Mood disorders and inflammation: High cortisol and low serotonin (Part 2 of 4)

There are multiple suspect pathways for causation of mood dysregulation in the setting of inflammation. One well described model hinges upon the ability of inflammatory mediators to impact the HPA axis, a system of hormone release that drives many physiologic functions in addition to the stress response.  Briefly, the central pathway of the HPA axis is that CRH causes production of ACTH, which causes production of cortisol, a stress hormone and a very potent anti-inflammatory under most circumstances.  Many molecules can affect the signaling of the HPA axis and contribute to inappropriate hormone regulation.

IL-1, IL-6, TNF and IFN-a are all inflammatory mediators released by mast cells and other cells. These mediators all activate the HPA axis, resulting in high production of CRH, ACTH and cortisol via a series of intertwined mechanisms. At the same time, inflammation also makes cortisol less effective.  There are several ways for this to occur. Inflammation can cause cells to make fewer receptors for cortisol, meaning that no matter how much cortisol is made, only a small fraction will be able to act on cells.  Persistently high cortisol levels decrease production of other anti-inflammatory molecules and molecules that mediate the anti-inflammatory action of cortisol.  High cortisol also tells the HPA axis that it doesn’t need to make more cortisol, so even though more may actually be necessary, your body doesn’t know that.

All of these factors coalesce to form a reality where cortisol may be elevated but with little anti-inflammatory effect because of the changes I mentioned above. High cortisol is associated with mood symptoms.

Decrease of serotonin activity is also seen in mood disorders. Tryptophan is a precursor to serotonin, a hormone and neurotransmitter that heavily regulates mood.  Cortisol increases the activity of a molecule called tryptophan 2,3-dioxygenase (TDO), which removes the amino acid tryptophan from the pool of molecules to break down. Inflammatory molecules like interferon increase activity of the enzyme IDO, which decreases serotonin production.  IDO breaks down tryptophan to molecules that cannot be made into serotonin, such as kynerenin and quinolonic acid.  These metabolites have been observed as elevated in models of depression and anxiety.

Another way that inflammatory mediators affect the action of serotonin is to hasten its degradation. Both TNF and IL-6 increase the breakdown of serotonin to 5-HIAA.


Furtado M, Katzman MA. Examining the role of neuroinflammation in major depression. Psychiatry Research 2015: 229, 27-36.

Rosenblat JD, et al. Inflamed moods: a review of the interactions between inflammation and mood disorders. Progress in Neuro-Psychopharmacology & Biological Psychiatry 2014; 53, 23-34.

3 Responses

  1. Kristin Elam May 25, 2016 / 10:00 pm

    Hi Lisa,

    I am always intrigued by the cortisol connection to all of this. Do you ahem any research that addresses those of us with adrenal insufficiency (Addison’s). I recall you mentioning once that you also do bot produce enough cortisol, but forget the topic. I would love to have a conservation with someone as intelligent and well studied as you are about how this. I take cortisone and fludrocortisone daily and do very well for the most part. But I feel the medical community has very little information on this and it seem like I have to look at some things in reverse when I read articles like this. Thank you for being you!

  2. Mark May 26, 2016 / 1:48 am

    Bears underscoring, if you haven’t elsewhere in your generally superb pieces, how Anaphylaxis is commonly associated with mood impairment, I believe before the culprits you discuss may even kick in, wreak havoc long-term, chronically.

    WAO lists “impending feelings of doom” or some such, for example, under common Anaphylaxis/ Anaphylactoid manifestations. (WAO prefers the term “nonallergic Anaphylaxis, though experts have stressed allergies can never definitively be ruled out.)

  3. Karen Holmes May 27, 2016 / 3:11 am

    How do we take a proactive approach to combat inflammation?

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