A very tepid positive take on the use of EPA in major depression

In a study by Rapaport et al., on the use of EPA in major depression there is this sentence in the abstract, ‘While overall treatment group differences were negligible (ES=−0.13 to +0.04), subjects with any “high” inflammation improved more on EPA than placebo…’ That is a very tepid positive take.

EPA enteric coated softgels do not work. EPA + DHA softgels must be bitten, the contents swallowed and then softgel capsules thrown away for EPA + DHA to work against major depression

ProEPAxtra was the EPA product used in the Rapoport study. Here is an ad for ProEPAxtra on Amazon. The ad does not explicitly state that the softgel is enteric coated, however, the ad states ‘no fishy aftertaste’ and ‘better absorbed’ both of which are warnings than the soft gel could have some sort of enteric coat. Enteric coated fish oil soft gel capsules appear to be frosty or dull. The softgels in the ad appear to be dull in appearance. The quality of the fish oils themselves is not being questioned.

Gut microbiota and mental illness

I have been arguing on this blog that supplements have to be available in the gastrointestinal tract as well as systematically for supplements to be helpful. There has been a growing realization that what happens in the gut can have a huge impact on mental health. See these reviews Microbes and mental health: A review; Harnessing Gut Microbes for Mental Health: Getting From Here to There and Brain-Gut-Microbiota Axis and Mental Health.

If supplements are not available in the gastrointestinal tract this cannot but affect gut microbiota differently compared to supplements that are available in the gastrointestinal tract. I am open to the possibility that differences in gut microbiota can play a big role in mental states, however, the gut could also be set up so the gut has to use nutrients when nutients first pass through the gut. Use of nutrients by the gut could be a necessary first step in the use of nutrients systematically.

There is a lot of talk about how the diet of our very distant ancestors is the diet that is appropriate for us. One thing is certain about the diet of our very distant ancestors. Our very distant ancestors did not take nutrients than were formulated not to be available in the gut.

Only taking supplements that are available in the gut, when taking supplements, is one way to address to address gut microbiota positively. As an example EPA + DHA combinations are frequently supplied in enteric coated softgels to avoid ‘fishy smells’. However, biting on the softgels, swallowing the contents and then throwing the softgels away works much better for depression. And what is more even given EPA + DHA work in clinical trials EPA + DHA will not work in the field as EPA + DHA supplements sold in stores are very frequently enteric coated.

Alzheimer’s disease and bone mineral density

Alzheimer’s disease patients are also at a higher risk for hip fractures than healthy controls. A meta-analysis indicated that the Odds Ratio for hip fractures in patients with Alzheimer’s disease is 1.80 compared to healthy controls. Low bone mineral density and increased loss rate of bone mineral density were associated with higher risk of Alzheimer’s disease.

There are a lot of illnesses where there are both high homocysteine levels and decreased bone mineral densities, for example, Alzheimer’s diseases. High homocysteine levels and decreased bone mineral densities in range of illnesses can be tied together by dysregulations of the transsulfuration pathway in such illnesses.

Morning coffee


Many studies report coffee as having beneficial effects and a couple of cups of coffee drink only in the morning could have beneficial effects. A meta-analysis indicates that there is at inverse relationship between coffee/caffeine and risk of Parkinson’s disease. A weakness of the forgoing meta-analysis is that the meta-anaylsis focuses on caffeine. Studied indivduals, however, were drinking coffee with is much different than taking caffeine pills. A meta-analysis indicates that moderate coffee intakes is associated with decreased cardiovascular risks. There are, however, increased risks for schizophrenia where there is heavy use of coffee. Where there is heavy use of coffee, coffee most likely is not drunk only in mornings.

Difficulties with coffee can arise given coffee is drunk throughout the day. Coffee inhibits iron absorption in a concentration-dependent fashion. Polyphenols in coffee inhibit iron absorption. A couple of cups of coffee drunk only in the morning would have minimal effects on iron metabolism. Coffee drunk throughout the day could have very adverse effects on iron metabolism.

