Serotonin, Depression and SSRI Antidepressants

[Orangeblossom]

Interesting that manipulating serotonin was associated with less Aβ accumulation.

We certainly understand that Aβ is an immune response. Leaves me wondering how/why would serotonin play into impacting that immune response under normal circumstances?

Immunomodulatory capacity of the serotonin receptor 5-HT2B in a subset of human dendritic cells.

Our results expand the biological role of 5-HT2B which may act not only as a neurotransmitter receptor, but also as an important modulator of both innate and adaptive immune responses.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5788853/ (Gonna have to reread this one when I have more time.)

Yes, I had a read and it mentioned that apart from its role in regulating gastrointestinal motility (GI tract), vasoconstriction, blood clotting, hemostasis (cardiovascular system), mood and cognition (CNS), serotonin is also involved in the regulation of inflammation and immune functions via controlling the release of cytokines and chemokines in a cell type-dependent manner. It is interesting as well as some think depression is related to, or caused by, inflammation, as well. Here it also describes anti-inflammatory effects http://onlinelibrary.wiley.com/doi/10.1 ... 2.231/full

"Studies have found the following important functions of fluoxetine related to the central nervous system: neuroprotection; anti-inflammatory properties similar to standard drugs for the treatment of inflammatory conditions; antioxidant properties, contributing to its therapeutic action and an important intracellular mechanism underlying the protective pharmacological effects seen in clinical practice in the treatment of different stress-related adverse health conditions; and antiapoptotic properties, with greater neuron survival and a reduction in apoptosis mediators as well as oxidative substances, such as superoxide dismutase and hydrogen peroxide."

And depression, which can reflect a serotonin problem, is linked to a higher risk of AD, but treating depression leads to lower conversion.

Impact of SSRI Therapy on Risk of Conversion From Mild Cognitive Impairment to Alzheimer's Dementia in Individuals With Previous Depression.

https://www.ncbi.nlm.nih.gov/pubmed/29179578

A long-term treatment with antidepressants such as selective-serotonin-reuptake inhibitors (SSRIs) is known to reduce the risk of AD in patients with depression and, SSRIs, such as fluoxetine, increase the release of TGF-β1 from astrocytes and exert relevant neuroprotective effects in experimental models of AD. We propose the TGF-β1 signaling pathway as a common pharmacological target in depression and AD, and discuss the potential rescue of TGF-β1 signaling by antidepressants as a way to prevent the transition from depression to AD.

https://www.ncbi.nlm.nih.gov/pubmed/29438781

That looks interesting, will have a read.

And another vote for omega-3s.

N-3 PUFA diet enrichment prevents amyloid beta-induced depressive-like phenotype. (Rat study)

Results showed that n-3 PUFA enriched diet prevented the Aβ- induced depressive-like behaviors, as reveled by the reduction in the immobility time in the FST test. Furthermore, n-3 PUFA rich diet exposure reverted also serotonin and neurotrophin level reduction in prefrontal cortex of Aβ treated rats. Taken together, our data support the concept that supplementation of diet with n-3 PUFA represents a valid approach to reduce the risk of developing depressive symptoms, as well as reducing the risk of Aβ-related pathologies, such as AD.

https://www.ncbi.nlm.nih.gov/pubmed/29203442

Omega 3 oil is definitely something I read was good for depression as well, in the past and mood. Might be a link there.

Interesting stuff. And now I wonder how the gut / vagus nerve play into all of this, in terms of serotonin and signaling from the microbiome in the gut...hmm. I see some new rabbit holes, here.

Yes I can see that! I read somewhere that most of the serotonin is in the gut, rather than the brain! It seems it may interact in several different ways.

Here is an interesting article about How to increase serotonin in the human brain without drugs


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2077351/

I was interested to see this section, as it seems to tie in with the recent article on here about positive thinking and ageing..and how that improved things for those with APOE4. Could it be a link to serotonin, perhaps, amongst other things?

"The constitution of the WHO states “Health is a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity.”20 This may sound exaggerated but positive mood within the normal range is an important predictor of health and longevity. In a classic study, those in the lowest quartile for positive emotions, rated from autobiographies written at a mean age of 22 years, died on average 10 years earlier than those in the highest quartile.21 Even taking into account possible confounders, other studies “found the same solid link between feeling good and living longer.”12 In a series of recent studies, negative emotions were associated with increased disability due to mental and physical disorders,22 increased incidence of depression,23 increased suicide24 and increased mortality25 up to 2 decades later. Positive emotions protected against these outcomes"

