Heather M. Burke

Depression and cortisol responses to psychological stress: A meta-analysis

The purpose of this meta-analysis is to examine the association between depression and cortisol responses to psychological stressors. A total of seven studies comparing plasma or cortisol responses to psychological stressors in clinically depressed (MDD) and non-depressed (ND) individuals (N = 196: 98 MDD, 98 ND; 83 men, 113 women; mean age = 40 years) were included. Sample size-adjusted effect sizes (Cohens d statistic) were calculated and averaged across baseline (before stressor onset), stress (stressor onset up to 25 min after stressor offset), and recovery (more than 25 min after stressor offset) periods. Overall, MDD and ND individuals exhibited similar baseline and stress cortisol levels, but MDD patients had much higher cortisol levels during the recovery period than their ND counterparts. There was also a significant time of day effect in which afternoon studies were more likely to reveal higher baseline cortisol levels, blunted stress reactivity, and impaired recovery in MDD patients. This blunted reactivity-impaired recovery pattern observed among the afternoon studies was most pronounced in studies with older and more severely depressed patients.

Glucocorticoids. Mood, memory, and mechanisms.

Elevated circulating levels of glucocorticoids are associated with psychiatric symptoms across several different conditions. It remains unknown if this hormonal abnormality is a cause or an effect of the psychiatric conditions. For example, the hypercortisolemia observed in a subset of patients with depression may have a direct impact on the symptoms of depression, but it is also possible that the hypercortisolemia merely reflects the stress associated with depression. Further, rather than causing depression, hypercortisolemia could represent a homeostatic attempt to overcome glucocorticoid resistance. Each of these possibilities will be considered, and correlational and causal evidence will be reviewed. This article will focus on the relationships between glucocorticoids and psychiatric symptoms in Cushings syndrome, major depression, and steroid psychosis/steroid dementia, as well as the effects of exogenously administered glucocorticoids in normal volunteers. Similarities and differences in the relationship of glucocorticoid hormones to psychiatric symptoms in these conditions will be reviewed. Possible mediators of glucocorticoid effects on the brain and behavior, as well as possible “pro‐aging” effects of glucocorticoids in certain cells of the body, will be reviewed. The article concludes with a conceptual model of glucocorticoid actions in the brain that may lead to novel therapeutic opportunities.

Dysregulated relationship of inflammation and oxidative stress in major depression.

Chronic inflammation and oxidative stress have been implicated in the pathophysiology of Major Depressive Disorder (MDD), as well as in a number of chronic medical conditions. The aim of this study was to examine the relationship between peripheral inflammatory and oxidative stress markers in un-medicated subjects with MDD compared to non-depressed healthy controls and compared to subjects with MDD after antidepressant treatment. We examined the relationships between IL-6, IL-10, and the IL-6/IL-10 inflammatory ratio vs. F2-isoprostanes (F2-IsoP), a marker of oxidative stress, in un-medicated MDD patients (n=20) before and after 8 weeks of open-label sertraline treatment (n=17), compared to healthy non-depressed controls (n=20). Among the un-medicated MDD subjects, F2-IsoP concentrations were positively correlated with IL-6 concentrations (p<0.05) and were negatively correlated with IL-10 concentrations (p<0.01). Accordingly, F2-IsoP concentrations were positively correlated with the ratio of IL-6/IL-10 (p<0.01). In contrast, in the control group, there were no significant correlations between F2-IsoPs and either cytokine or their ratio. After MDD subjects were treated with sertraline for 8 weeks, F2-IsoPs were no longer significantly correlated with IL-6, IL-10 or the IL-6/IL-10 ratio. These data suggest oxidative stress and inflammatory processes are positively associated in untreated MDD. Our findings are consistent with the hypothesis that the homeostatic buffering mechanisms regulating oxidation and inflammation in healthy individuals become dysregulated in untreated MDD, and may be improved with antidepressant treatment. These findings may help explain the increased risk of comorbid medical illnesses in MDD.

Low serum IL-10 concentrations and loss of regulatory association between IL-6 and IL-10 in adults with major depression

