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BackgroundDietary interventions did not prevent depression onset nor reduced depressive symptoms in a large multi-center randomized controlled depression prevention study (MooDFOOD) involving overweight adults with subsyndromal depressive symptoms. We conducted follow-up analyses to investigate whether dietary interventions differ in their effects on depressive symptom profiles (mood/cognition; somatic; atypical, energy-related).MethodsBaseline, 3-, 6-, and 12-month follow-up data from MooDFOOD were used (n = 933). Participants received (1) placebo supplements, (2) food-related behavioral activation (F-BA) therapy with placebo supplements, (3) multi-nutrient supplements (omega-3 fatty acids and a multi-vitamin), or (4) F-BA therapy with multi-nutrient supplements. Depressive symptom profiles were based on the Inventory of Depressive Symptomatology.ResultsF-BA therapy was significantly associated with decreased severity of the somatic (B = −0.03, p = 0.014, d = −0.10) and energy-related (B = −0.08, p = 0.001, d = −0.13), but not with the mood/cognition symptom profile, whereas multi-nutrient supplementation was significantly associated with increased severity of the mood/cognition (B = 0.05, p = 0.022, d = 0.09) and the energy-related (B = 0.07, p = 0.002, d = 0.12) but not with the somatic symptom profile.ConclusionsDifferentiating depressive symptom profiles indicated that food-related behavioral interventions are most beneficial to alleviate somatic symptoms and symptoms of the atypical, energy-related profile linked to an immuno-metabolic form of depression, although effect sizes were small. Multi-nutrient supplements are not indicated to reduce depressive symptom profiles. These findings show that attention to clinical heterogeneity in depression is of importance when studying dietary interventions.

Background: Childhood trauma (CT) is a risk factor for depressive and anxiety disorders. However, whether CT is more strongly linked to specific clinical features of these disorders remains inconclusive. The current study comprehensively examined cross-sectional and longitudinal associations between CT and depressive/anxiety symptomatology in a large adult sample with current and remitted depressive and/or anxiety disorders. Methods: Baseline (n = 1803), 2-year (n = 1735), 4-year (n = 1585), and 6-year follow-up (n = 1475) data from the Netherlands Study of Depression and Anxiety were used. CT (emotional neglect, emotional/physical/sexual abuse) was assessed at baseline, while depressive/anxiety symptomatology with relevant dimensions (e.g., mood/cognitive, melancholic, general distress, and somatic depression) was assessed at each wave using self-reported questionnaires. Linear regressions and linear mixed models determined cross-sectional and longitudinal associations. Results: Individuals with CT, especially, severe CT, compared to those without CT, had significantly higher scores in overall depressive symptomatology (Cohen's d = 0.674), mood/cognitive depression (d = 0.691), melancholic depression (d = 0.587), general distress (d = 0.561), and somatic depression severity (d = 0.549). Differences were lower, but still highly significant for anxiety (d = 0.418), worry (d = 0.362), and fear/phobic symptomatology (d = 0.359). Effects were consistent across CT types and maintained over six years. Limitations: Retrospectively-reported CT. Conclusions: CT is a risk factor for depressive and anxiety symptomatology across all dimensions and enduring over multiple years. Screening for CT is essential to identify individuals at risk for more severe and chronic manifestations of affective disorders.

Background: Structural 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. Method: Individuals 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. Results: Depression 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. Conclusion: Overall 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.

BACKGROUND: In a substantial subgroup of depressed patients, atypical, energy-related depression symptoms (e.g. increased appetite/weight, hypersomnia, loss of energy) tend to cluster with immuno-metabolic dysregulations (e.g. increased BMI and inflammatory markers). This clustering is proposed to reflect a more homogeneous depression pathology. This study examines to what extent energy-related symptoms are associated and share sociodemographic, lifestyle and clinical characteristics.METHODS: Data were available from 13,965 participants from eight Dutch cohorts with DSM-5 lifetime major depression assessed by the Lifetime Depression Assessment Self-report (LIDAS) questionnaire. Information on four energy-related depression symptoms were extracted: energy loss, increased appetite, increased weight, and hypersomnia. Tetrachoric correlations between these symptoms, and associations of these symptoms with sociodemographic (sex, age, education), lifestyle (physical activity, BMI, smoking) and clinical characteristics (age of onset, episode duration, history, treatment and recency, and self-reported comorbidity) were computed.RESULTS: Correlations between energy-related symptoms were overall higher than those with other depression symptoms and varied from 0.90 (increased appetite vs increased weight) to 0.11 (increased appetite vs energy loss). All energy-related symptoms were strongly associated with higher BMI and a more severe clinical profile. Patients with increased appetite were more often smokers, and only patients with increased appetite or weight more often had a self-reported diagnosis of PTSD (OR = 1.17, p = 2.91E-08) and eating disorder (OR = 1.40, p = 4.08E-17).CONCLUSIONS: The symptom-specific associations may have consequences for a profile integrating these symptoms, which can be used to reflect immuno-metabolic depression. They indicate the need to study immuno-metabolic depression at individual symptom resolution as a starting point.

