Monday, December 13, 2010

That Tapeworm Ate Your Depression

I'm a little embarrassed that Mark Sisson got to this one before I did.  But I'm sure he has several minions to scan the literature for him, whereas I have a few loyal friends and fellow bloggers.  Here it is, though, a new paper from the Archives of General Psychiatry, "Inflammation, Sanitation, and Consternation: Loss of Contact With Coevolved, Tolerogenic Microoganisms and the Pathophysiology and Treatment of Major Depression."

And I have to admit, after reading Mark's little blurb, I went to the paper expecting to be annoyed.  There are a lot of versions of the hygiene hypothesis (basically the idea that our environments are too clean) that make it sound as if your mom is a crazy germophobe and that's why you have asthma. Which doesn't make sense, because that remote control your kid is chewing on has about a billion microbes on it.  Also, you will often hear that "children just aren't exposed to childhood infections anymore" as we have vaccines and smaller family sizes and antibacterial soap.  But the typical childhood infections such as chicken pox, whooping cough, diphtheria, etc. are all as modern as eating grains, and were established in humans as we developed higher population densities and domesticated animals, so lack of exposure to those bugs wouldn't necessarily mess with our evolved immune system (also, there is some (association) evidence that exposure to common viruses increases inflammation and may increase our risk for depression).  That particular version of the hygiene hypothesis is dealt a death blow by the fact that inner city kids rife with childhood infections have the highest rates of asthma, much higher than isolated rural kids living out in the country with all the ragweed (1).

But I set aside my preconceptions and took a look at the paper, and thank goodness I did, because it is epic, amazing, and brilliant.  All psychiatrists, psychologists, and other doctors download it now if you have access and have a look.  It even includes the Dobzhansky quote "nothing in biology makes sense except in the light of evolution."

So here we go.  I've made a point before that depression is a result of inflammation.  Specifically, depression is associated with higher serum levels of IL-6, NFkappabeta, TNF alpha, and a host of other pro-inflammatory cytokines.  Medically healthy individuals with depression and a history of early life stress mount a larger inflammatory response to laboratory psychosocial stressors than do nondepressed controls.   The prevalence of major depressive disorders is increasing in all age cohorts, but especially in younger people, and countries transitioning to be part of the developed world experience increasing rates of depression along the way.  One would hypothesize, then, that something environmental in the modern world makes us vulnerable to depression (and other inflammatory diseases of civilization, such as MS, inflammatory bowel disease, type I diabetes, asthma, etc.).

"Overwhelming data demonstrate the prevalence of helper T cell type I...mediated autoimmune and inflammatory bowel and Th2 mediated allergic/asthmatic conditions have increased dramatically in the developed world during the 20th century, with increases in immune-mediated disease incidence in the developing world during the same period closely paralleling the adoption of first world lifestyles." 

Asthma, hay fever, type I diabetes, inflammatory bowel disease, and multiple sclerosis have all increased 2-3 fold in the developed world in the last 60 years.  Many of these conditions are highly comorbid with major depressive disorder.

I've focused on a pro-inflammatory diet as a hypothetical cause for increasing depression (along with obesity and the other diseases of civilization).  The vast majority of the depression literature, I would say, has focused on the pro-inflammatory aspects of a stressful modern life (which I contend isn't necessarily more stressful than life was 60 years ago, or 800 years ago, during the Bubonic Plague, for example).  This paper focuses on "the loss of a microbial modulated immunoregulation" of our Th1 and Th2 immune cells.

Quick review - childhood viral infections tend to mobilize type I T helper cells.   Since Th1 cells seem to balance and modulate the Th2 cells, one might expect that a lack of Th1 activation due to a sanitized environment would lead to naughty Th2 cells running rampant, causing asthma and allergy and the like.  That makes sense, except naughty Th1 cells seem to cause other autoimmune issues, like Crohn's disease, and the incidence of Crohn's disease has increased steadily along with asthma and allergy.   In fact, "most follow up studies have failed to show an association between childhood infection and increased autoimmune and/or atopic conditions in the modern world while continuing, in general, to find correlations between a first-world lifestyle and increases in these conditions."

