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.

The Mighty Mighty Bosstones: The Impression That I Get 

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.