Serotonin/endotoxin/PUFA As Primary Causes Of Depression And Diabetes; Can Be Easily Blocked

Discussion in 'Scientific Studies' started by haidut, Mar 13, 2018.

  1. haidut

    haidut Member

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    This is one of the unique studies that breaks away from the mainstream dogma that serotonin is the "happy hormone" and increasing it with drugs like SSRI can lead to nothing but goodness. The study not only directly states that past/current SSRI use is a risk for developing diabetes but show how elevated levels of gut serotonin (5-HT) due to low expression of serotonin transporter (5-HTT) leads to increased intestinal permeability and thus systemic inflammation, insulin resistance, diabetes, and depression. I really hope the FDA is taking notes, but even if they are not Big Pharma certainly is well aware of what us going on. As of 2017 virtually all of the big international pharma companies had at least one serotonin antagonist (or TPH inhibitor) in their pipelines, often running multiple clinical trials with a single drug for indications as diverse as diabetes, cancer, obesity, stroke, fibrosis, etc.
    Perhaps the most important takeaways from this study are as follows: (1) high PUFA (cafeteria) diet leads to increased intestinal serotonin levels, subsequent endotoxin absorption into the blood, activation of TLR4 and thus systemic inflammation which causes all sorts of diseases (especially depression and diabetes); (2) SSRI drugs have virtually the same detrimental effects as the high-PUFA diet; (3) 5-HT3 antagonists (ondansetron, tropisetron, granisetron, etc) block the activation of TLR4 by endotoxin and thus may prevent treat a host of conditions related to endotoxemia including liver disease, obesity, diabetes, depression, psychosis, neurodegenerative disease, and even cancer.

    Metabolic Endotoxemia Initiates Obesity and Insulin Resistance
    Endotoxaemia resulting from decreased serotonin tranporter (5-HTT) function: a reciprocal risk factor for depression and insulin resistance? - PubMed - NCBI
    "...Interestingly, a bi-directional positive correlation between diabetes and depression has been found to be asymmetrical(Fig. 1): patients with depression have an increased risk of becoming diabetic by 60% (95% CI 37–88%) [24], 65% (95% CI 2–166%) [25], and 56% (95% CI 37–77%, p < 0.001) [26]; whereas a risk for depression in diabetic patients is elevated only by 24% (95% CI 9–40%) [27] and 25% (95% CI 10–44%, p = 0.001) [28]. Recently, a longitudinal study in Taiwan has shown a 43%-increased risk of depression in diabetic individuals (95% CI 16–77%) and a 102%-increased risk of diabetes in depressed patients (95% CI 80–127%) [29]."

    "...On another hand, there is growing evidence suggesting that treatment with antidepressant drugs from different classes and mechanisms-of-action is associated with an increased risk of diabetes which might contribute to the increased incidence of insulin resistance in large cohorts of depressed patients [32–39]. One of these studies showed that long-term antidepressant medication with selective serotonin (5-HT) reuptake inhibitors (SSRIs) or tricyclic antidepressants increased the risk for type-2 diabetes in patients with obesity, while elevated fasting glucose and impaired glucose tolerance was treatable with metformin [32,33]. Moreover, it was reported that a medication history of ≥200 defined daily doses of conventional antidepressant therapies primarily based on SSRIs and tricyclics increased the risk of diabetes in patients with moderate or severe depression by 93% (95% CI 48–151%) and 165% (95% CI 31–439%) over the rate found in the general population, respectively [37]. Another publication has reported that an 18-year long study has revealed the incidence of diabetes to be 3.1-fold higher among antidepressant users than in non-users (95% CI 1.66–5.78, p < 0.0001) [38]. Notably, these results refer, rather than to individual drugs, to the class of antidepressants or combined pharmacotherapies that are most broadly used in clinic and probably the most representable for common cases of depressive disorder."

    "...In summary, epidemiological studies have established a bidirectional association between depression, on one side, and medical conditions defined by insulin resistance on the other side (Fig. 1). This relationship appears to be asymmetrical as most studies show that depressed patients are at a considerably higher risk to become diabetic than diabetic individuals are prone to develop depression. As many data suggest, conventional antidepressant medications of various nature, that includes SSRIs, tryciclics and adjunctive drugs, might be an additional factor which may notably contribute to the increased risk of diabetes during depression."