"Several studies found an association between measures related to serotonin and mood in the normal range. Lower platelet serotonin2 receptor function was associated with lower mood in one study,30 whereas better mood was associated with higher blood serotonin levels in another.31 Two studies found that greater prolactin release in response to fenfluramine was associated with more positive mood.32,33 The idea that these associations indicate a causal association between serotonin function and mood within the normal range is consistent with a study demonstrating that, in healthy people with high trait irritability, tryptophan, relative to placebo, decreased quarrelsome behaviours, increased agreeable behaviours and improved mood.34 Serotonin may be associated with physical health as well as mood"

Ways shown to improve levels without drugs include:

self-induced changes in mood can influence serotonin synthesis.
exposure to bright light
exercise
possibly diet but unclear (tryptophan)

I definitely find personally exercise and music help me, and being outside in the sunshine, as much as the meds. Or the combination together. I wonder if any of this would be helpful for those who are not suffering or have had depression in the past, or whether it is mainly helpful to those people. I guess, it may be particularly of benefit to them. Around 1 in 4 of us do struggle with it at some point so i guess it is something to be aware of. And it seems to be linked with first stages of AD as well, as well as possibly being linked to APOE4 in women https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2583456/

[Orangeblossom]

Just to mention please take care if trying any supplements such as 5HTP, and St John's Wort in particular in combination with meds or things like Curcumin and antidepressants, it can lead to serotonin syndrome if you take too much together.

https://en.wikipedia.org/wiki/Serotonin_syndrome

I wonder about talking therapies such as CBT and mindfulness which have been shown to have great benefit in terms of treating depression and anxiety, as well. It would be nice to see a study looking at those people and if they were helped in a similar way in terms of brain changes.

[Orangeblossom]

Folate is linked to depression and low serotonin levels. maybe a good idea to keep folate intake high. I have two MTHFR variants wonder if that is linked?

might be a possible link between AD and depression, too...

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1810582/

"An entirely reversible environmental factor known to lower serotonin synthesis—folate deficiency. The purpose of this editorial is to draw attention to what is known about the epidemiology and biochemical and clinical effects of folate deficiency, to point out what studies are needed and to consider the recent recommendation that patients with depression should be treated with 2 mg of folic acid.."

"There is also a decrease in serotonin synthesis in patients with 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency, a disorder of folate metabolism.11,12 While the mechanism relating folate deficiency to low serotonin is not known, it may involve S-adenosylmethionine (SAMe)."

- goes on to mention MTHFR variants and need for more folate and B12..

[SusanJ]

Yes, with MTHFR variants there is a good chance you will need some folate and B12 support.

One place to look is your homocysteine levels, and you might consider testing folate, B12 and MMA levels if that would be available.

Or just try some methyl B12 (for about a week), then add methylfolate and see if you notice any difference. I'd start low (not 2 mg of folic acid) with 500 mcg/day methylB12 and 400 mcg/day of methylfolate. I think those of us with MTHFR variants are sensitive to "opening the floodgates" as it were. If you get brain effects (I call it busy brain), headaches or don't feel well, back off both until the symptoms disappear.

[Orangeblossom]

Thanks yes I have those. It's interesting you mention that as have been getting headaches and wondered if might be the folate. Was only the low levels you mention. I have a good multi vit now which has even lower levels of both so trying that, now. 20 micrograms B12 and 200 micrograms methyl folate. Still a bit achey so may well just have one a day (is a split 2 a day doe to get that level) Trying to eat plenty of folate rich foods as well. B12 levels usually come up quite on Chronometer as well, well on fish eating days particularly!

Maybe we are more sensitive to folate. I have two heterozygote variants so could be worse I know. But they can combine I think.

[SusanJ]

The more I read, the more I wonder if it's harder for those of us with MTHFR variants to find the sweet spot.

Dr. Ben Lynch, who does a lot of writing about methylation, says that you keep backing off until you don't get symptoms. And even though he has variants, he doesn't take B's daily, just when he feels he is going to be busy, a bit more stressed, etc. I'm starting to appreciate that approach works better for me, so I don't over-methylate.

[Orangeblossom]

The more I read, the more I wonder if it's harder for those of us with MTHFR variants to find the sweet spot.

Dr. Ben Lynch, who does a lot of writing about methylation, says that you keep backing off until you don't get symptoms. And even though he has variants, he doesn't take B's daily, just when he feels he is going to be busy, a bit more stressed, etc. I'm starting to appreciate that approach works better for me, so I don't over-methylate.

I know. It is tricky. I want to take care with it, as think some of the side effects might even made mental health worse. It made me feel quite anxious, as well as the headaches (it seems this is common with it when I looked online). I also wonder about simply taking more un-methylated forms, for example in foods, maybe that might be a good way forward while giving it a miss for a while.

