After fatigue the most commonly reported symptom of vitamin B12 deficiency is
depression.
Depression is common in conditions such as CFS, dementia and in many with
autism.
Post Natal
Depression/Post Partum Depression Post
Natal Depression/Post Partum Depression is extremely in women with reports of 1
in 10 or 1 in 5 women experiencing PND (Van Neil and Payne, 2020; Bagheri and
Rostrami, 2021GTS). Over 50% of doctors fail to diagnose PND. If the depression
extends to longer than 6 months it can often be accompanied by fatigue, with the
result being the development of Chronic Fatigue Syndrome. This can have a
devastating effect on the mother, and her enjoyment of her new born child or
children. Even those that do diagnose the condition, fail to diagnose the cause,
and so cannot effectively treat the condition. Interestingly, the risk factors
for PND are similar to those for having a child with autism, and include,
preterm delivery, preeclampsia, low birth weight, and behavioural disturbances
in the baby (Van Neil and Payne, 2020), and is associated with a higher risk of
maternal suicide (Shi etal, 2018). PND is also associated with impaired bonding
between mother and child, poor development, marital discord, and infanticide
(Wilkinson et al, 2017). Despite this, the standard of care (a curious misnomer)
is NOT to screen for PND!! Recently an association between lower absolute levels
of vitamin B12, and lower levels of functional B12 and post natal depression has
been found (Dhiman
et al, 2021; Ramadam, et al, 2022; Bodnar and Wisner, 2008)
Major Depressive Disorder
Major Depressive Disorder (MDD) at some time during the lifetime,
is estimated to occur in at least 21% of individuals in the US, however its
cause is not well understood (Maletic etal, 2023). The majority of doctors and psychiatrists believe that depression
is caused by low serotonin levels, a theory that was first proposed in the 1960s
and recent surveys suggest that over 80% of individuals with depression believe
in the theory. The standard method of treatment has been the use of Selective
Serotonin Reuptake Inhibitors (SSRIs) HOWEVER, recent a recent review has shown
no evidence of low serotonin levels in depression (Moncrieff etal, 2022), and
more recently Organic Acids tests of those with depression have shown exactly
the opposite (Russell-Jones, 2022). Using
a standard symptom check-list of over 250 individuals with functional vitamin
B12 deficiency, over 54% listed depression as a symptom.
Vitamin B12
Deficiency and Depression Low
levels of serum B12 and folate have been associated with low levels of vitamin
B12 and folate (Khosravi
etal, 2020). The
following text will describe the potential reason for why vitamin B12 deficiency
is linked to depression.
You have two "happiness" neuropeptides,
dopamine and serotonin. These two molecules, though, are also precursors for the
production of nor-adrenalin, followed by adrenalin (epinephrine) and melatonin.
In vitamin B12 deficiency (more specifically methyl B12 deficiency), you cannot
convert the precursors nor-adrenalin to adrenalin and serotonin to melatonin,
but the body tries to drive these reactions by increasing the levels of both
dopamine and serotonin (a Principle called Le Chatelier's Principle), hoping to
get at least a little bit, and in some people the levels of serotonin, as
measured by the breakdown product 5HIAA, are over 200 times the levels in normal
individuals, and some long term very depleted people are even higher.
The final step in production of Melatonin is the methylation of
N-Acetyl-Serotonin (NAcSer) by the enzyme HydroxyIndole-O-methyltransferase (HIOMT),
which has an absolute requirement for S-Adenosylmethionine (SAM), a product of
the methylation cycle
(Axelrod and Weissbach 1960, Weissbach and Axelrod 1960).
Melatonin synthesis and SAM
In Methyl B12 deficiency, there is a greatly reduced production of SAM, and
breakdown products of tryptophan, Kynurenic acid (KA) and Quinolinic acid (QA),
as well as the breakdown product of Serotonin, 5-Hydroxyindoleacetic acid
(5HIAA) start to accumulate and can be detected as elevated levels in urine.
Metabolites increased in SAM deficiency
Increased amounts of QA, KA and 5HIAA in vitamin B12
deficiency are shown in the following scattergrams. Of particular note is the
extremely elevated 5HIAA, the degradation product of serotonin, reflecting the
highly elevated levels of serotonin produced in vitamin B12 deficiency.
(Russell-Jones 2022)
Quinolinic Acid in B12 Deficiency
Kynurenic Acid in B12 Deficiency
5HIAA in B12 deficiency
The body though is very clever and so it turns off, or dims, the response to
dopamine and serotonin, by reducing the numbers of receptors (the proteins or
pores that detect the neuropeptides) for them - Receptor down-regulation, which
eventually leads to depression in its own right. Depression is one of the most
common symptoms of B12 deficiency, and in surveys, 53% of individuals with
functional vitamin B12 deficiency report depression as a major symptom.
