Depression and Inflammation: Treatment Options

Peter ForsterMajor Depression, Physical Conditions and Health, Treatments of Depression

inflammation-and-depression-treatmentA host of conditions have been associated with mild to moderate levels of inflammation in the body. Depression is one of these. Elsewhere in this blog we have discussed the relationship between depression and inflammation, evidence that treatment with an antidepressant (escitalopram) reduces inflammation in depression, and talked about how exercise prevents depression. We have also noted that elevated levels of inflammation (simple test may predict which antidepressant will work) may predict who will respond to an SSRI (generally those with lower levels of inflammation) as opposed to a tricyclic antidepressant (nortryptiline for those with higher levels of inflammation).

What to do when working with someone with low grade inflammation and depression if there is no evidence of infection or any specific rheumatologic disorder?
inflammatory spectrum

First, though, let’s consider different types of inflammation. As you can see in the figure above, inflammation exists on a continuum from a marker of mild stress to a sign of an acute emergency, such as a severe infection.

Here we will be talking about the middle range in that figure ranging from “stress response” to “para-inflammation.” To give something of a context, “stress response” would be associated with near normal or normal markers of inflammation (c reactive protein less than 1.0) while para-inflammation would be associated with mild elevations in acute stress reactants (c reactive protein of less than 10).

The different roles of these two states are summarized in an image from Medzhitov’s article in Nature, “Origin and physiological roles of inflammation.”


What to do from a treatment standpoint in people with depression and para-inflammation?

We recently queried a couple of experts on the subject at  UCSF (Owen Wolkowitz and Daniel Lindqvist).

Dr. Lindqvist noted that a study by Rapaport that came out in 2015 showed that depressed (unipolar) subjects with “high inflammation” (defined using multiple inflammatory markers including CRP) were more likely to respond to EPA (omega 3 fatty acid) than placebo. This was not seen in the group without signs of inflammation. He adds the caution that these analyses were done post hoc and the N was small in the “inflammatory subgroups”.

What about anti-inflammatory medications, such as non steroidal anti-inflammatory drugs (NSAIDs)? Dr. Lindqvist writes that:

“There are a total of 4 studies showing positive benefit for Celecoxib as an add-on to SSRI. No studies, that I know of, have tested the hypothesis that inflammatory biomarkers might predict this response… I know there is also one study on bipolar disorder and Celecoxib with positive results. Of note, many of these Celecoxib-studies were done by the same Iranian group. I think more studies are needed before Celecoxib can be used in the clinic. Studies exploring if biological/symptom subgroups of depressed/bipolar patients can benefit from this treatment would be especially helpful. I know that the first Celecoxib study by Muller et al (Molecular Psychiatry) had problems with high drop out rates (partly due to lack of effect but also side effects) which I think is noteworthy.”

So, in terms of treatment recommendations, if the patient has not yet started an antidepressant, it might make sense to select either an SNRI or a tricyclic antidepressant like nortriptyline.

In any event, addition of fish oil (EPA) makes sense, and probably a strong recommendation to encourage aerobic exercise.

Anti-inflammatory supplements are hard to recommend since so many large well-controlled studies have failed to find benefits from many anti-inflammatory nutritional supplements (such as vitamin C, vitamin E, beta-carotene, etcetera) although any Google search will come across scores of recommendations for supplements.

However, there is some evidence that a particular diet (the Mediterranean diet) may be helpful.

References and Notes

Appleton KM, Sallis HM, Perry R, Ness AR, Churchill R. Omega-3 fatty acids for depression in adults. Cochrane Database Syst Rev. 2015 Nov 5;(11):CD004692. doi: 10.1002/14651858.CD004692.pub4. Review. PubMed PMID: 26537796.

Chovatiya R, Medzhitov R. Stress, Inflammation, and Defense of Homeostasis. Molecular cell. 2014;54(2):281-288. doi:10.1016/j.molcel.2014.03.030.

Medzhitov R. Origin and physiological roles of inflammation. Nature. 2008 Jul 24;454(7203):428-35. doi: 10.1038/nature07201. Review. PubMed PMID: 18650913.

Miller AH, Haroon E, Felger JC. Therapeutic Implications of Brain-Immune Interactions: Treatment in Translation. Neuropsychopharmacology. 2016 Oct 5. doi: 10.1038/npp.2016.167. PubMed PMID: 27555382.

Rapaport MH, Nierenberg AA, Schettler PJ, Kinkead B, Cardoos A, Walker R, Mischoulon D. Inflammation as a predictive biomarker for response to omega-3 fatty acids in major depressive disorder: a proof-of-concept study. Mol Psychiatry. 2016 Jan;21(1):71-9. doi: 10.1038/mp.2015.22. Epub 2015 Mar 24. PubMed PMID: 25802980; PubMed Central PMCID: PMC4581883.

The figure of the inflammation spectrum is from the Chovatiya, et al, article and is used with permission according to the following conditions:

Molecular Biology of the Cell (MBoC) ©2016 by The American Society for Cell Biology (ASCB). Individual articles are distributed by The American Society for Cell Biology under license from the author(s), who retain copyright. Two months after being published at, the material in MBoC is available for non-commercial use by the general public under an Attribution-Noncommercial-Share Alike 3.0 Unported Creative Commons License ( Under this license, the content may be used at no charge for noncommercial purposes by the general public, provided that: the authorship of the materials is attributed to the author(s) (in a way that does not suggest that the authors endorse the users or any user’s use); users include the terms of this license in any use or distribution they engage in; users respect the fair use rights, moral rights, and rights that the authors and any others have in the content.