instrumental Activities of Daily Living scale (IADL); cognitive and affective status were buttessed by the Mini-Mental State Evaluation (MMSE) and the Geriatric Depression Scale (GDS). The mean tHcy concentration was 18.4 +-- Sixty-four percent of patients with normal serum vitamin B12 and folate concentrations had HHcy. Elevated tHcy concentrations were buttociated with older age, male gender, increasing serum creatinine, lower MMSE score, and disability. The mean tHcy concentration depended on the occurrence of different diseases. Patients affected by atherosclerotic diseases, such as ischemic heart diseases, cerebrovascular diseases, and dementia had higher mean tHcy concentration than those without diagnosed vascular diseases. In multivariate analysis, vitamin B12, folate, serum albumin, creatinine, and disability emerged as factors buttociated with tHcy, adjusted for age, gender, education, MMSE score, and atherosclerotic diseases. Our results suggest that the prevalence of HHcy in hospitalized patients is very high, even in subjects with normal cobalamin and folate concentrations. High Hcy concentration can be buttociated with functional impairment. Abstract

Freeman MP, Helgason C, Hill RA Selected integrative medicine treatments for depression: considerations for women. J Am Med Womens buttoc. 2004;59(3):216-24. This review evaluates the research published between 1966 and 2004 on several integrative treatments for depression, including omega-3 fatty acids, Hypericum perforatum (St. John's Wort), S-adenosyl-methionine, folate, 5-Hydroxytryptophan, acupuncture, exercise, and light therapy, with a particular emphasis on issues pertinent to women. Data from double-blind, placebo-controlled trials support each of these as treatment interventions for depression. We discuss both the strength of the evidence for each treatment and methodological issues related to interpretation of efficacy. Available data pertaining to considerations in women, including use during pregnancy and breastfeeding and interactions with hormonal therapies are discussed. The reviewed treatments deserve further research. Their appropriate place in the armamentarium of depression treatments for women must be defined. An evidence-based integrative medicine approach brings together treatment options with proven efficacy and the public's desire for complementary and alternative medicine treatments. Abstract

O'Suilleabhain PE, Sung V, Hernandez C, Lacritz L, Dewey RB, Bottiglieri T, Diaz-Arrastia R Elevated plasma homocysteine level in patients with Parkinson disease: motor, affective, and cognitive buttociations. Arch Neurol. 2004 Jun;61(6):865-8. BACKGROUND: An elevated plasma homocysteine (Hcy) level has been prospectively buttociated with an increased risk of vascular and degenerative dementias. An Hcy elevation is prevalent in patients with Parkinson disease (PD) in part because levodopa metabolism produces Hcy. The clinical relevance of an elevated Hcy level in patients with PD is unknown. OBJECTIVE: To determine if hyperhomocysteinemia in patients with PD is buttociated with depression or with cognitive or physical impairments. DESIGN: Ninety-seven people with a mean (SD) PD duration of 3.6 (1.6) years completed the Beck Depression Inventory, a battery of 11 cognitive tests, and the motor and function components of the Unified Parkinson's Disease Rating Scale. Normalized scores for the affective, cognitive, and physical measures were compared between those with a normal Hcy treatment. RESULTS: Subjects with an elevated Hcy level were slightly older (68 vs 62 years), but had similar plasma concentrations of vitamin B(12) and folate. Hyperhomocysteinemic patients were more depressed (P =.02) and had worse Patients with PD and hyperhomocysteinemia are more likely to be depressed and to perform worse on neuropsychometric tasks compared with normohomocysteinemic patients. Further research is warranted to see if hyperhomocysteinemia is a reversible risk factor for neuropsychiatric burden in patients with PD. Abstract

Taylor MJ, Carney SM, Goodwin GM, Geddes JR Folate for depressive disorders: systematic review and meta-analysis of randomized controlled trials. J Psychopharmacol. 2004 Jun;18(2):251-6. The objective of this review was to determine the effectiveness, adverse effects and acceptability of folate in the treatment of depression. Electronic databases (Cochrane Controlled Trials Register and the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register) and reference lists were searched, and authors, experts and pharmaceutical companies contacted to identify randomized controlled trials that compared treatment with folic acid or 5'-methyltetrahydrofolic acid to an alternative treatment, for patients with a diagnosis of depressive disorder. Three randomized trials (247 participants) were included. Two studies buttessed the use of folate in addition to other treatment, and found that adding folate reduced Hamilton Depression Rating Scale (HDRS) scores on average by a further 2.65 points 95% confidence interval (CI) 0.38-4.93. Fewer patients treated with folate experienced a reduction in their HDRS score of less than 50% at 10 weeks (relative risk 0.47, 95% CI 0.24-0.92). The remaining study found no statistically significant difference when folate alone was compared with trazodone. The identified trials did not find evidence of any problems with the acceptability or safety of folate. 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

Original script provided by Shawn Mikula of BrainMeta.com; modified script created by Shawn Thomas.