After a bad day yesterday when I took a small amount I'm going off it for at least a week to have a think.

I found this article reassuring, https://www.dietvsdisease.org/mthfr-folic-acid-folate/ it said "Most of the folate and folic acid we eat must be converted into the active form, known as L-methylfolate or 5-MTHF. However, some dietary folate is already in the active form when we eat it and therefore does not rely on MTHFR." "Natural folate we eat comes in a variety of compounds. This includes the active form of L-methylfolate. That means we all need to eat more natural folate, MTHFR mutation or not." I didn't realise that. I have a whole foods supplement which has some natural folate from greens it in, maybe I'll use that for a while instead. Avocados and greens, also.

On another page of that site, it worried me as it said the 'compound heterozygous' type is the more severe / at risk, I didn't realise that either. But I read elsewhere it means about 50% reduced activity, whereas homozygotes for the TT have 70% less so must be even more difficult.

On a more positive note there was a big study today in the news in the UK about how anti-ds are effective, and helpful and some more than others.

http://www.bbc.co.uk/news/health-43143889

"Scientists say they have settled one of medicine's biggest debates after a huge study found that anti-depressants work."
"We found the most commonly prescribed anti-depressants work for moderate to severe depression and I think this is very good news for patients and clinicians."


https://www.theguardian.com/society/201 ... -they-work

The drugs do work: antidepressants are effective, study shows

"They are not a multibillion-dollar conspiracy dreamed up by Big Pharma Bond villains. They are not a snake oil distilled in secret laboratories, designed to stupefy us all. They are not a futile cop-out from overextended family doctors.

They are an effective treatment to alleviate symptoms of depression, a global scourge that affects as many as one in 20 people on the planet. Even the least effective antidepressants are better than placebos, the sugar pills dished out in trials. And placebos are better than nothing.

The upshot of this, the most intensive piece of meta-analysis ever conducted into antidepressants, is that the millions of people (including me) who take them – reluctantly, sceptically, hopefully – can continue to do so without feeling guilt, shame or doubt about the course of treatment.

Moreover, doctors should feel no compunction about prescribing these drugs, though really they should be reserved for serious cases, and should be offered as part of a mix of interventions such as CBT, group therapy, work sabbaticals, mindfulness-based cognitive therapy, exercise, education and local support networks."

Interesting that Amitrptilline comes out tops- I have taken that in low doses for pain in the past. I was told it is 'cheap as chips and old as the hills'. It does also help with neuropathic pain. Maybe it is individual, as prozac comes out low, but I have tried others and find it the best one for me. i think this is because it has a long half life and works over a longer time.

[SusanJ]

Lots of leafy greens will help decrease the folate supplement need, even with MTHFR variants.

Smart to drop taking them. Ben Lynch emphasizes if you feel bad, you probably need to fix something else first. He argues that your body is always changing, so the right amount of any supplement is always changing, too. I think that's smart advice. Over supplementing is just as bad as not giving your body what it needs.

The other thing to consider, both Masterjohn and Lynch suggest supplementing with phosphatidylcholine and creatine, which will lessen the need for folate/methyl groups because those two supplements are ready to use, without using up methyl groups to activate them.

I decided to try phosphatidylcholine because I know I have some choline processing variants. Too early to tell with any labs, but the early body signs are mostly positive. I have some creatine on order, so haven't tried that yet. But I'm interested - Lynch says that creatine has helped his patients who were unable to take methylfolate, B12 or other methyl donors.

If you decide to try either of them, start one at a time, start really low and go up slow. If you get side effects, back off or quit for a while. I use sunflower lecithin powder for the phosphatidylcholine and use only about half of the bag's recommended dose and usually only on days when my choline intake is low.

Oh, and anytime you take folate and it bothers you, try 50mg of niacin and it will counteract the side effects. You'll also likely get a flush, so don't panic, it will go away.

Hang in there Orange. I feel that MTHFR variants are one of the toughest things to supplement properly, because the resulting methyl groups can run rampant in so many other pathways, including neurotransmitters, where we might also have variants or other problems. In fact Lynch recommends in his latest book (Dirty Genes) to treat other bad actor genes first, and only supplement B vitamins after "fixing" the other genes. And that seems to match up with my experience as I unwind the effects that might be the result of too many years of too much methylfolate.

[Orangeblossom]

"The other thing to consider, both Masterjohn and Lynch suggest supplementing with phosphatidylcholine and creatine, which will lessen the need for folate/methyl groups because those two supplements are ready to use, without using up methyl groups to activate them."

I decided to try phosphatidylcholine because I know I have some choline processing variants. Too early to tell with any labs, but the early body signs are mostly positive. I have some creatine on order, so haven't tried that yet. But I'm interested - Lynch says that creatine has helped his patients who were unable to take methylfolate, B12 or other methyl donors.

