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Background: Previous mobile health (mHealth) studies have revealed significant links between depression and circadian rhythm features measured via wearables. However, the comprehensive impact of seasonal variations was not fully considered in these studies, potentially biasing interpretations in real-world settings., Objective: This study aims to explore the associations between depression severity and wearable-measured circadian rhythms while accounting for seasonal impacts., Methods: Data were sourced from a large longitudinal mHealth study, wherein participants' depression severity was assessed biweekly using the 8-item Patient Health Questionnaire (PHQ-8), and participants' behaviors, including sleep, step count, and heart rate (HR), were tracked via Fitbit devices for up to 2 years. We extracted 12 circadian rhythm features from the 14-day Fitbit data preceding each PHQ-8 assessment, including cosinor variables, such as HR peak timing (HR acrophase), and nonparametric features, such as the onset of the most active continuous 10-hour period (M10 onset). To investigate the association between depression severity and circadian rhythms while also assessing the seasonal impacts, we used three nested linear mixed-effects models for each circadian rhythm feature: (1) incorporating the PHQ-8 score as an independent variable, (2) adding seasonality, and (3) adding an interaction term between season and the PHQ-8 score., Results: Analyzing 10,018 PHQ-8 records alongside Fitbit data from 543 participants (n=414, 76.2% female; median age 48, IQR 32-58 years), we found that after adjusting for seasonal effects, higher PHQ-8 scores were associated with reduced daily steps (β=-93.61, P<.001), increased sleep variability (β=0.96, P<.001), and delayed circadian rhythms (ie, sleep onset: β=0.55, P=.001; sleep offset: β=1.12, P<.001; M10 onset: β=0.73, P=.003; HR acrophase: β=0.71, P=.001). Notably, the negative association with daily steps was more pronounced in spring (β of PHQ-8 × spring = -31.51, P=.002) and summer (β of PHQ-8 × summer = -42.61, P<.001) compared with winter. Additionally, the significant correlation with delayed M10 onset was observed solely in summer (β of PHQ-8 × summer = 1.06, P=.008). Moreover, compared with winter, participants experienced a shorter sleep duration by 16.6 minutes, an increase in daily steps by 394.5, a delay in M10 onset by 20.5 minutes, and a delay in HR peak time by 67.9 minutes during summer., Conclusions: Our findings highlight significant seasonal influences on human circadian rhythms and their associations with depression, underscoring the importance of considering seasonal variations in mHealth research for real-world applications. This study also indicates the potential of wearable-measured circadian rhythms as digital biomarkers for depression., (©Yuezhou Zhang, Amos A Folarin, Shaoxiong Sun, Nicholas Cummins, Yatharth Ranjan, Zulqarnain Rashid, Callum Stewart, Pauline Conde, Heet Sankesara, Petroula Laiou, Faith Matcham, Katie M White, Carolin Oetzmann, Femke Lamers, Sara Siddi, Sara Simblett, Srinivasan Vairavan, Inez Myin-Germeys, David C Mohr, Til Wykes, Josep Maria Haro, Peter Annas, Brenda WJH Penninx, Vaibhav A Narayan, Matthew Hotopf, Richard JB Dobson, RADAR-CNS consortium. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 28.06.2024.)

Background: Adiposity has been shown to be linked with atypical energy-related symptoms (AES) of depression. We used genomics to separate the effect of adiposity from that of metabolic dysregulations to examine whether the link between obesity and AES is dependent on the presence of metabolic dysregulations., Method: Data were from NEO (n = 5734 individuals) and NESDA (n = 2238 individuals) cohorts, in which the Inventory of Depressive Symptomatology (IDS-SR30) was assessed. AES profile was based on four symptoms: increased appetite, increased weight, low energy level, and leaden paralysis. We estimated associations between AES and two genetic risk scores (GRS) indexing increasing total body fat with (metabolically unhealthy adiposity, GRS-MUA) and without (metabolically healthy adiposity, GRS-MHA) metabolic dysregulations., Results: We validated that both GRS-MUA and GRS-MHA were associated with higher total body fat in NEO study, but divergently associated with biomarkers of metabolic health (e.g., fasting glucose and HDL-cholesterol) in both cohorts. In the pooled results, per standard deviation, GRS-MUA was specifically associated with a higher AES score (β = 0.03, 95%CI: 0.01; 0.05), while there was no association between GRS-MHA and AES (β = -0.01, 95%CI: -0.03; 0.01)., Conclusion: These results suggest that the established link between adiposity and AES profile emerges in the presence of metabolic dysregulations, which may represent the connecting substrate between the two conditions., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Brenda Penninx reports grants from Janssen Research and Development, LLC, and grants from Boehringer Ingelheim, outside the submitted work. All other co-authors declared no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Worldwide, oral contraceptive (OC) use is a very common form of birth control, although it has been associated with symptoms of depression and insomnia. Insomnia is a risk factor for major depressive disorder (MDD) but may also be a symptom of the disorder. Despite the large number of women who use OC, it is yet unknown whether women with previous or current diagnosis of depression are more likely to experience more severe depressive and insomnia symptoms during concurrent OC use than women without diagnosis of depression., Aim: This study examined associations between OC use and concurrent symptoms of depression (including atypical depression) and insomnia as well as between OC and prevalences of concurrent dysthymia and MDD. Participants were adult women with and without a history of MDD or dysthymia. We hypothesized that OC use is associated with concurrent increased severity of depressive symptoms and insomnia symptoms, as well as with an increased prevalence of concurrent diagnoses of dysthymia and MDD. We also hypothesized that a history of MDD or dysthymia moderates the relationship between OC use and depressive and insomnia symptoms., Methods: Measurements from premenopausal adult women from the Netherlands Study of Depression and Anxiety (NESDA) were grouped, based on whether participants were using OC or naturally cycling (NC). OC use, timing and regularity of the menstrual cycle were assessed with a structured interview, self-reported symptoms of depression (including atypical depression), insomnia with validated questionnaires, and MDD and dysthymia with structured diagnostic interviews., Results: We included a total of 1301 measurements in women who reported OC use and 1913 measurements in NC women (mean age 35.6, 49.8% and 28.9% of measurements in women with a previous depression or current depression, respectively). Linear mixed models showed that overall, OC use was neither associated with more severe depressive symptoms (including atypical depressive symptoms), nor with higher prevalence of diagnoses of MDD or dysthymia. However, by disentangling the amalgamated overall effect, within-person estimates indicated increased depressive symptoms and depressive disorder prevalence during OC use, whereas between-person estimated indicated lower depressive symptoms and prevalence of depressive disorders. OC use was consistently associated with more severe concurrent insomnia symptoms, in the overall estimates as well as in the within-person and between-person estimates. Presence of current or previous MDD or dysthymia did not moderate the associations between OC use and depressive or insomnia symptoms., Discussion: The study findings showed consistent associations between OC use and more severe insomnia symptoms, but no consistent associations between OC and depressive symptoms or diagnoses. Instead, post-hoc analyses showed that associations between OC and depression differed between within- and between person-estimates. This indicates that, although OC shows no associations on the overall level, some individuals might experience OC-associated mood symptoms. Our findings underscore the importance of accounting for individual differences in experiences during OC use. Furthermore, it raises new questions about mechanisms underlying associations between OC, depression and insomnia., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Clinical staging is a paradigm in which stages of disease progression are identified; these, in turn, have prognostic value. A staging model that enables the prediction of long-term course in anxiety disorders is currently unavailable but much needed as course trajectories are highly heterogenic. This study therefore tailored a heuristic staging model to anxiety disorders and assessed its validity., Methods: A clinical staging model was tailored to anxiety disorders, distinguishing nine stages of disease progression varying from subclinical stages (0, 1A, 1B) to clinical stages (2A-4B). At-risk subjects and subjects with anxiety disorders ( n  = 2352) from the longitudinal Netherlands Study of Depression and Anxiety were assigned to these nine stages. The model's validity was assessed by comparing baseline (construct validity) and 2-year, 4-year and 6-year follow-up (predictive validity) differences in anxiety severity measures across stages. Differences in depression severity and disability were assessed as secondary outcome measures., Results: Results showed that the anxiety disorder staging model has construct and predictive validity. At baseline, differences in anxiety severity, social avoidance behaviors, agoraphobic avoidance behaviors, worrying, depressive symptoms and levels of disability existed across all stages (all p -values < 0.001). Over time, these differences between stages remained present until the 6-year follow-up. Differences across stages followed a linear trend in all analyses: higher stages were characterized by the worst outcomes. Regarding the stages, subjects with psychiatric comorbidity (stages 2B, 3B, 4B) showed a deteriorated course compared with those without comorbidity (stages 2A, 3A, 4A)., Conclusion: A clinical staging tool would be useful in clinical practice to predict disease course in anxiety disorders.

