One-carbon metabolism and bipolar disorder

Abstract

Objective:

Folate is one of the most widely used nutraceuticals for the treatment of mood disorders. In this article, we review folate metabolism, its relationship with bipolar disorder, and its therapeutic potential.

Methods:

We searched PubMed and the Cochrane Library for relevant articles up to and including the year 2012. Background information, proposed mechanisms of action, and results from clinical trials were reviewed.

Results:

Folate is an essential cofactor involved in methylation reactions, which are critical for monoamine synthesis and homocysteine regulation. Folate level is thought to be associated with mood disorders and limited response to antidepressants. Functional deficiency, due to a common genetic variant of the methylenetetrahydrofolate reductase (NAD(P)H) (MTHFR) gene, could also affect the presentation of bipolar disorder. Sodium valproate and lamotrigine, commonly used mood stabilizers for the treatment of bipolar disorder, can potentially interfere with folate and homocysteine metabolism. Previous studies consistently support the efficacy of folate in the treatment of depression; one study showed efficacy in the treatment of mania. Biologically active forms of folate formulations, which do not require biochemical conversion, could be beneficial in the treatment of bipolar disorder.

Conclusions:

Folate augmentation could be effective for the treatment of bipolar disorder. A common genetic variant of the MTHFR gene might impact the treatment effect of folate augmentation. The biologically active form of folate could potentially correct mood stabilizer-associated functional folate deficiency, help normalize monoamine synthesis, and improve outcomes.

Keywords

Bipolar disorder mood disorder folate nutraceuticals

Introduction

Despite recent advances in pharmacotherapy for bipolar disorder, many patients experience residual symptoms after responding to treatment and continue to have a high risk of relapse and recurrence of additional mood episodes. Bipolar I disorder patients spend almost half of their time symptomatic, with depressive spectrum symptoms 31.9% of the time, mania spectrum symptoms 9.3% of the time, and mixed symptoms 5.9% of the time; bipolar II disorder patients spend over half of their time depressed, with depressive symptoms associated with dysfunction (Altshuler et al., 2002; Joffe et al., 2004; Judd et al., 2002; Judd et al., 2003; Post et al., 2003). Even with guideline-concordant treatment, only about 30% of patients with bipolar depression remit and do not relapse for up to a year (Perlis et al., 2006). Because the outcomes of bipolar patients with currently available treatments are suboptimal, there has been growing interest in non-pharmaceutical supplements. Among these, folate is one of the most studied nutraceuticals for the treatment of depression and may also be relevant for the treatment of bipolar disorder. In this article, we review folate, one-carbon metabolism in general and specifically its relevance to bipolar disorder, and the therapeutic potential of using folate-related nutraceuticals for treatment.

Methods

We searched PubMed and The Cochrane Library for pertinent publications involving humans published in English using the search terms: depression, bipolar disorder, bipolar mania, bipolar depression, mania, hypomania, cyclothymia, and mood disorder, along with folate supplementation-relevant terms, such as folate, folic acid, folinic acid, methylfolate, nutritional supplement, nutraceuticals, and nutrient-based therapy. Major textbooks of mood disorders were hand-searched. Due to the limited number of studies related to bipolar disorder and folate, the literature related to depression and general mood disorders was also reviewed. The background information, possible mechanism of actions, and results from clinical trials were explored.

Folate: One-carbon metabolism

Folate is an essential cofactor nutrient involved in the one-carbon metabolism cycle (methylation). Methylation reactions are necessary for the synthesis of neurotransmitters, pyrimidines, and purines as well as for the regulation of promoter regions of DNA (Abdolmaleky et al., 2004). Dietary folate requires four steps of biochemical conversion to be bioavailable. Dihydrofolate reductase (DHFR) and methylenetetrahydrofolate reductase (MTHFR) are critical enzymes in this process. The metabolically active form of folate, 5-methyltetrahydrofolate (5-MTHF), acts as an important regulator of tetrahydrobiopterin (BH4); BH4 is a critical cofactor for tryptophan hydroxylase, the rate-limiting enzyme for serotonin synthesis and tyrosine hydroxylase, the rate-limiting enzyme for dopamine and norepinephrine (noradrenaline) synthesis. 5-MTHF is also known as a trimonoamine modulator (TMM), enhancing the synthesis of the three monoamines (Stahl, 2007).

