Brief Summary
Dr. Deb Simkin discusses integrative approaches to autism and psychosis, emphasizing the importance of addressing neurophysiological and metabolic factors. She highlights the role of methylation cycles, oxidative stress, and the gut microbiome in these conditions. Dr. Simkin advocates for a personalized approach, considering genetic predispositions, environmental insults, and lifestyle factors to improve outcomes for individuals with autism and psychosis.
- Neurophysiological and metabolic factors play a significant role in autism.
- Methylation cycles and oxidative stress are crucial considerations in both autism and psychosis.
- Gut health and the microbiome are integral to overall health and can impact brain function.
Introduction
Dr. Deb Simkin, an integrative psychiatrist with extensive experience and training in functional medicine and neurofeedback, will discuss integrative approaches to autism and psychosis. She will cover aspects applicable to both conditions, drawing from her expertise and co-authored works on the subject.
Three Approaches to Autism
There are three ways to approach autism: neurophysiologically, metabolically, and through research domain criteria. Neurophysiologically, autism involves decreased synaptic pruning, excessive local connectivity, reduced long-range connectivity, increased excitatory/inhibitory neurotransmitter ratios, and inflammation, with 20-50% of autistic children experiencing seizures. Metabolically, mitochondrial function is crucial, with factors like mold, candida, and heavy metals interfering with the electron transport system. Oxidative stress also impacts mitochondria, and assessing levels of succinate and fumerate can indicate metabolic interference.
Mitochondrial Damage and Electron Transport
Mitochondria can be damaged by oxidative stress from medications, heavy metals, toxic chemicals, PCBs, pesticides, gene mutations, vitamin and mineral deficiencies, and certain bacteria and viruses. The electron transport system requires key nutrients like CoQ10, niacin, riboflavin, Vitamin K, and Vitamin C. Deficiencies in these nutrients should be addressed to support mitochondrial function.
Methylation Cycles and Research Domain Criteria
Methylation cycles play a significant role in psychosis, autism, and depression. Environmental insults, the age at which they occur, epigenetic effects, and inflammation all influence brain connectivity. The research domain criteria from the National Institute of Mental Health (NIMH) are used to understand the source of these disorders, moving beyond the limitations of the DSM.
Folate and Methylation Cycle
When considering folate and methylation cycles, it's important to be aware of factors like MTHFR gene variants (AC, CT, TT alleles). These variants affect the conversion of inactive vitamin B9 (folate) to its active form. Defective genes and disbiosis can also prevent folate absorption. Meta-analyses of folate effectiveness should account for MTHFR gene status, folate antibody receptors, and absorption issues.
SAM-e and DNA Methylation
To properly assess the methylation cycle, all involved genes and the folate cycle must be evaluated. Proper function is essential for producing SAM-e, which is responsible for neurotransmitter production and DNA methylation. Early disruptions in these processes can have lifelong effects.
Detailed Look at the Methylation Cycle
Folate, in its inactive form, must be converted to L-methylfolate (5-MTHF), the active form. This process involves multiple steps and requires B6. Active L-methylfolate combines with homocysteine and methyl B12 to produce methionine, which then leads to SAM-e and DNA methylation. Homocysteine may be diverted from the methylation cycle due to oxidative stress, being used instead to produce glutathione.
MTHFR and Autism Risk
A meta-analysis of MTHFR and autism association indicates that the MTHFR C>T variant may increase the risk of autism overall. The 1298 A>C variant was significantly associated with autism risk, particularly in Caucasians, highlighting the role of ethnicity.
Factors Affecting Folate and B12 Absorption
Factors beyond the folate and methylation cycle can indirectly affect these processes. Poor absorption of B12 and B9, disbiosis, and leaky gut can hinder nutrient uptake. The FOH1L gene can prevent folate absorption even in a healthy gut. Folate receptor antibodies prevent folate from entering the brain. MTHFR gene variants (CT and TT) reduce the conversion rate of inactive to active folate.
Homocysteine Levels and Schizophrenia
High homocysteine levels, especially with MTHFR gene variants, indicate impaired folate utilization. In schizophrenia, elevated homocysteine worsens cognitive problems. Functional medicine considers optimal homocysteine levels to be between 4 and 8, while standard labs may have a range of 4 to 12. Supplementation with B6, B12, and L-methylfolate may be necessary.
Alternative Folate Cycle
An alternative cycle exists to the left of the traditional folate cycle, influencing DNA formation, oxidative stress, and neurotransmitter production. Folate becomes dihydrofolic acid (DHF), then tetrahydrofolate (THF), and finally N5-N10 methylin THF. However, DHF can cycle back, interacting to produce pyrimidine bases (cytosine and thymine) for DNA. Defects in this process impair DNA methylation.
THF and Purine Bases
THF can convert to 10-formyl THF, forming purine bases (adenine and guanine). If this process is impaired, DNA methylation is compromised. This process also produces GTP, crucial for neurotransmitter production and reducing oxidative stress.
GTP and Oxidative Stress
Folate or decreased THF production due to DHFR enzyme defects can affect DNA synthesis. Oxidative stress increases if GTP is not adequately produced. Defects in the DHFR enzyme, common in autistic children, lead to increased oxidative stress due to reduced GTP production.
BH4 Production and Neurotransmitters
GTP produces BH4, a co-actor for enzymes that produce serotonin, dopamine, and nitric oxide, which reduces oxidative stress. Low BH4 levels impair serotonin and dopamine production, leading to increased free radicals. DHFR can convert BH2 to BH4 if enough GTP is available. Low BH4 levels can also reduce THF and L-methylfolate production.