Depression and obesity are common conditions with major public health implications that tend to co-occur within individuals. The relationship between these conditions is bidirectional: the presence of one increases the risk for developing the other. It has thus become crucial to gain a better understanding of the mechanisms responsible for the intertwined downward physiological spirals associated with both conditions. The present review focuses specifically on shared biological pathways that may mechanistically explain the depression-obesity link, including genetics, alterations in systems involved in homeostatic adjustments (HPA axis, immuno-inflammatory activation, neuroendocrine regulators of energy metabolism including leptin and insulin, and microbiome) and brain circuitries integrating homeostatic and mood regulatory responses. Furthermore, the review addresses interventional opportunities and questions to be answered by future research that will enable a comprehensive characterization and targeting of the biological links between depression and obesity.

Background: The genetics of depression has been explored in genome-wide association studies that focused on either major depressive disorder or depressive symptoms with mostly negative findings. A broad depression phenotype including both phenotypes has not been tested previously using a genome-wide association approach. We aimed to identify genetic polymorphisms significantly associated with a broad phenotype from depressive symptoms to major depressive disorder., Methods: We analyzed two prior studies of 70,017 participants of European ancestry from general and clinical populations in the discovery stage. We performed a replication meta-analysis of 28,328 participants. Single nucleotide polymorphism (SNP)-based heritability and genetic correlations were calculated using linkage disequilibrium score regression. Discovery and replication analyses were performed using a p-value-based meta-analysis. Lifetime major depressive disorder and depressive symptom scores were used as the outcome measures., Results: The SNP-based heritability of major depressive disorder was 0.21 (SE = 0.02), the SNP-based heritability of depressive symptoms was 0.04 (SE = 0.01), and their genetic correlation was 1.001 (SE = 0.2). We found one genome-wide significant locus related to the broad depression phenotype (rs9825823, chromosome 3: 61,082,153, p = 8.2 × 10 -9 ) located in an intron of the FHIT gene. We replicated this SNP in independent samples (p = .02) and the overall meta-analysis of the discovery and replication cohorts (1.0 × 10 -9 )., Conclusions: This large study identified a new locus for depression. Our results support a continuum between depressive symptoms and major depressive disorder. A phenotypically more inclusive approach may help to achieve the large sample sizes needed to detect susceptibility loci for depression., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background/objectives: The roles of vitamin B 12 and homocysteine concentration in depression are not clear. We investigated cross-sectional and prospective associations of serum vitamin B 12 and plasma homocysteine with depressive symptoms in Dutch older adults., Subjects/methods: In the Longitudinal Aging Study Amsterdam (LASA), blood was collected in 1995/1996 among 1352 men and women aged ⩾65 years. Depressive symptoms were assessed with the Center for Epidemiologic Studies Depression Scale (CES-D) six times from 1995/1996 to 2011/2012. Multiple linear regression and mixed models were used to assess whether vitamin B 12 and homocysteine were associated with severity at baseline and course of depressive symptoms over 16 years. Cox regression analyses were performed for the associations with incidence of depression (CES-D ⩾16 and/or antidepressant use). All analyses were adjusted for sociodemographic characteristics and lifestyle factors., Results: Vitamin B 12 was neither cross-sectionally (n=1205) nor prospectively (n=1012) associated with depressive symptoms (adjusted β for CES-D over time, lowest versus highest quartile: -0.04 (95% confidence interval (CI): -0.15-0.06)). We also found no association with incident depression (n=853), except for a higher risk of depression over time in younger participants (aged 64.8-73.4 years; continuous vitamin B12, adjusted hazard ratio per s.d.: 1.38 (95% CI: 1.10-1.72)). For homocysteine, no associations were found, except for a lower risk of depression in younger participants., Conclusions: Our study did not confirm earlier shown associations of serum vitamin B 12 and plasma homocysteine with severity and course of depressive symptoms and incidence of depression in older adults. Further research into the influence of homocysteine metabolism on mental health is needed.

Depression's burden of disease goes beyond functioning and quality of life and extends to somatic health. Results from longitudinal cohort studies converge in illustrating that major depressive disorder (MDD) subsequently increases the risk of cardiovascular morbidity and mortality with about 80%. The impact of MDD on cardiovascular health may be partly explained by mediating mechanisms such as unhealthy lifestyle (smoking, excessive alcohol use, physical inactivity, unhealthy diet, therapy non-compliance) and unfavorable pathophysiological disturbances (autonomic, HPA-axis, metabolic and immuno-inflammatory dysregulations). A summary of the literature findings as well as relevant results from the large-scale Netherlands Study of Depression and Anxiety (N=2981) are presented. Persons with MDD have significantly worse lifestyles as well as more pathophysiological disturbances as compared to healthy controls. Some of these differences seem to be specific for (typical versus 'atypical', or antidepressant treated versus drug-naive) subgroups of MDD patients. Alternative explanations are also present, namely undetected confounding, iatrogenic effects or 'third factors' such as genetics., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Study Objective: The temporal relationships among sleep, depressive symptoms, and pain are unclear. This longitudinal study examines whether insomnia and sleep duration predict the onset of chronic multisite musculoskeletal pain over 6 years and whether this association is mediated by depressive symptoms., Methods: 1860 subjects of the Netherlands Study of Depression and Anxiety, free from chronic multisite musculoskeletal pain at baseline, were followed up for the onset of chronic multisite musculoskeletal pain over 6 years (Chronic Pain Grade Questionnaire). We determined baseline insomnia (Women's Health Initiative Insomnia Rating Scale ≥9) and sleep duration (short: ≤6 hr, normal: 7-9 hr, long: ≥10 hr). Depressive symptoms were assessed at baseline and as a change score over time (Inventory of Depressive Symptomatology)., Results: Insomnia (hazard ratio [HR] [95% confidence interval, 95%CI] = 1.60 [1.30-1.96], p < .001) and short sleep duration (HR [95%CI] = 1.52 [1.22-1.90], p < .001) were associated with chronic pain onset. Adding baseline depressive symptoms as a mediator attenuated the associations for insomnia and short sleep with chronic pain onset (∆B = 40% and 26%, respectively). Adding the change score of depressive symptoms further weakened the association for insomnia (∆B = 16%) but not for short sleep. All direct effects for sleep measures with chronic pain onset remained statistically significant (p < .05)., Conclusions: This longitudinal study shows that insomnia and short sleep duration are risk factors for developing chronic pain. Depressive symptoms partially mediate the effect for insomnia and short sleep with developing chronic pain., (© Sleep Research Society 2016. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

Lowering elevated plasma homocysteine (Hcy) concentrations by supplementing vitamin B 12 and folic acid may reduce depressive symptoms and improve health-related quality of life (HR-QoL) in older adults. This study aimed to test this hypothesis in a randomized controlled trial. Participants ( N = 2919, ≥65 years, Hcy concentrations ≥12 µmol/L) received either 500 µg vitamin B 12 and 400 µg folic acid daily or placebo for two years. Both tablets contained 15 µg vitamin D₃. Depressive symptoms were measured with the Geriatric Depression Scale-15 (GDS-15). HR-QoL was assessed with the SF-12 Mental and Physical component summary scores and the EQ-5D Index score and Visual Analogue Scale. Differences in two-year change scores were analyzed with Analysis of Covariance (ANCOVA). Hcy concentrations decreased more in the intervention group, but two-year change scores of the GDS-15 and three of four HR-QoL measures did not differ between groups. The EQ-5D Index score declined less in the intervention group than in the placebo group (mean change 0.00 vs. -0.02, p = 0.004). In conclusion, two-year supplementation with vitamin B 12 and folic acid in older adults with hyperhomocysteinemia showed that lowering Hcy concentrations does not reduce depressive symptoms, but it may have a small positive effect on HR-QoL., Competing Interests: The authors declare no conflict of interest. The funding sources had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

Background: Anxiety disorders and depression are the most common mental disorders worldwide and have a striking impact on global disease burden. Although depression has consistently been found to increase mortality; the role of anxiety disorders in predicting mortality risk is unclear., Aims: To assess mortality risk in people with anxiety disorders., Method: We used nationwide Danish register data to conduct a prospective cohort study with over 30 million person-years of follow-up., Results: In total, 1066 (2.1%) people with anxiety disorders died during an average follow-up of 9.7 years. The risk of death by natural and unnatural causes was significantly higher among individuals with anxiety disorders (natural mortality rate ratio (MRR) = 1.39, 95% CI 1.28-1.51; unnatural MRR = 2.46, 95% CI 2.20-2.73) compared with the general population. Of those who died from unnatural causes, 16.5% had comorbid diagnoses of depression (MRR = 11.72, 95% CI 10.11-13.51)., Conclusions: Anxiety disorders significantly increased mortality risk. Comorbidity of anxiety disorders and depression played an important part in the increased mortality., Competing Interests: Declaration of interest None., (© The Royal College of Psychiatrists 2016.)