But humans have been living with some microorganism and parasites for much longer than the childhood infectious diseases of the last 10,000 years of agriculture.  These ubiquitous organisms seemed to keep Th1 and Th2 cells busy without causing problems, in other words, the "old friends" germs "induced and maintained an adaptive level of immune suppression."  Or:

"the mammalian genome does not encode for all functions required for immunological development, but rather that mammals depend on critical interactions with their microbiome (the collective genomes of the microbiota) for health."

What are these organisms?  First off are the pseudocommensals, saprophytic mycobacteria that are found in mud and untreated water and on unwashed food.  They don't colonize the body, apparently, but were known to pass through it in large quantities historically:

A bunch of commensal species are known to inhabit our gut, among them Bacteroides, Lactobacilli, and Bifidobacteria.  And finally, the helminths (internal parasites, such as tapeworms) are the third member of the triad of "old friends."

There is a whole body of literature dedicated to animal studies showing how exposure to these "old friends" reduces autoimmine, inflammatory conditions, and even cancer.  A sugar molecule from Bacteroides species protected against colitis and distorted immune system development in germ-free mice.  Prebiotics known to increase Bifidobacteria in the rodent gut reduced serum concentrations of cytokines such as TNF alpha and IL-6.  "Metabolic products from gut microbiota reduce inflammation in animal models of a variety of human autoimmune and allergic disorders, as well as in [test tube] preparations of human [immune cells].  The health of the human gut microbiome has been shown to impact varied physiologic processes such as pain sensitivity, sleep, and metabolism (all of which are abnormal, by the way, in major depressive disorder.)  A parasitic worm, Schistosoma mansoni, can make a friendly phospholipid for us, phosphotidylserine.  Exposure to a pseudocommensal organism, M vaccae, reduced serum TNF alpha concentrations over a three month period compared to placebo (in humans and human monocyte cell lines).  Recall that TNF-alpha is increased in depression, and antidepressants reduce TNF-alpha - it does make one wonder if these "old friends" have antidepressant effects.

Without constant exposure to these immune modulating "old friends,"  it is plausible that modern humans are at risk for mounting inappropriate inflammatory responses, leading to many of those undesirable diseases of modern civilization, including depression.  I wonder if using inappropriate food, such as vast quantities of fructose, could destabilize the gut microbes and be part of the inflammatory process.  One could further postulate that exposing depressed individuals to "old friends" could act as a treatment.

Gut-depression links are already well known - psychological stress in humans is associated with reduced fecal Lactobacilli, and individuals with major depressive disorders had some fragments gut bacteria inappropriately floating around in their blood, suggesting the presence of leaky guts.  One small study showed that giving people a prebiotic that favors Bifidobacteria reduced anxiety in patients with irritable bowel (2), and another 2 month placebo-controlled study showed that lactobacillus treatment reduced anxiety (but not depression) in people with chronic fatigue (3).  Probiotic treatment did not reduce depressive symptoms in chronic fatigue patients in another small study, but it did improve some cognitive symptoms that are common in major depressive disorder (4).  M vaccae was administered to patients with renal cell cancer, reducing serum IL-2 and some depression symptoms (5), and in another larger study, killed M vaccae reduced depression and anxiety symptoms in lung cancer patients receiving chemotherapy (6). 

There is a long way to go before we start feeding people dirt and worms as an evidenced-based strategy for treating depression.  But...the ideas are intriguing, based in common sense, and scientifically sound.  People with the "short" genetic form of the serotonin receptor, for example, are known to be more vulnerable to major depressive disorder, and they are also more vulnerable to known forms of depression caused by inflammation, such as depression caused by interferon alpha treatment.  These findings link genetic vulnerability to environmental inflammatory factors to depressive symptoms.  Priming the body with known anti-inflammatory modulators should help depression.  Even if it might not seem that...tasty.

