Inflammation theory of Depression

April 12, 2011 8:08 AM

Have you been keeping up with research on the inflammation theory of depression and mental illness? If you'd like to explore the pathology if inflammatory cytokines in the development of depression, this paper breaks it down.

The negatives: Apparantly, being poor/uneducated, adverse psychosocial experiences in childhood, peer rejection, childhood trauma, and having experienced childhood adversity, high fat diet, all predict higher levels of inflammation. Further more, prenatal exposure to inflammation in the womb can cause brain damage in mice, and a host of negative responses in the human infant.

The good news: Having positive social support, exercise, anti-inflammatory components in nutritious food, yoga, and mind body awareness all seem to reduce these inflammatory markers. The ease with which one can take a blood test and see how the body is responding to environmental factors, lifestyle changes, and social support may open up new doors in understanding the environmental origins of many common chronic conditions, as well as being able to measure how we can create positive environments and supports that will directly reduce such inflammation. Of course, pharma is hoping we choose NSAIDs.

The research also has found that inflammation seems to be a common link between obesity, heart disease, neuroinflammation, diabetese, PTSD, liver disorders, HPA axis dysregulation, irritable bowel syndrome and mental illness. Finding ways to reduce or reverse the inflammatory process before drugs are necessary may be more easy to measure now than ever before (although we are just now at the beginnings of studying how inflammation fits into such a multi faceted process.)

Interesting to note, as of yet there have been no studies that I can find on how various talk therapies might influence the inflammatory process (please link up in comments if you know of any!). There is too much drooling over being the one to discover the NEW ANTIDEPRESSANT NSAID!

".The importance of the inflammation hypothesis of depression lies in raising the possibility that psychotropic drugs that have a central anti-inflammatory action might provide a new generation of antidepressants."

posted by xarnop (51 comments total)

Note: I feel the importance of the inflammation hypothesis of depression to mean nothing of the sort. The opportunities to measure the efficacy of non-drug related therapies, lifestyle changes, and supports being the first that comes to my mind.

But then I don't have ego/career investment in pharma.
posted by xarnop at 8:11 AM on April 12, 2011

I once stumbled upon this site, which seems to have a giant following. I stopped reading when I realized that I wasn't qualified to figure out whether this line of thought was potentially revolutionary or a cult.

A lot of people seem to think that inflammation is the root of most chronic disease - sounds cultish to me - but maybe the science is sound and its just the adherents that make it seem culty. I'd love it if someone more qualified than myself could settle the question.
posted by tempythethird at 8:13 AM on April 12, 2011

How many paragraphs do I have to read before I find a clue as to what is inflamed?
posted by DU at 8:14 AM on April 12, 2011 [20 favorites]

(Note-- my bias is that whatever treatments we apply, I would like to be finding cures that actually heal the brain such that no drugs are need, the same as IDEALLY we would be attempting to cure any other disease. Therefore, I am not opposed to drugs being used, I am opposed to pharma assuming that long term drug treatment is considered a cure.)

Tempty--- I agree, the research can be manipulated by either pharma or culty new age groups-- both having ego investments in being right.

I too am curious to find out the direction this research will go, and am not qualified to give you a difinitive answer myself. I do however find it fascinating.
posted by xarnop at 8:16 AM on April 12, 2011

"Inflammation" does seem to be a common factor linking all kinds of diseases. I have noticed this before. Think about the digestion troubles that are linked with autism. And allergies. The inflammation is an automatic response of the body sending too many reinforcements to the site of a detected problem. Just like when you sprain your ankle and it swells up. This is just my own pondering of observations, not backed up by anything.
posted by amethysts at 8:18 AM on April 12, 2011

Are you in my health psychology class? This is eerie, it's like you're preparing for today's test in much the same vain I am.

Perhaps I'll weigh in more after school, but in my skimming of the links and post I'm not seeing much about stress. Stress stress stress. The core of so many negative health outcomes. Perhaps it's not the cult of inflammation, but the cult of evolutionary mismatch between evolved stress response and today's modern living. Sorry for the relative incoherence, I've been up all night studying for three tests and a writing a paper based on the *other* health psychology paper which showed up on the front page, about unhealthy behaviors mitigating the stress response leading to lower incidence of depression but greater chronic disease rates...which you probably linked in your well formed post which I only skimmed
posted by lizjohn at 8:22 AM on April 12, 2011 [1 favorite]

Lifestyle changes are almost always less effective than medicine, sad but true. Focusing on dramatic shifts in diet and other factors is counterproductive, especially in the case of depression, where the patient is already feeling terrible about themselves - adding a big dollop of holier-than-thou shame to that strikes me as being extremely unsound therapy.
posted by Slap*Happy at 8:37 AM on April 12, 2011 [12 favorites]

Perhaps I'll weigh in more after school, but in my skimming of the links and post I'm not seeing much about stress. Stress stress stress.

I'm really rusty on this topic, but isn't inflammation and stress linked? My layman's working understanding is that any stressor on the body leads to an inflammatory response.
posted by psp200 at 8:44 AM on April 12, 2011

Slap Happy--- life style changes are ineffective because people with inflammatory condition have compromised ability to function on a daily basis, much less enact a radical lifestyle change. Further more, the findings that social supports are important buffers in the the infmallatory process imply that manifesting healthy conditions is beyond the scope if an individual to create all by themselves.

The goal would still be support from the outside to create a supportive healing environment for the person. This is not popular because it's expensive and requires much more comprehensive programs than we have now. Further more, treatment is heavily vested in the ease and low cost of handing out pills, and the funding available for research is heavily vested in this model of treatment.

That doesn't mean that it's the best treatment model, or that it gets the best results. It works the best because we don't have a better system set up, and due to backlashes from pharma and people vested in beleiving in pharma, it's very difficult to challene this model.
posted by xarnop at 8:46 AM on April 12, 2011

I'm really rusty on this topic, but isn't inflammation and stress linked? My layman's working understanding is that any stressor on the body leads to an inflammatory response.

