The role of explicit and implicit self-esteem in the relationship between childhood trauma and adult depression and anxiety.

BACKGROUND: Self-esteem is an important psychological concept that can be measured explicitly (reflective processing) and implicitly (associative processing). The current study examined 1) the association between childhood trauma (CT) and both explicit and implicit self-esteem, and 2) whether self-esteem mediated the association between CT and depression/anxiety. METHODS: In 1479 adult participants of the Netherlands Study of Depression and Anxiety, CT was assessed with a semi-structured interview, depression/anxiety symptoms with self-report questionnaires and explicit and implicit self-esteem with the Rosenberg Self-Esteem Scale and Implicit Association Test, respectively. ANOVAs and regression analyses determined the association between CT (no/mild/severe CT), its subtypes (abuse/neglect) and self-esteem. Finally, we examined whether self-esteem mediated the relationship between CT and depression/anxiety. RESULTS: Participants with CT reported lower explicit (but not lower implicit) self-esteem compared to those without CT (p < .001, partial η2 = 0.06). All CT types were associated with lower explicit self-esteem (p = .05 for sexual abuse, p < .001 for other CT types), while only emotional neglect significantly associated with lower implicit self-esteem after adjusting for sociodemographic characteristics (p = .03). Explicit self-esteem mediated the relationship between CT and depression/anxiety symptoms (proportion mediated = 48-77 %). LIMITATIONS: The cross-sectional design precludes from drawing firm conclusions about the direction of the proposed relationships. CONCLUSIONS: Our results suggested that the relationship between CT and depression/anxiety symptoms can at least partly be explained by explicit self-esteem. This is of clinical relevance as it points to explicit self-esteem as a potential relevant treatment target for people with CT.

Antidepressants or running therapy: Comparing effects on mental and physical health in patients with depression and anxiety disorders.

BACKGROUND: Antidepressant medication and running therapy are both effective treatments for patients with depressive and anxiety disorders. However, they may work through different pathophysiological mechanisms and could differ in their impact on physical health. This study examined effects of antidepressants versus running therapy on both mental and physical health. METHODS: According to a partially randomized patient preference design, 141 patients with depression and/or anxiety disorder were randomized or offered preferred 16-week treatment: antidepressant medication (escitalopram or sertraline) or group-based running therapy ≥2 per week. Baseline (T0) and post-treatment assessment at week 16 (T16) included mental (diagnosis status and symptom severity) and physical health indicators (metabolic and immune indicators, heart rate (variability), weight, lung function, hand grip strength, fitness). RESULTS: Of the 141 participants (mean age 38.2 years; 58.2 % female), 45 participants received antidepressant medication and 96 underwent running therapy. Intention-to-treat analyses showed that remission rates at T16 were comparable (antidepressants: 44.8 %; running: 43.3 %; p = .881). However, the groups differed significantly on various changes in physical health: weight (d = 0.57; p = .001), waist circumference (d = 0.44; p = .011), systolic (d = 0.45; p = .011) and diastolic (d = 0.53; p = .002) blood pressure, heart rate (d = 0.36; p = .033) and heart rate variability (d = 0.48; p = .006). LIMITATIONS: A minority of the participants was willing to be randomized; the running therapy was larger due to greater preference for this intervention. CONCLUSIONS: While the interventions had comparable effects on mental health, running therapy outperformed antidepressants on physical health, due to both larger improvements in the running therapy group as well as larger deterioration in the antidepressant group. TRIAL REGISTRATION: Trialregister.nl Number of identification: NTR3460.

Design and rationale of the REStoring mood after early life trauma with psychotherapy (RESET-psychotherapy) study: a multicenter randomized controlled trial on the efficacy of adjunctive trauma-focused therapy (TFT) versus treatment as usual (TAU) for adult patients with major depressive disorder (MDD) and childhood trauma.