Background: Metabolic syndrome components-waist circumference, high-density lipoprotein cholesterol (HDL-C), triglycerides, systolic blood pressure and fasting glucose-are cross-sectionally associated with depression and anxiety with differing strength. Few studies examine the relationships over time or whether antidepressants have independent effects., Methods: Participants were from the Netherlands Study of Depression and Anxiety (NESDA; N = 2,776; 18-65 years; 66% female). At baseline, 2- and 6-year follow-up, participants completed diagnostic interviews, depression and anxiety symptom inventories, antidepressant use assessment, and measurements of the five metabolic syndrome components. Data were analyzed for the consistency of associations between psychopathology indicators and metabolic syndrome components across the three assessment waves, and whether psychopathology or antidepressant use at one assessment predicts metabolic dysregulation at the next and vice versa., Results: Consistently across waves, psychopathology was associated with generally poorer values of metabolic syndrome components, particularly waist circumference and triglycerides. Stronger associations were observed for psychopathology symptom severity than diagnosis. Antidepressant use was independently associated with higher waist circumference, triglycerides and number of metabolic syndrome abnormalities, and lower HDL-C. Symptom severity and antidepressant use were associated with subsequently increased number of abnormalities, waist circumference, and glucose after 2 but not 4 years. Conversely, there was little evidence that metabolic syndrome components were associated with subsequent psychopathology outcomes., Conclusions: Symptom severity and antidepressant use were independently associated with metabolic dysregulation consistently over time and also had negative consequences for short-term metabolic health. This is of concern given the chronicity of depression and anxiety and prevalence of antidepressant treatment., (© 2016 The Authors. Depression and Anxiety published by Wiley Periodicals, Inc.)

Anxiety and depression frequently co-occur with borderline personality disorder. Relatively little research examined the presence of borderline personality features and its main domains (affective instability, identity problems, negative relationships and self-harm) in individuals with remitted and current anxiety and depression. Participants with current (n=597) or remitted (n=1115) anxiety and/or depression and healthy controls (n=431) were selected from the Netherlands Study of Depression and Anxiety. Assessments included the Personality Assessment Inventory - Borderline Features Scale and several clinical characteristics of anxiety and depression. Borderline personality features were more common in depression than in anxiety. Current comorbid anxiety and depression was associated with most borderline personality features. Anxiety and depression status explained 29.7% of the variance in borderline personality features and 3.8% (self-harm) to 31% (identity problems) of the variance in the four domains. A large part of the variance was shared between anxiety and depression but both disorders also explained a significant amount of unique variance. The severity of anxiety and depression and the level of daily dysfunctioning was positively associated with borderline personality features. Individuals with a longer duration of anxiety and depression showed more affective instability and identity problems. These findings suggest that patients with anxiety and depression may benefit from an assessment of personality pathology as it may have implications for psychological and pharmacological treatment., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Obesity and depression are two prevalent conditions that are costly to individuals and society. The bidirectional association of obesity with depression, in which unhealthy dietary patterns may play an important role, has been well established. Few experimental studies have been conducted to investigate whether supplementing specific nutrients or improving diet and food-related behaviors can prevent depression in overweight persons., Method/design: The MooDFOOD prevention trial examines the feasibility and effectiveness of two different nutritional strategies [multi-nutrient supplementation and food-related behavioral change therapy (FBC)] to prevent depression in individuals who are overweight and have elevated depressive symptoms but who are not currently or in the last 6 months meeting criteria for an episode of major depressive disorder (MDD). The randomized controlled prevention trial has a two-by-two factorial design: participants are randomized to daily multi-nutrient supplement (omega-3 fatty acids, calcium, selenium, B-11 vitamin and D-3 vitamin) versus placebo, and/or FBC therapy sessions versus usual care. Interventions last 12 months. In total 1000 participants aged 18-75 years with body mass index between 25-40 kg/m(2) and with a Patient Health Questionnaire-9 score ≥ 5 will be recruited at four study sites in four European countries. Baseline and follow-up assessments take place at 0, 3, 6, and 12 months. Primary endpoint is the onset of an episode of MDD, assessed according to DSM-IV based criteria using the MINI 5.0 interview. Depressive symptoms, anxiety, food and eating behavior, physical activity and health related quality of life are secondary outcomes. During the intervention, compliance, adverse events and potentially mediating variables are carefully monitored., Discussion: The trial aims to provide a better understanding of the causal role of specific nutrients, overall diet, and food-related behavior change with respect to the incidence of MDD episodes. This knowledge will be used to develop and disseminate innovative evidence-based, feasible, and effective nutritional public health strategies for the prevention of clinical depression., Trial Registration: ClinicalTrials.gov. Number of identification: NCT02529423 . August 2015.

It has been postulated that many peripheral and (neuro)biological systems are involved in psychiatric disorders such as depression. Some studies found associations of depression and antidepressant treatment with insulin-like growth factor 1 (IGF-I) - a pleiotropic hormone affecting neuronal growth, survival and plasticity - but evidence is mixed. We therefore studied whether depressive and anxiety disorders were associated with plasma IGF-I, and explored the role of antidepressant medication in this association in a large observational study. The sample consisted of 2714 participants enrolled in The Netherlands Study of Depression and Anxiety, classified as healthy controls (n=602), antidepressant users (76 remitted and 571 with current depressive and/or anxiety disorder(s), n=647), persons having remitted depressive and/or anxiety disorder(s) without antidepressant use (n=502), and persons having current depressive and/or anxiety disorder(s) without antidepressant use (n=963). Associations with IGF-I concentrations were studied and adjusted for socio-demographic, health, and lifestyle variables. Relative to healthy controls, antidepressant-free individuals with current disorders had significantly higher IGF-I levels (Cohen's d=0.08, p=0.006), whereas antidepressant-free individuals with remitted disorders had a trend towards higher IGF-I levels (d=0.06, p=0.09). Associations were evident for depressive and for anxiety disorders. In contrast, antidepressant users had significantly lower IGF-I levels compared to healthy controls (d=-0.08, p=0.028). Our findings suggests that antidepressant medication use modifies the association between depressive/anxiety disorders and plasma IGF-I. These results corroborate with findings of some previous small-scale case-control and intervention studies. The higher IGF-I levels related to depression and anxiety might point to a compensatory mechanism to counterbalance the impaired neurogenesis, although future studies are needed to support this hypothesis., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Women have a consistently higher prevalence of major depressive disorder (MDD) than men. Hypotheses implicating hypothalamic-pituitary -adrenal, -gonadal, and -thyroid axes, immune response, genetic factors, and neurotransmitters have emerged to explain this difference. However, more evidence for these hypotheses is needed and new explanations must be explored. Here, we investigated sex differences in MDD markers using multiplex immunoassay measurements of 171 serum molecules in individuals enrolled in the Netherlands Study of Depression and Anxiety (NMDD = 231; Ncontrol = 365). We found 28 sex-dependent markers of MDD, as quantified by a significant interaction between sex and log2-transformed analyte concentration in a logistic regression with diagnosis (MDD/control) as the outcome variable (p<0.05; q<0.30). Among these were a number of male-specific associations between MDD and elevated levels of proteins involved in immune response, including C-reactive protein, trefoil factor 3, cystatin-C, fetuin-A, β2-microglobulin, CD5L, FASLG receptor, and tumor necrosis factor receptor 2. Furthermore, only male MDD could be classified with an accuracy greater than chance using the measured serum analytes (area under the ROC curve = 0.63). These findings may have consequences for the generalization of inflammatory hypotheses of depression to males and females and have important implications for the development of diagnostic biomarker tests for MDD. More studies are needed to validate these results, investigate a broader range of biological pathways, and integrate this data with brain imaging, genetic, and other relevant data.