Objective: While research found heterogeneous changes in mental health during the COVID-19 pandemic, less is known about the long-term changes in mental health in psychiatric groups. Therefore, we applied a data-driven method to detect sub-groups with distinct trajectories across two years into the pandemic in psychiatric groups, and described their differences in socio-demographic and clinical characteristics. Method: We conducted sixteen rounds of questionnaires between April 2020 and February 2022 among participants (n = 1722) of three psychiatric case–control cohorts that started in the 2000's. We used Growth Mixture Modelling and (multinomial) logistic regression to identify characteristics associated with trajectory membership. Results: We found low decreasing (1228 [72%] participants), intermediate (n = 348 [22%] participants) and high stable (106 [6%] participants) trajectories of depressive symptoms; decreasing low/intermediate (1507 [90%] participants) and high stable (161 [10%] participants) trajectories of anxiety symptoms; and stable low (1109 [61%] participants), stable high (315 [17%] participants), temporary lowered (123 [9%]) and temporary heightened (175 [13%] participants) trajectories of loneliness. Chronicity and severity of pre-pandemic mental disorders predicted unfavourable sub-group membership for all outcomes. Being female, having a low education and income level were associated with unfavourable trajectories of depression, being younger with unfavourable trajectories of anxiety and being female and living alone with unfavourable trajectories of loneliness. Conclusion: We found relatively stable trajectories of depression and anxiety symptoms over two years, suggesting low heterogeneity in outcomes during the pandemic. For loneliness, we found two specific sub-groups with temporary increase and decrease in loneliness during the pandemic.

BackgroundThe treatment of depression in patients with somatic disorders is crucial, given its negative impact on quality of life (QoL), functioning, and even on the somatic disease prognosis. We aimed to examine the most updated evidence on the effects of psychotherapy in patients with depression and somatic disorders, including HIV, oncological, cardiometabolic, and neurological disorders.MethodsWe conducted a meta-analysis of 75 randomized trials (8209 participants) of psychotherapy for adults with somatic disorders and a diagnosis or elevated symptoms of depression. Outcomes included depression, QoL, somatic health-related outcomes, and mortality.ResultsPsychotherapy significantly reduced the severity of depression at post-treatment across all categories of somatic disorders (Hedges'g = 0.65; 95% CI 0.52–0.79), with sustained effects at 6–11 months (g = 0.38; 95% CI 0.22–0.53) and at 12 months follow-up or longer (g = 0.13; 95% CI 0.04–0.21). Psychotherapy also showed significant effects on QoL (g = 0.26; 95% CI 0.17–0.35), maintained up to 11 months follow-up (g = 0.25; 95% CI 0.16–0.34). No significant effects were observed on the most frequently reported somatic health-related outcomes (glycemic control, pain), and neither on mortality. Heterogeneity in most analyses was very high, and only 29 (38%) trials were rated at low risk of bias (RoB).ConclusionsPsychotherapy may be an effective treatment option for patients with depression and somatic disorders, with long-term effects on depression severity and QoL. However, these results should be interpreted with caution due to heterogeneity and RoB.

Objectives Obsessive-compulsive disorder (OCD) is a debilitating psychiatric disorder, often complicated with comorbidities. Social phobia (SP) is the most frequent co-occurring anxiety disorder in OCD, associated with increased clinical severity. However, no study had examined the relevance of interpersonal processes in this comorbidity, which are at the core of SP. This study characterized the clinical (i.e., symptom profile, age of onset, chronicity, and comorbidity), vulnerability (i.e., childhood trauma, negative life events), and interpersonal (attachment style, expressed emotion, and social support) correlates of comorbid SP in a large sample of OCD patients. Methods We analysed the data of 382 OCD patients participating in the Netherlands Obsessive Compulsive Disorder Association (NOCDA) study. We examined the correlates of SP in OCD using self-report questionnaires and structured clinical interviews. In addition, data of 312 non-OCD SP patients were drawn from the Netherlands Study of Depression and Anxiety (NESDA), to compare the age of onset of SP between groups. Descriptive univariate analyses were followed by backward stepwise logistic regression analyses. Results Social phobia was present among approximately 20% of OCD patients. Social phobia in OCD was associated with increased depression severity and decreased ratings of secure attachment style. Among OCD patients, SP had a significantly earlier age onset as compared to SP in non-OCD patients. Conclusion Social phobia in OCD might render a vulnerable clinical picture, characterized with early onset of SP symptoms, insecure attachment style, and increased depressive symptoms. Future studies should use prospective designs to better understand the nature of comorbid SP in OCD. Practitioner points Approximately one fifth of OCD patients were diagnosed with comorbid social phobia in a large representative clinical sample. OCD patients with comorbid social phobia presented with a vulnerable clinical picture, characterized with increased depression severity and decreased ratings of secure attachment style. Social phobia in OCD was associated with an earlier AOO as compared to the AOO of social phobia without OCD. The findings are limited by a cross-sectional design; thus, causality could not be assessed. Research is needed to further examine the mechanisms of comorbid social phobia in OCD.

Emerging evidence suggests that obesity impacts brain physiology at multiple levels. Here we aimed to clarify the relationship between obesity and brain structure using structural MRI (n = 6420) and genetic data (n = 3907) from the ENIGMA Major Depressive Disorder (MDD) working group. Obesity (BMI > 30) was significantly associated with cortical and subcortical abnormalities in both mass-univariate and multivariate pattern recognition analyses independent of MDD diagnosis. The most pronounced effects were found for associations between obesity and lower temporo-frontal cortical thickness (maximum Cohen´s d (left fusiform gyrus) = −0.33). The observed regional distribution and effect size of cortical thickness reductions in obesity revealed considerable similarities with corresponding patterns of lower cortical thickness in previously published studies of neuropsychiatric disorders. A higher polygenic risk score for obesity significantly correlated with lower occipital surface area. In addition, a significant age-by-obesity interaction on cortical thickness emerged driven by lower thickness in older participants. Our findings suggest a neurobiological interaction between obesity and brain structure under physiological and pathological brain conditions.

