Review article
Homocysteine and folate metabolism in depression

https://doi.org/10.1016/j.pnpbp.2005.06.021Get rights and content

Abstract

Homocysteine is a sensitive marker of folate and vitamin B12 deficiency. Numerous studies have confirmed the association between folate deficiency and depression. It is not completely understood whether homocysteine is solely a marker for folate deficiency or if it may play a more direct role in the expression of mood disorders. This review describes the biochemical, neurochemical and clinical correlations of folate deficiency and hyperhomocysteinemia in relation to depression.

Introduction

Since the discovery of folate in 1945, and vitamin B12 in 1948 numerous reports have described the neuropsychiatric complications associated with deficiencies in these vitamins. There are similarities and differences in the clinical presentation observed in folate and vitamin B12 deficiency, which stem largely in part to their intimate metabolic relationship. The one central biochemical reaction that unifies folate and vitamin B12 metabolism involves the methylation of homocysteine (Hcy) to methionine, which is catalyzed by methionine synthetase (MS). Diminish activity of MS and the ensuing increase in Hcy can lead to severe metabolic consequences. High concentrations of Hcy are toxic not only to vascular endothelial cells (Austin et al., 2004, Weiss et al., 2002) but also to neuronal cells (Mattson and Shea, 2003, Parnetti et al., 1997). Elevated blood levels of Hcy have been associated with several psychiatric and neurodegenerative disorders including depression, schizophrenia, Alzheimer's disease, and Parkinson's disease. Although research in this field has intensified over the last decade there is a lack of a complete mechanistic understanding of homocysteine toxicity in vascular and central nervous system disorders (CNS). Several potential mechanisms have been proposed, supported by extensive experimental studies, which may aid in defining the development of effective prevention and treatment approaches. This review will focus on the biochemical and neurochemical aspects of methylation and altered homocysteine metabolism with particular reference to depression.

Section snippets

Homocysteine metabolism and the folate-methylation cycle

Homocysteine is a sulfur containing amino acid that cannot be obtained from any dietary source. It is solely the product of the methylation cycle, which is critical not only for its formation but also its removal. All methylation reactions that utilize S-adenosylmethionine (SAM) as the methyl-donor generate S-adenosylhomocysteine (SAH) (Fig. 1). Inside cells SAH is rapidly converted to Hcy by SAH-hydrolase. Although this reaction is reversible, the metabolic flow under normal physiological

Hyperhomocysteinemia

Hyperhomocysteinemia may be defined as a sustained elevation above normal of Hcy in plasma or serum. The term is used to designate a biochemical abnormality, and not a specific disease. Folate and vitamin B12 deficiencies are strong primary determinants, however there are a number of genetic and non-genetic causes of hyperhomocysteinemia. These are summarized in Table 1. Hcy is efficiently exported out of cells (Svardal et al., 1986), and the amount present in plasma or urine reflects a balance

Neurotoxicity of homocysteine

Several mechanisms of Hcy neurotoxicity have been proposed (Fig. 2). When Hcy metabolism is restricted through the MS or CBS dependent pathways conversion back to SAH will occur leading to inhibition of methylation reactions. In vitro studies have demonstrated that two methyltransferases related to catecholamine methylation, catehol-O-methyltransferase (COMT) and (PNMT), are significantly inhibited with increasing concentrations of SAH within the physiological range found in brain tissue (

Methylation, homocysteine metabolism and neurotransmitter function

An adequate amount of folate is required to maintain low levels of homocysteine in the CNS. The developing brain is particularly vulnerable to the effect of folate deficiency. Nowhere is this more evident than in severe MTHFR deficiency, the most common inborn error of folate metabolism. The main clinical findings in MTHFR deficiency are neurologic signs such as severe developmental delay, marked hypotonia, seizures, microcephaly, apnea, and coma. More recently case reports of a specific

Folate and homocysteine metabolism in depression

Studies on the association of folate deficiency with depression extend back to the mid 1960's. The initial reports were conducted in epileptic patients and showed that anticonvulsant treatment, which led to low serum folate levels, resulted in a higher incidence of mental symptoms including depression and psychosis (Reynolds et al., 1966, Reynolds et al., 1970, Reynolds, 1967). The first major study of the incidence of folate deficiency in psychiatric patients was described by Carney (1967),

Folate in the treatment of depression

Despite numerous reports on the association between folate deficiency and depression there are surprisingly relatively few controlled clinical trials that have looked at the effect of folate supplementation on mood disorders. Six clinical trials, 2 open and 4 double blind controlled, have used different forms of folate; 2 trials used folic acid, 1 trial used folinic acid, and 3 trials used 5-methyltetrahydrofolate (MTHF). These are summarized in Table 2. All but one of the six trials used

Concluding remarks

There appears to be considerable variation in the strength and degree of associations between folate, Hcy and depressive symptoms. Whether Hcy is directly involved and acts as primary cause of depressive symptoms, or if it is just a marker of folate and B vitamin deficiencies is not clear. Indeed, some of the reported variation in these associations may be attributed to geographical, cultural dietary habits, and genetic differences between various populations. The mandatory fortification of

References (82)

  • F.J. Hansen et al.

    Cerebral folate deficiency: life-changing supplementation with folinic acid

    Mol. Genet. Metab.

    (2005)
  • S.M. Innis et al.

    Increased plasma homocysteine and S-adenosylhomocysteine and decreased methionine is associated with altered phosphatidylcholine and phosphatidylethanolamine in cystic fibrosis

    Pediatrics

    (2003)
  • G. Le Fur et al.

    Evidence for a coupling between dopaminergic receptors and phospholipid methylation in mouse B lymphocytes

    Life Sci.

    (1981)
  • M.P. Mattson et al.

