ArticleLiterature Review

The Homocysteine Hypothesis of Depression

July 2007
American Journal of Psychiatry 164(6):861-7

July 2007
164(6):861-7

DOI:10.1176/appi.ajp.164.6.861

Source
PubMed

Authors:

Inga Peter

Icahn School of Medicine at Mount Sinai

Jennifer S. Buell

Agenus

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High levels of homocysteine are associated with cerebrovascular disease, monoamine neurotransmitters, and depression of mood. A plausible hypothesis for these associations is that high homocysteine levels cause cerebral vascular disease and neurotransmitter deficiency, which cause depression of mood. The homocysteine depression hypothesis, if true, would mandate inclusions of imaging studies for cerebrovascular disease and measures of homocysteine, folate, and B12 and B6 vitamins in the clinical evaluation of older depressed patients. Longitudinal studies and clinical trials should be designed to challenge the hypothesis.

The Effect of Omega-3 Fatty Acids on Thromboxane, Brain-Derived Neurotrophic Factor, Homocysteine, and Vitamin D in Depressive Children and Adolescents: Randomized Controlled Trial

Article

Full-text available

Mar 2021

In the DEPOXIN project, we have found that a high ratio of omega-6/omega-3 fatty acids (FA) is associated with worsening of depressive symptoms in children and adolescents with depressive disorder (DD) and that the 12-week omega-3 FA supplementation modulates DD symptoms. Here we present our results of the secondary outcomes: the levels of thromboxane (TXB), brain-derived neurotrophic factor (BDNF), homocysteine (HCy) and vitamin D. Fifty-eight patients were randomized into two arms. One group received a fish oil emulsion enriched with omega-3 FA, and the other received a sunflower oil emulsion containing omega-6 FA, for 12 weeks. Depressive symptoms were evaluated, using the Child’s Depressive Inventory (CDI). The patients with DD had elevated TXB levels and decreased vitamin D levels, as compared to healthy controls. Both CDI and omega-6/omega-3 ratio correlated positively with TXB and negatively with BDNF at baseline. Compared to the omega-6 FA group, the supplementation with omega-3 FA for 12 weeks significantly reduced plasma TXB (p = 0.024) and increased BDNF (p = 0.011) levels. No changes in HCy and vitamin D were observed. Our results demonstrate the possible role of TXB and BDNF in the pathophysiology of DD and the benefits of omega-3 FA supplementation. The study was registered with the ISRCTN registry (ISRCTN81655012).

Impact of Supplementation and Nutritional Interventions on Pathogenic Processes of Mood Disorders: A Review of the Evidence

Article

Full-text available

Feb 2021

This narrative review was conducted using searches of the PubMed/Medline and Google Scholar databases from inception to November 2019. Clinical trials and relevant articles were identified by cross-referencing major depressive disorder (and/or variants) with the following terms: folate, homocysteine, S-adenosylmethionine (SAMe), L-acetylcarnitine, alpha-lipoic acid, N-acetylcysteine, L-tryptophan, zinc, magnesium, vitamin D, omega-3 fatty acids, coenzyme Q10, and inositol. Manual reviews of references were also performed using article reference lists. Abnormal levels of folate, homocysteine, and SAMe have been shown to be associated with a higher risk of depression. Numerous studies have demonstrated antidepressant activity with L-methylfolate and SAMe supplementation in individuals with depression. Additionally, the amino acids L-acetylcarnitine, alpha-lipoic acid, N-acetylcysteine, and L-tryptophan have been implicated in the development of depression and shown to exert antidepressant effects. Other agents with evidence for improving depressive symptoms include zinc, magnesium, omega-3 fatty acids, and coenzyme Q10. Potential biases and differences in study designs within and amongst the studies and reviews selected may confound results. Augmentation of antidepressant medications with various supplements targeting nutritional and physiological factors can potentiate antidepressant effects. Medical foods, particularly L-methylfolate, and other supplements may play a role in managing depression in patients with inadequate response to antidepressant therapies.

Mechanistic Insights into the Link between Gut Dysbiosis and Major Depression: An Extensive Review

Article

Full-text available

Apr 2022

Depression is a highly common mental disorder, which is often multifactorial with sex, genetic, environmental, and/or psychological causes. Recent advancements in biomedical research have demonstrated a clear correlation between gut dysbiosis (GD) or gut microbial dysbiosis and the development of anxiety or depressive behaviors. The gut microbiome communicates with the brain through the neural, immune, and metabolic pathways, either directly (via vagal nerves) or indirectly (via gut- and microbial-derived metabolites as well as gut hormones and endocrine peptides, including peptide YY, pancreatic polypeptide, neuropeptide Y, cholecystokinin, corticotropin-releasing factor, glucagon-like peptide, oxytocin, and ghrelin). Maintaining healthy gut microbiota (GM) is now being recognized as important for brain health through the use of probiotics, prebiotics, synbiotics, fecal microbial transplantation (FMT), etc. A few approaches exert antidepressant effects via restoring GM and hypothalamus–pituitary–adrenal (HPA) axis functions. In this review, we have summarized the etiopathogenic link between gut dysbiosis and depression with preclinical and clinical evidence. In addition, we have collated information on the recent therapies and supplements, such as probiotics, prebiotics, short-chain fatty acids, and vitamin B12, omega-3 fatty acids, etc., which target the gut–brain axis (GBA) for the effective management of depressive behavior and anxiety.

Nutritional and Dietary Role in Neuropsychiatric Disorders Depression and Obsessive- Compulsive Disorder (OCD)

Preprint

Full-text available

Apr 2024

Neuropsychiatric disorders are neurobiological alterations in the brain that manifest psychiatric symptoms which substantially burden the system of health care, economy, and well-being of the affected persons as well as their care providers worldwide. Two common neuropsychiatric disorders discussed in this chapter are Depressive disorder and Obsessive Compulsive Disorder (OCD). Current treatment strategies for depression generally focus on biological and psychological pathways through pharmacotherapy, somatic and psychosocial interventions. Whereas the treatment of OCD includes behavioural therapy, pharmacotherapy with mega doses of antidepressants and psychosurgery. Most of these treatment methods are not permanent solutions and pose several potential adverse effects. Thus, considering its impact, natural preventive approaches are needed to be explored. Accumulating evidence suggests that lifestyle modification, including dietary changes, can play a significant role in improving such neuropsychiatric disorders. Consumption of different foods leads to the synthesis and metabolism of various neurotransmitters, which affect human psychology. Not only dietary improvement supports preventive strategies, but it could also provide a novel therapeutic approach for the adjuvant treatment of neuropsychiatric disorders. Based on epidemiological evidence, this chapter focuses on the role of various nutrients and dietary patterns in the prevention and management of depression and OCD.

Increased fruit intake is associated with reduced risk of depression: evidence from cross-sectional and Mendelian randomization analyses

Article

Full-text available

Dec 2023

Background The association between dietary patterns and depression has gained significant attention, but the relationship between fruit intake and depression remains unclear. This study aimed to investigate the role of fruit intake in the risk of depression using data from the National Health and Nutrition Examination Survey (NHANES) and Mendelian randomization (MR) analysis, and further explore the causal relationship between them. Materials and methods Cross-sectional analysis was conducted using the 2005–2018 NHANES data. Specialized weighted complex survey design analysis software was used for multivariate logistic analysis. Additionally, genetic variants for fruit intake and depression, as well as its related neuroticism traits, from the GWAS were used as instrumental variables in MR analysis. The inverse variance weighted (IVW) method was employed as the primary analysis method to evaluate the causal relationship between them. MR-Egger regression, MR-PRESSO test, and leave-one-out analysis were conducted to assess heterogeneity and pleiotropy. Results In NHANES, compared to the lowest quartile (Q1, <0.12 cup], the highest quartile (Q4, >1.49 cups) of fruit intake showed a significant reduction in the risk of depression after adjusting for relevant covariates. Model 3, after rigorous adjustment for multiple covariates, demonstrated improved predictive performance in both Receiver operating characteristic (ROC) curve and Decision curve analysis (DCA). In Model 3, the proportion of reduced depression risk associated with fruit intake reached 31% (OR = 0.69, 95% CI: 0.50–0.95). This association remained significant in the MR analysis (OR = 0.92, 95% CI = 0.87–0.96; p = 5.09E-04). Fruit intake was also associated with a decreased risk of neuroticism traits related to depression, including feeling lonely (OR = 0.82, 95% CI = 0.74–0.90; p = 2.91E-05), feeling miserable (OR = 0.79, 95% CI = 0.72–0.87; p = 2.35E-06), feeling fed-up (OR = 0.75, 95% CI = 0.68–0.83; p = 2.78E-08), irritable mood (OR = 0.89, 95% CI = 0.79–0.99; p = 0.03), and neuroticism (OR = 0.85, 95% CI = 0.76–0.96; p = 9.94E-03). The causal relationship between feeling lonely and fruit intake was bidirectional. Conclusion Increased fruit intake has a causal effect in reducing the risk of depression and is beneficial for related psychological well-being.

The association between circulating Hcy and Lp-PLA2 levels and poststroke depression: A meta-analysis

Article

Full-text available

Nov 2023
MEDICINE

Objective To analyze the correlation between circulating homocysteine (Hcy) and lipoprotein-associated phospholipase A2 (Lp-PLA2) levels and poststroke depression (PSD). Materials and methods Chinese (Chinese National Knowledge Infrastructure, Wanfang, and VIP) and English (PubMed, EMBASE, MEDLINE, and Cochrane Library) databases on the correlation between circulating Hcy and Lp-PLA2 and PSD were collected. Meta-analysis was performed to compare the distinctions in circulating Hcy and Lp-PLA2 levels between PSD and non-PSD groups. Meta-analysis was conducted by using STATA 15.0 software. Results A total of 20 literatures were included in this study. The level of circulating Lp-PLA2 in the PSD group was obviously higher than that in the non-PSD group (weighted mean differences: 2.75, 95%CI: 0.10–5.39, P = .002), which was an independent predictor of PSD (effect size = 0.05, 95%CI: 0.03, 0.07, P < .001). The level of circulating Hcy in the PSD group was obviously higher than that in the non-PSD group (weighted mean differences = 1.41, 95%CI: 1.01, 1.81, P < .001), which was an independent influencing factor for the occurrence of PSD (effect size = 0.07, 95%CI: 0.04, 0.09, P = .011). Conclusion Circulating Hcy and Lp-PLA2 levels are linked to the development of PSD, and can be applied as predictive or diagnostic indicators.

Nutritional and Dietary Role in Neuropsychiatric Disorders: Depression and Obsessive-Compulsive Disorder (OCD)

Chapter

Oct 2023

Neuropsychiatric disorders are neurobiological alterations in the brain that manifest psychiatric symptoms which substantially burden the system of health care, economy, and well-being of the affected persons as well as their care providers worldwide. Two common neuropsychiatric disorders discussed in this chapter are depressive disorder and obsessive-compulsive disorder (OCD). Current treatment strategies for depression generally focus on biological and psychological pathways through pharmacotherapy and somatic and psychosocial interventions. Whereas the treatment of OCD includes behavioral therapy, pharmacotherapy with mega doses of antidepressants and psychosurgery, most of these treatment methods are not permanent solutions and pose several potential adverse effects. Thus, considering its impact, natural preventive approaches are needed to be explored. Accumulating evidence suggests that lifestyle modification, including dietary changes, can play a significant role in improving such neuropsychiatric disorders. Consumption of different foods leads to the synthesis and metabolism of various neurotransmitters, which affect human psychology. Not only does dietary improvement support preventive strategies, but it could also provide a novel therapeutic approach for the adjuvant treatment of neuropsychiatric disorders. Based on epidemiological evidence, this chapter focuses on the role of various nutrients and dietary patterns in the prevention and management of depression and OCD.

Depression, antidepressants and pulmonary embolism Editorial

Article

Jul 2018

A 66-year old male, ex-smoker (10 pack/years), with no known history from the respiratory system, was admitted to our department due to right-sided pleuritic chest pain and progressive dyspnea on exertion during the last 20 days. With regards to his medical history, the patient was receiving escilatopram due to depression, antihypertensive drugs and had a history of acute ischemic stroke. On admission, clinical examination unveiled: body's temperature 37,4°C, SaO2 97% FiO2 21%, heart rate 80 beats per minute, blood pressure 125/65 mmHg and reduction in the intensity of breath sounds in the right side. A computed tomography pulmonary angiogram (CTPA) was performed demonstrating an embolus in the right pulmonary artery, as well as pleural effusion in the right side. Based on PESI score, pulmonary embolism was considered as low risk (class II). Blood tests for mutations in homocysteine, V-Leiden, prothrombin G20210A, protein C & S, antithrombin were performed. At his exit, patient was in good condition. He was asked to continue his treatment for pulmonary embolism at least for 3 months (a reevaluation was scheduled) and to perform a new chest computerized tomography and possibly a Positron Emission Tomography in the next month for the evaluation of the nodule. Based on that case, we aimed to highlight the current evidence about the association of antidepressants and the spectrum of venous thrombo-embolism (VTE) (pulmonary embolism and deep vein thrombosis). Several factors including immobilization, cancer, trauma, surgery,obesity, hormonal therapy and inherited thrombophilia have been associated with VTE 1,2 ; yet, several cases of VTE present with no known risk factors and thus there is still interest for identification of more causes. A plethora of studies have investigated the association among anxiety, stress, depression, antidepressants and VTE development. The majority of previous studies, but not all, have reported increased VTE risk for patients with depression and/or antidepressant use 3-10. Importantly, a recent meta-analysis had further corroborated the evidence that depression and use of antidepressants are associated with an increased risk of VTE 11. In particular, there are both studies investigating the risk for VTE in patients with depression and patients with no depression and studies comparing antidepressants use versus no use (Table 1). Patients with depression presented with increased risk for VTE, as the relative risk ranged between 1.19

Popping Up A Multivitamin Pill: Should We or Should We Not?

Article

Full-text available

Jan 2020

Gurmeet Singh Sarla

Selected Biomarkers of Oxidative Stress and Energy Metabolism Disorders in Neurological Diseases

Article

Full-text available

Apr 2023
MOL NEUROBIOL

Neurological diseases can be broadly divided according to causal factors into circulatory system disorders leading to ischemic stroke; degeneration of the nerve cells leading to neurodegenerative diseases, such as Alzheimer’s (AD) and Parkinson’s (PD) diseases, and immune system disorders; bioelectric activity (epileptic) problems; and genetically determined conditions as well as viral and bacterial infections developing inflammation. Regardless of the cause of neurological diseases, they are usually accompanied by disturbances of the central energy in a completely unexplained mechanism. The brain makes up only 2% of the human body’s weight; however, while working, it uses as much as 20% of the energy obtained by the body. The energy requirements of the brain are very high, and regulatory mechanisms in the brain operate to ensure adequate neuronal activity. Therefore, an understanding of neuroenergetics is rapidly evolving from a “neurocentric” view to a more integrated picture involving cooperativity between structural and molecular factors in the central nervous system. This article reviewed selected molecular biomarkers of oxidative stress and energy metabolism disorders such as homocysteine, DNA damage such as 8-oxo2dG, genetic variants, and antioxidants such as glutathione in selected neurological diseases including ischemic stroke, AD, PD, and epilepsy. This review summarizes our and others’ recent research on oxidative stress in neurological disorders. In the future, the diagnosis and treatment of neurological diseases may be substantially improved by identifying specific early markers of metabolic and energy disorders.

Articles HARCP-2023-V25-I1-P5 YILDIRIM OZBEK

Article

Full-text available

Feb 2023

Background. To examine blood S100B and homocysteine levels and to evaluate their possible roles in neurobiological processes in male patients with opioid use disorder. Methods. The study group consisted of 30 male inpatients who were admitted to an outpatient clinic with a diagnosis of “Opioid Use Disorder” according to DSM-5 diagnostic criteria. The control group consisted of 30 healthy male individuals. The first blood samples of the patients were taken at the time of withdrawal symptoms after the psychiatric interview was completed. The patients were started on buprenorphine/ naloxone detoxification therapy. The second blood samples were taken during the stabilization period on the 15th day, with the cessation of withdrawal symptoms. Results. S100B levels were higher in patients during both the withdrawal and stabilization periods compared to those of the control group. Homocysteine levels did not differ between the patient and control groups. S100B and homocysteine levels measured in the patient group did not fluctuate during the withdrawal and stabilization periods. S100B levels increased in both withdrawal and stabilization periods of opioid use disorder while homocysteine values remained unaltered. Conclusions. S100B may play an active role in pathophysiological processes associated with opioid use disorder. S100B levels remained high during the treatment, suggesting that the compensatory process continued throughout its duration.

Plant and animal protein intake and its association with depression, anxiety, and stress among Iranian women

Article

Full-text available

Jan 2023
BMC PUBLIC HEALTH

Background Mental disorders are conditions that affect the usual function of the brain, causing a huge burden on societies. The causes are often unclear, but previous research has pointed out, as is the case with many other diseases, that nutrition could have a major role in it. Amino acids, the building blocks of proteins, are the main precursor of neurotransmitters (the chemical messengers in the brain) malfunction of which is heavily associated with a wide range of brain disorders. Methods We assumed different sources of dietary protein could have different impacts on mental well-being. Hence, we decided to collect the nutritional data (with a validated and reliable semi-quantitative food-frequency questionnaire) from a sample of 489 Iranian women and investigate the association between animal and plant protein sources and the risk of depression, anxiety, and stress. Symptoms of these mental disorders were assessed using a validated Depression, Anxiety, and Stress Scales (DASS) questionnaire with 21 items. Results After multivariable adjustment, it was shown that women in the highest tertile of animal protein intake were more likely to show symptoms of depression (OR: 2.63; 95% CI: 1.45, 4.71; P = 0.001), anxiety (OR: 1.83; 95% CI: 1.04, 3.22; P = 0.03), and stress (OR: 3.66; 95% CI: 2.06, 6.50; p < 0.001). While no significant association was seen between plant protein and any of the studied mental disorders. Conclusion Overall, our findings suggest that a diet high in animal protein could predispose individuals to mental illnesses.