DHFR Deficits in Autism
High BH2 levels decrease THF levels because DHFR has a higher affinity for BH2 than DHF, prioritizing BH4 production. DHFR deficits are common in autism, influencing these processes. Measuring these factors at birth could potentially mitigate the severity of the disease.
Oxidative Stress and SAM-e Levels
Oxidative stress lowers SAM-e levels because homocysteine is diverted to produce glutathione. SAM-e is sacrificed, producing SAH and more homocysteine to combat reactive oxygen species. Genova diagnostics can assess these enzymes and components, potentially improving outcomes, though it is costly.
Glutathione and Oxidative Stress
Glutathione, an antioxidant, requires selenium. The GSH to GSSH ratio indicates oxidative stress levels. Low GSH and high GSSH suggest significant oxidative stress, warranting the use of NAC to increase glutathione and reduce homocysteine diversion.
MTHFR and Cardiac Disease Risk
Individuals with MTHFR (TT) convert inactive folate to active folate only about 65% of the time. TT carriers with a history of chronic abuse are prone to more severe depressions. Elevated homocysteine levels in TT carriers increase the risk of cardiac disease, highlighting the importance of a functional medicine approach.
Factors Influencing Oxidative Stress
Besides glutathione, environmental toxins and heavy metals contribute to oxidative stress and neurotoxicity. This leads to intestinal tract degeneration, increased permeability, and autoimmunity. Gram-negative bacteria disbiosis produces LPS, triggering immune reactions and cytokine production.
Vitamin C, E, and Decreased Methylation
Vitamin C and E are also antioxidants that influence oxidative stress. Decreased methylation can result from various factors, causing cell damage. The COMT gene influences dopamine breakdown, with Val/Val variants indicating faster dopamine breakdown and impaired DNA methylation.
Arsenic, Immune System, and Disbiosis
Arsenic significantly increases oxidative stress. Autism is associated with a higher risk of allergies, autoimmunity, and inflammation, often due to microbiome depletion from stress, toxins, antibiotics, H2 blockers, antiacids, and glyphosate. Lifestyle factors are crucial in integrative medicine.
Brain HPA Hypersensitivity and Disbiosis
Brain HPA hypersensitivity, linked to autism and psychosis, occurs when the vagal nerve detects cytokines from disbiosis, opening the blood-brain barrier and preventing HPA axis shutdown. Chronic abuse before age seven can epigenetically alter the brain, reducing cortisol receptor numbers.
Disbiosis and Chronic Illness
Disbiosis results from LPS crossing the blood-brain barrier. Lack of beneficial bacteria reduces short-chain fatty acids, impairing gut integrity and serotonin production. This triggers cytokine production and activates TNF Kappa Beta, leading to cancer, autoimmune diseases, diabetes, and high blood pressure. The gut is linked to many chronic illnesses.
Methylation Cycle and Autism Study
A study on the methylation cycle in autistic children found low methionine and SAM-e, high homocysteine and SAH, and low cystathionine, cysteine, and total glutathione. SAM-e is diverted, reducing DNA methylation and neurotransmitter production. Low methionine levels are also associated with autism.
Folinic Acid and Bentaine
Folinic acid and bentaine can be used to bypass methylation issues. Folinic acid can enter the brain even with a folate receptor antibody, while bentaine provides a folate-independent pathway for regenerating methionine. Folinic acid comes in right here at the 5-10 methylin THF.
Folate Receptor Antibody and Folinic Acid
For individuals with a folate receptor antibody, folinic acid can be effective. Folinic acid can get in when folate can't pass through the blood-brain barrier. Insurance companies may cover folinic acid (leucovorin) if proven necessary.
GSH/GSSH Ratio and Folinic Acid
Studies show that folinic acid can reverse the GSH/GSSH ratio, enabling appropriate homocysteine utilization. SAM-e levels increase, SAH levels decrease, and adenosine levels decrease.
Mega Cisterna Magna and Methylation
Individuals with mega cisterna magna, associated with psychosis, have shown remarkable improvement with methylation and folate cycle interventions. Markers for oxidative stress, such as lactate and pyruvate levels, can also be assessed.
Integrative Medicine Training
Dr. Simkin recommends certification in functional medicine and emphasizes the importance of integrating this knowledge with complementary integrative medicine. Functional medicine involves looking at antecedents, genetic predispositions, triggers, and sustaining factors. The Institute of Functional Medicine provides comprehensive training.
Training in Integrative Medicine
For integrative medicine training, Dr. Simkin suggests the program in Arizona as a premier model. She also recommends the book "Complementary Integrative Medicine and Child and Adolescent Psychiatric Disorders."
Folate Receptor Antibody and Milk
If someone has a folate receptor antibody, avoiding milk is crucial, as it can keep the antibody levels high even with folinic acid supplementation.
Key Considerations for Autism
Key considerations for autism include folate, folinic acid supplementation, and omega-3 fatty acids. It's essential to assess MTHFR genes, MS (which utilizes B12 and homocysteine), and MTRR (which remethylates B12). The FOLH1 gene prevents folate absorption from the gut.
Melatonin and Omega-3 Fatty Acids
Melatonin is effective in autism due to defects in a specific gene. Omega-3 fatty acids should have a 2:1 ratio of EPA to DHA, with at least 2,000 milligrams.