True that, I just wanted to point out that it's not just a inflammation response (like this magical woo-woo thing), but there's a causal mechanism in there was well. Perhaps it's obviously implied and I'm just being dense.
posted by lizjohn at 8:47 AM on April 12, 2011

lizjohn: I mighe be confusing a stress response with an inflammatory response. Isn't cortisol an anti-inflammatory? Haha sorry folks I sense a derail. I'll get some coffee.
posted by psp200 at 8:52 AM on April 12, 2011

Ok, one more thing before class, I'd like to recommend this book for anyone interested in the subject: Why Zebra's Don't Get Ulcers. I was going to also link to the wikipedia synopsis, but I think the Amazon review is pretty good.
posted by lizjohn at 8:55 AM on April 12, 2011

Liz--- you're absolutely right and I simply pressumed that would be the logical implication. Stress and trauma are absolutely at the root of it. What we are finding is that the affects of stress are cumulative, and in fact involve stressors that affected epigenetic gene tagging in parents and grandparents, as well as inflammation and HPA dysregulation in the pregnant mother.

The root of all disease is involved in the accumulation of stress and trauma without positive buffers to assist in bringing the body back to healthy homeostasis before the new stressor occurs. Stressors that occur during prenatal, infant and childhood development will have the deepest long term affects on responses to stress in adulthoodm, but trauma in adulthood and chronic stress can be enough to set off the disease process itself. Further more chronic stress and trauma will predispose the CHILD of that adult to hightened responses to stress if the parent hasn't brought their system back to healthy functioning before birth.
posted by xarnop at 8:55 AM on April 12, 2011 [1 favorite]

I don't want to threadshit, but a book called "Why Zebras don't get ulcers" sounds as reliable as the now-debunked "why sharks don't get cancer" claptrap nonsense..
posted by k5.user at 8:57 AM on April 12, 2011

DU said it, and nobody's answered it: inflammation of what? I'm suspicious when people can't seem to put things into clear, plain language. That's something science is supposed to be able to do.
posted by koeselitz at 9:02 AM on April 12, 2011 [5 favorites]

I know, I *know* I said I was going, but I just have to comment

I don't want to threadshit, but a book called "Why Zebras don't get ulcers" sounds as reliable as the now-debunked "why sharks don't get cancer" claptrap nonsense..

Granted, I have not read the shark book, so I am basing my knowledge on a cursory search on the web. You're right, the whole cancer and shark thing sounds like a load of bull. However, I think it is a mistake to dismiss the Zebra book on the basis of name similarity. Robert Sapolsky, author of Zebra, seems to have nothing to do with any sort of woo. He is not touting any miracle claims, nor does he recommend we should we eat Zebras for health benefits or such. The guy knows his shit. Perhaps it's a shame he named his book what he did, it's used as a primarily a framing mechanism, not some sort of wonder claim.
posted by lizjohn at 9:10 AM on April 12, 2011 [3 favorites]

Note- my use of the word homeostasis does not mean to imply I believe in homeopathy which is the epitome of the new age health movement abusing science to promote and sell a sugar pill. I have the same concerns with new age health movements as I do with pharma.

Alternahealth is filled with all the same agendas as pharma "Our method of healing is RIGHT (by the way buy my book)" which is even more dangerous than pharma because there is absolutely no regulation, and similar to religion often requires believers to apply the techniques being sold based on "belief beyond science" or grotesque manipulations of science put together to sound reasonable.

That being said, the reality that stress raises inflammatory markers has been demonstrated time and time again in research found from fairly reputable research search engines such as pubmed. Further more, it's been demonstrated that inflammatory makers seem to lower in response to numrous interventions such as exercise. What that means and how it fits into the disease process and treatment options is up for debate.

Koeslitz--- Are you familiar with positive and negative feedback? Basically immune response is part of the bodies positive feedback system--- molecules are sent out to address a pathogen, toxin or stressor in the body. This process involves the release of pro-inflammatory cytokines which sttimulate hormonal and immune response to the problem. When the body has finished addressing the problem situation, anti-inflammatory cytokins are released to rid the body of the biomolecules and macrophages that we upregulated to address the process.

This might help clarify:

"Cytokines are several different types of substances that are produced by cells within the immune system. These substances relay signals between the immune system cells. Sometimes referred to as polypeptide regulators, there are two groups of inflammatory cytokines, each with their own particular characteristics and functions.


One form of inflammatory cytokines is known as the pro-inflammatory polypeptide regulators. These types of cytokines are created primarily by immune cells that are engaged in the process of amplifying inflammatory reactions as a means of dealing with some sort of health threat to the body. By relaying messages between the cells, these cytokines help to trigger the immune system’s rate of response to whatever threat is present."
posted by xarnop at 9:12 AM on April 12, 2011 [3 favorites]

Oh--- sorry everyone, this was my first post--- I was nudged that participating in your own thread is bad form... (thanks for the heads up!)

Carry on then... : )
posted by xarnop at 9:18 AM on April 12, 2011

I find your post-post clarifications helpful, xarnop.
posted by psp200 at 9:21 AM on April 12, 2011 [3 favorites]

I'm sorry, an explanation of feedback is not a part of the body. Is it arms? Are arms inflamed? Livers? Toenails? Or is it just floating "markers" of inflammation?
posted by DU at 9:25 AM on April 12, 2011

They're not saying inflammation of the (e.g.) pineal gland is the source of all woes, but that there is a correlation between inflammation immune response and various maladies.
posted by fleacircus at 9:27 AM on April 12, 2011 [2 favorites]

I've done some lab research on inflammation/cytokines and the etiology of schizophrenia and mood disorders. There's even a paper (out RSN, hopefully) on a new way to image (via a secondary marker) some inflammation and oxidative processes happening in *real-time* in living brains (of mice). No killing necessary, optically image right through the skull, follow the effects of therapeutics designed to affect the oxidative cascade. Could help find a cure for schizophrenia in mice...

