Schizophrenia risk factors may also be Alzheimer's risk factors; Experimental design and variables.
Porridge update; Why bother with multifactorial problems? It's all so complicated! Why bother? Because pain hurts, health is better - and possible more often than admitted or recognized by mainstream.
Porridge update - A Tale of Two Porridges - the why bother was to increase protein in a daily meal for both my parents and remove the histamine triggers from my mother’s porridge. The Good News update - I asked my dad recently what he wanted for breakfast, “I want porridge. It is yummy.” This may seem mild, but from him, it is praise.
The good news from my mom, more lucid moments and daily function improvements, and less panicky paranoia, wandering and trying to leave. My mom to me: “I’m glad you’re here.” and “Help me survive. I like myself.” I about cried, she has been so ashamed of her lack of function and too much was being expected of her when I wasn’t here. I regularly tell her that she is retired now, and that I am here to help. She forgets during worse times why there is a stranger in the house and can be threatening when feeling threatened.
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Dementia is not kind to the person or the family.
Why bother making so many complicated changes?
To protect function and help to have better quality of life. Dementia with brain cell damage is not a standard part of aging.
Why look at schizophrenia in depth? It can cause severe dysfunction and lead to self harm and suicide and other life problems. Treatments for it often have very negative side effects and patients may be forced to comply by legal means. AND schizophrenia does seem to be related to having an increased risk for dementia later in life, possibly very increased: Relative Risk 2.29 with a Confidence Interval range of 1.35-3.88. (100)
“Evidence suggests that schizophrenia may be associated with an increased risk of dementia, but results from prior studies have been inconsistent. […]
Results: Six studies met our inclusion criteria for this meta-analysis, which included 206,694 cases of dementia and 5,063,316 participants. All individuals were without dementia at baseline. Overall, the quantitative meta-analysis suggested that subjects with schizophrenia were associated with a significantly greater risk of dementia incidence (RR 2.29; 95% CI 1.35–3.88) than those without.
Conclusion: The results of this meta-analysis indicate that individuals with schizophrenia may have an increased risk for the development of dementia. Future studies should explore whether schizophrenia is a modifiable risk factor for dementia.” (Cai & Huang, 2018) (100)
Relative risk (RR) compares the health risk facing the condition group (schizophrenia) compared to the health risk for a person of general health (control group). Any Relative risk number above one, 1.0, means the person with the condition or exposure to something is more at risk for the outcome; and a RR below one, 1.0, means they would be less at risk for that condition than the average population.
The Confidence Interval (CI) range suggests precision of the average or lack of precision. A wide range means there was more variation in individual results and a narrow range would mean the individuals were all fairly close to having a similar Relative Risk instead of some of the group being at much higher risk: “3.88,” compared to others with only a slightly elevated risk above the norm: “1.35.” (100)
What are the underlying causal factors involved? Why are some at very high risk (“3.88 RR”) for developing dementia while others are only at slightly elevated risk (“1.35 RR”)? (100)
Does having schizophrenia increase risk for dementia later in life?
Yes, according to various studies “…but results from prior studies have been inconsistent.” (100)
Why are some at more risk than others? Why are all at increased risk on average?
In reading about histamine excess I saw that having it was associated with an increased risk for a schizophrenia diagnosis eventually and later a dementia diagnosis - both of which I would prefer to avoid. Alzheimer’s dementia is in my family medical history with my mother and a maternal uncle.
Variability though is present even within my group of two - my mother and I both have the histamine excess problem but over activation of vitamin A to Retinoic Acid does not seem to be a problem for her. Just me. I give her carrots and other healthy carotenoid sources frequently and there seems to be no link to when the paranoia fear episodes occur. Eating Chinese takeout though is an obvious trigger, seen within a few hours. It would be a histamine trigger with the soy sauce and a glutamate excitatory risk. It feels good to eat trigger foods initially - exciting, then the inflammation happens later.
Therapeutic Trial -
Do the symptoms fit? Is the treatment safe? Just try it and see if it helps.
Individuals vary, potential risk factors mean there may or may not be a problem with each item. We don’t know though without screening or just trying the mitigation solution and see if it helps.
Prior to the ease of lab testing many physicians would have a Therapeutic Trial - if the symptoms suggest a diagnosis and the treatment is safe and available, then just try it. If it works, then there you go, it was the correct diagnosis probably and the patient/customer is healthier. Problem solved with no modern lab test used.
