Inflammation Testing and Antidepressant Selection

Peter ForsterBest Practices, Major Depression, Physical Conditions and Health, Testing Leave a Comment

Inflammation and C Reactive Protein

Inflammation is often seen in people with depression. And there is evidence to suggest that it predicts treatment response.

The most widely accepted standard test to measure inflammation is the C-reactive protein, or CRP. This is a protein that is produced by the liver in inflammatory states. The American Heart Association and the Centers for Disease Control and Prevention consider a CRP greater than 3 mg/L to be a marker of high inflammation. In psychiatry, you need to order it as a high-sensitivity CRP because the regular-sensitivity CRP generally does not pick up the lower levels below 3 that can inform practice.

We don’t have a universally accepted cutoff in psychiatry. Some studies have used 1 mg/L. For example, a CRP above 1 mg/L predicts a more favorable response to bupropion than to an SSRI. Inflammation is on a spectrum, and the higher the CRP is, the more inflamed the patient tends to be (Jha MK et al, Psychoneuroendocrinology 2017;78:105–113).

There are other markers of inflammation, like interleukin-6 (IL6), but these tests are not as stable as CRP. They tend to fluctuate with circadian rhythms and acute stress, including the stress of a venous puncture when blood is drawn. CRP has a long half-life, so it stays more constant and is not as vulnerable to those perturbations.

Patients with inflammation may appear somewhat different than those without inflammation who are depressed; the typical patient with high inflammation would be expected to have anhedonia and low motivation (Miller AH and Raison CL, Nat Rev Immunol 2016;16(1):22–34). There’s a global lack of pleasure and enjoyment. They may also have prominent anxiety, fatigue, and psychomotor retardation.

An elevated CRP predicts a better response to dopaminergic or norepinephrine agents and a poorer response to SSRIs. The first study that looked at this compared nortriptyline to escitalopram (Lexapro) in 241 patients with depression. The patients with a high CRP > 3 mg/L did better on nortriptyline, while those with a low CRP below 1 mg/L did better on the escitalopram (Uher R et al, Am J Psychiatry 2014;171(12):1278–1286). More recently we have the CO-MED trial, which looked at bupropion augmentation of an SSRI (escitalopram) in 106 patients with major depression. When the results were first published in 2011, bupropion augmentation worked no better than a placebo. Later, the researchers parsed out the data by inflammatory markers. It turned out bupropion worked in the subset of patients with a mildly elevated CRP (> 1 mg/L), while the SSRI monotherapy worked better when the CRP was low (Jha MK et al, Psychoneuroendocrinology 2017;78:105–113).

SSRI’s may be less effective because inflammation activates the serotonin transporter, increasing both its expression and its function. The result is that serotonin is cleared more rapidly from the synapse. SSRIs target that transporter, and it’s harder for them to make an impact when there is a greater volume and number of those transporters

We do have some evidence, though, that omega-3s and L-methylfolate work better when inflammatory biomarkers are elevated. L-methylfolate is an essential cofactor in the production of dopamine, and inflammation hinders that particular pathway, so there’s reason to think that L-methylfolate would be especially useful in the context of inflammation (Shelton RC et al, J Clin Psychiatry 2016;76(12):1635–1641; Rapaport MH et al, Mol Psychiatry 2016;21(1):71–79). Other options would be to use pramipexole or even l-dopa to boost dopamine.