BACKGROUND: Major depressive disorder (MDD) is a common, recurrent mental disorder and a leading cause of disability worldwide. A large part of adult MDD patients report a history of childhood trauma (CT). Patients with MDD and CT are assumed to represent a clinically and neurobiologically distinct MDD subtype with an earlier onset, unfavorable disease course, stress systems' dysregulations and brain alterations. Currently, there is no evidence-based treatment strategy for MDD that specifically targets CT. Given the central role of trauma in MDD patients with CT, trauma-focused therapy (TFT), adjunctive to treatment as usual (TAU), may be efficacious to alleviate depressive symptoms in this patient population. METHODS: The RESET-psychotherapy study is a 12-week, single-blind, randomized controlled trial testing the efficacy of TFT in 158 adults with moderate to severe MDD, as a 'stand-alone' depression diagnosis or superimposed on a persistent depressive disorder (PDD), and CT. TFT (6-10 sessions of Eye Movement Desensitization and Reprocessing and/or imagery rescripting) + TAU is compared to TAU only. Assessments, including a wide range of psychological/psychiatric and biological characteristics, take place before randomization (T0), during treatment (T1), at post-treatment (T2) and at 6-month follow-up (T3). Pre-post treatment stress-related biomarkers in hair (cortisol) and blood (epigenetics and inflammation) will be assessed to better understand working mechanisms of TFT. A subgroup of 60 participants will undergo structural and functional Magnetic Resonance Imaging (MRI) assessments to determine pre-post treatment brain activity. The primary outcome is self-reported depression symptom severity at post-treatment, measured with the 30-item Inventory of Depressive Symptomatology - Self Report (IDS-SR). DISCUSSION: If adjunctive TFT efficaciously alleviates depressive symptoms in MDD patients with CT, this novel treatment strategy could pave the way for a more personalized and targeted MDD treatment. TRIAL REGISTRATION: ClinicalTrials.gov, registered at 08-12-2021, number of identification: NCT05149352.

An integrative study of five biological clocks in somatic and mental health.

Biological clocks have been developed at different molecular levels and were found to be more advanced in the presence of somatic illness and mental disorders. However, it is unclear whether different biological clocks reflect similar aging processes and determinants. In ~3000 subjects, we examined whether five biological clocks (telomere length, epigenetic, transcriptomic, proteomic, and metabolomic clocks) were interrelated and associated to somatic and mental health determinants. Correlations between biological aging indicators were small (all r < 0.2), indicating little overlap. The most consistent associations of advanced biological aging were found for male sex, higher body mass index (BMI), metabolic syndrome, smoking, and depression. As compared to the individual clocks, a composite index of all five clocks showed most pronounced associations with health determinants. The large effect sizes of the composite index and the low correlation between biological aging indicators suggest that one's biological age is best reflected by combining aging measures from multiple cellular levels.

A DNA methylation clock associated with age-related illnesses and mortality is accelerated in men with combat PTSD.

DNA methylation patterns at specific cytosine-phosphate-guanine (CpG) sites predictably change with age and can be used to derive "epigenetic age", an indicator of biological age, as opposed to merely chronological age. A relatively new estimator, called "DNAm GrimAge", is notable for its superior predictive ability in older populations regarding numerous age-related metrics like time-to-death, time-to-coronary heart disease, and time-to-cancer. PTSD is associated with premature mortality and frequently has comorbid physical illnesses suggestive of accelerated biological aging. This is the first study to assess DNAm GrimAge in PTSD patients. We investigated the acceleration of GrimAge relative to chronological age, denoted "AgeAccelGrim" in combat trauma-exposed male veterans with and without PTSD using cross-sectional and longitudinal data from two independent well-characterized veteran cohorts. In both cohorts, AgeAccelGrim was significantly higher in the PTSD group compared to the control group (N = 162, 1.26 vs -0.57, p = 0.001 and N = 53, 0.93 vs -1.60 Years, p = 0.008), suggesting accelerated biological aging in both cohorts with PTSD. In 3-year follow-up study of individuals initially diagnosed with PTSD (N = 26), changes in PTSD symptom severity were correlated with AgeAccelGrim changes (r = 0.39, p = 0.049). In addition, the loss of CD28 cell surface markers on CD8 + T cells, an indicator of T-cell senescence/exhaustion that is associated with biological aging, was positively correlated with AgeAccelGrim, suggesting an immunological contribution to the accelerated biological aging. Overall, our findings delineate cellular correlates of biological aging in combat-related PTSD, which may help explain the increased medical morbidity and mortality seen in this disease.