Not all inflammation is bad. Overshoot and get rid of too much inflammation on a cellular level and all the microparasites will have a better chance of eating you from the inside out. We inflame for some very good reasons. There's a lot of poor information in this thread. For instance, re. the above? Cortisol is actually the *opposite* of anti-inflammatory, and it's crucial for life.
posted by meehawl at 9:41 AM on April 12, 2011 [2 favorites]

Why Zebra's Don't Get Ulcers

Intriguing title. Due to peculiarities of their digestive system, horses get ulcers. A *lot* of horses get ulcers. Part of this is influenced by domestication and management, but part of it is just some extremely poorly designed innards. So I wonder if zebras really have much better digestive systems than their cousins, or if it's just that no one has actually *looked* for ulcers in zebras.
posted by galadriel at 9:47 AM on April 12, 2011 [1 favorite]

galadriel- it's a bad title. Iirc the author is arguing that animals are less prone to disorders that result from psychological stress. But it turns out that ulcers in specific aren't a result of psychological stress, but of helicobacter pylori.
posted by Jpfed at 9:51 AM on April 12, 2011

That is all to say that I don't think Sapolski actually looked at any animal species to determine whether they had ulcers; I think he (incorrectly) used ulcers in his title as a commonly-understood proxy for disorders induced by psychological stress.
posted by Jpfed at 9:54 AM on April 12, 2011

Acute inflammation certainly is mood-altering- (ever been sick as fuck? How did you feel?) and this is thought to be in large part due to direct or indirect effects of the cytokine response. Whether chronic inflammation is causally related to mood disorders is considerably more hand-wavey. It's not implausible: certainly in vitro and in vivo studies have provided several potential mechanisms by how this could be so, and people with chronic autoimmune diseases certainly are more prone to mood disorders, but this may simply be related to the simple psychological stress of dealing with chronic disease-- no intervening steps required. Again, while I think inflammatory processes are plausible contributors to depression, I wouldn't put them super high up on the causal waterfall.

Lifestyle changes are almost always less effective than medicine, sad but true. Focusing on dramatic shifts in diet and other factors is counterproductive, especially in the case of depression, where the patient is already feeling terrible about themselves - adding a big dollop of holier-than-thou shame to that strikes me as being extremely unsound therapy.

Lifestyle changes actually work very well and are the best possible intervention for a large number of common primary-care issues. It is, however, perversely difficult to get people to make changes. As regards depression, the studies that have been performed to date are pretty poorly designed, as most non-drug psychiatric trials are. The big problem is performing an intention to treat analysis-- for lifestyle interventions, 'noncompliance' is extremely high, and there may be some phenotypic sifting towards milder depression in compliant patients that may bias resulting analysis. However, as an intervention strategy it has a lot to recommend it- even if it doesn't result in a substantial effect on depression, change to a 'good' diet and exercise program is clearly established to be good for you. I don't know about the shame thing- you know that there are other ways to recommend these things, right?

life style changes are ineffective because people with inflammatory condition have compromised ability to function on a daily basis, much less enact a radical lifestyle change. Further more, the findings that social supports are important buffers in the the infmallatory process imply that manifesting healthy conditions is beyond the scope if an individual to create all by themselves.

Don't put inflammation at the base of the pyramid- the phenotype of depression is in itself a substantial barrier to effecting changes. Depression is self-enforcing.
posted by monocyte at 9:54 AM on April 12, 2011 [1 favorite]

The "next big thing" NSAID that cures depression is not on my list of things to try after the Bextra and Vioxx disasters, thanks. To the extent that we need NSAIDs, and there are plenty of folks out there with inflammatory disease who do, social support, improved diet, yoga, etc., aside, there are a lot of them out on the market already and a lot of what we're seeing with them is twiddling to keep patent monies flowing in from chronically ill/partially disabled patients who'll be on these drugs for a lifetime.

I'm going to be very interested to read the links--that first paper looks like a great, if dense for the lay reader, read--but as a person who's dealt with immune-related disorders all her life, and one who has no love for the pharmaceutical industry, I'm also skeptical of the "if you do enough yoga you'll feel better and stop being so sick" approach that's likely to come out of this research. I get enough (kindly intended) shit about all the things I don't do already from family and friends while I'm trying to make sustainable changes for myself (Health Month ftw!). I'm not looking forward to another source of low-level harassment about how if I just try yoga, surely my problems will go away.
posted by immlass at 9:59 AM on April 12, 2011 [1 favorite]

Not all inflammation is bad. Overshoot and get rid of too much inflammation on a cellular level and all the microparasites will have a better chance of eating you from the inside out. We inflame for some very good reasons. There's a lot of poor information in this thread. For instance, re. the above? Cortisol is actually the *opposite* of anti-inflammatory, and it's crucial for life.

Thanks for the correction, I recognize that cortisol is necessary. Can you explain why cortisol is used as an anti-inflammatory in medicine?
posted by psp200 at 10:03 AM on April 12, 2011

I can't believe all the inflammatory comments.
Flagged.
posted by Kabanos at 10:04 AM on April 12, 2011 [4 favorites]

Or is it just floating "markers" of inflammation?

Yes. You're confusing the typical use of the word inflammation with a more specific medical use that is invoked here. Just because a limb isn't red and swollen doesn't mean nothing is going on; these are all cell and tissue-level processes.
posted by slow graffiti at 10:05 AM on April 12, 2011 [2 favorites]

I'm intrigued; my gut sense is that with time the answer will probably turn out to be "some of everything." Inflammation no doubt matters, but i would guess so that it matters in addition to, not instead of, the causes and solutions we already know about.
posted by Forktine at 10:06 AM on April 12, 2011 [1 favorite]

Why horses Don't Get Eaten By a Fucking Great Lion
posted by Artw at 10:12 AM on April 12, 2011 [10 favorites]

Lifestyle changes are almost always less effective than medicine, sad but true.