23 comments:

  1. "Dr. Deans' Dirt, Worm, and Psychiatry Shop". Could be the next big thing!

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  2. Three cheers for the microbiom! Since eating a non-inflammatory, primal diet with plenty of pre and pro biotics, I've reduced my toothbrushing to only once per day (before bed). My gums and teeth are in such good shape now that I don't want to be overzealous and mess up the good germs in my mouth. I knew this whole enterprise was working when on my last two dental visits, the dentist said my mouth looks "good". (High praise from this dentist who's never said "good" to me until these two visits.)

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  3. David Pritchard at University of Nottingham in the UK have been studying the effects of hookworms on allergies.

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  4. Along the same line have you watched the lecture by Robert Sapolsky about Toxo :- http://www.edge.org/3rd_culture/sapolsky09/sapolsky09_index.html

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  5. well, that's why one of my favorite probiotic has some nice dirt, err, "Homeostatic Soil Organisms" in it http://is.gd/iICBp

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  6. Not totally unrelated to this post, as it is about enhancing/restoring immune system in young and old people with homoeopathic doses of lenalidomide (a derivative of the old thalidomide).

    Extreme low dose lenalidomide (0.03μM to 1μM) is the 'Fountain of Youth'? at ScienceDaily:

    http://www.sciencedaily.com/releases/2010/12/101213140945.htm

    and Pubmed:

    http://www.ncbi.nlm.nih.gov/pubmed/21130040

    Emily or any other kind soul with access to this paper, if you can e-mail it to me (mripoa .a t. g m a i l dot c o m), I'll be deeply grateful. :-)

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  7. this is very interesting :) i dont understand it all but i think i get it

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  8. A while ago, I listened to this extremely interesting WNYC program on parasites:
    http://www.radiolab.org/2009/sep/07/

    I loved especially the interview with Jasper Laurence (at around 31:30 minutes into the program), who infected himself with hookworms to improve his asthma. It worked. Laurence has his website at www.jasper-lawrence.com Didn't check it out, but supposedly he sells his own worms online

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  9. More stories on "parasitic" relationships...

    Radiolab story on parasites.

    ACT THREE. AS THE WORM TURNS.

    trichuris suis worm in treating ulcerative colitis

    More on Jasper Lawerence (from the This American Life story).

    I was fascinated by this topic last year, and to some extent still am. But, now I'm leaning towards autoimmune diseases being caused by the foods we eat. Particularly, for my dad and I, brown rice caused weird skin problems for us, eczema specifically for me.

    For those who can't be treated by diet, helminthic therapy is probably a lot better than the "medically approved" alternative of drugs and surgery.

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  10. In late Latin laetamen stood for manure. Since laetus means cheerful, etymologists have always thought that laetamen was what made fields happy and rich with nutrients. Nobody has ever wondered about the side effects of mycobacterium vaccae on human beings. By the way there are still a few people around in Italy who use helminths as a popular remedy for multiple sclerosis. No idea about results.

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  11. http://pubget.com/search?q=authors:%22Joseph%20P%20Garner%22
    http://www.medicalnewstoday.com/articles/211328.php

    havent had a good chance to look at this, but thought you would love it. Researchers used a high carb/sugar high tryptophan diet to treat hair pulling in mice, and paradoxically found it got worse.
    any thoughts on whats going on here?
    :-)
    Jad

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  12. Thanks for all the comments and links! Amazing stuff out there. I think overall I am grateful for a clean municipal water system - cholera is no picnic, after all. And it also should be noted that hookworms do kill 75,000 people a year in Africa (according to one of the Jasper Lawrence articles up in the comments) so I'm deifnitely not advocating creating the 3rd world here in America (or in the developed world) to solve all our autoimmune/inflammation problems. I do wish that for desperate cases, like Jasper, that medical science could be more open-minded sometimes in a *sensible* way. It's not the weirdest treatment, after all. However I think I would rather eat some M vaccae than become deliberately infected with hookworms myself...

