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The Coronavirus Disease 2019 (COVID-19) pandemic has threatened global mental health, both indirectly via disruptive societal changes and directly via neuropsychiatric sequelae after SARS-CoV-2 infection. Despite a small increase in self-reported mental health problems, this has (so far) not translated into objectively measurable increased rates of mental disorders, self-harm or suicide rates at the population level. This could suggest effective resilience and adaptation, but there is substantial heterogeneity among subgroups, and time-lag effects may also exist. With regard to COVID-19 itself, both acute and post-acute neuropsychiatric sequelae have become apparent, with high prevalence of fatigue, cognitive impairments and anxiety and depressive symptoms, even months after infection. To understand how COVID-19 continues to shape mental health in the longer term, fine-grained, well-controlled longitudinal data at the (neuro)biological, individual and societal levels remain essential. For future pandemics, policymakers and clinicians should prioritize mental health from the outset to identify and protect those at risk and promote long-term resilience. This Review discusses the impact of COVID-19 on mental health, from pandemic-related societal effects to direct infection-related neuropsychiatric sequelae, highlighting the lessons learned and outstanding knowledge gaps.

Major depressive disorder (MDD) is characterized by persistent depressed mood, loss of interest or pleasure in previously enjoyable activities, recurrent thoughts of death, and physical and cognitive symptoms. People with MDD can have reduced quality of life owing to the disorder itself as well as related medical comorbidities, social factors, and impaired functional outcomes. MDD is a complex disorder that cannot be fully explained by any one single established biological or environmental pathway. Instead, MDD seems to be caused by a combination of genetic, environmental, psychological and biological factors. Treatment for MDD commonly involves pharmacological therapy with antidepressant medications, psychotherapy or a combination of both. In people with severe and/or treatment-resistant MDD, other biological therapies, such as electroconvulsive therapy, may also be offered.This Primer summarizes the epidemiology, mechanisms, diagnosis and treatment of major depressive disorder (MDD). This Primer also reviews how this disorder affects patient quality of life, and provides an overview of future research.

We examined whether inflammation is uniformly associated with all depressive and anxiety symptoms, and whether these associations are potentially causal. Data was from 147,478 individuals from the UK Biobank (UKB) and 2,905 from the Netherlands Study of Depression and Anxiety (NESDA). Circulating C-reactive protein (CRP) was measured in both cohorts and interleukin-6 (IL-6) in NESDA. Genetic instruments for these proteins were obtained from published GWAS and UKB. Depressive and anxiety symptoms were assessed with self-report questionnaires. In NESDA, neurovegetative (appetite, sleep, psychomotor) symptoms were disaggregated as increased vs. decreased. In joint analyses, higher CRP was associated with depressive symptoms of depressed mood (OR = 1.06, 95% CI = 1.05–1.08), altered appetite (OR = 1.25, 95%CI = 1.23–1.28), sleep problems (OR = 1.05, 95%CI = 1.04–1.06), and fatigue (OR = 1.12, 95% CI = 1.11–1.14), and with anxiety symptoms of irritability (OR = 1.06, 95% CI = 1.05–1.08) and worrying control (OR = 1.03, 95% CI = 1.02–1.04). In NESDA, higher IL-6 was additionally associated with anhedonia (OR = 1.30, 95% CI = 1.12–1.52). Higher levels of both CRP (OR = 1.27, 95% CI = 1.13–1.43) and IL-6 (OR = 1.26, 95% CI = 1.07–1.49) were associated with increased sleep. Higher CRP was associated with increased appetite (OR = 1.21, 95% CI = 1.08–1.35) while higher IL-6 with decreased appetite (OR = 1.45, 95% CI = 1.18–1.79). In Mendelian Randomisation analyses, genetically predicted higher IL-6 activity was associated with increased risk of fatigue (estimate = 0.25, SE = 0.08) and sleep problems (estimate = 0.19, SE = 0.07). Inflammation was associated with core depressive symptoms of low mood and anhedonia and somatic/neurovegetative symptoms of fatigue, altered sleep and appetite changes. Less consistent associations were found for anxiety. The IL-6/IL-6R pathway could be causally linked to depression. Experimental studies are required to further evaluate causality, mechanisms, and usefulness of immunotherapies for depressive symptoms.