Getting under the skin: Does biology help predict chronicity of depression?

BACKGROUND: Depressed patients are at risk of an unfavourable course including chronic episodes. Various psychiatric characteristics have shown to be predictive of depression's course trajectory, but whether indicators of somatic health further contribute to course prediction remains unclear. This study aimed to identify somatic health indicators (i.e. biomarkers, health status and lifestyle) that predict 2-year chronicity above and beyond an extensive list of sociodemographic and psychiatric characteristics. METHODS: Data are from patients with current depression at baseline (n = 903) and available 2-year follow-up participating in a longitudinal cohort study. Baseline demographic, psychiatric and somatic health indicators were associated with 2-year course trajectories, classified as non-chronic versus chronic RESULTS: At 2-year follow up, 40% of the patients showed a chronic course. Of the twenty tested somatic health indicators, short sleep and high interleukin-6 improved the regression model predicting chronicity with a significant, but modest, effect (ROC = 0.78; p = 0.03). LIMITATIONS: Due to the observational design we did not have the ability to reliably consider the impact of psychiatric treatment. More elaborate information on somatic health such as dietary patterns would strengthen the study. CONCLUSIONS: This study showed that short sleep duration and high interleukin-6 contributed significantly to the regression model as independent predictors, suggestive of clinical implications for patients with sleep disturbances and elevated inflammation levels. Other somatic health indicators did not add to the model. Overall, somatic health indicators showed modest additive value for predicting chronic course above and beyond sociodemographic and psychiatric indicators.

Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length.

Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1, PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.

Delayed sleep-onset and biological age: late sleep-onset is associated with shorter telomere length.

STUDY OBJECTIVES: We evaluated the relationship between leukocyte telomere length (LTL) and sleep duration, insomnia symptoms, and circadian rhythm, to test whether sleep and chronobiological dysregulations are associated with cellular aging. METHODS: Data from the Netherlands Study of Depression and Anxiety (N = 2,936) were used at two waves 6 years apart, to measure LTL. Telomeres shorten during the life span and are important biomarkers for cellular aging. LTL was assessed by qualitative polymerase chain reaction and converted into base pair number. Sleep parameters were: sleep duration and insomnia symptoms from the Insomnia Rating Scale. Circadian rhythm variables were: indication of Delayed Sleep Phase Syndrome (DSPS), mid-sleep corrected for sleep debt on free days (MSFsc), sleep-onset time, and self-reported chronotype, from the Munich Chronotype Questionnaire. Generalized estimating equations analyzed the associations between LTL, sleep, and chronobiological factors, adjusted for baseline age, sex, North European ancestry, and additionally for current smoking, depression severity, obesity, and childhood trauma. RESULTS: Indicators of delayed circadian rhythm showed a strong and consistent effect on LTL, after adjustment for sociodemographic and health indicators. Late MSFsc (B = -49.9, p = .004), late sleep-onset time (B = -32.4, p = .001), indication of DSPS (B = -73.8, p = .036), and moderately late chronotype in adulthood (B = -71.6, p = .003) were associated with significantly shorter LTL across both waves; whereas sleep duration and insomnia symptoms were not. Extremely early chronotype showed significantly less LTL shortening than intermediate chronotype (B = 161.40, p = .037). No predictors showed accelerated LTL attrition over 6 years. CONCLUSIONS: Individuals with delayed circadian rhythm have significantly shorter LTL, but not faster LTL attrition rates.

Accelerating research on biological aging and mental health: Current challenges and future directions.

