The Role of Inflammation in the Success and Failure of Antidepressants

Jill Littrell, PhD

The evidence is fast accumulating that systemic inflammation has a causative role in depression, or, at minimum, is a major factor in the chain of events leading to depression. Pioneer animal work was done by Robert Dantzer, Linda Watkins, and Steven Maier. The perspective of depression as an inflammatory condition is being espoused by Andrew Miller and Chuck Raison at Emory as well as Micheal Maes and his colleagues in Europe. These psychiatrists have amassed considerable data supporting the view that inflammation in the brain manifests as behavioral depression. The current thinking is that there are two inflammation-based roads to brain inflammation. The more direct route is when stress leads to brain inflammation with associated inflammatory markers in blood. This link appears to have strong empirical support. (In fact, a test for depression announced in this week’s news, by Papakostas and colleagues, uses inflammatory markers in blood as a screen for depression.) The indirect road to depression is when there is inflammation in the periphery, such as occurs with an infection, or an inflammatory condition such as arthritis. The peripheral inflammation then spreads to the brain.

Michael Maes and colleagues have published extensively on the impact of antidepressant medications on brain inflammation. Mice exposed to antidepressants for about 6 weeks do display less brain inflammation when stressed or provoked with a pathogen. There is a parallel literature in humans who have been exposed to antidepressants for 8 weeks. Humans, taking antidepressants for 8 weeks, do show lower levels of systemic inflammation as measured by markers in blood.

The problem is that the data making the case that antidepressants decrease inflammation is based on short term exposure in people and in mice. In the last decade reports have come out on the inflammatory status of persons who have taken antidepressants for over a year. Elevations in CRP, a measure of inflammation, are noted in those taking antidepressants for over two years. Those taking antidepressants over the long term are at elevated risk for Type II diabetes, widely acknowledged to be an inflammatory disease. They are more likely to be obese and exhibit metabolic syndrome, two conditions widely viewed as promoting systemic inflammation. They display lower levels of heart rate variability, another inflammatory marker. Moreover, among those individuals with cardiovascular disease, even after equating on prior levels of depression, those taking antidepressants display greater hardening of the blood vessels, which is the result of systemic inflammation.

While short term exposure to antidepressants decreases systemic inflammation, when taken over years, the opposite occurs. The literature on depression being an inflammatory state offers proof that activation of the immune system in the periphery will result in brain inflammation. Thus, drugs that are associated with strong peripheral inflammation are predicted to induce chronic depression. In fact, the prediction is verified by the facts. The phenomenon of more relapses to depression among those taking antidepressants compared to the unmedicated has been the theme of several publications. This phenomenon was discussed in Anatomy of an Epidemic. It was the subject of publications by Giovanni Fava (1994), Fava & Offindani (2011), and Andrews, Kornstein, Halberstadt, Gardner, & Neale (2011).

The CDC reports that 14% of the 11% of Americans taking antidepressants have been taking them for a decade or longer, while 60% have taken them for two years or more. For these individuals, the prevalence of inflammatory diseases such as Type II diabetes, cardiovascular disease, cancer, and chronic depression are likely to increase. Ironically, the very condition for which they are taking the antidepressants, depression, will also be exacerbated.

Fortunately, more consistent ways of decreasing systemic inflammation are available. In coming weeks, I will be blogging on these other more salubrious alternatives.

Andersohn, F., Schade, R., Suissa, S., & Garbe, E. (2009). Long-term use of antidepressants for depressive disorders and the risk of diabetes mellitus. American Journal of Psychiatry, 166(5), 591-598.
Fava, M. (2000). Weight gain and antidepressants. Journal of Clinical Psychiatry, 61 (Suppl. 11), 37-41.
Hamer, M., Batty, G. D., Marmot, M. G., Singh-Manoux, A., & Kivimaki, M. (2011). Anti-depressant medication use and C-reactive protein: results from two population-based studies. Brain, Behavior, and Immunity, 25(1), 168-173.
Kivimaki, M., Hamer, M., Batty, G. D., Geddes, J. R., Tabak, A. G., Pentti, J., et al. (2010). Antidepressant medication use, weight gain, and risk of type 2 diabetes: a population-based study. Diabetes Care, 33(12), 2611-2616.
Licht, C. M., de Geus, E. J., Zitman, F. G., Hoogendijk, W. J., van Dyck, R., & Penninx, B. W. (2008). Association between major depressive disorder and heart rate variability in the Netherlands Study of Depression and Anxiety (NESDA). Archives of General Psychiatry, 65(12), 1358-1367.
Raeder, M. B., Bjelland, I., Emil Vollset, S., & Steen, V. M. (2006). Obesity, dyslipidemia, and diabetes with selective serotonin reuptake inhibitors: the Hordaland Health Study. Journal of Clinical Psychiatry, 67(12), 1974-1982.
Shah, A. (2011). Antidepressant use linked to thicker arteries. Emory University. Atlanta, GA. Retrieved 12/12/11 from


Mad in America hosts blogs by a diverse group of writers. These posts are designed to serve as a public forum for a discussion—broadly speaking—of psychiatry and its treatments. The opinions expressed are the writers’ own.

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Jill Littrell, PhD
Life Style Can Change the Brain: A clinical psychologist, Jill Littrell writes about research studies of psychiatric medications, and interventions to bolster natural resilience through talk therapy, proper diet, exercise, and support from your friends.


  1. Thanks so much for this post – it confirms something I’ve been wondering about for the past year. I came across the inflammation link when I was researching the impact of fish oil on depression for the book I’m writing on transforming depression into happiness ( Inflammation seems linked to a bunch of other diseases (I notice you mention diabetes). Did you find any studies on the link between diet and inflammation? particularly ratios of omega 6 fatty acids to omega 3 fatty acids, which have changed dramatically in recent decades so that people are eating not only less omega 3 than they need for optimal functioning but much, much more omega 6 fatty acids that is healthy.

  2. Thank you for this post. My interest in inflammation is purely personal. I am so tired of all the pain I am having to endure and doctors telling me I have to make lifestyle changes, but not telling me specifically what I need to do. I think I am a perfect specimen for future studies. Lol I have had typeII diabetes for over 10 years along with high blood pressure, cholesterol, etc. I have also been taking anti-depressants for over 10 years. However, when I tried to stop taking them, the depression took over. Anyway, I could go on and on, but I won’t. I look foreward to your future posts.

    • I’ll be talking more later. For now, I would try omega-3s. (see literature by Jan Kiecolt-Glaser) Omega-3s decrease stress and depression. Also, turmeric is in clinical trials as treatment for depression. Black pepper will increase absorption of tumeric. (I put tumeric, ginger, pepper, black mustard seeds in olive oil. toss vegetables in and microwave. Tastes good.) Walk. Aspirin (non-acetylated salicylates so avoid bledding risks available by perscription) work with animals to decrease depression. See if you can get help for tapering anti-depressants. Withdrawal symptoms from antidepressants are terrible. Don’t think its you.