Treatment of depression: time to consider folic acid and vitamin B12

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 association 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 associated 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 associated 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 association. 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.     

Plasma folate and homocysteine levels may be related to interictal "schizophrenia-like" psychosis in patients with epilepsy

Genetic and clinical data suggest that folate and homocysteine may play a role in the pathogenesis of psychiatric disorders. The total plasma homocysteine level is a sensitive measure of a functional folate deficiency. We thus investigated whether a functional folate deficiency and/or elevated levels of plasma homocysteine may be related to interictal "schizophrenia-like" psychosis (interictal psychosis ) of epilepsy. We studied the plasma folate, vitamin B12, and homocysteine levels of 32 age- and sex-matched epileptic patients with or without interictal psychosis. Each group included 25 localization-related epilepsies and 7 generalized epilepsies. The epileptic patients with interictal psychosis had significantly lower folate levels and higher homocysteine levels than those without interictal psychosis. There were no significant differences in the vitamin B12 levels between the two groups. The present study suggests that low plasma folate and high plasma homocysteine levels may be related to the pathophysiology of interictal psychosis of epilepsy. In future studies, we should investigate whether folate supplementation, in addition to antipsychotics, might play a beneficial role in the treatment of interictal psychosis in epileptic patients. Furthermore, the present findings should be confirmed by prospective longitudinal studies in a larger group of patients with epilepsy.     

Clinical significance of pharmacological modulation of homocysteine metabolism

The metabolic fate of homocysteine is linked to vitamin B12, reduced folates, vitamin B6 and sulfur amino acids. Clinical and experimental data suggest that elevated plasma homocysteine is an independent risk factor for premature vascular disease. This is particularly significant because plasma homocysteine levels are altered in several diseases, including folate and vitamin B12 deficiencies, and because many commonly used drugs have now been shown to interfere with homocysteine metabolism. In summarizing the data, Helga Refsum and Per Ueland highlight the clinical implications for these metabolic changes.     

Evidence of poor vitamin status in coeliac patients on a gluten-free diet for 10 years

BACKGROUND: Patients with coeliac disease are advised to keep to a lifelong gluten-free diet to remain well. Uncertainty still exists as to whether this gives a nutritionally balanced diet. AIM: To assess the vitamin nutrition status of a series of coeliac patients living on a gluten-free diet for 10 years. METHODS: Thirty adults with coeliac disease (mean age, 55 years; range, 45-64 years; 60% women), in biopsy-proven remission following 8-12 years of dietary treatment, were studied. We measured the total plasma homocysteine level, a metabolic marker of folate, vitamin B-6 and vitamin B-12 deficiency, and related plasma vitamin levels. The daily vitamin intake level was assessed using a 4-day food record. Normative data were obtained from the general population of the same age. RESULTS: Coeliac patients showed a higher total plasma homocysteine level than the general population, indicative of a poor vitamin status. In accordance, the plasma levels of folate and pyridoxal 5'-phosphate (active form of vitamin B-6) were low in 37% and 20%, respectively, and accounted for 33% of the variation of the total plasma homocysteine level (P < 0.008). The mean daily intakes of folate and vitamin B-12, but not of vitamin B-6, were significantly lower in coeliac patients than in controls. CONCLUSIONS: Half of the adult coeliac patients carefully treated with a gluten-free diet for several years showed signs of a poor vitamin status. This may have clinical implications considering the linkage between vitamin deficiency, elevated total plasma homocysteine levels and cardiovascular disease. The results may suggest that, when following up adults with coeliac disease, the vitamin status should be reviewed.     

The MTHFR C677T polymorphism is associated with depressive episodes in patients from Northern Ireland

Low plasma folate and its derivatives have been linked with depressive disorders in studies dating back over 30 years. A thermolabile variant (677C>T) of the enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) is associated with low serum folate. The present study aimed to explore whether the thermolabile variant of MTHFR is associated 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 sex-matched controls. Serum levels of folate, homocysteine and vitamin B(12) 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 associated with increased risk of depressive episodes in this homogenous patient population.     