Vitamin B12 produced by gut bacteria modulates excitatory neurotransmission

Preprint

Full-text available

Sep 2022

A growing body of evidence indicates that gut microbiota influence brain function and behavior. However, the molecular basis of how gut bacteria modulate host nervous system function is largely unknown. Here we show that vitamin B12-producing bacteria that colonize the intestine can modulate excitatory synaptic transmission and behavior in the host Caenorhabditis elegans. We find that vitamin B12 reduces cholinergic signaling in the nervous system through rewiring of the methionine (Met)/S-Adenosylmethionine (SAM) cycle in the intestine. We identify a conserved metabolic crosstalk between the Met/SAM cycle and the choline oxidation pathway. We show that metabolic rewiring of these pathways by vitamin B12 reduces cholinergic transmission by limiting the availability of free choline required by neurons to synthesize acetylcholine. Our study reveals a gut-brain communication pathway by which enteric bacteria modulate host behavior and may affect mental health.

Predictive Significance of High-Sensitivity C-Reactive Protein Combined with Homocysteine for Coronary Heart Disease in Patients with Anxiety Disorders

Article

Full-text available

Aug 2022
BMRI

Background: Currently, there are few studies on biomarkers for predicting coronary heart disease (CHD) with anxiety disorders. Objective: To explore risk factors and investigate the predictive value of common clinical peripheral blood indicators, such as high-sensitivity C-reactive protein (hs-CRP) and homocysteine (Hcy) for CHD patients with anxiety disorders. Methods: One hundred fifty-three hospitalized patients with chest pain as the main symptom and a Hamilton Anxiety Scale score > 14 were recruited from October 2020 to September 2021 in the hospital. Then, they were divided into an anxiety disorder with CHD group (observation group, n = 64) and a simple anxiety disorder group (control group, n = 89), according to coronary angiography (CAG) findings. Patients' demographic and clinical messages were collected and compared. Diabetes mellitus and hypertension, body mass index (BMI), and peripheral blood interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), homocysteine (Hcy), fibrinogen, D-dimer, cortisol, and norepinephrine expression levels were compared. Binary logistic regression analysis screened independent risk factors of CHD patients with anxiety disorders. The effectiveness of independent risk factors in predicting CHD with anxiety disorders was analyzed using receiver operating characteristic (ROC) curves. Results: IL-6, hs-CRP, and Hcy levels of anxiety disorder in the CHD group were significantly higher than those in the simple anxiety disorder group. Binary multiple logistic regression analysis indicated that IL-6, hs-CRP, and Hcy were independent risk factors for CHD in patients with anxiety disorders. hs-CRP and Hcy levels were positively correlated with the Gensini score. ROC curve analysis indicated that the detection of hs-CRP or Hcy alone or the combined detection of the 2 had clinical predictive value for CHD in patients with anxiety disorders, and the area under the curve (AUC) of the combined detection of the 2 was significantly larger than that of any single factor alone (vs. hs-CRP, P = 0.045; vs. Hcy, P = 0.045). Conclusion: IL-6, hs-CRP, and Hcy are related to CHD with anxiety disorders. Serum levels of the combined detection of hs-CRP and Hcy have a high clinical predictive value for CHD in patients with anxiety disorders.

The Efficacy of S-Adenosyl Methionine and Probiotic Supplementation on Depression: A Synergistic Approach

Article

Full-text available

Jul 2022

Depression is a common and serious health issue affecting around 280 million people around the world. Suicidal ideation more frequently occurs in people with moderate to severe depression. Psychotherapy and pharmacological drugs are the mainstay of available treatment options for depressive disorders. However, pharmacological options do not offer complete cure, especially in moderate to severe depression, and are often seen with a range of adverse events. S-adenosyl methionine (SAMe) supplementation has been widely studied, and an impressive collection of literature published over the last few decades suggests its antidepressant efficacy. Probiotics have gained significant attention due to their wide array of clinical uses, and multiple studies have explored the link between probiotic species and mood disorders. Gut dysbiosis is one of the risk factors in depression by inducing systemic inflammation accompanied by an imbalance in neurotransmitter production. Thus, concomitant administration of probiotics may be an effective treatment strategy in patients with depressed mood, particularly in resistant cases, as these can aid in dysbiosis, possibly resulting in the attenuation of systemic inflammatory processes and the improvement of the therapeutic efficacy of SAMe. The current review highlights the therapeutic roles of SAMe and probiotics in depression, their mechanistic targets, and their possible synergistic effects and may help in the development of food supplements consisting of a combination of SAMe and probiotics with new dosage forms that may improve their bioavailability.

The role of mixed B vitamin intakes on cognitive performance: Modeling, genes and miRNAs involved

Article

Full-text available

Jun 2022
J PSYCHIATR RES

Objective: To assess the relationships between mixed B vitamin intakes (B1, B2, B3, B6, B9, B12) and cognitive performance, as well as their molecular mechanisms. Methods: The associations of mixed B vitamin intakes with cognitive function were assessed using multivariate regression models, weighted quantile sum (WQS), quantile g-computation (qgcomp), and Bayesian kernel machine regression (BKMR). GeneMANIA, Comparative Toxicogenomics Database, MIENTURNET, miRNAsong were employed as the main data-mining methods. Results: Overall effects of the B vitamin intake mixture were significantly associated with global cognition in the WQS, qgcomp, and BKMR models. A mixture of B vitamins (B1, B2, B3, B9) interacted with the five genes (IL1B, BCL2, CASP3, BAX, PTGS2) and was associated with better cognitive function, especially CASP3 and BAX. Physical interactions (77.6%) were observed to be the most important interactions in gene networks. The IL-18 signaling pathway, apoptosis, and Alzheimer's disease were annotated as the key molecular mechanisms involved in mixed B vitamins' improving cognitive function. NFKB1, ATF3, and NR3C1 were the key significant transcription factors associated with cognitive function targeted by a mixture of B vitamins. The strong interaction and expression of hsa-miR-34a-5p, hsa-miR-128-3p, hsa-miR-181a-5p, and hsa-miR-204-5p are involved in mixed B vitamins' better cognitive performance. We also created and evaluated miRNA sponge sequences for these miRNAs, which might be used to alleviate cognitive decline. The cutoff thresholds for B vitamin intake levels that are associated with cognition performance were reported. Conclusions: Given the increased incidence of dementia across the world, increasing daily mixed B vitamin intake via regular meals may contribute to minimizing dementia risk. Further studies are warranted to identify these links in well-characterized cohorts of diverse populations, either independently or together.

Changes of Serum Homocysteine and Vitamin B12, but Not Folate Are Correlated With Obsessive-Compulsive Disorder: A Systematic Review and Meta-Analysis of Case-Control Studies

Article

Full-text available

May 2022

Background Obsessive–compulsive disorder (OCD) a complex neuropsychiatric disorder, is characterized by irresistible obsessive thinking and compulsive behavior. Folate is a member of water-soluble vitamins in the human body and sustains many normal daily activities (e.g., exercise, sleep, and memory). Homocysteine, a sulfur-containing non-essential amino acid, has been investigated in numerous psychiatric disorders (e.g., OCD). Vitamin B12 is a type of complex organic compound with cobalt contained. Moreover, vitamin B12 and folate deficiency and high levels of homocysteine were found to have an effect on brain functions and also lead to non-specific psychiatric symptoms. Objectives This study aimed to confirm the epidemiological evidence of OCD and investigate whether vitamin B12, folate, and homocysteine have an effect on the etiology of OCD. Methods A systematic search was conducted on eight databases (i.e., PubMed, Embase, Web of Science, the Cochrane Library, China Biology Medicine disc, China National Knowledge Infrastructure, Wanfang Database, China Science and Technology Journal Database), and the retrieval time was up to March 2021. The available articles involving patients with OCD with/without abnormal serum levels of vitamin B12, folate, and homocysteine were comprehensively reviewed and analyzed. Results A total of 5 studies involving 309 patients were included in this meta-analysis, including 172 cases in the experimental group and 137 in the control group. The content of folate in the OCD group was not significantly different from that in the control group (SMD = −0.089, 95%CI −0.755 to 0.577, p = 0.794). And serum homocysteine was significantly higher in the patients with OCD (SMD = 1.132, 95%CI 0.486 to 1.778, p = 0.001). Vitamin B12 was significantly lower in patients with OCD (SMD = −0.583, 95%CI −0.938 to −0.229, p = 0.001). Conclusions This meta-analysis shows serum high levels of homocysteine, low levels of vitamin B12, and normal folate level are closely correlated with OCD. However, high-quality case-control studies should be further conducted to explore the correlation between serum levels of vitamin B12, folate, homocysteine, and OCD. Systematic Review Registration https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021262161; PROSPERO (Number CRD#42021262161).

EFFECTS OF PHYSICAL TRAINING AND BEHAVIOURAL STRATEGIES TOWARDS MUSCLE STRENGTH AND MENTAL HEALTH IN THE ELDERLY: Physical and Behavioural on Strengths and Mental Health in Elderly

Article

Full-text available

Nov 2021

The promotion of physical training (PT) and positive behavior in the elderly requires effective interventions. This study shows the effect of PT during an 11-week intervention program by applying behavioral strategies. A total of 63 participants aged 65 years old were randomly divided into three groups: Physical with a behavioral group, PB (n=18), Physical group, PG (n=23), and Control group, CG (n=22). PB and PG participants underwent a six-week group-based multi-component PT for one hour per session, three sessions a week. After PT, participants in PB began five-week behavioral exercises for 30 min, twice a week. Meanwhile, CG participants only have to maintain their daily routines. Upper and lower limb muscle strength and mental health were assessed. Results from repeated measures ANOVA showed significant differences between groups due to time factor, group and time interaction, and between-group factor (p<0.05) for Right UL, Left UL, and LL strength. Analysis of covariance (ANCOVA) for mental health [F(2.58) = 33.49] (p<0.05)] showed significant main effects among participants in PB, thus indicating improved mental health. In conclusion, combined of PT and behavioral strategies may be a promising strategy in enhancing better physical and mental well-being of the elderly.

Mixtures modeling identifies vitamin B1 and B3 intakes associated with depression

Article

Jan 2022
J AFFECT DISORDERS

Background We aim to identify the association between a mixture of vitamin B1, B2, and B3 intakes and depression. Methods Daily intake of vitamins was measured by a one-day 24 h recall. Multivariate logistic regression, weighted quantile sum (WQS), quantile g-computation (qgcomp), and Bayesian kernel machine regression (BKMR) were used. Results Of 9,848 adults included in the final analysis, 4.38% had depression. In the logistic regression model, daily vitamin B1 and B3 intakes were associated with depression, and significant trends were observed for these vitamin intake tertiles (p < 0.001). The WQS index was significantly associated with depression (OR = 0.24, 95% CI: 0.23–0.24). The gqcomp index also found a significant association between a mixture of vitamin B1 and B3 intake and depression (OR = 0.67, 95% CI: 0.44–0.98). Vitamin B1 intake was the most heavily weighed vitamin intake in this model. In BKMR analysis, the overall effect of vitamin B1 and B3 intake mixture was negatively associated with depression. Vitamin B1 and B3 intake showed negative trends and was observed as the most important factor associated with depression. The cutoff levels for B vitamin intake levels related to depression were reported. Limitations A 24-hour recall and cross-sectional design were used. Conclusions Given the rising prevalence of depressive symptoms in Korea, an increase in daily intake of vitamin B1 and/or B3 through regular diets may help to reduce the risk of depression. Therefore, there is an ongoing need to investigate these associations between B vitamin supplementation and depression, either separately or jointly, in well-characterized cohorts of depression population.

Biomarkers in Child and Adolescent Depression

Article

Full-text available

Sep 2021
CHILD PSYCHIAT HUM D

Despite the significant prevalence of Major Depressive Disorder in the pediatric population, the pathophysiology of this condition remains unclear, and the treatment outcomes poor. Investigating tools that might aid in diagnosing and treating early-onset depression seems essential in improving the prognosis of the future disease course. Recent studies have focused on searching for biomarkers that constitute biochemical indicators of MDD susceptibility, diagnosis, or treatment outcome. In comparison to increasing evidence of possible biomarkers in adult depression, the studies investigating this subject in the youth population are lacking. This narrative review aims to summarize research on molecular and biochemical biomarkers in child and adolescent depression in order to advocate future directions in the research on this subject. More studies on depression involving the youth population seem vital to comprehend the natural course of the disease and identify features that may underlie commonly observed differences in treatment outcomes between adults and children.

Role of heavy metal concentrations and vitamin intake from food in depression: a national cross-sectional study (2009–2017)

Article

Full-text available

Aug 2021
ENVIRON SCI POLLUT R

Little is known about associations between depression and serum heavy metal levels, dietary vitamin intakes. Thus, we sought to determine the nature of these associations and to predict risks of depression using marginal effects. A data set of 16,371 individuals aged ≥10 years that participated in Korea National Health and Nutrition Examination Surveys (KNHANES) conducted from 2009 to 2017 (excluding 2014 and 2015) was used to obtain information on sociodemographics, family histories, lifestyles, serum heavy metal levels, food intakes, and depression. Serum cadmium (Cd) and lead (Pb) levels were analyzed by graphite furnace atomic absorption spectrometry and mercury (Hg) levels using a mercury analyzer. Daily vitamin intakes were calculated by 24-h dietary recall. The results obtained showed that females are at higher risk of depression than males. A doubling of serum Cd was associated with a 21% increase in depression (AOR 1.21, 95% CI: 1.07–1.37, p = 0.002), whereas twofold increases in daily vitamin B1, B3 and vitamin A intakes reduced the risk of depression by 17% (0.83, 95% CI: 0.73–0.95, p = 0.005), 20% (0.80, 95% CI: 0.70–0.91, p = 0.001), and 8% (0.92, 95% CI: 0.85–0.99, p = 0.020), respectively. Interactions between heavy metals, vitamin intakes, and sex did not influence the risk of depression. The result shows that increased daily dietary vitamin intake might protect the public against depression. Further studies are needed to reduce the risks posed by heavy metals and to determine more comprehensively the effects of daily dietary vitamin intake on depression.

Serum Vitamins and Homocysteine Levels in Obsessive-Compulsive Disorder: A Systematic Review and Meta-Analysis

Article

Mar 2021
NEUROPSYCHOBIOLOGY

Vitamin and homocysteine (Hcy) alternations have been associated with psychiatric disorders. The aim of this meta-analysis was to assess the association of serum vitamin and Hcy levels with obsessive-compulsive disorder (OCD). Following PRISMA protocol, we used the databases including Scopus, PubMed, Google Scholar, and Web of Science with no time restriction. Data were pooled using a random-effects model and/or fixed-effects model to estimate the standard mean difference (SMD) for evaluation of the strength of association analyses. Our data showed a significant reduction in vitamin B12 (SMD = −0.58, 95% CI = −1.08 to −0.08, p = 0.02, I2 = 65%; pheterogeneity = 0.06), vitamin E (SMD = −0.89, 95% CI = −1.23 to −0.56, p < 0.00001, I2 = 23%; pheterogeneity = 0.26), and vitamin C (SMD = −1.40, 95% CI = −2.44 to −0.36, p = 0.008, I2 = 92%; pheterogeneity < 0.0001) in OCD patients. In addition, the findings showed significantly higher levels of Hcy (SMD = 1.11, 95% CI = [0.48, 1.75], p = 0.0006, I2 = 73%; ph = 0.02) in patients compared to controls. Also, our data showed that vitamin B9 and D levels are not associated with OCD (vitamin B9: SMD = −0.23, 95% CI = −1.01 to 0.55, p = 0.56, I2 = 88%; pheterogeneity < 0.0001; vitamin D: SMD = −0.63, 95% CI = −1.41 to 0.15, p = 0.11, I2 = 88%; pheterogeneity = 0.0002). Our findings support significant impacts of Hcy and vitamin B12, E, and C levels in OCD pathogenesis. This will be important for prevention and treatment of OCD. However, further studies are recommended to elucidate more accurate conclusions.

Saccharomyces cerevisiae Yeast-Based Supplementation as a Galactagogue in Breastfeeding Women? A Review of Evidence from Animal and Human Studies

Article

Full-text available

Feb 2021

Perceived insufficient milk production (PIM) adversely affects breastfeeding duration. Women sometimes use galactagogues with the intent to increase breast milk production and support lactation. Saccharomyces cerevisiae yeast-based supplement (SCYS) is an inactive form of Saccharomyces cerevisiae yeast (SCY) either obtained from the fermentation process or grown on molasses. Anecdotal evidence suggests SCYS is a galactagogue. SCYS is promoted on the internet as a galactagogue in various forms and doses. Dietary supplementation with SCYS during gestation and lactation significantly increases milk yield in ruminants. No human study has evaluated efficacy of SCYS as a galactagogue. SCYS is rich in B vitamins, beta-glucan, mannan oligosaccharides and bioavailable chromium; these may impact breast milk production or composition, thus may alleviate PIM. The safety of taking SCYS during lactation is not well studied. Studies have reported contamination of SCYS with ochratoxin A (OTA) as well as minor side effects from SCYS. Studies are needed to evaluate the efficacy of SCYS on breast milk production and composition and to assess the safety of taking SCYS during lactation in humans.

