Sunday, November 25, 2012

Inflammation and Depression: Cause or Effect

Longest hiatus ever. We've been out of town, and then there is the business involved in preparing to go out of town and all the stuff piled up to do when you get back into town. I've been wanting to finish up the anxiety and depression chapter from The Hygiene Hypothesis and Darwinian Medicine (I started that chapter with "What is Evolutionary Psychiatry?" a month ago.  So here we are.

Depression (and anxiety) are associated with multiple markers of inflammation in the body, though a source for inflammation is often not apparent. Mere exposure to psychological stress can cause elevations in pro-inflammatory cytokines, and the ability of stress to drive inflammation is increased in depressed individuals (as measured by levels of IL-6 and DNA binding of NF-kappaB. The most stressed students had larger increases in interferon gamma, IL-1receptor alpha, TNF, and IL-6 than students who were less stressed about an exam in one study. Since there is a truckload of evidence that stress is a major factor mediating depression, here is evidence that the stress causes the inflammation that causes the depression, not the other way around. And yet…

Just the administration of certain cytokines alone (as we've discussed at length before) can cause depression symptoms in humans and animals. Blocking the action of IL-1 in the central nervous system in animals will stop this effect. Humans with a depression syndrome caused by administration of proinflammatory cytokines will also respond to treatment with antidepressant medications. 

There are genetic studies of different families with depression vulnerabilities, and some of the genes implicated are in the inflammatory pathway (such as IL-1and TNF). In addition, folks with a certain type of serotonin (5HT) 1A receptor seem to be more vulnerable to the induction of depression by interferon alpha 2 beta. Interferon alpha will downregulate the production of the 5HT-1A receptor. Both anxiety and depression patients have been showed to have decreased 5HT-1A receptor, and certain folks with a subtype of the receptor are more vulnerable to anxiety and depression, and they also seem to be less responsive to certain antidepressant medications.

Inflammation also seems to impair the function of glucocorticoid receptors. That would explain why people with depression and anxiety seem to have high levels of cortisol, but decreased ability to respond to it in an effective way (so people feel fatigued and overwhelmed rather than energized and capable despite mountains of cortisol running through the body). The term "adrenal fatigue" which I often see in blogs and whatnot is misleading and "glucocorticoid resistance" is much more meaningul.

Anti-inflammatory agents have been shown to help with depression symptoms in certain cases. Usually the research uses fancy-schmancy anti-inflammatories (such as anti-TNF antibodies used in Crohn's disease and psoriasis), but celecoxib has also been shown to have some positive effects on major depressive disorder.

More standard antidepressant medications (of most of the major classes) have been shown to be anti-inflammatory in vivo and in vitro. For example, tricyclic antidepressants, norepinephrine reuptake inhibitors, and SSRIs have all been shownn to reduce the toxin-induced secretion of IFN gamma and IL-10 in a solution of red blood cells exposed to toxin.  In addition, in certain studies, people treated with antidepressants have decreased c-reactive protein levels after treatment, and decreased levels of release of TNF from whole blood samples. Electroshock treatment also decreases TNF in patients with major depression, as does vagus nerve electrode stimulation.

SSRIs in particular could have a direct action on a person's T cells. SSRIs work on the SERT (serotonin transporter). Certain immune cells have SERT and they use it to take up serotonin from mature T cells. The serotonin is eventually transferred to naive T-cells and seems to enhance their activation. This mechanism would explain how SSRIs at least could reduce pro-inflammatory cytokine expression (many of the pro-inflammatory cytokines are released from certain types of T cells). Since genetic polymorophisms in the promotor region of the SERT gene have also been shown to cause increased vulnerability to depression in those exposed to stress, this inflammatory mechanism may be the cause. We will have to look outside the brain to really understand all the systemic vulnerabilities and expressions of depression and anxiety. 

And finally we get to some mechanisms that I've actually discussed previously (the most common and widely accepted mechanisms of how depression goes hand in hand with inflammation, and how antidepressants seem to help when they do). Antidepressant drugs tend to reduce the activity of TDO which metabolizes tryptophan, the dietary precursor to serotonin. This action tends to oppose those of pro-inflammatory cytokines (such as IFN-gamma and IL-1) to increase the catabolism of tryptophan by IDO and of glucocorticoid hormones to increase catabolism of tryptophan by TDO. These medicines seem to increase plasma and brain tryptophan concentrations, and secondarily increased production of serotonin in the brain. Tryptophan and serotonin are also known immune regulators. So, once more, stress hormones and pro-inflammatory cytokines antagonize serotonin, tryptophan, and antidepressant drugs, and vice-versa.