Elevated circulating pro-inflammatory cytokines are associated with symptoms of depression, and disorders involving chronic inflammation are often co-morbid with major depression. Since healthy immune regulation is accomplished through counter-balancing effects of pro- and anti-inflammatory cytokines, we hypothesized that depressed subjects (compared to controls) would express lower concentrations of the anti-inflammatory/immunoregulatory cytokine interleukin (IL)-10, and a higher IL-6/IL-10 ratio. We also examined the possibility that depressed subjects may exhibit a deficiency in the regulatory loop involving IL-6 induced secretion of IL-10. Therefore, we hypothesized that circulating IL-6 and IL-10 would be positively correlated in controls, while the correlation would be weaker in depressed subjects. Resting state serum cytokine concentrations were quantified in 12 unmedicated depressed subjects, and 11 age, gender, and ethnicity-matched controls. Depressed subjects showed significantly lower IL-10 (p=0.03, Cohens d=-0.96), non-significantly higher IL-6, and significantly higher IL-6/IL-10 ratios (p=0.05, Cohens d=0.50). Across all participants, higher scores on the self-rated Inventory of Depressive Symptoms were associated with lower IL-10 (r(21)=-0.57, p=0.005) and non-significantly higher IL-6/IL-10 ratios (r(21)=0.38, p=0.07), but not related to IL-6 concentrations. As hypothesized, IL-6 and IL-10 concentrations were strongly and positively correlated in controls (r(9)=0.81, p=0.003), but were completely dissociated in depressed subjects (r(10)=0.01, p=0.98). These results suggest that lower IL-10 levels, a higher IL-6/IL-10 ratio, and the apparent absence of a counter-balancing, immunoregulatory increase in IL-10 in response to elevated IL-6 concentrations contribute to the pro-inflammatory physiological milieu that is known to be associated with major depression. Therefore, reduced induction/availability of IL-10, that would normally inhibit pro-inflammatory cytokine actions and resolve inflammation, may contribute to the depressogenic as well as the inflammatory disease-promoting effects of chronic, low-level elevations in pro-inflammatory cytokines.

Resting leukocyte telomerase activity is elevated in major depression and predicts treatment response

Telomeres are DNA-protein complexes that cap linear DNA strands, protecting DNA from damage. When telomeres critically shorten, cells become susceptible to senescence and apoptosis. Telomerase, a cellular ribonucleoprotein enzyme, rebuilds the length of telomeres and promotes cellular viability. Leukocyte telomeres are reportedly shortened in major depression, but telomerase activity in depression has not been previously reported. Further, there are no published reports of the effects of antidepressants on telomerase activity or on the relationship between telomerase activity and antidepressant response. Peripheral blood mononuclear cell (PBMC) telomerase activity was assessed in 20 medication-free depressed individuals and 18 controls. In total, 16 of the depressed individuals were then treated with sertraline in an open-label manner for 8 weeks, and PBMC telomerase activity was reassessed in 15 of these individuals after treatment. Pre- and post-treatment symptom severity was rated with the Hamilton Depression Rating Scale. All analyses were corrected for age and sex. Pre-treatment telomerase activity was significantly elevated in the depressed individuals compared with the controls (P=0.007) and was directly correlated with depression ratings (P<0.05) across all subjects. In the depressed group, individuals with relatively lower pre-treatment telomerase activity and with relatively greater increase in telomerase activity during treatment, showed superior antidepressant responses (P<0.05 and P<0.005, respectively). This is the first report characterizing telomerase activity in depressed individuals. PBMC telomerase activity might reflect a novel aspect of depressive pathophysiology and might represent a novel biomarker of antidepressant responsiveness.

Depressive Symptoms Are Associated With Blunted Cortisol Stress Responses in Very Low-income Women

Objective: The purpose of this study was to examine the association between depressive symptoms and salivary cortisol responses to stress in a high-risk population of very poor Mexican women. Methods: Adult women (N = 1109) between the ages of 18 and 44 years (mean age, 29) were identified in a house-to-house survey in low-income areas (income <20th percentile nationally) of urban Mexico. An interview containing the Spanish version of the Center for Epidemiologic Studies—Depression Scale (CES-D) was administered to all women. The naturalistic stressor was defined as the unexpected arrival of a team of researchers at the participants’ homes followed by an in-depth interview and physical assessment, with saliva samples taken at time of arrival (baseline), 25 minutes, and 50 minutes after arrival. Results: The mean CES-D score was 19.42 (range, 0–53). Results of hierarchical linear modeling analyses revealed no effect of depressive symptoms on baseline salivary cortisol levels. However, a significant depressive symptom by time interaction revealed that women with elevations in depressive symptoms (CES-D scores = 35) failed to exhibit a cortisol response to the stressor. In contrast, in women with lower CES-D scores, cortisol levels significantly increased in response to the stressor. Conclusion: Consistent with research on individuals with major depressive disorder, results of this study demonstrate that women with very high levels of depressive symptoms exhibit blunted cortisol responses to a naturalistic psychological stressor. Results also contribute to previous research by generalizing findings to a high risk, underserved population of women. HPA = hypothalamic-pituitary-adrenal; MDD = major depressive disorder; SES = socioeconomic status; CES-D = Center for Epidemiological Studies—Depression Scale; PSS = Perceived Stress Scale.