Plasma Homocysteine Concentrations and Depression: A Twin Study

Article

Full-text available

Jan 2021

Background : Homocysteine is an amino acid formed during metabolism of the essential amino acid methionine that plays an important role in energy metabolism and neurotransmitter synthesis. High levels of homocysteine have been linked to both depression and cardiovascular disease, however studies of depression have not always been consistent, possibly related to differences in methodology among studies. The study of twins in clinical research can be useful in controlling for confounding factors. The purpose of this study was to assess the relationship between depression and plasma homocysteine in a study of twins. Methods : Homocysteine concentration was assessed in twins (N=202) from the Vietnam Era Twin Registry, including twin pairs discordant for the diagnosis of Major Depressive Disorder (MDD) and twin pairs without MDD. Self reported depressive symptom levels were also measured as a continous variable using the Beck Depression Inventory (BDI). Results : The average homocysteine concentration was 7.9 µmol/L (2.1 µmol/L SD, range of 2.0 to 17.1 µmol/L). There were no within twin pair differences in homocysteine concentration within twin pairs discordant for MDD and within twin pairs that differed for BDI score. There was a significant pair-level relationship between depressive symptoms as measured by mean BDI score and homocysteine concentration, such that the higher the mean BDI score of the twin pair, the higher the mean homocystein of the pair (p<.001). Every 10 point increase in BDI score was associated with an 0.8 µmol/L increase in homocysteine concentration at the pair level. Conclusions : These findings are not consistent with a causal role for elevated homocysteine in the development of depression, but rather point to familial confounding or other factors that are shared by twin brothers and that contribute to both depression and homocysteine levels.

The association between serum homocysteine and depression: A systematic review and meta‐analysis of observational studies

Article

Jan 2021

Background Hyperhomocysteinemia is known to interfere with neurological functions; however, there is a controversy regarding the relationship between homocysteine and depression. Methods Science Direct, MEDLINE, and ISI Web of Science were searched to find relevant articles, published up to August 2020. Studies were included if they compared homocysteine levels in healthy subjects with subjects with depression. Also, articles that reported the association between hyperhomocysteinemia and risk of depression were included. Odds ratios of depression and means of homocysteine were used to ascertain the overall effect size. Results Homocysteine level was higher in subjects with depression in comparison with healthy controls (weight mean difference =2.53 µmol/L, 95% confidence interval: 1.77, 3.30), and the depression diagnostic tool was a source of heterogeneity. Homocysteine level was significantly higher in subjects with depression in studies that used Diagnostic and Statistical Manual of Mental Disorders‐IV (DSM‐IV), Geriatric Depression Scale (GDS), Zung Self‐Rating Depression Scale (ZDRS), and Beck Depression Index II (BDI‐II) as depression diagnostic tools. Also, participants with hyperhomocysteinemia had a higher chance of depression (Pooled risk =1.34, 95% confidence interval: 1.19, 1.52), where the depression diagnostic tool was a source of heterogeneity. In contrast to ZDRS and Patient Health Questionnaire (PHQ) subgroups, hyperhomocysteinemia yielded a significantly higher risk of depression in DSM‐IV, GDS, and “other” subgroups. Conclusion Homocysteinemia level is higher in individuals with depression. However, the depression diagnostic tool used is instrumental in influencing their association, and thus, future studies should focus on the tools for depression assessment.

Chronic unpredictable mild stress produces depressive-like behavior, hypercortisolemia, and metabolic dysfunction in adolescent cynomolgus monkeys

Article

Full-text available

Jan 2021

Adolescent depression is a common and serious mental disorder with unique characteristics that are distinct from adult depression. The adult non-human primate stress-induced model of depressive-like behavior is an excellent model for the study of mechanisms; however, an adolescent nonhuman primate model is still lacking. Ten male adolescent cynomolgus monkeys were divided into a chronic unpredictable mild stress (CUMS, n = 5) group and a control (CON, n = 5) group by age and weight-matched pairs. The CUMS group was exposed to multiple unpredictable mild stressors for five cycles over 55 days. At baseline, there were no differences between CUMS and CON groups. At endpoint, the CUMS group demonstrated significantly higher depressive-like behavior (huddle posture), and significantly lower locomotion compared with the CON group. Furthermore, depressive-like behavior increased from baseline to endpoint in the CUMS group, but not changed in the CON group. In the attempt for apple test, the CUMS group made significantly fewer attempts for the apple than the CON group. In the human intruder test, the CUMS group showed significantly higher anxiety-like behaviors in the stare phase than the CON group. Hair cortisol level was significantly higher in the CUMS group than the CON group at endpoint, and was also elevated from baseline to endpoint. Metabolic profiling of plasma at endpoint identified alterations in metabolite pathways which overlapped with those of adolescent depression patients. CUMS can induce depressive-like and anxiety-like behaviors, hypercortisolemia, and metabolic perturbations in adolescent cynomolgus monkeys. This is a promising model to study the mechanisms underlying adolescent depression.

Role of Hippophae rhamnoides L. in the Management of Depression by Regulating Hyperhomocysteinemia

Research

Full-text available

Jan 2019

Depression is one of the major health burden in almost all the societies particularly in urban community. As per the World Health Organization, depression will be the second largest disease burden due to the urban way of lifestyle. The modern era is full of stress and strains the people are living in the most competitive society than the previous year. Although many antidepressant drugs have been develop to manage anxiety, stress and depression due to adverse side reaction, most of the drug could show satisfactory results. Considering the above fact, we have selected a drug Hippophae rhamnoides which contain many phyto molecules showing preventing role of anxiety and depression by regulating some of the biochemical parameters.

"UP REGULATING MRNA EXPRESSION OF CLOCK AND MTHFR GENE AND DECREASED LEVEL OF PLASMA HOMOCYSTEINE INVOLVED IN THE ANTIDEPRESSANT EFFECT OF POLYHEBRAL FORMULATION IN A RAT FST MODEL"

Research

Full-text available

Jan 2021

ARTICLE INFO ABSTRACT Polyherbal formulation (PF) is an Indian herbal medicine containing four herbal drugs-Nyctanthes arbortristis (65 mg/kg), Hippophae salicifolia(50 mg/kg), Ocimum tenuiflorum (45 mg/kg) and Reinwardtia indica (40 mg/kg). Previous pharmacological studies have shown that four herbs in PH have antagonistic effects on mRNA level of COMT and MAO A & B. Furthermore, oleanceae, elaeagnaceae, lamiaceae and linaceae from the four herbs in PF may provide protective effect in depression. Highly expressed mRNA level of CLOCK& MTHFR gene, leads to decreased level of plasma homocysteine in an individual,thus increasing receptor concentration of neurotransmitter in neurons. However, antidepressant effect has not been reported before and its mechanism has not been fully clarified. The present study aims to investigate the antidepressant potential of ethanol extract of PF and its effect on mRNA level of CLOCK& MTHFR gene. Albino rats models of depression including forced swim test (FST) and tail suspension test (TST) were used to evaluate the effects of the ethanol extract of PF. A possible mechanism was explored in the tests of antagonism of COMT and MAO-A & B in rats in the previous study. The force swim stress-(FSS-) induced depressive rats were applied in exploring the mechanisms of PF treatment as an antidepressant. Daily oral administration of PF for 28 days significantly alleviated the FSS-induced depressive symptoms. In addition, effect of PF on mRNA level of CLOCK& MTHFR gene were determined by using RT-PCR in the frontal, hippocampus and hypothalamus brain region of rats and also investigated the level of hcy by ELISA, the expressions of those molecular bio-markers relating to depression in rat brains were altered by the treatment of PF. These PF-regulated the mRNA levels of Clock and MTHFR and maintained the level of plasma homocysteine (hcy). In previous study, oral administration of the ethanol extract of PF (200, 400, 800mg/kg) or Sertraline (10mg/kg) significantly reduced the duration of immobility in FST and TST. However, the effect was dose-dependent. The results suggested that the anti-depressant-action of PF might be mediated by an increase in level of mRNA of Clock and MTHFR in different areas of rat's brain and decreases the level of plasma hcy in blood. The rats treated with ethanol extract of PF (200, 400, 800mg/kg) or Sertraline (10mg/kg), which acted agonistic on mRNA level of Clock and MTHFR gene in the frontal cortex, hippocampus and hypothalamus , moreover the maximal up regulation of Clock and MTHFR mRNA levels by PF was obtained at a dose of 200 mg/kg in FSS-exposed rats. Thus, PF could serve as alternative medicine for depressive patients. These results indicate that the ethanol extract of PF produced antidepressant-like effect and the possible mechanism. Being a poly herbal formulation, the observed activity profile may be attributed to one or more bioactive principles present in the components of this formulation. Out of these two preclinical study it is concluded that the PF is effective and safe antidepressant drug.

Effect of one year krill oil supplementation on depressive symptoms and self-esteem of Dutch adolescents: A randomized controlled trial

Article

Full-text available

Dec 2020
PROSTAG LEUKOTR ESS

Introduction Observational studies have shown a relationship between omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) and depression in adolescents. However, n-3 LCPUFA supplementation studies investigating the potential improvement in depressive feelings in adolescents from the general population are missing. Methods A one-year double-blind, randomized, placebo controlled krill oil supplementation trial was conducted in two cohorts. Cohort I started with 400 mg eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) or placebo, after three months this increased to 800 mg EPA and DHA per day, whilst cohort II started with this higher dose. Omega-3 Index (O3I) was monitored via finger-prick blood measurements. At baseline, six and 12 months participants completed the Centre for Epidemiologic Studies Depression Scale (CES-D) and the Rosenberg Self Esteem questionnaire (RSE). Adjusted mixed models were run with treatment allocation/O3I as predictor of CES-D and RSE scores. Results Both intention-to-treat and assessing the change in O3I analyses did not show significant effects on CES-D or RSE scores. Conclusion There is no evidence for less depressive feelings, or higher self-esteem after one year of krill oil supplementation. However, due to a lack of adherence and drop-out issues, these results should be interpreted with caution.

Hyperhomocysteinemia Induced by Methionine Excess Is Effectively Suppressed by Betaine in Geese

Article

Full-text available

Sep 2020

The objective of our study was to investigate the effects of excess Methionine (Met) on the growth performance, serum homocysteine levels, apoptotic rates, and Bax and Bcl-2 protein levels in geese and to study the role of Bet (betaine) in relieving excess Met-induced hyperhomocysteinemia (HHcy). In this study, 150 healthy male 14-day-old Yangzhou geese of similar body weight were randomly distributed into three groups with five replicates per treatment and 10 geese per replicate: the control group (fed a control diet), the Met toxicity group (fed the control diet +1% Met), and the Bet detoxification group (fed the control diet +1% Met +0.2% Bet). At 28, 49, and 70 d of age, the geese in the Met toxicity group had significantly lower body weights than those in the control group (p < 0.05). The serum homocysteine levels in geese at 70 d of age in the detoxification group were significantly lower than those in the Met toxicity group (p < 0.05). Compared with the control, Met significantly increased cardiomyocyte apoptosis rates, while Bet reduced them. In conclusion, our results suggest that excess methionine reduces body weight induced by myocardial apoptosis, and Bet can be used to effectively lower plasma homocysteine levels.

Interactive Effects of Elevated Homocysteine and Late-life Depression on Cognitive Impairment

Article

Aug 2020
J AFFECT DISORDERS

Background Both an elevated homocysteine (Hcy) level and depression are risk factors for cognitive impairment in the general population, but no study has analyzed whether the coexistence of an elevated Hcy level and late‐life depression (LLD) is associated with worse cognitive performance. Objective We aimed to investigate the relationship between Hcy levels and cognitive function in individuals with LLD and whether the coexistence of an elevated Hcy level and LLD is associated with worse cognitive performance. Methods A total of 113 LLD patients and 89 normal controls underwent a standardized clinical interview and comprehensive neuropsychological assessment battery. Plasma concentrations of Hcy were detected. Factorial analyses were performed to examine the impact of the coexistence of an elevated Hcy level and LLD on cognitive performance. Results Plasma Hcy levels in patients with LLD were significantly higher than that in normal controls. Only for LLD patients, Hcy level was negatively correlated with global cognition, executive function, attention, and visual space. The factorial analysis showed that there was a significant interactive effect of Hcy level (normal and elevated levels) and LLD (with and without LLD) on global cognition. In post hoc comparisons, the elderly individuals with both elevated Hcy levels and LLD tended to have the worst global cognitive function compared with those with LLD or elevated Hcy levels alone. Conclusions The coexistence of an elevated Hcy level and LLD was associated with worse cognitive performance. Early intervention should be initiated to protect cognition in LLD patients with elevated Hcy levels.

S-Adenosine Methionine (SAMe) and Valproic Acid (VPA) as Epigenetic Modulators: Special Emphasis on their Interactions Affecting Nervous Tissue during Pregnancy

Article

Full-text available

May 2020
INT J MOL SCI

S-adenosylmethionine (SAMe) is involved in many transmethylation reactions in most living organisms and is also required in the synthesis of several substances such as monoamine neurotransmitters and the N-methyl-D-aspartate (NMDA) receptor. Due to its important role as an epigenetic modulator, we discuss in some length the process of DNA methylation and demethylation and the critical periods of epigenetic modifications in the embryo, fetus, and thereafter. We also discuss the effects of SAMe deficiency and the attempts to use SAMe for therapeutic purposes such as the treatment of major depressive disorder, Alzheimer disease, and other neuropsychiatric disorders. SAMe is an approved food additive and as such is also used during pregnancy. Yet, there seems to scanty data on the possible effects of SAMe on the developing embryo and fetus. Valproic acid (VPA) is a well-tolerated and effective antiepileptic drug that is also used as a mood stabilizer. Due to its high teratogenicity, it is contraindicated in pregnancy. A major mechanism of its action is histone deacetylase inhibition, and therefore, it acts as an epigenetic modulator, mainly on the brain. This prompted clinical trials using VPA for additional indications i.e., treating degenerative brain disease such as Alzheimer disease, dementia, HIV, and even cancer. Therefore, we discuss the possible effects of VPA and SAMe on the conceptus and early postnatally, during periods of susceptibility to epigenetic modifications. VPA is also used as an inducer of autistic-like behavior in rodents and was found by us to modify gene expression when administered during the first postnatal week but not when administered to the pregnant dams on day 12 of gestation. In contrast, SAMe modified gene expression when administered on day 12 of pregnancy but not postnatally. If administered together, VPA prevented the changes in gene expression induced by prenatal SAMe administration, and SAMe prevented the gene expression changes and autistic-like behavior induced by early postnatal VPA. It is concluded that both VPA and SAMe are powerful epigenetic modifiers with antagonistic actions on the brain that will probably be used in the future more extensively for the treatment of a variety of epigenetic diseases of the nervous system.

The relationship of severity of depression with homocysteine, folate, vitamin B12, and vitamin D levels in children and adolescents

Article

Apr 2020

Background Depression is a heterogeneous disorder and is thought to develop as a result of complex interactions between genetic and environmental factors. One‐carbon metabolism that includes vitamin B12, folic acid, and homocysteine has been investigated in psychiatric disorders like depression. In recent years, vitamin D has also been considered to contribute to psychiatric disorders. In this study, serum levels of folate, vitamin B12, and homocysteine related to one‐carbon metabolism and vitamin D were investigated in children and adolescents with depression and to assess possible roles in depression pathogenesis. Methods The study included 89 children and adolescents with depression (69 female, 20 male; mean age ± SD = 15.08 ± 1.46) and 43 control subjects (31 female, 12 male; mean age ± SD = 14.41 ± 2.32) without any DSM‐5 diagnosis. Each subject completed a sociodemographic form, Childhood Depression Inventory, State‐Trait Anxiety Inventory 1‐2 and measured serum folate, vitamin B12, homocysteine, and 25‐OH vitamin D levels. Results There was no significant difference between the groups in terms of folate levels (p = .052). In the patient group, the vitamin B12 and vitamin D levels were clearly low (p values for both levels were <.001), while homocysteine levels were found to be remarkably high (p < .001). In addition, there was a negative correlation between depression severity and vitamin B12 and vitamin D, while a positive correlation was found with homocysteine. Conclusions The results of the study show that vitamin B12 deficiency or insufficiency and elevated homocysteine may contribute to the etiopathogenesis of depression. Additionally, it was shown that lower vitamin D levels may be associated with depression.

Blood plasma B vitamins in depression and the therapeutic response to electroconvulsive therapy

Article

Full-text available

Mar 2020

A growing body of research has indicated a role for B vitamins in depression, with some previous studies suggesting that B vitamin status in patients with depression can impact on antidepressant response. Here we aimed to investigate B vitamin plasma concentrations in medicated patients with depression (n = 94) compared to age- and sex-matched healthy controls (n = 57), and in patients with depression after electroconvulsive therapy (ECT) in a real-world clinical setting. Our results show that nicotinamide (vitamin B3), N1-methylnicotinamide (vitamin B3 metabolite), and pyridoxal 5′-phosphate (PLP; vitamin B6) concentrations were significantly reduced in patients with depression compared to controls. The Cohen’s d effect sizes for nicotinamide, N1-methylnicotinamide, and PLP were moderate–large (-0.47, -0.51, and -0.59, respectively), and likely to be of clinical relevance. Functional biomarkers of vitamin B6 status (PAr index, 3-hydroxykynurenine: hydroxyanthranilic acid ratio, 3-hydroxykynurenine: xanthurenic acid, and HKr) were elevated in depressed patients compared to controls, suggestive of reduced vitamin B6 function. Over 30% of the patient cohort were found to have low to deficient PLP concentrations, and exploratory analyses revealed that these patients had higher IL-6 and CRP concentrations compared to patients with PLP levels within the normal range. Treatment with ECT did not alter B vitamin concentrations, and B vitamin concentrations were not associated with depression severity or the therapeutic response to ECT. Overall, reduced plasma PLP, nicotinamide, and N1-methylnicotinamide concentrations could have wide ranging effects on pathways and systems implicated in depression. Further studies are required to understand the reasons why patients with depression present with low plasma B vitamin concentrations.