Aging is associated with complex biological changes that can be accelerated, slowed, or even temporarily reversed by biological and non-biological factors. This article focuses on the link between biological aging, psychological stressors, and mental illness. Rather than comprehensively reviewing this rapidly expanding field, we highlight challenges in this area of research and propose potential strategies to accelerate progress in this field. This effort requires the interaction of scientists across disciplines - including biology, psychiatry, psychology, and epidemiology; and across levels of analysis that emphasize different outcome measures - functional capacity, physiological, cellular, and molecular. Dialogues across disciplines and levels of analysis naturally lead to new opportunities for discovery but also to stimulating challenges. Some important challenges consist of 1) establishing the best objective and predictive biological age indicators or combinations of indicators, 2) identifying the basis for inter-individual differences in the rate of biological aging, and 3) examining to what extent interventions can delay, halt or temporarily reverse aging trajectories. Discovering how psychological states influence biological aging, and vice versa, has the potential to create novel and exciting opportunities for healthcare and possibly yield insights into the fundamental mechanisms that drive human aging.

The impact of depression and anxiety treatment on biological aging and metabolic stress: study protocol of the MOod treatment with antidepressants or running (MOTAR) study.

BACKGROUND: Depressive and anxiety disorders have shown to be associated to premature or advanced biological aging and consequently to adversely impact somatic health. Treatments with antidepressant medication or running therapy are both found to be effective for many but not all patients with mood and anxiety disorders. These interventions may, however, work through different pathophysiological mechanisms and could differ in their impact on biological aging and somatic health. This study protocol describes the design of an unique intervention study that examines whether both treatments are similarly effective in reducing or reversing biological aging (primary outcome), psychiatric status, metabolic stress and neurobiological indicators (secondary outcomes). METHODS: The MOod Treatment with Antidepressants or Running (MOTAR) study will recruit a total of 160 patients with a current major depressive and/or anxiety disorder in a mental health care setting. Patients will receive a 16-week treatment with either antidepressant medication or running therapy (3 times/week). Patients will undergo the treatment of their preference and a subsample will be randomized (1:1) to overcome preference bias. An additional no-disease-no-treatment group of 60 healthy controls without lifetime psychopathology, will be included as comparison group for primary and secondary outcomes at baseline. Assessments are done at week 0 for patients and controls, and at week 16 and week 52 for patients only, including written questionnaires, a psychiatric and medical examination, blood, urine and saliva collection and a cycle ergometer test, to gather information about biological aging (telomere length and telomerase activity), mental health (depression and anxiety disorder characteristics), general fitness, metabolic stress-related biomarkers (inflammation, metabolic syndrome, cortisol) and genetic determinants. In addition, neurobiological alterations in brain processes will be assessed using structural and functional Magnetic Resonance Imaging (MRI) in a subsample of at least 25 patients per treatment arm and in all controls. DISCUSSION: This intervention study aims to provide a better understanding of the impact of antidepressant medication and running therapy on biological aging, metabolic stress and neurobiological indicators in patients with depressive and anxiety disorders in order to guide a more personalized medicine treatment. TRIAL REGISTRATION: Trialregister.nl Number of identification: NTR3460, May 2012.

Unraveling the association between depression and telomere length using genomics.