中老年脑白质疏松症同型半胱氨酸叶酸及维生素B12测定的临床意义

目的 探讨中老年脑白质疏松症(leukoaraiosis,LA)与同型半胱氨酸(Homocysteine,Hcy)、叶酸及维生素B12的相关性.方法 选择CT、MRI证实的中老年LA患者30例,测定其血浆总Hcy、血清叶酸及维生素B12水平,与对照组比较.结果 中老年LA患者血浆总Hcy升高,血清叶酸、维生素B12降低,与对照组相比差异有统计学意义(P＜0.001),即Hcy水平与中老年LA呈正相关,叶酸、维生素B12水平与中老年LA呈负相关.结论 Hcy、叶酸及维生素B12与中老年LA具有相关性,是中老年LA的重要危险因素.     

Drugs affecting homocysteine metabolism: impact on cardiovascular risk

Elevated total plasma homocysteine has been established as an independent risk factor for thrombosis and cardiovascular disease. A strong relationship between plasma homocysteine levels and mortality has been reported in patients with angiographically confirmed coronary artery disease. Homocysteine is a thiol containing amino acid. It can be metabolised by different pathways, requiring various enzymes such as cystathionine beta-synthase and methylenetetrahydrofolate reductase. These reactions also require several co-factors such as vitamin B6 and folate. Medications may interfere with these pathways leading to an alteration of plasma homocysteine levels. Several drugs have been shown to effect homocysteine levels. Some drugs frequently used in patients at risk of cardiovascular disease, such as the fibric acid derivatives used in certain dyslipidaemias and metformin in type 2 (non-insulin-dependent) diabetes mellitus, also raise plasma homocysteine levels. This elevation poses a theoretical risk of negating some of the benefits of these drugs. The mechanisms by which drugs alter plasma homocysteine levels vary. Drugs such as cholestyramine and metformin interfere with vitamin absorption from the gut. Interference with folate and homocysteine metabolism by methotrexate, nicotinic acid (niacin) and fibric acid derivatives, may lead to increased plasma homocysteine levels. Treatment with folate or vitamins B6 and B12 lowers plasma homocysteine levels effectively and is relatively inexpensive. Although it still remains to be demonstrated that lowering plasma homocysteine levels reduces cardiovascular morbidity, surrogate markers for cardiovascular disease have been shown to improve with treatment of hyperhomocystenaemia. Would drugs like metformin, fibric acid derivatives and nicotinic acid be more effective in lowering cardiovascular morbidity and mortality, if the accompanying hyperhomocysteinaemia is treated? The purpose of this review is to highlight the importance of homocysteine as a risk factor, and examine the role and implications of drug induced modulation of homocysteine metabolism.     

Homocysteine and cerebral stroke in developing countries

Two-thirds of stroke deaths worldwide occur in developing countries. The higher prevalence of undernutritional states and parasitic infestations in many of these countries could lead to vitamin B(12) and folate deficiencies. Hyperhomocysteinemia, a proxy measure for the nutritional status of B vitamins, has been reported in many developing countries and is found to be associated with nutrition-related low plasma folate and vitamin B(12). Several epidemiological observations have linked hyperhomocysteinemia to increased risk for stroke. The exact molecular mechanism by which homocysteine promotes atherothrombosis is not clear, although several possible roles have been suggested. Homocysteine is believed to cause atherogenesis and thrombogenesis via endothelial damage, focal vascular smooth muscle proliferation probably causing irregular vascular contraction, and coagulation abnormalities. Supplementation with the nutrient cofactors required for optimal functioning of the homocysteine metabolic pathways significantly impacts plasma homocysteine levels, and offers a new integrated possibility for prevention of stroke in the underdeveloped and rapidly developing countries.     

