My ideas about the etiology of schizophrenia are presented in Treatment-resistant schizophrenia: focus on the transsulfuration pathway which was published in Reviews in the Neurosciences. The treatment section of the paper is out of date.
Everything should be made as simple as possible, but not simpler. – Albert Einstein.
First of all do no harm. Most importantly do not take any supplement that could raise L-cysteine levels except taurine which could spare cysteine. Second of all avoid the too be avoided supplements. Third of all cut out sodas, tea including herbal teas and greatly limit coffee intake. Two cups of coffee in the morning taken an hour before iron is supplemented seems the least harmful way to drink coffee. Supplemented iron from iron carbonyl is an antipsychotic. Anemia panels must be obtained. Se-methylselenocysteine will address disorganization. Taurine is taken to assist with absorption of fatty acids, spare cysteine and regulate calcium metabolism. Calcium hydroxyapatite is supplmented to assist with calcium metabolism. Pantothenic acid, biotin and sodium bicarbonate are supplemented. The sodium-dependent multivitamin transporter ( SMVT) is pH and sodium dependent. Sodium bicarbonate would stabilize the SMVT. The SMVT also transports iodine. Iodine is supplemented. Butter or ghee will support increased beta-oxidation and supply non-essential fatty acids. With dysregulation of biotin metabolism there are shortages of malonyl-CoA which leads to increased beta-oxidation and impaired synthesis of non-essential fatty acids. Fats in butter are first in line in terms of synthesis of non-essential fatty acids. Some non-essential fatty acids have become essential fatty acids. That iron carbonyl, Se-methylselenocysteine, taurine, pantothenic acid,biotin, sodium bicarbonate, iodine, and butter or ghee and calcium from calcium hydroxyapatite can address psychosis, disorganization and negative symptoms in schizophrenia is highly noteworthy.
With a dysregulation of the transsulfuration pathway (homocysteine to L-cysteine) sufficient L-cysteine for iron-sulfur cluster formation is not synthesized. Sulfur for iron-sulfur cluster biogenesis is derived from L-cysteine. Supplemental iron increases levels of iron-sulfur proteins. Supplemental iron can partly compensate for dysregulation of the transsulfuration pathway in schizophrenia. Selenomethionine, the food form of selenium is metabolized by enzymes in the transsulfuration pathway. Metabolism off Se-methylselenocysteine by-passes the transsulfuration pathway whereby Se-methylselenocysteine can provide bioavailable selenium for individuals with schizophrenia. Taurine is synthesized from L-cysteine. With L-cysteine not synthesized appropriately taurine will not be synthesized at appropriate levels. Taurine is needed to form various bile acids. With low levels of taurine there will not be sufficient taurine conjugated bile acids. Fat absorption requires bile acids. With low levels of taurine due to low levels of L-cysteine fat absorption will be impaired. Supplemental taurine will compensate for low levels of taurine due to low levels of L-cysteine which are in turn due to dysregulation of the transsulfuration pathway. Taurine by sparing L-cysteine will also increase levels of L-cysteine. Taurine will assist in the absorption of fatty acids. The SMVT is dysregulated, likely due to dysregulated sodium homeostasis attendant on dysregulation of taurine. Dysregulation of the SMVT calls for supplementation with biotin, pantothenic acid, iodine, sodium bicarbonate, butter or ghee and taurine. What happens in the gut is key to successful treatment. Aconitase 1 in the gut must be addressed by iron from iron carbonyl and taurine will improve fat absorption.
Iron from iron carbonyl and Se-methylselenocysteine can end treatment resistant schizophrenia. There would still be a humongous difficulty. Iron from iron carbonyl and Se-methylselenocysteine do not treat negative symptoms. Other supplements are needed to address negative symptoms and depression. A lot of the difficulties I had could be avoided if the ‘to be avoided supplements’ are avoided. Individuals could take iron carbonyl and Se-methylselenocysteine alone for psychosis and disorganization but at that point individuals would almost be committed to the complete treatment as even when one is not hallucinating or disorganized one can feel absolutely wretched. The treatment may not be totally effective against negative symptoms.