OBJECTIVE: A growing literature suggests that neighbourhood characteristics are associated with mental health outcomes, but the evidence in older adults is inconsistent. We investigated the association of neighbourhood characteristics, pertaining to demographic, socio-economic, social and physical environment domains, with the subsequent 10-year incidence of depression and anxiety, in Dutch older adults.METHODS: In the Longitudinal Aging Study Amsterdam depressive and anxiety symptoms were assessed four times between 2005/2006 and 2015/2016, using the Center for Epidemiological Studies Depression Scale (n = 1365) and the Anxiety subscale of the Hospital Anxiety and Depression Scale (n = 1420). Neighbourhood-level data on urban density, percent population over 65 years of age, percent immigrants, average house price, average income, percent low-income earners, social security beneficiaries, social cohesion, safety, proximity to retail facilities, housing quality, percent green space, percent water coverage, air pollution (particulate matter (PM2.5)), and traffic noise, were obtained for study baseline years 2005/2006. Cox proportional hazard regression models, clustered within neighbourhood, were used to estimate the association between each neighbourhood-level characteristic and the incidence of depression and anxiety.RESULTS: The incidence of depression and anxiety was 19.9 and 13.2 per 1000 person-years, respectively. Neighbourhood characteristics were not associated with the incidence of depression. However, various neighbourhood characteristics were associated with an increased incidence of anxiety, including: higher urban density level, higher percent immigrants, greater proximity to retail facilities, lower housing quality score, lower safety score, higher PM2.5 levels and less green space.CONCLUSION: Our results indicate that several neighbourhood characteristics are associated with anxiety but not with depression incidence in older age. Several of these characteristics have the potential to be modifiable and thus could serve as a target for interventions at the neighbourhood-level in improving anxiety, provided that future studies replicate our findings and provide further evidence for a causal effect.

Objective Depression has been associated with metabolomic alterations. Depressive and anxiety disorders are often comorbid diagnoses and are suggested to share etiology. We investigated whether differential metabolomic alterations are present between anxiety and depressive disorders and which clinical characteristics of these disorders are related to metabolomic alterations.Methods Data were from the Netherlands Study of Depression and Anxiety (NESDA), including individuals with current comorbid anxiety and depressive disorders (N = 531), only a current depression (N = 304), only a current anxiety disorder (N = 548), remitted depressive and/or anxiety disorders (N = 897), and healthy controls (N = 634). Forty metabolites from a proton nuclear magnetic resonance lipid-based metabolomics panel were analyzed. First, we examined differences in metabolites between disorder groups and healthy controls. Next, we assessed whether depression or anxiety clinical characteristics (severity and symptom duration) were associated with metabolites.Results As compared to healthy controls, seven metabolomic alterations were found in the group with only depression, reflecting an inflammatory (glycoprotein acetyls; Cohen's d = 0.12, p = 0.002) and atherogenic-lipoprotein-related (e.g., apolipoprotein B: Cohen's d = 0.08, p = 0.03, and VLDL cholesterol: Cohen's d = 0.08, p = 0.04) profile. The comorbid group showed an attenuated but similar pattern of deviations. No metabolomic alterations were found in the group with only anxiety disorders. The majority of metabolites associated with depression diagnosis were also associated with depression severity; no associations were found with anxiety severity or disease duration.Conclusion While substantial clinical overlap exists between depressive and anxiety disorders, this study suggests that altered inflammatory and atherogenic-lipoprotein-related metabolomic profiles are uniquely associated with depression rather than anxiety disorders.

In this study, we tested potential mediators that may explain change in depressive symptoms following exposure to a food-related behavioral activation intervention (F-BA). These included behavioral activation, avoidance and rumination, eating styles, body mass index, and dietary behavior at baseline and 3-month and 12-month follow-up. The trial used a community sample of 1,025 overweight adults with elevated depressive symptoms without current major depression. Participants were randomly assigned to one of four trial arms: either daily nutritional supplements (vs. placebo) alone or in combination with F-BA (vs. no F-BA) over 12 months. Although F-BA did not significantly reduce depressive symptoms (standardized regression coefficient [ b] = −0.223, SE = 0.129; p = .084), significant mediators included emotional eating ( b = −0.028, SE = 0.014; p = .042) and uncontrolled eating ( b = −0.039, SE = 0.016; p = .013), suggesting that learning adaptive responses to emotional and food cues may underlie effects of F-BA on depressive symptoms.

Background Notwithstanding the firmly established cross-sectional association of happiness with psychiatric disorders and their symptom severity, little is known about their temporal relationships. The goal of the present study was to investigate whether happiness is predictive of subsequent psychiatric disorders and symptom severity (and vice versa). Moreover, it was examined whether changes in happiness co-occur with changes in psychiatric disorder status and symptom severity. Methods In the Netherlands Study of Depression and Anxiety (NESDA), happiness (SRH: Self-Rated Happiness scale), depressive and social anxiety disorder (CIDI: Composite Interview Diagnostic Instrument) and depressive and anxiety symptom severity (IDS: Inventory of Depressive Symptomatology; BAI: Beck Anxiety Inventory; and FQ: Fear Questionnaire) were measured in 1816 adults over a three-year period. Moreover, we focused on occurrence and remittance of 6-month recency Major Depressive Disorder (MDD) and Social Anxiety Disorders (SAD) as the two disorders most intertwined with subjective happiness. Results Interindividual differences in happiness were quite stable (ICC of .64). Higher levels of happiness predicted recovery from depression (OR = 1.41; 95% CI = 1.10–1.80), but not social anxiety disorder (OR = 1.31; 95%CI = .94–1.81), as well as non-occurrence of depression (OR = 2.41; 95%CI = 1.98–2.94) and SAD (OR = 2.93; 95%CI = 2.29–3.77) in participants without MDD, respectively SAD at baseline. Higher levels of happiness also predicted a reduction of IDS depression (sr = − 0.08; 95%CI = -0.10 - -0.04), and BAI (sr = − 0.09; 95%CI = -0.12 - -0.05) and FQ (sr = − 0.06; 95%CI = -0.09 - -0.04) anxiety symptom scores. Conversely, presence of affective disorders, as well as higher depression and anxiety symptom severity at baseline predicted a subsequent reduction of self-reported happiness (with marginal to small sr values varying between −.04 (presence of SAD) to −.17 (depression severity on the IDS)). Moreover, changes in happiness were associated with changes in psychiatric disorders and their symptom severity, in particular with depression severity on the IDS (sr = − 0.46; 95%CI = −.50 - -.42). Conclusions Results support the view of rather stable interindividual differences in subjective happiness, although level of happiness is inversely associated with changes in psychiatric disorders and their symptom severity, in particular depressive disorder and depression severity.

