Treatment-resistant depression and peripheral C-reactive protein
Authors: Chamberlain Samuel R. , Cavanagh Jonathan , de Boer Peter , Mondelli Valeria , Jones Declan , Drevets Wayne C. , Cowen Philip J. , Harrison Neil A. , Pointon Linda ,   NIMA Consortium, Pariante Carmine M. , Bullmore Edward T. 
Published: October 2017

Research in context

Evidence before this study

Dysregulation of the peripheral innate immune system has been implicated in the pathophysiology of major depressive disorder (MDD), and may partly account for why many patients do not experience symptomatic improvement. Elevated CRP has been demonstrated in meta-analysis for MDD compared to healthy volunteers, but little is known about whether this is the case for particular clinical phenotypes of the disorder, as opposed to MDD in general.

Added value of this study

This study recruited a large cohort of MDD patients, stratified by prior exposure to monoamine reuptake inhibitor treatment. MDD participants were carefully screened for physical comorbidity, and were compared to healthy volunteers matched for age, sex, body mass indices, and cigarette smoking status. Using group-wise comparisons and the innovative statistical approach of partial least squares, we demonstrated that elevated CRP was associated with treatment-resistance, childhood adversity, and specific depressive and anxious symptoms.

Implications of all the available evidence

CRP is significantly increased “on average” in MDD patients, However, CRP was most abnormally increased in the subgroup of patients with treatment-resistant depression. High BMI, high scores on vegetative symptoms of depression, low scores on calmness, and a history of childhood adversity, were all predictive of increased CRP. In future, stratification of MDD patients using pro-inflammatory biomarkers, like CRP, may be valuable for sample enrichment and targeted treatment interventions.

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.

Methods

We recruited 102 treatment-resistant, depressed MDD patients, 48 treatment-responsive, non-depressed MDD patients, 48 depressed but un-medicated patients, 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, before and after correction for BMI. Partial least squares (PLS) analysis explored the relationships between CRP and specific clinical phenotypes.

Outcomes

Compared to healthy volunteers, BMI-corrected CRP was significantly elevated in treatment-resistant patients (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. The 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.

Interpretation

Peripheral CRP was elevated in MDD, especially in treatment-resistant cases. Other phenotypes associated with elevated CRP included childhood adversity, and specific depressive and anxious symptoms. We suggest that MDD patients stratified for pro-inflammatory biomarkers, like CRP, have a distinctive clinical profile that might be responsive to second-line treatment with anti-inflammatory drugs.

Funding

Wellcome Trust strategy award to the Neuroimmunology of Mood Disorders and Alzheimer’s Disease (NIMA) Consortium.