The elephant in the room here is that medicine is not particularly effective against some chronic diseases, and that lifestyle changes seem to be. When the choice for your auto-immune arthritis is "strong NSAIDS for life, followed by a GI bleed caused by NSAIDS" or "TNF inhibitors for life, followed by illness caused by the low immune-system response TNF inhibitors induce", diet and exercise start looking like a much more effective alternative, especially when backed up by an occasional over-the-counter NSAID.

Like monocyte said above, the problem with diet and exercise is compliance, not effectiveness... and compliance is even less likely if doctors don't explore these options with their patients because "lifestyle changes are almost always less effective than medicine". Hell, I've had doctors tell me to stop eating the low-starch diet that works for me, presumably because they thought getting a good serving of potatoes with every meal was more important than not being in constant goddamned pain.
posted by vorfeed at 10:35 AM on April 12, 2011

This is a huge and difficult topic, that I just discovered yesterday (thanks xarnop!), so this has got to be one of those threads where a lot of the good discussion comes late, after everything's been read. Still, I know the pace of metafilter threads, so I'm posting after only having read the first link, in reply to a lot of unsorted people.

Note: I feel the importance of the inflammation hypothesis of depression to mean nothing of the sort. The opportunities to measure the efficacy of non-drug related therapies, lifestyle changes, and supports being the first that comes to my mind. But then I don't have ego/career investment in pharma.

Part of why this is really cool is because it's not pharma driven. After the failure of COX-2s, pharma actually has no stake in the anti-inflammatory market. Sure, aspirin is a huge seller, but nobody owns it, and it's completely affordable. If anything, the rise of anti-inflammatory treatment for depression would mean reduced revenues for pharma, as some of their big money makers might be supplanted. (They probably wouldn't be supplanted, but instead, anti-inflammatories would be given additionally. First link mentions improvement with aspirin on top of an anti-depressant vs. anti-depressant alone.)

How many paragraphs do I have to read before I find a clue as to what is inflamed?

Xarnop answered it, but it sounds as if there's still confusion. This isn't inflammation in the same way that you think of inflammation typically (5 cardinal signs aren't present, for instance), but system inflammation. Nothing is swollen or red. Systemic inflammation means that various markers of inflammation are present-- the kinds of things that would be present if something was big and red and hurty, even though nothing is (except your SOUL)

"Inflammation" does seem to be a common factor linking all kinds of diseases. I have noticed this before.

And one that you didn't mention: coronary artery disease. And one of the reasons this is really interesting is because coronary artery disease is mysteriously comorbid with depression, even when you control for things like the fact the people who suffer depression smoke much more frequently. (And hey, we treat CAD with aspirin-- sure, supposedly for its antiplatelet properties, but that's kind of after the fact. We treat it with aspirin because aspirin works, and then we decide what the mechanism is.)

And definitely, definitely, definitely, chronic pain, which is linked with depression, without any established causality either way. (Does depression cause chronic pain? Does chronic pain cause depression?)

I'm really rusty on this topic, but isn't inflammation and stress linked? My layman's working understanding is that any stressor on the body leads to an inflammatory response.

Right, and this is again a reason why this is interesting. Because depression rarely comes on out of nowhere like the proverbial black cloud; it tends to show up in the face of a precipitating stressors. Now, you have to be careful about the language, because medicine distinguishes between physical stressors and psychosocial stressors, but research has shown that even psychosocial stressors are correlated with these same markers of inflammation.

It's not a matter of depression being caused by inflammation instead of stress-- it's more like stress causes inflammation causes depression.



Lifestyle changes are almost always less effective than medicine, sad but true.
vs

Lifestyle changes actually work very well and are the best possible intervention for a large number of common primary-care issues. It is, however, perversely difficult to get people to make changes.

You're kind of both right, of course. Medicine is usually focused on effective interventions. "Increasing activity" is not an intervention. "Advocating increased activity" is. You can imagine that the second is much less effective than the first.

Judging the actual effects of lifestyle changes rather than advocacy for lifestyle changes is almost impossible, however, because they're involved with depression in a feedback loop. Remitting depression leads to lifestyle changes just as much as lifestyle change leads to remittance. So if you just take a group of depressed people and say, "People who had more activity were less depressed," you're not really saying anything about causality.

Not all inflammation is bad. Overshoot and get rid of too much inflammation on a cellular level and all the microparasites will have a better chance of eating you from the inside out.

Right. As is famously said, the dose makes the poison. Just like not all coagulation is bad, but we still treat people that need them with anticoagulants. Without inflammation, we'd never heal. But inflammation definitely has its down-sides as well, and controlling local inflammation is already a crucial part of medicine.

I wouldn't be surprised if we found treating systemic inflammation in people suffering depression led to remission of depression, with increased incidence of other problems, but I think most people suffering recalcitrant depression would say that it'd be worth it.

Acute inflammation certainly is mood-altering- (ever been sick as fuck? How did you feel?) and this is thought to be in large part due to direct or indirect effects of the cytokine response. Whether chronic inflammation is causally related to mood disorders is considerably more hand-wavey. It's not implausible: certainly in vitro and in vivo studies have provided several potential mechanisms by how this could be so, and people with chronic autoimmune diseases certainly are more prone to mood disorders, but this may simply be related to the simple psychological stress of dealing with chronic disease-- no intervening steps required. Again, while I think inflammatory processes are plausible contributors to depression, I wouldn't put them super high up on the causal waterfall.

But this isn't just a plausible pathophysiology for depression. Here:

In addition to correlative data linking inflammatory markers with depressive symptoms, several lines of evidence demonstrate that both acute and chronic administration of cytokines (or cytokine inducers such as lipopolysaccharide [LPS] or vaccination) can cause behavioral symptoms that overlap with those found in major depression.