Background: Altered metabolism of acylcarnitines – transporting fatty acids to mitochondria – may link cellular energy dysfunction to depression. We examined the potential causal role of acylcarnitine metabolism in depression by leveraging genomics and Mendelian randomization. Methods: Summary statistics were obtained from large GWAS: the Fenland Study (N = 9363), and the Psychiatric Genomics Consortium (246,363 depression cases and 561,190 controls). Two-sample Mendelian randomization analyses tested the potential causal link of 15 endogenous acylcarnitines with depression. Results: In univariable analyses, genetically-predicted lower levels of short-chain acylcarnitines C2 (odds ratio [OR] 0.97, 95% confidence intervals [CIs] 0.95–1.00) and C3 (OR 0.97, 95%CIs 0.96–0.99) and higher levels of medium-chain acylcarnitines C8 (OR 1.04, 95%CIs 1.01–1.06) and C10 (OR 1.04, 95%CIs 1.02–1.06) were associated with increased depression risk. No reverse potential causal role of depression genetic liability on acylcarnitines levels was found. Multivariable analyses showed that the association with depression was driven by the medium-chain acylcarnitines C8 (OR 1.04, 95%CIs 1.02–1.06) and C10 (OR 1.04, 95%CIs 1.02–1.06), suggesting a potential causal role in the risk of depression. Causal estimates for C8 (OR = 1.05, 95%CIs = 1.02–1.07) and C10 (OR = 1.05, 95%CIs = 1.02–1.08) were confirmed in follow-up analyses using genetic instruments derived from a GWAS meta-analysis including up to 16,841 samples. Discussion: Accumulation of medium-chain acylcarnitines is a signature of inborn errors of fatty acid metabolism and age-related metabolic conditions. Our findings point to a link between altered mitochondrial energy production and depression pathogenesis. Acylcarnitine metabolism represents a promising access point for the development of novel therapeutic approaches for depression.

Background Comorbidity of depressive and anxiety disorders is common and remains incompletely comprehended. This paper summarizes findings from the Netherlands Study of Depression and Anxiety (NESDA) regarding prevalence, temporal sequence, course and longitudinal patterns; sociodemographic, vulnerability and neurobiological indicators; and functional, somatic and mental health indicators of comorbidity. Methods Narrative synthesis of earlier NESDA based papers on comorbidity (n=76). Results Comorbidity was the rule in over three-quarter of subjects with depressive and/or anxiety disorders, most often preceded by an anxiety disorder. Higher severity and chronicity characterized a poorer comorbidity course. Over time, transitions between depressive and anxiety disorders were common. Consistent comorbidity risk indicators in subjects with depressive and anxiety disorders were childhood trauma, neuroticism and early age of onset. Psychological vulnerabilities, such as trait avoidance tendencies, were more pronounced in comorbid than in single disorders. In general, there were few differences in biological markers and neuroimaging findings between persons with comorbid versus single disorders. Most functional, somatic, and other mental health indicators, ranging from disability to cardiovascular and psychiatric multimorbidity, were highest in comorbid disorders. Limitations The observational design of NESDA limits causal inference. Attrition was higher in comorbid relative to single disorders. Conclusions As compared to single disorders, persons with comorbid depressive and anxiety disorders were characterized by more psychosocial risk determinants, more somatic and other psychiatric morbidities, more functional impairments, and poorer outcome. These results justify specific attention for comorbidity of depressive and anxiety disorders, particularly in treatment settings.

International audience; A growing number of studies are pointing out the need for a conceptual shift from a brain-centered to a body-inclusive approach in mental health research. In this perspective, the link between the immune and the nervous system, which are deeply interconnected and continuously interacting, is one of the most important novel theoretical framework to investigate the biological bases of major depressive disorder and, more in general, mental illness. Indeed, depressed patients show high levels of inflammatory markers, administration of pro-inflammatory drugs triggers a depressive symptomatology and antidepressant efficacy is reduced by excessive immune system activation. A number of molecular and cellular mechanisms have been hypothesized to act as a link between the immune and brain function, thus representing potential pharmacologically targetable processes for the development of novel and effective therapeutic strategies. These include the modulation of the kynurenine pathway, the crosstalk between metabolic and inflammatory processes, the imbalance in acquired immune responses, in particular T cell responses, and the interplay between neural plasticity and immune system activation. In the personalized medicine approach, the assessment and regulation of these processes have the potential to lead, respectively, to novel diagnostic approaches for the prediction of treatment outcome according to the patient's immunological profile, and to improved efficacy of antidepressant compounds through immune modulation.