"If you decide to try either of them, start one at a time, start really low and go up slow. If you get side effects, back off or quit for a while. I use sunflower lecithin powder for the phosphatidylcholine and use only about half of the bag's recommended dose and usually only on days when my choline intake is low."

Thanks for the ideas, I will look into these. I have started having a handful of sunflower seeds most days- they contain some lecithin but not sure exactly how much. And eggs sometimes. I might try the powder mentioned, as well. Can i ask how much you take specifically, the one I saw has no mention of dosage. Just had a quick look at my CHAT snps and they seem mostly OK, I mean not double recessive / red in anything, but a few hetero type ones.- no double good anything haha. (wouldn't that be nice for a change ) It seems a good idea to look into anyway. My GP recently tested my creatinine levels, which I understand is like to creatine, anyway it was in normal range. I eat quite a bit of fish so think that is OK for the time being. Again, might be something we don't want too much of.

"Oh, and anytime you take folate and it bothers you, try 50mg of niacin and it will counteract the side effects. You'll also likely get a flush, so don't panic, it will go away."

Ok, well with the Wholefoods one I mentioned, it has niacin in it as well. It has a lowish amount of folate and some niacin, so could work OK, to start with anyway, alongside a folate rich diet. It is mainly made from Acerola powder (a kind of berry, I think). Each one has 70 micrograms Folate and 2.2mg Thiamine.

"Hang in there Orange. I feel that MTHFR variants are one of the toughest things to supplement properly, because the resulting methyl groups can run rampant in so many other pathways, including neurotransmitters, where we might also have variants or other problems. In fact Lynch recommends in his latest book (Dirty Genes) to treat other bad actor genes first, and only supplement B vitamins after "fixing" the other genes. And that seems to match up with my experience as I unwind the effects that might be the result of too many years of too much methylfolate."

It is tricky isn't it. At the moment I'm going to try low levels of B Vitamins such as in the Wholefood vitamins, and keeping an eye on Chronometer, it is often surprising to me how much of these are in food I eat anyway. Yes in De Longo's book he said about maybe taking a mutivitamin every 3 days, but maybe every day of at risk of AD...it was certainly more about avoiding being too deficient in something rather than taking really high amounts, which he thinks can sometimes lead to problems. (I think he was referring more to the vitamins which can build up in the body here though). It can all be a but of a minefield at times! Thank you for the tips.

[Orangeblossom]

Lots of leafy greens will help decrease the folate supplement need, even with MTHFR variants.

Smart to drop taking them. Ben Lynch emphasizes if you feel bad, you probably need to fix something else first. He argues that your body is always changing, so the right amount of any supplement is always changing, too. I think that's smart advice. Over supplementing is just as bad as not giving your body what it needs.

The other thing to consider, both Masterjohn and Lynch suggest supplementing with phosphatidylcholine and creatine, which will lessen the need for folate/methyl groups because those two supplements are ready to use, without using up methyl groups to activate them.

I decided to try phosphatidylcholine because I know I have some choline processing variants. Too early to tell with any labs, but the early body signs are mostly positive. I have some creatine on order, so haven't tried that yet. But I'm interested - Lynch says that creatine has helped his patients who were unable to take methylfolate, B12 or other methyl donors.

If you decide to try either of them, start one at a time, start really low and go up slow. If you get side effects, back off or quit for a while. I use sunflower lecithin powder for the phosphatidylcholine and use only about half of the bag's recommended dose and usually only on days when my choline intake is low.

Oh, and anytime you take folate and it bothers you, try 50mg of niacin and it will counteract the side effects. You'll also likely get a flush, so don't panic, it will go away.

Hang in there Orange. I feel that MTHFR variants are one of the toughest things to supplement properly, because the resulting methyl groups can run rampant in so many other pathways, including neurotransmitters, where we might also have variants or other problems. In fact Lynch recommends in his latest book (Dirty Genes) to treat other bad actor genes first, and only supplement B vitamins after "fixing" the other genes. And that seems to match up with my experience as I unwind the effects that might be the result of too many years of too much methylfolate.

Sorry forgot to quote you in the post above.

I notice when I go to buy sunflower lecithin on Amazon it is loads cheaper in the baking section that the supplement section and looked like the same thing! Do they hike the price up I wonder when they call it a health product (sneaky) or maybe it is better quality. Anyway just mentioning it in case you wanted to take advantage of this. Do we need the more expensive type I wonder? I think when checking the cheaper one looks fine, it says no chemicals used and description looks OK.

For example 500g (around £5) here vs 225g (over £20) here