Dysregulated diurnal cortisol pattern is associated with glucocorticoid resistance in women with major depressive disorder

Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis is believed to play a role in the pathophysiology of depression. To investigate mechanisms that may underlie this effect, we examined several indices of HPA axis function - specifically, diurnal cortisol slope, cortisol awakening response, and suppression of cortisol release following dexamethasone administration - in 26 pre-menopausal depressed women and 23 never depressed women who were matched for age and body mass index. Salivary cortisol samples were collected at waking, 30 min after waking, and at bedtime over three consecutive days. On the third day, immediately after the bedtime sample, participants ingested a 0.5mg dexamethasone tablet; they then collected cortisol samples at waking and 30 min after waking the following morning. As predicted, depressed women exhibited flatter diurnal cortisol rhythms and more impaired suppression of cortisol following dexamethasone administration than non-depressed women over the three sampling days. In addition, flatter diurnal cortisol slopes were associated with reduced cortisol response to dexamethasone treatment, both for all women and for depressed women when considered separately. Finally, greater self-reported depression severity was associated with flatter diurnal cortisol slopes and with less dexamethasone-related cortisol suppression for depressed women. Depression in women thus appears to be characterized by altered HPA axis functioning, as indexed by flatter diurnal cortisol slopes and an associated impaired sensitivity of cortisol to dexamethasone. Given that altered HPA axis functioning has been implicated in several somatic conditions, the present findings may be relevant for understanding the pathophysiology of both depression and depression-related physical disease.

Salivary cortisol levels in children of low-income women with high depressive symptomatology.

Children (N = 324 boys, 315 girls) between the ages of 2.5 and 6 (mean age = 3.63) were identified in a house to house survey in low-income areas (income <20th percentile nationally) of urban Mexico. The Center for Epidemiologic Studies-Depression Scale was administered to mothers of all children. Salivary cortisol samples were taken in children as a measure of hypothalamic-pituitary-adrenocortical (HPA) system activity at time of arrival (baseline, Time 0), 25 min after arrival (Time 1), and 50 min after arrival (Time 2). Between Time 0 and Time 1, children were administered several cognitive tests. Results of hierarchical linear modeling analyses revealed that higher levels of maternal depressive symptoms were associated with lower baseline cortisol levels in their children (p < .05), while controlling for age, gender, and time since awakening. Higher levels of maternal depressive symptoms were associated with less of an increase in salivary cortisol to the arrival of the experimenters and subsequent cognitive testing (p < .05). All results were moderated by gender, with enhanced cortisol response in girls and no response in boys. These results suggest that among very low-income families, high maternal depressive symptoms are associated with hypoactivity of the HPA system in children, particularly boys.

A preliminary report on a skills-based telephone-administered peer support programme for patients with multiple sclerosis.

Objective: Peer-support interventions have shown no statistically significant or clinically meaningful effect on quality of life (QOL) or depressive symptoms for multiple sclerosis (MS) patients. Peer-support interventions for MS generally provide support but no skills training. The aim of this study was to evaluate a brief telephone-administered skills-training model of peer-support for patients with MS. Methods: Sixteen patients with MS showing signs of moderate distress received eight sessions of telephone-administered peer support (TAPS). TAPS is a manualized programme administered by peer-support counsellors diagnosed with MS. Using a workbook, peer-support counsellors teach skills to manage distress and MS symptoms. Subjective depression was assessed using the Center for Epidemiological Studies Depression Scale while objective depression was rated using the Hamilton Rating Scale for Depression. QOL was measured preand post-treatment using the SF-36. Results: The participants showed significant improvements on both the CESD (p=0.04) and the HRSD (p=0.01). Overall QOL improved significantly (p=0.045), however this was not reflected in either the Physical Health composite score or the Mental Health Composite Scale (p-0.17). Conclusions: These findings suggest that TAPS may prove to be an efficacious peer-support model for patients with MS.

Adverse childhood experiences and leukocyte telomere maintenance in depressed and healthy adults

BACKGROUND Adverse childhood experiences (ACEs) are associated with poor physical and mental health outcomes in adulthood. Adverse childhood experiences are also associated with shortened leukocyte telomere length (LTL) in adults, suggesting accelerated cell aging. No studies have yet assessed the relationship of ACEs to LTL in individuals with major depressive disorder (MDD), despite the high incidence of antecedent ACEs in individuals with MDD. Further, no studies in any population have assessed the relationship of ACEs to the activity of telomerase, the major enzyme responsible for maintaining LTL, or the relationship between telomerase and LTL in individuals with ACEs. METHODS Twenty healthy, unmedicated adults with MDD and 20 healthy age-, sex- and ethnicity-matched controls had ACEs assessed and had blood drawn for LTL and peripheral blood mononuclear cell (PBMC) resting telomerase activity. RESULTS In healthy controls, greater ACE exposure was associated with shorter LTL (p<.05) but was unassociated with telomerase activity. In MDD, however, the opposite pattern was seen: greater ACE exposure was unrelated to LTL but was associated with increased telomerase activity (p<.05) and with a higher telomerase:LTL ratio (p=.022). LIMITATIONS Study limitations include the small sample size, a single timepoint assessment of telomerase activity, and the use of retrospective self-report to assess ACEs. CONCLUSIONS These results replicate prior findings of shortened LTL in healthy adults with histories of multiple ACEs. However, in MDD, this relationship was substantially altered, raising the possibility that activation of telomerase in ACE-exposed individuals with MDD could represent a compensatory response to endangered telomeres.