Netherlands Study Of Depression And Anxiety Research Articles

Borderline personality features in relationship to childhood trauma in unipolar depressive and bipolar disorders

BackgroundChildhood trauma, including emotional neglect, emotional abuse, physical abuse, and sexual abuse, may contribute to borderline personality features like affective instability, identity problems, negative relationships, and self-harm. This study aims to explore how different types of childhood trauma affect these features in bipolar versus unipolar depressive disorders. MethodsWe included 839 participants of the Netherlands Study of Depression and Anxiety (NESDA) with a lifetime diagnosis of major depressive disorder single episode (MDDS; N = 443), recurrent major depressive disorder (MDD-R; N = 331), or bipolar disorder (BD; N = 65). Multivariate regression was used to analyze data from the Childhood Trauma Interview and borderline features (from the self-report Personality Assessment Inventory). ResultsOn average, participants were 48.6 years old (SD: 12.6), with 69.2 % being women, and 50.3 % of participants assessed positive for childhood trauma. Adjusted analyses revealed that participants diagnosed with BD, followed by MDD-R, exhibited the highest number of borderline personality features. Additionally, within the entire group, a strong association was found between childhood trauma, especially emotional neglect, and the presence of borderline personality features. ConclusionGiven the high prevalence of childhood trauma and borderline personality features, screening for these factors in individuals with mood disorders is crucial. Identifying these elements can inform and enhance the management of the often fluctuating and complex nature of these comorbid conditions, leading to more effective and tailored treatment strategies.

Association of CYP2D6 and CYP2C19 metabolizer status with switching and discontinuing antidepressant drugs: an exploratory study

BackgroundTailoring antidepressant drugs (AD) to patients’ genetic drug-metabolism profile is promising. However, literature regarding associations of ADs’ treatment effect and/or side effects with drug metabolizing genes CYP2D6 and CYP2C19 has yielded inconsistent results. Therefore, our aim was to longitudinally investigate associations between CYP2D6 (poor, intermediate, and normal) and CYP2C19 (poor, intermediate, normal, and ultrarapid) metabolizer-status, and switching/discontinuing of ADs. Next, we investigated whether the number of perceived side effects differed between metabolizer statuses.MethodsData came from the multi-site naturalistic longitudinal cohort Netherlands Study of Depression and Anxiety (NESDA). We selected depression- and/or anxiety patients, who used AD at some point in the course of the 9 years follow-up period (n = 928). Medication use was followed to assess patterns of AD switching/discontinuation over time. CYP2D6 and CYP2C19 alleles were derived using genome-wide data of the NESDA samples and haplotype data from the PharmGKB database. Logistic regression analyses were conducted to investigate the association of metabolizer status with switching/discontinuing ADs. Mann–Whitney U-tests were conducted to compare the number of patient-perceived side effects between metabolizer statuses.ResultsNo significant associations were observed of CYP metabolizer status with switching/discontinuing ADs, nor with the number of perceived side effects.ConclusionsWe found no evidence for associations between CYP metabolizer statuses and switching/discontinuing AD, nor with side effects of ADs, suggesting that metabolizer status only plays a limited role in switching/discontinuing ADs. Additional studies with larger numbers of PM and UM patients are needed to further determine the potential added value of pharmacogenetics to guide pharmacotherapy.

Effect of religion on the course of anxiety disorders and symptoms over 9-years follow-up

BackgroundReligion can be an important aspect in life for people and may therefore be important to consider in anxiety disorders. However, there has been limited research into the longitudinal relationship between religiousness and the prevalence of anxiety disorders or anxiety severity and no such research up to date looking at specific anxiety disorders. MethodsWe made use of data from the Netherlands Study of Depression and Anxiety (NESDA), a large clinical cohort study, including 2981 participants at baseline. Based on religious affiliation, commitment to affiliation and religious attendance at baseline as demographic variables, three groups (non-affiliated; affiliated, low commitment/attendance; affiliated, higher commitment/attendance) were compared regarding the prevalence of specific anxiety disorders and anxiety severity at baseline and at two, four, six, and nine years follow-up. For the analyses, we used graphs and Linear Mixed Models. ResultsOverall, no differences were found for the prevalence of specific anxiety disorders and of comorbidity between anxiety disorders or comorbidity with depressive disorders. Furthermore, results showed no differences between the groups regarding the anxiety severity over time. LimitationsThe main limitations relate to the operationalization of religiousness based on demographic variables at baseline. ConclusionsOn a population level, being religiously affiliated with more or less commitment/attendance does not seem to protect against specific anxiety disorders or more anxiety symptoms, nor is it a risk factor. Further research should focus on more internal religious aspects, and more specifically on anxiety in specific groups of religious people or people with specific religion related anxiety.