Probiotics, which also seem to have anti-inflammatory effects, have had antidepressant and antianxiety actions in animal studies. The human studies are very few and far between (I reviewed them here and then a later mouse study here). The pseudocommensal M vaccae, which induces T regs and downregulates the chronic inflammatory state has also been shown to (unexpectedly) improve quality of life scores in people receiving it experimentally for asthma or psoriasis.  

There is a very new explosion of research concerning regulatory T cells and depression in animal models and even in human cell lines. The published studies seem to show that there is a type of autoimune dysregulation in depressive disorders and that the same old suspects of pro-inflammatory cytokines mediate the symptoms. Thinking about depression and anxiety as immune disorders helps us to frame a whole health approach for its treatment: anti-inflammatory diet, exercise (in personalized amount and difficulty) counseling, meditation, and appropriate use of different immune modulators (antidepressants are well studied, of course) as more studies come out showing efficacy and safety. 


  1. Hi! I just want to say that finding this blog is like a breath of fresh air. After years of going going to psychiatrists who told me that I would not survive without medication, I finally quit everything at the beginning of this year, only going by simple intuition based on a little research I'd done relating to diet and mental health. Once I quit all medication, took grains and diary out of my diet, and stopped smoking tobacco, my anxiety and depression went away so fast and so significantly that I no longer consider myself to be mentally ill. And I am thriving, not just surviving, and happy to prove my doctors wrong.

    Your entry on inflammation makes a lot of sense when I think of it as applying to my life. I do struggle with anxious and depressive days still, but they happen far less often and can always be traced to a physical cause (ie. accidentally eating grain proteins). They are easier to deal with now because I know that the feelings will pass quickly. Exercise (which reduces inflammation) helps them pass faster, too.

    I wish there were more psychiatrists like you. Thank you for all that you do!

  2. But if, as we've discussed here, antidepressants have effectively failed their clinical trials, how much practical relevance do you think their mechanisms of action really have?

    I'm still not clear if they're really nothing more than active placebos, or if they somehow work well for a small subset of people with an overall minimal effect in the much larger population they're used on, or if they work on most people but with a minimal effect size, or if something else is going on.

    1. My guess from clinical experience is "major depressive disorder" is a combination of disorders, different genetic and environmental risks cobbled together into a basket DSMIV diagnosis, and that antidepressants work very well for some, and terribly for others, but are not placebos per se. We're also missing folks with methylation issues and whatnot because we don't test for it routinely. They are just starting to do that sort of thing but it is unclear how clinically useful it is at the moment.

  3. Maybe the unwanted effects of antidepressants tend to overwhelm those mechanisms of action that support their use.
    I.E. the spill-over effect onto other receptors that should be left alone if the drug is to work as advertised.
    Also, antibodies will be formed to many drugs, which might alter their effects, especially if their mechanism when they do work is antiinflammatory.

  4. Hey Emily,

    I just read your post on the link between fructose and depression, then this post. Do you think it's possible that fructose malabsorption could increase depression by feeding gut microbes and disturbing the gut environment? Increased serum endotoxin, for example, seems well known to increase TNF-a as well as some of the inflammatory cytokines listed above.

    Also, gotta love the Mighty Mighty Bosstones!


  5. Hi, I'm asking for a friend, Paula Carnes: The latest research on Zoloft suggests that it reduces fungal brain infection. Do you think there might be reason to suspect Zoloft is reducing brain inflammation and infection which might reduce depression symptoms?

  6. You post made me to pay more attention on what my gynecologist said about the IWD mechanism of action "it prevents pregnancy by causing a low-grade inflammation in the womb". May be it is not so benign after all, better than taking hormone pills, but not completely harmless .

  7. thanks, Emily, that's exciting information about inflammation. The inflammation model seems to be at the core of so much of the modern disease(s) epidemic.

  8. Hi, just wanted to let you know I recently read that Kathleen Light and Alan Light are developing an gene-expression based blood test for major depressive "disorder" (I'd call it a illness or disease, but hey, I'm not the DSM). I don't know what gene's they found that are expressed differentially, but this sure will be interesting. And will be interesting to see how nutrition ties into this.

    BTW: Alan Light comes from research into pain, in the last years he has done much in CFS, and he is developing there a blood test too, to identify CFS, and also to differentiate it from depression. Looks promising.

