Could depression be an autoimmune disorder?

In researching rheumatoid arthritis, I noticed that one of the common symptoms of it and other related autoimmune disorders is major depression. It’s understandable that the stress of dealing with an illness that saps your energy, deforms your joints, and doubles your chance of heart disease could cause a bout of depression, but several of the articles I read mentioned that after statistical analysis, there is still a higher prevalence of depression among those with autoimmune disorders than the general population.

Then, there’s the idea that depression mimics what is referred to as sickness behavior, the adaptive behavior responses individuals show when they become ill. These behaviors - lethargy, loss of appetite, lower threshold for pain, fatigue, difficulty concentrating, and increased sleep - appear to help the individual reserve their resources to fight off an infectious pathogen and limit opportunities for passing on the pathogen. These behaviors are considered part and parcel of the immune system’s response to a bacterial or viral infection.

And, autoimmune diseases, by definition, occur when the immune system inappropriately responds to the body’s cells as foreign bodies. The dramatic increase in autoimmune diseases in the last century is often blamed on the rise of hygienic practices and the precipitous drop in parasitic infections. Those parasitic infections, especially “old friends” which evolved alongside our species, may moderate the immune response and prevent autoimmune disorders from taking hold.

So here I am, on a short course of prednisone - a steroid that reverses inflammation - for a case of post-viral lung inflammation, and . . . the major depression I’ve lived with for the last three years is gone. Poof. Fatigue, obsessive dark thoughts, lack of interest, hypersomnia, et cetera have all evaporated. I noticed it near the end of the second day of treatment when it occurred to me that I’d gotten up without an alarm, I hadn’t taken a nap, I’d done several hours of physically demanding chores without complaint, and I’d accomplished more in one day that I had in the previous two weeks. And, I’d been in a good mood the whole time, singing, joking, and chatting with all present.

It won’t last. Prednisone is not a medication you can take for extended periods of time. Things like psychosis, mania, adrenal suppression, weight gain, osteoporosis, and 'roid rage tend to happen if you take it for too long. So I am making hay while the sun shines, if you will.

In the meantime, I’m really wondering. While many bouts of major depression can be linked to obvious external causes - psychological trauma, grief, injury, illness, lack of sunlight - the vast majority fall into a realm of “we dunno”. We just don’t know. Medical science can describe the symptoms, can chart differences between people with depression and those without, can point to possible genetic predispositions, and can throw a few occasionally effective treatments at the illness without really understanding why and how they work.

What if, instead of being a neurological condition, depression is an autoimmune condition? Are there any studies that explore this possibility? Is there any indication that treatments which help autoimmune disorders such as rheumatoid arthritis, Crohn’s disease, or lupus help depression? Are there any maverick doctors proclaiming breakthroughs of this sort? The most I can find on PubMed is a couple of papers that acknowledge, by golly, depression is correlated with systemic lupus erythematosus (SLE), and people with depression are more likely to self-report symptoms of SLE.

Not even a TLDR?

Man, this is depressing.

Traffic tends to be slower on the boards on weekends. Wait to see if you get anything tomorrow.

Count me interested. I don’t have any answers, though.

Isn’t high IQ correlated with depression (I can’t immediately find a reputable cite)? I’m not suggesting all or even most depression is a result of existential ennui, but it should be pointed out that some of it probably is :wink:

Asked and answered.

Angst, not ennui. Important difference, as my brow is furrowed, not knitted.

Important difference, sure, but personally I’m more of an existential ennui man myself. (existential ennui isn’t wrong, though less common a phrase)

I think you could be on to something.

If I eat an anti inflammatory diet I am much less depressed. The worse my diet, the worse my depression. I started to look up inflammation and autoimmune reactions and it looked like they could be related, but I don’t feel like reading a lot now.

I suggest an anti inflammatory diet for you after you’re done with your steroids.

Interesting idea, but . . .