Background Depressive and anxiety disorders are often associated with suicide ideation (SI) and attempt (SA). However, analyses of prevalence, course, and more specific risk mechanisms are needed to improve knowledge and detection of high risk individuals with depressive and anxiety disorders. Previous studies often lacked statistical power, assessment of detailed determinants and follow-up measurements. Methods The Netherlands Study of Depression and Anxiety (NESDA), a large cohort study, overcomes some earlier limitations. Scale for Suicide Ideation and Compositive Interview Diagnostic Instrument data were analyzed to report on prevalence of SI and SA. Additionally, important sociodemographic, clinical, psychological, environmental, and neurobiological determinants and course of SI and SA identified in depressive and/or anxiety disorder respondents in 16 NESDA articles were summarized. Results Within respondents with 12-month diagnosis (n=1,783), SI and 12-month SA prevalence ranged from 17.1-20.1% and 0.8-3.0% respectively across 5 waves during 9-year follow-up and SI was highly recurrent. Both SI and SA were especially associated with comorbid depression and anxiety, higher clinical severity, sleep dysfunctions, higher aggression and hopelessness, and childhood trauma. In the (neuro)biological domain, SI was linked with immune dysregulation and SA with abnormal brain activity during emotion processing and genetic risk. Limitations Most articles were cross-sectional in nature, preventing causal inferences and no conclusions could be drawn about the overall magnitude of results. Conclusion SI and SA are multifactorial phenomena and especially prevalent amongst comorbid depressive and anxiety respondents. Considering many overlapping SI and SA determinants, more neurobiological determinants and use of innovative methodological techniques are desirable.

Introduction: Depressive symptoms are highly prevalent and clinically relevant in schizophrenia spectrum disorder (SSD) patients. So far, little is known about to what extent the depressive symptom profile in SSD is comparable to that seen in major depressive disorder (MDD).Methods: Data were derived from the Genetic Risk and Outcome of Psychosis study (GROUP) and the Netherlands Study of Depression and Anxiety (NESDA). We examined differences in severity of depressive symptom profiles and distribution of mood/cognition and somatic/vegetative depressive symptoms using the Quick Inventory of Depressive Symptomatology - Self Report (QIDS-SR) within SSD patients (n = 449), MDD patients (n = 816) and healthy controls (n = 417), aged 18 to 50. Within SSD, associations between depression severity and clinical and demographic data were examined.Results: 60.4% of SSD patients showed substantial depressive symptomatology (QIDS-SR >= 6). The difference in mood/cognition symptoms between SSD and MDD was larger (higher symptoms in MDD, effect size = 1.13), than the differences in somatic/vegetative symptoms (effect size 0.74). In patients with SSD, multivariable regression analyses showed that lower social functioning, male gender, use of benzodiazepine and more severe positive symptoms were associated with higher overall depressive symptomatology. The use of antipsychotics or anti-depressants was associated with more somatic/vegetative symptoms.Conclusion: More than half of SSD patients have considerable depressive symptomatology, with a relative preponderance of somatic/vegetative symptoms compared to the profile seen in MDD. Future research could explore whether depressive symptom profile in SSD may also be associated with biological dysregulations like in MDD.

BackgroundThis meta-analysis on peripheral blood compounds in drug-naïve first-episode patients with either schizophrenia or major depressive disorder (MDD) examined which compounds change following psychopharmacological treatment.MethodsThe Embase, PubMed and PsycINFO databases were systematically searched for longitudinal studies reporting measurements of blood compounds in drug-naïve first-episode schizophrenia or MDD.ResultsFor this random-effects meta-analysis, we retrieved a total of 31 studies comprising 1818 schizophrenia patients, and 14 studies comprising 469 MDD patients. Brain-derived neurotrophic factor (BDNF) increased following treatment in schizophrenia (Hedges' g (g): 0.55; 95% confidence interval (CI) 0.39–0.70; p < 0.001) and MDD (g: 0.51; CI 0.06–0.96; p = 0.027). Interleukin (IL)-6 levels decreased in schizophrenia (g: −0.48; CI −0.85 to −0.11; p = 0.011), and for MDD a trend of decreased IL-6 levels was observed (g: −0.39; CI −0.87 to 0.09; p = 0.115). Tumor necrosis factor alpha (TNFα) also decreased in schizophrenia (g: −0.34; CI −0.68 to −0.01; p = 0.047) and in MDD (g: −1.02; CI −1.79 to −0.25; p = 0.009). Fasting glucose levels increased only in schizophrenia (g: 0.26; CI 0.07–0.44; p = 0.007), but not in MDD. No changes were found for C-reactive protein, IL-1β, IL-2 and IL-4.ConclusionsPsychopharmacological treatment has modulating effects on BDNF and TNFα in drug-naïve first-episode patients with either schizophrenia or MDD. These findings support efforts for further research into transdiagnostic preventive strategies and augmentation therapy for those with immune dysfunctions.

Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10−11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10−10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10−122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.

© 2020 The Authors. Suicide and Life-Threatening Behavior published by Wiley Periodicals LLC on behalf of American Association of SuicidologyBackground: Suicidal behavior is the result of complex interactions between many different factors that change over time. A network perspective may improve our understanding of these complex dynamics. Within the network perspective, psychopathology is considered to be a consequence of symptoms that directly interact with one another in a network structure. To view suicidal behavior as the result of such a complex system is a good starting point to facilitate moving away from traditional linear thinking. Objective: To review the existing paradigms and theories and their application to suicidal behavior. Methods: In the first part of this paper, we introduce the relevant concepts within network analysis such as network density and centrality. Where possible, we refer to studies that have applied these concepts within the field of suicide prevention. In the second part, we move one step further, by understanding the network perspective as an initial step toward complex system theory. The latter is a branch of science that models interacting variables in order to understand the dynamics of complex systems, such as tipping points and hysteresis. Results: Few studies have applied network analysis to study suicidal behavior. The studies that do highlight the complexity of suicidality. Complexity science offers potential useful concepts such as alternative stable states and resilience to study psychopathology and suicidal behavior, as demonstrated within the field of depression. To date, one innovative study has applied concepts from complexity science to better understand suicidal behavior. Complexity science and its application to human behavior are in its infancy, and it requires more collaboration between complexity scientists and behavioral scientists. Conclusions: Clinicians and scientists are increasingly conceptualizing suicidal behavior as the result of the complex interaction between many different biological, social, and psychological risk and protective factors. Novel statistical techniques such as network analysis can help the field to better understand this complexity. The application of concepts from complexity science to the field of psychopathology and suicide research offers exciting and promising possibilities for our understanding and prevention of suicide.