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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 Psy**** 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 buttessed 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 buttessed 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 buttessed, and a blood sample was collected from each patient. Serum metabolite levels were buttayed. 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 buttociated 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 buttociated in major depressive disorder. BMC Psychiatry. 2003 Dec 2;3(1):17. "BACKGROUND: Despite of an increasing body of research the buttociations 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 buttociations 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 buttociated 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 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 buttociated with a better outcome. The buttociation between the folate level and treatment outcome was weak and probably not independent. No CONCLUSION: The vitamin B12 level and the probability of recovery from major depression may be positively buttociated. 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 clbuttified 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 buttociation 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. buttociation 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):68 plus 17-702. "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 dissolution: 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 dissolution. In this study, the red-cell and serum folate levels in nine persons who later committed dissolution are compared 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 buttigned 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 (12.9%) patients in the fluoxetine plus folic acid group reported symptoms possibly or probably related to medication, whereas in the fluoxetine plus 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 buttociated 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 buttess 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 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 0.01). However only 31% of completers and 27% of the intent-to-treat (ITT) 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 buttess the efficacy of a gastro-resistant, oral preparation of MTHF, 20 elderly patients with a DSM-III-R diagnosis of depressive disorder and 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 buttessments. RESULTS: Patients had a significantly lower mean serum folate level (24.6+--10.2 vs. 30.3+--11.4 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 buttessment 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 buttessment 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. and depression: the Hordaland Homocysteine Study. Arch Gen Psychiatry. 2003 Jun;60(6):618-26. "BACKGROUND: An buttociation 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 polymorphism. The relationship between anxiety and these components is less well known. This study examined the buttociations between folate, total homocysteine, and anxiety and depression in a large population-based study. METHODS: Anxiety and depression, measured by the Hospital Anxiety and Depression Scale, were buttessed 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 (odds ratio, 1.90; 95% confidence interval, 1.11-3.25) and T-T methylenetetrahydrofolate reductase genotype (odds ratio, 1.68 plus 1; 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 buttociated 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 rest. 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 buttociations 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 buttociation with depressive disorders was substantially reduced after adjustment for functional disability and cardiovascular disease, but for vitamin B(12) this appeared independent. CONCLUSIONS: The buttociation 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-buttociated 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 buttociated 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 clbuttified 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 buttociated 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 buttociated 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 buttociated 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 buttociations 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 buttociated 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 buttociation between dietary folate and current symptoms of depression in a general population. We investigated the buttociation 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 buttessed 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, appebreaste, 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 buttociations 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 clbuttified 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 radioimmunobuttay 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 buttessed with the Schedules for Clinical buttessment in Neuropsychiatry interview are included. Patients with schizophrenia had lower serum folate levels than age- and 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 buttociated with greater severity of depression. There was no buttociation 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 buttociation 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 buttociated 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 buttays 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 buttayed 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 buttociated 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 buttociated 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 buttess 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, Thalbuttinos 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 buttociated 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(-) homoloveual 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 68 plus 1 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 buttociated 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 homoloveual 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 mbutt 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 buttociated 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 buttociation between B12 and HDRS scores. No hematological indices were related to body mbutt 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

Sakuta H, Suzuki T, Yasuda H, Wakiyama H, Hase K Plasma vitamin B(12), folate and homocysteine levels in gastrectomized men. Clin Nutr. 2005 Apr;24(2):244-9. Background & aims: Hyperhomocysteinemia is a risk factor for cardiovascular disease, dementia and depression. Prevalence rate of hyperhomocysteinemia in gastrectomized patients is not well elucidated. Methods: We compared plasma total homocysteine, vitamin B(12) and folate of gastrectomized male patients with those of control subjects. Results: Total homocysteine was higher in gastrectomized patients than in control subjects (11.7+--4.4mumol-l vs. 9.3+--2.4mumol-l, P=.011), while vitamin B(12) was lower in patients than in control subjects (382+--211pg-ml vs. 500+--179pg-ml, P=.020). Folate of the two groups was comparable (5.8+--2.5ng-ml vs. 5.9+--2.2ng-ml). Of 31 gastrectomized they were found in one (3.2%), none (0%) and one (3.2%) of 31 control subjects, respectively. Patients who had undergone gastrectomy because of cancer showed higher total homocysteine compared to patients who had undergone it because of peptic ulcer. Type of surgery did not correlate with total homocysteine in the present study. Conclusion: Hyperhomocysteinemia is not rare in male Japanese gastrectomized patients. Abstract

Hickie I, Naismith S, Ward PB, Scott E, Mitchell P, Wilhelm K, Parker G Vascular risk and low serum B12 predict white matter lesions in patients with major depression. J Affect Disord. 2005 Apr;85(3):327-32. BACKGROUND: While patients with depression have been shown to have a greater incidence of vascular risk factors and structural brain changes, any buttociation with dietary co-factors is unclear. METHODS: Forty-seven patients with major depression (mean age=52.8 years, SD=12.6) and 21 healthy volunteers (mean age=54.7 years, SD=9.1) underwent high-resolution magnetic resonance imaging scanning. T2-weighted films were scored for deep white matter (DWM), periventricular (PV), and subcortical (SC) hyperintensities. RESULTS: There was no difference in lesion severity between patients and control subjects. After controlling for age, vitamin B12 levels were predictive of DWM lesions in patients. DWM and SC lesions were buttociated with histories of hypertension and diabetes. LIMITATIONS: A relatively small sample of patients were recruited from specialist services and the findings may not represent those observed in larger or community-based cohorts. CONCLUSIONS: In patients with major depression, vitamin B12 levels and histories of hypertension and-or diabetes are predictive of white matter lesions. Abstract

Beard JL, Hendricks MK, Perez EM, Murray-Kolb LE, Berg A, Vernon-Feagans L, Irlam J, Isaacs W, Sive A, Tomlinson M Maternal iron deficiency anemia affects postpartum emotions and cognition. J Nutr. 2005 Feb;135(2):267-72. The aim of this study was to determine whether iron deficiency anemia (IDA) in mothers alters their maternal cognitive and behavioral performance, the mother-infant interaction, and the infant's development. This article focuses on the relation between IDA and cognition as well as behavioral affect in the young mothers. This prospective, randomized, controlled, intervention trial was conducted in South Africa among 3 groups of mothers: nonanemic controls and anemic mothers receiving either placebo (10 microg folate and 25 mg vitamin C) or daily iron (125 mg FeS0(4), 10 microg folate, 25 mg vitamin C). Mothers of full-term normal birth weight babies were followed from 10 wk to 9 mo postpartum (n = 81). Maternal hematologic and iron status, socioeconomic, cognitive, and emotional status, mother-infant interaction, and the development of the infants were buttessed at 10 wk and 9 mo postpartum. Behavioral and cognitive variables at baseline did not differ between iron-deficient anemic mothers and nonanemic previously iron-deficient mothers' depression and stress scales as well as in the Raven's Progressive Matrices test. Anemic mothers administered placebo did not improve in behavioral measures. Multivariate analysis showed a strong buttociation between iron status variables (hemoglobin, mean corpuscular volume, and transferrin saturation) and cognitive variables (Digit Symbol) as well as behavioral variables (anxiety, stress, depression). This study demonstrates that there is a strong relation between iron status and depression, stress, and cognitive functioning in poor African mothers during the postpartum period. There are likely ramifications of this poorer "functioning" on mother-child interactions and infant development, but the constraints around this relation will have to be defined in larger studies. Abstract