AFAIK, the brains of depressed people do not show any of the hallmarks of autoimmune attack. Neither microscopically (on biopsy specimens) nor macroscopically (say, by MRI) is there any evidence for such a phenomenon.

The prednisone effect to reverse depressive symptoms is something that happens even in non-depressed people. What I mean by that is that virtually everyone gets a bit of a “high” from prednisone (at least in the short term). In fact, sometimes prednisone is even given to cancer patients to ‘give them a lift’, restore their appetites, etc.

That being said, and you touched on this, there are substances made by the white blood cells of people suffering from autoimmune diseases (and things like infection, as well) that produce a set of symtoms that essentially make a state of depression. Prednisone, by inhibiting those cells (and also inhibiting the production of those substances - cytokines), does, in fact, sometimes make such individuals feel ‘undepressed’ or at least ‘revitalized’.

Still, as a bottom line, it’s hard to conceive of depression as being primarily autoimmune in many cases, and maybe any cases. There’s the lack of evidence on biopsy and MRI, the difficulty reconciling response of depression to treatment with lithium and various other meds (like SSRIs, tricyclics, etc. - drugs that have no effect on immune processes), and even the different genetic and familial associations. There’s more, a lot more, counter evidence, but you can see it’s a tough sell.

Aha! Someone Who Knows Stuff.

Karl, if you don’t mind me bugging you, what evidence of autoimmune disease would be visible by biopsy or MRI in affected brain tissue? I had figured with the brain/blood barrier, white blood cells would be unable to cross over to the brain tissue itself, and it would be primarily a response to cytokines, prostaglandins, and other immune cell-released chemicals. Are we talking edema? Necrosis? I ask as a fairly well read lay person, but not a doctor, let alone a neurologist or immunologist.

Here’s my hypothesis:

  • a dysregulated immune response, including cytokines, sets off “sickness behavior” as one of the emergent symptoms of an autoimmune disease.
  • this constellation of mood and behavior issues is identified as Major Depressive Disorder and is treated as a psychiatric condition.
  • sometimes this works, sometimes it doesn’t. MDD is infamous for the number of “treatment resistant” patients. Perhaps SSRIs, NSRIs, tricyclics, and such address one aspect of sickness behavior that is a linchpin in some but not in others. It does not, however, halt the growing immune dysregulation
  • the immune dysregulation progresses, branching off into a particular system focus (joints, nerves, muscles, skin, et cetera) based on immunological, genetic, epigenetic, and environmental factors as well as influences from other biological systems such as endocrine and gastrointestinal.
  • the immune dysregulation produces pronounced symptoms which allow diagnosis of one of the classic autoimmune diseases - SLE, rheumatoid arthritis, fibromyalgia, Type I Diabetes, celiac disease, and Gullain-Barre among others.
  • the use of prednisone and other immunosuppressants subdue the immune system, suppress the sickness behavior, and relieve the symptoms of depression in the patient along with other, more accepted symptoms of their autoimmune disease.

But . . .

What if, in some individuals, the immune dysregulation does not progress past sickness behavior, or if it does, the symptoms of whatever autoimmune disease it has progressed to are subclinical? Perhaps the depressive patient assigns symptoms that would otherwise get scrutiny to just another crappy day of living with depression.

What if the signs of immune dysregulation that causes only depressive symptoms does not match the typical signs of autoimmune neuropathy?

I don’t at all mean to suggest that all or most or even many cases of MDD are autoimmune, but I can’t help but wonder if there’s isn’t a subset. In my own progression from illness to illness, the one common thread I can find is a state of chronic inflammation which shows itself in allergies, gluten-intolerance, and now, possibly rheumatoid arthritis. Depression has simply existed side by side with all of these from the beginning, and it worsens progressively as new symptoms of some enigmatic immune dysfunction emerge.

Hell, I know anecdote does not equal data, but it’s hard not to connect dots.

Oh, I am full of questions, and it bugs me that I cannot frame them as well as I’d like.