Panic disorder with or without comorbid agoraphobia (PD/PDA) has been linked to an increased risk to develop subsequent depressive episodes, yet the underlying pathophysiology of these disorders remains poorly understood. We aimed to identify a biomarker panel predictive for the development of a depressive disorder (major depressive disorder and/or dysthymia) within a 2-year-follow-up period. Blood serum concentrations of 165 analytes were evaluated in 120 PD/PDA patients without depressive disorder baseline diagnosis (6-month-recency) in the Netherlands Study of Depression and Anxiety (NESDA). We assessed the predictive performance of serum biomarkers, clinical, and self-report variables using receiver operating characteristics curves (ROC) and the area under the ROC curve (AUC). False-discovery-rate corrected logistic regression model selection of serum analytes and covariates identified an optimal predictive panel comprised of tetranectin and creatine kinase MB along with patient gender and scores from the Inventory of Depressive Symptomatology (IDS) rating scale. Combined, an AUC of 0.87 was reached for identifying the PD/PDA patients who developed a depressive disorder within 2 years (n = 44). The addition of biomarkers represented a significant (p = 0.010) improvement over using gender and IDS alone as predictors (AUC = 0.78). For the first time, we report on a combination of biological serum markers, clinical variables and self-report inventories that can detect PD/PDA patients at increased risk of developing subsequent depressive disorders with good predictive performance in a naturalistic cohort design. After an independent validation our proposed biomarkers could prove useful in the detection of at-risk PD/PDA patients, allowing for early therapeutic interventions and improving clinical outcome., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Depression and disability are closely linked. Less is known regarding clinical and subclinical depressive symptoms over time and risk of disability and mortality., Methods: Responses to the Center for Epidemiologic Studies Short Depression scale (CES-D10) were assessed over a 4-year period in men (n = 1032) and women (n = 1070) aged 70-79 years initially free from disability. Depressive symptom trajectories were defined with group-based models. Disability (2 consecutive reports of severe difficulty walking one-quarter mile or climbing 10 steps) and mortality were determined for 9 subsequent years. Hazard ratios (HRs) were estimated using Cox proportional hazards adjusted for covariates., Results: Three trajectories were identified: persistently nondepressed (54% of men, 54% of women, mean baseline CES-D10: 1.16 and 1.46), mildly depressed and increasing (40% of men, 38% of women, mean baseline CES-D10: 3.60 and 4.35), and depressed and increasing (6% of men, 8% of women, mean baseline CES-D10: 7.44 and 9.61). Disability and mortality rates per 1,000 person years were 41.4 and 60.3 in men and 45.8 and 41.9 in women. Relative to nondepressed, men in the mildly depressed (HR = 1.45, 95% confidence interval [CI] 1.11-1.89) and depressed trajectories (HR = 2.12, 95% CI 1.33-3.38) had increased disability; women in the depressed trajectory had increased disability (HR = 2.02, 95% CI 1.37-2.96). Men in the mildly depressed (HR = 1.24, 95% CI 1.01-1.52) and depressed trajectories (HR = 1.63, 95% CI 1.10-2.41) had elevated mortality risk; women exhibited no mortality risk., Conclusions: Trajectories of depressive symptoms without recovery may predict disability and mortality in apparently healthy older populations, thus underscoring the importance of monitoring depressive symptoms in geriatric care., (Published by Oxford University Press on behalf of the Gerontological Society of America 2015.)

Background: Depressive symptoms and decreased physical functioning are interrelated conditions and common in older persons, causing significant individual and societal burden. Evidence suggests that vitamin D supplementation may be beneficial for both mental and physical functioning. However, previous randomized controlled trials have yielded inconsistent results and often had suboptimal designs. This study examines the effect of vitamin D supplementation on both depressive symptoms and physical functioning in a high-risk population of older persons with low vitamin D status., Methods/design: The D-Vitaal study is a randomized, double-blind, placebo-controlled trial investigating the effects of a daily dose of 1200 IU vitamin D3 versus placebo for one year on depressive symptoms and physical functioning (primary outcomes) in older adults. Participants (N = 155, age 60-80 years) were recruited from the general population. Eligibility criteria included the presence of depressive symptoms, ≥1 functional limitation and serum 25-hydroxyvitamin D levels between 15 and 50/70 nmol/L (depending on season). Secondary outcomes include incidence of major depressive disorder, anxiety symptoms, health-related quality of life, cognitive function and cost-effectiveness of the intervention., Discussion: With this study, we aim to elucidate the effects of vitamin D supplementation on depressive symptoms and physical functioning in older persons who are at high risk of developing more substantial mental and physical problems. If effective, vitamin D supplementation can be a preventive intervention strategy that is easy to implement in the primary care setting., Trial Registration: Netherlands Trial Register NTR3845. Registered 6 February 2013.

Objective: In adults, depression and inflammation are bidirectionally related. This association is less clear in adolescents. Moreover, somatic and cognitive depressive symptoms might be differentially related to inflammation. Lifestyle factors, as in adults, may play an important mediating role in adolescents. For the current study we evaluated trajectories of depressive symptoms in adolescence over a 5-year course and their relation with subsequent high-sensitivity C-reactive protein (hsCRP) levels, and examined lifestyle factors as mediators., Method: Participants of the TRacking Adolescents' Individual Lives' Survey (TRAILS; N = 1166) were followed from 2001 until 2008. Three biennial youth self-report (YSR) assessments of depressive symptoms were taken. Demographics, health, and lifestyle factors and levels of hsCRP were assessed at Wave 3. Latent-class analysis was used to determine trajectories of depression and general linear models to determine the association between depression trajectories and hsCRP. Finally, mediation analysis was performed to test mediation of lifestyle factors., Results: Persistently moderate to high depressive symptoms were associated with higher hsCRP levels. Results were unaltered when we adjusted for demographics and health variables. Smoking mediated the association between depressive symptoms total score and hsCRP, in large part. Persistently higher scores on somatic and cognitive symptom subscales were associated with higher levels of hsCRP than persistently low scores. These results were rendered nonsignificant after covariate adjustment., Conclusion: Persistent depressive symptoms were associated with subsequent higher levels of hsCRP, with somatic and cognitive symptoms contributing equally. The association was mediated by smoking behavior. These findings suggest that reducing adolescent depression and smoking are important starting points in the prevention of inflammatory diseases., ((c) 2015 APA, all rights reserved).)

This study aimed to examine cross-sectionally to what extent persons with higher symptom levels or a current or past emotional disorder report to be less happy than controls and to assess prospectively whether time-lagged measurements of extraversion and neuroticism predict future happiness independent of time-lagged measurements of emotional disorders or symptom severity. A sample of 2142 adults aged 18-65, consisting of healthy controls and persons with current or past emotional disorder according to DSM-IV criteria completed self-ratings for happiness and emotional well-being and symptom severity. Lagged measurements of personality, symptom severity and presence of anxiety and depressive disorder at T0 (year 0), T2 (year 2) and T4 (year 4) were used to predict happiness and emotional well-being at T6 (year 6) controlling for demographics. In particular persons with more depressive symptoms, major depressive disorder, social anxiety disorder and comorbid emotional disorders reported lower levels of happiness and emotional well-being. Depression symptom severity and to a lesser extent depressive disorder predicted future happiness and emotional well-being at T6. Extraversion and to a lesser extent neuroticism also consistently forecasted future happiness and emotional well-being independent of concurrent lagged measurements of emotional disorders and symptoms. A study limitation is that we only measured happiness and emotional well-being at T6 and our measures were confined to hedonistic well-being and did not include psychological and social well-being. In sum, consistent with the two continua model of emotional well-being and mental illness, a 'happy' personality characterized by high extraversion and to a lesser extent low neuroticism forecasts future happiness and emotional well-being independent of concurrently measured emotional disorders or symptom severity levels. Boosting positive emotionality may be an important treatment goal for persons personally inclined to lower levels of happiness.

Meta-analyses support the involvement of different pathophysiological mechanisms (inflammation, hypothalamic-pituitary (HPA)-axis, neurotrophic growth and vitamin D) in major depressive disorder (MDD). However, it remains unknown whether dysregulations in these mechanisms are more pronounced when MDD progresses toward multiple episodes and/or chronicity. We hypothesized that four central pathophysiological mechanisms of MDD are not only involved in etiology, but also associated with clinical disease progression. Therefore, we expected to find increasingly more dysregulation across consecutive stages of MDD progression. The sample from the Netherlands Study of Depression and Anxiety (18-65 years) consisted of 230 controls and 2333 participants assigned to a clinical staging model categorizing MDD in eight stages (0, 1A, 1B, 2, 3A, 3B, 3C and 4), from familial risk at MDD (stage 0) to chronic MDD (stage 4). Analyses of covariance examined whether pathophysiological mechanism markers (interleukin (IL)-6, C-reactive protein (CRP), cortisol, brain-derived neurotrophic factor and vitamin D) showed a linear trend across controls, those at risk for MDD (stages 0, 1A and 1B), and those with full-threshold MDD (stages 2, 3A, 3B, 3C and 4). Subsequently, pathophysiological differences across separate stages within those at risk and with full-threshold MDD were examined. A linear increase of inflammatory markers (CRP P=0.026; IL-6 P=0.090), cortisol (P=0.025) and decrease of vitamin D (P<0.001) was found across the entire sample (for example, from controls to those at risk and those with full-threshold MDD). Significant trends of dysregulations across stages were present in analyses focusing on at-risk individuals (IL-6 P=0.050; cortisol P=0.008; vitamin D P<0.001); however, no linear trends were found in dysregulations for any of the mechanisms across more progressive stages of full-threshold MDD. Our results support that the examined pathophysiological mechanisms are involved in MDD's etiology. These same mechanisms, however, are less important in clinical progression from first to later MDD episodes and toward chronicity.