120 milligrams of iron from iron carbonyl is taken four times day. Iron from iron carbonyl is slowly absorbed from the gut which is a large plus. Iron carbonyl is a non-toxic form of iron. Iron carbonyl is taken with the other supplements. Anemia panels must be obtained to insure that iron levels are not high. 200 micrograms of Se-methylselenocysteine is taken once a day. 1000 mg. of taurine is taken 3 times a day. Biotin is needed for synthesis of non-essential fatty acids. See the page on bipolar disorder on how biotin metabolism can be dysregulated. 5 milligrams of biotin is taken three times a day. 500 milligrams of pantothenic acid is taken once a day away from biotin. Biotin must apparently be available in the gut so sublingual biotin is not taken. 325 micrograms of iodine from kelp is taken three times a day away from pantothenic acid. Sodium bicarbonate is taken 4 times a day to stabilize the SMVT in the gut. Each time sodium bicarbonate is taken a large glass of water must be drunk to prevent dehydration which could raise blood pressure. A tablespoon of butter or ghee is taken 2-4 times a day. 1000 mg. of calcium from calcium hydroxyapatite is taken daily in four divided doses. Taurine is involved in calcium homeostasis. With low levels of taurine calcium homeostasis is lost whereby the calcium-sensing receptor becomes dysregulated. The calcium-sensing receptor is expressed in the duodenum. Calcium agonizes the calcium-sensing receptor while calcium phosphate antagonizes the calcium-sensing receptor. Blood pressure should be monitored.
Very unfortunately in terms of acceptability and likely in terms of cholesterol supplemented fatty acids must be from butter or ghee. Various saturated fats have become essential. The beef tallow that can be purchased on the Web does not seem to reliably be beef tallow. Beef tallow purchased on the Web melts at room temperature which beef tallow should not do. Butter and ghee have higher levels of saturated fats and the butter sold in markets should reliably be butter.
Iron must be iron from iron carbonyl as iron carbonyl stays in the gut for an extended time. Iron sulfate is avoided as iron sulfate is quickly absorbed. Iron bisglycinate is avoided as iron from iron bisglycinate may not be available in the gut. The difficulty with heme iron polypeptide is that the iron in heme iron polypeptide may not have much of an effect on iron metabolism in the gut. Supplementation with heme iron polypeptide is avoided at least for now.
Taurocholic acid, derived from taurine, is a bile acid which aids in fat absorption. Supplemental taurine upregulates cystathionine beta-synthase and cystathionine gamma-lyase which are the two enzymes in the transsulfuraiton pathway (Sun et al., 2016). Supplemental taurine reduces homocysteine levels (Ahn, 2009) likely due to the upregulation of the transsulfuration pathway by taurine. Taurine reduces cholesterol levels (Guo et al., 2017; Chen et al., 2012). Taurine also has an anti-obesity effect. Taurine deficiencies result in premature aging. Taurine is negatively associated with ischemic heart disease. Taurine ameliorates diabetes. The Observed Safe Level for supplementation with L-taurine is 3 grams a day (Shao and Hathcock, 2008). Supplemental taurine can by aiding fat absorption and calcium homeostasis positively affect brain function.
Deceased levels of biotin would lead to increased beta-oxidation as decreased levels of biotin would decrease levels of malonyl-CoA which inhibits beta-oxidation. Increased beta-oxidation sounds terrific. Rev up metabolism, increase energy, burn fats, loose weight, live life to the fullest. However increased beta-oxidation due to decreases is biotin transport would also lead to decreases in fatty acid elongation which requires malonyl-CoA, leading to serious difficulties. See the page on bipolar disorder as to why there could be difficulties in biotin transport.
500 milligrams of pantothenic acid taken once a day away from biotin should can supply all the pantothenic acid one needs by passive diffusion.
Selenium has a very low margin of safety. No more than 200 micrograms of selenium is taken a day.
Calcium from calcium hydroxyapatite is required. Taurine regulates calcium transport. With deficiencies in taurine difficulties in calcium transport and homeostasis can arise. Phosphate binds to the calcium-sensing receptor blocking the calcium-sensing receptor. I was diagnosed with hypoparathyroidism for which I need a calcium phosphate supplement. Any calcium supplement taken must also contain phosphate. A point about calcium supplements is that the wrong calcium supplement is much worse than no calcium supplement at all.
Treatments using supplements have an additional constraint. Treatments using supplements should be very safe. First of all avoiding the ‘to be avoided supplements’ is absolutely safe. Iron carbonyl is a non-toxic form of iron. Anemia panels can be easily obtained to monitor iron levels. The Tolerable Upper Limit for selenium is 400 mcg. per day. Only 200 micrograms of Se-methylselenocysteine is recommended. The Observed Safe Level for supplementation with L-taurine is 3 grams a day (Shao and Hathcock, 2008). Adverse reactions to pantothenic acid and biotin have not been observed. Greatly limiting drinks with polyphenols is extremely safe though somewhat of an annoyance. A couple of cups of coffee in the morning and cup of coffee in the afternoon drunk away from supplements and food could be okay. Avoiding supplements on the ‘supplements too be avoided’ list is very safe. Sodium bicarbonate must be taken with a large glass of water to prevent dehydration and increases in blood pressure. Blood pressure must be monitored. Supplements can be taken with prescribed medications.