All I know is that the euphoric effects of opiates is hypothesized to be the same as the pain relieving affects–that the same chemicals that transimit pain in other parts of the body transmit as depression in the brain.

I’ll also point out that pretty much everything that has systemic pain, including the flu, does seem to come with at least a low level of malaise.

Oh, I see better now what you’re getting at.

My answer above was based on the assumption that if depression was due to autoimmunity, it would be as a result of (or at least associated with) a direct autoimmune attack in the brain. And, that would reveal itself on brain biopsy by the presence of various histologic signs of inflammation of the brain parenchyma itself, e.g. mononuclear cell infiltrate, edema, apoptosis, vasculitis, gliosis, etc., AND/OR signs of vasculitis of the cerebral vessels. Moreover, on MRI, both parenchymal inflammation and vasculitis would have relatively distinct appearances (mostly on T2-weighted images IIRC) with plaque formation, areas of blood-brain barrier insufficiency, white matter changes, edema, and restricted diffusion.

But I now see that you weren’t thinking so much about direct brain or brain-blood vessel inflammation as you were about possible humoral effects on brain function which could occur as a result of the release elsewhere in the body of inflammatory mediators such as cytokines (with such mediators being released as a result of active autoimmune disease). In fact, that is the mechanism proposed for the depression which sometimes complicates influenza and other viral infections such as hepatitis C. Here is a free reference which reviews the concept, and the abstract of another.

Now, although established for (viral) infections, I’m not aware it is ever the case that depression arises strictly as a result of the humoral effects of autoimmune disease, especially where the autoimmune disease has no other clinical manifestations. If nothing else, you’d expect there to be a well established syndrome where depression is followed in some people by overt autoimmune disease (i.e. progression of the underlying autoimmune process to more classic signs of autoimmunity. Indeed, it would be strange, almost unheard of for there to be no cases of progression). Yet that is what you seem to be postulating. Likewise, to my knowledge at least, depression does not feature more than expected in families where autoimmune disease is present.

One other thing: An active autoimmune disease causing depression would still be expected to have biochemical signs even if there were no other overt manifestations of the disease. For example, there would be anemia, high ESR, etc., since these are also consequences of cytokines; the same cytokines you’d be invoking to explain the depression. However, as far as I know, such biochemical signs have never been shown to exist in depression. By definition in primary depression, there is no evidence, clinical or lab, of an underlying organic disease process.


Those two links are exactly what I was thinking about, and I’m excited to see that there is some research in that direction.

The second link states:

That’s exactly what I’m talking about. I suspect that a lack of clinical evidence for cytokine-caused depression could simply be because doctors don’t test depression patients for cytokines or other signs of immune dysregulation, specifically because no one has postulated an autoimmune cause or correlation to depression.

One case study of a young woman who presented with major depressive symptoms and was diagnosed with Lupus, published in Romania but the abstract is in English states “The fact is that not only the medical condition can be the cause for depression and, not always, the treatment for a medical illness can supply the treatment for depression.”

It’s hard to infer any nuance in the author’s statement, but I think there is the possibility that she means the disease process itself (and the associated immune response) is the cause of the depression, not the emotional toll of dealing with a chronic, sometimes life threatening illness. I think it’s also possible to infer that while treatment for the disease can be considered successful, it might not address a dysregulated immune response, leaving the patient’s depression unresolved.

Unfortunately, the abstract doesn’t indicate either way, and it doesn’t make any conclusion regarding the relationship between the initial presentation of depression and the diagnosis of SLE. Gee, I never wished I could read Romanian before.

So, now I have another question for you, Karl. Is it possible that a cytokine or other humoral crisis might “tip the balance” of the brain into acute sickness behavior, and while the original crisis resolves - leaving little or no evidence of a full autoimmune attack - the brain remains trapped in a chronic state of sickness behavior, which presents as a major depressive episode?

