Treatment-resistant depression and peripheral C-reactive protein
C-reactive protein (CRP) is an acute-phase protein that is widely used in clinical practice and has also been measured in many prior studies of MDD.8 A high-sensitivity assay for CRP is well-validated and accessible. CRP synthesis is induced in the liver by proinflammatory cytokines – especially interleukin 6 (IL-6) – in response to infection, inflammation and tissue damage.
Immunological mechanisms are increasingly implicated in the pathogenesis of depressive symptoms.1–3 Activation of the peripheral immune system has been consistently associated with major depressive disorder (MDD).4–8 However, it has also been anticipated that not all patients with MDD will be peripherally inflamed to the same extent. A deeper understanding of how peripheral immune biomarkers relate to some of the dimensions of clinical heterogeneity encompassed by a diagnosis of MDD could be an important step towards mechanistically stratified treatment of depression in the future.
This is the first study to measure peripheral CRP with the same high-sensitivity assay across a large sample of patients with MDD (n = 198) prospectively stratified in terms of their current and past history of treatment with monoaminergic antidepressant drugs. We replicated the well-established finding that CRP is significantly increased ‘on average’ in patients with MDD, screened for physical comorbidity, and compared with healthy volunteers who did not differ in terms of age, gender, BMI and cigarette smoking status. However, we also found some evidence for our primary hypothesis that CRP was most increased in the subgroup of patients with treatment-resistant depression (n = 102). The standardised size of the case–control difference in CRP between healthy volunteers and treatment-resistant patients (Cohen's d = 0.47) was higher than the case–control difference for treatment-responsive (0.29) or untreated patients (0.18). Controlling for non-normality of the CRP distribution, and for the strong positive correlation between CRP and obesity, we found that the case–control difference in CRP remained significant only for the subgroup of treatment-resistant patients. These results of planned analysis are consistent with the hypothesis that peripheral inflammation is a marker or risk factor for treatment-resistant depression. It should be noted that CRP was somewhat elevated even in treatment-responsive patients, suggesting that a degree of elevated CRP could be trait-related rather than related to current symptoms or treatment status.
Taking a convergent but more exploratory approach to the data, we used multivariate analysis to identify two dimensions of clinical heterogeneity that were predictive of CRP. We found that a subset of clinically measured phenotypes explained approximately 36% of the variance in CRP. 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. As expected from the results of our primary analysis, we confirmed that the group of patients defined a priori in terms of treatment resistance had the highest scores on this clinical profile associated with high-sensitivity CRP.
MDD is associated with increased CRP compared with healthy volunteers and the case–control difference appears higher in treatment-resistant depression. Increased CRP and treatment resistance were also associated with other aspects of clinical heterogeneity in depression including obesity, vegetative symptoms of fatigue and sleep disturbance, state anxiety and a history of childhood adversity. We suggest there may be a clinically and immunologically diagnosable subsyndrome of ‘inflamed depression’ comprising the patients with MDD most likely to benefit therapeutically from second-line treatment with anti-inflammatory drugs.