Anxiety disorders form the most common group of mental disorders and generally start before or in early adulthood. Core features include excessive fear and anxiety or avoidance of perceived threats that are persistent and impairing. Anxiety disorders involve dysfunction in brain circuits that respond to danger. Risk for anxiety disorders is influenced by genetic factors, environmental factors, and their epigenetic relations. Anxiety disorders are often comorbid with one another and with other mental disorders, especially depression, as well as with somatic disorders. Such comorbidity generally signifies more severe symptoms, greater clinical burden, and greater treatment difficulty. Reducing the large burden of disease from anxiety disorders in individuals and worldwide can be best achieved by timely, accurate disease detection and adequate treatment administration, scaling up of treatments when needed. Evidence-based psychotherapy (particularly cognitive behavioural therapy) and psychoactive medications (particularly serotonergic compounds) are both effective, facilitating patients' choices in therapeutic decisions. Although promising, no enduring preventive measures are available, and, along with frequent therapy resistance, clinical needs remain unaddressed. Ongoing research efforts tackle these problems, and future efforts should seek individualised, more effective approaches for treatment with precision medicine.

Depression is the most common psychiatric disorder worldwide. The burden of disease for depression goes beyond functioning and quality of life and extends to somatic health. Depression has been shown to subsequently increase the risk of, for example, cardiovascular, stroke, diabetes and obesity morbidity. These somatic consequences could partly be due to metabolic, immuno-inflammatory, autonomic and hypothalamic-pituitary-adrenal (HPA)-axis dysregulations which have been suggested to be more often present among depressed patients. Evidence linking depression to metabolic syndrome abnormalities indicates that depression is especially associated with its obesity-related components (for example, abdominal obesity and dyslipidemia). In addition, systemic inflammation and hyperactivity of the HPA-axis have been consistently observed among depressed patients. Slightly less consistent observations are for autonomic dysregulation among depressed patients. The heterogeneity of the depression concept seems to play a differentiating role: metabolic syndrome and inflammation up-regulations appear more specific to the atypical depression subtype, whereas hypercortisolemia appears more specific for melancholic depression. This review finishes with potential treatment implications for the downward spiral in which different depressive symptom profiles and biological dysregulations may impact on each other and interact with somatic health decline.

Background Exercise may be a promising target for depression interventions. However, evidence for a beneficial effect of exercise interventions on the prevention of depression differs substantially across different studies. Methods A systematic search was performed up to July 2018 using PubMed, Embase, PsycINFO, and Cochrane. Articles were included if a meta-analysis of randomized controlled trials was performed that examined the effect of exercise interventions on the onset of depression or depressive symptoms in the general population. Meta-analyses focusing on treatment of diagnosed depression were excluded. Two authors independently screened the articles and graded the quality of included meta-analyses using AMSTAR 2. Results Eight meta-analyses were included that showed little overlap in 134 included studies. All meta-analyses reported on depressive symptoms rather than onset of depression. Five of these were rated as moderate quality and three of low quality. Six meta-analyses found significant effects, and two found non-significant effects of exercise interventions in reducing depressive symptoms in children, adolescents, adults and the elderly (effect sizes ranging from − 0.10 to − 0.81). Scarce evidence did not allow to draw conclusions about the role of sex and characteristics of exercise on depression. However, some findings suggest that low intensity exercise was as effective as high intensity exercise. Heterogeneity among primary studies was high, likely caused by differences in study quality and exercise characteristics. Conclusions The evidence from this study suggests that exercise interventions have a beneficial effect on depressive symptoms in the general population across a wide age-range.