/goes and reads stuff on Wikipedia. Whoa. Cytokines are produced by almost every type of cell, including glial cells, so they’re made right in the brain. Whoa. An out of control positive feedback loop of cytokines, hypercytokinemia or cytokine storm, can happen when the host is attacked by a new and highly pathogenic invader. It can kill and is implicated in the number of deaths, especially of people with health immune systems, during the Spanish Flu pandemic and SARS. Holy Flarking Snick!

Okay, more questions:

  • can you recommend a basic Immunology 101 textbook for me to stuff my head in? This is fascinating.
  • do we have any idea which cytokines cause or are related to sickness behavior?
  • do we know which other cytokines/interleukins/whatevers moderate the former cytokines’ signals and tell the brain to let go of sickness behavior?
  • has anyone done any studies on this in relation to depression and autoimmune disorders?

Holy cow. I found at least one paper on PubMed that says I’m right:

From PubMed’s abstract of Depression is an Inflammatory Disease, but Cell-Mediated Immune Activation is the Key Component of Depression published in the Progress in Neuro-psychopharmacology and Biological Psychiatry (they’ve got a journal for EVERYTHING, don’t they?):

Interestingly, at least to me, Tumor Necrosis Factor-alpha is implicated in rheumatoid arthritis, which is probably the next diagnosis I’ll be getting.

Here, go crazy:

List of reviews on the topic of depression, cytokines, and inflammation


A psychoneuroimmunological review on cytokines involved in antidepressant treatment response

I’m fairly certain that what is called clinical depression is a family of disabling conditions all with the same symptoms but vastly different causes; nothing else can really explain for me the wide variety of treatments that work for a statistically significant portion of the population, but are very often useless for a larger portion.

Personally, apart from issues related to Asperger syndrome, ever since I had mono in college about 10 years ago I have felt more depressed. I believe I suffer from a post-viral fatigue syndrome, perhaps caused by the body continually fighting the virus that it can never actually eradicate. Perhaps a bit anecdotal, but I definitely would agree with the assessment that depression can be caused by an overreacting immune system, and that such a depression is not going to be solved by traditional antidepressants.

I figure I’m an example of depression AND rheumatoid arthritis being symptoms of autoimmune responses - rather than the other way around.

I will preface this with a disclaimer - I was not officially diagnosed with rheumatoid arthritis, but I had symptoms absolutely consistent with the disorder for about 18 months. My joint/muscle pain and inflammation was severe enough that I sometimes had difficulty walking or climbing stairs, and it affected my feet, ankles, knees, hip joints, wrists, and even elbows (when at its most severe). The pain varied a bit, but was always there during those 18 months. Please see this website for a description of the symptoms I was experiencing:

In addition to that, I had lifelong mild depression (mostly mild but always there, from as early as age 3 – I just thought it was normal, as that is all I knew). I was first treated at age 28 after what appeared to be a bout of major depression (again, the symptoms fit and antidepressants were prescribed). And the meds helped. I went off of them after a couple of years, and was totally fine for about three years - then suddenly ended up with another bout of major depression, followed by more meds.

As for the (presumably) arthritic pain, the onset correlates with a major change in my diet. I work in a remote location and live in a camp; at first, because I was trying to manage my weight, I was bringing and cooking my own food. The camp management found out about this after several months and forbade me from doing my own cooking, and that’s when my problems began… When I was forced to resort to camp food, I ended up back on anti-depressants within two weeks. Trying to make the best of a bad situation, and trying to avoid fattening fried and processed foods, particularly meats, I resorted to eating a lot of boiled eggs, egg salad sandwiches, etc. Eggs were really the only non-processed, healthy protein source I had available. Meanwhile, the antidepressants were stoking my appetite, so I was gaining a lot of weight very rapidly… My doctor was riding my butt about the weight gain (I had worked so hard to take off 70 lbs prior to that - I really didn’t like that I was gaining weight, either, and was very ashamed)… My feet were starting to hurt, but I didn’t bother telling her about that because I was convinced it was due to my out of control weight gain (which she obviously was convinced was due to a personal lack of willpower - I started to believe it, too, which only made me feel worse). The antidepressants were already causing me so much grief because of their side-effects, particularly the total shutting off of my ability to feel full, and I figured that my doctor would only throw more pills at me for the joint pain, potentially causing more unknown side effects.