Suicidal ideation across depressive episodes: 9-year longitudinal cohort study.

Depression is a highly recurrent disorder, with more than 50% of those affected experiencing a subsequent episode. Although there is relatively little stability in symptoms across episodes, some evidence indicates that suicidal ideation may be an exception. However, these findings warrant replication, especially over longer periods and across multiple episodes. To assess the relative stability of suicidal ideation in comparison with other non-core depressive symptoms across episodes. We examined 490 individuals with current major depressive disorder (MDD) at baseline and at least one subsequent episode during 9-year follow-up within the Netherlands Study of Depression and Anxiety (NESDA). The Inventory of Depressive Symptomatology (IDS) was used to assess DSM-5 non-core MDD symptoms (fatigue, appetite/weight change, sleep disturbance, psychomotor disturbance, concentration difficulties, worthlessness/guilt, suicidal ideation) at baseline and 2-, 4-, 6- and 9-year follow-up. We examined consistency in symptom presentation (i.e. whether the symptom met the diagnostic threshold, based on a binary categorisation of the IDS) using kappa (κ) and percentage agreement, and stability in symptom severity using Spearman correlation, based on the continuous IDS scores. Out of all non-core depressive symptoms, insomnia appeared the most stable across episodes (r = 0.55-0.69, κ = 0.31-0.47) and weight decrease the least stable (r = 0.03-0.33, κ = 0.06-0.19). For suicidal ideation, correlations across episodes ranged from r = 0.36 to r = 0.55 and consistency ranged from κ = 0.28 to κ = 0.49. Suicidal ideation is moderately stable in recurrent depression over 9 years. Contrary to prior reports, however, it does not exhibit substantially more stability than most other non-core symptoms of depression.

Childhood trauma and anger in adults with and without depressive and anxiety disorders.

Childhood trauma (CT) is associated with severe sequelae, including stress-related mental health disorders that can perpetuate long into adulthood. A key mechanism in this relationship seems to be emotion regulation. We aimed to investigate (1) whether childhood trauma is associated with anger in adulthood, and, if so, (2) to explore which types of childhood trauma predominate in the prediction of anger in a cohort that included participants with and without current affective disorders. In the Netherlands Study of Depression and Anxiety (NESDA), childhood trauma was assessed with a semi-structured Childhood Trauma Interview (CTI) at baseline, and analyzed in relation to anger as measured at a 4-year follow-up with the Spielberger Trait Anger Subscale (STAS), the Anger Attacks Questionnaire, and cluster B personality traits (i.e., borderline, antisocial) of the Personality Disorder Questionnaire 4 (PDQ-4), using analysis of covariance (ANCOVA) and multivariable logistic regression analyses. Post hoc analyses comprised cross-sectional regression analyses, using the Childhood Trauma Questionnaire-Short Form (CTQ-SF) also obtained at a 4-year follow-up. Participants (n = 2271) were on average 42.1 years (SD = 13.1), and 66.2% were female. Childhood trauma showed a dose-response association with all anger constructs. All types of childhood trauma were significantly associated with borderline personality traits, independently of depression and anxiety. Additionally, all types of childhood trauma except for sexual abuse were associated with higher levels of trait anger, and a higher prevalence of anger attacks and antisocial personality traits in adulthood. Cross-sectionally, the effect sizes were larger compared with the analyses with the childhood trauma measured 4 years prior to the anger measures. Childhood trauma is linked with anger in adulthood, which could be of particular interest in the context of psychopathology. Focus on childhood traumatic experiences and adulthood anger may help to enhance the effectiveness of treatment for patients with depressive and anxiety disorders. Trauma-focused interventions should be implemented when appropriate.

Transdiagnostic factors predicting the 2-year disability outcome in patients with anxiety and depressive disorders

