Depressogenic vulnerability and gender-specific patterns of neuro-immune dysregulation: What the ratio of cortisol to C-reactive protein can tell us about loss of normal regulatory control

We examined whether the ratio of cortisol (CORT) to high-sensitivity C-reactive protein (hsCRP), an index that captures the integrity of homeostatic regulation between the hypothalamic-pituitary-adrenal (HPA) axis and inflammatory processes, is associated with vulnerability to depression in a gender specific manner and whether glucocorticoid receptor (GR) sensitivity plays a role in these associations. Fasting blood samples were collected between 08:45 and 09:15 and assayed for CORT, hsCRP, and leukocyte count in 213 healthy, medication-free men and women. The NEO-Personality Inventory was used to assess neuroticism, extraversion and anxiety. We used the Hamilton Depression Interview to assess depressive symptoms, the Buss-Perry anger subscale to measure anger, and the Pittsburgh Sleep Quality Index to evaluate subjective sleep quality and its components. Log-transformed CORT/CRP values were analyzed using multiple regression with Holms' adjusted p-values and age, body mass index (BMI), and race as covariates. GR sensitivity was estimated using the log-transformed ratio of neutrophils (N)-to-monocytes (M). The log-transformed ratio of CORT/CRP did not differ between men and women but was significantly and negatively associated with age and BMI. Severity of depressive symptoms, extraversion, anxiety, and sleep quality were associated with the CORT/CRP ratio in a gender-specific manner. For women, decreasing CORT/CRP ratios, suggestive of an insufficient release of CORT coupled with a heightened inflammatory state, were associated with increasing severity of depressive symptoms, decreasing quality of sleep, increasing frequency of sleep disturbance, and decreasing extraversion. For men, increasing frequency of daytime disturbance and levels of anxiety were associated with increasing CORT/CRP ratio, suggestive of an enhanced release of CORT relative to attenuated levels of hsCRP. For both genders, increasing anger was associated with decreasing CORT/CRP ratios. Although results suggested GR downregulation in women but not men, such differences did not mediate the observed associations. With the use of the CORT/CRP ratio, we showed that vulnerability factors for depression are associated with a loss of normal regulatory controls resulting in gender-specific patterns of neuro-immune dysregulation. That GR downregulation did not influence these associations suggests that the loss of regulatory controls in at risk individuals is primarily at the level of the hormone. Beyond the individual contribution of each component of the CORT/CRP ratio, disruption of normal neuroimmune regulatory feedback provides a plausible biological framework useful in understanding biobehavioral vulnerabilities to depression in a gender specific manner. The CORT/CRP ratio may be a viable biomarker not only for delineating risk for MDD but also progression and treatment responses among patients with MDD; possibilities that are testable in future studies.