B Vitamins & Neuropsychiatric Disorders—A Causal Relationship

In this episode of Daily Value, we look at the latest research on B vitamins and their in neuropsychiatric disorders. A newly published meta-analysis suggests a causal relationship between B vitamin deficiencies and neuropsychiatric disorders. We will break down the scientific findings on B6, B12, and folate, shedding light on their roles in conditions like Parkinson’s disease.

Discussion Points:

• How recent genetic studies support a causal link between B vitamin deficiencies and mental health conditions.
• The role of B vitamins in reducing neurotoxicity and slowing brain atrophy.
• How vitamin B12 may protect against dopamine neuron loss and disease progression.
• Evidence linking low B6 levels to neurotransmitter imbalances and schizophrenia risk.
• The impact of folate on one-carbon metabolism and its protective role in neurodegeneration.

https://www.sciencedirect.com/science/article/abs/pii/S0149763425000685#:~:text=In a meta-analysis of,beneficial for certain specific diseases.

https://pubmed.ncbi.nlm.nih.gov/26757190/

https://pubmed.ncbi.nlm.nih.gov/32257364/

https://pubmed.ncbi.nlm.nih.gov/30858560/

https://pubmed.ncbi.nlm.nih.gov/32424116/

https://pubmed.ncbi.nlm.nih.gov/33941768/

Transcript

Speaker 0: 0:00

For the first time, a meta-analysis was just published suggesting a causal relationship between B vitamins, specifically not getting enough of certain B vitamins, and the development of neuropsychiatric disorders. Hello everyone and welcome back to Daily Value. I'm William Walsh and today we're taking a look at how B vitamins influence our mental health and brain function. In today's episode we'll break down the latest evidence on this topic, examining how B vitamins relate to neuropsychiatric disorders overall, how they interact with homocysteine and mild cognitive impairment, and their roles in Parkinson's disease and schizophrenia. We'll start with the meta-analysis I mentioned and then look at individual B vitamins to see how they may be exerting their effects. This meta-analysis that is slated for publication in the March issue of Nerve Science and Behavioral Reviews titled Causal Relationship Between B Vitamins and Neuropsychiatric Disorders a Systematic Review and Meta-Analysis. This review focused on studies that use Mendelian randomization. This was unique because these types of studies use genetic variants as proxies for an exposure, like levels of B vitamins, to test whether that exposure is causally related to an outcome such as a neuropsychiatric disorder. Because genetic variants are randomly assorted to people at conception, this method minimizes the confounding factors and reverse causation that often affect observational studies. This meta-analysis found that individual B vitamins have distinct impacts on mental health. For instance, vitamin B12 is protective against the development of Parkinson's disease, vitamin B6 was found to be protective against schizophrenia, and vitamin B9, that's folate is protective against intellectual disabilities and Alzheimer's disease. When broken down into subgroups, all three B vitamins were found to be strongly protective factors against the development of Alzheimer's and Parkinson's disease.

Speaker 0: 1:56

What do all three of these B vitamins have in common? Well, they're all cornerstone nutrients of what's called one-carbon metabolism. I covered this topic in episode 27, but I will briefly explain it again here. One-carbon metabolism is a network of biochemical pathways that transfers single-carbon units between molecules to support essential cellular functions like supporting DNA synthesis, repair and methylation. These three B vitamins are responsible for converting homocysteine, a neurotoxic amino acid, into methionine, a precursor to S-adenosylmethionine, or SAMe as most of us know it. Same is a universal methyl donor involved in DNA methylation.

Speaker 0: 2:38

It's well known that abnormally high levels of homocysteine often accompany neuropsychiatric disorders, with potential mechanisms behind this, including oxidative stress, vascular damage and neurotransmitter dysfunctions. Genetic variants in one-carbon metabolism pathways have been linked to altered B vitamin metabolism and increased susceptibility to neuropsychiatric disorders. Homocysteine has also been shown to interfere with metabolism of amyloid beta plaques, these plaques being one of the pathological hallmarks of Alzheimer's disease. One particular study, known as the VITACOG trial, looked at whether B vitamin supplementation, specifically 800 micrograms of folate, 20 milligrams of vitamin B6, and 500 micrograms of vitamin B12, could slow cognitive decline. In this study, b vitamin supplementation slowed brain atrophy by up to 30% in participants with elevated homocysteine levels, that's homocysteine over 11 micromoles per liter. Those results were found in people who had the best omega-3 status, showing the importance of how multiple nutrients work together as it pertains to Parkinson's disease.

Speaker 0: 3:47

Vitamin B12 has the strongest relationship of the B vitamin families. Research has consistently shown that patients with Parkinson's often present with lower vitamin B12 levels at the time of diagnosis, compared to patients with other neurodegenerative conditions, such as progressive supranuclear palsy, frontotemporal dementia or dementia with Lewy bodies. One study reported that while vitamin B12 levels in Parkinson's patients were, on average, lower, the rate of decline in vitamin B12 was far more striking. Parkinson's patients exhibit a decline in blood vitamin B12 levels between 17 and 47 picograms per milliliter per year. In a healthy person over 65 years old, b12 levels should only drop around 5 picograms per milliliter per year.