OBJECTIVE: While there is robust evidence for a cross-sectional association between depression and shorter telomere length, suggestive of advanced biological aging, the nature of this association remains unclear. Here, we tested whether both traits share a common genetic liability with novel methods using genomics. METHODS: Data were from 2032 participants of the Netherlands Study of Depression and Anxiety (NESDA) with genome-wide genetic information and multiple waves of data on DSM-IV lifetime depression diagnosis, depression severity, neuroticism and telomere length. Polygenic risk scores (PRS) for both traits were built using summary results from the largest genome-wide association studies (GWAS) on depression (59,851 cases and 113,154 controls) and telomere length (37,684 samples). Additionally, a PRS for neuroticism was built (337,000 samples). Genetic overlap between the traits was tested using PRS for same- and cross-trait associations. Furthermore, GWAS summary statistics were used to estimate the genome-wide genetic correlation between traits. RESULTS: In NESDA data, the PRS for depression was associated with lifetime depression (odds ratio = 1.36; p = 6.49e-7) and depression severity level (ß = 0.13; p = 1.24e-8), but not with telomere length. Similar results were found for the PRS for neuroticism. Conversely, the PRS for telomere length was associated with telomere length (ß = 0.07; p = 8.42e-4) and 6-year telomere length attrition rate (ß = 0.04; p = 2.15e-2), but not with depression variables. In summary-level analyses, the genetic correlation between the traits was small and not significant (rg=-0.08; p = .300). CONCLUSION: The use of genetic methods in this paper indicated that the established phenotypic association between telomere length and depression is unlikely due to shared underlying genetic vulnerability. Our findings suggest that short telomeres in depressed patients may simply represent a generic marker of disease or may originate from non-genetic environmental factors.

Epigenetic Age in Male Combat-Exposed War Veterans: Associations with Posttraumatic Stress Disorder Status.

DNA methylation patterns change with age and can be used to derive an estimate of "epigenetic age," an indicator of biological age. Several studies have shown associations of posttraumatic stress disorder (PTSD) with worse somatic health and early mortality, raising the possibility of accelerated biological aging. This study examined associations between estimated epigenetic age and various variables in 160 male combat-exposed war veterans with (n = 79) and without PTSD (n = 81). DNA methylation was assessed in leukocyte genomic DNA using the Illumina 450K DNA methylation arrays. Epigenetic age was estimated using Horvath's epigenetic clock algorithm and Δage (epigenetic age-chronological age) was calculated. In veterans with PTSD (Δage = 3.2), Δage was on average lower compared to those without PTSD (Δage = 5.0; p = 0.02; Cohen's d = 0.42). This between-group difference was not explained by race/ethnicity, lifestyle factors or childhood trauma. Antidepressant use, however, explained part of the association. In the PTSD positive group, telomerase activity was negatively related to Δage (ß = -0.35; p = 0.007). In conclusion, veterans with PTSD had significantly lower epigenetic age profiles than those without PTSD. Further, current antidepressant use and higher telomerase activity were related to relatively less epigenetic aging in veterans with PTSD, speculative of a mechanistic pathway that might attenuate biological aging-related processes in the context of PTSD.

[Complete recovery from depression is the exception rather than the rule: prognosis of depression beyond diagnostic boundaries]. / Volledig herstel van depressie is eerder uitzondering dan regel.

OBJECTIVE: To investigate whether the course of depression changes when (a) follow-up duration is longer and (b) in addition to depression other mood and anxiety disorders are considered as outcome measures. DESIGN: Longitudinal observational cohort study. METHOD: We selected patients from the Netherlands Study of Depression and Anxiety (NESDA) who had active depression at baseline (n=903) and for whom data from the 2, 4 and/or 6 year measurements were available. Using DSM-IV diagnoses and data from the 'Life chart interview', we divided participants in one of the following four course categories: (1) recovered (no diagnosis at 2-year measurement or later), (2) recurring without chronic episodes, (3) recurring with chronic episodes or (4) consistent chronic depression since baseline. We looked at the distribution of patients over the course categories from a short, diagnostically narrow perspective (over 2 years, only looking at depression) to a long, diagnostically broad perspective (over 6 years, looking at depression, dysthymia, hypomania, mania and anxiety). RESULTS: In the short, diagnostically narrow perspective, 58% of participants had recovered and 21% met the criteria for a chronic episode. In the long, diagnostically broad perspective however, only 17% had recovered while 55% had chronic episodes. CONCLUSION: Monitoring patients with depression over a longer period and with broader outcome measures (depression and related psychiatric disorders belonging to the mood disorder spectrum) shows that the course of depression is unfavourable and chronic for the majority. Conceptualising depression as a defined episodic disorder underestimates the severity of the prognosis for many patients and, as a consequence, the type of care indicated.