    It's not scientific, but I've seen a number of anecdotes about resolving inflammation on a paleolithic-style (primal-style for me) diet, and some of my own minor inflammatory issues such as a tiny bit of excema under my ring in the summer, seem to be gone for good except when I cheat a bit, which strikes me as intriguing evidence that diet has a lot to with inflammation. I did not go around eating dirt this summer, after all... and though I did spend a lot of time barefoot, there are no hookworms in my area that I know of!

    But as I see it, medical science is trying to isolate components of these "old friends" to give out as pharmaceudicals. I find that, in osme respects disheartening, because of course isolating and reducing everything to tiny components has left us with some mess and led us the wrong direction. Though we also don't want to throw out all of medical science with the treated bathwater.

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  13. Hmm, Jad, that is a great link - thanks. Wonder why he got the idea to feed the rodents EIGHT TIMES the normal amount of *sugar* with tryptophan to help them with their low serotonin problem? Wonder what would happen if he went to starch instead?

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  14. Jad - maybe even more interesting, because I pulled the paper and the sugar he increased was dextrose (glucose-glucose), though there was some sucrose (glucose-fructose), the amount was unchanged between the control and "treatment" diet. So this may not be a case of fruct-mal, as excess glucose should help the mice absorb the fructose from the sucrose portion even more efficiently. Wild!

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  15. Like many others I suffer from major depression AND chronic pain. As a patient it's impossible to get either a psychiatrist or an GP to discuss the link and the interaction. The psych. gives me drugs that bloat me and the G.P. gives me drugs that make me sleepy. Both sets of pills inflame my GERD. No help there.

    Anecdotally some things have helped. If I eat about a cup of brown rice daily I can control the gastric reflux and avoid post-meal coughing due to acid in my lungs. The herb cat's claw has been very helpful with inflammation without eating my gut as NSAID's do. Also consuming large quantities of cooked leafy greens helps. Mustard greens, bok choy, nettle tea, yerba mate or whatever as long as it's a green leaf to start with.

    If any docs want to do a study treating depression patients with helminths I'll volunteer. Compared to ECT what could go wrong?

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  16. Hookworms killing 75K people a year in a population of a billion is a tiny fraction. Compare that to the estimated 106K people killed in the US yearly by adverse drug reactions.(Lazarou J, Pomeranz B, Corey P. Incidence of adverse drug reactions in hospitalized patients. JAMA. 1998;279:1200-1205.)

    When we consider that we could selectively breed moderated lines of commensal organisms and modify their genetics without fussing with the human genome it's a mystery as to why this isn't getting more attention.

    Perhaps is more profitable to treat disease than to cure it.

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  17. I hope everyone who finds this blog looks towards solutions. Focusing on problems and pathology is not the solution, but once you are aware of the problem, immediately focus on solutions and wellness. AN answer will come

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  18. Pangolin - I can imagine the headline : "Psychiatrist pushes mutant hookworm infestation as cure for depression." I'm hopeful that a lot of the benefits from "old friends" can be obtained via probiotics and prebiotics (and playing in the mud every now and again).

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  19. I just read an article a few days ago about a man who sought treatment for a gastro condition that was untreatable - so he went to Thailand and consumed parasitic worms. Western doctors were surprised to find out in his case, it worked. He has to maintain that parasitic population to stay well. It has something to do with the worms consuming something in his system he was unable to process if I recall.

    Link:
    http://www.cnn.com/2010/HEALTH/12/09/worms.health/index.html

    Boy, I don't follow blogs much, but this Doctor is right up my alley. She TRULY is about finding causes and not treating symptoms, a must in psychiatry even if Eli Lilly would prefer it continue making a fortune treating symptoms.

    I am merely a software engineer who likes to read everything, and I've lately been interested in methyl donors. Seems homocysteine level increase as we age, and methyl donors decrease, seems simple enough to me to supplement. Some research even suggests aging itself is contingent upon HC levels being too high. I see resveratrol (I take Hu Zhang, Japanese Knotweed, very high in this) helps keep HC low. I also take Huang Qi (astragalus) which is believed to protect telomeres. Oh well. I probably said more than I'm support to share ! Keep up the GREAT work Doctor.