At this stage the body has a problem in that if you actually do get a stimulate
that would cause you happiness, the stimulus doesn't work, a little like trying
to see a firefly when all the lights are on, or trying to hear a pin-drop in a
very noisy hall. You cannot detect either, due to the "white noise" and neither
can the body detect the small increase that occurs when you do get a happy
feeling. Eventually you compensate a bit for this and so are not "too
depressed".
When you start to fix the B2 deficiency, one of the first things that is does is
to start up a little bit of methylation, and then you start to convert the
precusors, dopamine and serotonin to adrenalin and melatonin, and now you have a
new problem. The levels of dopamine and serotonin drop rapidly, BUT, the
receptors are now so few that they can't respond to the decreased levels of
dopamine and serotonin, and so you feel even more depressed. This is one of the
reasons why people who are on anti-depressants, such as SSRIs or SNRIs can't
easily get off them, and why doctors don't suggest it just in case you can't
cope. This would be more typical in major depressive disorder, but it can
result in attempted suicide. The
body, though, eventually (and the active word is eventually) adapts and starts
to turn up the number of receptors (Receptor up-regulation) in its quest to
"find perpetual happiness". The trouble being that this takes a very long time,
and so you have to do be very methodical and gradually reduce the dose,
potentially by as little as 1% per day. This is the same advice that doctors
suggest for coming off antidepressants or other addictive drugs. Curiously, the
B12 deficient person, is just like a person on SSRIs is addicted to their
own-overproduction of serotonin and dopamine. Not that you generally hear this
discussed like this.
Studies on use of high dose 5-methyl-folate support the concept that in
prolonged depression functional vitamin B12 may be the issue (Maletic etal,
2023). Unfortunately the authors looked neither at functional vitamin B2
sufficiency, nor functional B12 sufficiency.
Functional Vitamin B12
Deficiency due to functional B2 deficiency
Functional vitamin B2 deficiency, which can be the result of deficiency in
Iodine, Selenium and/or Molybdenum will also cause functional B12 deficiency,
however the consequences on the levels of neurotransmitter metabolites are
different. Hence as the amount of active B2, as FAD decreases, more and more
serotonin is synthesized, but due to Methyl B12 deficiency, it accumulates and
is degraded by the FAD-dependent enzyme MAO, leading to very high levels of the
degradation product 5HIAA. In functional B2 deficiency due to lack of Iodine or
Selenium, there is lower synthesis of FAD, and so the degradation product 5HIAA
rapidly declines. Further, this deficiency then causes a deficiency in the
synthesis of Pyridoxal-5-phosphate (P5P) and so synthesis of serotonin is
blocked, and the levels of QA go up. Degradation of Kynurenine to KA is also
dependent upon a P5P-dependent enzyme, and so as the deficiency increases the
ratio of QA:KA increases. Yet, as can be seen levels of QA keep increasing as
the functional B2 deficiency increases.
Vitamin B12
Deficiency, Drug Treatment and Depression The
most common treatments for depression are SSRIs, indicating that it is the
serotonin system that is being incorrectly treated. SSRIs are highly addictive
and include drugs such as Fluoxitene, Lexapro, Zooloft, Prozac, Paxil, Celexa,
Luvox, Paxil, Brisdelle, etc. Given that the market for antidepressants is $4
billion, it is not in the drug companies best interests to test for vitamin B12
deficiency. Further, prolonged treatments usually require a psychiatrist, at
over $250 per visit. Hence it is not in the psychiatrists best interests to test
for B12 deficiency in the patients. One
can see from the graphs above, that treatment for plain B12 deficiency, would
result in higher levels of melatonin, but would also result in rapid reduction
in the amount of serotonin, potentially leading to increased anxiety,
depression, suicidal tendencies, fear, anxiety, irritability, agitation, etc. In
contrast, if the functional vitamin B12 deficiency is due to Iodine, Selenium
and Molybdenum deficiency, then as the deficiency is reduced, there potentially
would be a sudden rise firstly in FMN, with concomitant production of P5P,
leading to a sudden increase in serotonin, which would persist until the
activation of MAO, at which time there would be an increase in 5HIAA. Further
treatment of the functional B2 deficiency, when combined with Methyl B12, would
then lead to a rapid drop in serotonin (once again leading to increased anxiety,
depression, suicidal tendencies, fear, irritability and agitation), and lead to
symptoms synonymous with SSRI withdrawal. This
is further compounded by what is happening to the receptors for serotonin.
i) In
extreme Iodine/Selenium deficiency, there is very little serotonin produced.
This will then result in very elevated levels of serotonin receptor expression.