Now for how I figured out what was going on…

As miserable as I was, somehow I got engaged during this time, and my fiancé and I decided, on a whim, to get married two weeks from the day we managed to find rings and an available marriage commissioner. We set the date, then I promptly went back up to work for several days prior to the wedding.

Man, was I nervous… I was so nervous I was barely able to eat anything during those two weeks leading up to the Big Day. And though I didn’t connect the dots until after the wedding, during those two weeks my severe joint and muscle pain disappeared totally (I had been very, very sore for 18 straight months prior to that – I just thought that whatever it was had run its course).

A few days after the wedding, back up to work I went, and I was feeling fine. But one morning I had a nice omelet for breakfast, and in a few hours my feet started to get sore again…

To me that was bizarre, but obvious – the eggs were connected to my joint pain. I scoured the internet to see if I could find something that explained this… and I succeeded. Food allergies? I’d had an allergy test (“scratch” test) a few years prior to that, that turned up absolutely nothing (my doctor was trying to get to the bottom of the chronic hives I had at the time), but it was the wrong kind of test. I’d had an IgE allergy test; what I needed was an IgG allergy test, which is done with a blood sample. I researched some more, and found a lab and a doctor who would be able to arrange for this testing.

The test confirmed that I was, indeed, allergic to eggs. It also turned up a second allergen I did not suspect, that I eventually learned was the cause of my lifelong depression – sunflower seeds/oil. The joint pain (of that severity, anyway) was new to me… or so I thought.

I noticed a pattern in that my major depressive episodes usually followed a period of either extreme stress (I had a major depressive episode at age 18 near exam time in college), or right after having lost a significant amount of weight (50+ lbs).

Here’s my take on why my depression symptoms came and went…

Funny in hindsight, but my “depressive” allergen is particularly common in fast food, convenience food, and other things I would naturally resort to when I was short on time. I would have consumed only small quantities of it under normal circumstances. To not have a reaction at all, I need to avoid it totally, and to do so takes vigilance. Small quantities result in mild depression - and mild depression was mostly what I experienced.

Frequent consumption of fast food over a couple of weeks = a lot of the allergen in my body over an extended period = major depression (even from a diagnostic standpoint). But even the major depression dissipated in time on its own, without antidepressants, once exams were over.

The weight loss connection is interesting, too; because my allergen happens to be one of those “fattening” substances, when I was on a strict diet (like during the three years of respite I had after I stopped taking antidepressants the first time), I didn’t have symptoms of depression. I didn’t eat junk food, or even so much as keep margarine in my fridge. BUT… as I got thinner, more men asked me out, so I dated more, and I went out to dinner and parties more, and I again unknowingly started consuming sunflower oil on a regular basis, sometimes in large quantities… And soon I’d end up majorly depressed and on antidepressants again! And gain 50-100 lbs, because the drugs seemed to take away my ability to feel full! Argh!

The severity of both reactions depends on the quantity of the allergen ingested. The only time I see either depression or joint/muscle pain is if I consume either offending substance. The effects are totally reproducible, but I avoid both allergens because it just isn’t worth the effect on my quality of life. I know my sunflower oil allergy has been there since early childhood, just from memories of how I interpreted the world at that age – something wasn’t right. After totally eliminating egg from my diet, I have also noticed that my wonky knees (knees that were always prone to injury and inflammation, from early on in life) are totally stable for the first time ever.

IgG food allergies result in an autoimmune response, producing inflammation in the body (in whatever body system is affected by the allergen, as well as the gut). For more info, the lab that ran my analysis has great info:

There is some evidence that SSRI’s work because they are anti-inflammatory, which I theorize is why they worked on my depression (though the side effects were not worth it):

This type of allergy is very difficult to figure out without testing because the reactions can take several hours to several days to manifest. With my egg allergy, I usually see a reaction within 12 hours, and the reaction takes about 4 days to run its course. With my sunflower allergy; I start to react about 24 hours later, and it takes a week to pass.