Another important feature of folate is that it decreases homocysteine by donating a methyl group to homocysteine to regenerate methionine. S-adenosyl-L-methionine, a natural compound used for the treatment of depression (Mischoulon et al., 2012a), shares with 5-MTHF the ability to regulate methylation in this cycle. This is a critical step in the regulation of homocysteine, an amino acid with the potential to make neurons more vulnerable to excitotoxicity-induced apoptosis. Homocysteine also activates poly(ADP-ribose) polymerase, activates glutamate receptors, and induces oxidative stress, endoplasmic reticulum stress, and mitochondrial dysfunction (Kruman et al., 2000). Oxidized forms of homocysteine, homocysteinesulfinic acid and homocysteic acid, appear to act as agonists at N-methyl-D-aspartate receptors, potentially increasing the risk of glutaminergic excitotoxicity (Görtz et al., 2004). An inverse relationship exists between homocysteine and folate; high homocysteine levels can be caused by low folate levels.

Folate and bipolar disorder

The relationship between folate deficiency and depression has received attention since the 1960s. Neuropsychiatric, particularly depressive, symptoms including apathy, fatigue, insomnia, irritability, and impaired concentration, have figured prominently in clinical descriptions of folate deficiency states associated with malabsorption (Botez et al., 1979), anticonvulsant-treated epilepsy (Edeh and Toone, 1985; Reynolds, 1981), megaloblastic anemia (Shorvon et al., 1980), and dietary folate restriction (Herbert, 1961). A recent epidemiological study found an association between dietary folate and depressive symptoms in men, such that participants with lower folate intake showed greater risk for depression (Tolmunen et al., 2003). Studies found that depressed patients had lower serum folate (Carney, 1967; Ghadirian et al., 1980), red blood cell (RBC) folate (Bottiglieri et al., 1992), or serum 5-MTHF (Wilkinson et al., 1994) levels, and higher homocysteine levels (Bottiglieri et al., 2000) compared to all psychiatric and non-psychiatric control subjects except for patients with alcoholism who had a similar prevalence of low folate (Carney et al., 1990). Furthermore, low serum or RBC folate and serum 5-MTHF were often associated with greater symptom severity among depressed patients (Abou-Saleh and Coppen, 1989; Reynolds et al., 1970; Wesson et al., 1994; Wilkinson et al., 1994), worse response to pharmacotherapy (Papakostas et al., 2004a), and higher likelihood recurrence of depression (Coppen and Bolander-Gouaille, 2005; Papakostas et al., 2004b). Patients with bipolar mania were also reported to show higher homocysteine levels (Ezzaher et al., 2011). Additionally, high homocysteine levels were found in patients with bipolar disorder who were euthymic, but functioning poorly as compared to those who were euthymic and functioning well, implicating low folate as a possible correlate of poor functioning (Osher et al., 2008; Reif et al., 2005).

Despite the well-established association between low folate/vitamin B12 status, mood disorders, and limited response to antidepressants, the mechanism of these relationships remains unclear. One proposed mechanism involves the deleterious effects of increased plasma homocysteine, which is harmful to neurons and blood vessels, and may increase the risk of developing a mood disorder, as well as cognitive decline and dementia (Folstein et al., 2007).

Folate pathway genetics

Functional folate levels can be influenced by folate enzymatic functions. A single-base variant in the MTHFR gene involved in the folate pathway has received much attention. The MTHFR C677T polymorphism is a common, single-nucleotide polymorphism (SNP) where cytosine is replaced by thymidine (C –> T) at nucleotide position 677 in exon 4. The frequency of C677T polymorphism is around 10–12% of the general population, and differs by ethnicity and geographic variation (Gilbody et al., 2007). The C677T polymorphism produces a thermolabile variant of the MTHFR gene, which is associated with low serum folate and impairs homocysteine metabolism.