BackgroundBoth anxiety and depressive disorders are associated with significant long-term disability. Since experienced impairments vary between patients independent of diagnosis and disease severity, identifying transdiagnostic factors that predict the course of disability may provide new targets to reduce disability. This study examines transdiagnostic factors predicting the 2-year disability outcome in patients with anxiety and/or depressive disorders (ADD), focusing on potentially malleable factors.MethodsSix hundred fifteen participants with a current diagnosis of ADD from the Netherlands Study of Depression and Anxiety (NESDA) were included. Disability was assessed at baseline and after 2 years of follow-up, using the 32-item WHODAS II questionnaire. Transdiagnostic predictors of 2-year disability outcome were identified using linear regression analysis.ResultsIn univariable analyses, transdiagnostic factors associated with the 2-year disability outcome were locus of control (standardized β = -0.116, p = 0.011), extraversion (standardized β = -0.123 p = 0.004) and experiential avoidance (standardized β = 0.139, p = 0.001). In multivariable analysis, extraversion had a unique predictive value (standardized β = -0.143 p = 0.003). A combination of sociodemographic, clinical and transdiagnostic variables resulted in an explained variance (R2) of 0.090). The explained variance of a combination of transdiagnostic factors was 0.050.ConclusionThe studied transdiagnostic variables explain a small but unique part of variability in the 2-year disability outcome. Extraversion is the only malleable transdiagnostic factor predictive of the course of disability independent of other variables. Due to the small contribution to the variance in the disability outcome, the clinical relevance of targeting extraversion seems limited. However, its predictive value is comparable to that of accepted disease severity measures, supporting the importance of looking beyond using disease severity measures as predictors. Furthermore, studies including extraversion in combination with other transdiagnostic and environmental factors may elucidate the unexplained part of variability of the course of disability in patients with ADD.

Increased affective reactivity among depressed individuals can be explained by floor effects: An experience sampling study

Experience sampling studies into daily-life affective reactivity indicate that depressed individuals react more strongly to both positive and negative stimuli than non-depressed individuals, particularly on negative affect (NA). Given the different mean levels of both positive affect (PA) and NA between patients and controls, such findings may be influenced by floor/ceiling effects, leading to violations of the normality and homoscedasticity assumptions underlying the used statistical models. Affect distributions in prior studies suggest that this may have particularly influenced NA-reactivity findings. Here, we investigated the influence of floor/ceiling effects on the observed PA- and NA-reactivity to both positive and negative events. Data came from 346 depressed, non-depressed, and remitted participants from the Netherlands Study of Depression and Anxiety (NESDA). In PA-reactivity analyses, no floor/ceiling effects and assumption violations were observed, and PA-reactivity to positive events, but not negative events, was significantly increased in the depressed and remitted groups versus the non-depressed group. However, NA-scores exhibited a floor effect in the non-depressed group and naively estimated models violated model assumptions. When these violations were accounted for in subsequent analyses, group differences in NA-reactivity that had been present in the naive models were no longer observed. In conclusion, we found increased PA-reactivity to positive events but no evidence of increased NA-reactivity in depressed individuals when accounting for violations of assumptions. The results indicate that affective-reactivity results are very sensitive to modeling choices and that previously observed increased NA-reactivity in depressed individuals may (partially) reflect unaddressed assumption violations resulting from floor effects in NA.

Childhood trauma and anger in adults with and without depressive and anxiety disorders

IntroductionChildhood trauma (CT) is associated with severe sequelae, including personality disorders and stress-related mental health disorders that can perpetuate long into adulthood.ObjectivesWe aimed to investigate (1) whether childhood trauma is associated with anger in adulthood, and, if so, (2) to explore which types of childhood trauma predominate in the prediction of anger, and (3) to explore whether the association is independent of psychopathology in a cohort that included participants without lifetime psychiatric disorders, with current or remitted depressive and anxiety disorders, or comorbid depressive and anxiety disorders.MethodsIn the Netherlands Study of Depression and Anxiety (NESDA), childhood trauma was assessed with a semi-structured Childhood Trauma Interview (CTI) at baseline, and analyzed in relation to anger as measured at 4-year follow-up with the Spielberger Trait Anger Subscale (STAS), the Anger Attacks Questionnaire, and cluster B personality traits (i.e., borderline, antisocial) of the Personality Disorder Questionnaire 4 (PDQ-4), using analysis of covariance (ANCOVA) and multivariable logistic regression analyses. Post-hoc analyses comprised cross-sectional regression analyses, using the Childhood Trauma Questionnaire – Short Form (CTQ-SF) obtained at 4-year follow-up.ResultsParticipants (n = 2,276) were on average 42.1 years (SD = 13.1), and 66.3% were female. Childhood trauma showed a dose-response association with all anger constructs. Zooming in, all types of childhood trauma except for sexual abuse were associated with higher levels of trait anger, and a higher prevalence of anger attacks and antisocial personality traits in adulthood, independently of depression and anxiety. Additionally, all types of childhood trauma were significantly associated with borderline personality traits. Cross-sectionally, the effect sizes were larger compared to the analyses with the childhood trauma measured four years prior to the anger measures.ConclusionsChildhood trauma is linked with anger in adulthood, most strongly for trait anger and borderline personality traits. It is of clinical importance to explore childhood traumatic experience and start trauma-focused interventions when appropriate.Disclosure of InterestNone Declared