    "...One of the common features of depression and insulin resistance is regarded to be low-grade inflammation [46–51]. Elevated endotoxin levels and increased production of pro-inflammatory cytokines in the periphery was suggested to contribute to the development of both depression and diabetes [46,52,53]. As has been reviewed recently, peripheral endotoxin triggers depressive-like behavior in both humans and rodents through elevation of levels of pro-inflammatory cytokines (e.g., IL-1 and TNF-) in brain and subsequent modulation of 5-HT neural circuits that drives behavioral responses [54]. IL-1 and TNF- stimulate 5-HT reuptake through an acute catalytic activation of neuronal 5-HTT activity [55]. Peripheral immune system activation has been shown to increase 5-HT turnover in the prefrontal cortex and to alter emotional behavior [56]. Furthermore, recent studies implicate altered 5-HT neurotransmissionin mechanisms associated with the increased production of pro-inflammatory cytokines which have been contributed to the development of both depression and type-2 diabetes [46,50]. While aberrant brain 5-HT signaling and inherited deficiency of 5-HTT in subjects with a short variant of the 5-HTT gene-related polymorphic region (5-HTTLPR) were attributed to the neurobiology of depression as a major pathogenic factor [57,58], genetically dependent deficits of 5-HTT function equally hamper 5-HT signaling on a systemic level [59–61]. Decreased 5-HTT can evoke pathological changes in the periphery that may affect brain function implying an, as of yet, unexplored mechanism linking the pathogenesis of depression and insulin resistance.

    "...A study in 5-HTT knockout (KO) mice has revealed enhanced intestinal permeability and a leakage of bacterial endotoxin into the blood stream resulting from a reduction of tight-junction proteins in the gut, which is an important source of circulating endotoxins [72,73]. These effects were shown to be mediated by excessive concentrations of 5-HT activating the 5-HT3 receptor [68,71], a widely distributed 5-HT receptor in the gut[64]. Interestingly, 5-HT3 receptor up regulation in 5-HTT deficient mice was earlier reported in a number of brain regions as well [74]. In line with the above mentioned findings, experiments with ob/ob mutant mice showed that antagonists of the 5-HT3 receptor can prevent endotoxin translocation into the portal blood and subsequently reduce inflammation in the liver as well as accumulation of fat in these mice [67,75,76]. The elevation of circulating endotoxin, referred to as “metabolic endotoxemia”, is considered to be an important pathogenic feature that is common for obesity, insulin resistance, and type-2 diabetes [52,53,73,75,77,78]. It was reported that circulating endotoxin stimulates toll-like receptor 4 (TLR4) in the brain [79] and induces insulin resistance in peripheral organs via the inhibitory effect of subsequently activated c-jun N-terminal kinase (JNK) on the IRS1/PI3K/Akt pathway [51,80]."

    "...Another mechanism of central JNK activation by excessive concentrations of 5-HT can be proposed based on the recently identified peripheral regulation of serotonin receptors. 5-HT was shown to activate JNK via a direct stimulation of 5-HT1B/1D, 5-HT2A, and 5-HT2B receptors in smooth muscle cells. However, whether this mechanism occurs in the brain, was not investigated and therefore it is unclear whether it is of relevance for the above-described cellular and molecular mechanisms of depression and insulin resistance [106]."

    "...Thus, endotoxemia related to decreased intestinal 5-HT signaling due to 5-HTTLPR polymorphism, conventional antidepressant pharmacotherapy and “cafeteria-type diet” may underlie a reciprocal risk factor for depression and insulin resistance via central and peripheral mechanisms of inflammation/insulin receptor signaling (Fig. 3). Taken together, summarized here literature further suggest the spectrum nature of neuropsychiatric syndromes and pathogenetic relationship between various disordered domains, such as symptoms of major depression, diabetes, insulin resistance, anxiety, obesity and pro-inflammatory changes that emphasizes the importance of integrated cross-domain concept as a good empowering approach for translational biological psychiatry [110,111]."

    "...In particular, diet-induced activation of TL4R was precluded by 5-HT3 receptor antagonist in 5-HTT deficient mice but it was not investigated whether or not endotoxemia occurs in this model of depressive-like behavior. Furthermore, besides the above described genetic and dietary factors, chronic treatment with antidepressants induces systemic hypofunction of 5-HTT [64,65]. Whether this results in increased levels of intestinal 5-HT and endotoxemia was however not reported and would be of essential clinical and fundamental importance to be elucidated. As such, central downstream factors of deficient 5-HTT function were shown to contribute to the pathogenetic mechanisms of depression. Thus peripheral elements may substantially contribute to its etiopathology and require experimental consideration."

    In regards to therapeutic interventions, one of the cited studies includes the one below, which shows that oral administration of HED 1mg - 2mg daily of a 5-HT3 antagonist like ondansetron for 6 weeks was therapeutic for endotoxemia, obesity, liver disease, and inflammation. This is quite a low dose and consistent with the other ones showing that low dose (1mg - 3mg daily), but not high dose (6mg+ daily), ondansetron was therepautic for depression. Both treatments also lowered serum serotonin levels, which is a rare effect among serotonin antagonists.

