Inflammation: Curb Your Enthusiasm

Even though my earlier research review¹ emphasized recognition of behaviors that increase inflammation as targets for prevention of mood disorders, especially bipolar disorders-such enthusiasm itself runs the risk of being inflammatory. Andrew Miller and Charles Raison, leaders in this research, have suggested caution about overexcitement. In their JAMA Psychiatry “Viewpoint” review, they summarize data on the role of inflammation in psychiatric disorders, emphasizing that evidence for anti-inflammatory treatment for mood disorders is limited, and mixed.²

In the article, Dr Raison enjoys using unique turns of phrase (eg, “inflammation is not for everyone”). He refers to the finding that only subgroups of patients with depression, for example, have increased inflammatory markers. Among those who do, response to infliximab was better than to placebo. Not so for patients whose C-reactive protein (CRP) was less than 5 mg/L.³ However, their data also suggested that anti-inflammatory treatments for depression can backfire: in patients with low inflammation, infliximab was worse than placebo. Miller and Raison remind us: first, do no harm.

[[{"type":"media","view_mode":"media_crop","fid":"40058","attributes":{"alt":"©AndreyYurlov-Shutterstock","class":"media-image media-image-right","id":"media_crop_4339311860570","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"4323","media_crop_rotate":"0","media_crop_scale_h":"185","media_crop_scale_w":"185","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right;","title":"","typeof":"foaf:Image"}}]]On the other hand (are you getting the rhythm here?), Raison and Miller’s group also showed that among patients with CRP over 5 mg/L, important aspects of sleep improved after infliximab-but again, only in the high-CRP subgroup.⁴ This included “wake after sleep onset,” aka middle insomnia: highly prevalent, highly problematic, and full of portent for bipolar disorder treatment.

Obviously, these data do not support simply giving patients with depression a nonsteroidal anti-inflammatory like naproxen. Indeed, as Miller and Raison caution, this could be counterproductive. On the other hand, using CRP as an inflammatory marker appears to be working rather well: it effectively differentiates populations who improve, or worsen, on infliximab, for example. Can it be used as a prospective marker to indicate which patients should be given what medication? Indeed, another research group found that patients with a CRP lower than 1 mg/L responded better to escitalopram, whereas those at or above 1 mg/L responded better to nortriptyline.⁵

Hallelujah-an inexpensive biomarker to tell you which antidepressant to use! No, sorry, the CRP levels merely predicted a slightly better response to one medication rather than the other, accounting for only about 10% of the differences in outcome. This is not likely to drive your decision regarding use of a tricyclic instead of an SSRI.

So heed Miller and Raison. CRP, tumor necrosis factor, and interleukin 6 are “reliably elevated” in psychiatric disorders. They could theoretically allow one to affirm that one’s treatment was indeed hitting the target of inflammation (Raison: “trust, but verify”). But we don’t even know yet, which anti-inflammatory medications to use (Raison: “not all anti-inflammatory drugs are created equal”). You, like me, may need to curb your enthusiasm. (Apologies to Dr Miller if some of those turns of phrase are actually his!)

This article was originally posted on 8/3/2015 and has since been updated.

Disclosures:

Dr Phelps is Director of the Mood Disorders Program at Samaritan Mental Health in Corvallis, Ore. He is the Bipolar Disorder Section Editor for Psychiatric Times. [full bio] He reports no conflicts of interest concerning the subject matter of this article.

References:

1. Phelps J. Before bipolar: is there a prodrome? Psychiatric Times. July 3, 2015. http://www.psychiatrictimes.com/bipolar-disorder/bipolar-there-prodrome. Accessed August 6, 2015.

2. Miller AH, Raison CL. Are anti-inflammatory therapies viable treatments for psychiatric disorders? Where the rubber meets the road. JAMA Psychiatry. 2015;72:527-528.

3. Raison CL, Rutherford RE, Woolwine BJ, et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry. 2013;70:31-41.

4. Weinberger JF, Raison CL, Rye DB, et al. Inhibition of tumor necrosis factor improves sleep continuity in patients with treatment resistant depression and high inflammation. Brain Behav Immun. 2015;47: 193-200.

5. Uher R, Tansey KE, Dew T, et al. An inflammatory biomarker as a differential predictor of outcome of depression treatment with escitalopram and nortriptyline. Am J Psychiatry. 2014;171:1278-1286.