The relationship between serum folate, vitamin B12, and homocysteine levels in major depressive disorder and the timing of improvement with fluoxetine

The objective of the present study was to examine the relationship between serum folate, vitamin B12, and homocysteine levels and the timing of clinical improvement to fluoxetine in major depressive disorder (MDD) patients. A total of 110 outpatients with MDD who responded to an 8-wk trial of fluoxetine had serum folate, B12, and homocysteine measurements at baseline (prior to fluoxetine initiation). Onset of clinical improvement was defined as a 30% decrease in Hamilton Depression Scale scores that led to a 50% decrease by week 8. Patients with low folate levels (0.05). In conclusion, low serum folate levels were found to be associated with a delayed onset of clinical improvement during treatment with fluoxetine in MDD by, on average, 1.5 wk.     

新生儿缺氧缺血性脑病临床分度与血清同型半胱氨酸及叶酸、维生素B12水平变化的临床研究

目的 探讨血清中高同型半胱氨酸（Hcy）及低叶酸、维生素B12水平与新生儿缺氧缺血性脑病（HIE）临床分度的相关性,为HIE患儿的诊疗提供参考。方法 2010年4月—2011年4月天津市儿童医院新生儿内科收治的患有不同程度HIE的新生儿共94例,其中轻度32例、中度40例、重度22例,对照组为同期收治的诊断为新生儿咽下综合征的新生儿20例。比较各组新生儿血清Hcy、叶酸及维生素B12水平。结果4组新生儿血清Hcy、叶酸、维生素B12水平差异均有统计学意义（均P＜0.05）。与对照组相比,HIE新生儿血清Hcy水平随着HIE临床分度加重而逐渐升高（P＜0.05）;患儿血清叶酸和维生素B12浓度均低于对照组,且重度组维生素B12水平低于中度组（P＜0.05）。结论 HIE患儿血清Hcy水平在对其病情严重程度的评估中具有一定参考价值。对HIE患儿及时给予叶酸及维生素B12的补充可能在疾病的治疗过程中发挥积极作用。     

Homocysteine, vitamin B12 and folic acid levels in psoriatic patients and correlation with disease severity

Hyperhomocysteinaemia represents an independent risk factor for atherosclerotic cardiovascular disease, stroke, peripheral arterial occlusive disease and venous thrombosis. Psoriasis is a chronic inflammatory skin disease associated with increased atherothrombosis and cardiovascular risk profile. The aim of this study is to investigate homocysteine, folic acid and vitamin B12 levels in a cohort of psoriatic patients and its relationship with the severity of the disease. A retrospective observational study in 98 patients with chronic plaque psoriasis and 98 healthy controls was performed. Total plasma homocysteine level, folic acid, vitamin B12 and PASI index were assessed in every patient. Patients with psoriasis had plasma homocysteine levels higher than controls (57% of cases and 25% of controls; p<0.0001). Folic acid and vitamin B12 plasma levels were lower in psoriatic patients than in controls (p = NS), lower levels of vitamin B12 were found in patients with hyperhomocysteinaemia compared to patients with a normal value of homocysteine (p = 0.0009). The severity of psoriasis assessed according to PASI (19.51+/-16.26) did not directly correlate either with higher levels of homocysteine or with vitamin B12 and folic acid plasma levels. In conclusion, a significantly higher prevalence of hyperhomocysteinaemia was found in psoriatic patients compared to healthy controls. A significant correlation between hyperhomocysteinaemia and lower vitamin B12 levels, but not folic acid, was evidenced. On the contrary, our data do not correlate the high level of homocysteine with higher PASI scores or psoriasis type, suggesting that homocysteine level can be considered an independent risk factor in psoriatic patients.     