Objective: To investigate the impact of current and remitted depression and anxiety disorders and sociodemographic and other related factors on medication nonadherence in a large cohort study., Method: The Medication Adherence Rating Scale was used to assess medication nonadherence of 1,890 medication users in the 4-year follow-up assessment of the Netherlands Study of Depression and Anxiety, which was conducted between 2008 and 2011. Psychiatric diagnoses according to the DSM-IV, sociodemographic and clinical characteristics, and medication use were determined. Medication nonadherence was defined by the tendency to forget a dose, change the dose, stop for a while, skip 1 dose, or take a smaller dosage than prescribed., Results: Overall medication nonadherence was 44%. In multivariate analyses, all current and remitted depression and anxiety diagnoses were risk factors for medication nonadherence as compared to subjects never having had a depressive or anxiety diagnosis (P < .05). Age (OR = 0.85, P < .001) and antidepressant use (OR = 0.66, P = .001) were associated with less medication nonadherence. Alcohol dependence (OR = 1.67, P = .05) and the number of dietary supplements (OR = 1.18, P = .02) proved risk factors for medication nonadherence. Associations of anxiety diagnosis with medication nonadherence were mainly driven by depression diagnosis., Conclusions: All current and remitted depression and anxiety disorders were risk factors for medication nonadherence. Since these disorders are highly comorbid with other medical conditions, health care workers should address medication nonadherence in patients with depression and/or anxiety disorders, even in those who are in symptomatic remission., (© Copyright 2015 Physicians Postgraduate Press, Inc.)

Background: Mixed evidence exists regarding the role of cognitive reactivity (CR; cognitive responsivity to a negative mood) as a risk factor for recurrences of depression. One explanation for the mixed evidence may lie in the number of previous depressive episodes. Heightened CR may be especially relevant as a risk factor for the development of multiple depressive episodes and less so for a single depressive episode. In addition, it is theoretically plausible but not yet tested that the relationship between CR and number of episodes is moderated by the strength of automatic depression-related self-associations., Aim: To investigate (i) the strength of CR in remitted depressed individuals with a history of a single vs. multiple episodes, and (ii) the potentially moderating role of automatic negative self-associations in the relationship between the number of episodes and CR., Method: Cross-sectional analysis of data obtained in a cohort study (Study 1) and during baseline assessments in two clinical trials (Study 2). Study 1 used data from the Netherlands Study of Depression and Anxiety (NESDA) and compared never-depressed participants (n=901) with remitted participants with either a single (n=336) or at least 2 previous episodes (n=273). Study 2 included only remitted participants with at least two previous episodes (n=273). The Leiden Index of Depression Sensitivity Revised (LEIDS-R) was used to index CR and an Implicit Association Test (IAT) to measure implicit self-associations., Results: In Study 1, remitted depressed participants with multiple episodes had significantly higher CR than those with a single or no previous episode. The remitted individuals with multiple episodes of Study 2 had even higher CR scores than those of Study 1. Within the group of individuals with multiple episodes, CR was not heightened as a function of the number of episodes, even if individual differences in automatic negative self-associations were taken into account., Limitations: The study employed a cross-sectional design, which precludes a firm conclusion with regard to the direction of this relationship., Conclusions: The findings are consistent with the view that high CR puts people at risk for recurrent depression and is less relevant for the development of an incidental depressive episode. This suggests that CR is an important target for interventions that aim to prevent the recurrence of depression., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Trauma-related rumination and worry predict chronic PTSD. This study examined whether habitual rumination and worry measured prior to trauma exposure make persons more vulnerable to the onset of PTSD, presumably because habitual ruminators and worriers will be more prone to cognitively appraise trauma exposure in a negative way. A sample of 2981 adults aged 18-65, consisting of healthy controls and persons with past or current depressive and/or anxiety disorders were assessed at baseline and at follow-up four years later (n = 2402). At follow-up, 359 participants reported exposure to a traumatic event during the last four years of whom 52 (14.4%) had developed PTSD. Pre-trauma self-reported depression severity and trait rumination - but not trait worry-predicted onset of PTSD during follow-up, controlling for demographic and clinical history variables, as well as psychiatric diagnoses at baseline. The relation of trait rumination with onset of PTSD was partly mediated by the cognitive appraisal of the traumatic event and not by the affective reaction to trauma exposure. Repetitive negative thinking in the form of rumination may be a risk factor for onset of PTSD amenable to prevention and intervention., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Although social anxiety disorder (SAD) is strongly associated with the subsequent development of a depressive disorder (major depressive disorder or dysthymia), no underlying biological risk factors are known. We aimed to identify biomarkers which predict depressive episodes in SAD patients over a 2-year follow-up period. One hundred sixty-five multiplexed immunoassay analytes were investigated in blood serum of 143 SAD patients without co-morbid depressive disorders, recruited within the Netherlands Study of Depression and Anxiety (NESDA). Predictive performance of identified biomarkers, clinical variables and self-report inventories was assessed using receiver operating characteristics curves (ROC) and represented by the area under the ROC curve (AUC). Stepwise logistic regression resulted in the selection of four serum analytes (AXL receptor tyrosine kinase, vascular cell adhesion molecule 1, vitronectin, collagen IV) and four additional variables (Inventory of Depressive Symptomatology, Beck Anxiety Inventory somatic subscale, depressive disorder lifetime diagnosis, BMI) as optimal set of patient parameters. When combined, an AUC of 0.86 was achieved for the identification of SAD individuals who later developed a depressive disorder. Throughout our analyses, biomarkers yielded superior discriminative performance compared to clinical variables and self-report inventories alone. We report the discovery of a serum marker panel with good predictive performance to identify SAD individuals prone to develop subsequent depressive episodes in a naturalistic cohort design. Furthermore, we emphasise the importance to combine biological markers, clinical variables and self-report inventories for disease course predictions in psychiatry. Following replication in independent cohorts, validated biomarkers could help to identify SAD patients at risk of developing a depressive disorder, thus facilitating early intervention., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Introduction: Differentiating bipolar depression (BD) from unipolar depression (UD) is difficult in clinical practice and, consequently, accurate recognition of BD can take as long as nine years. Research has therefore focused on the discriminatory capacities of biomarkers, such as markers of the hypothalamic-pituitary-adrenal (HPA) axis or immunological activity. However, no previous study included assessments of both systems, which is problematic as they may influence each other. Therefore, this study aimed to explore whether cortisol indicators and inflammatory markers were a) independently associated with and/or b) showed effect modification in relation to a lifetime (hypo)manic episode in a large sample of depressed patients., Methods: Data were derived from the Netherlands Study of Depression and Anxiety and comprised 764 patients with a DSM-IV depressive disorder at baseline, of which 124 (16.2%) had a lifetime (hypo)manic episode at the 2-year assessment, or a more recent episode at the 4-year or 6-year assessment. Baseline cortisol awakening response, evening cortisol and diurnal cortisol slope were considered as cortisol indicators, while baseline C-reactive Protein (CRP), Interleukin-6 (IL-6), and Tumor Necrosis Factor Alpha (TNF-α) were included as inflammatory markers., Results: In depressed men and women, none of the cortisol indicators and inflammatory markers were (independently) associated with a (hypo)manic episode. However, effect modification was found of diurnal cortisol slope and CRP in relation to a (hypo)manic episode. Further analyses showed that depressed men with high levels of diurnal cortisol slope and CRP had an increased odds (OR=10.99, p=.001) of having a (hypo)manic episode. No significant differences were found in women., Conclusion: Our findings suggest that the combination of high diurnal cortisol slope and high CRP may differentiate between UD and BD. This stresses the importance of considering HPA-axis and immunological activity simultaneously, but more research is needed to unravel their interrelatedness.

Background: Atypical response behavior on depression questionnaires may invalidate depression severity measurements. This study aimed to identify and investigate atypical profiles of depressive symptoms using a data-driven approach based on the item response theory (IRT)., Methods: A large cohort of participants completed the Inventory of Depressive Symptomatology self-report (IDS-SR) at baseline (n=2329) and two-year follow-up (n=1971). Person-fit statistics were used to quantify how strongly each patient׳s observed symptom profile deviated from the expected profile given the group-based IRT model. Identified atypical profiles were investigated in terms of reported symptoms, external correlates and temporal consistency., Results: Compared to others, atypical responders (6.8%) showed different symptom profiles, with higher 'mood reactivity' and 'suicidal ideation' and lower levels of mild symptoms like 'sad mood'. Atypical responding was associated with more medication use (especially tricyclic antidepressants: OR=1.5), less somatization (OR=0.8), anxiety severity (OR=0.8) and anxiety diagnoses (OR=0.8-0.9), and was shown relatively stable (29.0%) over time., Limitations: This is a methodological proof-of-principal based on the IDS-SR in outpatients. Implementation studies are needed., Conclusion: Person-fit statistics can be used to identify patients who report atypical patterns of depressive symptoms. In research and clinical practice, the extra diagnostic information provided by person-fit statistics could help determine if respondents׳ depression severity scores are interpretable or should be augmented with additional information., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Late-life depression and physical frailty are supposed to be reciprocally associated, however, longitudinal studies are lacking., Objectives: This study examines whether physical frailty predicts a higher incidence of depression, as well as a less favorable course of depression., Methods: A population-based cohort study of 888 people aged 65 years and over with follow-up measures at 3, 6, and 9 years. Cox proportional hazards models adjusted for age, sex, education, smoking, alcohol usage, and global cognitive functioning were applied to calculate the incidence of depressed mood in those nondepressed at baseline (n = 699) and remission in those with depressed mood at baseline (n = 189). Depressed mood onset or remission was defined as crossing the cut-off score of 20 points on the Center for Epidemiological Studies-Depression Scale combined with a relevant change in this score. Physical frailty was based on the presence of ≥ 3 out of 5 components (ie, weight loss, weakness, slowness, exhaustion, and low physical activity level)., Results: A total of 214 out of 699 (30.6%) nondepressed persons developed depressed mood during follow-up. Physical frailty predicted the onset of depressed mood with a hazard rate of 1.26 (95% confidence interval 1.09-1.45, P = .002). Of the 189 persons with depressed mood at baseline, 96 (50.8%) experienced remission during follow-up. Remission was less likely in the presence of a higher level of physical frailty (hazard rate = 0.72, 95% confidence interval 0.58-0.91, P = .005)., Conclusions: Because physical frailty predicts both the onset and course of late-life depressed mood, physical frailty should receive more attention in mental health care planning for older persons as well as its interference with treatment. Future studies into the pathophysiological mechanisms may guide the development of new treatment opportunities for these vulnerable patients., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2015 AMDA - The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