In other words, artificially increase markers of inflammation, and you cause depression.

Finally, several studies in humans suggest that immune-targeted therapies may have clinical benefit. For example, acetylsalicylic acid (which blocks both cyclooxygenase-1 and 2 and the production of prostaglandins) when added to fluoxetine led to increased remission rates in an open-label study of depressed patients previously nonresponsive to fluoxetine alone (18)

In other words, treat inflammation, and you treat depression.

You don't quite fulfill Koch's postulates, because you don't have some kind of 100% thing going on, but it's pretty strong.

I don't think anybody is suggesting that if you have systemic inflammation, you have depression. There are other factors going on, and there are people who have depression but not systemic inflammation. (There is quite easily the possibility that there are multiple etiologies for depression, just as there are multiple etiologies for shortness of breath; discovering one etiology is super important.)
posted by nathan v at 10:56 AM on April 12, 2011 [11 favorites]

It is also important to note that the floating 'markers' of inflammation are not just markers, but many are signalling molecules that participate in the inflammatory process, as opposed to end products.

Some major ones are IL-1 beta, IL-6, and TNF-alpha, and they are released into circulation in response to various stressors. For example, blood levels of IL-1 beta are elevated following psychosocial stress (cite).

My favourite paper on the relationship between inflammation and depression is here and the authors show some pretty interesting stuff. They compare the effects of the omega-3 fatty acid EPA, and the selective COX-2 inhibitor celecoxib (AKA Celebrex) on the levels of various signalling molecules and enzymes related to the inflammatory process, and ALSO to the behaviour of the mice used in the study.

Both EPA and celecoxib returned the levels of enzymes and signalling molecules (in the 'depressed' group) to the levels found in the control group, and had significant effects on their behaviour as well.

So there is no need for a NEW magic NSAID. The ones we have developed are already effective, and even better, Omega-3 fatty acids are also effective. I guess ibuprofen would also work, though maybe not as well as celecoxib and possibly with worse side effects, so that's one more option.

As others have mentioned, these things are probably better employed as one part of a broader approach, (definitely) involving lifestyle changes and (possibly) other foods/medications. Still I think it is great to see that (at least in this model) they can have such a large effect, especially when EPA is as cheap, abundant, and well tolerated as it is!
posted by benign at 11:00 AM on April 12, 2011

If there's a pill that helps I'll try it. I'm tired of feeling like this.

The real insidious thing is that everything that is supposed to help feels so ineffective, unobtainable, or just impossible...
posted by polyhedron at 11:09 AM on April 12, 2011 [7 favorites]

I am so sorry to be rude and write again, but plyhedron, your feeling is exactly what I want the medical community to address. We don't more ADVOCACY of lifestyle change. We need more SUPPORT for people who need help to get the nutrients in food, exercise, and social support they need to compliment their healing process. No one can make this happen when they are drowning in depression or physical illness that causes fatigue and misery. People need support to make this happen. If there is anything I can do in my lifetime, I hope to convince the medical system that these supports are worth providing.

It can't all fall on a person who is already drowning.
posted by xarnop at 11:23 AM on April 12, 2011 [3 favorites]

I am so sorry to be rude and write again, but plyhedron, your feeling is exactly what I want the medical community to address. We don't more ADVOCACY of lifestyle change. We need more SUPPORT for people who need help to get the nutrients in food, exercise, and social support they need to compliment their healing process.

I think this is exactly right. I don't want to get all anecdotal, so I'll just say that my life turned around after I discovered a supportive church, even though I am still a damned apostate. I was able to find a supportive community that takes me as I am, and I'm immune to their proselytizing because I used to be one of them, and now am not. Haha.

Being plugged into a community of less-cynical-than-average people helped me take the steps to become physically healthier by engaging in social activities, exercise, eating better-- none of these related to the religion itself.

Whatever mechanism is taking place, I'm getting physically fitter and feeling more human now than I did a year ago.

Just want to reiterate this too: This was a great post xarnop.
posted by psp200 at 11:49 AM on April 12, 2011

Of course, pharma is hoping we choose NSAIDs.

Yeah, because with the kind of money you'd get if everyone in the US went out and bought a years supply of aspirin, my corporate masters could almost cover their research budget for two months!
posted by Kid Charlemagne at 11:55 AM on April 12, 2011 [1 favorite]

Some major ones are IL-1 beta, IL-6, and TNF-alpha, and they are released into circulation in response to various stressors. For example, blood levels of IL-1 beta are elevated following psychosocial stress (cite).

Well, Il1b mRNA is upregulated in that study in PBMC- the generation of active IL-1b is a completely different question, due to a posttranslational complex called the inflammasome which serves as a secondary checkpoint on active IL-1b release. They do measure an increase in IL-6 directly, but the measured changes are on the order of a picogram/mL, less than normal diurnal variation of this factor in the blood.

But this isn't just a plausible pathophysiology for depression. Here:

In addition to correlative data linking inflammatory markers with depressive symptoms, several lines of evidence demonstrate that both acute and chronic administration of cytokines (or cytokine inducers such as lipopolysaccharide [LPS] or vaccination) can cause behavioral symptoms that overlap with those found in major depression.

In other words, artificially increase markers of inflammation, and you cause depression.

All of the cytokines mentioned were spiked at levels much higher than anything the stress response has been shown to accomplish. LPS more or less simulates septicemia (it's a bacterial cell wall product), even at the controlled doses used in human studies, while interferon alpha at chemotherapeutic levels more or less feels like a bad flu that never stops. At these doses, as with natural infections, I don't think there's much dispute that cytokines do this, but at much higher doses than any stress-associated response I've seen. As such these studies provide a starting point for addressing chronic inflammation's role but are not great in terms of defining a 'smoking gun'.