Deficit of nutrients and mental disorders

Article

Jan 2009

Dissecting hair breakage in alopecia areata: the central role of dysregulated cysteine homeostasis

Article

Full-text available

May 2024
AMINO ACIDS

In the initial stages of Alopecia Areata (AA), the predominance of hair breakage or exclamation mark hairs serves as vital indicators of disease activity. These signs are non-invasive and are commonly employed in dermatoscopic examinations. Despite their clinical salience, the underlying etiology precipitating this hair breakage remains largely uncharted territory. Our exhaustive review of the existing literature points to a pivotal role for cysteine—a key amino acid central to hair growth—in these mechanisms. This review will probe and deliberate upon the implications of aberrant cysteine metabolism in the pathogenesis of AA. It will examine the potential intersections of cysteine metabolism with autophagy, ferroptosis, immunity, and psychiatric manifestations associated with AA. Such exploration could illuminate new facets of the disease's pathophysiology, potentially paving the way for innovative therapeutic strategies.

Vitamin B12 and folate deficiencies, elevated homocysteine and their roles in the biochemical basis of neuropsychiatric diseases in children and adolescents: Case series, review and recommendations

Preprint

Full-text available

Jun 2023

Erman Esnafoglu

Vitamin B12 and folate deficiencies can be frequently seen in children and adolescents and may manifest with neuropsychiatric symptoms. Vitamin B12 and folate deficiencies and the associated increase in homocysteine are related to one-carbon metabolism (OCM) and may play a role in the pathogenesis of childhood and adolescent psychiatric disorders. Here, twelve adolescent cases with vitamin B12 and folate deficiencies and homocysteine increase, diagnosed with major depressive disorder, generalized anxiety disorder and obsessive compulsive disorder are presented. The possible biochemical roles of OCM in the pathogenesis of psychiatric disorders at these ages were explained. In addition, the diagnosis and treatment methods for vitamin B12 and folate deficiencies are summarized for clinicians.

Association Between MTHFR rs17367504 Polymorphism and Major Depressive Disorder in Taiwan: Evidence for Effect Modification by Exercise Habits

Article

Full-text available

Jun 2022

Background/Aim Recent studies reported that folate supplementation has beneficial effects on major depression. The Methylenetetrahydrofolate reductase (MTHFR) enzyme is crucial in folate metabolism. This population-based study examined the association between MTHFR rs17367504 polymorphism and major depressive disorder based on exercise habits. Methods Taiwan Biobank (TWB) provided demographic and genotype data between 2008 and 2015. The biobank participants were Taiwanese aged 30 to 70. Data on major depressive disorder (MDD) were obtained from the National Health Insurance Research Database (NHIRD). Results A total of 636 individuals were identified with MDD, whereas 17,298 individuals were considered controls. The associations of MTHFR rs17367504 and exercise with MDD risk were estimated using logistic regression models. The distribution of MTHFR rs17367504 genotype frequencies differed significantly between the MDD and control groups. We found that, compared with the AA genotype, the GG genotype was associated with a significantly increased risk of MDD [adjusted odds ratio (aOR), 1.76; 95% confidence interval (CI), 1.05–2.94; p = 0.033]. We found an interaction (p = 0.04) between rs17367504 and exercise, a well-known protective factor for MDD. A substantial increase in the risk of MDD was found among those with GG genotypes who did not exercise (aOR, 2.93; 95% CI, 1.66–5.17; p < 0.001). Conclusions Our findings indicate that MDD is related to MTHFR rs17367504 and exercise, though the mechanisms remain to be determined.

Perivascular spaces as a marker of psychological trauma in depression: A 7‐Tesla MRI study

Article

Full-text available

Jun 2022

Introduction Emerging evidence in depression suggests that blood–brain barrier (BBB) breakdown and elevated inflammatory cytokines in states of persistent stress or trauma may contribute to the development of symptoms. Signal‐to‐noise ratio afforded by ultra‐high field MRI may aid in the detection of maladaptations of the glymphatic system related to BBB integrity that may not be visualized at lower field strengths. Methods We investigated the link between glymphatic neuroanatomy via perivascular spaces (PVS) and trauma experience in patients with major depressive disorder (MDD) and in healthy controls using 7‐Tesla MRI and a semi‐automated segmentation algorithm. Results After controlling for age and gender, the number of traumatic events was correlated with total PVS volume in MDD patients (r = 0.50, p = .028) and the overall population (r = 0.34, p = .024). The number of traumatic events eliciting horror was positively correlated with total PVS volume in MDD patients (r = 0.50, p = .030) and the overall population (r = 0.32, p = .023). Age correlated positively with PVS count, PVS total volume, and PVS density in all participants (r > 0.35, p < .01). Conclusions These results suggest a relationship between glymphatic dysfunction related to BBB integrity and psychological trauma, and that glymphatic impairment may play a role in trauma‐related symptomatology.

Association between homocysteine levels in acute stroke and poststroke depression: A systematic review and meta‐analysis

Article

Full-text available

May 2022

Background Homocysteine (Hcy) has been confirmed to be associated with depression, but its relationship with poststroke depression (PSD) remains controversial. So far, there is no meta‐analysis of the correlation between Hcy level in acute stroke and PSD. Methods A systematic search of a sub‐database of studies reporting the level of Hcy in the acute phase of ischemic stroke and PSD as of November 2021 was performed. Data extraction was performed strictly according to the inclusion and exclusion criteria. All data were analyzed using STATA 11.0. The standardized root mean square difference (SMD) and 95% confidence interval (CI) were used to compare continuous variables. Results A total of 11 studies were included in this study, including 2789 participants. The results of this meta‐analysis showed that admission the levels of Hcy were significantly higher in PSD survivors, compared to non‐PSD survivors (SMD = 0.37, 95%CI = 0.07–0.66, P ＜ .001). Subgroup analysis showed that survivors with PSD diagnosed more than 3 months after stroke had significantly different the levels of from non‐PSD survivors (6 months: SMD = 0.61, 95%CI = 0.40–0.82, 9 months: SMD = 1.00, 95%CI = 0.59–1.41). Conclusion The level of Hcy in the acute phase of ischemic stroke is a risk factor for PSD.

Nutritional Psychiatry

Article

Full-text available

Nov 2021

Nutrition is a major game changer in the treatment of psychiatric disorder. Foods and supplements provide these essential nutrients the brain needs to develop and function effectively, which can also serve as an integra part in the treatment of psychiatric issues. As humans, we cannot survive without food, and when you eat complete (balance diet) and have the needed rest which the human body requires, you are more certain to be well and free from any mental challenges. Most scientific researchers focus more on the cause of mental disorder as being genetic, psychosocial, abuse or use of drugs, cannabis, alcohol etc. But little attention has been given to heavy metals such as Pb, Hg, Cd & As who are also been responsible for most psychiatric disorder such as depression, dementia, schizophrenia, hallucination etc. Which brings us to the type of nutrients that can help combat these excesses of these toxic metals before it escalates into psychiatric condition. Types of nutritional components that are of benefit to the mental health are niacin, folate, vitamin B6 & B12, phospholipids, cholesterol, and omega-3 fatty acids. Refined sugar and saturated fat are seen as dangerous precursor to cognitive function. The aim of this review is to establish the importance of nutrition in the treatment and management of psychiatric disorders.

Nutritional Psychiatry

Article

Full-text available

Feb 2022

Nutrition is a major game-changer in the treatment of the psychiatric disorder. Foods and supplements provide these essential nutrients the brain needs to develop and function effectively, which can also serve as an integral part of the treatment of psychiatric issues. As humans, we cannot survive without food, and when you eat a complete (balanced diet) and have the needed rest that the human body requires, you are more certain to be well and free from any mental challenges. Most scientific researchers focus more on the cause of the mental disorders as being genetic, psychosocial, abuse or use of drugs, cannabis, alcohol etc. But little attention has been given to heavy metals such as Pb, Hg, Cd & As who are also been responsible for most psychiatric disorders such as depression, dementia, schizophrenia, hallucination etc. This brings us to the type of nutrients that can help combat these excesses of these toxic metals before it escalates into a psychiatric condition. Types of nutritional components that are of benefit to mental health are niacin, folate, vitamin B6 & B12, phospholipids, cholesterol, and omega-3 fatty acids. Refined sugar and saturated fat are seen as dangerous precursors to cognitive function. The aim of this review is to establish the importance of nutrition in the treatment and management of psychiatric disorders.

Homocysteinylation and Sulfhydration in Diseases

Article

Full-text available

Dec 2021

Homocysteine (Hcy) is an important intermediate in methionine metabolism and generation of one-carbon unit, and its dysfunction is associated with many pathological states. Although Hcy is a non-protein amino acid, many studies have demonstrated protein-related homocysteine metabolism and possible mechanisms underlying homocysteinylation. Homocysteinylated proteins lose their original biological function and have a negative effect on the various disease phenotypes. Hydrogen sulfide (H2S) has been recognized as an important gaseous signaling molecule with mounting physiological properties. H2S modifies small molecules and proteins via sulfhydration, which is supposed to be essential in the regulation of biological functions and signal transduction in human health and disorders. This review briefly introduces Hcy and H2S, further discusses pathophysiological consequences of homocysteine modification and sulfhydryl modification, and ultimately makes a prediction that H2S might exert a protective effect on the toxicity of homocysteinylation of target protein via sulfhydration. The highlighted information here yields new insights for the role of protein modification by Hcy and H2S in diseases.

Impact of C-Reactive Protein on Cognition and Alzheimer Disease Biomarkers in Homozygous Apolipoprotein E ɛ4 Carriers

Article

Jul 2021

OBJECTIVE Previous research has shown that elevated blood C-reactive protein (CRP) is associated with increased Alzheimer’s disease (AD) risk only in apoliprotein E4 genotype ( APOE ε4) allele carriers. The objective of this study was to examine the interactive effects of plasma CRP and apoliprotein E ( APOE ) genotype on cognition and AD biomarkers. METHODS Data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study was analyzed, including APOE genotype; plasma CRP concentrations; diagnostic status (i.e., MCI and dementia due to AD); Mini-Mental State Exam (MMSE) and Clinical Dementia Rating (CDR) Dementia Staging Instrument; cerebral spinal fluid (CSF) concentrations of amyloid-β peptide (Aβ42), total tau (t-Tau) and phosphorylated tau (p-Tau); and amyloid (AV45) PET imaging. Multivariable regression analyses tested the associations between plasma CRP and APOE on cognitive and biomarker outcomes. RESULTS Among 566 ADNI participants, 274 (48.4%) had no, 222 (39.2%) had one, and 70 (12.4%) had two APOE ε 4 alleles. Only among participants who had two APOE ε4 alleles, elevated CRP was associated with lower MMSE at baseline [ β (95%CI): -0.52 ( -1.01, -0.12)] and 12-month follow-up [β (95%CI): -1.09 (-1.88, -0.17)] after adjusting for sex, age and education. The interaction of two APOE ε4 alleles and elevated plasma CRP was associated with increased CSF levels of t-Tau (β = +11.21, SE = 3.37, p < 0.001) and p-Tau (β = +2.74, SE = 1.14, p < 0.01). Among those who had no APOE ε4 allele, elevated CRP was associated with decreased CSF t-Tau and p-Tau. These effects were stronger at 12-month follow-up. CONCLUSIONS CRP released during peripheral inflammation could be a mediator in APOE ε4 related AD neurodegeneration and serve as a drug target for AD.

Homocysteine – from disease biomarker to disease prevention

Article

Mar 2021

We have reviewed the literature and have identified more than 100 diseases or conditions that are associated with raised concentrations of plasma total homocysteine. The commonest associations are with cardiovascular diseases and diseases of the central nervous system, but a large number of developmental and age‐related conditions are also associated. Few other disease biomarkers have so many associations. The clinical importance of these associations becomes especially relevant if lowering plasma total homocysteine by B vitamin treatment can prevent disease and so improve health. Five diseases can at least in part be prevented by lowering total homocysteine: neural tube defects, impaired childhood cognition, macular degeneration, primary stroke, and cognitive impairment in the elderly. We conclude from our review that total homocysteine values in adults of 10 μmol/L or below are probably safe, but that values of 11 μmol/L or above may justify intervention. Homocysteine is more than a disease biomarker: it is a guide for the prevention of disease. Abstract

Metabolic Groups Related to Blood Vitamin Levels and Inflammatory Biomarkers in Brazilian Children and Adolescents

Article

Full-text available

Dec 2020

Certain B-vitamins and vitamin A may be involved in inflammatory pathways associated with homocysteine and omega-3 fatty acids. The aims of this study were (i) to determine whether different metabolic profiles of B-vitamins and vitamin A in Brazilian children and adolescents were positively or negatively related to homocysteine and omega-3 fatty acids using k-means clustering analysis, (ii) compare nutrient intakes and metabolites between the different metabolic profiles, (iii) evaluate if the statistically significant metabolites found between the metabolic groups, can predict the variation of leukotriene A4 hydrolase (LTA4H) levels, a biomarker of low-grade inflammation, in the total studied population. This cross-sectional study included 124 children and adolescents, aged 9-13 y old. Dietary intake was assessed by the food frequency questionnaire and 24-hour recall. Biomarkers for vitamins B2, B6, B12, folate and vitamin A were measured in plasma. Omega-3 fatty acids and homocysteine were measured in red blood cells (RBC). Two different metabolic profiles were found. Thirty of these individuals had overall average higher riboflavin, pyridoxal, and vitamin B12 plasma levels (metabolic group 1) compared to 94 individuals (group 2). Group 2 had lower dietary intake of vitamin B2, vitamin A, and vitamin B12 and higher RBC levels of homocysteine. EPA and DHA erythrocyte levels were not different between metabolic groups. Multiple linear regression analyses showed that blood cobalamin, riboflavin, pyridoxal and homocysteine combined, explained 9.0% of LTA4H levels variation in the total studied population. The metabolic group that had low plasma levels of riboflavin, pyridoxal, and cobalamin also had a lower dietary intake of B-vitamin and higher RBC homocysteine. The combined levels of the riboflavin, pyridoxal, cobalamin and homocysteine biomarkers can predict the variation of LTA4H in the total population studied, but it is not clear how this regulation occurs.

Dementia: Psychosocial/Mental Health Risk Factors

Article

Jun 2020
J Nurse Pract

Cara Rachel Nasisi

Dementia currently is a major health concern plaguing the globe that will only become more prevalent as people age. Although medications are available to slow the progression of the disease or improve symptoms, or both, dementia is currently incurable, irreversible, and a major cause of disability for the world’s older population. Identifying risk factors early and applying these risk factors to nurse practitioner practice can help ward off the disease. Although risk factors related to dementia is a large topic, this review will focus specifically on psychosocial/mental health risk factors related to dementia and applications to nurse practitioner practice.

Hyperhomocysteinemia-Induced Oxidative Stress Exacerbates Cortical Traumatic Brain Injury Outcomes in Rats

Article

Full-text available

Apr 2021
CELL MOL NEUROBIOL

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality among military service members and civilians in the United States. Despite significant advances in the understanding of TBI pathophysiology, several clinical reports indicate that multiple genetic and epigenetic factors can influence outcome. Homocysteine (HCY) is a non-proteinogenic amino acid, the catabolism of which can be dysregulated by stress, lifestyle, aging, or genetic abnormalities leading to hyperhomocysteinemia (HHCY). HHCY is a neurotoxic condition and a risk factor for multiple neurological and cardiovascular disorders that occurs when HCY levels is clinically > 15 µM. Although the deleterious impact of HHCY has been studied in human and animal models of neurological disorders such as stroke, Alzheimer’s disease and Parkinson's disease, it has not been addressed in TBI models. This study tested the hypothesis that HHCY has detrimental effects on TBI pathophysiology. Moderate HHCY was induced in adult male Sprague Dawley rats via daily administration of methionine followed by impact-induced traumatic brain injury. In this model, HHCY increased oxidative stress, upregulated expression of proteins that promote blood coagulation, exacerbated TBI-associated blood–brain barrier dysfunction and promoted the infiltration of inflammatory cells into the cortex. We also observed an increase of brain injury-induced lesion size and aggravated anxiety-like behavior. These findings show that moderate HHCY exacerbates TBI outcomes and suggest that HCY catabolic dysregulation may be a significant biological variable that could contribute to TBI pathophysiology heterogeneity.

Vitamin B12, folic acid, homocysteine and vitamin D levels in children and adolescents with obsessive compulsive disorder.