One of the leading neurobiological hypotheses on depression states that decreased expression of brain-derived neurotrophic factor (BDNF) contributes to depression. This is supported by consistent findings of low serum BDNF levels in depressed patients compared with non-depressed controls. Whereas it has been generally assumed that this is a state characteristic of depression, strong inferences about state or trait effects require a longitudinal study design. To investigate the longitudinal association between serum BDNF and depression, we measured serum BDNF, (current and past) depression status, use of antidepressants, and all potential covariates at baseline and after 2 years in 1751 individuals, consisting of patients with an incident (n=153), remitted (n=420) and persistent depression (n=310) and non-depressed controls (n=868). We analyzed change/differences in serum BDNF across these four groups with analyses of covariance adjusted for covariates and baseline BDNF value, together with the effects of starting and stopping antidepressant treatment. Our analyses revealed a significant difference for the depression course groups (P=0.007). Compared with non-depressed controls, persistently depressed and remitted patients had a steeper decrease of BDNF levels over time (-1.33 (P=0.001) and -0.97 ng ml(-1) (P=0.011), respectively), whereas BDNF reductions in patients with incident depression were similar to those in healthy controls. Initiation or discontinuation of antidepressants was not associated with BDNF change (P=0.72). These findings suggest that BDNF not only contributes to depression, but that depression in turn may also contribute to low BDNF.