The list of nutrient deficiencies or imbalances that may be involved in schizophrenia is long - but would not be uncommon in the modern world with the modern diet.
Low vitamin D (can also be low magnesium or excess glyphosate) or gene differences in the Vitamin D Receptor (VDR). (47) VDR gene alleles are also seen in bipolar disorder. (48) Low vit D is a factor in Toxoplasmosis risk. (76)
Low iodine/hypothyroidism / excess fluoride, bromide and perchlorates. (55)
Excess copper in relation to a low zinc level - may be dietary or genetic - the copper/zinc transport protein dysbindin would be needed as a treatment if that was an underlying factor. (Dysbindin:56, 57, 58, 81),
Low trace minerals or excess, or imbalance - it is complex - some with individual impact: Zinc, Cobalt, Chromium, “Zn, Co and Cr”; or in combination with a group of minerals: Selenium, Lead, Phosphorus, Tellurium, Copper, and Thallium, “including Se, Pb, P, Te, Cu and Tl”, or a few that might affect it either individually or in a combination of minerals “such as Cs,” Cesium. Most were low or moderately low, a few were in excess (lead, iron). (83) Elevated iron is seen in chronic inflammation and adds to risk. Lead is a neurotoxin - avoid it.
Low Cesium is also seen in Alzheimer’s. The research team speculate that it may chelate misfolded proteins. “The potential relationship between Cs and Schizophrenia may be due to its chelating proteins, such as amyloid-β (Aβ) and apolipoprotein (APOE) and adjusting oxidative status in the brain 27.” (83)
B vitamins – gene methylation difference and/or pyroluria may be factors in chronic deficiency.
Low methyl folate and methyl B12; possibly methylation gene differences. (55)
Low B6, (82)
B6, B8 (Inositol), and B12 supplementation helped. (85)
Low niacin – or a need for more than average for an unknown reason at this time. (45)
Vit C, Cofactors, Essential omega 3 fatty acid DHA/EPA and endocannabinoids.
Vitamin C supplementation helped, along with standard medication. (88)
Alpha lipoic acid helped, “(100 mg/d) for 4 months” and standard med. (86)
CoQ10 supplementation found no difference – adherence taking the supplements may have dropped off. Blood levels of CoQ10 in the treatment group were raised at 3 months and not at 6 months compared to the control group. (87)
Low DHA/EPA, omega 3 fatty acid: Supplementation helped most in early stages, fewer patients advancing to worse psychosis was observed, particularly helpful for adolescents with a baseline low DHA. Symptom improvement was seen for patients with a long-term diagnosis of schizophrenia. (43)
Low 2-AG (CBD equivalent) in relation to anandamide (THC equiv.). (49)
There is a genetic risk for low 2-AG (CBD equivalent) in relation to anandamide (THC equivalent). (49) Providing CBD may help particularly in early stages of the condition. (50) The genetic difference that might make someone more susceptible to developing schizophrenia may involve a gene difference in Cannabinoid Receptor Type 2. (75) CBD/2-AG is the main agonist for them. (51, 77) People with Cystic Fibrosis or a BHMT gene allele can’t make cannabinoids for different reasons, and both would be low in both 2-AG and anandamide. They also have an increased risk for social anxiety conditions later in life. The risk was reduced when treatment with cannabinoids was given in early infancy (animal-based study, cystic fibrosis model). (52)
Glutathione levels were found to vary, with a wider range than the control, more elevated, and more low levels than in the non-schizophrenia group, but overall the average glutathione level was not significantly different in the schizophrenia group. (88)
Glutathione continued - The meta-analysis team suggest further study following the patients for a longer time period to see if there is an increase in glutathione during active psychosis phases as a response to increased glutamate activity, followed by a drop in glutathione to below average. (88) This is an example of how a group average can suggest “normal” when a closer look would show there was a wide range in response. Some below normal and some above normal would average out to “normal.” As a research result that would be unhelpful information for individuals who might be in the actually below normal group. They would need Nrf2 promoting foods and NAC or whey powder and glycine possibly, to promote glutathione production and provide the precursor amino acids.
Multifactorial conditions can have a few or many of multiple causal risk factors. Listing potential risks does not mean that all people with the condition have all of the concerns. It means - FIND OUT who does.
Trying to design a study that controlled for all of that list would require pre-screening, a baseline, for all of the known potential gene differences and nutrient deficiencies or imbalances. We need to know what our starting line is, then run the race to see what the outcome is for a proposed experimental change.
