In 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.

We aim to demonstrate that DTW could also be used to model the network structure in Ecological Momentary Assessment (EMA) data.

355 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.

DTW 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.

DTW 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.

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The role of the interaction between the serotonin-transporter-linked promoter region (5HTTLPR) and stressful condition in determining the vulnerability to depression has been widely investigated. Nevertheless, empirical research provides contrasting findings. Recently, the differential susceptibility to environment model proposed a conceptual shift respect to the classical interpretation of 5-HTTLPR: viewing the short (s) and the long (l) allele not as associated to different traits of vulnerability (respectively vulnerable or not), but determining different plasticity levels (respectively, more and less plasticity) and, thus, different susceptibilities to the environment (respectively, high and low susceptibility).

As 5-HTTLPR is involved in plasticity, the main goal of the present study is to demonstrate that the interaction between the polymorphism and stress emerges when assessing its effects according to temporal factors in a dynamic process perspective.

We explored our hypothesis, exploiting a meta analytic approach. We searched PubMed, PsychoINFO, Scopus and EMBASE databases and 1096 studies were identified and screened, resulting in 22 studies to be included in the meta-analyses. We applied the DerSimonian and Laird random-effects model to estimate crude odds ratios for risk of depression according to 5HTTLPR and we assessed heterogeneity using the I² and Cochran’s Q statistic. We stratified the staties according to (i) stress duration (i.e., chronic vs. acute stress) and (ii) time elapsed between the end of the stressful condition and the assessment of depression (i.e., within one year vs. more than one year).

When stratifying for the duration of stress, the effect of the 5-HTTLPR x stress interaction emerged only in the case of chronic stress (OR 1.43, 95%IC 1.16-1.77, I²= 52%, Q=25.25; Figure 1), with a significant subgroup difference (p=0.004). The stratification according to time interval revealed a significant interaction only for intervals within one year (OR 1.23, 95%IC 1.03-1-46, I²= 67%, Q=39.35), though no difference between subgroups was found. The critical role of time interval clearly emerged when considering only chronic stress: a significant effect of the 5-HTTLPR and stress interaction was confirmed exclusively within one year (OR 1.53, 95%IC 1.17-2.02, I²= 45%, Q=10.94; Figure 2) and a significant subgroup difference was found (p=0.01).

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Our results show that the 5-HTTLPR x stress interaction is a dynamic process, producing different effects at different time-points, and indirectly confirm that s-allele carriers are both at higher risk and more capable to recover from depression. Overall, these findings expand the current view of the interplay between 5-HTTLPR and stress adding the temporal dimension, resulting in a three-way interaction: gene x environment x time.

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Childhood trauma (CT) is associated with severe sequelae, including personality disorders and stress-related mental health disorders that can perpetuate long into adulthood.

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, 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.

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 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.

Participants (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.

Childhood 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.

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The burden on society by depression is undisputable, partly due to a chronic course pattern and depression’s large heterogeneity that contributes to non-response to standard treatments. Using data from the Netherlands Study of Depression and Anxiety (NESDA, www.nesda.nl), Penninx will illustrate both points. When examining the course of depression, especially when also considering the transitions into other affective disorders over time, chronicity is clearly more the rule than the exception (Verduijn et al. BMC Med 2017). Considering depression’s heterogeneity could lead to precision psychiatry approaches that help reduce depression’s chronicity. Immuno-metabolic dysregulations seem to vary as a function of depression heterogeneity: dysregulations map more consistently to “atypical” neurovegetative symptoms reflecting altered energy intake/expenditure balance (hyperphagia, weight gain, hypersomnia, fatigue and leaden paralysis). Findings are confirmed when utilizing genome-wide gene expression as well as DNA information (Milaneschi et al. Biol Psychiatry 2020). Preliminary treatment studies suggest that the presence of immuno-metabolic dysregulations in depression moderates antidepressant effects of standard or novel (immunomodulatory) interventions. An immuno-metabolic depression dimension could dissect depression’s heterogeneity and potentially match depressed subgroups to treatments with higher likelihood of clinical success.

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Alterations in heart rate (HR) may provide new information about physiological signatures of depression severity. This 2-year study in individuals with a history of recurrent major depressive disorder (MDD) explored the intra-individual variations in HR parameters and their relationship with depression severity.