Therapeutic potential of total homocysteine-lowering drugs on cardiovascular disease

An elevated total homocysteine (tHcy) plasma concentration is associated with increased morbidity and mortality due to cardiovascular disease in the general population and in patients with impaired renal function. The prevalence of hyperhomocysteinaemia (plasma levels above 15 micromol/l) in the general population is less than 5% and can be as high as 50% in patients with vascular disease. In patients with renal insufficiency, elevated tHcy plasma levels are detected in 50 - 100% of the patients. Total homocysteine plasma levels can be lowered or normalised by folic acid and/or vitamin B(6) and vitamin B(12) supplementation. In patients with advanced chronic renal insufficiency or end-stage renal disease, hyperhomocysteinaemia is partially resistant to folic acid or vitamin therapy. However, higher tHcy plasma levels may also reflect tissue damage and the increase in Hcy after an acute incident such as stroke or myocardial infarction may be necessary for tissue repair mechanisms. This implies, that lowering tHcy may even be harmful to some patients. Currently, prospective studies are underway to clarify whether folate supplementation, with or without additional other vitamins, improves cardiovascular disease morbidity and mortality in the general population, as well as in renal failure patients. While population-wide screening for and treatment of hyperhomocysteinaemia is generally not recommended, treatment of high risk patients may be considered.     

老年心脑血管病患者亚甲基四氢叶酸还原酶基因多态性与血清叶酸、同型半胱氨酸水平的关系

目的：探讨老年心脑血管病患者亚甲基四氢叶酸还原酶（ MTHFR ）基因多态性与血浆同型半胱氨酸（HCY）、叶酸、维生素B12的关系。方法检测104例老年心脑血管病患者的MTHFRC667T基因多态性,血清HCY、叶酸、维生素B12水平,分析老年心脑血管病患者MTHFRC667 T基因多态性与血清HCY、叶酸、维生素B12水平的关系。结果老年心脑血管病患者中MTHFRC667基因野生型（ CC型）比例为20苘．19%,杂合突变型（ CT型）和纯合突变型（TT型）比例为79．81%,心脑血管病组CT／TT型比例高于对照组,差异有统计学意义;血浆HCY与叶酸、维生素B12水平呈负相关（ P <0．05）,TT型的叶酸、维生素B12明显低于CC型（ P <0．05）, TT型、CT型的血HCY浓度高于CC型,差异有统计学意义（ P <0．05）。结论老年心脑血管患者MTHFR基因多态性与血浆HCY有一定关系,且血HCY与叶酸、维生素B12呈负相关。     

Hyperhomocysteinaemia and cardiovascular risk in female ovariectomized rats: role of folic acid and hormone replacement therapy

Hyperhomocysteinaemia is an independent risk factor for arteriosclerosis, recurrent thromboembolic complications and osteoporosis. After menopause, a high level of total homocysteine seems to be secondary to the altered hormonal status. Hormone replacement therapy (HRT) limits the development of coronary artery disease through a variety of mechanisms. One such mechanism is through affecting homocysteine metabolism. Folate and vitamin B12 deficiencies are considered to be major risks for hyperhomocysteinaemia. This study, therefore, was undertaken to examine whether lowering homocysteine with HRT or folic acid in ovariectomized rats could attenuate cardiovascular complications. Sixty sexually mature female Wistar rats were ovariectomized. Three weeks later, they were treated with estradiol (15 microg kg(-1), every two weeks, i.m.) or folic acid (90 microg daily, orally), either alone or in a combined form for four weeks. In addition, groups of ovariectomized rats (positive control) and healthy rats (negative control) were given cottonseed oil. Blood samples were then collected for serum and plasma separation. Serum total homocysteine, folate, estradiol, plasma nitric oxide (NO), lipid profile, and susceptibility of non-high-density-lipoprotein cholesterol (non HDLC) content to oxidation were determined. In ovariectomized rats, hyperhomocysteinaemia was established and associated with significant increments of both atherogenic indexes (total cholesterol/HDLC, low-density-lipoprotein cholesterol (LDLC)/HDLC) and susceptibility of their non HDLC to oxidation. However, plasma NO, serum folate, and estradiol levels significantly decreased. HRT and folic acid significantly reduced total homocysteine and susceptibility of non HDLC to oxidation and increased plasma NO content. Moreover, a significant negative correlation was found between total homocysteine versus folate and estradiol (r = -0.5, P < 0.01; r = -0.25, P < 0.05, respectively). Meanwhile, a positive correlation with the susceptibility of lipoprotein to oxidation was observed (r = 0.85, P < 0.001). In conclusion, a low folate level is found to be associated with elevated total homocysteine. Folic acid supplementation, either individually or in a combined form with HRT, has a beneficial effect in low estrogen status subsequent to ovariectomy.     