A study about schizophrenia that looked for the dysbindin gene allele in a population of Irish people (103, viewable at 102) might convince everyone that schizophrenia is a condition caused by dysbindin dysfunction - they need an external source to make up for loss of function.
But what if some people may have too much dysbindin activity and that is also a causal factor? A study that just averaged dysbindin levels together would make a experimental population with some low levels and some elevated levels average into “normal” - which would make it not be a factor in the group with schizophrenia compared to a control group without the condition - both groups averaged “normal”. Research teams would look for patterns in the raw data too.
Dysbindin over activity could be a risk factor for Alzheimer’s dementia as it seems to modulate glutamate release. Low dysbindin can lower glutamate release while elevated levels promote release. In a mixed group of people with schizophrenia who had varied activity levels of dysbindin, there might also be varied risk for Alzheimer’s - some reduced risk* with lower dysbindin activity, and some with elevated risk* with overactive expression of dysbindin. *Many things are involved in risk for developing Alzheimer’s and schizophrenia; one variable would not define overall risk.
“In vitro work indicates that reduction in dysbindin can lower glutamate release, whereas overexpression of dysbindin elevates glutamate release, suggesting a modulatory role for dysbindin in glutamate neurotransmission is indicated in cortical neuronal cultures (Numakawa et al., 2004).” (Von Cheong, O’Tuathaigh, 2016) (101, viewable at 102)
“Modifiable” ~ treatable, able to be improved or restored to function.
Much of the lengthy list of nutrients involved in schizophrenia is “modifiable”, (100), with nutrient supplementation and/or diet changes. Genetic screening would make it easier to identify some of the nutrient needs and would be critically important for identifying the dysbindin gene difference. Dysbindin or isoforms can be provided if the problem is a dysfunctional protein transport protein; the supplement/medication would be needed life-long, as it is a life-long genetic difference.
People with methylation differences would need methyl forms of B12 and folate in fortified foods or supplements, for life. People with pyroluria (frequently not screened for or treated still) would need B6 and zinc in above average doses, for life.
People with a BHMT double gene allele like me would need supplements of amino acids methionine and Dimethylglycine (DMG). I find avoiding rich sources of betaine (TMG) helpful, quinoa being the example food that seems to leave me queasy after eating. Without the BHMT enzyme, I can’t convert TMG/betaine to DMG). With the double BHMT gene allele, I also need an external source of balanced cannabinoids, for life. In moderate amounts it helps nerve transmission, or inhibition. Cannabinoids help with movement and memory formation or breakdown. Lack seems to be involved in PTSD - not forgetting trauma.
Epigenetic differences may be modifiable in a way that reverses the change, which can occur with Postural orthostatic tachycardia syndrome (POTS). Methyl donors are needed: choline, methyl folate and methyl/hydroxy cobalamin (B12 that isn’t cyanocobalamin). Also avoiding formaldehyde and other volatile chemicals is important. They are found in smog, smoking or old stale smokey furnishings, or new vinyl furnishings. Negative ionizers can help remove volatile chemicals by clumping with them and causing the larger particle to fall to the floor (mop more often - good exercise too).
20 Research Variables? No problem…well, it would be difficult and expensive. But trend setting and the type of treatment that likely IS needed.
Returning to the research design problem - we have a list of 19 potential problems associated with risk for schizophrenia or treatment of the condition. Rounding that to 20 to make an easier example - our research team needs to screen for 20 variables (some of which included many individual items, so 20 is a low estimate of the problem size). Ideally the control group without schizophrenia and the group with the diagnosis would be screened initially for a baseline and then periodically after treatment started. The prescreening would identify each individual’s own deficiencies, imbalances, or genetic differences, and treatment would be varied according to that individual need.
Statistically a complex analysis would be needed to look for clusters - are certain nutrient deficiencies primarily seen only in people with a matching genetic issue? Or are some more common throughout all the (schizophrenia) treatment group as a whole? Guidance would be easier when something can be recommended to a whole group without needing individual screening first.
Regional patterns are also seen - low selenium soil is a risk factor, but the average modern diet can also be low in selenium.
With our ‘20 things’, one of the experimental group might have ten issues to work on, another might share four of those and have six other deficiencies. A third person might have most of the list and be quite malnourished.