Article

Full-text available

Aug 2017

Elif Güdeloğlu

Obsessive compulsive disorder (OCD) is a complex disorder with a poorly understood aetiopathogenesis. One carbon metabolism that includes vitamin B12, folic acid and homocysteine has been investigated in many psychiatric disorders like OCD. In recent years, vitamin D has also been considered to contribute to many of these psychiatric disorders. In this study we investigated whether vitamin B12, homocysteine and vitamin D play a role in the aetiology of paediatric OCD. With this aim we compared 52 children and adolescent OCD patients with 30 healthy controls. The participants were tested for vitamin B12, folic acid, homocysteine and vitamin D levels and were evaluated with a sociodemographic form, state-trait anxiety inventory 1 and 2, Kovacs Depression Inventory and Yale-Brown Obsessive Compulsive Scale (Y-BOCS). As a result we found significantly lower levels of vitamin B12 and vitamin D and higher levels of homocysteine in the patient group compared to control group (p values for all three scores were <0.001), whereas there was no significant difference between groups in terms of folate levels (p=0.083). This demonstrates that one carbon metabolism and vitamin D deficiency can play a role in the aetiology of OCD. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved. KEYWORDS: Aetiopathogenesis; Folate; Homocysteine; Obsessive compulsive disorder; Vitamin B12; Vitamin D

Biología, patobiología y bioclínica de la homocisteína eh la especie humana

Article

Jun 2010

Grégory Alfonso García

La homocistinuria fue descrita en 19a2 en niños con dificultades de aprendizaje y en 19a9 McCully informó la evidencia en autopsias de trombosis arterial eztensa y aterosclerosis en niños con elevadas concentraciones de homocisteína plasmática y homocistinuria. La homocisteína, un aminoácido de azufre, es un metabolito intermedio de la metionina, y sobre la base de estos hallazgos bioquímicos, ellos propusieron que la homocisteína plasmática elevada puede causar lesión neural y enfermedad vascular aterosclerótica. Hoy se considera un factor de riesgo independiente para esta última. La hiperhomocistinemia leve es bastante prevalente en la población general. Puede deberse a defectos genéticos en las enzimas que participan en el metabolismo de la homocisteína, carencias nutricionales de vitaminas y cofactores, ciertos medicamentos, ingesta rica en metionina o enfermedad renal. La alta concentración puede reducirse con folato, y es así que la suplementación vitamínica ha sido propuesta en individuos con hiperhomocistinemia con el fin de reducir su riesgo de enfermedad cardiovascular. En este artículo hacemos una revisión de la biología, la patobiología y la bioclínica del metabolismo de la homocisteína.

A magnetic resonance imaging study of white matter lesions in depression and Alzheimer's disease [published erratum appears in Br J Psychiatry 1996 Jun;168:792]

Article

Full-text available

Apr 1996

Background White matter changes, as revealed by magnetic resonance imaging (MRI), may occur in depression and Alzheimer's disease. Method T2-weighted MRI scans were performed in 39 control subjects, 61 subjects with NINCDS/ADRDA Alzheimer's disease and 60 subjects with DSM–III–R major depression. Deep white matter lesions (DWML) and periventricular lesions (PVL) were rated on a standard 0–3 scale by two radiologists blind to clinical diagnosis. Results After controlling for differences in vascular risk factors and current blood pressure, DWML were significantly more common in depressed subjects and PVL in Alzheimer's disease subjects compared to controls. DWML were most common in those presenting in late life with their first ever depression and 50% of such subjects had severe (grade 3) DWML. Conclusion An association between DWML and depression and PVL and Alzheimer's disease is supported. The increase with DWML that occurs with ageing may predispose some elderly subjects to depression.

Homocysteine and Short-term Risk of Myocardial Infarction and Stroke in the ElderlyThe Rotterdam Study

Article

Full-text available

Feb 1999
ARCH INTERN MED

Background Elevated homocysteine level increases vascular disease risk. Most data are based on subjects younger than 60 years; data for the elderly are more limited. We examined the relationship of homocysteine level to incident myocardial infarction and stroke among older subjects in a nested case-control study. Methods Subjects were participants in the Rotterdam Study, a cohort study among 7983 subjects residing in the Ommoord district of Rotterdam, the Netherlands. Baseline examinations were performed from March 1, 1990, to July 31, 1993. The analysis is restricted to myocardial infarction and stroke that occurred before December 31, 1994. One hundred four patients with a myocardial infarction and 120 with a stroke were identified with complete data. Control subjects consisted of a sample of 533 subjects drawn from the study base, free of myocardial infarction and stroke. Nonfasting total homocysteine levels were measured. Results Results were adjusted for age and sex. The risk of stroke and myocardial infarction increased directly with total homocysteine. The linear coefficient suggested a risk increase by 6% to 7% for every 1-µmol/L increase in total homocysteine. The risk by quintiles of total homocysteine level was significantly increased only in the group with levels above 18.6 µmol/L (upper quintile): odds ratios were 2.43 (95% confidence interval, 1.11-5.35) for myocardial infarction and 2.53 (95% confidence interval, 1.19-5.35) for stroke. Associations were more pronounced among those with hypertension. Conclusions The present study, based on a relatively short follow-up period, provides evidence that among elderly subjects an elevated homocysteine level is associated with an increased risk of cardiovascular disease.

Altersassoziierte Veränderungen im Vitamin-B 12- und Folsäurestoffwechsel: Prävalenz, Ätiopathogenese und pathophysiologische Konsequenzen

Article

Full-text available

Apr 2004

Der steigende Anteil lterer Menschen an der Gesamtbevlkerung ist eine fr die meisten Industrienationen charakteristische Entwicklung mit bekannten psychosozialen und gesundheitskonomischen Folgen. Eine optimierte, zur Krankheitsprvention geeignete Nhrstoffzufuhr gewinnt deshalb an Bedeutung. Aus prventivmedizinischer Sicht ist die Versorgung mit Vitamin B12 und Folsure von besonderer Relevanz, da die Pathogenese verschiedener degenerativer Erkrankungen mit einer unzureichenden Versorgung dieser Vitamine in Zusammenhang steht. Vitamin B12 und Folsure wirken als Coenzyme und weisen eine enge molekulare Interaktion auf, was anhand der Regulation des Homocysteinstoffwechsels deutlich wird. Neben der Bestimmung der Serum-Vitaminspiegel stehen heute mit den Metaboliten Homocystein und Methylmalonsure sensitive Laborparameter zur Verfgung, die eine differenziertere Beurteilung des Vitaminstatus erlauben. Je nach zugrunde gelegtem Marker, weisen 3–60% der Senioren eine unzureichende Vitamin-B12-Versorgung und rund 29% einen unzureichenden Folatstatus auf. Der unzureichende Vitamin- B12-Status ist vorwiegend auf die mit dem Alter steigende Prvalenz der atrophischen Gastritis vom Typ B zurckzufhren. Etwa 20–50% der Senioren sind hiervon betroffen. Die damit in Verbindung stehende Abnahme der gastralen Sure- und Pepsinogensekretion vermindert die intestinale Freisetzung und Absorption von Vitamin B12. Dies trifft auch fr die Folatabsorption zu. Daneben beeintrchtigt eine Reihe von Medikamenten den Folsure- und Vitamin-B12-Stoffwechsel. Eine Vitamin-B12-Unterversorgung ist nur in Ausnahmefllen auf eine unzureichende Zufuhr des Vitamins zurckzufhren, in erster Linie bei veganer Ernhrung. Dagegen ist die Folsureaufnahme der meisten Senioren deutlich zu niedrig und erreicht durchschnittlich nur etwa ein Drittel der empfohlenen Zufuhr.Bereits moderat erhhte Homocysteinwerte bzw. niedrige Vitamin-B12- und Folsurewerte sind mit einem vermehrten Auftreten von Atherosklerose und Demenzerkrankungen assoziiert. Eine Meta-Analyse prospektiver Studien zeigt, dass ein um 25% geringerer Homocysteinwert (etwa 3 mol/l) mit einem um 11% verminderten Risiko fr ischmische Herzerkrankungen und mit einem um 19% geringeren Apoplexie-Risiko einhergeht. Ob es sich bei der Hyperhomocysteinmie um einen kausalen Faktor oder aber eine Folge der Atherogenese handelt, ist bislang allerdings nicht bekannt. Die Schtzungen zur Risikoreduktion basieren nicht auf Interventions-, sondern berwiegend auf Kohorten-Studien. Homocystein initiiert eine Reihe proatherogener Mechanismen, wie z. B. die Bildung reaktiver Sauerstoffspezies und die verstrkte Fibrinsynthese. Mittels Folsuresupplementierung (0,5–5 mg/Tag) lsst sich der Homocysteinwert um 25% reduzieren. Bei zustzlicher Vitamin-B12-Gabe (0,5 mg/Tag) verringert sich dieser Wert um weitere 7%. Im Bereich der Sekundrprvention konnten hierdurch bereits klinische Erfolge (Abnahme der Restenoserate und der Plaques) erzielt werden.Depressionen und Demenzerkrankungen sind ebenfalls hufig mit einem Defizit an Folsure und Vitamin B12 verbunden. Biochemisch lsst sich dieser Befund auf die Bedeutung von Folsure und Vitamin B12 bei der Transmethylierung neuroaktiver Verbindungen (Myelin, Neurotransmitter) zurckfhren, die im Vitaminmangel gestrt ist (Hypomethylierungshypothese).In den letzten Jahren mehren sich die Hinweise auf prventive Wirkungen von Folsure gegenber Tumoren. Auf molekularer Ebene bewirkt ein Folsuredefizit die Hypomethylierung bestimmter DNA-Abschnitte.Aufgrund der nicht sichergestellten Bedarfsdeckung bei lteren Menschen ist eine generelle Supplementierung von Vitamin B12 und Folsure in Betracht zu ziehen.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 B12 and folic acid play a major role, since deficiency of both vitamins is associated with the pathogenesis of different diseases such as declining neurocognitive function and atherosclerotic lesions. Vitamin B12 and folic acid act as coenzymes and show a close molecular interaction on the basis of the homocysteine metabolism. In addition to the serum concentrations of the vitamins, the metabolites homocysteine and methylmalonic acid are sensitive markers of cobalamin and folate status. Depending on the used marker, 3–60% of the elderly are classified as vitamin B12 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 B12 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 B12 status are associated with vascular disease and neurocognitive disorders. Results of a meta-analysis of prospective studies revealed that a 25% lower homocysteine level (about 3 mol/L) was associated with an 11% lower ischemic heart disease risk and 19% lower stroke risk. It is still discussed, whether hyperhomocysteinemia is causally related to vascular disease or whether it is a consequence of atherosclerosis. Estimated risk reduction is based on cohort studies, not on clinical trials. Homocysteine initiates different proatherogenetic mechanisms such as the formation of reactive oxygen species and an enhanced fibrin synthesis. Supplementation of folic acid (0.5–5 mg/d) reduces the homocysteine concentration by 25%. Additional vitamin B12 (0.5 mg/d) induces further reduction by 7%. In secondary prevention, supplementation already led to clinical improvements (reduction of restenosis rate and plaques).Depression, dementia, and mental impairment are often associated with folate and vitamin B12 deficiency. The biochemical reason of this finding may be the importance of folic acid and vitamin B12 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 B12 intake and status are mostly insufficient in elderly subjects, a supplementation can generally be recommended.

Mood disorder as a specific complication of stroke

Article

Full-text available

Nov 1977

In an effort to discern whether cerebral vascular injuries provoke specific emotional disturbances, 20 consecutively admitted stroke patients were compared with 10 orthopaedic patients. Both groups were examined for functional disabilities (Activities of Daily Living) and for psychiatric symptoms. Reliable and valid instruments, the Hamilton Rating Scale, the Visual Analogue Mood Scale, the Present State Exam, and the Mini-Mental State Exam were employed to display the psychopathology. More of stroke patients than orthopaedic patients were depressed (45% versus 10%) even though the level of functional disability in both groups were the same. Patients with right hemisphere stroke seemed particularly vulnerable and and displayed a syndrome of irritability, loss of interest, and difficulty in concentration, in addition to depression of mood (70% of right hemisphere stroke patients versus 0% left hemisphere stroke patients and 0% orthopaedic patients). We conclude that mood disorder is a more specific complication of stroke than simply a response to the motor disability. We suggest that a controlled trial of antidepressant medication is indicated for patients with this complication.

Folate, Vitamin B12, and Serum Total Homocysteine Levels in Confirmed Alzheimer Disease

Article

Full-text available

Dec 1998
ARCH NEUROL-CHICAGO

Recent studies suggest that vascular disease may contribute to the cause of Alzheimer disease (AD). Since elevated plasma total homocysteine (tHcy) level is a risk factor for vascular disease, it may also be relevant to AD. To examine the association of AD with blood levels of tHcy, and its biological determinants folate and vitamin B12. Case-control study of 164 patients, aged 55 years or older, with a clinical diagnosis of dementia of Alzheimer type (DAT), including 76 patients with histologically confirmed AD and 108 control subjects. Referral population to a hospital clinic between July 1988 and April 1996. Serum tHcy, folate, and vitamin B12 levels in patients and controls at entry; the odds ratio of DAT or confirmed AD with elevated tHcy or low vitamin levels; and the rate of disease progression in relation to tHcy levels at entry. Serum tHcy levels were significantly higher and serum folate and vitamin B12 levels were lower in patients with DAT and patients with histologically confirmed AD than in controls. The odds ratio of confirmed AD associated with a tHcy level in the top third (> or = 14 micromol/L) compared with the bottom third (< or = 11 micromol/L) of the control distribution was 4.5 (95% confidence interval, 2.2-9.2), after adjustment for age, sex, social class, cigarette smoking, and apolipoprotein E epsilon4. The corresponding odds ratio for the lower third compared with the upper third of serum folate distribution was 3.3 (95% confidence interval, 1.8-6.3) and of vitamin B12 distribution was 4.3 (95% confidence interval, 2.1-8.8). The mean tHcy levels were unaltered by duration of symptoms before enrollment and were stable for several years afterward. In a 3-year follow-up of patients with DAT, radiological evidence of disease progression was greater among those with higher tHcy levels at entry. Low blood levels of folate and vitamin B12, and elevated tHcy levels were associated with AD. The stability of tHcy levels over time and lack of relationship with duration of symptoms argue against these findings being a consequence of disease and warrant further studies to assess the clinical relevance of these associations for AD.

Plasma Homocysteine as a Risk Factor for Dementia and Alzheimer's Disease

Article

Full-text available

Mar 2002
NEW ENGL J MED

In cross-sectional studies, elevated plasma homocysteine levels have been associated with poor cognition and dementia. Studies of newly diagnosed dementia are required in order to establish whether the elevated homocysteine levels precede the onset of dementia or result from dementia-related nutritional and vitamin deficiencies. A total of 1092 subjects without dementia (667 women and 425 men; mean age, 76 years) from the Framingham Study constituted our study sample. We examined the relation of the plasma total homocysteine level measured at base line and that measured eight years earlier to the risk of newly diagnosed dementia on follow-up. We used multivariable proportional-hazards regression to adjust for age, sex, apolipoprotein E genotype, vascular risk factors other than homocysteine, and plasma levels of folate and vitamins B12 and B6. Over a median follow-up period of eight years, dementia developed in 111 subjects, including 83 given a diagnosis of Alzheimer's disease. The multivariable-adjusted relative risk of dementia was 1.4 (95 percent confidence interval, 1.1 to 1.9) for each increase of 1 SD in the log-transformed homocysteine value either at base line or eight years earlier. The relative risk of Alzheimer's disease was 1.8 (95 percent confidence interval, 1.3 to 2.5) per increase of 1 SD at base line and 1.6 (95 percent confidence interval, 1.2 to 2.1) per increase of 1 SD eight years before base line. With a plasma homocysteine level greater than 14 micromol per liter, the risk of Alzheimer's disease nearly doubled. An increased plasma homocysteine level is a strong, independent risk factor for the development of dementia and Alzheimer's disease.

Vitamin B 12 , Folate, and Homocysteine in Depression: The Rotterdam Study

Article

Full-text available

Jan 2003

The associations of vitamin B(12), folate, and homocysteine with depression were examined in a population-based study. 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. Hyperhomocysteinemia, vitamin B(12) deficiency, and to a lesser extent, folate deficiency were all related to depressive disorders. For folate deficiency and hyperhomocysteinemia, the association with depressive disorders was substantially reduced after adjustment for functional disability and cardiovascular disease, but for vitamin B(12) this appeared independent. The association of vitamin B(12) and folate with depressive disorders may have different underlying mechanisms. Vitamin B(12) may be causally related to depression, whereas the relation with folate is due to physical comorbidity.

Bjelland I, Tell GS, Vollset SE, Refsum H, Ueland PM. Folate, vitamin B12, homocysteine, and the MTHFR 677C->T polymorphism in anxiety and depression: the Hordaland Homocysteine Study. Arch Gen Psychiatry 40, 618-626

Article

Full-text available

Jun 2003
ARCH GEN PSYCHIAT

An association between depression and folate status has been demonstrated in clinical studies, whereas data are sparse on the relationship between depression and other components of 1-carbon metabolism such as vitamin B12, homocysteine, and the methylenetetrahydrofolate reductase 677C-->T polymorphism. The relationship between anxiety and these components is less well known. This study examined the associations between folate, total homocysteine, vitamin B12, and the methylenetetrahydrofolate reductase 677C-->T polymorphism, and anxiety and depression in a large population-based study. Anxiety and depression, measured by the Hospital Anxiety and Depression Scale, were assessed in 5948 subjects aged 46 to 49 years (mean, 47.4 years) and 70 to 74 years (mean, 71.9 years) from the Hordaland Homocysteine Study cohort. By means of logistic regression models, anxiety and depression scores were examined in relation to the factors listed above. Overall, hyperhomocysteinemia (plasma total homocysteine level > or =15.0 micro mol/L [> or =2.02 mg/dL]) (odds ratio, 1.90; 95% confidence interval, 1.11-3.25) and T/T methylenetetrahydrofolate reductase genotype (odds ratio, 1.69; 95% confidence interval, 1.09-2.62), but not low plasma folate or vitamin B12 levels, were significantly related to depression without comorbid anxiety disorder. Plasma folate level was inversely associated with depression only in the subgroup of middle-aged women. None of the investigated parameters showed a significant relationship to anxiety. Our results provide further evidence of a role of impaired 1-carbon metabolism in depression.