BACKGROUND: The impact of the COVID-19 pandemic on mental health in people with pre-existing mental health disorders is unclear. In three psychiatry case-control cohorts, we compared the perceived mental health impact and coping and changes in depressive symptoms, anxiety, worry, and loneliness before and during the COVID-19 pandemic between people with and without lifetime depressive, anxiety, or obsessive-compulsive disorders.METHODS: Between April 1 and May 13, 2020, online questionnaires were distributed among the Netherlands Study of Depression and Anxiety, Netherlands Study of Depression in Older Persons, and Netherlands Obsessive Compulsive Disorder Association cohorts, including people with (n=1181) and without (n=336) depressive, anxiety, or obsessive-compulsive disorders. The questionnaire contained questions on perceived mental health impact, fear of COVID-19, coping, and four validated scales assessing depressive symptoms, anxiety, worry, and loneliness used in previous waves during 2006-16. Number and chronicity of disorders were based on diagnoses in previous waves. Linear regression and mixed models were done.FINDINGS: The number and chronicity of disorders showed a positive graded dose-response relation, with greater perceived impact on mental health, fear, and poorer coping. Although people with depressive, anxiety, or obsessive-compulsive disorders scored higher on all four symptom scales than did individuals without these mental health disorders, both before and during the COVID-19 pandemic, they did not report a greater increase in symptoms during the pandemic. In fact, people without depressive, anxiety, or obsessive-compulsive disorders showed a greater increase in symptoms during the COVID-19 pandemic, whereas individuals with the greatest burden on their mental health tended to show a slight symptom decrease.INTERPRETATION: People with depressive, anxiety, or obsessive-compulsive disorders are experiencing a detrimental impact on their mental health from the COVID-19 pandemic, which requires close monitoring in clinical practice. Yet, the COVID-19 pandemic does not seem to have further increased symptom severity compared with their prepandemic levels.FUNDING: Dutch Research Council.

BackgroundBrothers and sisters growing up together share a large proportion of their genes and rearing environment. However, some siblings thrive whereas others struggle. This study investigated family-wide childhood bonding experiences with mother and father, in addition to individual-specific recollections, in relation to current depressive and anxiety symptom levels in adulthood. We examined whether extraversion and internal locus of control (iLoC) had a protective effect in this.MethodsThe sample consisted of 256 families with at least one lifetime depressed or anxious person (N = 596; ages 20–78). Multilevel modeling with cross-level interactions was used.ResultsAdult siblings showed moderate to high agreement in their childhood parental bonding (PB) recollections. Over-and-above the association between individual-specific recollections of PB and adult internalizing symptoms, family-wide poor PB was additionally linked to elevated symptom levels. Within families characterized by poor maternal bonding persons with an iLoC were relatively less anxious (but not less depressed), whereas extraversion was not protective in this context.LimitationAlthough evidence exists that poor childhood PB has an impact on (adult) psychopathology, causality cannot be determined and possible recall bias of PB should be noted. Moreover, next to their moderating effects, extraversion and LoC may also act as mediators.ConclusionsOur findings extend prior work by demonstrating the importance of siblings’ childhood PB experiences next to a person's own recollections when investigating adult internalizing symptoms, while also elucidating individual differences within families.

Contains fulltext : 227418.pdf (Publisher’s version ) (Closed access) The COVID-19 pandemic has led to unprecedented societal changes limiting us in our mobility and our ability to connect with others in person. These unusual but widespread changes provide a unique opportunity for studies using digital phenotyping tools. Digital phenotyping tools, such as mobile passive monitoring platforms (MPM), provide a new perspective on human behavior and hold promise to improve human behavioral research. However, there is currently little evidence that these tools can reliably detect changes in behavior. Considering the Considering the COVID-19 pandemic as a high impact common environmental factor we studied potential impact on behavior of participants using our mobile passive monitoring platform BEHAPP that was ambulatory tracking them during the COVID-19 pandemic. We pooled data from three MPM studies involving Schizophrenia (SZ), Major Depressive Disorder (MDD) and Bipolar Disorder (BD) patients (N = 12). We compared the data collected on weekdays during three weeks prior and three weeks subsequent to the start of the quarantine. We hypothesized an increase in communication and a decrease in mobility. We observed a significant increase in the total time spent on communication applications (median 179 and 243 min per week respectively, p = 0.005), and a significant decrease in the number of unique places visited (median 6 and 3 visits per week respectively, p = 0.007), while the total time spent at home did not change significantly (median 64 and 77 h per week, respectively, p = 0.594). The data provides a proof of principle that digital phenotyping tools can identify changes in human behavior incited by a common external environmental factor. 6 p.

Contains fulltext : 237012.pdf (Publisher’s version ) (Closed access) Background: Investigating siblings of probands with affective disorders enables the identification of psychopathology-related risk features. Leveraging data from an older adult sample, as compared to most previous sibling studies, enabled us to study more definitive clinical profiling across the lifespan. We examined prevalence of depressive/anxiety disorders in siblings, proband-sibling resemblance in psychopathology-related features, and whether unaffected siblings showed higher levels of these features than healthy controls. Methods: The sample (N=929; Mage=50.6) consisted of 256 probands with lifetime depressive and/or anxiety disorders, their 380 siblings, and 293 healthy controls without affected relatives. Fifteen psychopathology-related features were investigated across four domains: mental health symptoms, social vulnerabilities, cognitive vulnerabilities, and personality. Results: Lifetime disorders were present in 50.3% of siblings. Prevalence was 2-3 times higher than Dutch population frequencies. We found small to medium probandsibling resemblance across psychopathology-related features (ρ=0.10-0.32). Unaffected siblings reported poorer interpersonal functioning and more negative life events, childhood trauma, and rumination than healthy controls. Limitations Due to the cross-sectional study design, the directionality of effects cannot be determined. No inferences can be made about potential differences in familial resemblance in psychopathology-related features between high- and low-risk families. Conclusions: Siblings of probands with affective disorders are at higher risk for depressive/anxiety disorders. Even when unaffected, still show higher psychosocial vulnerability than healthy controls. Nevertheless, the only modest proband-sibling resemblance across psychopathology-related features suggests that individual mechanisms differentiate clinical trajectories across the lifespan. Identification of these mechanisms is crucial to improve resilience in subjects with familial risk. 10 p.

