Potential Biomarkers of Antidepressant Response to Arthritis Drug

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RESEARCH UPDATE

There is evidence that patients with depression have high levels of inflammatory markers, high body mass index, and/or markers of metabolic dysregulation, which may predispose them to medical comorbidity and treatment resistance.^1,2

A seminal study found that inhibition of tumor necrosis factor (TNF) signaling, a key regulator of inflammation, with infliximab reduced depressive symptoms in patients with treatment resistant depression (TRD) high baseline plasma C-reactive protein (CRP; > 5 mg/L), and also lowered concentrations of CRP and other inflammatory cytokines in these patients.³ Gene expression analysis showed that antidepressant response to infliximab were predicted by baseline transcripts related to inflammation and TNF-signaling, as well as glucose and lipid metabolism, suggesting a role for metabolic dysregulation in these patients.⁴

There is evidence that in patients with rheumatoid arthritis, treatment with infliximab is associated with improvements in indices of glucose and lipid metabolism.⁵ However, whether these relationships exist in patients with infliximab-treated patients with TRD remains unknown. Bekhbat and colleagues⁶ measured a panel of plasma biomarkers of glucose and lipid metabolism in patients with TRD to determine their association with (1) antidepressant response to infliximab, (2) gene transcripts predictive of infliximab response, and (3) baseline CRP levels.

Blood plasma and RNA samples were collected during a 12-week randomized, double-blind trial of infliximab versus placebo in patients with TRD.³ Depression severity was measured by the HAM-D-17. Treatment response was defined as a 50% reduction in the HAM-D-17 at any point during the 12-week study. Subjects received infliximab 5 mg/kg or placebo at baseline, week 2, and week 6. Blood was collected after 30 minutes of rest at baseline and again prior to the second infusion at week 2 for a panel of metabolic biomarkers (leptin, resistin, adiponectin, glucose, lipids, and CRP), as well as gene expression analysis.

Multivariate linear regression models were used to identify baseline plasma markers that differed between patients with and without antidepressant response to either infliximab or placebo. Multivariate repeated measures general linear models were used to assess the effects of a single infusion of infliximab at 2 weeks compared with placebo on metabolic biomarkers, and whether potential treatment effects over time were different in patients with plasma CRP >5 mg/L.

Metabolic biomarkers were available for n=26 infliximab treated patients (n=13 responders and n=13 non-responders), and n=26 placebo-treated patients (n=12 responders and n=15 non-responders). One patient did not have gene expression data.  There were no between-group differences based on demographic or baseline clinical characteristics.

Baseline lipids (total cholesterol, LDL cholesterol, non-HDL cholesterol, and non-esterified fatty acids [NEFA]) were all elevated in patients who exhibited an antidepressant response to infliximab (all p<0.05) but not placebo (all p>0.30), after controlling for clinical covariates. HDL and non-HDL cholesterol level was correlated with two lipid-related gene transcripts that were predictive of antidepressant response (r=0.33-0.39, p<0.05).

Resistin level was correlated with numerous glucose-related transcripts (r=−0.32 to 0.37, p<0.05) and was higher at 2 weeks post-infusion in patients treated with infliximab compared with placebo (p=0.028), although it was not associated with response to infliximab. Lipids (total, LDL, HDL, and non-HDL cholesterol) were also lower at 2 weeks in patients treated with infliximab compared with placebo, but only in those patients with CRP >5 mg/L at baseline (all p<0.05).

The authors concluded that patients with TRD who responded to infliximab compared with placebo had significantly higher baseline lipid markers. Furthermore, cholesterol, but not triglycerides or NEFA, were significantly lower at 2 weeks post-infliximab (versus placebo) in patients with high plasma CRP. Study limitations include a small sample size, and the use of historic blood samples collected at a non-standardized time of day between the two visits.

The bottom line

High inflammation in patients with depression is associated with metabolic alterations, which together predict response to both traditional and experimental (eg, infliximab) antidepressant therapies. Findings also suggest a causal relationship between increased inflammation and high cholesterol in depression, as a single infliximab infusion reduced cholesterol in patients with TRD and high CRP.

References:

1. Shelton RC, Falola M, Li L, et al. The proinflammatory profile of depressed patients is (partly) related to obesity. J Psychiatr Res. 2015;70:91–97.

2. Haroon E, Daguanno AW, Woolwine BJ, et al. Antidepressant treatment resistance is associated with increased inflammatory markers in patients with major depressive disorder. Psychoneuroendocrinology. 2018;95:43–49.

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. Mehta D, Raison CL, Woolwine BJ, et al. Transcriptional signatures related to glucose and lipid metabolism predict treatment response to the tumor necrosis factor antagonist infliximab in patients with treatment-resistant depression. Brain Behav Immun. 2013;31:205–215.

5. Tam LS, Tomlinson B, Chu T, et al. Impact of TNF inhibition on insulin resistance and lipids levels in patients with rheumatoid arthritis. Clin Rheumatol. 2007;26:1495–1498.

6. Bekhbat M, Chu K, Le N-A. Glucose and lipid-related biomarkers and the antidepressant response to infliximab in patients with treatment-resistant depression. Psychoneuroendocrinology 2018, https://doi.org/10.1016/j.psyneuen.2018.09.004