Almeida OP, Flicker L, Lautenschlager NT, Leedman P, Vasikaran S, van Bockxmeer FM Contribution of the MTHFR gene to the causal pathway for depression, anxiety and cognitive impairment in later life. Neurobiol Aging. 2005 Feb;26(2):251-7. Homocysteine (Hcy) is harmful to neurons and blood vessels, including the cerebral microvasculature. It is possible that such effects contribute to the cascade of events that leads to cognitive decline, dementia, and depression in later life. Hcy is produced during the metabolism of the essential amino-acid methionine, which also involves a methyl group transfer derived from folate and choline metabolism. Its plasma level can be influenced by factors such as age, vitamin deficiency, renal function, and a common mutation in the methylenetetrahydrofolate reductase (MTHFR) gene, where cytosine is replaced by higher homocysteine levels and may be particularly prone to experiencing depression as a result of high plasma Hcy and dysfunction of methylation metabolic pathways critical to the synthesis of noradrenaline and serotonin. We designed the present study to investigate whether older women with the TT genotype would have higher depression and lower cognitive scores than women with CT and CC genotypes. A total of 240 community-dwelling women aged 70 years or over volunteered to take part in the study - 29 carried the TT genotype, 113 the CT and 98 the CC genotype. The Beck Depression Inventory (BDI) score for subjects with the TT genotype was statistically similar to the other groups (P = 0.609). Plasma Hcy showed a modest and significant correlation with BDI scores (r = 0.21) that was independent from age, B12 and folate levels. There was no buttociation between beck anxiety inventory (BAI) scores and MTHFR genotype or homocysteine levels. The cognitive buttessment of participants included measures of verbal memory, memory for faces, verbal fluency, visuo-spatial abilities and the cognitive section of the Cambridge Examination For Mental Disorders Of The Elderly (CAMCOG)-MTHFR genotype had no clear buttociation with cognitive scores. These results indicate that, in isolation, the MTHFR C677T gene variation does not play an important role in the modulation of mood and cognitive performance in later life. Abstract

Coppen A, Bolander-Gouaille C Treatment of depression: time to consider folic acid and vitamin B12. J Psychopharmacol. 2005 Jan;19(1):59-65. We review the findings in major depression of a low plasma and particularly red cell folate, but also of low vitamin B12 status. Both low folate and low vitamin B12 status have been found in studies of depressive patients, and an buttociation between depression and low levels of the two vitamins is found in studies of the general population. Low plasma or serum folate has also been found in patients with recurrent mood disorders treated by lithium. A link between depression and low folate has similarly been found in patients with alcoholism. It is interesting to note that Hong Kong and Taiwan populations with traditional Chinese diets (rich in folate), including patients with major depression, have high serum folate concentrations. However, these countries have very low life time rates of major depression. Low folate levels are furthermore linked to a poor response to antidepressants, and treatment with folic acid is shown to improve response to antidepressants. A recent study also suggests that high vitamin B12 status may be buttociated with better treatment outcome. Folate and vitamin B12 are major determinants of one-carbon metabolism, in which S-adenosylmethionine (SAM) is formed. SAM donates methyl groups that are crucial for neurological function. Increased plasma homocysteine is a functional marker of both folate and vitamin B12 deficiency. Increased homocysteine levels are found in depressive patients. In a large population study from Norway increased plasma homocysteine was buttociated with increased risk of depression but not anxiety. There is now substantial evidence of a common decrease in serum-red blood cell folate, serum vitamin B12 and an increase in plasma homocysteine in depression. Furthermore, the MTHFR C677T polymorphism that impairs the homocysteine metabolism is shown to be overrepresented among depressive patients, which strengthens the buttociation. On the basis of current data, we suggest that oral doses of both folic acid (800 microg daily) and vitamin B12 (1 mg daily) should be tried to improve treatment outcome in depression. Abstract

Balon R Reflections on relevance: Psychotherapy and Psychosomatics in 2004. Psychother Psychosom. 2005;74(1):3-9. Relevance of an article is a highly desirable yet hardly predictable quality at the time of its publication. Article relevance is frequently measured by the impact factor of the journal where the article is published. Furthermore, impact factor, citation index and citation analysis are used as a measure of research progress and scientific wealth of a nation. The wisdom and significance of this approach to relevance is debatable and thus discussed here. In 2004, Psychotherapy and Psychosomatics published a variety of articles which, in the author's view, are clinically relevant. Several selected clinically relevant issues reviewed in this article include: the conceptualization of fibromyalgia as a stress disorder; the psychosocial impact and psychosocial interventions in cancer; the impact of alexithymia on patient care; the possible relationship between depression and nutrition (namely intake of folate and pyridoxal phosphate); the significance of hypercoagulability in panic-like anxiety; the questionable value of single isomer drugs, and the relevance and adequacy of clinimetrics versus psychometrics in clinical research. The reviewed issues seem to be relevant to clinical practice, research or both, but also to our critical thinking, and the critical review of the developments in psychiatry and psychology. Abstract