Objective: We aimed to investigate the prevalence of the metabolic syndrome (MetS) and its individual components in subjects with bipolar disorder (BD) compared to those with major depressive disorder (MDD) and non-psychiatric controls., Methods: We examined 2431 participants (mean age 44.3±13.0, 66.1% female), of whom 241 had BD; 1648 had MDD; and 542 were non-psychiatric controls. The MetS was ascertained according to NCEP ATP III criteria. Multivariable analyses were adjusted for age, sex, ethnicity, level of education, smoking status and severity of depressive symptoms, and in the case of BD subjects, also for psychotropic medication use., Results: Subjects with BD had a significantly higher prevalence of MetS when compared to subjects with MDD and non-psychiatric controls (28.4% vs. 20.2% and 16.5%, respectively, p<0.001), also when adjusted for sociodemographic and lifestyle factors (OR 1.52, 95% CI: 1.09-2.12, p=0.02 compared to MDD; OR 1.79, 95% CI: 1.20-2.67, p=0.005 compared to non-psychiatric controls). The differences between BD subjects with controls could partly be ascribed to a higher mean waist circumference (91.0 cm vs. 88.8, respectively, p=0.03). In stratified analysis, the differences in the prevalence of MetS between patients with BD and MDD were found in symptomatic but not in asymptomatic cases., Conclusion: This study confirms a higher prevalence of MetS in patients with BD compared to both MDD patients and controls. Specifically at risk are patients with a higher depression score and abdominal obesity., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Dispositional optimism, a personality trait characterized by generalized positive expectations towards the future, is thought to remain rather stable over time. It is however largely unknown to what extent affective disorders and its risk factors affect dispositional optimism., Methods: We examined the association between (lifetime) affective disorders and childhood trauma with dispositional optimism in a sample of 2104 subjects (aged 18-65 years) from the Netherlands Study of Depression and Anxiety (NESDA). Dispositional optimism was measured with the Life Orientation Test Revised (LOT-R). Diagnoses of depressive and anxiety disorders were based on the Composite Interview diagnostic Instrument (CIDI).Childhood trauma was assessed using the Childhood Trauma Interview (CTI) and life-events with the List of Threatening Events Questionnaire (LTQ)., Results: The 2104 participants were on average 46.0 (SD 13.1) years old and 65.8% were female. Multivariate analyses showed that dispositional optimism was inversely associated with current affective disorders (depression: B=-1.089 and anxiety: B=-1.066, both p<0.001), but also with remitted affective disorders (depression: B=-0.822 and anxiety: B=-0.558, both p<0.001) and severity of depression (B=-4.230; p<0.001). A history of childhood emotional maltreatment (B=-0.905, p<0.001) was related to lower optimism, whilst positive life-events were associated with higher levels of optimism (B=0.235, p>0.001)., Limitations: The cross-sectional design hampers inferences about causality., Conclusion: Lower levels of dispositional optimism are associated with stage of affective disorders, even after remission, and a history of childhood emotional maltreatment. Identification of the risk factors contributes to understand fluctuations in dispositional optimism., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Stress experienced during childhood or adulthood has been associated with cardiovascular disease (CVD), but it is not clear whether associations are already prevalent on a subclinical cardiovascular level. This study investigates associations between indicators of life stress and subclinical CVD, and whether these are mediated by depression and anxiety., Methods: Subjects were 650 participants of the Netherlands Study of Depression and Anxiety, aged 20-66 years, with or without (27.5%) depressive and anxiety disorders. Life stress included childhood trauma, negative life events and recently experienced daily hassles or job strain. Subclinical CVD was measured as 1) carotid atherosclerosis (intima-media thickness and the presence of plaques) using B-mode ultrasonography, and 2) central arterial stiffness (heart rate normalized augmentation index) using calibrated radial applanation tonometry., Results: Increased central arterial stiffness was shown in subjects who had experienced childhood trauma (per SD increase: β=.07; p=.01), or reported recently experienced daily hassles (per SD increase: β=.06; p=.02), negative life events (per SD increase: β=.05; p=.03), or job strain (high versus low: β=.09; p=.01). Associations between life stress and arterial stiffness appeared to be partly mediated by severity of depressive and anxiety symptoms. No significant associations were found for childhood life events, nor between indicators of life stress and carotid atherosclerosis., Conclusions: Childhood trauma and recent life stress were associated with increased central arterial stiffness. This suggests that life stress - partly via depression and anxiety - might enhance the development and progression of CVD., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The MR is an important regulator of the hypothalamic-pituitary-adrenal (HPA) axis and a prime target for corticosteroids. There is increasing evidence from both clinical and preclinical studies that the MR has different effects on behavior and mood in males and females. To investigate the hypothesis that the MR sex-dependently influences the relation between childhood maltreatment and depression, we investigated three common and functional MR haplotypes (GA, CA, and CG haplotype, based on rs5522 and rs2070951) in a population-based cohort (N = 665) and an independent clinical cohort from the Netherlands Study of Depression and Anxiety (NESDA) (N = 1639). The CA haplotype sex-dependently moderated the relation between childhood maltreatment and depressive symptoms both in the population-based sample (sex × maltreatment × haplotype: β = -4.07, P = 0.029) and in the clinical sample (sex × maltreatment × haplotype, β = -2.40, P = 0.011). Specifically, female individuals in the population-based sample were protected (β = -4.58, P = 2.0 e(-5)), whereas males in the clinical sample were at increased risk (β = 2.54, P = 0.0022). In line with these results, female GA haplotype carriers displayed increased vulnerability in the population-based sample (β = 4.58, P = 7.5 e(-5)) whereas male CG-carriers showed increased resilience in the clinical sample (β = -2.71, P = 0.016). Consistently, we found a decreased lifetime MDD risk for male GA haplotype carriers following childhood maltreatment but an increased risk for male CA haplotype carriers in the clinical sample. In both samples, sex-dependent effects were observed for GA-GA diplotype carriers. In summary, sex plays an important role in determining whether functional genetic variation in MR is beneficial or detrimental, with an apparent female advantage for the CA haplotype but male advantage for the GA and CG haplotype. These sex-dependent effects of MR on depression susceptibility following childhood maltreatment are relevant in light of the increased prevalence of mood disorders in women and point to a sex-specific role of MR in the etiology of depression following childhood maltreatment., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: Serum insulin-like growth factor 1 (IGF-1) concentration decreases, while the prevalence of depressive symptoms increases with advancing age. Although basic research indicates a link between low IGF-1 concentration and depression, this has scarcely been investigated in humans. This study investigates whether lower IGF-1 concentrations are associated with prevalent and incident late-life depression over a 3-year period., Methods: The study included 1188 participants, aged ≥ 65 years, from the Longitudinal Aging Study Amsterdam (LASA), an ongoing, population-based cohort study. Depression was assessed at baseline and after three years using the Center for Epidemiological Studies-Depression Scale (CES-D) and the Diagnostic Interview Schedule (DIS), and categorized into minor depression and major depression (MDD). Serum IGF-1 concentration was determined at baseline. Associations were adjusted for relevant confounders., Results: Serum IGF-1 concentrations were within the normal range (mean 13.9 nmol/l, standard deviation 5.3 nmol/l). At baseline, in men, as compared to high concentrations, mid concentrations decreased the probability of prevalent minor depression (odds ratio [OR] = 0.35, 95% confidence interval [CI] = 0.15-0.82). In women, as compared to high concentrations, low concentrations tended to increase the probability of prevalent MDD (OR = 2.66, 95% CI = 0.89-7.89). At three-year follow-up, in men, no significant prospective associations were detected. In women, as compared to high concentrations, mid concentrations decreased the probability of incident minor depression (OR = 0.43, 95% CI = 0.19-0.95)., Conclusions: Several associations, which differed across the genders, were observed between IGF-1 and depression. Cross-sectional findings were not supported by longitudinal findings, which suggest that IGF-1 may not play an important predictive role in the development of depression in older persons over time. However, a more acute role of IGF-1 in current depression, as indicated by the cross-sectional results, may be possible. Further studies are needed to elucidate the complex relation between IGF-1 and late-life depression., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: The receiver operating characteristics (ROC) of anhedonic depression and anxious arousal to detect the distress- (major depression, dysthymia, generalized anxiety disorder) and fear-disorder clusters (i.e. panic disorder, agoraphobia, social phobia) have not been reported in a large sample., Methods: A sample of 2981 persons underwent structured psychiatric interview; n=652 were without lifetime depression and anxiety disorder history. Participants also completed a neuroticism scale (Revised NEO Five Factor Inventory [NEO-FFI]), and the 30-item short adaptation of the Mood and Anxiety Symptoms Questionnaire (MASQ-D30) measuring anhedonic depression, anxious arousal and general distress. Maximal sensitivity and specificity was determined by the Youden Index and the area-under-the-curve (AUC) in ROC analysis., Results: A total of 2624 completed all measures (age M=42.4 years±13.1, 1760 females [67.1%]), including 1060 (40.4%) persons who met criteria for a distress-disorder, and 973 (37.1%) who met criteria for a fear-disorder. The general distress dimension provided the highest ROC values in the detection of the distress-disorders (AUC=.814, sensitivity=71.95%, specificity=76.34%, positive predictive value=67.33, negative predictive value=80.07). None of the measures provided suitable operating characteristics in the detection of the fear-disorders with specificity values <75%., Limitations: Over sampling of depression and anxiety disorders may lead to inflated positive- and negative predictive values., Conclusions: The MASQ-D30 general distress dimension showed clinically suitable operating characteristics in the detection of distress-disorders. Neither neuroticism nor the MASQ-D30 dimensions provided suitable operating characteristics in the detection of the fear-disorders., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Objective: To investigate the impact of differences in depressive symptom reporting across clinical groups (healthcare setting, chronic illness, depression diagnosis and anxiety diagnosis) on clinical interpretability and comparability of depression scores., Methods: Participants from the Netherlands Study of Depression and Anxiety (n=2981) completed the self-report Inventory of Depressive Symptomatology (IDS-SR). Differences in depressive symptom reporting between distinct clinical subpopulations were assessed using a Differential Item Functioning (DIF) analysis. The effects of DIF on symptom level were evaluated by examining whether DIF-adjustment had clinically relevant effects., Results: Significant DIF was detected across all tested clinical subpopulation groupings. Clinically relevant DIF was found on the symptom level for 13 IDS-SR items. However, impact of DIF on the aggregate level ranged from small to negligible: adjustment for DIF only led to salient changes in aggregate scores for 0.2-12.7% of individuals across tested sources of DIF., Conclusion: Differences in endorsement patterns of depressive symptoms were observed across clinical populations, challenging the assumptions regarding the measurement properties of self-reported depression. However, effects of DIF on the aggregate level of IDS-SR total scores were found to be minimal and not clinically important. The IDS-SR thus seems robust against DIF across clinical populations., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: It has been suggested that depressed persons have increased oxidative stress and decreased anti-oxidant defences. 8-Hydroxy-2'-deoxyguanosine (8-OHdG) and F2-isoprostanes, measures of oxidative DNA and lipid damage respectively, are among the most reliable oxidative stress markers, but studies on their association with depression show conflicting results. This meta-analysis quantifies the association between depression and these markers and explores factors that may explain inconsistencies in the results., Methods: A systematic literature search was conducted in PubMed, EMBASE and PsycINFO. Studies assessing the association of 8-OHdG or F2-isoprostanes with elevated depressive symptoms, major depressive disorder (MDD) or bipolar disorder (BD) were pooled in two random-effect models., Results: The pooled effect size (Hedges' g) for the association of depression with oxidative stress was 0.31 (p=0.01, I(2)=75%) for 8-OHdG (10 studies, 1308 subjects) and 0.48 (p=0.001, I(2)=73%) for F2-isoprostanes (8 studies, 2471 subjects), indicating that both markers are increased in depression. There was no indication of publication bias for either marker. The F2-isoprostane results did not differ by type of depression, biological specimen, laboratory method or quality, however subgroup analyses in the 8-OHdG studies showed significantly stronger associations in plasma/serum vs. urine samples (p<0.01), in measurements performed with immuno-assay vs. chromatography-mass spectrometry (p<0.01) and weaker associations in high quality studies vs. low (p=0.02)., Conclusion: This meta-analysis finds that oxidative stress, as measured by 8-OHdG and F2-isoprostanes, is increased in depression. Larger-scale studies are needed to extend the evidence on oxidative stress in depression, and examine the potential impact of treatment., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objective: Many patients with depression and/or anxiety (D/A) persistently report pain. However, it is not clear how the course of D/A is associated with pain over time. The present study assessed longitudinal associations between D/A and pain, and compared pain over time between D/A and healthy controls., Methods: 2676 participants of the Netherlands Study of Depression and Anxiety were followed-up for four years. At three waves (baseline, 2, 4years) we assessed depressive and anxiety symptom severity. Using DSM-IV criteria, we also assessed four different D/A disorder courses over time (n=2093): incident, remitted, chronic, and no D/A (reference group). Pain was assessed at the three waves by severity and number of locations., Results: Change in D/A symptoms was positively associated with change in pain symptoms. Compared to healthy controls (n=519), D/A subjects - incident (n=333), remitted (n=548) or chronic (n=693) - reported more severe pain (b=0.4-0.7, p<0.001) and more pain locations (b=0.8-1.4, p<.001) at all waves, with the highest ratings in chronic D/A. Remission of D/A during follow-up was associated with a significant decline in pain (severity; p=0.002, number of locations; p<.001), but pain levels remained significantly higher compared to healthy controls. Findings were similar for separate depression or anxiety course., Conclusions: This study largely confirms synchrony of change between depression, anxiety and pain. However, even after depression and anxiety remission, subjects report higher pain ratings over time. Individuals with D/A (history) seem to be at increased risk of chronic pain., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Systemic inflammation has emerged as a potential pathway linking depressive and anxiety disorders with disease risk. Short and long sleep duration, as well as insomnia, are common among psychiatric populations and have previously been related to increased inflammation. The aim of the present study was to investigate associations between sleep duration and insomnia with biomarkers of inflammation and to explore whether these associations varied by psychiatric diagnostic status. To this end, self-reported measures of sleep duration, insomnia symptoms, and markers of inflammation, including C-reactive protein (CRP), interleukin-(IL)-6, and tumor necrosis factor (TNF)-α, were obtained in 2553 adults (aged 18-65 years) diagnosed with current/recent or remitted depressive and/or anxiety disorders and healthy controls enrolled in the Netherlands Study of Depression and Anxiety (NESDA). Regression analyses revealed associations between sleep duration and levels of CRP and IL-6 with higher levels observed in long sleepers. These associations remained statistically significant after controlling for age, gender, education, body mass index, smoking, alcohol consumption, medical comorbidities, medication use, psychotropic medication use, and psychiatric diagnostic status. There were no clear associations between insomnia symptoms and levels of inflammation. Relationships between sleep duration and inflammation did not vary as a function of psychiatric diagnostic status. These findings suggest that elevated levels of systemic inflammation may represent a mechanism linking long sleep duration and disease risk among those with and without depressive and anxiety disorders., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Depression might be associated with accelerated cellular aging. However, does this result in an irreversible state or is the body able to slow down or recover from such a process? Telomeres are DNA-protein complexes that protect the ends of chromosomes and generally shorten with age; and therefore index cellular aging. The majority of studies indicate that persons with depression have shorter leukocyte telomeres than similarly aged non-depressed persons, which may contribute to the observed unfavorable somatic health outcomes in the depressed population. Some small-scale preliminary studies raise the possibility that behavioral or pharmacological interventions may either slow down or else reverse this accelerated telomere shortening, possibly through increasing the activity of the telomere-lengthening enzyme telomerase. This paper covers the current state of evidence in the relationship between depression and the telomere-telomerase system and debates whether depression-related cellular aging should be considered a reversible process or permanent damage., (© 2014 WILEY Periodicals, Inc.)

Background: Even though traumatic stress is a major risk factor for depression, most people do not develop a depression. The effects of stress may particularly emerge after repeated exposure in vulnerable individuals. Therefore, we hypothesized that (1) increased exposure to stress across the life span is associated with an increased depression risk and (2) this effect is the most pronounced in individuals with high levels of neuroticism., Methods: We investigated the effect of childhood maltreatment, major life events, daily hassles, and a composite index thereof (cumulative stress index) on depressive symptoms and major depressive disorder (MDD) including the possible moderating role of neuroticism in a discovery sample from the general population (N = 563) and an independent replication sample from the Netherlands Study of Depression and Anxiety (N = 2,274)., Results: All stress domains were independently associated with depressive symptoms in the discovery sample. In the replication sample, we confirmed these findings for childhood maltreatment and daily hassles but not for major life events with depressive symptoms as outcome. Nevertheless, all stress domains significantly contributed to the presence of MDD in the replication sample. The cumulative stress index was significantly associated with depression in the discovery (β = 1.42, P < .001) and replication sample (β = 3.79, P < .001), especially in those individuals with high levels of trait neuroticism (discovery: β = 0.013, P < .001; replication: β = 0.367, P < .001)., Conclusions: This is the first study to show that cumulative stress exposure across different stress domains contributes to depressive symptoms and MDD in adulthood. Moreover, we show that increased exposure to stress across the life span has more impact on vulnerable individuals with high levels of trait neuroticism., (© 2014 Wiley Periodicals, Inc.)

To study the psychometric properties of the Childhood Trauma Questionnaire-Short Form (CTQ-SF), we determined its dimensional structure, measurement invariance across presence of emotional disorders, the association of the CTQ-SF with an analogous interview-based measure (CTI) across presence of emotional disorders, and the incremental value of combining both instruments in determining associations with severity of psychopathology. The sample included 2,308 adults, ages 18-65, consisting of unaffected controls and chronically affected and intermittently affected persons with an emotional disorder at Time 0 (T0) or 4 years later at T4. Childhood maltreatment was measured at T0 with an interview and at T4 with the CTQ-SF. At each wave, patients were assessed for Diagnostic and Statistical Manual of Mental Disorders (4th ed., or DSM-IV; American Psychiatric Association, 1994)-based emotional disorders (Composite Interview Diagnostic Instrument) and symptom severity (Inventory of Depressive Symptomatology, Beck Anxiety Inventory, Fear Questionnaire). Besides the correlated original 5-factor solution, an indirect higher order and direct bifactorial model also showed a good fit to the data. The 5-factor solution proved to be invariant across disordered-control comparison groups. The CTQ-SF was moderately associated with the CTI, and this association was not attenuated by disorder status. The CTQ-SF was more sensitive in detecting emotional abuse and emotional neglect than the CTI. Combined CTQ-SF/CTI factor scores showed a higher association with severity of psychopathology. We conclude that although the original 5-factor model fits the data well, results of the hierarchical analyses suggest that the total CTQ scale adequately captures a broad dimension of childhood maltreatment. A 2-step measurement approach in the assessment of childhood trauma is recommended in which screening by a self-report questionnaire is followed by a (semi-)structured diagnostic interview., (PsycINFO Database Record (c) 2014 APA, all rights reserved.)

Objectives: Low serum BDNF levels have been found in depressed patients. No study has systematically investigated whether individual symptoms or symptom profiles within a depressed population contribute to low BDNF levels found in depressed subjects., Methods: All 1070 patients with a past 6-month diagnosis of major depressive disorder from the Netherlands Study of Depression and Anxiety (NESDA) were included. Composite International Diagnostic Interview (CIDI) and Inventory of Depressive Symptoms (IDS) items were tested individually in separate multiple regression analyses with serum BDNF level as the dependent and the CIDI or IDS item as independent variable. Subsequently, we compared BDNF levels between patients with seasonal affective disorder (based on the Seasonal Pattern Assessment Questionnaire) and melancholic depression, atypical depression and moderate depression (based on a latent class analysis). All analyses were adjusted for confounders., Results: Only one item was significantly associated with serum BDNF levels, namely the CIDI item "loss of interest" (β = 0.14; P < 0.01). Counterintuitively the presence of this symptom was associated with higher BDNF levels. Other items and the comparison between different types of depression did not reveal significant differences., Conclusions: Decreased serum BDNF levels in depression cannot be attributed to a specific symptom or symptom cluster.

Objectives: To evaluate race-related differences in depression onset and recovery in older persons, overall and by sex, and examine race-related differences in mortality according to depression., Design: Prospective cohort study., Setting: General community in pre-designated zip code areas in Memphis, Tennessee, and Pittsburgh, Pennsylvania., Participants: 3,075 persons aged 70-79 years at baseline in the Health, Aging, and Body Composition study., Measurements: Depression was assessed at eight time points over 10 years using the 10-item Center for Epidemiologic Studies-Depression scale; patients were categorized as nondepressed (score less than 8) or depressed (score of 8 or higher). We created variables for transitions across each 18-month time interval, namely, from nondepressed or depressed to nondepressed, depressed, or death, and determined the association between race and the average likelihood of these transitions over time., Results: A higher percentage of blacks than whites were depressed at nearly all time points. Adjusting for demographics, common chronic conditions, and body mass index, blacks had a higher likelihood of experiencing depression onset than whites (odds ratio [OR]: 1.22; 95% confidence interval [CI]: 1.03-1.43); among men, blacks were more likely to experience depression onset than whites (OR: 1.44; 95% CI: 1.24-2.89). Blacks also had a higher likelihood of transitioning from nondepressed to death (OR: 1.79; 95% CI: 1.30-2.46). Overall and in sex-stratified analyses, race was not associated with recovery from depression or with the transition from depression to death., Conclusion: Our findings highlight race differences in depression in older persons and encourage further research on the course of depression in older black patients., (Copyright © 2014 American Association for Geriatric Psychiatry. All rights reserved.)

Background: Several studies have suggested that induced tryptophan (TRP) degradation through the kynurenine (KYN) pathway by the enzyme indoleamine 2,3-dioxygenase (IDO) is implicated in the relation between depression and inflammation. We investigated the role of tryptophan degradation in the relationship between inflammatory markers and depressive symptoms in the Netherlands Study of Depression and Anxiety (NESDA) and hypothesized that tryptophan degradation would mediate (part of) this association., Methods: 2812 Participants of NESDA were included in this study including 1042 persons with current major depressive disorder (MDD). Assessments of C-reactive protein (CRP), interleukin (IL)-6, tumor-necrosis factor (TNF)-α, KYN and TRP were obtained from fasting blood samples at the baseline assessment. Tryptophan degradation was estimated by calculating the ratio [KYN/TRP]. Depressive symptoms were measured with the Inventory of Depressive Symptomatology., Results: Significant associations between inflammation and depressive symptoms were found for CRP and IL-6, for the total group and the subgroup of patients with current MDD. Adjustment for KYN/TRP did not attenuate these associations. There were no significant indirect effects for CRP on depressive symptoms mediated by KYN/TRP for the whole group (B=-0.032; 95% CI: -0.103 to 0.028) and for the subgroup of patients with current MDD (B=0.059; 95% CI: -0.037 to 0.165). Also IL-6 did not indirectly affect depressive symptoms through KYN/TRP in the total group (B=-0.023; 95% CI: -0.093 to 0.045) and in the MDD subgroup B=0.052; 95% CI: -0.019 to 0.144). Finally, no significant relation between depressive symptoms and KYN/TRP was found in the whole group (β=-0.019, p=0.311) nor in the subgroup with MDD (β=0.025, p=0.424)., Conclusions: We did not find indications for tryptophan degradation, measured by KYN/TRP, to mediate the relationship between inflammation and depressive symptoms., (Copyright © 2014 Elsevier Ltd. All rights reserved.)