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  10. i was curiouswhat you thought about using EPA omega 3 in conjunction with probiotics (mainly plain yougart) as a way to decrease inflamation. i have stopped eating sugars and am on a regimant of 1500mg of epa/ 400 mg dha daily. i beleive that i am tarting to notic a difference after 2 weeks of this.

  11. if depression is related to inflammation in the brain, and glucocorticoids are antiinflammatory, then couldn't glucocorticoids be placed next to the spinal cord in the back diffuse into the cerebrospinal fluid eventually getting into the brain and "cure" inflammation?

    I say this because I am a former 8 yr long zoloft user. I recently had an epidural steroid injection in th elumbar spine and had an impressive snowballing of side effects from complete muscle catabolism to stomach bleeding to cold to insomnia to tachycardia to muscle rigidity to altered consciousness-with no answer as to what could have caused these symptoms other than the cocktail of anesthetic, betamethasone, and sertraline I was taking at the time-high body temp from training(am high level) which is like cooking everything in a test tube- but the implication is that the horrendous experience has taken away the malaise thatwas me depression in the 1.5 months of altered consciousness.

    1. Good question. Glucocorticoids have been found to have depressogenic (i.e. pro-depression effects) due to their interaction with the stress system of the brain. In fact one theory regarding the cause of depression, was in fact, that it was due to cortisol (or hydrocortisone; a natural corticosteroid) hypersecretion. demonstrates a link. This is one reason why chronic stress can cause or, at least, contribute to depression.

  12. Hi, My name is Francisco and I am a researcher at the University of Texas at Dallas

    An inflammation that originates from the central nervous system or the peripheral system is able to worsen a mood condition such as depression. Several groups have reported that the pro-inflammatory cytokines cause depression to be resistant to medication. IL-6 a pro-inflammatory cytokine causes depression to be resistant to most classical depression medications. IL-6 causes an imbalance in the way the central nervous system functions, by decreasing Inhibition or increasing excitation by inducing a hyper-excitible condition, and as a result mood imbalances. A interesting fact is that, mice that lack the pro-inflammatory cytokine IL-6 (the so called IL-6 knockout mice) are resistant to stress, depression and anxiety. A very important finding in people who suffer from post-traumatic stress disorder (a psychiatry disorder) was, detecting higher levels of Interleukin-6 (IL-6) and IL-6 receptor concentrations.

    1. Transl Psychiatry. 2012 Dec 4;2:e199. doi: 10.1038/tp.2012.120.
    Evidence for sustained elevation of IL-6 in the CNS as a key contributor of depressive-like phenotypes.
    Sukoff Rizzo SJ, Neal SJ, Hughes ZA, Beyna M, Rosenzweig-Lipson S, Moss SJ, Brandon NJ.

    2. Neurobiol Dis. 2006 Sep;23(3):587-94. Epub 2006 Jul 12.
    IL-6 knockout mice exhibit resistance to stress-induced development of depression-like behaviors.
    Chourbaji S, Urani A, Inta I, Sanchis-Segura C, Brandwein C, Zink M, Schwaninger M, Gass P.

    3. Biol Psychiatry. 2012 Apr 1;71(7):574-82. doi: 10.1016/j.biopsych.2011.11.018. Epub 2011 Dec 22.
    The stress-induced cytokine interleukin-6 decreases the inhibition/excitation ratio in the rat temporal cortex via trans-signaling.
    Garcia-Oscos F, Salgado H, Hall S, Thomas F, Farmer GE, Bermeo J, Galindo LC, Ramirez RD, D'Mello S, Rose-John S, Atzori M.

    4. Nat Neurosci. 2010 May;13(5):584-91. doi: 10.1038/nn.2535. Epub 2010 Apr 25.
    Selective induction of astrocytic gliosis generates deficits in neuronal inhibition.
    Ortinski PI, Dong J, Mungenast A, Yue C, Takano H, Watson DJ, Haydon PG, Coulter DA.

    5. J Neuroinflammation. 2011 May 19;8:54. doi: 10.1186/1742-2094-8-54.
    Inhibition of interleukin-6 trans-signaling in the brain facilitates recovery from lipopolysaccharide-induced sickness behavior.
    Burton MD, Sparkman NL, Johnson RW.

    6. Biol Psychiatry. 1999 Apr 1;45(7):833-9.
    Elevated serum interleukin-6 (IL-6) and IL-6 receptor concentrations in posttraumatic stress disorder following accidental man-made traumatic events.
    Maes M, Lin AH, Delmeire L, Van Gastel A, Kenis G, De Jongh R, Bosmans E.


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