When the choice for your auto-immune arthritis is "strong NSAIDS for life, followed by a GI bleed caused by NSAIDS" or "TNF inhibitors for life, followed by illness caused by the low immune-system response TNF inhibitors induce", diet and exercise start looking like a much more effective alternative, especially when backed up by an occasional over-the-counter NSAID.

I think you are conflating osteoarthritis and rheumatoid (inflammatory) arthritis here. Good exercise practice and diet can be palliative or prophylactic for OA, by reducing joint loading and preventing physical damage. Lifestyle modifications may be somewhat palliative for RA (as are NSAIDS), but RA typically has a relentless course that diet and exercise will do little to alter- for damn sure it won't get you between TNF inhibitors or other disease-modifying agents and 'an occasional over the counter NSAID'.
posted by monocyte at 12:04 PM on April 12, 2011 [1 favorite]

Does X cause an inflamation or does inflamation bring about X?
posted by Postroad at 12:17 PM on April 12, 2011

All of the cytokines mentioned were spiked at levels much higher than anything the stress response has been shown to accomplish. LPS more or less simulates septicemia (it's a bacterial cell wall product), even at the controlled doses used in human studies, while interferon alpha at chemotherapeutic levels more or less feels like a bad flu that never stops. At these doses, as with natural infections, I don't think there's much dispute that cytokines do this, but at much higher doses than any stress-associated response I've seen. As such these studies provide a starting point for addressing chronic inflammation's role but are not great in terms of defining a 'smoking gun'.

No, you're right, it's no smoking gun.

A lot of this seems complicated by the research. It seems like it's mostly about stuff gathered during research on hep C treatment and animal research. Obviously the animal research is less than perfect, especially since there's no real way to ascertain depression in animals, not using diagnostic criteria similar to that used for people, and can't be compared to people directly-- is the stress of rat claustrophobia equivalent to the stress of bereavement? (In people, it sounds like there is a strong dose-response to at least several markers, but I don't want to suggest that that alone means causality.) And the Hep C stuff is going to be under very unusual circumstances.

But I don't know if there's been any research attempting to induce depression through administration of more controlled doses. (Might be hard to get through the ethics board.)

I'm curious, since you sound relatively informed on this: how strong of a response is seen in psychosocial stress? Is the strength of the response related to the intensity of stress? How high are markers in people who are depressed, especially in relation to people who have suffered stress but aren't depressed? How do marker levels in people (stressed and/or depressed) compare to induced responses? A lot of the sources are subscriber only.

Does X cause an inflamation or does inflamation bring about X?

If X is stress, stress causes inflammation. That's a pretty safe bet, based on helpless animal studies, and the uncontrollable nature of sources of human stress (in very few cases, for instance, would you expect that some unknown factor caused both inflammation and the death of a spouse, or that your own inflammation caused your spouse's death).

If X is depression, it's a valid question, but the evidence I'm reading is pointing more towards inflammation causing depression rather than vice versa. That's because when you induce inflammation, it seems to induce depression as well, although I want to hear more about what monocyte has to say on the subject. Are there ways of inducing depression in people that don't induce inflammation as well? That would be useful to know. But it can go both ways: inflammation can cause depression can cause inflammation.
posted by nathan v at 1:14 PM on April 12, 2011

I think you are conflating osteoarthritis and rheumatoid (inflammatory) arthritis here. Good exercise practice and diet can be palliative or prophylactic for OA, by reducing joint loading and preventing physical damage. Lifestyle modifications may be somewhat palliative for RA (as are NSAIDS), but RA typically has a relentless course that diet and exercise will do little to alter- for damn sure it won't get you between TNF inhibitors or other disease-modifying agents and 'an occasional over the counter NSAID'.

All I can tell you is: I have ankylosing spondylitis, and diet and exercise has gotten me from daily doses of prescription NSAIDS for constant, severe pain to an occasional over the counter NSAID for occasional, much less severe pain. I'm lucky enough to have a pretty mild case, I think, but it was still enough to wreck my daily life for three or four years; at the time, TNF inhibitors were suggested for me, as with just about everyone with AS, but I'm pleased to say I haven't had to make that choice so far.

Will lifestyle change stop the course of this disease? No. As you pointed out, nothing currently known to man (including TNF inhibitors or other disease-modifying agents) will do so. Will diet and exercise still keep my pain at a manageable level in another ten, twenty, or thirty years? Maybe not, and at that point I'll either be on effective medication or I'll kill myself. But it's worked for six years now, and that's all right -- if there's one thing I've learned since my hip started hurting one day and then didn't stop, it's that chronic pain does what it does, and you do what you can to deal with it.
posted by vorfeed at 1:17 PM on April 12, 2011

Postroad: Does X cause an inflamation or does inflamation bring about X

Correlation vs. causation. That is the question I have as well. Does inflammation cause depression, or is it just a physiological symptom of the disorder, one that just goes along with the psychological and behavioral symptoms.
posted by moonbiter at 2:23 PM on April 12, 2011

We need more SUPPORT for people who need help to get the nutrients in food, exercise, and social support they need to compliment their healing process.

The Metafilter community on Health Month is a fabulous support group for making improvements in diet and exercise. I'm less than two weeks in on my first month and it's been eye-opening how much both the public accountability and the support of my fellow Mefites is making in my efforts to get on the diet and exercise wagon. Ocherdraco deserves a lot of kudos for the effort she put in to organize the team, and so does Buster, the creator of Health Month, for devising and building the site.
posted by immlass at 2:40 PM on April 12, 2011

re: Inflammation of what? I (very probably) have RA. It's an autoimmune disease, characterized by chronic widespread inflammation, typically in the joints, but not uncommonly in other areas. I currently have inflammation in my feet, ankles, hands, wrists, lungs. Maybe other organs. Inflammation affects soft tissue, so pretty much any soft tissue can be affected by inflammation.

Why Zebra's Don't Get Ulcers - Sapolsky is a terrific writer with excellent credentials. I highly recommend Primate's Memoir, and just found some terrific lectures on youtube.