Iron chelators and Parkinson’s disease – always full of promise

A search for “iron chelation” and “Parkinson’s” pulls up 460 cites in PubMed. Given iron chelators worked in Parkinson’s disease that would be outstanding. Iron chelation in Parkinson’s disease, however, always seems to be full of promise but there have been no payoffs in terms of treatment. There are many, many ways available to chelate iron. Quercetin is for example a quite effective iron chelator. Polyphenols are quite effective iron chelators. Deferiprone, which an iron chelator, has been tried in Parkinson’s disease. Deferirone is not significantly effective in the treatment of Parkinson’s disease.

Why haven’t iron chelators worked by now in Parkinson’s disease? Perhaps because iron chelators can’t work in Parkinson’s disease. There could be difficulties with iron in Parkinson’s disease but those difficulties could be due dysregulations of iron metabolism rather than due to iron being toxic per se.

Parkinson’s disease, alpha-synuclein and iron

Alpha-synuclein aggregates are present in Parkinson’s disease. mRNAs of alpha-synuclein have iron-responsive elements in 5′ untranslated regions. Iron-responsive elements in mRNAs of iron regulated proteins bind iron regulatory proteins (IRP1 and IRP2) affecting stabililites of transcripts of iron regulated proteins. Iron levels can affect alpha-synuclein levels, however, apparently there is an asymmetry as to how iron affects alpha-synuclein levels. Iron chelators decrease alpha-synuclein levels though added iron does not increase alpha-synuclein levels. With alpha-synuclein homeostasis dysregulated via a dysregulated iron metabolism, rather than via high levels of alpha-synuclein per se, alpha-synuclein aggregates could form.

I wrote a paper on Parkinson’s disease, which addresses iron dysregulation in Parkinson’s disease, that was published in the International Journal of Neuroscience. The title of the paper is A novel treatment strategy to prevent Parkinson’s disease: focus on iron regulatory protein 1 (IRP1)

Bipolar disorder and bone mineral density

There are decreases in bone mineral density in drug naive individuals with bipolar disorder compared to age- and gender-matched healthy controls. Individuals with bipolar I disorder have have high homocysteine levels. High homocysteine levels in individuals with bipolar disorder point to the transsulfuration pathway being dysregulated. Via the transsulfuration pathway L-cysteine is synthesized from homocysteine. L-taurine is synthesized from L-cysteine.

Taurine is required for calcium homeostasis. Taurine, also, is conjugated to various bile acids. Bile acids are are required for absorption of fat-soluble vitamins. Vitamin D and vitamin K are fat-soluble vitamins. Individuals with bipolar disorder are 4.7 times more likely to be vitamin D deficient than individuals amongst the general population of the Netherlands, however, deficient levels of vitamin D are not specific to bipolar disorder but are also present in individuals with schizophrenia. The taurine transporter is present in osteoblasts. Osteoblasts synthesize bone.

With taurine metabolism dysregulated calcium homeostasis is dysregulated and absorption of vitamin D and vitamin K is decreased. Decreases in bone mineral density in bipolar disorder could be due to dysregulation of the transsulfuration pathway which dysregulates calcium homeostasis and vitamin D and vitamin K absorption resulting in low bone mineral density.

Huntington’s disease and selenoproteins

L-selenomethionine is metabolized by cystathionine gamma-lysase. Dysregulation of cystathionine gamma-lyase would dysregulate selenoprotein synthesis from L-selenomethionine, which is the food form of selenium. In the N171-82Q Huntington’s disease mouse model various selenoprotein levels are changed compared to controls. Changed levels of selenoproteins in the N171-82Q Huntington’s disease mouse model compared to controls could be due to dysregulation of cystathionine gamma-lyase.

Supplemental Se-methylselenocysteine could be useful in the treatment of Huntington’s disease as metabolism of Se-methylselenocysteine does not depend on cystathionine gamma-lyase. Se-methylselenocysteine is metabolized by kynurenine aminotransferase 1. Supplementation of Se-methylselenocysteine taken alone would be far from a completely effective treatment for Huntington’s disease as decreases in cystathionine gamma-lyase would dysregulate various pathways downstream from the transsulfuration pathway. Se-methylselenocysteine could be of assistance in the treatment of cognitive symptoms of Huntington’s disease. Se-methylselenocysteine taken daily in two divided dosages is more effective than Se-methylselenocysteine taken once daily.