Data from 510 participants (Number of observations of the HR parameters = 6666) were collected from three centres in the Netherlands, Spain, and the UK, as a part of the remote assessment of disease and relapse-MDD study. We analysed the relationship between depression severity, assessed every 2 weeks with the Patient Health Questionnaire-8, with HR parameters in the week before the assessment, such as HR features during all day, resting periods during the day and at night, and activity periods during the day evaluated with a wrist-worn Fitbit device. Linear mixed models were used with random intercepts for participants and countries. Covariates included in the models were age, sex, BMI, smoking and alcohol consumption, antidepressant use and co-morbidities with other medical health conditions.

Decreases in HR variation during resting periods during the day were related with an increased severity of depression both in univariate and multivariate analyses. Mean HR during resting at night was higher in participants with more severe depressive symptoms.

Our findings demonstrate that alterations in resting HR during all day and night are associated with depression severity. These findings may provide an early warning of worsening depression symptoms which could allow clinicians to take responsive treatment measures promptly.

Cognitive symptoms are common during and following episodes of depression. Little is known about the persistence of self-reported and performance-based cognition with depression and functional outcomes.

This is a secondary analysis of a prospective naturalistic observational clinical cohort study of individuals with recurrent major depressive disorder (MDD; N = 623). Participants completed app-based self-reported and performance-based cognitive function assessments alongside validated measures of depression, functional disability, and self-esteem every 3 months. Participants were followed-up for a maximum of 2-years. Multilevel hierarchically nested modelling was employed to explore between- and within-participant variation over time to identify whether persistent cognitive difficulties are related to levels of depression and functional impairment during follow-up.

508 individuals (81.5%) provided data (mean age: 46.6, s.d.: 15.6; 76.2% female). Increasing persistence of self-reported cognitive difficulty was associated with higher levels of depression and functional impairment throughout the follow-up. In comparison to low persistence of objective cognitive difficulty (<25% of timepoints), those with high persistence (>75% of timepoints) reported significantly higher levels of depression (B = 5.17, s.e. = 2.21, p = 0.019) and functional impairment (B = 4.82, s.e. = 1.79, p = 0.002) over time. Examination of the individual cognitive modules shows that persistently impaired executive function is associated with worse functioning, and poor processing speed is particularly important for worsened depressive symptoms.

We replicated previous findings of greater persistence of cognitive difficulty with increasing severity of depression and further demonstrate that these cognitive difficulties are associated with pervasive functional disability. Difficulties with cognition may be an indicator and target for further treatment input.

Major Depressive Disorder (MDD) is prevalent, often chronic, and requires ongoing monitoring of symptoms to track response to treatment and identify early indicators of relapse. Remote Measurement Technologies (RMT) provide an exciting opportunity to transform the measurement and management of MDD, via data collected from inbuilt smartphone sensors and wearable devices alongside app-based questionnaires and tasks.

To describe the amount of data collected during a multimodal longitudinal RMT study, in an MDD population.

RADAR-MDD is a multi-centre, prospective observational cohort study. People with a history of MDD were provided with a wrist-worn wearable, and several apps designed to: a) collect data from smartphone sensors; and b) deliver questionnaires, speech tasks and cognitive assessments and followed-up for a maximum of 2 years.

A total of 623 individuals with a history of MDD were enrolled in the study with 80% completion rates for primary outcome assessments across all timepoints. 79.8% of people participated for the maximum amount of time available and 20.2% withdrew prematurely. Data availability across all RMT data types varied depending on the source of data and the participant-burden for each data type. We found no evidence of an association between the severity of depression symptoms at baseline and the availability of data. 110 participants had > 50% data available across all data types, and thus able to contribute to multiparametric analyses.

RADAR-MDD is the largest multimodal RMT study in the field of mental health. Here, we have shown that collecting RMT data from a clinical population is feasible.

No significant relationships.

No significant relationships.

Toxoplasma gondii (T. gondii) is an obligate intracellular parasite that is estimated to be carried by one-third of the world population. While evidence has been found for a relationship between T. gondii infection and schizophrenia, its relationship with other psychiatric disorders like depressive and anxiety disorders shows inconsistent results.

The aim of the present study was to examine whether T. gondii seropositivity is associated with affective disorders, as well as with aggression reactivity and suicidal thoughts.