Big data networks: Dynamic Time Warping as a statistical tool for network analysis using Ecological Momentary Assessment data

IntroductionIn recent research, psychological disorders have been increasingly defined as complex dynamic systems in which symptoms are interconnected and influence each other, thereby forming symptom networks. This paradigm shift calls for the analysis and interpretation of relationships between symptoms that are complex, potentially non-linear, and dynamic. Dynamic Time Warping (DTW) is used to measure similarity in temporal sequences, and has recently been found effective in modelling psychopathology symptom networks.ObjectivesWe aim to demonstrate that DTW could also be used to model the network structure in Ecological Momentary Assessment (EMA) data.Methods355 participants of the Netherlands Study of Depression and Anxiety (NESDA), of which 100 with and 255 without current disorder, completed EMA assessments of 20 symptoms (e.g., feeling sad, tired, satisfied) five times a day for two weeks. DTW analysis was performed on the group level, comparing participants suffering from mood disorders to healthy controls. DTW distances were visualized as an undirected symptom network, in which we adjusted for the average symptom severity per item per person.ResultsDTW analysis of close to half a million symptom scores yielded six symptom dimensions based on their aggregated similarity of changes over time within the participants. Surprisingly, negative affect symptom networks were found to be less strongly connected in those currently suffering from mood disorders than in controls, whereas the network density of (reverse-coded) positive affect symptoms was more closely connected in this group. This is contrary to the results of previous studies, where negative affect-related symptom networks of those with mood disorders were found to be more strongly interconnected.ConclusionsDTW is a promising new technique for analyzing EMA data and modeling dynamic symptom networks at both the individual and group levels. Using EMA data, symptom networks and dimensions can be modeled with great structural and temporal detail. Incorporating the temporal symptom dynamics may highlight the importance of the independent trajectories of negative mood symptoms.Disclosure of InterestNone Declared

Basal and LPS-stimulated inflammatory markers and the course of depression and anxiety symptoms

IntroductionMultiple studies show an association between inflammation –characterized by increased blood levels of C-reactive protein (CRP) and pro-inflammatory cytokines– and major depressive disorder (MDD). People with chronic low-grade inflammation may be at an increased risk of MDD, often in the form of sickness behaviors. A cross-sectional relationship between low-grade inflammation and anxiety has also been reported, but the potential longitudinal relationship has been less well studied.ObjectivesWe aimed to examine whether basal and lipopolysaccharide (LPS-)induced levels of inflammatory markers are associated with depressive and anxiety symptom severity over the course of nine years. We hypothesized that inflammation is predictive of the severity and the course of a subset of symptoms, especially symptoms that overlap with sickness behavior, such as anhedonia, anorexia, low concentration, low energy, loss of libido, psychomotor slowness, irritability, and malaise.MethodsWe tested the association between basal and lipopolysaccharide (LPS)-induced inflammatory markers with individual depressive symptoms (measured using the Inventory of Depressive Symptomatology Self-Report) and anxiety symptoms (measured with the Beck’s Anxiety Inventory; BAI, Fear Questionnaire;FQ and Penn’s State Worry Questionnaire; PSWQ) over a period of up to 9 years using multivariate-adjusted mixed models in 1147 to 2872 Netherlands Study of Depression and Anxiety (NESDA) participants.ResultsAt baseline, participants were on average 42.2 years old, 66.5% were women, and 53.9% had a current mood or anxiety disorder. We found that basal and LPS-stimulated inflammatory markers were more strongly associated with sickness behavior symptoms at up to 9-year follow up compared to non-sickness behavior symptoms of depression. However, we also found significant associations with some symptoms that are not typical of sickness behavior (e.g., sympathetic arousal among others). The associations between inflammation and anxiety symptoms were attenuated by 25%-30% after adjusting for the presence of (comorbid) major depressive disorder (MDD), but remained statistically significant.ConclusionsInflammation was not related to depression as a unified syndrome but rather to the presence and the course of specific MDD symptoms, of which the majority were related to sickness behavior. With regard to anxiety symptoms, we found that participants with high levels of inflammatory markers have on average high levels of anxiety consisting of physical arousal and agoraphobia, which tended to persist over a period of nine years, albeit with small effect sizes. These associations were partly driven by co-morbid depression. Anti-inflammatory strategies should be tested in the subgroup of MDD patients who report depressive symptoms related to sickness behavior.Disclosure of InterestNone Declared

Impact of long-term exposure to PM2.5 on peripheral blood gene expression pathways involved in cell signaling and immune response.