Big Pharma wants to find a new NSAID that can be patented. Any reason not to use good old aspirin, other than known stomach upset & blood thinning?
posted by theora55 at 2:46 PM on April 12, 2011

The Metafilter community on Health Month is a fabulous support group for making improvements in diet and exercise.

It sounds like a great resource, but I'm not sure that's what xarnop was talking about.

One of the reasons depression is so difficult to treat is because depressed people have so much trouble actually seeking treatment. They feel like nothing is going to help, they haven't the energy to get out of bed, interaction with other people feels hopeless. This isn't true in all situations, but it's true in a lot of situations. Can't make necessary changes? Won't make necessary changes? Who knows, it amounts to the same thing, but the judgment that they're there because they won't (rather than can't) sure as hell doesn't help them any.

A lot of times, when they do manage to interact socially, they get a whole lot of "Gotta bootstrap!" Or, "It's all in your head," as if that's somehow useful information. Telling depressed people that they need to eat well or exercise or seek out people doesn't help very much, because mostly, they already have an understanding that these things might help (although they're pessimistic about the odds), but can't find a way to actually do them. Depressed people generally already have a feeling that other people don't want to be around them, and the really sad thing is that they're probably right. It's not easy or fun to be around depressed people. So depression cascades.

I'm don't know what to do for depressed people. I'm not certain about the role of food and exercise as divorced from spontaneous remission or attention/placebo (but if anybody's got links, rad!). But I believe in trying to help-- in being there-- not just because it's effective, but because it's the right thing to do, as a human. I hope that makes sense. It's not really well formulated even in my own head.

So if good diet helps? Saying so isn't enough, but cooking somebody a meal is a good idea. If activity helps? Saying so isn't enough, but going to somebody's house and saying, "Hey, will you come on a walk with me?" might help. It's just really hard work, because time after time, it's going to look like nothing's helping. They'll push food around on their plate, they'll decline to walk with you.

Not that I think you were being disrespectful at all, I'm sorry to use what you said to launch into my little rant :) It's just that the problem is a lot deeper than "Eat right." How the hell can I eat right when all I can think about is how much I'd prefer to be dead?
posted by nathan v at 3:42 PM on April 12, 2011 [2 favorites]

This IS a great thread, thanks xarnop.

Inflammation is a fascinating topic. And it does seem like the more complex the body seems, the simpler the solutions become. Example: many people who have inflammation (of all types) see benefits with magnesium supplementation. Most Americans are deficient, and magnesium is required in over 300 chemical reactions in the body. Without it, we die, but the symptoms of magnesium deficiency can present as as so many other disorders that it seems like it's almost never diagnosed.

polyhedron, and anyone else who is feeling deep fatigue, depression, pain, etc., I strongly urge you to check out the book "From Fatigued to Fantastic" by leading chronic fatigue expert Dr Teitelbaum. It's an incredible book - easy to read, and full of revelations at pretty much every turn. Am I lathering it on a little strong? Yes.

But only because the book is the first thing that's helped me feel better in 2 years. It helped me realize there is a diagnosis for me, that identified and listed all the "symptoms" I thought were meaningless because the doctors ignored them completely (e.g. "I seem to pee out everything I drink"), that explained why I was increasingly unable to cope with the tiniest bit of stress resulting in major, very uncharacteristic meltdowns.

_From Fatigued to Fantastic_ is the first health book I've found where the doctor lays out the multiple etiologies for a health problem like fatigue/constant aches & pains, helps you identify which ones may be at work in your situation (and chances are, it's more than one), then sets up a systematic way to treat them as a whole.

Here's my story, in case it's helpful to you... maybe it even sounds familiar.

My problems really started after a pneumonia-like viral infection knocked me on my ass for 6 weeks, 2 years ago. It was NOT pneumonia, but doctors didn't try to identify what it WAS. Now I think it was my mono recurring. Since then, I've never been the same. But I have had steadily worsening sleep, steadily worsening deep-bone fatigue, muscle pain, inability to cope with stress, etc. And been on antibiotics all the time, but they've never cleared up my sinusitis -- at first they worked for weeks at a time, now they don't help at all. Plus I seem to be unable to fully absorb nutrients from food (despite eating lots of meat, I'm low in a lot of meat-sourced vitamins and even very low on iron). Right before I got sick, I had been working on exercising daily for just over a month, having worked up to 45 minutes of aerobic activity a day. Since I got sick, my asthma returned, I have been unable to take asthma medications I used to tolerate very well (violent reactions, panic attacks, & hallucinations!), and if I exercise even a little, I suffer in unbelievable pain for days. In other words, textbook CFS/FMS.

Thank science I found the book "From Fatigued to Fantastic" a few weeks ago. Then, according to Dr Teitelbaum's SHIN protocol, I found a doctor who agrees with the medical basis and has put me on:

* anti-fungal for sinusitis (did you know fungus is indicated in >90% of chronic sinusitis cases), and suspected yeast overgrowth in the gut/gut dysbiosis, which can cause malabsorption and other issues -- made a noticeable difference

* Desyrel to improve my sleep, when I fall asleep (increases stage 3&4 sleep) -- made a HUGE difference

* magnesium and iron

* medical electrolyte mix, because my body underproduces vasopressin ("the antidiuretic hormone") so I can't hold water/potassium/sodium in

* and myself, I added B12, D-Ribose, and Adrenal Stress End, an OTC supplement designed by Dr Teitelbaum, with all profits donated to charity; includes a vitamin B-x panel and adrenal cortex extract (I actually tried this on a whim, bought it at Whole Foods, and it worked so well that I sought out the doctor's book. I didn't believe it would help, nothing else had. But lo and behold...)

