Can C-reactive protein inform antidepressant medication selection in depressed outpatients? Findings from the CO-MED trial

Abstract

Objective: Currently, no valid measures inform treatment selection for depressed patients. Whether C-reactive protein (CRP) in particular and two other acute phase reactants (inflammatory markers) could differentiate between patients responding to either of two treatments with different mechanisms of action was assessed.

Method: Subjects included Combining Medications to Enhance Depression Outcomes (CO-MED) trial participants randomly assigned to either escitalopram plus placebo (SSRI monotherapy, n=51) or bupropion plus escitalopram combination (bupropion-SSRI combination, n=55) with baseline plasma samples. CRP, serum amyloid P component, and alpha-2-macroglobulin were measured using the Bioplex Pro™ human acute-phase 4-plex panel. We conducted mixed model analyses of depressive symptom (Quick Inventory of Depressive Symptomatology Self-Report) and side-effect burden (Frequency, Intensity, and Burden of Side-Effects Rating Scale) obtained weekly or every other week over the 12-week acute-phase of CO-MED trial to evaluate the relationship between these outcomes and baseline CRP and other acute-phase reactants.

Results: The treatment arms did not differ in depressive symptom or side effect outcomes. Most participants (69.8%, 74/106) had baseline CRP levels greater than 1mg/L (indicative of systemic inflammatory activity). Higher baseline CRP levels were associated lower depression severity (correlation coefficient=-0.63) with bupropion-SSRI combination but not with SSRI monotherapy (correlation coefficient=0.40). The overall remission rate was 41.5%. The estimated remission rate with CRP threshold based assignment (SSRI monotherapy for <1mg/L and Bupropion-SSRI for ≥1mg/L) was 53.1%, with a number needed to treat of 8.6. Side effect burden was unrelated to any baseline inflammatory marker.

Conclusions: Baseline CRP levels relate differentially to antidepressant treatment outcomes in persons with major depressive disorder. Clinicaltrials.gov identifier: NCT00590863.

Keywords: Antidepressant response; Biomarker; C-reactive protein; Depression; Inflammation.

Figure 1.. Association of Baseline C-Reactive Protein and Changes in Depression Severity During Acute-Phase of CO-MED Trial

For individual participants in Combining Medications to Enhance Depression Outcomes (CO-MED) trial, depression severity averaged over all visits (baseline and weeks 1–12) of acute-phase was plotted against log of C-reactive protein (CRP) level at baseline.

Figure 2.. Differential changes in depression severity between SSRI monotherapy and bupropion-SSRI combination based on CRP level at baseline

Participants in SSRI monotherapy (escitalopram plus placebo) and bupropion-SSRI combination treatment arms were divided in two groups based on a priori defined C-reactive protein (CRP) threshold (< and ≥ 1 mg/L), and average of depression severity over the course of acute-phase (baseline and weeks 1–12) of Combining Medications to Enhance Depression Outcomes (CO-MED) trial were calculated for these four groups.

Figure 3.. Early reduction in depression severity with SSRI monotherapy in depressed patients with low (<1mg/L) CRP level at baseline

Mean depression severity at each visit of acute-phase of Combining Medications to Enhance Depression Outcomes (CO-MED) in SSRI monotherapy (Panel A) and bupropion-SSRI combination (Panel B). QIDS-SR is Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR) and CRP is C-reactive protein.

Figure 4.. Remission rates during acute-phase of CO-MED trial based on C-reactive protein (CRP) level at baseline

Remission rates in the full sample (n=106) as well as SSRI monotherapy and bupropion-SSRI treatment arms of Combining Medications to Enhance Depression Outcomes (CO-MED) were calculated after dividing participants in two groups based on a priori defined C-reactive protein (CRP) threshold < and ≥ 1 mg/L.