Exposure to ambient air pollution, even at low levels, is a major environmental health risk. The peripheral blood transcriptome provides a potential avenue for the elucidation of ambient air pollution related biological perturbations. We assessed the association between long-term estimates for seven priority air pollutants and perturbations in peripheral blood transcriptomics data collected in the Dutch National Twin Register (NTR) and Netherlands Study of Depression and Anxiety (NESDA) cohorts. In both the discovery (n=2438) and replication (n=1567) cohort, outdoor concentration of 7 air pollutants (NO2, NOx, particulate matter (PM2.5, PM2.5abs, PM10, PMcoarse), and ultrafine particles) was predicted with land use regression models. Gene expression was assessed by Affymetrix U219 arrays. Multi-variable univariate mixed-effect models were applied to test for an association between the air pollutants and the transcriptome. Functional analysis was conducted in DAVID. In the discovery cohort, we observed for 335 genes (374 probes with FDR<5%) a perturbation in peripheral blood gene expression that was associated with long-term average levels of PM2.5. For 69 genes pooled effect estimates from the NTR and NESDA cohorts were significant. Identified genes play a role in biological pathways related to cell signaling and immune response. Sixty-two out of 69 genes had a similar direction of effect in an analysis in which we regressed the probes on differential PM2.5 exposure within monozygotic twin pairs, indicating that the observed differences in gene expression were likely driven by differences in air pollution, rather than by confounding by genetic factors. Our results indicate that PM2.5 can elicit a response in cell signaling and the immune system, both hallmarks of environmental diseases. The differential effect that we observed between air pollutants may aid in the understanding of differential health effects that have been observed with these exposures.

The association between clinical and biological characteristics of depression and structural brain alterations

BackgroundStructural brain alterations are observed in major depressive disorder (MDD). However, MDD is a highly heterogeneous disorder and specific clinical or biological characteristics of depression might relate to specific structural brain alterations. Clinical symptom subtypes of depression, as well as immuno-metabolic dysregulation associated with subtypes of depression, have been associated with brain alterations. Therefore, we examined if specific clinical and biological characteristics of depression show different brain alterations compared to overall depression. MethodIndividuals with and without depressive and/or anxiety disorders from the Netherlands Study of Depression and Anxiety (NESDA) (328 participants from three timepoints leading to 541 observations) and the Mood Treatment with Antidepressants or Running (MOTAR) study (123 baseline participants) were included. Symptom profiles (atypical energy-related profile, melancholic profile and depression severity) and biological indices (inflammatory, metabolic syndrome, and immuno-metabolic indices) were created. The associations of the clinical and biological profiles with depression-related structural brain measures (anterior cingulate cortex [ACC], orbitofrontal cortex, insula, and nucleus accumbens) were examined dimensionally in both studies and meta-analysed. ResultsDepression severity was negatively associated with rostral ACC thickness (B = -0.55, pFDR = 0.03), and melancholic symptoms were negatively associated with caudal ACC thickness (B = -0.42, pFDR = 0.03). The atypical energy-related symptom profile and immuno-metabolic indices did not show a consistent association with structural brain measures across studies. ConclusionOverall depression- and melancholic symptom severity showed a dose-response relationship with reduced ACC thickness. No associations between immuno-metabolic dysregulation and structural brain alterations were found, suggesting that although both are associated with depression, distinct mechanisms may be involved.

Basal and LPS-stimulated inflammatory markers and the course of individual symptoms of depression and anxiety

IntroductionA cross-sectional relationship between low-grade inflammation –characterized by increased blood levels of C-reactive protein (CRP) and pro-inflammatory cytokines– and both MDD and anxiety has been reported, but the potential longitudinal symptom-specific relationships has been less well studied.ObjectivesWe aimed to test our hypothesize that inflammation is predictive of the severity and the course of a subset of MDD and anxiety symptoms, especially symptoms that overlap with sickness behavior, such as anhedonia, anorexia, low concentration, low energy, loss of libido, psychomotor slowness, irritability, and malaise.MethodsWe tested the association between basal and lipopolysaccharide (LPS)-induced inflammatory markers with individual MDD symptoms (measured using the Inventory of Depressive Symptomatology Self-Report) and several measures for symptom domains of anxiety over a period of up to 9 years using multivariate-adjusted mixed models in up to 2872 Netherlands Study of Depression and Anxiety (NESDA) participants.ResultsAt baseline, 53.9% of the participants had a current mood or anxiety disorder. We found that basal and LPS-stimulated inflammatory markers were more strongly associated with sickness behavior symptoms at up to 9-year follow up compared to non-sickness behavior symptoms of depression. The associations with anxiety symptoms attenuated by 25%-30% after adjusting for the presence of (comorbid) MDD.ConclusionsInflammation was related to the presence and the course of specific MDD symptoms, of which the majority overlaped with sickness behavior. The associations between inflammatory markers and anxiety symptoms were partly driven by co-morbid MDD. Anti-inflammatory strategies should be tested in the subgroup of MDD patients who report depressive symptoms related to sickness behavior.DisclosureNo significant relationships.