The C677T polymorphism has been shown to be overrepresented in depressed patients. Kelly et al. (2004) found that C677T was significantly more common in a group of 100 depressed patients (p = 0.03) compared to sex- and age-matched controls. In a Japanese sample, Arinami et al. (1997) found that the prevalence of the C677T homozygote (TT) SNP was 21% in schizophrenia, 28% in major depression, and 13% in bipolar disorder. The CT heterozygote was present in 40–50% of the sample, regardless of psychiatric status, and CC homozygotes comprised approximately 30–40% of the healthy controls. In a Norwegian sample (N = 5948), Bjelland et al. (2003) found an association between the C677T homozygote and depression, but not anxiety. More recently, Almeida et al. (2005) investigated a population of 240 older women (of which 29 had the TT genotype, 113 the CT, and 98 the CC), to determine whether the C677T homozygote was associated with a higher rate of depression and lower cognitive scores. The group found no significant difference in the severity of depressive symptoms in subjects with the C677T homozygote compared to the other groups (p = 0.609). However, plasma homocysteine correlated with Beck Depression Inventory (BDI) scores (r = 0.21) when corrected for age, and vitamin B12 and folate levels. There was no association between the presence of MTHFR C677T and cognitive scores. Meta-analytic studies showed mixed results for the association of C677T with bipolar disorder (Cohen-Woods et al., 2010; Gilbody et al., 2007; Zintzaras et al., 2009) and depression (Gaysina et al., 2008; Gilbody et al., 2007; Zintzaras et al., 2009). Individuals with the C677T homozygote have higher homocysteine levels and may experience depression as a result of high plasma homocysteine and subsequent dysfunction of methylation pathways involved in the synthesis of norepinephrine (noradrenaline) and serotonin (Almeida et al., 2005).

Taken together, these findings suggest that, while the presence of depression or bipolar spectrum disorders may not be unequivocally associated with the MTHFR C677T gene variation per se, the higher homocysteine levels may impact mood in such individuals. Recent studies by Mischoulon et al. (2012b) have reported no significant MTHFR genotype effect on folate, homocysteine level, and antidepressant response in major depressive disorder. However, due to limited sample size, the result was inconclusive. Another study documented that the C677T polymorphism impacted the effect of folate supplementation in patients with schizophrenia (Hill et al., 2011). Thus, to identify the best candidates for folate augmentation, it might be necessary to determine MTHFR genotypes. Also, other common genetic variations, such as the A1298C polymorphism (Gilbody et al., 2007), could impact the folate augmentation treatment.

Mood stabilizers and their effects on the folate pathway

Interestingly, sodium valproate and lamotrigine, the major mood stabilizers used in the treatment of bipolar disorder, are known to impact the one-carbon metabolism pathway; sodium valproate inhibits methionine adenosyltransferase and decreases methionine levels (Ubeda et al., 2002), which can lead to functional folate deficiency with increased homocysteine. Lamotrigine is a weak inhibitor of DHFR in vitro (Glaxo SmithKline, 2011), which can lead to decreases in functional folate even with normal folate blood levels. Theoretically, sodium valproate and lamotrigine can induce a decrease in active brain folate and an increase in homocysteine, but studies about these relationships have been mixed. Patients taking sodium valproate for epilepsy have shown increased homocysteine levels (Bochyńska et al., 2012; Karabiber et al., 2003; Linnebank et al., 2011; Verrotti et al., 2000), which are reversible with folate supplementation (Bochyńska et al., 2012). On the other hand, patients treated with lamotrigine did not show significant differences in folate and homocysteine levels (Belcastro et al., 2010; Gidal et al., 2005; Tamura et al., 2000).

It is unclear if the anti-methionine and antifolate actions of mood stabilizers lead to significant functional folate deficiency and worsening of mood. To complicate the issue further, some have postulated that the sodium valproate-induced decrease in methionine is actually part of its mechanism of action as a mood stabilizer (Tremolizzo et al., 2002). However, at the very least, a possible, under-recognized contribution to mood instability is abnormal one-carbon metabolism with increased homocysteine, either as a part of disease process or as a consequence of taking mood stabilizer (Ubeda et al., 2002).

Folate supplementation in the treatment of mood disorders

There are three commercially available folate formulations on the market: folic acid, 5-MHTF (also known as methylfolate and L-methylfolate), and folinic acid (also known as L-leucovorin and mainly used as an adjuvant chemotherapy agent for rescue from methotrexate). The forms of folate differ in their bioavailability; folinic acid does not require DHFR for conversion to an active form that can penetrate the blood–brain barrier, and 5-MHTF does not need DHFR or MTHFR. For this reason, folinic acid and 5-MHTF can be used for those who have genetic variants that limitfolate-related enzyme activities. Also, compared to folic acid, 5-MHTF is seven times more bioavailable (Willems et al., 2004) and less likely to mask a vitamin B12 deficiency (Akoglu et al., 2007; Scott and Weir, 1981).