    Serotonin receptor type 3 antagonists improve obesity-associated fatty liver disease in mice. - PubMed - NCBI
    "...Obesity is a major cause for nonalcoholic fatty liver disease (NAFLD). Previous studies suggested that alterations in intestinal motility and permeability contribute to the development of NAFLD. Serotonin and serotonin receptor type 3 (5-HT(3)R) are key factors in the regulation of intestinal motility and permeability. Therefore, we studied the effect of the 5-HT(3)R antagonists tropisetron and palonosetron on the development of NAFLD in leptin-deficient obese mice. Four-week-old ob/ob mice and lean controls were treated for 6 weeks orally with tropisetron or palonosetron at 0.2 mg/kg per day. We determined markers of liver damage and inflammation, portal endotoxin levels, and duodenal concentrations of serotonin, serotonin-reuptake transporter (SERT), occludin, and claudin-1. Tropisetron treatment significantly reduced liver fat content (-29%), liver inflammation (-56%), and liver cell necrosis (-59%) in ob/ob mice. The beneficial effects of tropisetron were accompanied by a decrease in plasma alanine aminotransferase and portal vein plasma endotoxin levels, an attenuation of enhanced MyD88 and tumor necrosis factor-α mRNA expression in the liver, and an increase of tight junction proteins in the duodenum. Tropisetron treatment also caused a reduction of elevated serotonin levels and an increase of SERT in the duodenum of ob/ob mice. Palonosetron had similar effects as tropisetron with regard to the reduction of liver fat and other parameters. Tropisetron and palonosetron are effective in attenuating NAFLD in a genetic mouse model of obesity. The effect involves the intestinal nervous system, resulting in a reduction of endotoxin influx into the liver and subsequently of liver inflammation and fat accumulation."
     
  2. Fractality

    Fractality Member

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    How will the medical/pharmaceutical industry reconcile their previous endorsements of serotonin as the "happy hormone" in light of newly developed anti-serotonin compounds. How will they try and reconfigure the narrative?
     
  3. Vinero

    Vinero Member

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    They will say the anti-serotonin drug "modulates" serotonin or it's receptor, instead of saying that it decreases the exposure to serotonin.
     
  4. Vinero

    Vinero Member

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    Memantine and Adamantane also act as a non-competitive antagonist at the 5-HT3 receptor. This means you can use Diamant or memantine to block those TLR4 receptors and prevent endotoxin causing damage.

    Here is a list of agonists and antagonists of the 5-ht3 receptor
    https://en.wikipedia.org/wiki/5-HT3_receptor
    Ethanol (alcohol) is also an agonist, which explains why drinking straight liquor causes vomiting in many people.
    Activating the 5-HT3 receptor causes vomiting and nausea:

    "If irritants are present in the food, the enterochromaffin cells release more serotonin to make the gut move faster, i.e., to cause diarrhea, so the gut is emptied of the noxious substance. If serotonin is released in the blood faster than the platelets can absorb it, the level of free serotonin in the blood is increased. This activates 5-HT3 receptors in the chemoreceptor trigger zone that stimulate vomiting.[49] The enterochromaffin cells not only react to bad food but are also very sensitive to irradiation and cancer chemotherapy. Drugs that block 5HT3 are very effective in controlling the nausea and vomiting produced by cancer treatment, and are considered the gold standard for this purpose."

     
  5. aguilaroja

    aguilaroja Member

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    In some, to say it kindly, confused investigation, there is movement to “salvage” SSRI therapy (with its dangers, side effects, and equivocal actions) with 5-HT3 receptor antagonism. So the argument is to “improve” serotonin-boosting pharma with an anti-serotonin effect ?!
    It does add evidence for benefit of “selective” serotonin ANTAGONISM.

    https://www.ncbi.nlm.nih.gov/pubmed/29477299
    Serotonin 5-HT3 receptor antagonism potentiates the antidepressant activity of citalopram.
    “Activation of serotonin 5-HT3 receptor (5HT3R) in the locus coeruleus (LC), the principal somatodendritic noradrenergic area, decreases LC firing activity and noradrenaline (NA) release in prefrontal cortex (PFC).”
    “In mice FST, systemic coadministration of citalopram (2.5 mg/kg i.p.) and Y25130 (10 mg/kg i.p.) potentiated the decrease of immobility time through the increase of both swimming and climbing behaviours.”
     