血浆同型半胱氨酸与脑分水岭梗死的关系探讨

目的 探讨同型半胱氨酸(Hcy)与脑分水岭梗死(CWI)的关系.方法 58例CWI患者(观察组)和56例健康者(对照组),采用荧光偏振免疫分析法检测两组及CWI各亚组的Hcy、叶酸和维生素B12水平.结果 CWI患者Hcy水平明显高于对照组,维生素B12及叶酸水平则明显低于对照组,差异均有统计学意义(t=2.013、2.842、3.051,均P＜0.05);CWI患者不同亚组之间血浆Hcy、叶酸和维生素B12水平差异均无统计学意义(均P＞0.05).结论 高血浆Hcy可能是CWI发生的重要原因之一.     

Atrophic gastritis as a cause of hyperhomocysteinaemia

BACKGROUND: Hyperhomocysteinaemia is an independent risk factor for atherosclerosis. It is often related to low levels of vitamin B12 and/or folate, enzymatic co-factors of methionine metabolism. Atrophic gastritis, often caused by Helicobacter pylori infection, may impair vitamin absorption. AIM: To assess whether the presence of atrophic gastritis is associated with hyperhomocysteinaemia via deficiency of its vitamin co-factors. METHODS: Thirty-one patients with atrophic gastritis were recruited. The control group consisted of 28 patients with non-atrophic gastritis, matched with patients for sex, age and body mass index. The presence and degree of gastric atrophy were assessed by histology. H. pylori infection was assessed by histology/serology. Blood samples were collected for the measurement of homocysteine, vitamin B12 and folates. RESULTS: Multiple logistic regression analysis showed that atrophic gastritis (odds ratio, 5.3; 95% confidence interval, 1.23-25.26; chi2=5.2; P=0.01) and low vitamin B12 (odds ratio, 3.7; 95% confidence interval, 1.03-22.08; chi2=3.6; P<0.05) were both predictors of hyperhomocysteinaemia. None of the other variables considered in the analysis, including H. pylori status, showed a significant association with hyperhomocysteinaemia. CONCLUSIONS: The present study suggests that atrophic gastritis, rather than H. pylori infection per se, may be a contributing factor to hyperhomocysteinaemia, possibly via vitamin B12 malabsorption.     

Fenofibrate-induced hyperhomocysteinaemia: clinical implications and management.

Fenofibrate is among the drugs of choice for treatment of hypertriglyceridaemia and low levels of high-density lipoprotein (HDL)-cholesterol, both recognised as risk factors for cardiovascular disease. Recently, a number of studies have shown an elevation of homocysteine levels with fenofibrate or bezafibrate therapy. Homocysteine is an atherogenic amino acid derived from the methionine cycle. At present, the underlying mechanism for this elevation has not been elucidated. While deterioration of vitamin status does not seem to be involved, impairment of renal function or changes in creatine metabolism are regarded as probable mechanisms. In patients not receiving lipid-lowering drugs, vitamin supplementation with folic acid and vitamin B12 effectively reduces the plasma homocysteine level. Two studies have shown that addition of folic acid or a vitamin combination to fenofibrate prevented most of the homocysteine increase associated with fenofibrate. Although the consequence of increasing homocysteine levels for cardiovascular risk has not been proven at present, it has to be considered that fenofibrate will be given for long-term treatment. Therefore, addition of folic acid and vitamin B12 to fenofibrate can be recommended to prevent the increase of homocysteine associated with fenofibrate, or treatment could be changed to gemfibrozil, which does not increase plasma homocysteine levels.     