Background: Antidepressants are a first-line treatment for depression. However, only a third of individuals experience remission after the first treatment. Common genetic variation, in part, likely regulates antidepressant response, yet the success of previous genome-wide association studies has been limited by sample size. This study performs the largest genetic analysis of prospectively assessed antidepressant response in major depressive disorder to gain insight into the underlying biology and enable out-of-sample prediction.Methods: Genome-wide analysis of remission (nremit = 1852, nnonremit = 3299) and percentage improvement (n = 5218) was performed. Single nucleotide polymorphism–based heritability was estimated using genome-wide complex trait analysis. Genetic covariance with eight mental health phenotypes was estimated using polygenic scores/AVENGEME. Out-of-sample prediction of antidepressant response polygenic scores was assessed. Gene-level association analysis was performed using MAGMA and transcriptome-wide association study. Tissue, pathway, and drug binding enrichment were estimated using MAGMA.Results: Neither genome-wide association study identified genome-wide significant associations. Single nucleotide polymorphism–based heritability was significantly different from zero for remission (h2 = 0.132, SE = 0.056) but not for percentage improvement (h2 = −0.018, SE = 0.032). Better antidepressant response was negatively associated with genetic risk for schizophrenia and positively associated with genetic propensity for educational attainment. Leave-one-out validation of antidepressant response polygenic scores demonstrated significant evidence of out-of-sample prediction, though results varied in external cohorts. Gene-based analyses identified ETV4 and DHX8 as significantly associated with antidepressant response.Conclusions: This study demonstrates that antidepressant response is influenced by common genetic variation, has a genetic overlap schizophrenia and educational attainment, and provides a useful resource for future research. Larger sample sizes are required to attain the potential of genetics for understanding and predicting antidepressant response.

Background There is ambiguity on how omega-3 (n-3) polyunsaturated fatty acids (PUFAs) are associated with depression, and what the temporality of the association might be. The present study aimed to examine whether (intervention-induced changes in) n-3 PUFA levels were associated with (changes in) depressive symptoms. Methods Baseline, 6- and 12-month follow-up data on 682 overweight and subclinically depressed persons from four European countries that participated in the MooDFOOD depression prevention randomized controlled trial were used. Participants were allocated to four intervention groups: (a) placebos, (b) placebos and food-related behavioral activation therapy (F-BA), (c) multinutrient supplements (fish oil and multivitamin), and (d) multinutrient supplements and F-BA. Depressive symptoms were measured using the inventory of depressive symptomatology. PUFA levels (mu mol/L) were measured using gas chromatography. Analyses were adjusted for sociodemographics, lifestyle, and somatic health. Results Increases in n-3 PUFA, docosahexaenoic acid, and eicosapentaenoic acid levels over time were significantly larger in the supplement groups than in placebo groups. Change in PUFA levels was not significantly associated with the change in depressive symptoms (beta = .002, SE = 0.003,p = .39;beta = .003, SE = 0.005,p = .64;beta = .005, SE = 0.005,p = .29;beta = -.0002, SE = 0.0004,p = .69). Baseline PUFA levels did not modify the intervention effects on depressive symptoms. Conclusions In overweight and subclinical depressed persons, multinutrient supplements led to significant increases in n-3 PUFA levels over time, which were not associated with changes in depressive symptoms. Multinutrient supplements do not seem to be an effective preventive strategy in lowering depressive symptoms over time in these at-risk groups., European Union FP7 MooDFOOD project, Grant/Award Number: 613598; National Institute for Health Research (NIHR), through the Primary Care Research Network and the NIHR Exeter Clinical Research Facility

Objective: Depression and obesity are bi-directionally related, eating styles and diet quality are two important factors associated with both. It remains uncertain if and how these two factors can be modified. Therefore the current study aims to investigate whether food-related behavioral activation therapy (F-BA), targeting mood, dietary habits and food related behavior, can improve eating styles, and diet quality and reduce body weight in adults with overweight or obesity and subsyndromal depressive symptoms. Methods: Data were derived from the MooDFOOD prevention trial, a 2x2 factorial RCT investigating the effect of nutritional strategies on prevention of depression. Changes in emotional, uncontrolled, and cognitive restrained eating (Three Factor Eating Questionnaire Revised), Mediterranean Diet Score (MDS), and body weight were analyzed among 1025 adults who either received F-BA or no intervention for 12 months. Intervention effect was tested by longitudinal analysis of covariance using mixed model analysis. Results: The F-BA group showed a small decrease in emotional (β=-5.68, p

Epidemiological evidence indicates the presence of dysregulated homeostatic biological pathways in depressed patients, such as increased inflammation and disrupted energy-regulating neuroendocrine signaling (e.g., leptin, insulin). Alterations in these biological pathways may explain the considerable comorbidity between depression and cardiometabolic conditions (e.g., obesity, metabolic syndrome, diabetes) and represent a promising target for intervention. This review describes how immunometabolic dysregulations vary as a function of depression heterogeneity by illustrating that such biological dysregulations map more consistently to atypical behavioral symptoms reflecting altered energy intake/expenditure balance (hyperphagia, weight gain, hypersomnia, fatigue, and leaden paralysis) and may moderate the antidepressant effects of standard or novel (e.g., anti-inflammatory) therapeutic approaches. These lines of evidence are integrated in a conceptual model of immunometabolic depression emerging from the clustering of immunometabolic biological dysregulations and specific behavioral symptoms. The review finally elicits questions to be answered by future research and describes how the immunometabolic depression dimension could be used to dissect the heterogeneity of depression and potentially to match subgroups of patients to specific treatments with higher likelihood of clinical success.