T2-weighted image hyperintensities in major depression: Focus on the basal ganglia

Article

Full-text available

Oct 2003

A major focus of attention in structural brain-imaging research in major depression is the increased prevalence of T2-weighted image 'hyperintensities' (T2-WIH). Our aims in this study were to characterize the distribution and magnetic resonance imaging (MRI) presentation of brain hyperintensities in major depression patients compared to healthy control subjects and to explore the association between the presence of T2-WIH and measures of clinical and cognitive state. Thirty-seven patients suffering from major depression and 27 age- and sex-matched healthy controls underwent brain MRI and were evaluated by the Hamilton Rating Scale for Depression, the Mini Mental State Examination and the Haschinsky Ischaemia Index. T2-WIH (at least one) were found in 26 out of 37 major depression patients and 7 out of 27 controls (p=0.0001). The number of brain T2-WIH was significantly and positively correlated with age in depressed (p=0.001) but not in healthy subjects. Mean volume of T2-WIH was significantly greater (p=0.004) in depressed subjects. In the control group T2-WIH were exclusively located in the supratentorial hemispheral white matter while in the depressed group T2-WIH were also found in basal ganglia, temporal lobe, cerebellum and brainstem. More (52 vs. 20%; p=0.018) T2-WIH were demonstrable on T1 in depressed subjects. Depressed patients with T2-WIH in basal ganglia were clearly the most severely depressed and cognitively impaired subjects, and may constitute a clinically distinct subgroup within major depression.

Lowering Homocysteine in Patients With Ischemic Stroke to Prevent Recurrent Stroke, Myocardial Infarction, and Death: The Vitamin Intervention for Stroke Prevention (VISP) Randomized Controlled Trial

Article

Full-text available

Feb 2004
J Am Med Assoc

In observational studies, elevated plasma total homocysteine levels have been positively associated with ischemic stroke risk. However the utility of homocysteine-lowering therapy to reduce that risk has not been confirmed by randomized trials. To determine whether high doses of folic acid, pyridoxine (vitamin B6), and cobalamin (vitamin B12), given to lower total homocysteine levels, reduce the risk of recurrent stroke over a 2-year period compared with low doses of these vitamins. Double-blind randomized controlled trial (September 1996-May 2003). 3680 adults with nondisabling cerebral infarction at 56 university-affiliated hospitals, community hospitals, private neurology practices, and Veterans Affairs medical centers across the United States, Canada, and Scotland. All participants received best medical and surgical care plus a daily multivitamin containing the US Food and Drug Administration's reference daily intakes of other vitamins; patients were randomly assigned to receive once-daily doses of the high-dose formulation (n = 1827), containing 25 mg of pyridoxine, 0.4 mg of cobalamin, and 2.5 mg of folic acid; or the low-dose formulation (n = 1853), containing 200 microg of pyridoxine, 6 microg of cobalamin and 20 microg of folic acid. Recurrent cerebral infarction (primary outcome); coronary heart disease (CHD) events and death (secondary outcomes). Mean reduction of total homocysteine was 2 micromol/L greater in the high-dose group than in the low-dose group, but there was no treatment effect on any end point. The unadjusted risk ratio for any stroke, CHD event, or death was 1.0 (95% confidence interval [CI], 0.8-1.1), with chances of an event within 2 years of 18.0% in the high-dose group and 18.6% in the low-dose group. The risk of ischemic stroke within 2 years was 9.2% for the high-dose and 8.8% for the low-dose groups (risk ratio, 1.0; 95% CI, 0.8-1.3) (P =.80 by log-rank test of the primary hypothesis of difference in ischemic stroke between treatment groups). There was a persistent and graded association between baseline total homocysteine level and outcomes. A 3- micromol/L lower total homocysteine level was associated with a 10% lower risk of stroke (P =.05), a 26% lower risk of CHD events (P<.001), and a 16% lower risk of death (P =.001) in the low-dose group and a nonsignificantly lower risk in the high-dose group by 2% for stroke, 7% for CHD events, and 7% for death. In this trial, moderate reduction of total homocysteine after nondisabling cerebral infarction had no effect on vascular outcomes during the 2 years of follow-up. However, the consistent findings of an association of total homocysteine with vascular risk suggests that further exploration of the hypothesis is warranted and longer trials in different populations with elevated total homocysteine may be necessary.

Selhub J, Jacques PF, Wilson PW, Rush D, Rosenberg IHVitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA 270:2693-2698

Article

Dec 1993

Jacob Selhub

Objective —To describe the distribution of plasma homocysteine concentrations in an elderly population and to analyze the relationship between homocysteine level and intake of vitamins and serum levels of vitamins that serve as coenzymes in homocysteine metabolism. Design —Cross-sectional analysis of homocysteine levels and vitamin blood levels and intake in elderly participants in the Framingham Study. Setting —Population-based cohort in Framingham, Mass. Participants —A total of 1160 adult survivors, aged 67 to 96 years, from the original Framingham Heart Study cohort. Main Outcome Measures —Plasma homocysteine concentration correlated with plasma folate, vitamin B12, pyridoxal-5'-phosphate (PLP), and oral intakes of these vitamins, and the contribution of these vitamins to the prevalence of elevated homocysteine in the population. Results —Homocysteine levels were positively correlated with age after controlling for vitamin concentrations. After controlling for age, sex, and levels of other vitamins, homocysteine exhibited a strong inverse association with plasma folate. When subjects were grouped by deciles of plasma folate, mean homocysteine was significantly higher in the lowest two folate deciles (15.6 and 13.7 μmol/L, respectively) than in the highest decile (11.0 μmol/L). Homocysteine demonstrated weaker, inverse associations with plasma vitamin B12 and PLP. Similar inverse associations were demonstrated between homocysteine and intakes of folate and vitamin B6, but not vitamin B12. Prevalence of high homocysteine (>14 μmol/L) was 29.3% in this cohort, and was greatest among subjects with low folate status. Inadequate plasma concentrations of one or more B vitamins appear to contribute to 67% of the cases of high homocysteine. Conclusions —These results indicate a strong association between homocysteine concentration and folate, vitamin B12, and vitamin B6 status, as well as age. It is possible that a substantial majority of the cases of high homocysteine in this older population can be attributed to vitamin status.(JAMA. 1993;270:2693-2698)

Distribution and Correlates of Elevated Total Homocyst(e)ine

Article

Jul 1999
ANN EPIDEMIOL

PURPOSE: To determine the distribution and correlates of elevated total homocyst(e)ine (tHcy) concentration in a population of premenopausal black and white women.METHODS: Data from the Stroke Prevention in Young Women Study (N = 304), a population-based study of risk factors for stroke in women aged 15–44 years of age, were used to determine the distribution and correlates of elevated tHcy in black (N = 103) and white women (N = 201).RESULTS: The mean tHcy level for the population was 6.58 μmol/L (range 2.89–26.5 μmol/L). Mean tHcy levels increased with age, cholesterol level, alcohol intake, and number of cigarettes smoked (all: p < 0.05). There were no race differences (mean tHcy 6.72 μmol/L among blacks and 6.51 μmol/L among whites; p = 0.4346). Regular use of multivitamins and increasing education was associated with significant reductions in tHcy concentration. Approximately 13% of the sample had elevated tHcy levels, defined as a tHcy concentration ⩾ 10.0 μmol/L. Multivariate-adjusted correlates of elevated tHcy included education > 12 vs. ⩽ 12 (odds ratio [OR] = 0.4, 95% confidence interval [CI] = 0.2–0.8); smoking ⩾ 20 cigarettes/day vs. nonsmokers (OR = 2.8, 95% CI = 1.1–7.3); and the regular use of multivitamins (OR = 0.4, 95% CI = 0.2–0.9).CONCLUSIONS: These results suggest that a substantial proportion of healthy young premenopausal women have tHcy levels that increase their risk for vascular disease. A number of potentially modifiable behavioral and environmental factors appear to be significantly related to elevated tHcy levels in young women.

Homozygous thermolabile variant of the methylenetetrahydrofolate reductase gene: A potential risk factor for hyperhomocysteinaemia, CVD, and stroke in childhood

Article

Apr 2001
DEV MED CHILD NEUROL

In this study of 118 children (median age 5.1 years; range 6 months to 17 years) with ischaemic stroke or transient ischaemic attack (TIA), 22 children (19%) were homozygous for the thermolabile variant of the methylenetetrahydrofolate reductase allele (t-MTHFR), compared with nine of 78 (12%) of a reference population (p=0.18, OR 1.76, 95% CI 0.76 to 4.04). Of those with cerebrovascular disease (CVD), 17 of 84 were homozygous for the t-MTHFR allele (p=0.13 compared with the reference population (OR 1.95, 95% CI 0.81 to 4.65). There was a significant (p<0.025) increment of plasma total homocysteine concentration in homozygotes for the t-MTHFR allele compared with heterozygotes, negatives for the t-MTHFR allele, and control children with no history of stroke. In four of 12 homozygotes for the t-MTHFR allele, plasma homocysteine levels were raised, compared with three of 38 of those who were negative or heterozygous (p=0.047; OR 5.8, 95% CI 1.1 to 31.2). Homozygotes for the t-MTHFR allele were significantly more likely to have a recurrent event than those who were negative or heterozygous (Cox regression p=0.031, hazard ratio 2.18, 95% CI 1.08 to 4.42). These data suggest that homozygosity for the t-MTHFR allele is associated with raised homocysteine levels in children and is a risk factor for primary and secondary stroke and TIA.

Homocystine theory of arteriosclerosis

Article

Sep 1975
Atherosclerosis

Arteriosclerotic plaques were found in the aorta and arteries of rabbits given homocysteine thiolactone, methionine or homocysteic acid, both parenterally and in a synthetic diet. Animals given large doses of parenteral methionine or homocysteine thiolactone died of pulmonary embolism and pulmonary infarct. Pyridoxine prevented thrombosis and pulmonary embolism but did not prevent arteriosclerotic plaques. These findings and previous work, showing a new matabolic pathway for sulfate ester synthesis from methionine, the somatotrophic activity of homocysteic acid, and control of cellular growth and intercellular matrix synthesis by homocysteine derivatives, suggest a theory to explain aspects of the pathogenesis of arteriosclerosis.

Reduction of CSF monoamine metabolites in post-stroke depression

Article

Feb 1992

Monoamine metabolites were measured in the cerebrospinal fluid (CSF) of depressed and nondepressed patients with acute stroke lesions and in nondepressed patients without stroke lesions. Depressed stroke patients had a significantly lower concentration of CSF 5-hydroxyindoleacetic acid (5-HIAA; a serotonin metabolite) than the other two groups. These findings suggest that poststroke depression may be mediated by serotonergic mechanisms.

Enhancement of Recovery From Psychiatric Illness by Methylfolate

Article

Sep 1990

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.

Red cell folate concentrations in psychiatric patients

Article

Aug 1990
J AFFECT DISORDERS

Red cell folate and vitamin B12 estimations were performed on 243 successively admitted in-patients at a District General Hospital Psychiatric Unit and 42 out-patients (29 attending a lithium clinic). Patients were classified into five diagnostic groups. The mean ages of the manic and schizophrenic patients were lower than of the depressed or euthymic patients but age was not correlated with red cell folate or serum B12 levels in any group. There were 89 (31%) patients with red cell folate below 200 ng/ml and 35 (12%) with concentrations below 150 ng/ml. Significantly more of these low-folate patients were in-patients than out-patients. The mean red cell folate in the depressed patients was significantly lower than in the euthymic, manic and schizophrenic groups. Alcoholics had a similar mean red cell folate to depressed patients which was not quite significantly lower than the other groups. The mean serum B12 level in the alcoholics was, however, significantly raised. There were no significant differences in red cell folate or serum B12 between lithium-treated and untreated euthymic patients. The highest proportions of values below 200 ng/ml and 150 ng/ml were found in depressed and alcoholic patients. Endogenous depressives had the highest percentage of values below 150 ng/ml (folate-deficient) of all psychiatric groups and alcoholic patients. The significance of these findings is discussed.

Plasma homocysteine, a risk factor for premature vascular disease. Plasma levels in healthy persons; during pathologic conditions and drug therapy

Article

Feb 1989
Nord Med

Homocysteine is a branch-point metabolite, the biological fate of which is linked to vitamin B12, reduced folates and vitamin B6. Various inborn defects in homocysteine metabolism, among which cystathionine beta-synthase deficiency is most common, lead to the clinical condition homocystinuria. A central feature of this clinical state is premature arteriosclerosis. These patients benefit from agents serving as cofactors in homocysteine metabolism which both reduce the homocysteine levels in plasma and the incidence of vascular episodes. Experimental data point to homocysteine as an arteriosclerotic agent. Homocysteine in human plasma exists mainly as mixed disulfides with albumin (70 per cent) and cysteine. New methods determine total plasma homocysteine which includes all these species. Normal values for plasma homocysteine are lower in premenopausal women than in men and postmenopausal women. Impaired homocysteine metabolism seems to exist in 15-30 per cent of patients with premature cardiovascular disease. Moderate homocysteinemia is as a risk factor for cardiovascular disease, independent of conventional risk factors. Apart from homocystinuria, vitamin B12 deficiency causes the most extreme elevations of plasma homocysteine, and it has been established that plasma homocysteine is a more responsive parameter to impaired vitamin B12 function than serum cobalamin. Massive increase in plasma homocysteine level is also observed in folate deficiency, whereas renal failure, some malignant states and psoriasis cause a moderate homocysteinemia. High doses of folic acid reduce plasma homocysteine, and this innocuous mean should be considered as an intervention in patients with increased plasma level. Drugs like methotrexate, some anticonvulsants and 6-azauridine triacetate induce moderate elevation of plasma homocysteine, whereas a reduction is observed after penicillamine administration.(ABSTRACT TRUNCATED AT 250 WORDS)

S-adenosylmethionine treatment of depression: A controlled clinical trial

Article

Oct 1988

The antidepressant properties of S-adenosylmethionine, an endogenous methyl donor, were studied in inpatients who met the DSM-III criteria for major depression. Nine patients given intravenous S-adenosylmethionine and nine given low oral doses of imipramine were compared in a double-blind design for 14 days. The S-adenosylmethionine produced superior results by the end of the first week of treatment. By the end of the second week, 66% of the S-adenosylmethionine patients had a clinically significant improvement in depressive symptoms, compared to 22% of the imipramine patients. Side effects appeared to be fewer with S-adenosylmethionine than with imipramine during the last 5 days of the study.

Leukoencephalopathy in Elderly Depressed Patients Referred for ECT

Article

Jul 1988
BIOL PSYCHIAT

Using brain magnetic resonance imaging (MRI) and high-resolution computed tomography (CT), we identified changes in the subcortical white matter in 44 of 67 elderly depressed inpatients (66%) referred for electroconvulsive therapy (ECT). This "leukoencephalopathy" was frequently associated with other structural brain changes, including cortical atrophy, lateral ventricular enlargement, and lacunar infarctions of the basal ganglia and thalamus. Many (58%) of the patients had developed late-onset depressive disorders, and the majority (86%) had been refractory to and/or intolerant of antidepressant drug therapy. Nevertheless, all but 1 of the 44 patients subsequently responded to a course of ECT, which in general was well tolerated. Although the precise etiology of the leukoencephalopathy remains unclear, clinical data suggest that it may result from arteriosclerotic disease of the medullary arteries that supply the subcortical brain regions. Several lines of evidence suggest that leukoencephalopathy may have implications for the pathophysiology of depressive illness, at least in some elderly patients.

Folic acid, S-adenosylmethionine and affective disorder

Article

Dec 1983

Kinetic studies on the O-methylation of dopamine by human brain membrane-bound catechol-O-methyltransferase

Article

May 1982

Km values for dopamine and S-adenosylmethionine (AdoMet) of human brain membrane-bound catechol O-methyltransferase are 3.3 microM and 3.1 microM, respectively. S-Adenosylhomocysteine is a very potent competitive inhibitor with respect to AdoMet with a Ki value of 1 microM. Product inhibition patterns strongly support a steady-state compulsory-order ternary complex mechanism in which AdoMet binds to the enzyme before dopamine. Inhibition of membrane-bound COMT by tropolone is competitive with respect to dopamine (Ki = 5 microM) and uncompetitive with respect to AdoMet and is consistent with this type of mechanism. The mechanism proposed is different from that suggested for soluble catechol O-methyltransferases.

Enhancement of the antidepressant action of fluoxetine by folic acid: A randomised, placebo controlled trial

Article

Nov 2000
J AFFECT DISORDERS

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. 127 patients were randomly assigned to receive either 500 microg folic acid or an identical looking placebo in addition to 20 mg fluoxetine daily. All patients met the DSM-III-R criteria for major depression and had a baseline Hamilton Rating Scale (17 item version) score for depression of 20 or more. Baseline and 10-week estimations of plasma folate and homocysteine were carried out. Patients receiving folate showed a significant increase in plasma folate. This was less in men than in women. Plasma homocysteine was significantly decreased in women by 20.6%, but there was no significant change in men. Overall there was a significantly greater improvement in the fluoxetine plus folic acid group. This was confined to women where the mean Hamilton Rating Scale score on completion was 6.8 (S.D. 4. 1) in the fluoxetine plus folate group, as compared to 11.7 (S.D. 6. 7) in the fluoxetine plus placebo group (P<0.001).A percentage of 93. 9 of women, who received the folic acid supplement, showed a good response (>50% reduction in score) as compared to 61.1% of women who received placebo supplement (P<0.005). Eight (12.9%) patients in the fluoxetine plus folic acid group reported symptoms possibly or probably related to medication, whereas in the fluoxetine plus placebo group 19 (29.7%) patients reported such symptoms (P<0.05). 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.