Very surprisingly iodine is helpful. Thyroid tests can be completely normal but still supplemental iodine is required. There is no need for hyroid hormones. Supplemental iodine addresses an intense sadness. Iodine works quickly. The sodium-dependent multivitamin transporter (SMVT) transports iodide. Transports of iodide is apparently a very important function of the SMVT. There is another transporter of of iodide, the sodium/iodide cotransporter, (SLC5A5) which is largely expressed in the thyroid. The SMVT is expressed in the digestive tract. The SMVT is apparently not a spare in terms of the transport of iodine.
The treatment could also be effective in Alzheimer’s disease. There are a lot of biological commonalities between schizophrenia and Alzheimer’s disease. See my papers Treatment-resistant schizophrenia: focus on the transsulfuration pathway and A disease-modifying treatment for Alzheimer’s disease: focus on the trans-sulfuration pathway. One might wonder whether taking iron from iron carbonyl for Alzheimer’s disease would be appropriate. A meta-analysis, however, indicates that serum iron levels are significantly lower in AD patients than in healthy controls. Another meta-analysis also indicates that serum iron is significantly lower in patients with Alzheimer’s disease than in healthy controls. Iron from iron carbonyl is regulating aconitase 1 in the gut, the citric acid cycle in the gut and iron metabolism in the gut. As iron levels are only regulated by absorption and excretion regulating iron levels in the gut can affect iron metabolism systematically.
Below are some comments on supplements that could also be helpful and also some comments on what must be avoided.
Pyruvate is almost always bound to calcium when taken as a supplement. Calcium pyruvate is not a useful supplement due to the calcium. Some formulation of pyruvate could be useful. Pyruvate is metabolized by the pyruvate dehydrogenase complex. An increase in acetyl CoA and NADH production by the pyruvate dehydrogenase (PDH) complex can directly inhibit fatty acid β-oxidation. in the context of biotin shortages Inhibition of beta-oxidation is the desired direction.
A ketogenic diet is not advisable as a ketogenic diet would increase beta-oxidation. Low carbohydrate diets could result in weight loss but the side-effects are too significant. None of us would have weight problems if ketogenic diets improved health. Individuals could live with the bland ketogenic diet. Ideas that should work but do not work are terrible ideas to put into practice. Ketogenic diets, unless used to treat epilepsy, are ill advised. There still could be a benefit to avoiding high glycemic foods as long as ketosis is avoided.
A difficulty with polyphenols is that polyphenols complex with iron making iron unavailable in the gut. Another difficulty with polyphenols is that polyphenols can increase beta-oxidation which can result in difficulties if there are problems in fat absorption and fatty acid metabolism.
Polyphenols in sodas, coffee and tea can adversely affect absorption of iron. Caffeine is apparently not the culprit. Polyphenols in polyphenol supplements could be highly available and should be particularly avoided. Flavonoids are polyphenols. Flavonoid supplements should be avoided.
Sodas, for example, Mountain Dew, as this advertisement shows are frequently associated with goofyness where the goofyneness could be due to polyphenols in the sodas adversely affecting iron metabolism in the gut. Citric acid drinks really do befuddle thinking. Someone might say, ‘Individuals would have to consistently take substances that befuddle thinking. Is that even possible?’ I cite the horrendous narcotics problem throughout the world and rest my case.
Polyphenols increase beta-oxidation. This can be extremely problematical given there are difficulties in fat absorption and fat metabolism, I have been emphasizing how polyphenols decrease iron absorption but increases in beta-oxidation due to polyphenols where those increases are unsupportable due to difficulties in fat absorption and fat metabolism could also lead to serious difficulties. Even after fat absorption and fat metabolism are re-regulated polyphenol laden drinks would still be drunk very sparingly and away from supplemental iron from iron carbonyl and away from food due to the effects of polyphenols on iron.
Clearly no general argument is being made that beta-oxidation is ‘bad’ and fatty acid synthesis is ‘good’. All depends on what illnesses individuals have and metabolic states that individuals are in.
A very significant difference between the socioeconomic classes may be that the higher socioeconomic classes very frequently drink bottled water rather than sodas while the lower socioeconomic classes very frequently drink sodas rather than bottled water.
Coffee drinking is very widespread. Here is a coffee advertisement from another planet.
