Importance and role played by the folic acid in mental disorders mainly depression anxiety and psychosis. Role in neurotransmitters manufacturing.

1. Folic Acid in
Mental Health
Dr Vijay Bhatia

2. L-Methylfolate:
monoamine
modulator
L- Methylfolate, synthesised in the body from
folate or dihydrofolate in the diet.
Is an important regulator of a critical cofactor
for monoamine neurotransmitter synthesis,
namely tetra-hydrobiopterin or BH4.
BH4 is required by tryptophan hydroxylase to
convert tryptophan into serotonin.
BH4 is required by Tyrosine hydroxylase to
make dopamine and norepinephrine

3. Formation of L-methylfolate from Folic acid
DHFR
DHF
THF
F
Serine hydroxy
methyl
transferase
SHMT
Methylene
THF
L-Methylfolate
MTHFR
Methionine
Synthase
DHFR

4. Tetrahydrobiopterin (BH4) is a critical enzyme cofactor for tyrosine hydroxylase, the
rate limiting enzyme for dopamine and norepinephrine synthesis, and tryptophan
hydroxylase for 5HT.
Because L-methylfolate regulates BH4 production, it therefore plays an indirect role.
• Tyrosine Dopamine Norepinephrine
• Tryptophan 5HT
• Histidine Glutamate
BH4 BH4
F
BH4
Tyrosine
Hydroxylase
Tryptophan
Hydroxylase

5. BH4
This Photo by Unknown Author is licensed under CC BY

6. Glutamate synthesis
• THF is required for synthesis of
Glutamate

7. Low levels of
L-
methylfolate
Can lead to low synthesis of monoamines.
This can contribute to depression or to the resistance of
some patients to treatment with antidepressants.
Antidepressants such as SSRI’s/SNRI’s and others rely upon
continued synthesis of monoamines in order to work.
If there are no monoamines released, reuptake blockade is
ineffective.
However, repletion of monoamine synthesis by L-
methylfolate would theoretically make such patients
responsive to antidepressants.

8. Methylation
of genes
silences them.
L – Methylfolate provides the methyl group for this silencing.
So if L-Methylfolate is low, potentially silencing of various genes could also
be low.
If the silencing of the gene for the enzyme COMT (Catechol –O-methyl –
transferase) is low, more copies of this enzyme are made and enzyme
activity goes up, causing dopamine levels to go down particularly in
prefrontal cortex, potentially compromising information processing and
causing symptoms such as cognitive dysfunction.
Hypothetically, silencing of COMT synthesis by L-methylfolate could result
in higher dopamine levels in prefrontal cortex.

9. Causes of low
L-
methylfolate
Dietary deficiency.
High levels of homocysteine, Folate Trap, B12 deficiency.
Functional – e.g. anaemia.
Genetic variants in enzymes that regulate L-methylfolate levels.
DHFR
Methylene tetrahydrofolate reductase: MTHFR C677T; MTHFR
A1298C
Methionine synthase: MTR A2756G
Methionine synthase reductase: MTRR A66G

10. Inheriting
variants of
MTHFR, MTR,
MTRR
Leads to less availability of L-methylfolate could
potentially compromise monoamine levels by
impacting their synthesis and metabolism.
This can contribute to cause depression or some
symptoms of depression or be linked to treatment
resistance.
Studies on MTHFR and COMT in schizophrenia
suggests that effects of some gene variants on the
efficiency of information processing might be greater
if variants in two or more particular Genes are
inherited together.

11. Risk genes
and efficiency
of information
processing in
schizophrenia.
The single gene with the greatest risk may be
the COMT - Val allele.
Methylene tetrahydrofolate reductase T
allele.
Risk may be even greater for individuals with
multiple risk individuals who carry the
neuregulin 1 (NRG1), ErbB4 and AKT risk
genes.