Laxative treatment elevates plasma homocysteine: a study on a population-based Swedish sample of old people

Objectives Elevated plasma homocysteine might indicate an increased risk of cancer, and cardiovascular and neurological diseases. The homocysteine level depends on the supply of folate and cobalamine, and constipation and/or laxative treatment might compromise this supply. The present study examined the impact of constipation and laxative treatment on the blood levels of homocysteine, folate and cobalamine in a population-based sample of aged people, including consideration of frailty and impaired renal function, both of which may also influence the homocysteine level.Methods The study was based on biochemical tests in 341 females and 183 males aged 82 years or older. The concentrations of homocysteine (plasma), folate, cobalamine and urea (serum) were measured in subjects with and without ongoing treatment with laxative drugs. Values were adjusted for age, gender and frailty, as well as for clinical diagnoses and drug therapies known to affect homocysteine levels.Results Homocysteine levels were increased and those of folate reduced in aged subjects on laxatives. Homocysteine remained elevated after adjusting for frailty and various neurological disorders. There was no significant effect on homocysteine and folate in constipated subjects without laxatives.     

血清同型半胱氨酸、叶酸及维生素B12与老年血管性痴呆的相关性研究

目的探讨血清同型半胱氨酸（Hcy）、叶酸（FA）及维生素B12（VitB12）与老年血管性痴呆（VD）的相关性。方法检测96例VD患者、152例脑梗死非痴呆患者及80例健康对照者Hcy、FA、VitB12水平并分析其变化;按MMSE评分标准评估VD患者的认知功能,按痴呆程度将其分为重度、中度及轻度三组,并检测各组血清Hey浓度,分析Hcy水平与痴呆程度的关系。结果VD组及脑梗死非痴呆组血清Hcy水平均显著高于对照组（t=3．26、3．14,均P〈0．01）,其中以VD组最高;VD组及脑梗死非痴呆组血清FA及VitBl2水平均显著低于对照组（t=3．16、2．98、3．21、2．91,均P〈0．01）,其中以VD组最低。VD患者血清Hcy水平随痴呆程度的加重而升高,Hcy浓度与MMSE评分呈负相关（r=-0．69,P〈0．05）。结论高Hcy血症与VD具有相关性,高Hcy血症可能是导致VD发生的危险因素之一;FA及VitB,2缺乏可引起Hcy的增高,FA及VitBl2缺乏可能是导致VD发生的间接因素。     

Therapeutic potential of total homocysteine-lowering drugs on cardiovascular disease

An elevated total homocysteine (tHcy) plasma concentration is associated with increased morbidity and mortality due to cardiovascular disease in the general population and in patients with impaired renal function. The prevalence of hyperhomocysteinaemia (plasma levels above 15 μmol/l) in the general population is less than 5% and can be as high as 50% in patients with vascular disease. In patients with renal insufficiency, elevated tHcy plasma levels are detected in 50 - 100% of the patients. Total homocysteine plasma levels can be lowered or normalised by folic acid and/or vitamin B₆ and vitamin B₁₂ supplementation. In patients with advanced chronic renal insufficiency or end-stage renal disease, hyperhomocysteinaemia is partially resistant to folic acid or vitamin therapy. However, higher tHcy plasma levels may also reflect tissue damage and the increase in Hcy after an acute incident such as stroke or myocardial infarction may be necessary for tissue repair mechanisms. This implies, that lowering tHcy may even be harmful to some patients. Currently, prospective studies are underway to clarify whether folate supplementation, with or without additional other vitamins, improves cardiovascular disease morbidity and mortality in the general population, as well as in renal failure patients. While population-wide screening for and treatment of hyperhomocysteinaemia is generally not recommended, treatment of high risk patients may be considered.