Very surprisingly vitamin C supplements must be avoided. Vitamin C increases iron absorption by binding to iron which could reduce availability of iron in the gut which can have negative effects. Citric acid drinks must also be avoided even though citric acid increases iron absorption. Citric acid like vitamin C binds iron reducing the availability of iron in the gut.
Linus Pauling, the greatest chemist of the 20th century, starts taking megadosages of vitamin C and his work deteriorates. That mental illnesses are orthomolecular in nature is the correct viewpoint, however, the devil is in the details.
Zinc is not supplemented in more than RDA amounts. Zinc can adversely affect copper absorption.
Sulfur amino acids can be very toxic. L-cysteine taken as supplements can be very toxic. Very unfortunately, as the hypothesis posits a basic L-cysteine deficiency, strategies to directly increase L-cysteine levels directly can be disastrous. N-acetyl-l-cysteine and alpha lipoic acid are, for example,totally disastrous as supplements. Any supplement that increases L-cysteine by decreasing levels of cystine, as do n-acetyl-l-cysteine and lipoic acid, must be avoided. Pantethine is also avoided as pantethine could decrease cystine levels. N-acetyl-l-cysteine and alpha lipoic acid should not be OTC. Alpha lipoic acid should never be used and N-acetyl-l-cysteine should only be used for acetaminophen poisoning if then. Lipoic acid could also competively inhibit biotin and pantothenic acid transport by the SMVT as biotin, pantothenic acid and lipoic acid are all transported by the SMVT. L-methionine taken as a supplement could result in inappropriate DNA methylation. Cystine supplements must not be taken.
Absolutely the worst supplement strategy, that has some scientific support, is trying to increases L-cysteine levels except via taurine which spares cysteine. This is likely due to the fact that cystine has to be available to enter cells via the cystine/glutamate antiporter. Supplemental cystine would very likely be reduced to cysteine in the context of other supplements taken. Anyone who has been on n-acetyl-l-cysteine or lipoic acid for awhile should have copper and manganese levels tested I think somehow or other n-acety-l-cysteine and/or lipoic acid can increase gene hypermethylation dysregulating copper and manganese absorption.
Lipoic acid is also a total disaster. Lipoic acid will competitively inhibit biotin and pantothenic acid transport. Lipoic acid and pantethine must not be supplemented as lipoic acid and pantethine will reduce cystine to L-cysteine but cystine must be available to enter cells via the cystine/glutamate antiporter. Import of L-cystine into cells and export of glutamate out of cells are both important. Cysteine is very toxic and is not supplemented. Cystine must not be supplemented either. Cystine can be quite toxic.
Ubiquinol is avoided. Ubiquinol is the reduced form of coenzyme Q10. Ubiquinol could increase succinate levels.
That there is oxidant stress is many illnesses is well established however thousands and thousands of oxidation reactions are needed. Increasing levels of free antioxidants, such as vitamin C, vitamin E and beta-carotene via supplementation is not of assistance.
That increasing re-methylation of homocysteine to L-methionine, via supplemental folic acid and vitamin B12 in more that RDA amounts, is counterproductive, is another surprising rule. Homocysteine must be available to be metabolized to cysteine via the transsulfuration pathway. Decreasing homocysteine levels via increasing activity of enzymes in the transsulfuration pathway, which taurine does, is the only helpful way to reduce homocysteine levels. Supplementation with taurine decreases homocysteine levels. Folic acid and vitamin B12 supplements do not prevent cognitive decline though the supplements can reduce homocysteine levels.
Sulbutiamine will support activities of pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase which are the E1 components of pyruvate dehydrogenase complex and 2-oxoglutarate dehydrogenase complex respectively. The E1 step in the pyruvate dehydrogenase complex is the rate-limiting step in the whole pyruvate dehydrogenase complex. To increase activities of the E2 components of the pyruvate dehydrogenase complex and 2-oxoglutarate dehydrogenase complex activities of the E1 components must first be increased. The E1 components have thiamine diphosphate as cofactors. Thiamine diphosphate levels are greatly increasded by sulbutiamine. There are no genetic mutations so systematic dysregulations of the pyruvate dehydrogenase complex and 2-oxoglutarate complex do not occur.
Carnitine is avoided as carnitine could promote beta-oxidation.
Sublingual thiamine cocarboxylase is very unhelpful. Benfotiamine is not helpful.
A combination of EPA and DHA could be a useful supplement. EPA and DHA levels where EPA levels are greater than 60% are effective against depression. Some DHA is apparently needed. EPA levels should be about around 60% to 65% of the EPA and DHA combination. The International Society for Nutritional Psychiatry recommends for depression that a supplement with a total of 1-2 grams of EPA can be taken daily. EPA and DHA are not sufficient in terms of fatty acid supplementation.