In the Netherlands Study of Depression and Anxiety (NESDA), T. gondii antibodies were assessed in patients with current depressive (n=133), anxiety (n=188), comorbid depressive and anxiety (n=148), and remitted disorders (n=889), as well as in healthy controls (n=373) based on DSM-IV criteria. Seropositivity was analyzed in relation to disorder status, aggression reactivity and suicidal thoughts using multivariate analyses of covariance and regression analyses.

Participants were on average 51.2 years (SD = 13.2), and 64.4% were female. Seropositivity was found in 673 participants (38.9%). A strong positive association between T. gondii seropositivity and age was observed. No significant associations were found between T. gondii seropositivity and disorder status, aggression reactivity and suicidal thoughts. The adjusted odds ratio (OR) for any remitted disorder versus controls was 1.13 (95% CI: 0.87-1.49), and for any current disorder versus controls was 0.94 (95% CI: 0.69- 1.28).

No evidence was found for a relationship between affective disorders and T. gondii infection

No significant relationships.

No significant relationships.

Depression is the mental disorder with the largest disease burden impact. That is due to its high prevalence, chronicty, early onset but also due to its impact on various aging-related somatic morbidities and mortality. This talk will describes to what extent depression characteristics are related to chronologial and biological aging patterns.

Data will be shown from the Netherlands Study of Depression and Anxiety (NESDA, www.nesda.nl). In this study, a large cohort of over 3000 individuals (18-65 years), among which over 1200 with a DSM-based major depressive disorder (MDD), are now followed for 9 years. The association between depression characteristics and chronological and biological age will be described. Biological age was determined at various biological system-levels, including telomere length, epigenetics, transcriptomics, metabolomics and proteomics.

Older persons with a current MDD do not differ in overall disease severity as compared to younger persons with a current MDD. However, older depressed persons do differ in the types of symptoms they experience (more neurovegetative, somatic symptoms and less mood symptoms) and in their chronic course (with twice more chronicity in the oldest depressed persons compare to the younges depressed persons). At all biological system-levels, there was evidence for more advaned biological aging among persons with depression. This was not differential across chronological age groups. Discussion: Findings suggest that depression characteristics are linked to both chronological and biological age. It will be discussed what this could mean for clinical practice and intervention.

No significant relationships.

To determine possible associations between guideline-concordant care and clinical outcome in general practice patients with anxiety and depression, and identification of patient characteristics associated with poor clinical outcome.

Data from the Netherlands Study of Anxiety and Depression (NESDA) was used. NESDA is a longitudinal cohort study to measure the long-term course and consequences of anxiety and depressive disorders. Adult patients were interviewed to measure DSM-IV diagnoses during the baseline assessment, and completed questionnaires measuring symptom severity, sociodemographic variables and social support at baseline and 12 months later. The definition of guideline adherence was based on an algorithm on care that was received.

721 patients with a current (6-month recency) anxiety or depressive disorder participated. While patients who received guideline-concordant care (N=281) suffered from more severe symptoms than patients who received non-guideline concordant care (N=440), both groups improved equally on their depressive or anxiety symptoms after 12 months. Patients who (still) had moderate or severe symptoms at follow-up, were more often unemployed, had smaller personal networks and more severe depressive symptoms at baseline than patients with low symptoms at follow-up.

The added value of guideline-concordant care could not be demonstrated in this study. While patients with comorbidity of both anxiety and depressive disorders, those with smaller social networks and the unemployed were more likely to suffer from moderate or severe symptoms after 12 months, severity of depressive symptoms at baseline was most strongly associated. Findings have practical implications as well as implication for future research.

To determine whether chronic medical conditions mediate the association between depression and cardiovascular disease (CVD) mortality.

Data analyzed were from 6,394 subjects aged 25–74 years who participated in extensive health examinations in the NHEFS conducted between 1971 and 1975 and follow-up studies to 1992. CVD mortality was the endpoint. Depression predictors were clinically significant depressive symptoms at baseline by the GWB-D, and/or at 1982–84 by the CES-D (‘baseline’, ‘new’, or ‘twice’ depression). Chronic conditions were prevalent/incident high blood pressure, diabetes, and nonfatal CVD by examination and/or self-report. Mediation effects were assessed by stepwise adjustments of covariates and additive interactions in competing-risks regression models (accounting for other mortality causes) and logit models.

