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Can a Folic Acid Deficiency Make You Unhappy?

Folic acid is one of the most popular B vitamins. It serves diverse roles in the body and it is absolutely essential to metabolism. Available studies indicate that the health benefits of folic acid may include the relief of depressive symptoms. How effective is folic acid in the treatment of depression? Can it be used alone or along with standard antidepressants? How exactly does it improve depressive symptoms? Read on to find out.
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What is Folic Acid?

Folic acid is a B vitamin also known as folate or vitamin B9.  Like all B vitamins, it is essential to a long list of metabolic functions in the body.

This vitamin is needed by the body to synthesize, utilize and repair DNA. It is also useful for promoting rapid cell growth and division, and can as well act as a co-factor in some biological reactions. Folic acid is also essential for the functioning of the nervous system.

Dietary sources of folic acid include spinach, collard greens, turnip greens, asparagus, broccoli, grape fruit, oranges, straw berries, celery, brussel sprouts, cauliflower, beets, corn, carrots and okra. The vitamin is also commonly added to fortified cereals and bread.

Folic acid itself is biologically inactive, but in the body it is converted to dihydrofolic acid, which is further converted to tetrahydrofolate and other derivatives which are metabolically active.

The conversion of folic acid to its biologically active forms depends on the action of the enzyme, dihydrofolate reductase, in the liver.

Because the body utilizes vitamin B9 in diverse ways, folic acid deficiency can cause very serious complications. Some of the signs of this deficiency are seizures, vascular changes, depression, cognitive impairment and movement abnormalities.

Vitamin B9 supplements are available to treat folic acid deficiency. To prevent this deficiency, experts recommend the following:

  • For adults (14 years and above), the recommended daily intake of folic acid is 400 micrograms. The daily intake for breastfeeding women is 500 micrograms and pregnant women should take 600 microgram.

However, doses higher than these are required to treat depression.

  • The upper limit for daily folic acid intake is 800 micrograms for adolescents but adults are allowed a maximal daily dose of 1000 micrograms.

Very high doses of folic acid (more than 1000 micrograms daily) may cause seizures, stomach discomfort, insomnia, skin problems, diarrhea, cramps, bloating and rash.

Folic acid is used as a supplement in the treatment of depression. In this role, it is used to improve patients’ response to standard antidepressant. The recommended dosage of the vitamin for this use is 200 - 500 micrograms per day.

Folate Deficiency and Depression

A significant number of scientific studies suggests that depression is associated with folate deficiency. In addition, folate deficiency in depressed patients can also reduce the effectiveness of antidepressant drugs.

The importance of folate in depression can be traced to the role of the vitamin in transmethylation reactions. A transmethylation reaction involves the transfer of a methyl group from one compound to another. Such methyl transfers are necessary for the formation of certain neurotransmitters.

The relationship between folate and depression is also supported by observations that a common genetic variant of an enzyme that reduces a person’s ability to convert folic acid to L-methyl folate (which is its active metabolite), is more common in patients with depression.

This means that the genetic anomaly would affect transmethylation reactions and, by extension, neurotransmitter syntheses.

Furthermore, because low levels of folate disrupt transmethylation reactions, it can lead to the accumulation of homocysteine along with the disruption of neurotransmitters, phospholipids, myelin, and receptors.

Homocysteine is a toxic intermediate of amino acid syntheses and it is an amino acid not used in making proteins. It is formed from methionine and converted to its homologue, cysteine. Both the conversion and recycling of homocysteine back to methionine require B vitamins such as folic acid.

When low folate levels promote the accumulation of homocysteine, the toxic intermediate increases oxidative stress especially in the bones, heart and the central nervous system.

In the brain, homocysteine is responsible for kinds of neurological damage that can cause depression.

Regarding the effect of folate on standard antidepressants, there is now conclusive proof that low folate levels cause poor response to antidepressant treatments. Other studies suggest that a high level of folate can be used for better treatment outcomes.

In a study published in the American Journal of Psychiatry, a group of researchers gave fluoxetine to 213 patients who were suffering from major depressive disorders. The researchers measured the blood levels of folate in each member of the study group.

At the end of eight weeks on fluoxetine, the patients with lower folate levels showed the least signs of improvement on the drug therapy.

In summary, folic acid supplementation helps to relieve depression, and is also effective in the treatment of depression when used with standard antidepressant drugs.

How Folic Acid and L-methyl Folate Improve the Efficacies of Antidepressants

Once absorbed, folic acid becomes metabolically active after it is being converted to dihydrofolate and then to tetrahydrofolate through a series of enzymatic reactions.