Associations Between Cellular Aging Markers and Metabolic Syndrome: Findings From the CARDIA Study.

Background: Metabolic syndrome (MetS) is thought to promote biological aging, which might lead to cardiovascular and aging-related complications. This large-scale study investigated longitudinal relationships between MetS, its components, and cellular aging markers: leukocyte mitochondrial DNA copy number (mtDNAcn) and telomere length (TL). Methods: We included 989 participants from the Coronary Artery Risk Development in Young Adults Study. MtDNAcn [study year (Y) 15, Y25] and TL (Y15, Y20, Y25) were measured via quantitative polymerase chain reaction. MetS components [waist circumference, triglycerides, high-density lipoprotein (HDL) cholesterol, systolic blood pressure, and fasting glucose] were determined (Y15, Y20, Y25). Generalized estimated equation and linear regression models, adjusting for sociodemographics and lifestyle, were used to examine associations between MetS and cellular aging at all time points, baseline MetS and 10-year changes in cellular aging, baseline cellular aging and 10-year changes in MetS, and 10-year changes in MetS and 10-year changes in cellular aging. Results: MtDNAcn and TL were negatively associated with age [mtDNAcn unstandardized ß (B) = -4.76; P < 0.001; TL B = -51.53; P < 0.001] and positively correlated (r = 0.152; P < 0.001). High triglycerides were associated with low mtDNAcn and low HDL cholesterol with short TL. Greater Y15 waist circumference (B = -7.23; P = 0.05), glucose (B = -13.29; P = 0.001), number of metabolic dysregulations (B = -7.72; P = 0.02), and MetS (B = -28.86; P = 0.006) predicted greater 10-year decrease in mtDNAcn but not TL. The 10-year increase in waist circumference was associated with 10-year telomere attrition (B = -27.61; P = 0.04). Conclusions: Our longitudinal data showed that some metabolic dysregulations were associated with mtDNAcn and TL decreases, possibly contributing to accelerated cellular aging but not the converse.

Reconsidering the prognosis of major depressive disorder across diagnostic boundaries: full recovery is the exception rather than the rule.

BACKGROUND: Major depressive disorder (MDD) is often handled as an episodic and isolated disorder, resulting in an optimistic view about its prognosis. Herein, we test the idea that the prognosis of MDD changes if we vary the perspective in terms of (1) a longer time frame and (2) a broader diagnostic conceptualisation including dysthymia, (hypo)mania and anxiety disorders as relevant outcomes. METHODS: Patients with current MDD at baseline (n = 903) and available 2-, 4-, and/or 6-year follow-up assessments were selected from the Netherlands Study of Depression and Anxiety, a psychiatric cohort study. Combining psychiatric DSM-IV-based diagnoses and life-chart data, patient course trajectories were classified as (1) recovered (no diagnoses at 2-year follow-up or thereafter), (2) recurrent without chronic episodes, (3) recurrent with chronic episodes or (4) consistently chronic since baseline. A chronic episode was defined as having a current diagnosis at the follow-up assessment and consistent symptoms over 2 years. Proportions of course trajectories were provided moving from a short, narrow perspective (2-year follow-up, considering only MDD diagnosis) to a long, broad perspective (6-year follow-up, including MDD, dysthymia, (hypo)mania and anxiety diagnoses). RESULTS: With the short, narrow perspective, the recovery rate was 58% and 21% had a chronic episode. However, in the long, broad perspective the recovery rate was reduced to 17%, while 55% of the patients experienced chronic episodes. CONCLUSIONS: Results from a long and rigorous follow-up in a large cohort suggests that most MDD patients have an unfavourable prognosis. Longer follow-up and broader diagnostic conceptualisation show that the majority of patients have a disabling and chronic disorder. Conceptualising and handling MDD as a narrowly defined and episodic disorder may underestimate the prognosis of the majority of depressed patients and, consequently, the type of care that is appropriate.