This is predominantly seen as glutaric acid levels rise above 1.5. If at that
stage I/Se are introduced too quickly, there is a sudden increase in the rate of
conversion of 5HTP to serotonin, and as the enzyme MAO requires FAD, it is
unable to 'cope" with this rise and so you have a combination of very high
serotonin levels and very high serotonin receptor levels resulting in some
extreme serotonin overload symptoms. ii)
As Iodine and Selenium become replete, there is a gradual increase in the rate
of serotonin synthesis, and the QA:KA ratio decreases, and there is gradual
decrease in the numbers of serotonin receptors, until the levels of receptors
gets very low, to balance the increased amount of serotonin that is produced. iii)
At this stage if Molybdenum is very low, then degradation of serotonin is very
slow, but if Molybdenum is introduced, there can be a rapid conversion of
serotonin to 5HIAA, whose levels can rise to exceedingly high levels. There is
still a serotonin over-load. iv).
Once I/Se/Mo are replete, there is still a high production of serotonin, with
low serotonin receptor numbers, if Methyl B12 is now introduced there is a rapid
conversion of serotonin to melatonin. Serotonin receptor numbers are very low,
serotonin becomes very low and now there are symptoms of serotonin deficiency,
such as increased anxiety, depression, suicidal tendencies, fear, irritability
and symptoms of similar to SSRI withdrawal occur.
Treatment
Depression is an extremely common disorder with as much as 10% of the population
above 12 years of age being affected. in the US the cost of treatment of
depression is over $70 billion. Much of the treatment of depression is based on
the use of anti-depressants with the antidepressant market projected to reach
US$30.59 by 2029. Much of the treatment revolves around the mis-guided notion
that the person with depression is NOT making sufficient dopamine and/or
serotonin, and so involves the use of SSRIs, SNRIs and TCA. Given the size of
the market it is highly unlikely that one could convince the drug companies,
that actually the problem is due to over-production of dopamine and serotonin,
due ot functional B12 deficiency, with resultant receptor down-regulation. A
somewhat "unfortunate truth" for the pharmaceutical industry.
Treatment resistant depression
The data on the lack of production of serotonin would explain Treatment
Resistant Depression. In this case, persons who are Iodine or Selenium
deficient, are not making serotonin, and so treatment options using SSRIs, or
SNRIs will be unsuccessful. Treatment Resistant Depression has been quoted as
representing up to 50% of all cases of depression.
According to the World Health Organization (WHO), MDD is the single largest
contributor to loss of healthy life.
the majority of individuals with MDD are inadequately responsive
to first‐line treatments. Moreover, a substantial proportion of them
fail multiple antidepressant interventions, resulting in what is described as
treatment‐resistant depression (TRD) (McIntyre etal, 2023). Associative
conditions for TRD are diabetes, obesity and CVD, all of which are associated
with low functional vitamin B2.
Treatment with Antipyschotics Even a
preliminary comparison to the processes outlined above, quickly draws
similarities between treatment of depression and the use of highly addictive
anti-psychotic medications such as Tiotthixine, pimozide, ueiapnie,
chlorpromazine, clozapine, and fluphenzaine. The action of these drugs
involves the inhibition of different receptors,
including 5-HT (serotonin), dopaminergic, histaminergic,
and adrenergic receptors,
all of which are over-stimulated in Methyl B12 deficiency. Withdrawal symptoms
are compensurate with this including insomnia (lack of melatonin), anxiety and
depression (Storck et al, 2024). Given
that SSRIs are used to treat a range of conditions from depression, anxiety,
OCD, panic disorder, severe phobias, PTSD, etc, one could assume that they have
similar mechanisms to that outlined for depression. Drugs include Zooloft,
Lexapro, Celexa, Prosac, Brisdelle, Paxil, etc. The current market is over
US$150 billion, and one can assume that it is definitely NOT in the best
interests of the drug companies and the psychiatrists, who charge $300-650 per
visit, and who are urging patients to see them one or two times per week, to be
made aware that the majority of these conditions are due to simple nutritional
deficiency(ies).. It is clear from the literature that many experts in the field
do not have a clue (Fuentes-Claramonte
etal, 2024; Wang et al, 2022; Prata et al, 2014; Goff et al, 2016; Mirzakhanian
et al, 2014; Bhatia and Singh, 2015). This is despite tell tale markers such as
elevated homocysteine (Moradi et al, 2021; Bremner et al, 2021; Almeida et al,
2008_ elevated folate (Bottiglieri et al, 2005; Khosravi et al, 2020) There are many
neuropsychiatric symptoms associated with functional vitamin B12 deficiency,
including, depression, anxiety, psychosies, dementia, delirium, apathy,
agitation, impraired concentration, insomnia, persecutory delusions, auditory
and visual hallucinations, and disorganized thought processes.
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relationship between dietary patterns and depression mediated by serum levels of
Folate and vitamin B12. BMC Psychiatry. 2020 Feb 13;20(1):63. doi:
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Sites on depression in the young
http://prp.jasonfoundation.com/facts/youth-suicide-statistics/
https://afsp.org/about-suicide/suicide-statistics/
https://afsp.org/about-suicide/suicide-statistics/
Support sites for treatment of depression
https://www.beyondblue.org.au/
Spoke to a Bloke | Men's Mental Health
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B12 Deficiency and Depression
Other signs of Vitamin B12
Deficiency in Adults
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