Childhood trauma and anger in adults with and without depressive and anxiety disorders

IntroductionChildhood trauma is associated with an increased risk of anxiety and depressive disorders, but its association with anger, irritability, and related constructs has received less attention.ObjectivesWe aimed to investigate (1) the relationship between childhood trauma and anger constructs in adulthood, and (2) which types of childhood trauma is most predictive.MethodsIn the Netherlands Study of Depression and Anxiety (NESDA), childhood trauma at baseline was assessed with a semi-structured interview. Childhood trauma was analyzed in relation to the Spielberger Trait Anger Subscale (STAS), the Anger Attacks Questionnaire, and the cluster B personality traits part of the Personality Disorder Questionnaire 4 (PDQ-4), measured at 4-year follow-up, using analysis of covariance (ANCOVA) and multivariable logistic regression analyses, adjusting for sex, age, level of education, BMI, smoking, alcohol dependency/abuse, disorder status.ResultsParticipants were on average 42.1 years (SD = 13.1), and 66.3% (n = 1.508) were female. Childhood trauma showed a dose-response association with all anger constructs. Zooming in, emotional neglect, and psychological, and physical abuse were associated with all anger constructs, independently of depression or anxiety. Additionally, sexual abuse and childhood life events were associated with trait anger and borderline personality traits, and trait anger and antisocial personality traits retrospectively.ConclusionsChildhood trauma is linked with anger in adulthood. Childhood trauma may cause not only anxiety and depression, but also anger, and tailored interventions (at both childhood trauma and anger itself ) might help to improve unsatisfactory relationships and prevent violent behaviors.DisclosureNo significant relationships.

Associations of three major physiological stress systems with suicidal ideation and suicide attempts in patients with a depressive and/or anxiety disorder

BackgroundPeople with depressive and/or anxiety disorders are at increased risk of suicidal ideation and suicide attempts, but biological correlates signaling such risk remain unclear. Independent and cumulative dysregulations in physiological stress systems, in particular the hypothalamic–pituitaryadrenal axis (HPA-axis), immune-inflammatory system, and autonomous nervous system (ANS), may contribute to this risk. However, findings have either been heterogeneous or absent thus far. MethodsAssociations between individual markers and cumulative indices of the HPA-axis (cortisol awakening response and evening cortisol), immune-inflammatory system (C-reactive protein, interleukin-6 (IL-6), and tumor necrosis factor-α), and the ANS (heart rate, respiratory sinus arrhythmia, and pre-ejection period) and the outcomes no suicide ideation with suicide attempt (SI-SA+), suicide ideation without suicide attempt (SI+SA-) and suicide ideation with suicide attempt (SI+SA+) were investigated in 1749 persons with depressive and/or anxiety disorders from the Netherlands Study of Depression and Anxiety (NESDA). ResultsHigh levels of CRP and IL-6 were associated with SI-SA+ and SI+SA+ respectively when compared to non-suicidal patients after adjusting for confounders and multiple testing. Also, cumulative immune-inflammatory dysregulations were positively associated with SI+SA+, suggesting a dose–response effect. No significant associations were found between HPA-axis or ANS indicators and suicide-outcomes and between immune-inflammatory system markers or cumulative stress system dysregulations and SI+SA-. ConclusionAlthough stress system markers could not differentiate between SI+SA- and non-suicidal patients, findings indicate that dysregulations of individual and cumulative immune-inflammatory markers are associated with suicide attempts in depressive and/or anxiety patients. Thus, immune-inflammatory system dysregulation may be involved in the pathophysiology of suicidal behavior, supporting further examination of the effects of anti-inflammatory interventions on suicidality.