Previous studies have consistently supported the efficacy of folate augmentation, regardless of formulation, in the treatment of major depressive disorder; to the best of our knowledge, no studies of folate augmentation for the treatment of bipolar depression have been published. To date, we are aware of only one study of folate for the treatment of bipolar mania.

Three randomized controlled studies have examined folic acid as an augmentation therapy for depression. The first study (Coppen et al., 1986) enrolled 53 unipolar depressive patients, 17 bipolar depressive patients and five schizoaffective patients. A significant decrease in depressive symptoms measured by the BDI was only observed in unipolar depressive patients; however, the baseline depressive symptoms of bipolar patients were almost within normal range. In the second study (Coppen and Bailey, 2000), a significant decrease in depressive symptoms was only observed in women who received folic acid, compared with those who received placebo; no significant difference was detected in men. Resler et al. (2008) observed greater improvement with adjunct folic acid in patients with major depression treated with fluoxetine compared to those receiving fluoxetine and placebo. One randomized controlled study examined the efficacy of folic acid in patients with bipolar mania; 88 patients with bipolar mania received folic acid or placebo with sodium valproate for 3 weeks (Behzadi et al., 2009). Those who received folic acid plus sodium valproate showed significantly greater decreases in Young Mania Rating Scale scores.

One open-label study examined the efficacy of folinic acid as an adjunct therapy in patients with major depression who had failed to respond to 4 weeks of selective serotonin reuptake inhibitor (SSRI) treatment (Alpert et al., 2002). Modest improvements in the Hamilton Rating Scale for Depression were observed. Six additional studies explored the effect of 5-MTHF on depression. Two randomized controlled trials showed statistically non-significant clinical improvements in the 5-MTHF augmented groups (Crellin et al., 1993; Godfrey et al., 1990). Also, 5-MTHF monotherapy was better than trazodone monotherapy (Passeri et al., 1993). Recently, Papakostas et al. (2012) reported that adjunct 5-MTHF was effective for major depressive disorder patients who had poor response to SSRIs. In two open studies, 5-MTHF showed statistically significant efficacy and produced rapid improvements in depressive symptoms (Di Palma et al., 1994; Guaraldi et al., 1993). A recent Cochrane review of the efficacy of folate for depression found that ‘the currently available evidence suggests that folate supplementation may be effective when used in addition to conventional antidepressant medication. The evidence does not support the use of folate as a replacement for antidepressant medication in the treatment of depression. There is no evidence that supplementation is only effective in those with low folate results’ (Taylor et al., 2003). However, the efficacy of 5-MTHF has not been studied along with the C677T MTHFR genotype. Also, no sufficiently powered studies of folate or 5-MTHF augmentation have been done for patients with bipolar disorder. Considering that many patients with bipolar disorder are treated with sodium valproate or lamotrigine, 5-MTHF may represent a useful addition to the usual treatment of bipolar depression, but a definitive recommendation awaits confirmation with prospective clinical trials.

Conclusions

The folate metabolism pathway is essential for monoamine synthesis and can be closely linked to the development and treatment of depression. Folate augmentation for the treatment of bipolar depression might be most appropriate for patients who have C677T, a common genetic variant of the MTHFR gene. Furthermore, mood stabilizers commonly used for the treatment of bipolar disorder can potentially interfere with folate and homocysteine metabolism; also, the antifolate actions of mood stabilizers could limit their ability to completely treat bipolar depressive symptoms. The biologically active form of folate, 5-MTHF, could potentially correct mood stabilizer-associated functional folate deficiency, help normalize monoamine synthesis, and improve outcomes.

Footnotes

Declaration of interest

Dr Nierenberg served as a consultant and received a research grant from Pamlab, LCC (Covington, Louisiana, USA). Dr Baek and Ms Bernstein report no relevant funding or support that may represent a conflict of interest on this article.

Funding

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

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