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For this article, let’s take a look at some exciting new advances in the understanding of the relationship between depression and inflammation.
This is an article about C-reactive protein, something you’re familiar with from your medical training and available to us as a simple lab test. And one of the questions is going to be: Are we ready to start routinely measuring CRP? The data has been accumulating on this. There’s a good review on this subject by Dr. Philip Cowen at the Psychopharmacology Institute website. The title is Experimental Treatments: Anti-inflammatory Agents, and it’s from January 2018. That’s a great summary on this issue.
Here’s a new bit of data to add to that: We have recognized then there’s a relationship between depression and inflammation; that connection is very clear. But the new article from the 2018 British Journal of Psychiatry takes us a step further by showing that elevated CRP levels are related not to all depressions but to treatment-resistant depression in particular.
Just a little more background in case you haven’t been up reading this stuff late at night. The connection between depression and inflammation was shown by Andrew Miller and Chuck Raison more than 5 years ago. They used a powerful anti-inflammatory medication called infliximab, and that’s a tumor necrosis factor (TNF) monoclonal antibody, which basically antagonizes the immune response through TNF-alpha. They used that to treat depression. And you’ll remember this study. It was really quite a turning point. The result overall was negative, but the result in a subset of patients was quite strong, those patients with elevated CRP levels. In other words, patients with an existing elevated level of inflammation, those were the ones in whom an anti-inflammatory, infliximab, was effective.
The new study by Dr. Samuel Chamberlain and colleagues at Cambridge and largely across the rest of the UK showed a connection between the inflammatory marker CRP, available to us all, and treatment-resistant depression, which they defined using a typical calibration from the literature: 2 or more antidepressants have been tried and were not successfully treating the depression. Interestingly, they did not see a connection or an association with depression overall, only with treatment-resistant depression. And the association was much stronger when they controlled for body mass index, BMI. Elevated BMI is itself strongly associated with increased CRP. So, you have to get that out of the way in order to really see this connection between CRP and treatment-resistant depression.
What does this mean? Does it mean we should all start getting a CRP on our patients with depression? Dr. Cowen, in his review for the Psychopharmacology Institute that I mentioned, thinks maybe so. There’s another paper that showed that people with even slightly elevated CRP were somewhat more likely to respond to nortriptyline than to escitalopram. The difference was not really pronounced, maybe just enough to guide a choice if you’re at a treatment-resistant depression stage. And the CRP elevation there was greater than 2. That isn’t much. In Dr. Raison’s study on infliximab, the high inflammatory state where infliximab worked was greater than 5, which is way up there. So, clinically, is it worth getting a CRP? It might influence your choice if there’s some doubt as to what the next medication is to try. It might steer you toward nortriptyline, but that study hasn’t been replicated yet. So, we’re a little premature drawing that conclusion.
Lastly, what about using an anti-inflammatory medication that we can all access, like a nonsteroidal anti-inflammatory? Here, we also only have preliminary results. They’re also not replicated using celecoxib, one of the possibly stronger nonsteroidal anti-inflammatories. And the data there were somewhat suggestive, again, in treatment-resistant depression. There was a signal for response but not in depression across the board. And this was adjunctive to antidepressants that were continued adding the nonsteroidal anti-inflammatory. So, if you were to use it, you would use it in that fashion. And of course, we have to factor in the risks of the nonsteroidals themselves, which can be substantial, especially in some subsets of patients.
So, our Quick Take summary here is, there is a fascinating connection between depression and inflammation. An explanation for this has been offered by Dr. Andrew Miller and his colleague, Charles Raison. They called this an evolutionary model of depression, which I really like because it’s an explanation of depression that actually makes sense to me. I have not really heard of another one anywhere near as good as this. Why is it that depression is still around in such high proportion in our society when it can be lethal? It must have some sort of value, if one is thinking evolutionarily. Their logic goes like this: Infection was the big problem over human time. Anything that could help us fight off infection would have evolutionary value. If when you get an infection, you slow down, socially withdraw, don’t feel motivated to do things, you focus on your resources and energy and try to just get well first, that might have evolutionary value. So, depression is a byproduct of the mechanisms that we’ve developed to fight infection, so say Drs. Miller and Raison. They mustered a good bit of data to make this connection. Dr. Miller has a YouTube video offering the explanation, and Dr. Raison has a wonderful presentation on this if you ever get a chance to hear it. So, lots of things that don’t make any sense make more sense in this context if you think about ways in which depression and being sick with an infection resemble one another. Again, I recommend to you Drs. Miller’s and Raison’s presentations on this.
Abstract
Treatment-Resistant Depression and Peripheral C-Reactive Protein
Samuel R Chamberlain, Jonathan Cavanagh, Peter de Boer, Valeria Mondelli, Declan N C Jones, Wayne C Drevets, Philip J Cowen, Neil A Harrison, Linda Pointon, Carmine M Pariante, Edward T Bullmore
Background: C-reactive protein (CRP) is a candidate biomarker for major depressive disorder (MDD), but it is unclear how peripheral CRP levels relate to the heterogeneous clinical phenotypes of the disorder.AimTo explore CRP in MDD and its phenotypic associations.
Method: We recruited 102 treatment-resistant patients with MDD currently experiencing depression, 48 treatment-responsive patients with MDD not currently experiencing depression, 48 patients with depression who were not receiving medication and 54 healthy volunteers. High-sensitivity CRP in peripheral venous blood, body mass index (BMI) and questionnaire assessments of depression, anxiety and childhood trauma were measured. Group differences in CRP were estimated, and partial least squares (PLS) analysis explored the relationships between CRP and specific clinical phenotypes.
Results: Compared with healthy volunteers, BMI-corrected CRP was significantly elevated in the treatment-resistant group (P = 0.007; Cohen’s d = 0.47); but not significantly so in the treatment-responsive (d = 0.29) and untreated (d = 0.18) groups. PLS yielded an optimal two-factor solution that accounted for 34.7% of variation in clinical measures and for 36.0% of variation in CRP. Clinical phenotypes most strongly associated with CRP and heavily weighted on the first PLS component were vegetative depressive symptoms, BMI, state anxiety and feeling unloved as a child or wishing for a different childhood.
Conclusions: CRP was elevated in patients with MDD, and more so in treatment-resistant patients. Other phenotypes associated with elevated CRP included childhood adversity and specific depressive and anxious symptoms. We suggest that patients with MDD stratified for proinflammatory biomarkers, like CRP, have a distinctive clinical profile that might be responsive to second-line treatment with anti-inflammatory drugs.Declaration of interestS.R.C. consults for Cambridge Cognition and Shire; and his input in this project was funded by a Wellcome Trust Clinical Fellowship (110049/Z/15/Z). E.T.B. is employed half time by the University of Cambridge and half time by GlaxoSmithKline; he holds stock in GlaxoSmithKline. In the past 3 years, P.J.C. has served on an advisory board for Lundbeck. N.A.H. consults for GlaxoSmithKline. P.d.B., D.N.C.J. and W.C.D. are employees of Janssen Research & Development, LLC., of Johnson & Johnson, and hold stock in Johnson & Johnson. The other authors report no financial disclosures or potential conflicts of interest.
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Reference
Chamberlain, S. R., Cavanagh, J., De Boer, P., Mondelli, V., Jones, D. N., Drevets, W. C., Cowen, P. J., Harrison, N. A., Pointon, L., Pariante, C. M., & Bullmore, E. T. (2018). Treatment-resistant depression and peripheral C-reactive protein. British Journal of Psychiatry, 214(1), 11-19.