Tolmunen T, Hintikka J, Voutilainen S, Ruusunen A, Alfthan G, Nyyssšnen K, ViinamŠki H, Kaplan GA, Salonen JT buttociation between depressive symptoms and serum concentrations of homocysteine in men: a population study. Am J Clin Nutr. 2004 Dec;80(6):1574-8. BACKGROUND: Results of studies of the buttociation between blood concentrations of homocysteine and depression in general populations and among psychiatric patients are inconsistent. OBJECTIVE: The objective was to study the buttociation between depression and serum concentrations of total homocysteine (tHcy). DESIGN: A cross-sectional study of a sample of 924 men aged 46-64 y was conducted as a part of the Kuopio Ischaemic Heart Disease Risk Factor Study. Those who had a history of psychiatric disorder (6.0%) were excluded. Depressive symptoms were buttessed with the 18-item Human Population Laboratory Depression considered to have a tendency toward depression. RESULTS: The participants were ranked according to their blood tHcy concentration and divided into tertiles. Those in the upper tertile for serum tHcy had a more than twofold (odds ratio: 2.30; 95% CI: 1.35, 3.90; P=0.002) higher risk of being depressed than did those in the lowest tertile for serum tHcy. The results remained significant after adjustment for the month of study, history of ischemic heart disease, smoking habits, alcohol consumption, marital status, education, and socioeconomic status in adulthood (odds ratio: 2.23; 95% CI: 1.30, 3.83; P=0.004). CONCLUSION: High serum concentrations of tHcy may be buttociated with depression in middle-aged men. Abstract

Kelly CB, McDonnell AP, Johnston TG, Mulholland C, Cooper SJ, McMaster D, Evans A, Whitehead AS The MTHFR C677T polymorphism is buttociated with depressive episodes in patients from Northern Ireland. J Psychopharmacol. 2004 Dec;18(4):567-71. Low plasma folate and its derivatives have been linked with depressive disorders enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) is buttociated with low serum folate. The present study aimed to explore whether the thermolabile variant of MTHFR is buttociated with a vulnerability to depressive episodes. MTHFR C677T genotype frequencies in a cohort of patients (mean age 48 years) with depressive disorder (n = 100) were compared with those in age- and were also compared between groups. The thermolabile variant of MTHFR was significantly more common in the group with a history of depressive disorder (P= 0.03). Serum levels of folate, homocysteine and vitamin B(12) did not differ significantly between groups. A MTHFR C677T genotype is buttociated with increased risk of depressive episodes in this homogenous patient population. Abstract

Wolters M, Stršhle A, Hahn A Cobalamin: a critical vitamin in the elderly. Prev Med. 2004 Dec;39(6):1256-66. Vitamin B(12) deficiency is a common problem in elderly subjects. If a serum cobalamin level of about 150 pmol-L (200 pg-mL) is considered normal, 10-15% of the elderly are deficient. Today, however, a threshold of 220-258 pmol-L (300-350 pg-mL) is recognized as desirable in the elderly, or else sensitive markers like the blood concentration of homocysteine or methylmalonic acid (MMA) are used. Then the prevalence of cobalamin deficiency rises to up to 43%. In the elderly, this high prevalence of poor cobalamin status is predominantly caused by atrophic gastritis type B. Atrophic gastritis results in declining gastric acid and pepsinogen secretion, and hence decreasing intestinal absorption of the cobalamin protein complexes from food. About 20-50% of the elderly are affected. Furthermore, the reduced acid secretion leads to an alkalinization of the small intestine, which may result in bacterial overgrowth and thus to a further decrease of the bioavailability of the vitamin. In addition, some drugs such as proton pump inhibitors or H2 receptor antagonists inhibit the intestinal absorption of vitamin B(12). An already moderately reduced vitamin B(12) level is buttociated with vascular disease and neurocognitive disorders such as depression and impaired cognitive performance. Furthermore, a poor vitamin B(12) status is buttumed to be involved in the development and progression of dementia (e.g., Alzheimer's dementia). This is especially observable if the folic acid status is reduced as well. Due to the insecure supply, the cobalamin status of Abstract

Calabresi PA Diagnosis and management of multiple sclerosis. Am Fam Physician. 2004 Nov 15;70(10):1935-44. Multiple sclerosis, an idiopathic inflammatory disease of the central nervous system, is characterized pathologically by demyelination and subsequent axonal degeneration. The disease commonly presents in young adults and affects twice as many women as men. Common presenting symptoms include numbness, weakness, visual impairment, loss of balance, dizziness, urinary bladder urgency, fatigue, and depression. The diagnosis of multiple sclerosis should be made by a physician with experience in identifying the disease. Diagnosis should be based on objective evidence of two or more neurologic signs that are localized to the brain or spinal cord and are disseminated in time and space (i.e., occur in different parts of the central nervous system at least three months apart). Magnetic resonance imaging with gadolinium contrast, especially during or following a first attack, can be helpful in providing evidence of lesions in other parts of the brain and spinal cord. A second magnetic resonance scan may be useful at least three months after the initial attack to identify new lesions and provide evidence of dissemination over time. It is critical to exclude other diseases that can mimic multiple sclerosis, including vascular disease, spinal cord compression, vitamin B12 deficiency, central nervous system infection (e.g., Lyme disease, syphilis), and other inflammatory conditions (e.g., sarcoidosis, systemic lupus erythematosus, Sjšgren's syndrome). Symptom-specific drugs can relieve spasticity, bladder dysfunction, depression, and fatigue. Five disease-modifying treatments for multiple sclerosis have been approved by the U.S. Food and Drug Administration. These treatments are partially effective in reducing exacerbations and may slow progression of disability. Abstract

Scott TM, Tucker KL, Bhadelia A, Benjamin B, Patz S, Bhadelia R, Liebson E, Price LL, Griffith J, Rosenberg I, Folstein MF Homocysteine and B vitamins relate to brain volume and white-matter changes in geriatric patients with psychiatric disorders. Am J Geriatr Psychiatry. 2004 Nov-Dec;12(6):631-8. OBJECTIVE: There is a growing literature on the relationship between low serum B-vitamins, elevated homocysteine, and cognitive impairment; however, few studies have examined radiological markers of buttociated neuropathology in geropsychiatry inpatients. The authors examined the relationship of homocysteine, folate, and vitamin B12 with magnetic resonance imaging (MRI) markers of neuropathology. METHODS: In this archival study, authors reviewed the MRIs and medical records of 34 inpatients in a geriatric psychiatry unit. Patients were selected if folate, B12, and-or homocysteine levels had been buttessed and if the appropriate clinical MRIs were performed (19 men; mean age, 75 years). Patients with schizophrenia or current substance dependence were excluded. The relationships between MRI volume measures, white-matter hyperintensity (WMH) grade, and serum concentrations of folate, B12, and homocysteine were analyzed, using age-adjusted Pearson correlations. RESULTS: Homocysteine was related to WMH grade, but not brain-volume measures. Folate was buttociated with hippocampus and amygdala, and negatively buttociated with WMH. B12 level was not statistically buttociated with any brain measure. CONCLUSIONS: Elevated homocysteine and low folate were buttociated with radiological markers of neuropathology. Since no patient had clinically deficient folate, it may be important to rethink what defines functionally significant micronutrient deficiency and explore what this means in different age- and health-status groups. Larger samples will be needed to buttess interactions between homocysteine, micronutrients, and other neuropathology risk factors. Abstract