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  20. I'm 42, and just an arm chair scientist. About 10 years or so ago I began contemplating whether life as we know it is more composite than we may think.

    Perhaps we can create a formal term - the Howard Hughes Syndrome ! All respect to Howard. But if one begins to adopt a sense that isolationism of an organism in the biosphere can lead to a stronger position ? Perhaps we need to say goodbye to nationalism too ! Seriously though, even eating yogurt we can realize there exists friendly bacteria. Somewhere our thinking system can sway us towards isolationism, whether it be political ? or even attempts at hygiene. Perhaps eating though should be a warning sign that we DO have to at some point, rely on some other life form ( for veggies, alive, for meats, let's hope not alive, but I see people eat live squid in China ). Clearly though we are composite life forms. I suppose I'm entertaining here what is the hegonomy of parasites. I'm asking perhaps, if parasites are capable of being part of us, perhaps we are capable of being part of something else ? (and probably seen AS parasites to IT ? )

    I could write all day on this subject - I love thinking. Maybe the doctor will post an email to write to ?

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  21. I am also one to say- why do we think that life is fair ? After watching the Razor's Edge from Somerset Maugham (the Bill Murray version) - where he arrives at this conclusion that nobody 'owes' anybody anything ? (Odd, Groundhog Day started WITH this premise for his character Phil Connors - heh - I'm convinced the message in GHD is - life is a never ending hell UNTIL you recognize compassion) I am not so sure that we should expect NOT to be depressed at times.

    Materialistic consumerism seems to suggest that if we are successful, we can have the new car, and the persona derived from it too! the new house, the Suzie Orman 40x income saved away, but these are ideals not reals. Reality is, we DO stub our toe, we DO get terminal illnesses, or watch loved ones with them, and it life CAN be equally as sad of an experience as it can be happy. Perhaps there is a lacking balance in polarity - such that we think 'depression' is an unnatural state. It's a bold move here to suggest this, but perhaps as much as we expect the ups on one side, we should learn to 'deal' with the downs on the other, rather than attempt to interfere in any biochemical means. Perhaps we need to embrace depression and gain a meaningful experience from it ? As with many of my thoughts, I'm not hanging onto this one ! heh, but worth a consideration.

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  22. Hi Emily,

    What a fascinating post, I love the way you bring the topic alive. Also feel sorry for the mice in your subsequent post, who have to eat that crap, be miserable and die. They must be depressed, too.

    Art Ayers at Cooling Inflammation touches on almost every concept in your post, and further to speculation about fecal transplants to restore gut health. The ideas and hypothesis' are sprinkled throughout his posts, though I don't believe he makes the connection to depression. This post is very supportive of his interpretations about health matters, and his disdain for antibiotics and encouragement to access bacteria via a diversified diet of vegetables. Like you, he worries about pathogens and thus isn't advocating eating raw dirt, or tainting the water supply.

    You mention a possible association between diet and inflammation in one of the comments above. In my n=1, my hsCRP number saw a pretty significant reduction when I reduced carbs to 75gm-ish (from maybe 300-400gms). To be sure it is not a paleo diet, as I eat a significant amount of dairy, but did eliminate grains. Surely lots of confounders, but hsCRP number dropped steadily from 2.5 to .95 over about 2 years.

    My theory is that the removal of gluten and large doses of glucose/fructose reduced inflammation, and there went my allergies, joint pain and swollen ankles and wrists and hopefully improved insulin resistance.

    Best,
    Nick

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  23. Emily, have you read Gut and Psychology Syndrome? I recently did and she's very convincing that depression, anxiety, autism, schizophrenia, adhd, allergies among other conditions are caused by an unhealthy gut. She doesn't go into as much detail biochemically as you do here on your blog, but it was a very interesting read. In November the author released a new edition (which is 100 pages longer) which I ordered because I thought the first edition was so good.

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