Speaker 0: 4:35

Now there are two active forms of vitamin B12. There is methylcobalamin, which is the form involved in one-carbon metabolism and the breakdown of homocysteine. And then there is the lesser appreciated adenosylcobalamin, which is the form involved in one-carbon metabolism and the breakdown of homocysteine. And then there is the lesser-appreciated adenosylcobalamin, which serves a different function. It is situated inside mitochondria and is used by the enzyme methylmalonyl-CoA mutase to convert methylmalonyl-CoA into succinyl-CoA. If adenosylcobalamin is lacking, methylmalonyl-coa will convert into methylmalonic acid, which is a marker of vitamin B12 deficiency.

Speaker 0: 5:08

Now a very interesting and groundbreaking molecular-based study published in 2019 showed that adenosylcobalamin acts as what is known as a mixed-type allosteric inhibitor of LRK2 kinase, a protein whose hyperactivity is closely linked to neurotoxicity in Parkinson's. Mutations to LRK2 are the most common causal genetic variants for Parkinson's disease. When this enzyme activity is increased, alpha-synuclein proteins form and build up. These are toxic to dopamine neurons In vitro, so this was again a mechanistic cell-based study. Adenosylcobalamin inhibited LRK2 activity. This study also had an animal-based portion, where adenosylcobalamin not only reduced LRK2 hyperactivity, but also improved dopamine release and sustained the life of dopamine neurons, which are eventually overcome by toxic protein buildup caused by some LRK2 mutations in Parkinson's disease. Collectively, the body of work suggests that adequate B12 levels might not only prevent deficiency-related complications, but they could also modulate B12. Disease processes at the molecular level in Parkinson's disease.

Speaker 0: 6:17

Now on to vitamin B6 and its interesting connection to schizophrenia. Several meta-analyses have shown that individuals with schizophrenia have significantly lower levels of vitamin B6, specifically reduced pyridoxal levels, compared to healthy controls. Three clinical trials between 2010 and 2014 showed that peripheral blood levels of pyridoxal in patients with schizophrenia was significantly less than that of healthy controls. This was replicated by another study in 2014 and yet another in 2018. Interestingly, a review paper published in 2020 by Carvalho et al screened 162 peripheral biomarkers for major mental disorders and determined that vitamin B6 may be the most compelling evidence as a peripheral biomarker for schizophrenia, meaning that blood levels may be useful when attempting to diagnose someone with schizophrenia or evaluating risk for schizophrenia.

Speaker 0: 7:13

There was a notable rodent study published in 2021 by Toriumi et al, where the researchers generated a mouse model of vitamin B6 deficiency. In these vitamin B6 deficient mice, vitamin B6 levels dropped to just 2.9%. Behaviorally, these mice exhibited striking social deficits and significant impairments in recognition memory. Social deficits and significant impairments in recognition memory. Beyond behavior, biochemical analysis revealed that, while baseline levels of noradrenaline in the brain remained unchanged, the release of noradrenaline was significantly enhanced in both the prefrontal cortex and the striatum. This hyperactivation of the noradrenergic system is thought to contribute to the social and cognitive impairments that are seen in schizophrenia. Importantly, when researchers administered vitamin B6 directly into the brain of the rodents, the behavioral deficits were restored nearly to normal. Collectively available evidence to date points to reduced vitamin B6 contributing to schizophrenia's pathophysiology by disrupting neurotransmitter balance.

Speaker 0: 8:18

And finally, let's turn to folate. The meta-analysis referenced at the beginning of this episode suggests that folate was linked to a significantly reduced risk of developing Alzheimer's, with an odds ratio of around 0.35. This suggests that individuals with higher folate levels may have approximately a 65% lower risk of Alzheimer's compared to those with lower levels of folate. Again, this finding is interesting because Mendelian randomization helps confirm that the association isn't merely correlational but is more likely to reflect a causal relationship. To sum up, the emerging evidence from genetic studies, clinical trials and animal models converges on one key message B vitamins are potent modulators of brain health, each with a unique profile of benefits and risks.

Speaker 0: 9:07

Vitamin B6, while protective against Alzheimer's and schizophrenia, its deficiency might exacerbate symptoms of schizophrenia through hyperactivation of the neuroadrenergic system. On the other hand, it's important to note that, while moderate vitamin B6 supports neurotransmitter balance, excessive intake has been linked to sensory neuropathy. Vitamin B12 deficiency is prevalent in Parkinson's disease and may directly impact disease progression by modulating gene activity that is thought to be causal to Parkinson's disease. While folate not only supports cognitive function through all life stages, it also appears to be protective against Alzheimer's disease, likely through its role in one-carbon metabolism. Thank you for joining me today on Daily Value. If you found this episode insightful, please share with your network. As always, stay curious and stay healthy.