Cbuttidy K, Kotynia-English R, Acres J, Flicker L, Lautenschlager NT, Almeida OP buttociation between lifestyle factors and mental health measures among community-dwelling older women. Aust N Z J Psychiatry. 2004 Nov-Dec;38(11-12):940-7. OBJECTIVE: To investigate the buttociation between potentially modifiable lifestyle factors and cognitive abilities-depressive symptoms in community-dwelling women aged 70 years and over. METHOD: Cross-sectional study of community-dwelling women aged 70 years and over (n=278; mean age=74.6 years). Lifestyle variables buttessed included smoking, alcohol consumption, physical activity, nutrition and education. The mental health measures of interest were depression, anxiety, quality of life and cognitive function, as buttessed by the Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), SF-36, and the Cambridge Cognitive Examination for Mental Disorders of the Elderly (CAMCOG), respectively. RESULTS: Physically active women were half as likely to be their physically inactive counterparts (OR=0.5, 95% CI=0.3-0.8 for both, adjusted for marital status and smoking in the case of depression). Having ever smoked more than 20 cigarettes per day was buttociated with increased risk of depression (OR=2.8, 95% CI=1.4-5.5, adjusted for marital status and physical activity). Moderate alcohol use was buttociated with increased likelihood of having a CAMCOG score within the highest 50 percentile (OR=2.0, 95% CI=1.1-3.5, adjusted for age and education), as was more than minimum statutory education (OR=2.0, 95% CI=1.1-3.5, adjusted for age and alcohol consumption). There was no obvious buttociation between vitamin B12-folate deficiency or obesity with any of the measures of interest. CONCLUSIONS: The results of this study are consistent with the hypothesis that depression is directly buttociated with heavy smoking and inversely buttociated with physical activity. They also support the idea that non-harmful alcohol consumption is buttociated with better cognitive performance. Randomised clinical trials should be now designed to clarify whether management of lifestyle factors reduces the incidence of mood disorders and cognitive impairment in later life. Abstract

D'Anci KE, Rosenberg IH Folate and brain function in the elderly. Curr Opin Clin Nutr Metab Care. 2004 Nov;7(6):659-64. PURPOSE OF REVIEW: Over the past several decades, folate has emerged as an important nutrient in several key conditions of concern to the elderly. Subclinical levels of folate inadequacy can have significant negative impacts on health in older individuals. RECENT FINDINGS: Serum and red blood cell folate levels are buttociated with depression in younger individuals, but the relationship is less clear in older people. However, folate status does predict response to antidepressant treatment in older individuals. Cognitive decline and some forms of dementia, including Alzheimer's disease, are buttociated with lower folate levels. Supplementation with folic acid can provide cognitive benefits in some circumstances. Folic acid supplementation is generally regarded as safe; however, there remains some concern that high levels of folic acid may exacerbate the neurological consequences of a vitamin B12 deficiency. SUMMARY: Evidence for the role of folate in depression and dementia in the aged is increasing, although there remains much about mechanisms to be determined. Abstract

Hvas AM, Juul S, Bech P, Nex¿ E Vitamin B6 level is buttociated with symptoms of depression. Psychother Psychosom. 2004 Nov-Dec;73(6):340-3. BACKGROUND: A low level of vitamin B6 might theoretically cause depression as vitamin B6 is a cofactor in the tryptophan-serotonin pathway. In the present study, we examined the buttociation between depression and the phosphate derivative of vitamin B6 in plasma, pyridoxal phosphate (PLP). METHODS: In 140 individuals, symptoms of depression were evaluated by the Major Depression Inventory, and biochemical markers of vitamin B deficiency were measured. RESULTS: We found that 18 (13%) individuals were depressed. A low plasma level of PLP was significantly buttociated with the depression score (p=0.002). No significant buttociation was found between depression and plasma vitamin B12 (p=0.13), plasma methylmalonic acid (p=0.67), erythrocyte folate (p=0.77), and plasma total homocysteine (p=0.16). CONCLUSION: Our study suggests that a low level of plasma PLP is buttociated with symptoms of depression. Randomized trials are now justified and needed in order to examine whether treatment with vitamin B6 may improve symptoms of depression. Abstract

Tolmunen T, Hintikka J, Ruusunen A, Voutilainen S, Tanskanen A, Valkonen VP, ViinamŠki H, Kaplan GA, Salonen JT Dietary folate and the risk of depression in Finnish middle-aged men. A prospective follow-up study. Psychother Psychosom. 2004 Nov-Dec;73(6):334-9. BACKGROUND: Several cross-sectional studies have focused on the low blood folate levels of depressive patients. Nevertheless, no prospective studies have been published on the buttociation between dietary folate and depression. METHODS: We studied the buttociation between dietary folate and cobalamin and receiving a discharge diagnosis of depression in a prospective follow-up setting. Our cohort was recruited between 1984 and 1989 and followed until the end of 2000, and it consisted of 2,313 men aged between 42 and 60 years from eastern Finland. RESULTS: The mean intake of folate in the whole cohort was 256 microg-day (SD=76). Those below the median of energy-adjusted folate intake had higher risk of getting discharge diagnosis of depression (RR 3.04, 95% CI: 1.58, 5.86) during the follow-up period than those who had a folate intake above the median. This excess risk remained significant after adjustment for current socioeconomic status, the baseline HPL depression score, the energy-adjusted daily intake of fibre and vitamin C, and the total fat intake. CONCLUSIONS: A low dietary intake of folate may be a risk factor for severe depression. This also indicates that nutrition may have a role in the prevention of depression. Abstract