12. S-adenosyl
Methionine
L-Methylfolate is converted into methionine and finally into
SAMe which is direct methyl donor for methylation
reactions.
If L-methylfolate is deficient so might be SAMe, and it may
be possible to administer methionine or SAMe to such
patients as well as L-methylfolate.
However, administering methionine or SAMe can cause
build up of unwanted homocysteine that could theoretically
interfere with epigenetic mechanisms and can eventually
deplete precursors to SAMe.
Nevertheless high doses of SAMe may be effective in
augmenting antidepressants in patients with major
depression.

13. Recycle of THF by B12
• Cobalamin is first converted to
methyl cobalamin by the n5
methyl THF
• Methyl cobalamin is required for
the conversion of homocysteine
to methionine by enzyme
methionine synthase. In the
process methyl cobalamin is
converted back to cobalamin
and regenerates THF back to n5
methyl TH folate.
• Methyl THF is the active form of
folate.This Photo by Unknown Author is licensed under CC BY-SA

14. • BH4 is coenzyme for Tyrosine
Hydroxylase. BH4 is regenerated
from BH2 by THF.
• Vitamin C is cofactor in conversion
of dopamine to norepinephrine.
• BH4 is required for Dopamine
beta hydroxylase to make
norepinephrine.
• SAMe is generated by methyl THF
required for conversion of
norepinephrine to epinephrine.

15. Folate cycle
This Photo by Unknown Author is licensed under CC BY-SA

16. Folate
receptor
Folate receptors bind folate and reduced folic acid derivatives and
mediates delivery of tetrahydrofolate to the interior of cells.[1] It is
then converted from monoglutamate to polyglutamate forms -
such as 5- methyltetrahydrofolate - as only monoglutamate forms
can be transported across cell membranes.
FRA can be overexpressed by a number of epithelial-derived
tumors including ovarian, breast, renal, lung, colorectal, and brain.
Hence antibodies to it are used in targeted therapies and
diagnostic tests, e.g. farletuzumab in phase III trial for ovarian
cancer.
Autoantibodies to the FRA have been linked to
neurodevelopmental diseases,[7] particularly cerebral folate
deficiency[8] schizophrenia[8] and autism spectrum
disorder.[9] Recent studies have shown that these
neurodevelopmental disorders can be treated with folinic
acid.[9][10]

17. Cerebral
folate
deficiency
Cerebral folate deficiency is a condition in which
concentrations of 5-methyltetrahydrofolate are low in
the brain as measured in the cerebral spinal
fluid despite being normal in the blood.[3] Symptoms
typically appear at about 5 to 24 months of
age.[3][2] Without treatment there may be poor muscle
tone, trouble with coordination, trouble talking,
and seizures.[3]
One cause of cerebral folate deficiency is a mutation in
a gene responsible for folate transport,
specifically FOLR1.[2][4] This is inherited from a person's
parents in an autosomal recessive manner.[2] Other
causes appear to be Kearns–Sayre
syndrome[5] and autoantibodies to the folate
receptor.[6][7][8]

19. Folate
deficiency
due to other
drugs
A number of drugs such as aminopterin,
methotrexate (amethopterin), pyrimethamine,
trimethoprim and triamterene act as folate
antagonists and produce folate deficiency by
inhibiting this enzyme.
With other drugs which produce low serum and
tissue concentrations of folate such as
anticonvulsants, antituberculosis drugs, alcohol
and oral contraceptives, the mechanism of this
effect is uncertain.
Possible mechanisms include reduced
absorption, prevention of release of folate from
tissue stores, altered plasma protein binding, or
increased folate metabolism in the liver..

20. Symptoms of
children born
to women who
had folate
deficiency
during
pregnancy
Low birth weight
Neural tube defects
Microcephaly
Developmental delays and seizures

21. In Summary
Folic acid plays a vital role in the mental health.
It can cause low levels of dopamine, serotonin, noradrenaline
and adrenaline.
It can cause mental retardation in children as in cerebral folate
deficiency, neural tube defects like spina bifida, microcephaly.
Megaloblastic anaemia
In contributes to weakness, tiredness due to anaemia.
B12 is essential for regeneration of methyl THF
It can help with information processing in schizophrenia, autism,
ADHD, dementia.

22. The End
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