Huntington’s disease and pathways downstream from the transsulfuration pathway

Huntington’s disease is associated with dysregulation of the transsulfuration pathway. Research points to cystathionine gamma-lyase, the second enzyme in the transsulfuration pathway, as being profoundly depleted in Huntington’s disease. L-cysteine is synthesized via the transsulfuration pathway.

Huntington’s disease develops in later decades. By the time Huntington disease manifests dysregulations of the transsulfuration pathway could have resulted in epigenetic changes. See Treatment-resistant schizophrenia: focus on the transsulfuration pathway and A disease-modifying treatment for Alzheimer’s disease: focus on the trans-sulfuration pathway as to how dysregulation of the transsulfuration pathway could result in epigenetic changes. Pathways downstream of the transsulfuration pathway, for example, iron-sulfur cluster formation where sulfur for iron-sulfur cluster formation is derived from cysteine, seleonprotein synthesis where the transsulfuration pathway is required to metabolize selenomethionine which is the food form selenium, glutathione synthesis where cysteine is the rate limiting amino acid in glutathione synthesis and taurine synthesis where taurine is synthesized from L-cysteine could all be dysregulated due to the transsulfuration pathway being dysregulated.

Since mutation in genes that confer Huntington’s disease are present from birth but Huntington’s disease only develops in later decades manifestations of Huntington’s disease must be due to accumulated changes where such accumulated changes could be epigenetic changes attendant on dysregulations of cystathionine gamma-lyase. Supplementation of sulfur containing free form amino acids, except L-taurine, would not be of assistance in the treatment of Huntington’s disease both due to the toxicities of such supplements and due to pathways downstream of the transsulfuration pathway being dysregulated due to epigenetic changes attendant on dysregulations of the transsulfuration pathway.

Correction of osteomalicias can increase bone mineral density

There can be very large increases in bone mineral densities upon osteomalicias being corrected.

Long-term bone mineral density changes after surgical cure of patients with tumor-induced osteomalicia

L Colangelo , J Pepe, L Nieddu, C Sonato, A Scillitani, D Diacinti, M Angelozzi , C Cipriani, S Minisola


Introduction: No systematic data are available regarding long-term bone mineral density (BMD) changes after surgical cure of patients with tumor-induced osteomalacia.

Methods: From October 2001 through April 2018, we studied 10 consecutive patients (mean age ± SD, 45.5 ± 13.8 years; 5 males and 5 females) with tumor-induced osteomalacia. We evaluated BMD when initially presented at our Center and after surgical removal of the tumor.

Results: Basal BMD and corresponding Z-score values (mean values ± SD) measured by DXA were as follows: L1-L4 = 0.692 ± 0.15 g/cm2, Z-score = – 2.80 ± 1.60; femur neck 0.447 ± 0.10 g/cm2, Z-score = – 2.66 ± 0.93; total femur = 0.450 ± 0.08 g/cm2, Z-score = -3.04 ± 0.85). Furthermore, Trabecular Bone Score (TBS) was evaluated in three patients (basal values, 0.990 ± 0.32). Seven patients were intermittently followed after surgical excision of the tumor while supplemented with cholecalciferol and calcium salts; the remaining three were lost to follow-up. There was a striking increase of BMD values that peaked at 26.7 ± 6.50 months: L1-L4 = 1.289 ± 0.247 g/cm2, p < 0.001, Z-score + 1.75 ± 1.42; femur neck = 0.890 ± 0.235 g/cm2, p = 0.028, Z-score = + 0.50 ± 1.40; total femur = 0.834 ± 0.150 g/cm2, p = 0.005, Z-score = – 0.74 ± 1.14. In patients with the greatest bone involvement at lumbar site, there was a striking increase of an average 1.5% (p < 0.01) in respect to baseline Z-score value for each additional month of observation during the first 2-3 years post-surgery. An improvement of trabecular microarchitecture was also documented (TBS, 1.255 ± 0.16).

Conclusion: This is the first case series documenting an impressive increase of BMD at both lumbar and femoral sites, together with an improvement of trabecular microarchitecture as documented by TBS. This is the consequence of huge mineralization of the large amount of osteoid tissue after resolution of the disease.