  6. OP
    haidut

    haidut Member

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    Good point. Opioids are also 5-HT3 agonists and they are also TLR4 agonists - so probably the worst possible combination for gut/brain health. Other 5-HT antagonists include the steroids peat often talks about. I supposed it explains why so many people using 5a-DHP reported improved digestion and even blood sugar levels.
    https://raypeatforum.com/community/...opregnanolone-are-serotonin-antagonists.6609/
     
  7. OP
    haidut

    haidut Member

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    I think those therapies are simply creating more and more effective serotonin antagonists. As I posted a few times before, and you undoubtedly know as well, all effective SSRI have been found to have these two characteristics - (1) upregulate allopregnanolone synthesis and (2) act as antagonist at 5-HT2C. Prozac is perhaps the most famous and most potent in both respects. It just so happens that allopregnanolone is already a 5-HT3 antagonist: https://raypeatforum.com/community/...opregnanolone-are-serotonin-antagonists.6609/

    So adding another 5-HT3 antagonist on top of these drugs likely creates a drug that is a VERY potent antagonist on 5-HT3 and 5-HT2C, which as a net effect will reduce gut serotonin (as per the study above) and also lower cortisol (due to 5-HT2C antagonism).
    Both of these effects (and especially the latter) are known to be therapeutic for depression. Unfortunately, the SSRI will still remain highly serotonergic through other 5-HT receptors and reduction in SERT levels, so their fibrotic (5-HT2B agonism) and hypogonadic/hyperprolactinemic (5-HT1 agonism) effects will continue unabated. But I am sure the medical industry will tout these drug combinations as "new and improved antidepressants with MUCH milder side effects than before", which in a perverted way would be true.
    Incidentally, more recent versions of the SSRI drugs have been found to be ever more antagonistic on more than one serotonin receptor, which I highly doubt is by accident. It may be, just like you said, the medical industry's nefarious approach to saving the SSRI concept by gradually developing more and more encompassing serotonin antagonists who eventually remain an SSRI just in name while in reality they block serotonin everywhere. A case in point is Vortioxetine (a Prozac derivative), which is an antagonist on 5-HT1, 5-HT3, and 5-HT7.
    https://en.wikipedia.org/wiki/Vortioxetine
     
  8. Dhair

    Dhair Member

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    Sounds like just pregnenolone or progesterone could be enough to yield dramatic improvements in these areas.
     
  9. Wagner83

    Wagner83 Member

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    If block you those receptors long-term with very potent drugs what happens when you discontinue their use? Same question but when diet, digestion and environment are crap?
    Wow does anyone eat cow dairy? :ss2
     
  10. jayegray

    jayegray Member

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    All of those compounds that are beneficial are prescription drugs. Any alternatives that are strong receptor 3 antagonists?
     
  11. Dobbler

    Dobbler Member

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    Haidut with the big bombs again. Good stuff, much appreciated.
     
  12. Wagner83

    Wagner83 Member

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    That's what the toilet said.
     
  13. cyclops

    cyclops Member

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    Would Kratom fit this description?
     
  14. raypeatclips

    raypeatclips Member

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    You talk about 5-ht antagonists having an effect against tlr4, and mentioned pharmaceutical drugs mainly. Would the opposite relationship work too, that action against tlr4 would lower serotonin? I have seen you mention the simple fat soluble vitamins having an effect against tlr4 in the past and wondered if these could be seriously considered to help the issues presented above?
     
  15. Vinero

    Vinero Member

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    Vitamin A, D, B2, and B3 have been shown to antagonize TLR4 receptor. I am sure B2(by increasing MAO) and B3 lower serotonin. Vitamin A in high doses has been shown to improve autism symptoms which hints at an anti-serotonin effect.
    Vitamin D is very dopaminergic and dopamine lowers serotonin synthesis.
     
  16. OP
    haidut

    haidut Member

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    Not all of them. Look at my responses mentioning steroids which are 5-HT3 antagonists.
     
  17. OP
    haidut

    haidut Member

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    As Peat said recently, if digestion is good the opioid peptides in milk should be degraded to simple amino acids.
     
  18. OP
    haidut

    haidut Member

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    I am suspicious of all opioids, but so far there is not much data on Kratom. It seems to be an antagonist on 5-HT2A and NMDA, both of which can lead to stimulating and antidepressant effects, which explains why people like it so much.
    Mitragyna speciosa - Wikipedia
    "...Both mitragynine and 7-HMG are selective full agonists of the μ-opioid receptor; 7-HMG appears to have higher affinity.[9] The stimulant effects appear to be mediated via prevention of activation of serotonin 5-HT2A receptors and postsynaptic α2-adrenergic receptors.[9]Rhynchophylline is a non-competitive NMDA antagonist found in kratom.[9]"
     
  19. Wagner83

    Wagner83 Member

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    That's a big "if " though, and maybe an other point for not pushing dairy and milk so much when people are not in optimal health.
     
  20. OP
    haidut

    haidut Member

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    I agree on both counts and in fact I do not do well when consuming more than 1L of milk daily. Cheese seems fine in any amount though, especially the feta variety.
     
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