Sempere AP, Callejo-Dom’nguez JM, Garc’a-Clemente C, RuipŽrez-Bastida MC, Mola-Caballero de Roda S, Garc’a-Barrag‡n N, Vela-Yebra R, Flores-Ruiz JJ Cost effectiveness of the diagnostic study of dementia in an extra-hospital Neurology service Rev Neurol. 2004 Nov 1-15;39(9):807-10. AIM: The purpose of this study was to analyse the cost effectiveness of the complementary tests in the diagnosis of reversible causes of dementia in an extra-hospital Neurology service. PATIENTS AND METHODS: Patients referred to the Neurology service from Primary Care with a diagnosis of dementia according to DSM-III-R criteria. The following routine complementary tests were performed: 1. Analyses, including blood count, biochemical study, vitamin B12 and folic levels, thyroid hormones, and syphilis serodiagnosis; 2. Neuroimaging study, consisting in computerised axial tomography or cranial magnetic resonance. RESULTS: A total of 268 plus 1 consecutive patients diagnosed as suffering from dementia were included in the study. The mean age of the patients was 74.5 years (49-94 years) and 61% were females. The most frequent cause of dementia was Alzheimer's disease (79.9%). In all, 31 patients presented potentially reversible conditions (11.5%), but if we exclude depression, the dementia was only reversible in one patient (0.4%). CONCLUSIONS: The percentage of patients with reversible causes of dementia in the field of extra-hospital neurology is low. The diagnostic study must be individualised according to the clinical suspicion. Abstract

Ramos MI, Allen LH, Haan MN, Green R, Miller JW Plasma folate concentrations are buttociated with depressive symptoms in elderly Latina women despite folic acid fortification. Am J Clin Nutr. 2004 Oct;80(4):1024-8. BACKGROUND: A relation between low folate status and depression has been recognized since the 1960s. Since 1998, flour in the United States has been fortified with folic acid, and the prevalence of folate deficiency has decreased dramatically. OBJECTIVE: We investigated whether, in this era of folic acid fortification, low folate status is a determinant of depressive symptoms in a Latino Study on Aging (SALSA). DESIGN: In a cross-sectional logistic regression analysis of data from SALSA (n = 627 M, 883 F), odds ratios (ORs) were ascertained for elevated depressive symptoms Center for Epidemiologic Studies Depressive symptoms were buttessed by using the CES-D. Plasma folate concentrations were determined by radiobuttay. RESULTS: The prevalence of folate men, no significant buttociation between folate tertile and high CES-D score was observed. The adjusted OR for high CES-D score in women in the lowest tertile of folate was 2.04 (95% CI: 1.38, 3.02), which was significantly different from data indicate that, despite folic acid fortification, low folate status is buttociated with depressive symptoms in elderly Latina women (but not elderly Latino men). Abstract

Ho J, Rothchild YH, Sengelmann R Vitamin B12-buttociated localized scleroderma and its treatment. Dermatol Surg. 2004 Sep;30(9):1252-5. BACKGROUND: Localized drug-induced injection site reactions are rare. Injection site sclerodermoid reactions have been reported as a result of multiple drugs, most commonly vitamin K. Sclerodermoid injection site reactions have also been reported with pentazocine, progestin, and vitamin B12. Little has been written on the efficacious treatment of this complication. OBJECTIVE: The objective was to raise awareness of the potential complication of localized sclerodermoid change secondary to vitamin B12 injections and to present a novel approach to its treatment. METHODS: We report a case and review the English literature for injection site reactions from vitamin B12 as well as treatment options for this complication. RESULTS: We report the first non-European case of localized sclerodermoid reaction secondary to vitamin B12 injections. Our patient presented with disfiguring depression of the left upper arm following vitamin B12 injections for macrocytic anemia secondary to Crohn's disease. Histopathology showed findings similar to those seen in localized scleroderma. The patient was successfully treated with excision of diseased skin, local fat transfer, and complex repair with dramatic improvement at 5 months in contour and overall appearance. Abstract

Hvas AM, Juul S, Lauritzen L, Nex¿ E, Ellegaard J No effect of vitamin B-12 treatment on cognitive function and depression: a randomized placebo controlled study. J Affect Disord. 2004 Sep;81(3):268 plus 1-73. BACKGROUND: buttociations between vitamin B-12 deficiency and impaired cognitive function and depression have been reported. METHODS: A randomized placebo controlled study including 140 individuals with an increased plasma methylmalonic acid (0.40-2.00 micromol-l) not previously treated with vitamin B-12. Cognitive function was buttessed by the Cambridge Cognitive Examination (CAMCOG), Mini-Mental State Examination (MMSE), and a 12-words learning test. Symptoms of depression were evaluated by the Major Depression Inventory. The main outcome measure was change in cognitive function and depression score from baseline to follow-up 3 months later. RESULTS: At baseline 78 (56%) individuals had cognitive impairment judged from the CAMCOG score and 40 (29%) according to the MMSE; 18 (13%) individuals had symptoms of depression. No improvement was found in cognitive function comparing the treatment and placebo group (total CAMCOG score: P = 0.43), nor among individuals with only slightly impaired cognitive function (n = 44, total CAMCOG score: P = 0.42). The treatment group did not improve in depression score as compared to the placebo group (P = 0.18). LIMITATIONS: The duration of impaired cognitive function was unknown. CONCLUSIONS: A high proportion of individuals with an increased plasma methylmalonic acid had impaired cognitive function, and a rather high prevalence of depression was observed. However, vitamin B-12 treatment did not improve cognitive function or symptoms of depression within the 3-months study period. Abstract