Even though they all attack totally different problems, they all help -- it's a very noticeable cumulative effect. If I skip any of them, I can really tell the difference. Until I got in the antifungal & magnesium, for example, my body temperature was always under 97.5 (96.5ish in the mornings) AND all over the place, very poorly regulated. Just a few days later and I'm a roasty 98.x most of the time. Two days ago, my husband felt my forehead and said it felt like I had a fever. Nope! I was 98.4! He'd just forgotten what that felt like.

Another serious symptom that resolved when I added the combo of electrolyte and magnesium? POTS! Postural orthostatic tachycardia syndrome is when your heart rate jumps 30bpm or goes over 120bpm within 12 minutes of transitioning from lying down to standing up. My heart rate would usually DOUBLE, from about 65 to 130+. That is very very bad, not to mention it made me feel dizzy and weak as a kitten. And all it took was some freaking electrolytes and minerals.

I don't think I ever would have found a doctor who would A) listen to my long laundry list of problems long enough, or B) be considerate enough to try to treat them all together. So yeah, I'm a total Team "From Fatigued & Fantastic" Fan Girl.

For me, it's a continuing journey. Case in point: now my sleep is much higher quality, when I can actually fall asleep. But it seems like, as with many CFS sufferers, my cortisol body clock is totally off. I am my most mentally awake at night. It's not that I lie in bed stressing about stuff... I just can't fall asleep, no matter what I do or how relaxed I am. Regular schedule, eyemask, ear plugs, comfy new bed, warm milk, green tea extract, the works. Nothing helps. Next week I'll start trying different drugs to help me fall asleep. The Desyrel helped me feel so much better it made it very clear how bad my sleep problems were, and how much they were contributing to my illness.

I really love this book!

Even if you DON'T think you have chronic fatigue syndrome, it's a valuable & interesting read. The info on the hypothalamus-pituitary-adrenal axis, the role of d-ribose and other sugars in the production of ATP, the role of CRP, the information about how the body replenishes the energy stores in muscles, the explanation of mitochondrial function and dysfunction, gut dysbiosis, the reason that the standard thyroid panel cannot be trusted, why thyroid/adrenal/cortisol underproduction is so common and underrecognized, and generally speaking what nutrients/minerals you need to be healthy (that, if you are an American, you are almost surely lacking)... well, the book's worth it just for that.

Example: chances are you are low in magnesium and potassium, since most Americans are. Magnesium and potassium deficiencies can cause a huge range of symptoms, including brain fog, constant pain, low body temp, and depression! It (along with many other mineral deficiencies) can act just like hypothyroidism, depression, rheumatoid arthritis, and more. But doctors seem to generally ignore this very simple, core, easy-to-fix source of suffering.

So maybe you have a blood test (for magnesium, potassium, thyroid, cortisol, anything) and hear your levels are "normal" -- but you could still be very low, just not low enough to put you in the hospital. As it turns out, lab "normal ranges" vary from lab to lab & are based off broad population studies. You'd expect blood levels to be Recommended, like your intake of vitamins are, but nope. They're average. And since the average person is deficient, it's a cycle of doom.

That's one of the many things I've learned from this book. Now I read my own damn blood tests and check the levels against as many other sources as possible.

That said: there are 2 downsides. On every topic, Dr. Teitelbaum cites study after study... except 2. One, he suggests that (failing antifungal and saline treatment) you might use small amounts of colloidal silver for chronic sinusitis. There's no evidence for this. Secondly, he seems to believe that NAET exposure therapy works for allergies. There's no evidence for that, either. These two seem to be blind spots of his. I accept that, and verify the medical advice myself, and move on. (Hell, even Isaac Newton believed in God. Nobody's perfect.)

In short: If you feel badly, tired, achey, unmotivated, depressed -- try _From Fatigued to Fantastic_. It might help you the way it helped me.

My apologies if this bored you, but every time I've spoken out about what I've gone thru, people have thanked me for helping them feel less alone & helping them realize what they have, so they can make their doctors listen. That's worth it to me.

Energy & happiness to everyone!
posted by amyh at 3:45 PM on April 12, 2011 [3 favorites]

I have not read the paper yet but want to clear up a couple of the comments:

SlapHappy: Funny you'd pick depression a subject to tout medicine's benefits since a recent study showed that anti-depressants are generally ineffective except in cases of extreme acute depression.

Xarnop: I think the primary goal would be to discover what was causing the cytokine barrage against the brain and correct it. That might help more in the long run than a "support group."

In general, cytokines (cellular proteins) can be inflammatory or anti-inflammatory. The inflammatory cytokines are at this point recognized in causing disease process and depression is only one malady associated with abnormal cytokine expression.

Autoimmune diseases - the most common being Hashimoto's thyroid, are hypothesized to be caused by an imbalance of cytokine family types.

The TH-1 family of cytokines are involved in an initial immune expression and involve with attacking an antigen. The TH-2 cytokines flag and tag intruders to make the TH-1 cytokines more efficient.

Abnormalities in the gastrointestinal tract that regularly go unrecognized in the medical model can ultimately create inflammatory cytokine cascades which will potentially attack tissues throughout the body. This is well recognized in the literature but not in standard medical practice at this point.

amethysts mentions this above as it relates to autism but it's effecting a significant part of the population in ALL socioeconomic groups.

Anyway, long story and I'll read the article now.....
posted by noaccident at 9:11 PM on April 12, 2011 [2 favorites]

It sounds like a great resource, but I'm not sure that's what xarnop was talking about.

Yes, but it's here now, which puts it an arm and a leg above a lot of medical support for various things you can try to improve. (Finger-wagging doesn't count as support in my book.)
posted by immlass at 10:22 PM on April 12, 2011

We're doing quite a bit of work on gut inflammation as a reservoir for latent HIV in my lab (as opposed to the "latency period" referenced in the link below. Inflammation (again, not the kind where the finger is red and warm but a cytokine reaction) is a huge field in HIV research these days.
posted by Sophie1 at 7:07 AM on April 13, 2011 [1 favorite]