Okay… I know this is getting long… But I know some of you are going through chronic symptoms that are making your life a living hell, too. I was lucky to have figured out the actual causes of what I was going through, and I have met many other people who also determined their chronic issues were food related.

Today, I am completely medication-free and have zero symptoms of depression and rheumatoid arthritis (it only took a week for all those symptoms to totally disappear, too).

Other issues connected with food allergies: food addiction and weight gain. Food allergies cause the body to release a hormone, ghrelin, which stimulates the appetite. Ironically, one usually tends to crave the very foods they are allergic to, because initially, these foods actually create a sort of “high” in the sufferer (of course, to be followed by a crash, resulting once more in a craving for the allergen to recreate that “high” and make them feel better). The weight gain is two-fold; appetite increases because of the addiction response, and because reactions to food allergens often result water retention – it’s like the body is throwing water at the allergen in order to dilute it and thus limit its damage to the body.

When consuming my allergens, I was particularly prone to water retention; if I consumed a little extra sodium one day, I could put on as much as 15 lbs in 36 hours. (I am a very tall woman with a very large frame, but that’s still a lot of weight to put on almost overnight.)

After cutting out my allergens, I dropped about 30 lbs (without trying) in about 2 months. Much of it was water loss, but also my appetite almost disappeared. My weight has been stable (literally within a 5 lb window) since I dropped the weight, which is well over a year ago. Never before has my weight been stable, and without any effort on my part other than avoiding my allergens.

In summary:

• Don’t stop searching. Doctors are a resource, but they can be wrong, too, and often are. Go to the library. Search the internet. Get second opinions from alternative medicine practitioners.
• Drugs are not always the answer – in fact, they can cause a lot of unanticipated side effects that lead to other issues. Depression is not a Prozac deficiency, I’ve heard it said, though the drug companies would obviously prefer you to believe otherwise. Keep in mind that the big drug companies also fund most of the research on treatments for disease – and the focus is on drugs, not on prevention.
• Do not confuse a “disease” with a “symptom”. From my experience, I would consider my depression and joint/muscle pain symptoms of the underlying issue(s), not diseases in their own right.
• Never. Give. Up.

My “close relative not wishing to be identified” spent years being shuffled from doctor to specialist to naturopath to doctor and round and round. He said the worst part of it all was being treated like a hypochondriac the whole time when he was obviously sick - enough to be admitted to hospital several times a year.

He never gave up.

He was in his late fifties before someone sent the right blood test to the right specialist and they could actually point to some specific cells and say : Right there, that only occurs in people with Chronic Fatigue Syndrome. Which then allowed them to ask the right questions and pin it down to his body still reacting to the scarlet fever virus he’d contracted when he was 19 years old.

The main symptoms? Depression and Rheumatoid Arthritis.

So, after almost forty years of trying, he had a diagnosis but no cure, just the same ‘treat the symptoms’ he’d been doing for decades.

Over the last couple of years (he’s almost seventy now) he’s been on the Hay Diet, lots of fresh vegetables, no processed foods and keeping carbohydrate based meals and protein based meals separated by at least five hours.

It works very well for him and he’s been able to drop many of his medications.

I’m not suggesting it will work for everyone (it makes me twitchy, I seem to need carbs and protein together), but it confirms a lot of what you were saying in your post.

Seriously, as a depressed man, I’m interested in this thread, and in the Hay Diet.

Non-seriously, I remember that Lewis Carroll’s Red Queen told Alice that there’s nothing like eating hay for a headache.

Alice disagreed, saying that eating hay wouldn’t help a headache.

The Red Queen said, “I didn’t say it would help. I said there’s nothing like it.” :smack: