Folate and Depression

What is Folate?

Folate, also called vitamin B-9 or folic acid, is a B vitamin found mainly in dark green leafy vegetables, beans, peas, nuts, oranges, lemons, bananas, melons and strawberries. Folate has important roles in red blood cell formation, cell growth, and cell functioning. It is also a very important vitamin during neurodevelopment. Let’s first discuss how folate is transformed in the body.

Folate is converted into L-methylfolate (L-MF)

  1. Folate, also called folic acid, is converted to dihydrofolate (DHF) and then tetrahydrofolate (THF) by the enzyme dihydrofolate reductase (DHFR).
  2. Serine hydroxymethyl-transferase (SHMT) then converts tetrahydrofolate (THF) to methylene-tetrahydrofolate (THF).
  3. Methylene tetrahydrofolate (THF) is converted by methylene tetrahydrofolate reductase (MTHFR) to L-methylfolate.

What does Folate have to do with Depression?

As we just reviewed, folate (and dihydrofolate) are converted to L-Methylfolate in our bodies. L-Methylfolate is involved in a number of biochemical pathways including the production of dopamine, serotonin, and norepinephrine (i.e., “mood chemicals”). L-Methylfolate is involved indirectly. That is, L-methylfolate is an important regulator or “control operator” for the production of something called tetrahydrobiopterin (BH4). BH4, in turn, is an essential component of the machinery our bodies use to produce dopamine, serotonin, and norepinephrine. The “gate keeper” for making serotonin is an enzyme called tryptophan hydroxylase whereas the gate keeper for making dopamine and norepinephrine is an enzyme called tyrosine hydroxylase.



Confused yet? Here is an analogy: 

It’s like using a battery-powered food processor. L-Methylfolate is the battery, tetrahydrobiopterin (BH4) is the container, tryptophan hydroxylase or tyrosine hydroxylase is the blade, and the food is serotonin or dopamine or norepinephrine. In order for the food processor to chop up and process the food (i.e., make dopamine, serotonin, or norepinephrine), we are going to need the container (i.e., BH4) and the blade (Tyrosine hydroxylase or Tryptophan Hydroxylase) to “turn on.” L-Methylfolate is the battery. No battery, no processed food (i.e., no serotonin, dopamine, or norepinephrine). You can have all the food processors in the world, but without a battery you won’t get any serotonin, dopamine, or norepinephrine. 


This means that reduced levels of L-methylfolate could lead to “ineffective” food processors and therefore reduced production of serotonin, dopamine, and norepinephrine. Reduced serotonin, dopamine, and norepinephrine could contribute to both depressed mood and/or resistance to antidepressant medications.  Recall that selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) depend on the presence of serotonin, dopamine, and norepinephrine.  That is, if there is little to no serotonin available to be released, then reuptake inhibition of serotonin won’t do much. Therefore, by supplementing with L-methylfolate, we can increase production of serotonin, dopamine, and norepinephrine and improve the responsiveness to antidepressants and other medications that rely upon the presence of those mood chemicals.

Genetic Variants and MTHFR

Folate and L-methylfolate (L-MF) deficiency can occur from either a diet low in folate or a body that can’t convert folate to L-methylfolate. Recall that L-methylfolate is produced by the enzyme MTHFR (see figure above). In some individuals, the MTHFR gene is slightly different and less efficient.  Below are a few genetic variants of MTHFR:

Methylene tetrahydrofolate reductase: MTHFR C677T; MTHFR A1298C

If MTHFR is less efficient in some people, then their levels of L-methylfolate may be reduced. Decreased levels of L-methylfolate may result in lower serotonin, dopamine, and norepinephrine levels by impacting their synthesis and metabolism (remember the food processor analogy above?). This is why supplementing with L-methylfolate makes more sense than supplementing with folate. If we can’t convert folate to L-methylfolate efficiently, then supplementing with L-methylfolate makes more sense.

MTHFR, COMT, and Schizophrenia?

Studies of MTHFR and COMT in schizophrenia suggest that a variant of MTHFR combined with a variant of COMT in the same individual may be enough to decrease the efficiency of information processing in those patients’ dorsolateral prefrontal cortex (DLPFC), an area of the brain important in cognition. These findings have motivated researchers to look into these types of genetic interactions as playing a role in patients with other psychiatric disorders such as depression and may help identify those individuals who are better candidates for L-Methylfolate supplementation.

Methylation and COMT

Recall that when DNA is methylated, it becomes more tightly coiled and prevents gene expression. In other words, methylation of genes silences them.

L-Methylfolate is considered a “methylator” as it provides a methyl group for this type of DNA methylation. COMT, or Catechol-O-methyl-transferase, is an enzyme that breaks down monoamines like dopamine. The more COMT, the more dopamine is broken down and therefore less is available for neurotransmission. If L-methylfolate is low, then perhaps this means less methylation of various genes such as COMT. Since methylation reduces genetic expression, decreased methylation of, say, COMT, would mean INCREASED genetic expression of COMT. The more COMT, the more breakdown of monoamines. Studies have shown genetic variability in the expression of COMT in patients with Schizophrenia. Some variants of the COMT gene result in greater expression of COMT and less dopamine availability in areas like the prefrontal cortex. Decreased dopamine levels in the dorsolateral prefrontal cortex (DLPFC) could potentially impair information processing and cause symptoms such as cognitive dysfunction. Therefore, L-methylfolate supplementation could result in higher dopamine levels in those brain areas and improve cognitive deficits in individuals with that gene variant of COMT.

Folate and Drug Interactions

Anticonvulsants: Taking folic acid with fosphenytoin (Cerebyx), phenytoin (Dilantin, Phenytek) or primidone (Mysoline) might decrease the drug’s concentration in your blood.
Barbiturates: Taking folic acid with a drug that acts as a central nervous system depressant (barbiturate) might decrease the drug’s effectiveness.
Methotrexate (Trexall): Taking folic acid with this medication used to treat cancer could interfere with its effectiveness.
Pyrimethamine (Daraprim): Taking folic acid with this antimalarial drug might reduce the effectiveness of the drug.

Folate Facts

The recommended daily amount of folate for adults is about 400 micrograms (mcg). For adult women who are planning pregnancy or could become pregnant the recommended daily amount of folate is usually 400 to 1,000 mcg per day. Additionally, folate works together with other vitamins such as B-6 and B-12 to regulate high levels of something called homocysteine. Elevated homocysteine levels in the blood have been shown to increase the risk of cardiovascular diseases. Lastly, it is important to mention that increased intake of folate can mask the megaloblastic anemia associated with vitamin B-12 deficiency, which may go undiagnosed and cause irreversible nerve damage.


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