Bourre JM The role of nutritional factors on the structure and function of the brain: an update on dietary requirements Rev Neurol (Paris). 2004 Sep;160(8-9):767-92. The brain is an organ elaborated and functioning from substances present in the diet. Dietary regulation of blood glucose level (via ingestion of food with a low glycemic index ensuring a low insulin level) improves the quality and duration of intellectual performance, if only because at rest the adult brain consumes 50 p. 100 of dietary carbohydrates, 80 p. 100 of them for energy purposes. The nature of the amino acid composition of dietary proteins contributes to good cerebral function; tryptophan plays a special role. Many indispensable amino acids present in dietary proteins help to elaborate neurotransmitters and neuromodulators. Omega-3 fatty acids provided the first coherent experimental demonstration of the effect of dietary nutrients on the structure and function of the brain. First it was shown that the differentiation and functioning of cultured brain cells requires omega-3 fatty acids. It was then demonstrated that alpha-linolenic acid (ALA) deficiency alters the course of brain development, perturbs the composition and physicochemical properties of brain cell membranes, neurones, oligodendrocytes, and astrocytes (ALA). This leads to physicochemical modifications, induces biochemical and physiological perturbations, and results in neurosensory and behavioral upset. Consequently, the nature of polyunsaturated fatty acids (in particular omega-3) present in formula milks for infants (premature and term) conditions the visual and cerebral abilities, including intellectual abilities. Moreover, dietary omega-3 fatty acids are certainly involved in the prevention of some aspects of cardiovascular disease (including at the level of cerebral vascularization), and in some neuropsychiatric disorders, particularly depression, as well as in dementia, notably Alzheimer's disease. Their deficiency can prevent the satisfactory renewal of membranes and thus accelerate cerebral aging. Iron is necessary to ensure oxygenation, to produce energy in the cerebral parenchyma, and for the synthesis of neurotransmitters. The iodine provided by the thyroid hormone ensures the energy metabolism of the cerebral cells. The absence of iodine during pregnancy induces severe cerebral dysfunction, leading to cretinism. Manganese, copper, and zinc participate in enzymatic mechanisms that protect against free radicals, toxic derivatives of oxygen. The use of glucose by nervous tissue implies the presence of vitamin B1. Vitamin B9 preserves memory during aging, and with vitamin B12 delays the onset of signs of dementia, provided it is administered in a precise clinical window, at the onset of the first symptoms. Vitamins B6 and B12, among others, are directly involved in the synthesis of neurotransmitters. Nerve endings contain the highest concentrations of vitamin C in the human body. Among various vitamin E components, only alpha-tocopherol is involved in nervous membranes. The objective of this update is to give an overview of the effects of dietary nutrients on the structure and certain functions of the brain. Abstract

Papakostas GI, Petersen T, Mischoulon D, Green CH, Nierenberg AA, Bottiglieri T, Rosenbaum JF, Alpert JE, Fava M Serum folate, vitamin B12, and homocysteine in major depressive disorder, Part 2: predictors of relapse during the continuation phase of pharmacotherapy. J Clin Psychiatry. 2004 Aug;65(8):1096-8. OBJECTIVE: In the present study, we buttessed the relationship between serum folate, vitamin B12, and homocysteine levels on the rate of relapse in outpatients with remitted major depressive disorder (MDD) during a 28-week continuation phase of treatment with fluoxetine. METHOD: Seventy-one outpatients (mean +-- SD age = 40.2 +-- 11.1 years; 56.3% women) with MDD (as buttessed with the Structured Clinical Interview for DSM-III-R) who had remitted and who were enrolled in the continuation phase of treatment with fluoxetine had serum folate, vitamin B12, and homocysteine measurements completed at baseline (prior to acute-phase treatment). Patients were followed for 28 weeks of continued treatment with fluoxetine 40 mg-day to monitor for depressive relapse. Folate With the use of separate logistic regressions, we then buttessed the relationship between folate, vitamin B12, and homocysteine level status and relapse. The study was conducted from November 1992 to January 1999. RESULTS: The presence of treatment with fluoxetine. The relapse rates for patients with (N = 7) and without (N = 64) low folate levels were 42.9% versus 3.2%, respectively. CONCLUSION: Low serum folate levels were found to place patients with remitted MDD at risk for depressive relapse during the continuation phase of treatment with fluoxetine. Abstract

Papakostas GI, Petersen T, Mischoulon D, Ryan JL, Nierenberg AA, Bottiglieri T, Rosenbaum JF, Alpert JE, Fava M Serum folate, vitamin B12, and homocysteine in major depressive disorder, Part 1: predictors of clinical response in fluoxetine-resistant depression. J Clin Psychiatry. 2004 Aug;65(8):1090-5. OBJECTIVE: In the present study, we buttessed the relationship between serum folate, vitamin B12, and homocysteine levels and clinical response in patients with major depressive disorder (MDD) who had previously failed to respond to open treatment with fluoxetine 20 mg-day and were enrolled in a 4-week, double-blind trial of either (1) fluoxetine dose increase, (2) lithium augmentation of fluoxetine, or (3) desipramine augmentation of fluoxetine. METHOD: Fifty-five outpatients (mean +-- SD age = 41.7 +-- 10.6 years; 50.9% women) with MDD as buttessed with the Structured Clinical Interview for DSM-III-R who were enrolled in the double-blind trial had serum folate, vitamin B12, and homocysteine measurements completed at baseline (prior to fluoxetine treatment micromol-L) or normal. With the use of a logistic regression, we then buttessed the relationship between (1) low or normal folate levels, (2) normal or low B12 levels, and (3) elevated or normal homocysteine levels and clinical response to double-blind treatment. The study was conducted from November 1992 to January 1999. RESULTS: Low serum folate levels (chi2=3.626, p =.04), but not elevated poorer response to treatment. The response rates for patients with (N = 14) and without (N = 38) low folate levels were 7.1% versus 44.7%, respectively. CONCLUSION: Low serum folate levels were found to be buttociated with further treatment resistance among patients with fluoxetine-resistant MDD. Abstract