Background The chronotype, being a morning or an evening type, can influence an individual's psychological health. Studies have shown a link between depressed mood and being an evening type; however, most studies have used symptom scales and not diagnostic criteria, and confounding factors such as sleep patterns and somatic health factors have often not been considered. This study aims to examine the association between chronotype and depressive (major depressive disorder (MDD), dysthymia) and anxiety (generalized anxiety disorder, panic disorder, agoraphobia, and social phobia) disorders diagnosed using clinical interviews, while taking into account relevant sociodemographic, clinical, somatic health, and sleep parameters. Methods Data from a large cohort, the Netherlands Study of Depression and Anxiety were used (n = 1,944), which included 676 currently depressed and/or anxious patients, 831 remitted patients, and 437 healthy controls. Chronotype was assessed using the Munich Chronotype Questionnaire. Results Our results showed that current depressive and/or anxiety disorders were associated with a late chronotype (β = .10, P = .004) even when adjusting for sociodemographic, somatic health, and sleep‐related factors (β = .09, P = .03). When examining each type of disorder separately, MDD only, but not dysthymia or specific anxiety disorders, was associated with the late chronotype. The late chronotype also reported significant diurnal mood variation (worse mood in the morning). Conclusions Our findings show a clear association between MDD and late chronotype (being an evening type), after controlling for a range of pertinent factors. A late chronotype is therefore associated with a current status of MDD and deserves the relevant clinical attention when considering treatments.

Abstract Study Objectives Major depressive disorder (MDD) is the leading cause of disability worldwide. Its high recurrence rate calls for prevention of first-onset MDD. Although meta-analysis suggested insomnia as the strongest modifiable risk factor, previous studies insufficiently addressed that insomnia might also occur as a residual symptom of unassessed prior depression, or as a comorbid complaint secondary to other depression risks. Methods In total, 768 participants from the Netherlands Study of Depression and Anxiety who were free from current and lifetime MDD were followed-up for four repeated assessments, spanning 6 years in total. We performed separate Cox proportional hazard analyses to evaluate whether baseline insomnia severity, short-sleep duration, and individual insomnia complaints prospectively predicted first-onset MDD during follow-up. The novel method of network outcome analysis (NOA) allowed us to sort out whether there is any direct predictive value of individual insomnia complaints among several other complaints that are associated with insomnia. Results Over 6-year follow-up, 141 (18.4%) were diagnosed with first-onset MDD. Insomnia severity but not sleep duration predicted first-onset MDD (HR = 1.11, 95% CI: 1.07–1.15), and this was driven solely by the insomnia complaint difficulty initiating sleep (DIS) (HR = 1.10, 95% CI: 1.04–1.16). NOA likewise identified DIS only to directly predict first-onset MDD, independent of four other associated depression complaints. Conclusions We showed prospectively that DIS is a risk factor for first-onset MDD. Among the different other insomnia symptoms, the specific treatment of DIS might be the most sensible target to combat the global burden of depression through prevention.

Background Comorbidity between depressive and anxiety disorders is common. A hypothesis of the network perspective on psychopathology is that comorbidity arises due to the interplay of symptoms shared by both disorders, with overlapping symptoms acting as so-called bridges , funneling symptom activation between symptom clusters of each disorder. This study investigated this hypothesis by testing whether (i) two overlapping mental states “worrying” and “feeling irritated” functioned as bridges in dynamic mental state networks of individuals with both depression and anxiety as compared to individuals with either disorder alone, and (ii) overlapping or non-overlapping mental states functioned as stronger bridges. Methods Data come from the Netherlands Study of Depression and Anxiety (NESDA). A total of 143 participants met criteria for comorbid depression and anxiety (65%), 40 participants for depression-only (18.2%), and 37 for anxiety-only (16.8%) during any NESDA wave. Participants completed momentary assessments of symptoms (i.e., mental states) of depression and anxiety, five times a day, for 2 weeks (14,185 assessments). First, dynamics between mental states were modeled with a multilevel vector autoregressive model, using Bayesian estimation. Summed average lagged indirect effects through the hypothesized bridge mental states were compared between groups. Second, we evaluated the role of all mental states as potential bridge mental states. Results While the summed indirect effect for the bridge mental state “worrying” was larger in the comorbid group compared to the single disorder groups, differences between groups were not statistically significant. The difference between groups became more pronounced when only examining individuals with recent diagnoses (< 6 months). However, the credible intervals of the difference scores remained wide. In the second analysis, a non-overlapping item (“feeling down”) acted as the strongest bridge mental state in both the comorbid and anxiety-only groups. Conclusions This study empirically examined a prominent network-approach hypothesis for the first time using longitudinal data. No support was found for overlapping mental states “worrying” and “feeling irritable” functioning as bridge mental states in individuals vulnerable for comorbid depression and anxiety. Potentially, bridge mental state activity can only be observed during acute symptomatology. If so, these may present as interesting targets in treatment, but not prevention. This requires further investigation.