Hyperhomocysteinemia and inflammatory bowel disease: Prevalence and predictors in a cross-sectional study

Article

Aug 2001

Homocysteine is a sulfur-containing amino acid formed during the demethylation of methionine. Vitamin B12 and folate deficiency and therapy with antifolate drugs may predispose patients with inflammatory bowel disease (IBD) to hyperhomocysteinemia. The known associations between hyperhomocysteinemia and smoking, osteoporosis, and thrombosis make it an interesting candidate as a pathogenetic link in IBD. The aim of this study was to identify the prevalence and risk factors of hyperhomocysteinemia in patients with IBD. Sixty-five consecutive IBD patients were recruited from a tertiary outpatient gastroenterology practice. Fasting plasma homocysteine levels were measured, along with vitamin B12 and folate. Data regarding medication use, multivitamin use, disease location and severity, and extraintestinal manifestations of IBD were gathered. Homocysteine levels in 138 healthy control subjects were compared with the IBD cohort, and adjustments for age and sex were made using logistic regression. Multivariate analysis was performed to seek predictors of homocysteine levels. The mean age in the IBD cohort was 42+/-13.4 yr (+/-SD), and 43% were male. The mean disease duration was 13.8+/-9.4 yr, and 32% had used steroids within the last 3 months. Immunomodulator therapy had been used in 32%, and 75% had had an intestinal resection. Osteoporosis was present in 33% of patients. Five patients had experienced venous thrombosis or stroke, but only one of these had hyperhomocysteinemia. Of the 10 IBD patients (15.4%) with hyperhomocysteinemia, only two had vitamin B12 deficiency. The homocysteine levels in the IBD cohort cases and controls were 8.7 and 6.6 micromol/L, respectively (p < 0.05). IBD significantly increased the risk of hyperhomocysteinemia (adjusted odds ratio = 5.9 [95% CI: 1.5-24]). Advanced age, male sex, vitamin B12 deficiency or lower vitamin B12 serum levels, and multivitamin therapy were independently associated with higher homocysteine levels in the multivariate analysis (R2 = 0.55; p = 0.001). Hyperhomocysteinemia is significantly more common in patients with IBD compared with healthy controls, and is associated with lower (but not necessarily deficient) vitamin B12 levels.

Depressive Disorder, Dysthymia, and Risk of Stroke Thirteen-Year Follow-Up From the Baltimore Epidemiologic Catchment Area Study

Article

Oct 2001
STROKE

This study examined depressive disorder as a risk factor for incident stroke in a prospective, population-based design. The Baltimore Epidemiologic Catchment Area Study is a prospective 13-year follow-up of a probability sample of household residents from Baltimore, Md. Depressive disorder was measured with the diagnostic interview schedule, and stroke was assessed by questions from the health interview survey or by documentation on a death certificate. During the 13-year follow-up of 1703 individuals, 66 strokes were reported and 29 strokes were identified by death certificate search. Individuals with a history of depressive disorder were 2.6 times more likely to report stroke than those without this disorder after controlling for heart disease, hypertension, diabetes, and current and previous use of tobacco. Medications used in the treatment of depressive disorder at baseline did not alter this finding. A history of dysthymia demonstrated a similar relationship to stroke, although the estimate was not statistically significant. Depressive disorder is a risk factor for stroke that appears to be independent of traditional cardiovascular risk factors. Further research on mechanisms for the association and the impact of treatment for depressive disorder on subsequent stroke is needed.

Hyperhomocysteinemia and related factors in 600 hospitalized elderly subjects

Article

Dec 2001
METABOLISM

Hyperhomocysteinemia (HHcy) is a metabolic disorder frequently occurring in the elderly population. Recently several reports have suggested abnormalities in homocysteine (tHcy) metabolism implicating HHcy as a metabolic link in the multifactorial processes characterizing many geriatric illnesses-with special emphasis on atherosclerotic vascular diseases and cognitive impairment. The present study was undertaken in a large sample of elderly hospitalized subjects to determine (1) the prevalence of HHcy, (2) the association of HHcy with vascular and cognitive disorders, and (3) the factors independently predicting Hhcy. Six hundred elderly subjects (264 men and 336 women; mean age, 79 +/- 9 years) were randomly chosen from those admitted as inpatients over a period of 3 years. In all patients, body mass index (BMI), mid-upper arm muscle area (MUAMA), plasma cholesterol, triglycerides, total proteins, albumin, lymphocyte count, creatinine, homocysteine (fasting and 4 hours after methionine oral load), serum vitamin B(6), vitamin B(12), and folate concentrations were measured. The presence of disease or use of medications known to affect homocysteine plasma levels were also recorded. The mean fasting tHcy level was 16.8 +/- 12 micromol/L in the whole sample, 18.18 +/- 13.25 micromol/L in men, and 15.86 +/- 12.14 micromol/L in women (P =.005 men v women). The mean Hcy level 4 hours after methionine load was 37.95 +/- 20.9 in the whole sample. Prevalence of hyperhomocysteinemia (fasting Hcy > or = 15 micromol/L or 4 hours after methionine load > or = 35 micromol/L) was 61% (365/600) (67% in men and 56% in women, P <.05). HHcy was rarely (8%) an isolated disorder; in addition to diabetes (20%), renal failure (48.2%), and malnutrition (20.2%), it was often associated with heart failure (30%), malignancies (20.5%), and the use of diuretics (56%) and anticonvulsant drugs (13%). Plasma homocysteine progressively increases across subjects from those with no diabetes, malnutrition, renal failure, obesity, inflammatory bowel disease, heart failure to those with 1, 2, or more concurrent diseases. Multiple stepwise regression analysis showed that 72% of plasma total fasting tHcy variability was explained by age, serum folate, plasma albumin, use of diuretics, and renal function (measured as plasma creatinine clearance). In conclusion, the present study documents that hyperhomocysteinemia, in elderly hospitalized patients is (1) a common finding, (2) frequently associated with vascular and cognitive disorders, and (3) probably a secondary phenomenon in most cases. The major predictor of high plasma homocysteine levels were age, serum folate, plasma albumin, plasma creatinine clearance, and use of diuretic drugs. These variables explain a large proportion of plasma Hcy variability.

Cognitive Dysfunction in Recovered Depressive Patients with Silent Cerebral Infarction

Article

Feb 2002

In this study, we characterized cognitive functioning in patients with major depression and silent cerebral infarction (SCI), as detected by magnetic resonance imaging (MRI), after they had recovered from depression. Thirty-five patients with unipolar depression who experienced the onset of depression after the age of 50 underwent MRI and were classified as SCI(+) (n = 17) or SCI(-) (n = 18). The Wechsler Adult Intelligence Scale-Revised (WAIS-R) and the Uchida-Kraepelin psychodiagnostic test were administered after the patients had recovered from depression. In addition, the intelligence quotient (IQ) and mental speed of the patients in the two groups were compared. The total, verbal and performance IQ scores, as determined by the WAIS-R, were significantly lower in the SCI(+) group than in the SCI(-) group. The mental speed of patients in the SCI(+) group, as assessed by the Uchida-Kraepelin psychodiagnostic test, was almost half that of the SCI(-) group. Our findings provide further evidence that a comprehensive impairment of cognitive functioning, especially a severe reduction in mental speed, remains after recovery from depression in patients with major depression and SCI.

Homocysteine, silent brain infarcts, and white matter lesions: The Rotterdam Scan Study

Article

Mar 2002

Silent brain infarcts and white matter lesions are frequently seen on magnetic resonance imaging in healthy elderly people and both are associated with an increased risk of stroke and dementia. Plasma total homocysteine may be a potentially modifiable risk factor for stroke and dementia. We examined whether elevated total homocysteine levels are associated with silent brain infarcts and white matter lesions. The Rotterdam Scan Study is a population-based study of 1,077 people aged 60 to 90 years who had cerebral magnetic resonance imaging. The cross-sectional relation of total homocysteine with silent infarcts and white matter lesions was analyzed with adjustment for cardiovascular risk factors. The mean plasma total homocysteine level was 11.5 micromol/l (standard deviation 4.1). The risk of silent brain infarcts increased with increasing total homocysteine levels (odds ratio 1.24/standard deviation increase, 95% confidence interval 1.06-1.45). The severity of periventricular white matter lesions and extent of subcortical white matter lesions were also significantly associated with total homocysteine levels, even after excluding those with silent brain infarcts. The overall risk of having either a silent brain infarct or severe white matter lesions was strongly associated with total homocysteine levels (odds ratio 1.35/standard deviation increase, 95% confidence interval 1.16-1.58). We concluded that total homocysteine levels are associated with silent brain infarcts and white matter lesions independent of each other and of other cardiovascular risk factors.

Association of Plasma Homocysteine Concentration With Atherosclerotic Carotid Plaques and Lacunar Infarction

Article

Jul 2002
STROKE

Higher plasma total homocysteine (tHcy) levels have been associated with carotid atherosclerosis and cerebral infarction in whites. However, data regarding such associations are limited for Asians. This study examined associations between tHcy levels and severity of carotid atherosclerosis in Japanese subjects. Additionally, because lacunar infarction is the most prevalent type of ischemic stroke in Japan, we also investigated its associations with tHcy levels. The subjects were 152 Japanese patients (age, 66.2+/-11.0 years) at our hospital. Using ultrasound, we evaluated severity of carotid atherosclerosis by plaque score, which is defined by the sum of all plaque (intima-media thickness > or =1.1 mm) height in bilateral carotid arteries. In 112 of 152 patients, the existence of lacunar infarction was evaluated on brain MRI scans. A moderate linear association was found between tHcy levels and plaque score (r=0.48, P<0.0001). Moreover, tHcy level was associated with plaque score (beta=0.26, P<0.001) independently of traditional atherosclerotic risk factors. In logistic regression analyses, each 1-micromol/L-higher tHcy level was associated with a 1.37-fold-higher [95% confidence interval (CI), 1.19 to 1.58] likelihood for lacunar infarction, increasing the likelihood by 1.22-fold (95% CI, 1.04 to 1.43) independently of traditional atherosclerotic risk factors. Higher tHcy levels appear to have associations with increased severity of carotid atherosclerotic plaques and prevalent lacunar infarction in the Japanese. Larger prospective studies are necessary to establish whether higher tHcy levels serve as a harbinger for insidious carotid and cerebrovascular diseases.

Catechol-O-Methyltransferase (COMT)-Mediated Methylation Metabolism of Endogenous Bioactive Catechols and Modulation by Endobiotics and Xenobiotics: Importance in Pathophysiology and Pathogenesis

Article

Jul 2002

Bao Ting Zhu

The metabolic O-methylation of endogenous catecholamines and other catechols catalyzed by catechol-O-methyltransferase (COMT; EC 2.1.1.6) was first described by Dr. Julix Axelrod and his colleagues almost half a century ago. In the past several years, research interest in this catechol-metabolizing system has been renewed because of its potential pathophysiological and pathogenic significance in estrogen-induced hormonal cancers, in the development of degenerative brain disorders, as well as in the development of cardiovascular diseases. In this review paper, I provide a brief overview of the COMT metabolic system, with particular attentions being paid to the following three areas: (i) the regulation of this catechol-metabolizing system by endogenous regulatory factors (mainly S-adenosyl-L-homocysteine and homocysteine) as well as by exogenous factors such as dietary phytochemicals; (ii) decreased metabolic O-methylation of endogenous catecholamines as an important risk factor for the development of neurodegenerative disorders such as Parkinson's and Alzheimer's diseases in the elderly and also as a risk factor for the development of a variety of cardiovascular diseases; and (iii) the relative importance of the COMT-catalyzed O-methylation metabolism of endogenous catechol estrogens in the causation and prevention of estrogen-induced hormonal cancers. Some unifying hypotheses are also discussed in this paper with the hope that they may provide useful mechanistic insights into our understanding of the biological functions that are associated with this important metabolic system.

Anatomic location and laterality of MRI signal hyperintensities in late-life depression

Article

Sep 2002
J PSYCHOSOM RES

Evidence is mounting linking cerebrovascular disease with the development of major depression in the elderly. Lesions in both white and gray matter have been associated with geriatric depression. In addition, the literature on poststroke depression suggests that left-sided lesions are associated with depression. We sought to examine the severity and location of white- and gray-matter lesions in a group of elderly depressives and nondepressed control subjects. 115 depressed patients (69 with late onset, 46 with early onset) and 37 controls, all over age 45, received magnetic resonance imaging (MRI). Semiquantitative severity ratings and quantitative measurements of number and size of MRI hyperintensities were obtained, and groups were compared using Cochran-Mantel-Haenszel (CMH) analyses and repeated-measures analyses of covariance adjusting for age. Late-onset depressed patients had more severe hyperintensity ratings in deep white matter than early-onset patients and controls. Late- and early-onset patients had more severe subcortical gray-matter hyperintensities (particularly in the putamen) compared with controls. Left-sided white-matter lesions were significantly associated with older age of depression onset, whereas right-anterior white matter and left-subcortical lesions (particularly in the putamen) were associated with melancholia in the depressed group. These findings extend previous reports of an association between cerebrovascular disease and depression, as well as recent studies showing lateralized lesion involvement in geriatric depression. Such vascular pathology may disrupt neural pathways involved in affective processing and the maintenance of a normal mood and psychomotor state.

Ischemic Basis for Deep White Matter Hyperintensities in Major Depression: A Neuropathological Study

Article

Sep 2002
ARCH GEN PSYCHIAT

White matter hyperintensities on magnetic resonance imaging are increased in major depression in the deep white matter, especially in frontal areas. These lesions have been hypothesized to be ischemic in origin, but there have been no previous neuropathological studies in depression. We investigated the neuropathological basis of these lesions in depression, hypothesizing that they would be more frequently ischemic in origin in depressed subjects. We carried out in vitro magnetic resonance imaging on 3 slices of brain tissue (2 frontal, 1 occipital) from 20 elderly subjects who had a history of major depression and 20 elderly controls. The films were blindly rated, and sections were prepared for neuropathological analysis from the same slices and stained conventionally and by means of immunohistochemistry for microglia, macrophages, and astroglia. Lesions on the films were identified in the tissue, blindly described neuropathologically, and subsequently divided into ischemic and nonischemic lesions. All the deep white matter hyperintensities in the depressed group were found to be ischemic, compared with less than a third of those in the control group, a highly significant difference (P<.001). This difference was due to smaller punctate lesions (<3 mm), which were predominantly ischemic in depressed subjects but not in control subjects. Larger lesions were usually ischemic in both groups. Compared with control subjects, ischemic lesions were significantly more likely to be in the dorsolateral prefrontal cortex compared with the anterior cingulate cortex (P =.003) and the occipital cortex (P =.01) in the depressed subjects. Deep white matter hyperintensities are more frequently due to cerebral ischemia, and such ischemic lesions are more frequently located at the level of dorsolateral prefrontal cortex in depressed subjects. Our findings strongly support the "vascular depression" hypothesis of late-life depression.

Mattson, M. P. & Shea, T. B. Folate and homocysteine metabolism in neural plasticity and neurodegenerative disorders. Trends Neurosci. 26, 137-146

Article

Apr 2003
TRENDS NEUROSCI

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

Depression and Folate Status in the US Population

Article

Mar 2003

Folate deficiency and low folate status have been linked in clinic studies to depression, persistent depressive symptoms, and poor antidepressant response. These relationships have not been demonstrated in general populations. This study examined associations between depression and folate status indicators in an ethnically diverse general US population sample aged 15-39 years. 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. 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. 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.

Antihypertensive treatment and homocysteine concentrations

Article

Apr 2003
METABOLISM

Thiazides and angiotensin-converting enzyme (ACE) inhibitors are first-choice drugs for lowering elevated blood pressure and hence risk of cardiovascular disease. Homocysteine (tHcy) is another and independent cardiovascular risk factor and has been reported to be elevated in patients on antihypertensive therapy. As these studies reported only associations, a preliminary, randomized, prospective treatment study was performed in 40 hypertensive patients. We investigated the major determinants of tHcy concentrations after treatment with hydrochlorothiazide (HCT) or captopril: vitamins B6, B12, folic acid, and creatinine and cystatin C as parameters of renal function. A total of 21 Patients were treated with HCT and 19 with captopril, for, respectively, 31 and 29 days. HCT, but not captopril, raised tHcy by 16% (P =.003) and also creatinine and cystatin C (P =.025 and P =.004, respectively). This tHcy increase may offset the desired cardioprotection conferred by lowering the blood pressure.

MTHFR Gene Polymorphism as a Risk Factor for Silent Brain Infarcts and White Matter Lesions in the Japanese General Population: The NILS-LSA Study

Article

May 2003
STROKE

Silent brain infarcts (SBI) and white matter lesions are relatively common neuroimaging findings, especially in the elderly population. The genetic background for SBI and white matter lesions in a large Japanese general population was investigated. Subjects were recruited from participants in the National Institute for Longevity Sciences, Longitudinal Study of Aging. Genotyping of methylenetetrahydrofolate reductase (MTHFR) C677T gene mutation and brain MRI examination were performed in 1721 subjects free of any history of stroke. SBI and white matter lesions were diagnosed from MRI findings. Of 1721 MRI examinations, SBI was observed in 178 (10.3%). The prevalence of SBI and white matter lesions increased with age. The prevalence of SBI was significantly higher in subjects with the MTHFR TT genotype compared with the TC+CC genotype (14.6% versus 9.5%; 42 of 288 versus 136 of 1433; chi2=6.71; P=0.010). The stage of white matter lesions was not significantly different. In subjects >or=60 years of age (n=849), the prevalence of SBI was significantly higher in TT than TC+CC (27.7% versus 16.6%; 36 of 130 versus 119 of 719; chi2=9.16; P=0.002). The prevalence of moderately advanced white matter lesions was also significantly higher in TT than TC+CC (60.7% versus 49.0%; 79 of 130 versus 352 of 719; chi2=9.16; P=0.002). After correction for other risk factors, the MTHFR TT genotype was independently associated with SBI (odds ratio [OR], 1.72; 95% CI, 1.10 to 2.68; P=0.018) and moderately advanced white matter lesions (OR, 1.58; 95% CI, 1.07 to 2.33; P=0.02). These findings indicate that the MTHFR TT genotype is an independent risk factor for SBI and white matter lesions in the general Japanese population, especially in elderly subjects.

Homocysteine, renal function, and risk of cardiovascular disease

Article

Jun 2003
Kidney Int Suppl

Patients with renal impairment have markedly elevated homocysteine levels and are at particularly high risk of ischemic heart disease (IHD) and stroke, but the relevance of elevated homocysteine levels in this population is uncertain. We examined the association with IHD from a meta-analysis of 30 population studies of differences in homocysteine concentrations (involving 5000 IHD and 1100 stroke events in apparently healthy individuals), and from a meta-analysis of 40 studies (involving 11,000 IHD events) of the association of methylene-tetrahydrofolate reductase (MTHFR) and homocysteine with IHD. We explored the association of renal function with homocysteine levels in a cross-sectional study of 1200 healthy elderly individuals. Among prospective studies, a 25% lower blood homocysteine level was associated with an 11% lower risk of IHD and about a 20% lower risk of stroke, after adjustment for known cardiovascular risk factors. Individuals who had the TT genotype for MTHFR compared with those with CC had 25% higher homocysteine levels and a 16% higher risk of IHD. Among individuals aged over 65 years, a 1% higher serum creatinine level was associated with about a 1% higher homocysteine concentration. The concordance of the IHD risks obtained in the studies of genetically determined differences in homocysteine and the population-based studies of homocysteine suggest that these associations are likely to be causal. Renal function is an important determinant of circulating homocysteine concentrations. Results of ongoing randomized trials of folic acid-based vitamins in patients with renal disease are required to clarify the relevance of lowering homocysteine for vascular disease.

Poststroke depression: Prevalence, diagnosis, treatment, and disease progression

Article

Sep 2003
BIOL PSYCHIAT

Robert G. Robinson

In recent years, poststroke depression has attracted worldwide interest. This review focuses on the major research themes that have emerged. Pooled data from studies conducted throughout the world have found prevalence rates for major depression of 19.3% among hospitalized patients and 23.3% among outpatient samples. The diagnosis of poststroke depression is most appropriately based on a structured mental state exam and DSM-IV criteria for depression due to stroke with major depressive-like episode or depressive features. Rarely, poststroke patients may also develop bipolar mood disorder. The treatment of poststroke depression has been examined in several placebo-controlled randomized clinical trials with both nortriptyline and citalopram showing efficacy. The progression of recovery following stroke can be altered by treating depression, which has been shown to improve recovery in activities of daily living and cognitive impairment and to decrease mortality. In addition, two studies have demonstrated that poststroke depression can be prevented using antidepressant medication, which also decreases the frequency of associated physical illness. Furthermore, two studies have shown that premorbid depression can significantly increase the risk of stroke over the subsequent 10-15 years. The mechanisms underlying the association of cerebrovascular diseases and mood disorder are important areas for future investigation.

Elevated Plasma Homocysteine Was Associated With Hemorrhagic and Ischemic Stroke, but Methylenetetrahydrofolate Reductase Gene C677T Polymorphism Was a Risk Factor for Thrombotic Stroke: A Multicenter Case-Control Study in China

Article

Sep 2003
STROKE

It is still controversial whether elevated plasma homocysteine and the C677T polymorphism of methylenetetrahydrofolate reductase (MTHFR) gene are risk factors for stroke. The aim of the present study was to investigate the association between the 2 factors and stroke in Chinese in a large case-control study. We recruited 1823 stroke patients (807 cerebral thrombosis, 513 lacunar infarction, 503 intracerebral hemorrhage) and 1832 controls. Total plasma homocysteine was determined by high-performance liquid chromatography. C677T polymorphism was genotyped by polymerase chain reaction and HinfI digestion. Total plasma homocysteine levels were significantly higher in cases than controls (median, 14.7 versus 12.8 micromol/L; P<0.001) and associated with an increased risk of 1.87-fold (95% confidence interval [CI], 1.58 to 2.22) for overall stroke, 1.72-fold (95% CI, 1.39 to 2.12) for cerebral thrombosis, 1.89-fold (95% CI, 1.50 to 2.40) for lacunar infarction, and 1.94-fold (95% CI, 1.48 to 2.55) for intracerebral hemorrhage. The C677T mutation of the MTHFR gene was positively correlated with plasma homocysteine levels in both controls (beta=0.250, P<0.001) and cases (beta=0.272, P<0.001) and more frequently in cases than in controls (47.0% versus 44.2%, P=0.017). The TT genotype was associated with an increased risk for overall stroke (odds ratio, 1.27; 95% CI, 1.04 to 1.56) and thrombotic stroke (odds ratio, 1.37; 95% CI, 1.06 to 1.78). The C677T polymorphism of the MTHFR gene was associated with increased risk of cerebral thrombotic stroke in Chinese. Total plasma homocysteine was correlated with both ischemic and hemorrhagic stroke, suggesting potential initiation of homocysteine-lowering therapy in this population.

Homocystinuria studies of 20 families with 38 affected members

Article

Sep 1965

White matter hyperintensities in bipolar and unipolar patients with relatively mild-to-moderate illness severity

Article

Jan 2004
J AFFECT DISORDERS

Increased rates of white matter hyperintense lesions have been reported in mood disorder patients. However, the potential effects of age and illness severity on reported findings are not fully established. We examined the rates of hyperintense lesions in adult, non-elderly bipolar and unipolar patients, with a relatively mild-to-moderate illness severity, and in matched healthy controls. We examined brain MRI images in 24 bipolar (19-56 years, mean+/-S.D.=34.2+/-9.9 years) and 17 unipolar patients (24-59 years, 42.8+/-9.2 years), and 38 healthy controls (21-59 years, 36.8+/-9.7 years). T2-weighted and proton-density axial MRI images were obtained at 1.5 Tesla. The lesions were rated by two independent raters, using a semi-quantitative rating scale. There were no significant differences in the frequency of hyperintensities between bipolar or unipolar patients and healthy controls. Age was related to the presence of subcortical gray matter hyperintensities for the whole sample. Among the unipolar patients, length of illness and presence of mood disorder in a first-degree relative were related to deep and periventricular white matter lesions, respectively. The methodology utilized for measurement of the white matter hyperintensities was semi-quantitative. Increased rates of white matter hyperintensities do not appear to be present in a group of relatively young mood disorder patients, with relatively mild to moderate illness severity. These brain lesions may be more directly related to late-life and more severe cases of these illnesses.

Homozygous C677T mutation in the MTHFR gene as an independent risk factor for multiple small-artery occlusions

Article

Feb 2003
THROMB RES

Hyperhomocysteinemia is an independent risk factor for cerebrovascular disease and the homozygous C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene can induce hyperhomocysteinemia. However, the association between this 677TT genotype and ischemic stroke still remains controversial. Therefore, we carried out this study to determine whether the MTHFR TT genotype is associated with certain subtypes of ischemic stroke. We enrolled 195 ischemic stroke patients and 198 healthy individuals and checked their fasting plasma homocysteine levels and analyzed the C677T polymorphism in the MTHFR gene. Our findings concur with previous reports that stroke occurrence is associated with hyperhomocysteinemia, but not with the 677TT genotype. However, when we re-analyzed the data based on a subtype classification, the adjusted odds ratio (AOR) and 95% confidence intervals (CI) of the 677TT genotype were found to be significantly higher in patients with small-artery occlusion than that in controls (AOR, 2.92; 95% CI, 1.01-8.48). Moreover, the AOR of the 677TT genotype was found to be much bigger in patients with multiple small-artery occlusions (AOR, 6.90; 95% CI, 1.70-27.99), but not in those with single small-artery occlusion (AOR, 1.19; 95% CI, 0.27-5.35). The homozygous C677T mutation in the MTHFR gene is associated with multiple small-artery occlusions, but not with single small-artery occlusion. Our findings suggest a genetic basis for certain subtypes of ischemic stroke.

Association between factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations and events of the arterial circulatory system: A meta-analysis of published studies

Article

Jan 2004

The association between the inherited gene mutations of factor V, prothrombin, and homocysteine metabolism and venous thromboembolic events is accepted widely; however, their influence on the arterial circulatory system remains controversial. We performed a MEDLINE search to identify published case-control and cohort studies correlating the factor V Leiden, prothrombin (PT) G20210A, and methylenetetrahydrofolate reductase (MTHFR) C677T (TT genotype) mutations with myocardial infarction, ischemic stroke, or peripheral vascular disease. Studies were included only when they adhered to specific diagnostic criteria for ischemic events and met the published methodological criteria. Odds ratios (ORs) with accompanying 95% CIs were calculated for each mutation and clinical end points with a random-effects model (DerSimonian and Laird method). The association between inherited gene mutations and arterial ischemic events was modest: factor V Leiden mutation (OR, 1.21; 95% CI, 0.99-1.49), PT G20210A mutation (OR, 1.32; 95% CI, 1.03-1.69), and MTHFR TT mutation (OR, 1.20; 95% CI, 1.02-1.41). Subgroup analyses of younger patients (<55 years old) and of women revealed slightly stronger associations overall. Genetic abnormalities specific to factor V, prothrombin,and homocysteine metabolism increase the risk for myocardial infarction and ischemic stroke, particularly among younger patients and women. Because the overall association is only modest, screening studies should be limited to carefully selected patient populations. The individual propensity for arterial and venous thrombosis is likely influenced by differing local mechanisms, systemic mechanisms, or both.

Folate, Vitamin B6, and B12 Intakes in Relation to Risk of Stroke among Men

Article

Feb 2004
STROKE

Folate, vitamin B6, and B12 deficiency are related to elevated blood homocysteine level. However, the effects of intakes of these vitamins on risk of stroke are still uncertain. This study examines intakes of folate, vitamin B6, and B12 in relation to risk of ischemic and hemorrhagic stroke. We enrolled 43 732 men, aged 40 to 75 years, who were free of cardiovascular diseases and diabetes at baseline. Participants were followed from 1986 to 2000. Dietary information was assessed every 4 years using a detailed and validated semiquantitative food frequency questionnaire. The main outcome measures were incident ischemic and hemorrhagic strokes. A total of 725 incident strokes, including 455 ischemic, 125 hemorrhagic, and 145 unknown types of stroke, were documented during the 14-year follow-up. After adjustment for major lifestyle and dietary factors, intake of folate was associated with a significantly lower risk of ischemic but not hemorrhagic stroke. The multivariate relative risk of ischemic stroke was 0.71 (95% CI, 0.52 to 0.96; P for trend=0.05) for men in the highest quintile of intake compared with those who in the lowest quintile. Intake of vitamin B12, but not B6, was also inversely associated with risk of ischemic stroke. Our findings suggest that increased folate intake is associated with decreased risk of ischemic stroke in men.

Plasma Total Homocysteine Levels and Cranial Magnetic Resonance Imaging Findings in Elderly Persons: The Cardiovascular Health Study

Article

Feb 2004
ARCH NEUROL-CHICAGO

An elevated plasma total homocysteine (tHcy) level is associated with an increased risk of vascular disease. Some studies have shown associations between tHcy level and small-vessel disease of the brain on magnetic resonance imaging (MRI). In the Cardiovascular Health Study, 622 elderly participants without a history of transient ischemic attack or stroke had results for tHcy level and cranial MRI. We sought associations between tHcy level and MRI findings of ventricular grade, sulcal grade, white matter grade, and infarcts. We controlled for other factors, including levels of creatinine, folate, and vitamins B(6) and B(12) and methylenetetrahydrofolate reductase genotype. After controlling for age and sex, tHcy level was not associated with the individual MRI findings. Further adjustments for other factors and other blood tests had little effect on these findings. The only significant finding was a linear trend across quintiles of tHcy level and a pattern of MRI findings combining infarcts and high white matter grade. The linear trend remained significant after controlling for other risk factors and atherosclerotic markers (top quintile vs bottom quintile odds ratio, 3.3; 95% confidence interval, 0.96-11.20; P =.04 for linear trend) but was slightly diminished after further controlling for creatinine, folate, and vitamins B(6) and B(12) (odds ratio, 3.2; 95% confidence interval, 0.81-13.10; P =.07 for linear trend). We were unable to confirm the results of previous studies with respect to tHcy level and individual MRI findings, although an association was seen for an MRI pattern combining infarcts and high white matter grade.

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

Article

Apr 2004

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. 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. 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.

Clinical characteristics of magnetic resonance imaging-defined subcortical ischemic depression

Article

Mar 2004
BIOL PSYCHIAT

There is a substantial body of research supporting the vascular depression hypothesis of late-life depression. To update this hypothesis so it incorporates recent research, we propose that the term subcortical ischemic vascular depression may be a more accurate representation of the disease process. We sought to investigate this diagnosis as a construct by examining differences between depressed subjects with and without magnetic resonance imaging defined subcortical ischemic vascular depression. This case-control study examined 139 depressed elderly subjects. Demographic data, psychiatric, medical, and family history, depressive symptomatology, and functional impairment were compared between groups dichotomized based on neuroimaging findings. Seventy-five (54%) of the subjects met neuroimaging criteria for subcortical ischemic vascular depression. Age was most strongly associated with increased prevalence of subcortical ischemic vascular depression. Lassitude and a history of hypertension were also positively associated with the diagnosis; a family history of mental illness and loss of libido were negatively associated with the diagnosis. These data support that subcortical ischemic vascular depression may be a specific syndrome from other types of late-life depression. Further research is needed to further characterize this disorder, particularly in regards to cognitive function and treatment implications.

Distribution of total serum homocysteine and its association with parental history and cardiovascular risk factors at ages 12-16 years: The Third National Health and Nutrition Examination Survey

Article

Apr 2004
ANN EPIDEMIOL

R F Gillum

To describe the distribution and to assess the association of serum total homocysteine (tHcy) concentration with variables associated with insulin resistance syndrome in adolescent boys and girls. In the Third National Health and Nutrition Examination Survey, adolescents aged 12 to 16 years (n = 941) had parental medical history ascertained and glycated hemoglobin, systolic blood pressure, body mass index (BMI), body fat distribution, HDL cholesterol, and serum tHcy concentrations were measured. Cumulative distribution of serum tHcy in boys was shifted to the right compared with that in girls. A parental history of high blood pressure or stroke before age 50 was significantly positively associated with the subjects' log serum tHcy after adjustment for confounders (beta 0.156, p = 0.003). Log serum tHcy was significantly positively associated with systolic blood pressure in boys after adjustment for confounders (beta = 0.21, p = 0.03). Log serum tHcy was not significantly associated with glycated hemoglobin percent or most other risk factors other than age. Log serum tHcy concentration showed borderline significant (r = -0.15, p = 0.044) inverse association with BMI in girls. tHcy was associated with parental history of high blood pressure or stroke before age 50 and with systolic blood pressure in adolescent boys.

Folate Intake and Risk of Stroke Among Women

Article

Jul 2004
STROKE

Few studies have examined the association between folate intake and risk of stroke, although numerous studies have suggested that high levels of homocysteine are positively related to stroke. We aim to assess the relation between folate intake and stroke incidence among women participating in the Nurses' Health Study. 83,272 female nurses aged 34 to 59 years in 1980 and residing in 11 US states were followed-up for 18 years. Follow-up questionnaires were sent biennially to update information on diet and to identify newly diagnosed cases of stroke and other illnesses. During 1,379614 person-years of follow-up from 1980 to 1998, we identified 1140 incident cases of stroke. Using age-adjusted and multivariable-adjusted models, no appreciable association between the intake of folate and total incidence of stroke was observed [relative risk in the multivariable-adjusted model for the highest quintile of folate intake (median=696 microg/d) compared with the lowest quintile (median=158 microg/d) was 1.01 (95% confidence interval [CI]: 0.79 to 1.29), P for trend=0.8]. Similar null results were found in secondary analyses on stroke subtypes (ischemic, thrombotic, embolic, subarachnoid hemorrhage, intraparenchymal hemorrhage) and in analyses that separately assessed dietary folate (excluding supplement users) and folate supplement intake. Folate intake was not associated with incident stroke among women participating in the Nurses' Health Study.

MTHFR C677T Polymorphism and Its Relation to Ischemic Stroke in the Black Sea Turkish Population

Article

Jun 2004

The MTHFR C677T mutation has been shown to be associated with venous thrombosis. The role of this mutation in ischemic stroke is unclear. We investigated whether the MTHFR mutation is a risk factor for patients with ischemic stroke in the Black Sea Turkish population or not. We analyzed 30 patients (19 male, 11 female) [median age: 50 years (range: 28-78)] with ischemic stroke who had no known predisposition factors for stroke and 242 (182 male, 60 female) healthy controls [median age: 42 years (range: 18-65)]. Detection of the MTHFR C677T mutation was performed by using commercially available allele-specific PCR-ELISA kits. Prevalence of the MTHFR C677T genotype was 49.1% (CT, 45.8%; TT, 3.3%) in controls and 50% (CT, 43.3%; TT, 6.6%) in patients [OR: 1.03, 95% CI (0.45-2.35]). The prevalence of homozygous gene mutation for MTHFR was higher among patients with stroke than control subjects, but this difference was not statistically significant. The MTHFR gene mutation is not a risk factor for ischemic stroke formation in patients from the Black Sea region in Turkey.

The Homocysteine Hypothesis of Depression

Abstract

No full-text available

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