    Folate and homocysteine metabolism in neural plasticity and neurodegenerative disorders

    Trends Neurosci.

    (2003)
  • J.W. Olney

    Excitatory amino acids and neuropsychiatric disorders

    Biol. Psychiatry

    (1989)
  • A. Sharma et al.

    Protein kinase C regulates dopamine D4 receptor-mediated phospholipid methylation

    Eur. J. Pharmacol.

    (2001)
  • S.L. Sunden et al.

    Betaine-homocysteine methyltransferase expression in porcine and human tissues and chromosomal localization of the human gene

    Arch. Biochem. Biophys.

    (1997)
  • T. Tolmunen et al.

    Association between depressive symptoms and serum concentrations of homocysteine in men: a population study

    Am. J. Clin. Nutr.

    (2004)
  • P.M. Ueland et al.

    Biological and clinical implications of the MTHFR C677T polymorphism

    Trends Pharmacol. Sci.

    (2001)
  • P.C. Waldmeier et al.

    On the role of O-methylation in the metabolism of S-adenosylmethionine in rat brain

    Biochem. Pharmacol.

    (1987)
  • P. Yi et al.

    Increase in plasma homocysteine associated with parallel increases in plasma S-adenosylhomocysteine and lymphocyte DNA hypomethylation

    J. Biol. Chem.

    (2000)
  • J.H. Yoo et al.

    A common mutation in the methylenetetrahydrofolate reductase gene is a determinant of hyperhomocysteinemia in epileptic patients receiving anticonvulsants

    Metabolism

    (1999)
  • E. Zieminska et al.

    Role of group I metabotropic glutamate receptors and NMDA receptors in homocysteine-evoked acute neurodegeneration of cultured cerebellar granule neurones

    Neurochem. Int.

    (2003)
  • J.E. Alpert et al.

    Folinic acid (Leucovorin) as an adjunctive treatment for SSRI-refractory depression

    Ann. Clin. Psychiatry

    (2002)
  • S.G. Amur et al.

    Correlation between inhibition of myelin basic protein (arginine) methyltransferase by sinefungin and lack of compact myelin formation in cultures of cerebral cells from embryonic mice

    J. Neurosci. Res.

    (1986)
  • R.C. Austin et al.

    Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease

    Cell Death Differ.

    (2004)
  • I. Bjelland et al.

    Folate, vitamin B12, homocysteine, and the MTHFR 677C->T polymorphism in anxiety and depression: the Hordaland Homocysteine Study

    Arch. Gen. Psychiatry

    (2003)
  • M.I. Botez et al.

    Effects of anticonvulsant treatment and low levels of folate and thiamine on amine metabolites in cerebrospinal fluid

    Brain

    (1991)
  • M.I. Botez et al.

    Folate deficiency and decreased brain 5-hydroxytryptamine synthesis in man and rat

    Nature

    (1979)
  • T. Bottiglieri et al.

    Folate deficiency, biopterin and monoamine metabolism in depression

    Psychol. Med.

    (1992)
  • T. Bottiglieri et al.

    Homocysteine, folate, methylation, and monoamine metabolism in depression

    J. Neurol. Neurosurg. Psychiatry

    (1992)
  • G.L. Cantoni

    The role of S-adenosylhomocysteine in the biological utilization of S-adenosyl-methionine

    Prog. Clin. Biol. Res.

    (1985)
  • M.W. Carney

    Serum folate values in 423 psychiatric patients

    Br. Med. J.

    (1967)
  • R. Crellin et al.

    Folates and psychiatric disorders. Clinical potential

    Drugs

    (1993)
  • M. Cuenod et al.

    Sulphur-containing excitatory amino acids in intercellular communication

    Biochem. Soc. Trans.

    (1993)
  • S. Dayal et al.

    Deficiency of glutathione peroxidase-1 sensitizes hyperhomocysteinemic mice to endothelial dysfunction

    Arterioscler. Thromb. Vasc. Biol.

    (2002)
  • S. Dayal et al.

    Cerebral vascular dysfunction mediated by superoxide in hyperhomocysteinemic mice

    Stroke

    (2004)
  • A. Di Rocco et al.

    S-adenosyl-methionine improves depression in patients with Parkinson's disease in an open-label clinical trial

    Mov. Disord.

    (2000)
  • M. Fava et al.

    Folate, vitamin B12, and homocysteine in major depressive disorder

    Am. J. Psychiatry

    (1997)
  • U.C. Garg et al.

    Short-term and long-term variability of plasma homocysteine measurement

    Clin. Chem.

    (1997)
  • P. Goyette et al.

    Seven novel mutations in the methylenetetrahydrofolate reductase gene and genotype/phenotype correlations in severe methylenetetrahydrofolate reductase deficiency

    Am. J. Hum. Genet.

    (1995)

    • Cited by (233)

    • Association of CBS 844ins68, MTR A2756G and MTRR A66G gene polymorphisms with depression: A population-based study from North India

      2023, Gene Reports

    • Isotretinoin and neuropsychiatric side effects: Continued vigilance is needed

      2021, Journal of Affective Disorders Reports

    • Gut microbiota-derived vitamins – underrated powers of a multipotent ally in psychiatric health and disease

      2021, Progress in Neuro-Psychopharmacology and Biological Psychiatry

    • Plasma homocysteine concentrations and depression: A twin study

      2021, Journal of Affective Disorders Reports

    • Dietary methyl donor micronutrients intake in relation to psychological disorders in adults

      2022, British Journal of Nutrition

    • Association between consumption of fruits and vegetables with suicidal ideation

      2022, Public Health Nutrition
    View all citing articles on Scopus
    View full text
    Copyright © 2005 Elsevier Inc. All rights reserved.