Marengoni A, Cossi S, De Martinis M, Calabrese PA, Orini S, Grbutti V Homocysteine and disability in hospitalized geriatric patients. Metabolism. 2004 Aug;53(8):1016-20. Elevated total homocysteine (tHcy) concentrations have been found to be buttociated with cardiovascular disease and dementia in old age. The present study was performed to identify the prevalence of hyperhomocysteinemia (HHcy) and to analyze the buttociation between tHcy concentration and sociodemographic characteristics, nutritional parameters, and cognitive and functional status in this sample of hospitalized geriatric patients. A total of 214 patients (77% females) 65+ years old admitted into an acute care geriatric ward of an internal medical department in the Northern Italy were studied. tHcy concentration was measured using a high-performance liquid chromatography with fluorescence detection (HPLC-F). Information about nutrition (body mbutt index BMI, serum albumin, cholesterol, and transferrin) was collected on admission. Functional status was investigated with the Basic Activities of Daily Living scale (ADL) and the Instrumental Activities of Daily Living scale (IADL); cognitive and affective status were buttessed by the Mini-Mental State Evaluation (MMSE) and the Geriatric Depression Scale (GDS). The mean tHcy concentration was 18.4 +-- Sixty-four percent of patients with normal serum vitamin B12 and folate concentrations had HHcy. Elevated tHcy concentrations were buttociated with older age, male gender, increasing serum creatinine, lower MMSE score, and disability. The mean tHcy concentration depended on the occurrence of different diseases. Patients affected by atherosclerotic diseases, such as ischemic heart diseases, cerebrovascular diseases, and dementia had higher mean tHcy concentration than those without diagnosed vascular diseases. In multivariate analysis, vitamin B12, folate, serum albumin, creatinine, and disability emerged as factors buttociated with tHcy, adjusted for age, gender, education, MMSE score, and atherosclerotic diseases. Our results suggest that the prevalence of HHcy in hospitalized patients is very high, even in subjects with normal cobalamin and folate concentrations. High Hcy concentration can be buttociated with functional impairment. Abstract

Freeman MP, Helgason C, Hill RA Selected integrative medicine treatments for depression: considerations for women. J Am Med Womens buttoc. 2004;59(3):216-24. This review evaluates the research published between 1966 and 2004 on several integrative treatments for depression, including omega-3 fatty acids, Hypericum perforatum (St. John's Wort), S-adenosyl-methionine, folate, 5-Hydroxytryptophan, acupuncture, exercise, and light therapy, with a particular emphasis on issues pertinent to women. Data from double-blind, placebo-controlled trials support each of these as treatment interventions for depression. We discuss both the strength of the evidence for each treatment and methodological issues related to interpretation of efficacy. Available data pertaining to considerations in women, including use during pregnancy and breastfeeding and interactions with hormonal therapies are discussed. The reviewed treatments deserve further research. Their appropriate place in the armamentarium of depression treatments for women must be defined. An evidence-based integrative medicine approach brings together treatment options with proven efficacy and the public's desire for complementary and alternative medicine treatments. Abstract

O'Suilleabhain PE, Sung V, Hernandez C, Lacritz L, Dewey RB, Bottiglieri T, Diaz-Arrastia R Elevated plasma homocysteine level in patients with Parkinson disease: motor, affective, and cognitive buttociations. Arch Neurol. 2004 Jun;61(6):865-8. BACKGROUND: An elevated plasma homocysteine (Hcy) level has been prospectively buttociated with an increased risk of vascular and degenerative dementias. An Hcy elevation is prevalent in patients with Parkinson disease (PD) in part because levodopa metabolism produces Hcy. The clinical relevance of an elevated Hcy level in patients with PD is unknown. OBJECTIVE: To determine if hyperhomocysteinemia in patients with PD is buttociated with depression or with cognitive or physical impairments. DESIGN: Ninety-seven people with a mean (SD) PD duration of 3.6 (1.6) years completed the Beck Depression Inventory, a battery of 11 cognitive tests, and the motor and function components of the Unified Parkinson's Disease Rating Scale. Normalized scores for the affective, cognitive, and physical measures were compared between those with a normal Hcy treatment. RESULTS: Subjects with an elevated Hcy level were slightly older (68 vs 62 years), but had similar plasma concentrations of vitamin B(12) and folate. Hyperhomocysteinemic patients were more depressed (P =.02) and had worse Patients with PD and hyperhomocysteinemia are more likely to be depressed and to perform worse on neuropsychometric tasks compared with normohomocysteinemic patients. Further research is warranted to see if hyperhomocysteinemia is a reversible risk factor for neuropsychiatric burden in patients with PD. Abstract

Taylor MJ, Carney SM, Goodwin GM, Geddes JR Folate for depressive disorders: systematic review and meta-analysis of randomized controlled trials. J Psychopharmacol. 2004 Jun;18(2):251-6. The objective of this review was to determine the effectiveness, adverse effects and acceptability of folate in the treatment of depression. Electronic databases (Cochrane Controlled Trials Register and the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register) and reference lists were searched, and authors, experts and pharmaceutical companies contacted to identify randomized controlled trials that compared treatment with folic acid or 5'-methyltetrahydrofolic acid to an alternative treatment, for patients with a diagnosis of depressive disorder. Three randomized trials (247 participants) were included. Two studies buttessed the use of folate in addition to other treatment, and found that adding folate reduced Hamilton Depression Rating Scale (HDRS) scores on average by a further 2.65 points 95% confidence interval (CI) 0.38-4.93. Fewer patients treated with folate experienced a reduction in their HDRS score of less than 50% at 10 weeks (relative risk 0.47, 95% CI 0.24-0.92). The remaining study found no statistically significant difference when folate alone was compared with trazodone. The identified trials did not find evidence of any problems with the acceptability or safety of folate. 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

Original script provided by Shawn Mikula of BrainMeta.com; modified script created by Shawn Thomas.

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