Multifactorial issues can’t be treated with a single “cure”, therefore the research design may need to plan for the screening, the individualized treatment, and documenting the individual plans in a way that the data can be looked at as a whole and grouped as needed into smaller sets - how are the B vitamin levels? the trace minerals? Iodine and DHA? Mitochondrial support nutrients? Methyl donors? Lipid and inflammation lab panels?
My hypothesis would be that many people with schizophrenia would have multiple deficiencies beyond zinc and copper or dysbindin gene differences. Preparing and eating balanced meals is not easy with a good budget, plenty of time, and well stocked kitchen - it is harder without those things, and even harder without rational thinking ability.
When histamine excess is an issue, rational thinking might not be present, every single day. It can become hard to remember there had been a “normal” that was not so whirly and anxious and jittery. It can be even harder to remember when health professionals tell you that your symptoms must be psychological as your lab tests are normal. Which lab tests were taken? What was the “normal” range based on?
Standard diets include many histamine trigger foods leading to symptoms the next day, which equals every day when it is the daily food choices. Not many people stop eating all of their normal foods all at the same time - and switch to low inflammatory foods that provide adequate protein and trace nutrients at the same time* - so they can see that their daily “mental illness” was actually food related. *Substituting a balanced non-inflammatory diet is needed to prevent other symptoms of malnourishment which can resemble “mental illness”.
Results we would hope for is an improvement in negative symptoms and a return of function and cognitive clarity. Reversal or improvement in psychosis frequency or severity would also be goals and possible if nutritional imbalance or histamine excess was a primary factor. It would be a goal to see if such a thorough screening and individualized treatment plan did not help some types of symptoms or for some subgroups of individuals. Another goal would be to assess for presence of misfolded proteins or other early signs of Alzheimer’s dementia and see whether treatment leads to an improvement in those numbers also.
In the field of nutrition, we play with the whole team. Any research that looks at one nutrient and whether it can treat a condition (other than deficiency of that nutrient) as a solo ‘medication’, is trying to send a baseball player out without the rest of the team. Is that solo player going to win the match? No, probably not.
Do we want patients to win the match? Get back on the playing field of life? It isn’t easy to be around people with mental illness symptoms, or odd personality traits, but it isn’t easy being them either.
Why bother? The increased suicide rate in children, and particularly children with ADHD, (94), that is the reason to bother. They may have Fetal Alcohol Syndrome effects of Retinoic Acid activation and might be a lot healthier and happier on a diet that restricts vitamin A and carotenoids. See later sections of this post: Rest in peace Dr. Zelenko - (substack.com) It would be nice to know if carrots are helping or harming - on an individual basis. We know on average they are helpful. No one person is an “average”. If we are pro-life, we need to be pro-child, and pro-adult, and that requires being pro-nutrition - the whole team.
Disclaimer: This information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.
Full Reference List is in a Word document - Rough times ahead.
100. Cai L, Huang J. Schizophrenia and risk of dementia: a meta-analysis study. Neuropsychiatr Dis Treat. 2018 Aug 13;14:2047-2055. doi: 10.2147/NDT.S172933. PMID: 30147318; PMCID: PMC6095111. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6095111/
101. E. Von Cheong, Colm M.P. O’Tuathaigh, Chapter 19 - Modeling Gene–Gene Interactions in Schizophrenia, Editor(s): Mikhail V. Pletnikov, John L. Waddington, Handbook of Behavioral Neuroscience, Elsevier, Volume 23, 2016, Pages 327-343, ISSN 1569-7339, ISBN 9780128009819, https://doi.org/10.1016/B978-0-12-800981-9.00019-5. https://www.sciencedirect.com/science/article/pii/B9780128009819000195
102. Dysbindin, ScienceDirect.com, https://www.sciencedirect.com/topics/neuroscience/dysbindin
103. Ruoqi Gao, Theron A. Russell, Peter Penzes, Chapter 22 - Synaptic Abnormalities and Neuroplasticity: Molecular Mechanisms of Cognitive Dysfunction in Genetic Mouse Models of Schizophrenia, Editor(s): Mikhail V. Pletnikov, John L. Waddington, Handbook of Behavioral Neuroscience, Elsevier, Volume 23, 2016, Pages 375-390, ISSN 1569-7339, ISBN 9780128009819, https://doi.org/10.1016/B978-0-12-800981-9.00022-5. https://www.sciencedirect.com/science/article/pii/B9780128009819000225
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