Metabolomic and inflammatory signatures of symptom dimensions in major depression

BackgroundMajor depressive disorder (MDD) is a highly heterogenous disease, both in terms of clinical profiles and pathobiological alterations. Recently, immunometabolic dysregulations were shown to be correlated with atypical, energy-related symptoms but less so with the Melancholic or Anxious distress symptom dimensions of depression in The Netherlands Study of Depression and Anxiety (NESDA) study. In this study, we aimed to replicate these immunometabolic associations and to characterize the metabolomic correlates of each of the three MDD dimensions. MethodsUsing three clinical rating scales, Melancholic, and Anxious distress, and Immunometabolic (IMD) dimensions were characterized in 158 patients who participated in the Predictors of Remission to Individual and Combined Treatments (PReDICT) study and from whom plasma and serum samples were available. The NESDA-defined inflammatory index, a composite measure of interleukin-6 and C-reactive protein, was measured from pre-treatment plasma samples and a metabolomic profile was defined using serum samples analyzed on three metabolomics platforms targeting fatty acids and complex lipids, amino acids, acylcarnitines, and gut microbiome-derived metabolites among other metabolites of central metabolism. ResultsThe IMD clinical dimension and the inflammatory index were positively correlated (r = 0.19, p = 0.019) after controlling for age, sex, and body mass index, whereas the Melancholic and Anxious distress dimensions were not, replicating the previous NESDA findings. The three symptom dimensions had distinct metabolomic signatures using both univariate and set enrichment statistics. IMD severity correlated mainly with gut-derived metabolites and a few acylcarnitines and long chain saturated free fatty acids. Melancholia severity was significantly correlated with several phosphatidylcholines, primarily the ether-linked variety, lysophosphatidylcholines, as well as several amino acids. Anxious distress severity correlated with several medium and long chain free fatty acids, both saturated and polyunsaturated ones, sphingomyelins, as well as several amino acids and bile acids. ConclusionThe IMD dimension of depression appears reliably associated with markers of inflammation. Metabolomics provides powerful tools to inform about depression heterogeneity and molecular mechanisms related to clinical dimensions in MDD, which include a link to gut microbiome and lipids implicated in membrane structure and function.

Dissection of depression heterogeneity using proteomic clusters.

The search for relevant biomarkers of major depressive disorder (MDD) is challenged by heterogeneity; biological alterations may vary in patients expressing different symptom profiles. Moreover, most research considers a limited number of biomarkers, which may not be adequate for tagging complex network-level mechanisms. Here we studied clusters of proteins and examined their relation with MDD and individual depressive symptoms. The sample consisted of 1621 subjects from the Netherlands Study of Depression and Anxiety (NESDA). MDD diagnoses were based on DSM-IV criteria and the Inventory of Depressive Symptomatology questionnaire measured endorsement of 30 symptoms. Serum protein levels were detected using a multi-analyte platform (171 analytes, immunoassay, Myriad RBM DiscoveryMAP 250+). Proteomic clusters were computed using weighted correlation network analysis (WGCNA). Six proteomic clusters were identified, of which one was nominally significantly associated with current MDD (p = 9.62E-03, Bonferroni adj. p = 0.057). This cluster contained 21 analytes and was enriched with pathways involved in inflammation and metabolism [including C-reactive protein (CRP), leptin and insulin]. At the individual symptom level, this proteomic cluster was associated with ten symptoms, among which were five atypical, energy-related symptoms. After correcting for several health and lifestyle covariates, hypersomnia, increased appetite, panic and weight gain remained significantly associated with the cluster. Our findings support the idea that alterations in a network of proteins involved in inflammatory and metabolic processes are present in MDD, but these alterations map predominantly to clinical symptoms reflecting an imbalance between energy intake and expenditure.

Chronotype, daily affect and social contact: An ecological momentary assessment study

Eveningness is associated with lower daily positive affect (PA). The relationship between negative affect (NA) and chronotype, however, is less consistent in the literature. Eveningness may be further characterized by increased social isolation, which could explain the associations between chronotype and PA/NA. In the present longitudinal study, we used ecological momentary assessment (EMA) to investigate the associations of chronotype with daily PA, NA, and social contact in individuals with current and remitted major depressive disorder (MDD) and healthy controls. As part of the Netherlands Study of Depression and Anxiety (NESDA), 279 participants (n = 49 depressed, n = 172 remitted, n = 58 controls) monitored daily PA, NA, and social contact (i.e., being alone vs. with others) for two weeks, five times per day. Overall, eveningness was associated with less social contact. This effect became nonsignificant, however, after accounting for sociodemographics (gender, age, education, living situation). Chronotype was not related to PA or NA. Less social contact was associated with lower PA and higher NA independent of chronotype. In conclusion, we could not replicate the finding of lower PA among evening types, but found social contact to associate with both daily PA and NA.

Hair cortisol, obesity and the immune system: Results from a 3 year longitudinal study

ObjectivesHigher long-term glucocorticoid levels, measured in scalp hair (HairGC), are associated with obesity. This may represent the state of obesity (perhaps interrelated with chronic immune activation), but could also promote further weight gain. We studied whether hair cortisol (HairF) and hair cortisone (HairE) predict changes in body mass index (BMI) and waist circumference (WC) over time, and assessed the association between HairGC and common immune parameters. MethodsWe measured HairGC in 1604 participants of the Netherlands Study of Depression and Anxiety (NESDA), and investigated their associations to BMI, WC, and immune parameters (interleukin-6 (IL-6), C-reactive protein (CRP), and leukocyte subsets). Also, we assessed whether baseline HairGC predict changes in BMI and WC at follow-up (three years later). ResultsIn cross-sectional analyses, HairF and HairE were positively associated to BMI (β = 2.06 kg/m2, 95% confidence interval (CI)= 1.22–2.90 kg/m2) and β = 2.84 kg/m2 (95%CI 1.75–3.93 kg/m2) respectively) and WC (β = 5.36 cm (95%CI 3.09–7.62 cm) and β = 8.54 cm (95%CI 5.60–11.48 cm) respectively, all p < 0.001). HairF was also positively associated to IL-6 (β = 0.15 (95%CI 0.003–0.292) p < 0.05) and leukocyte count (β = 0.57 (95%CI 0.234–0.909), p < 0.01), and HairE to IL-6 (β = 0.21 (95%CI 0.016–0.399), p < 0.05).In the longitudinal analyses, higher HairF was associated with yearly increases in BMI (β = 0.58% BMI change per year (95%CI 0.14–1.01%), p = 0.009) and higher HairE with increases in WC (β = 0.84% WC change per year (95%CI 0.02–1.69%), p = 0.049). Adjusting for baseline IL-6 or leukocytes did not change the found associations between HairGC and WC or BMI change. ConclusionsHairGC levels are positively associated to BMI, WC, IL-6 and leukocyte numbers in cross-sectional analyses, and to increases in BMI and WC in longitudinal analyses. Although causality is yet to be proven, higher long-term glucocorticoid levels could represent a relevant risk factor for the development of obesity.

Incident Major Depressive Disorder Predicted by Three Measures of Insulin Resistance: A Dutch Cohort Study.

Major depressive disorder is the leading cause of disability worldwide. Yet, there remain significant challenges in predicting new cases of major depression and devising strategies to prevent the disorder. An important first step in this process is identifying risk factors for the incidence of major depression. There is accumulating biological evidence linking insulin resistance, another highly prevalent condition, and depressive disorders. The objectives of this study were to examine whether three surrogate measures of insulin resistance (high triglyceride-HDL [high-density lipoprotein] ratio; prediabetes, as indicated by fasting plasma glucose level; and high central adiposity, as measured by waist circumference) at the time of study enrollment were associated with an increased rate of incident major depressive disorder over a 9-year follow-up period and to assess whether the new onset of these surrogate measures during the first 2 years after study enrollment was predictive of incident major depressive disorder during the subsequent follow-up period. The Netherlands Study of Depression and Anxiety (NESDA) is a multisite longitudinal study of the course and consequences of depressive and anxiety disorders in adults. The study population comprised 601 NESDA participants (18-65 years old) without a lifetime history of depression or anxiety disorders. The study's outcome was incident major depressive disorder, defined using DSM-IV criteria. Exposure measures included triglyceride-HDL ratio, fasting plasma glucose level, and waist circumference. Fourteen percent of the sample developed major depressive disorder during follow-up. Cox proportional hazards models indicated that higher triglyceride-HDL ratio was positively associated with an increased risk for incident major depression (hazard ratio=1.89, 95% CI=1.15, 3.11), as were higher fasting plasma glucose levels (hazard ratio=1.37, 95% CI=1.05, 1.77) and higher waist circumference (hazard ratio=1.11 95% CI=1.01, 1.21). The development of prediabetes in the 2-year period after study enrollment was positively associated with incident major depressive disorder (hazard ratio=2.66, 95% CI=1.13, 6.27). The development of high triglyceride-HDL ratio and high central adiposity (cut-point ≥100 cm) in the same period was not associated with incident major depression. Three surrogate measures of insulin resistance positively predicted incident major depressive disorder in a 9-year follow-up period among adults with no history of depression or anxiety disorder. In addition, the development of prediabetes between enrollment and the 2-year study visit was positively associated with incident major depressive disorder. These findings may have utility for evaluating the risk for the development of major depression among patients with insulin resistance or metabolic pathology.