Telomere length is inversely correlated with urinary stress hormone levels in healthy controls but not in un-medicated depressed individuals-preliminary findings.

OBJECTIVE: Leukocyte telomere length (LTL) is a biomarker of cellular aging affected by chronic stress. The relationship of LTL to the stress hormones, cortisol and catecholamines, is unclear, as are possible differences between healthy controls (HC) and individuals with Major Depressive Disorder (MDD). This small pilot study is the first to examine the relationship between cortisol, catecholamines and LTL specifically in un-medicated MDD in comparison with HC. METHODS: Participants included 16 un-medicated MDD subjects and 15 HC for assay of LTL, 12-hour overnight urinary free cortisol and catecholamine levels. RESULTS: LTL, cortisol and catecholamine levels did not significantly differ between groups. In HC, a hierarchical regression analysis indicated that higher levels of cortisol were correlated with shorter LTL (p=0.003) above and beyond age and sex. Higher catecholamine levels were nearly-significant with shorter LTL (p=0.055). Neither hormone was correlated with shorter LTL in MDD (p's>0.28). To assess a possible cumulative effect of stress hormone activation, a summary score was calculated for each subject based on the number of stress hormone levels above the median for that group (HC or MDD). A significant inverse graded relationship was observed between LTL and the number of activated systems in HC (p=0.001), but not in MDD (p=0.96). CONCLUSION: This pilot study provides preliminary evidence that stress hormone levels, especially cortisol, are inversely related to LTL in HC, but not in un-medicated MDD. Clarification of these relationships in larger samples could aid in understanding differential mechanisms underlying stress-related cellular aging in healthy and depressed populations.

Oxidative stress, inflammation and treatment response in major depression.

OBJECTIVE: Increased inflammation and oxidative stress have been shown in Major Depressive Disorder (MDD), although there is significant heterogeneity across studies. Whether markers of inflammation and oxidative stress are associated with antidepressant treatment response in MDD is currently unclear. The goals of the present study are to investigate markers of inflammation and oxidative stress in unmedicated MDD subjects and controls and test the relationship between these markers and antidepressant response in MDD subjects. METHODS: Interleukin (IL)-6, tumor necrosis factor (TNF)-α, C-reactive protein, F2-isoprostanes, 8-OH 2-deoxyguanosine (8-OHdG), glutathione peroxidase, glutathione, and vitamin C were quantified in blood samples from 50 unmedicated MDD subjects and 55 healthy controls. Depression symptom severity was rated with the 17-item Hamilton Depression Rating Scale (HDRS). All subjects were somatically healthy and free from medications that could interfere with inflammation and oxidative stress markers. A subgroup of 22 MDD subjects underwent open-label selective serotonin reuptake inhibitor (SSRI) antidepressant treatment for eight weeks, after which blood sampling and the HDRS were repeated. Antidepressant treatment "response" was defined as ≥50% decrease in HDRS ratings over 8 weeks of treatment. RESULTS: After controlling for the effects of age, sex, body mass index and smoking, MDD subjects had significantly higher levels of IL-6 (p<0.001), TNF-α (p<0.001), 8-OHdG (p=0.018), and F2-isoprostanes (p=0.012). Compared to Responders, Non-responders to SSRI antidepressant treatment had higher levels of F2-isoprostanes at baseline (p=0.006), and after eight weeks of treatment (p=0.031). Non-responders showed a significant increase in 8-OHdG over the course of treatment (p=0.021), whereas Responders showed a significant decrease in IL-6 over the course of treatment (p=0.019). CONCLUSION: Our results are in line with previous reports of increased levels of markers of inflammation and oxidative stress in MDD. Moreover, poorer antidepressant treatment response was related to higher baseline levels of the major oxidative stress marker, F2-isoprostanes, in vivo. Further, antidepressant response was associated with changes in oxidative (8-OHdG) and inflammatory (IL-6) markers.