Baseline, new, and twice depression were significant predictors of CVD mortality in competing-risks models adjusted for demographics (HRs 1.3, 1.4, and 2.0), but effects were progressively weakened and became non-significant after adjustment for lifestyle factors, prevalent and incident medical conditions, respectively. CVD mortality risk was 80% higher for depression plus incident nonfatal CVD than without (HR 4.0 vs. 3.2, additive interaction), and mediation effects of depression via chronic medical conditions (particularly via incident nonfatal CVD) increased the risk by 2 to 11% in logit models, independent of all covariates.

Several levels of evidence suggest that the association between depression and CVD mortality is partially mediated by prevalent/incident chronic medical conditions, as well as unhealthy lifestyle behaviors. Patients presenting with clinically significant depressive symptoms, particularly if persistent, should be assessed for both chronic conditions and lifestyle risk factors.

Depression and obesity are highly prevalent major public health problems that frequently co-occur. Shared aetiological factors have been found between depression and obesity. The role of the fat mass and obesity associated (FTO) gene in body mass index (BMI) and obesity has been confirmed in many independent studies. Recently, we reported the first study implicating FTO in the association between depression and obesity.

We aimed to confirm these findings by investigating the FTO rs9939609 polymorphism in a meta-analysis of 13,701 individuals.

The sample consists of 6,902 depressed cases and 6,799 controls from five studies (Radiant, PsyCoLaus, GSK, MARS and NESDA/NTR). Common inclusion criteria were information available on a lifetime DSM-IV diagnosis of major depressive disorder (MDD), BMI and genotype data. Linear regression models for quantitative traits assuming an additive genetic model were performed to test for association and interaction between rs9939609, BMI and depression. Fixed and random-effects meta-analyses were performed.

Fixed-effects meta-analyses support a significant association between rs9939609 polymorphism and BMI (whole-sample: ß=0.07, p=1.29×10-12, depressive-cases: ß=0.12, p=6.92×10-12). No association was found in controls (ß=0.02, p=0.15). Meta-analyses further support a significant interaction between FTO, BMI and depression (fixed-effects: ß=0.13, p=3.087×10-7; random-effects: ß=0.12, p=0.027), wherein depressed carriers of the risk allele have an additional increase of 2.2% in BMI.

This meta-analysis demonstrates a significant interaction between FTO, depression and BMI, indicating that depression increases the effect of FTO on BMI. Depression-related alterations in key biological processes may interact with the rs9939609 FTO risk allele to increase obesity risk.

There is increasing interest in day-to-day affect fluctuations of patients with depressive and anxiety disorders. Few studies have compared repeated assessments of positive affect (PA) and negative affect (NA) across diagnostic groups, and fluctuation patterns were not uniformly defined. The aim of this study is to compare affect fluctuations in patients with a current episode of depressive or anxiety disorder, in remitted patients and in controls, using affect instability as a core concept but also describing other measures of variability and adjusting for possible confounders.

Ecological momentary assessment (EMA) data were obtained from 365 participants of the Netherlands Study of Depression and Anxiety with current (n = 95), remitted (n = 178) or no (n = 92) DSM-IV defined depression/anxiety disorder. For 2 weeks, five times per day, participants filled-out items on PA and NA. Affect instability was calculated as the root mean square of successive differences (RMSSD). Tests on group differences in RMSSD, within-person variance, and autocorrelation were performed, controlling for mean affect levels.

Current depression/anxiety patients had the highest affect instability in both PA and NA, followed by remitters and then controls. Instability differences between groups remained significant when controlling for mean affect levels, but differences between current and remitted were no longer significant.

Patients with a current disorder have higher instability of NA and PA than remitted patients and controls. Especially with regard to NA, this could be interpreted as patients with a current disorder being more sensitive to internal and external stressors and having suboptimal affect regulation.

Although depression with anxious distress appears to be a clinically relevant subtype of Major Depressive Disorder (MDD), whether it involves specific pathophysiology remains unclear. Inflammation has been implicated, but not comprehensively studied. We examined within a large MDD sample whether anxious distress and related anxiety features are associated with differential basal inflammation and innate cytokine production capacity.

Data are from 1078 MDD patients from the Netherlands study of depression and anxiety. Besides the DSM-5 anxious distress specifier, we studied various dimensional anxiety scales (e.g. Inventory of Depressive Symptomatology anxiety arousal subscale [IDS-AA], Beck Anxiety Inventory [BAI], Mood and Anxiety Symptoms Questionnaire Anxious Arousal scale [MASQ-AA]). Basal inflammatory markers included C-reactive protein, interleukin (IL)-6 and tumor-necrosis factor (TNF)-α. Innate production capacity was assessed by 13 lipopolysaccharide (LPS)-stimulated inflammatory markers. Basal and LPS-stimulated inflammation index scores were created.