Objective:To examine mediation by (i) diet quality and (ii) diet quantity in the associations of mindful eating domains with 3-year change in depressive symptoms.Design:Depressive symptoms were measured with the Center for Epidemiologic Studies Depression scale at baseline and 3-year follow-up. Four mindful eating domains (Focused Eating; Eating in response to Hunger and Satiety Cues; Eating with Awareness; Eating without Distraction) were measured with the Mindful Eating Behavior Scale. Food intake was measured with a 238-item FFQ. Diet quality was defined as the Mediterranean Diet Score (MDS). Diet quantity was defined as total energy intake (kcal/d; 1 kcal = 4·184 kJ). Mediation analyses with percentile-corrected bootstrap confidence intervals were conducted to calculate indirect effects.Setting:Longitudinal Aging Study Amsterdam.Participants:Adults aged 55 years or above (n 929).Results:Diet quality (MDS) did not mediate associations of any of the four mindful eating domains with change in depressive symptoms. In contrast, total energy intake did mediate the associations with change in depressive symptoms for the mindful eating domains Eating with Awareness (indirect effects fully adjusted models: B = −0·014, 95 % CI −0·037, −0·002) and Eating without Distraction (B = −0·013, 95 % CI −0·033, −0·001), but not for the other two domains. Post hoc multiple mediation analyses showed similar results.Conclusions:Higher scores on two mindful eating domains were associated with a decrease in depressive symptoms through lower total energy intake. Diet quantity, but not diet quality, could be a possible underlying mechanism in the associations between mindful eating and change in depressive symptoms.

Background: Chronotype is an individual's preferred timing of sleep and activity, and is often referred to as a later chronotype (or evening-type) or an earlier chronotype (or morning-type). Having an evening chronotype is associated with more severe depressive and anxiety symptoms. Based on these findings it is has been suggested that chronotype is a stable construct associated with vulnerability to develop depressive or anxiety disorders. To examine this, we test the stability of chronotype over 7 years, and its longitudinal association with the change in severity of depressive and anxiety symptoms. Methods: Data of 1,417 participants with a depressive and/or anxiety disorder diagnosis and healthy controls assessed at the 2 and 9-year follow-up waves of the Netherlands Study of depression and anxiety were used. Chronotype was assessed with the Munich chronotype questionnaire. Severity of depressive and anxiety symptoms were assessed with the inventory of depressive symptomatology and Beck anxiety inventory. Results: Chronotype was found to be moderately stable (r = 0.53) and on average advanced (i.e., became earlier) with 10.8 min over 7 years (p

Objective: We investigated whether physical exercise interventions improve cognitive functioning in nondementia populations. Methods: We conducted a systematic review of meta-analyses including only randomized controlled trials (RCTs). Two reviewers completed a systematic search of PubMed, Embase, PsychInfo, and Cochrane Controlled Register of Trials. Study characteristics, effect size data, and heterogeneity estimates were extracted and presented in tabular form. Methodological quality was assessed by 2 reviewers using the AMSTAR-2 checklist. The validity of results was considered based on AMSTAR-2 scores and study characteristics. Results: We included 11 meta-analyses: 6 focused on disease-free older adults and 5 on mild cognitive impairment (MCI) excluding dementia. These meta-analyses summarized 97 unique RCTs. Methodological quality ranged from critically low to high. For overall cognitive functioning, which was the outcome of 6 meta-analyses, 1 showed improvement due to exercise interventions in disease-free older adults ( g = 0.29, P < .01), while 2 reported nonsignificant effects. In patients with MCI, 3 meta-analyses reported significant benefits of exercise interventions on overall cognitive functioning ( g = 0.25-0.57, P < .01). For cognitive domains such as attention and memory, there was limited evidence of beneficial effects of exercise demonstrated in either disease-free or MCI samples. Conclusions: Exercise may improve overall cognitive functioning in disease-free older adults, but there is too little high-quality evidence to conclude whether this is achieved through improvement in any of the specific cognitive domains assessed. There is clearer evidence that exercise may improve cognitive functioning in MCI, but again there is limited evidence across most cognitive domains.

Minimal phenotyping refers to the reliance on the use of a small number of self-reported items for disease case identification, increasingly used in genome-wide association studies (GWAS). Here we report differences in genetic architecture between depression defined by minimal phenotyping and strictly defined major depressive disorder (MDD): the former has a lower genotype-derived heritability that cannot be explained by inclusion of milder cases and a higher proportion of the genome contributing to this shared genetic liability with other conditions than for strictly defined MDD. GWAS based on minimal phenotyping definitions preferentially identifies loci that are not specific to MDD, and, although it generates highly predictive polygenic risk scores, the predictive power can be explained entirely by large sample sizes rather than by specificity for MDD. Our results show that reliance on results from minimal phenotyping may bias views of the genetic architecture of MDD and impede the ability to identify pathways specific to MDD.Genetic analyses of depression based on minimal phenotyping identify nonspecific genetic risk factors shared between major depressive disorder (MDD) and other psychiatric conditions, suggesting that this approach may have limited ability to identify pathways specific to MDD.