Supplemental vitamin B6 could be helpful. Alanine transaminase EC 126.96.36.199 alanine-glyoxylate transaminase EC 188.8.131.52 which are are involved in pyruvate, 2-oxoglutarate, and glutamate metabolism as shown in the KEGG alanine aspartate and glutamate metabolism map are vitamin B6 dependent enzymes. Enzymes involved in cysteine metabolism and enzymes involved in the transsulfuration pathway are also vitamin B6 dependent enzymes.
Supplmental niacin and riboflavin are avoided as supplemental niacin and riboflavin could increase activity of the E3 components of the pyruvate dehydrogenase complex and and alpha-ketoglutarate dehydrogenase complex whose products can inhibit E1 components of the pyruvate dehydrogenase complex and and alpha-ketoglutarate dehydrogenase complex.
All B-50 vitamin formulations are avoided. One Centrum a day could be okay.
Molybdenum from molybdenum bound to Krebs cycle intermediates will increase levels of xanthine oxidase. Xanthine oxidase, is a molybdenum containing protein. Xanthine oxidase is a powerful ferroxidase and could assist with iron transport. Molybdenum from molybdenum bound to Krebs cycle intermediates would be readily available in the gut which could be a strong advantage. Molybdenum chelated to glycine is avoided as xanthine oxidase levels must be increased in the gut. Molybdenum from molybdenum glycinate may not be readily available in the gut. Douglas Laboratories sells a 500 microgram molybdenum supplement where the molybdenum is complexed with Krebs cycle intermediates, which is not ideal, however, the Krebs cycle intermediates must be in such low amounts that the Krebs cycle intermediates would not present difficulties. Douglas Labs also sells a 250 microgram molybdenum supplement, which is an an amino acid chelate, that is not purchased. The 250 microgram supplement of Douglas Laboratories use to to be chelated to glycine. Whether this is still true or not is unclear. The advertising of Albion Minerals which states that glycine is very tightly bound to minerals in glycine chelates is absolutely accurate.
Iron, molybdenum, zinc and selenium should not be bound to glycine.
At this time the treatment is complementary medicine rather than alternative medicine. Prescribed medications should not be stopped without consultation with MDs.
Supplements are a minefield. Do not start the treatment unless contraindicated supplements are at the same time avoided.
What not to supplement is as important as what to supplement. Supplementing with L-methionine or S-adenosyl-l-methionine is avoided. Supplementing with N-acetyl-l-cysteine, L-cysteine, cystine, r-lipoic acid and/or alpha lipoic acid supplements is avoided. N-acetyl-l-cysteine and alpha lipoic acid increase L-cysteine levels by decreasing cystine levels which is not of assistance. Supplementing with iron sulfate is avoided. Iron carbonyl will reside in the gut longer whereby aconitase 1 in the gut can be better regulated by iron carbonyl compared to iron sulfate. Iron carbonyl is also safer that iron sulfate. Pantetheine is not supplemented as pantetheine could decrease cystine levels. Sodium selenite, sodium selenate and any form of L-selenomethionine are not supplemented. Minerals bound to succinate should be avoided. Folic acid and vitamin B12 are not supplemented in much more than RDA amounts. To produce L-cysteine via homocysteine there must be homocysteine. Increasing re-methylation of homocysteine to L-methionine by taking more that RDA amounts of folic is counterproductive. Huge doses of B12 are not helpful. Supplemental niacin and supplemental riboflavin are avoided . B-50 formulations are avoided. Whey protein is not supplemented. Supplementation with iron sulfate and ferrous bisglycinate are avoided. All minerals bound to citrate must be avoided unless amounts are minuscule. All minerals bound to succinate must be avoided unless amounts are minuscule. Iron, molybdenum, zinc and selenium bound to glycine should not be taken. L-carnitine is avoided as L-carnitine could increase beta-oxidation. Calcium pyruvate is avoided due to the calcium. Vitamin C supplements and all citric acid based drinks are avoided. Carotenoid supplements, like beta-carotene and lycopene are avoided. Vitamin E is avoided. Apparently there are various needed oxidant reactions that vitamin E can adversely affect. Free antioxidants are only healthy is amounts found in food. Soft drinks and tea are completely avoided. A couple of cups of coffee in the morning an hour before supplements are taken is the least worse way to drink coffee though not advisable. Water is the only safe drink. In terms of polyphenol drinks constant drinking throughout the day, drinking while eating and drinking when taking supplements are the major things to avoid.
Treatment failure is predicted unless the recommendations as to what not to supplement with are adhered to.