Basal inflammation was not associated with anxious distress in MDD patients (anxious distress prevalence 54.3%), except for modest positive associations for IDS-AA and BAI scores. However, anxious distress was associated with higher LPS-stimulated levels (interferon-ɣ, IL-2, IL-6, monocyte chemotactic protein (MCP)-1, macrophage inflammatory protein (MIP)-1α, MIP-1β, matrix metalloproteinase-2, TNF-α, TNF-β, LPS-stimulated index). Oher anxiety indicators (number of specifier items and anxiety diagnoses, IDS-AA, BAI, MASQ-AA) were also associated with increased innate production capacity.

Within a large MDD sample, the anxious distress specifier was associated with increased innate cytokine production capacity but not with basal inflammation. Results from dimensional anxiety indicators largely confirm these results. These findings provide new insight into the pathophysiology of anxious depression.

It has been hypothesized that lowered antioxidant capacity, which leads to increased oxidative stress, may be involved in the pathophysiology of major depressive disorder (MDD) and anxiety disorders and might be altered by antidepressant treatment.

This study investigated the association of plasma uric acid, the greatest contributor to blood antioxidant capacity, with MDD, generalized anxiety disorder, social phobia, panic disorder, agoraphobia and antidepressants in a large cohort.

Data was derived from the Netherlands Study of Depression and Anxiety including patients with current (n = 1648) or remitted (n = 609) MDD and/or anxiety disorder(s) (of which n = 710 antidepressant users) and 618 controls. Diagnoses were established with the Composite Interview Diagnostic Instrument. Symptom severity was ascertained in all participants with the Inventory of Depressive Symptoms and the Beck Anxiety Inventory. ANCOVA and regression analyses were adjusted for sociodemographic, health and lifestyle variables.

Plasma uric acid was lower in those with current MDD and/or anxiety disorder(s) (adjusted mean 270 μmol/L) compared to those with remitted disorders (280 μmol/L, P < 0.001) or to controls (281 μmol/L, P < 0.001; Cohen's d 0.14). Within patients antidepressants were not associated with uric acid levels. Increasing symptom severity was associated with lower uric acid levels for both depression (β = –0.05, P = 0.001) and anxiety symptoms (β = –0.05, P = 0.004).

This large scale study finds that the antioxidant uric acid is lower in current, but not remitted, MDD or anxiety disorders and in persons with higher symptom severity, suggesting disturbances in redox homeostasis play a role in the pathophysiology of depression and anxiety disorders.

The authors have not supplied their declaration of competing interest.

Oxidative stress has been implicated in the pathophysiology of depression and anxiety disorders and may be influenced by antidepressant use.

This study investigated the association of oxidative stress, measured by plasma levels of F2-isoprostanes and 8-hydroxy-2′-deoxyguanosine (8-OHdG), reflecting oxidative lipid and DNA damage respectively, with major depressive disorder (MDD), generalized anxiety disorder, social phobia, panic disorder, agoraphobia and antidepressant use in a large cohort.

Data was derived from the Netherlands Study of Depression and Anxiety including patients with current (n = 1641) or remitted (n = 610) MDD and/or anxiety disorder(s) (of which n = 709 antidepressant users) and 633 controls. Diagnoses were established with the Composite Interview Diagnostic Instrument. Plasma 8-OHdG and F2-isoprostanes were measured using UHPLC-MS/MS. ANCOVA was performed adjusting for sampling, sociodemographic, health and lifestyle variables.

F2-isoprostanes did not differ between controls and patients, or by antidepressant use. Patients (current or remitted) using antidepressants had lower 8-OHdG (adjusted mean 38.3 pmol/L) compared to patients (current or remitted) without antidepressants (44.7 pmol/L) and controls (44.9 pmol/L, P < 0.001; Cohen's d 0.26). Findings for 8-OHdG were similar over all disorders and all antidepressant types (SSRIs, TCAs, SNRIs; P < 0.001).

Contrary to previous findings this large-scale study did not find increased oxidative stress measured by F2-isoprostanes or 8-OHdG in MDD or anxiety disorders. 8-OHdG levels were lower in antidepressant users, which suggests antidepressants may have antioxidant properties.

The authors have not supplied their declaration of competing interest.