The first reaction is catalyzed by the enzyme, dihydrofolate reductase. The tetrahydrofolate is thereafter converted to the biologically active L-methyl folate by the enzyme, methylenetetrahydrofolate reductase.

L-methyl folate acts as an important regulator of a critical co-factor for trimonoamine neurotransmitter syntheses. This critical co-factor is known as tetrahydrobiopterin.

Tetrahydrobiopterin helps in the conversion of phenylalanine to tyrosine and in the hydroxylation of tyrosine and tryptophan, which are the important steps involved in the syntheses of monoamine neurotransmitters.

Therefore l-methyl folate can increase the production of one or more of the three monoamines (trimonoamine) neurotransmitters:

  • Dopamine
  • Norepinephrine
  • Serotonin

Like other neurotransmitters, these neurotransmitters are endogenous chemicals that transmit signals across synapses between nerve cells. However, the three monoamine neurotransmitters are important in the regulation of mood.

By augmenting the syntheses of trimonoamine neurotransmitters through the enhancement of tetrahydrobiopterin, L-methyl folate is able to boost the antidepressant effects of standard antidepressants.

Studies have shown that low serum folate levels and low cerebrospinal fluid levels of L-methyl folate may be related to depression in some patients.

Since L-methyl folate indirectly controls monoamine levels, a low level of L-methyl folate could impair the actions of the enzymes involved in the syntheses of trimonoamine neurotransmitters. This causes monoamine deficiency, which most experts believe is responsible for depression.

L-methyl folate is also believed to be involved in monoamine neurotransmitter metabolism.

In this role, it promotes the synthesis of tetrahydrobiopterin enzymatic cofactor, modulates the enzymes that break down monoamine neurotransmitters, and contribute to the actions of monoamine transporters and neurotransmitter receptors.

Studies on Folic Acid and Depression

In a 1980 study published in the journal, Psychosomatics, the link between folic acid deficiency and depression was explored. The study consisted of 48 patients that were divided into three groups: depressed patients, psychiatrically ill patients (but not depressed) and medically ill patients.

All the patients were hospitalized and given a standard diet with no drugs and vitamins for one week.

At the end of the week, depressed patients had significantly lower serum folic acid level than the patients in the other two groups.

The results also showed that the patients with lower serum folic acid levels scored higher in the Hamilton Rating Scale, the clinical standard for measuring the severity of depression.

In another study published in the journal, Psychological Medicine in 2004, the relationship between low folic acid, vitamin B12 and homocysteine as possible predictors for depression was demonstrated.

For this study, 412 persons aged 60 to 64 years where randomly recruited from a large community. They all underwent psychiatric and physical assessments and were also given brain MRI (magnetic resonance imaging) scans.

The subjects were assessed and checked for various depressive symptoms using the PRIME-MD PATIENT HEALTH questionnaire. Folic acid, serum, vitamin B12, folic acid, homocysteine and creatinine levels were also measured in the blood samples taken from the study participants.

The results of the study showed that the participants who had the lowest homocysteine levels also had fewer depressive symptoms even after adjusting for creatinine, folic acid and B12 levels.

On the other hand, the participants with the lowest levels of folic acid had the highest numbers of depressive symptoms even after adjusting for other causes of depression.   

The results also showed that vitamins B12 levels did not have any significance on depressive symptoms.

In a 1989 study published in the Journal of Affective Disorders, the link between folate deficiency and tetrahydrobiopterin was demonstrated.

The researchers measured the biopterin and neopterin levels in the participants. Neopterin is the product of the breakdown of guanine triphosphate and its measurement is taken as an indication of oxidative stress mounted by the immune system.

Biopterin, on the other hand, is the product of the breakdown of tetrahydropterin.

The average neopterin-biopterin ratio was higher in the 76 patients than in the 61 controls involved in this study. In female patients, biopterin levels were considerably lower than in controls.

In the control group there was a significant correlation between the molar concentration of biopterin and neopterin, but there were no such correlations found in the patients. These data show that tetrahydrobiopterin biosynthesis is reduced in this group.

A significant positive correlation was found between urinary biopterin and plasma folate levels.

This study suggests that folate deficiency can impair the synthesis of tetrahydrobiopterin, a cofactor that essential to the production of monoamine neurotransmitters.

In another 1989 study published in the journal, Acta Psychiatrica Scandinavica, the levels of serum folate were measured in patients with major depressive orders and normal controls. Red blood cell folate concentrations were also measured in different subgroups of the participants.

The results showed that the patients with major depressive disorders had lower serum and red blood cell folate concentrations than the normal controls.

Lower serum folate concentrations were also related with increased severity of depression.






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