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The Coronavirus disease 2019 (COVID-19) pandemic is an unprecedented traumatic event influencing the healthcare, economic, and social welfare systems worldwide. In order to slow the infection rates, lockdown has been implemented almost everywhere. Italy, one of the countries most severely affected, entered the \"lockdown\" on March 8, 2020. The COvid Mental hEalth Trial (COMET) network includes 10 Italian university sites and the National Institute of Health. The whole study has three different phases. The first phase includes an online survey conducted between March and May 2020 in the Italian population. Recruitment took place through email invitation letters, social media, mailing lists of universities, national medical associations, and associations of stakeholders (e.g., associations of users/carers). In order to evaluate the impact of lockdown on depressive, anxiety and stress symptoms, multivariate linear regression models were performed, weighted for the propensity score. The final sample consisted of 20,720 participants. Among them, 12.4% of respondents (N = 2,555) reported severe or extremely severe levels of depressive symptoms, 17.6% (N = 3,627) of anxiety symptoms and 41.6% (N = 8,619) reported to feel at least moderately stressed by the situation at the DASS-21.According to the multivariate regression models, the depressive, anxiety and stress symptoms significantly worsened from the week April 9-15 to the week April 30 to May 4 (p < 0.0001). Moreover, female respondents and people with pre-existing mental health problems were at higher risk of developing severe depression and anxiety symptoms (p < 0.0001). Although physical isolation and lockdown represent essential public health measures for containing the spread of the COVID-19 pandemic, they are a serious threat for mental health and well-being of the general population. As an integral part of COVID-19 response, mental health needs should be addressed.

Current evidence points to a research-practice gap in mental health. There is a specific unmet need to identify novel strategies to improve diagnostic criteria, especially when clinical manifestations overlap as in the case of bipolar (BD) and major depressive disorder (MDD). Based on the rapidly evolving notion that affective disorders are characterized by disrupted brain-body communication, current efforts of neuropsychiatric research are converging towards the identification of specific clusters of peripheral interconnected biomarkers. We argue that these can capture the complexity of the disease as they are linked to the fundamental pathophysiological mechanisms underlying BD or MDD, and can thus deliver an unbiased biosignature. Here we provide a critical viewpoint on the promises and challenges of biomarkers to identify reliable biosignatures of affective disorders. Novel methodological insight and relevant biomarkers are discussed with a main focus on immunometabolic derangements and disrupted redox balance. Major advancements are reviewed taking into consideration that an unbiased diagnosis can only derive from a deep understanding of how biological, psychological, and social factors interact ultimately affecting the clinical manifestation of affective disorders.

Stress and glucocorticoid hormones regulate hippocampal neurogenesis, but the molecular mechanisms underlying their effects are unknown. We, therefore, investigated the molecular signaling pathways mediating the effects of cortisol on proliferation, neuronal differentiation, and astrogliogenesis, in an immortalized human hippocampal progenitor cell line. In addition, we examined the molecular signaling pathways activated in the hippocampus of prenatally stressed rats, characterized by persistently elevated glucocorticoid levels in adulthood. In human hippocampal progenitor cells, we found that low concentrations of cortisol (100 nM) increased proliferation (+16%), decreased neurogenesis into microtubule-associated protein 2 (MAP2)-positive neurons (-24%) and doublecortin (Dcx)-positive neuroblasts (-21%), and increased differentiation into S100β-positive astrocytes (+23%). These effects were dependent on the mineralocorticoid receptor (MR) as they were abolished by the MR antagonist, spironolactone, and mimicked by the MR-agonist, aldosterone. In contrast, high concentrations of cortisol (100 μM) decreased proliferation (-17%) and neuronal differentiation into MAP2-positive neurons (-22%) and into Dcx-positive neuroblasts (-27%), without regulating astrogliogenesis. These effects were dependent on the glucocorticoid receptor (GR), blocked by the GR antagonist RU486, and mimicked by the GR-agonist, dexamethasone. Gene expression microarray and pathway analysis showed that the low concentration of cortisol enhances Notch/Hes-signaling, the high concentration inhibits TGFβ-SMAD2/3-signaling, and both concentrations inhibit Hedgehog signaling. Mechanistically, we show that reduced Hedgehog signaling indeed critically contributes to the cortisol-induced reduction in neuronal differentiation. Accordingly, TGFβ-SMAD2/3 and Hedgehog signaling were also inhibited in the hippocampus of adult prenatally stressed rats with high glucocorticoid levels. In conclusion, our data demonstrate novel molecular signaling pathways that are regulated by glucocorticoids in vitro, in human hippocampal progenitor cells, and by stress in vivo, in the rat hippocampus.

Several biogerontology databases exist that focus on genetic or gene expression data linked to health as well as survival, subsequent to compound treatments or genetic manipulations in animal models. However, none of these has yet collected experimental results of compound-related health changes. Since quality of life is often regarded as more valuable than length of life, we aim to fill this gap with the “Healthy Worm Database” (http://healthy-worm-database.eu). Literature describing health-related compound studies in the aging model Caenorhabditis elegans was screened, and data for 440 compounds collected. The database considers 189 publications describing 89 different phenotypes measured in 2995 different conditions. Besides enabling a targeted search for promising compounds for further investigations, this database also offers insights into the research field of studies on healthy aging based on a frequently used model organism. Some weaknesses of C. elegans-based aging studies, like underrepresented phenotypes, especially concerning cognitive functions, as well as the convenience-based use of young worms as the starting point for compound treatment or phenotype measurement are discussed. In conclusion, the database provides an anchor for the search for compounds affecting health, with a link to public databases, and it further highlights some potential shortcomings in current aging research.

When facing a traumatic event, some people may experience positive changes, defined as posttraumatic growth (PTG). Understanding the possible positive consequences of the pandemic on the individual level is crucial for the development of supportive psychosocial interventions. The present paper aims to: 1) evaluate the levels of PTG in the general population; 2) to identify predictors of each dimension of post-traumatic growth. The majority of the sample (67%, N = 13,889) did not report any significant improvement in any domain of PTG. Participants reported the highest levels of growth in the dimension of \"appreciation of life\" (2.3 ± 1.4), while the lowest level was found in the \"spiritual change\" (1.2 ± 1.2). Female participants reported a slightly higher level of PTG in areas of personal strength (p < .002) and appreciation for life (p < .007) compared to male participants, while no significant association was found with age. At the multivariate regression models, weighted for the propensity score, only the initial week of lockdown (between 9-15 April) had a negative impact on the dimension of \"relating to others\" (B = -.107, 95% CI = -.181 to -.032, p < .005), while over time no other effects were found. The duration of exposure to lockdown measures did not influence the other dimensions of PTG. The assessment of the levels of PTG is of great importance for the development of ad hoc supportive psychosocial interventions. From a public health perspective, the identification of protective factors is crucial for developing ad-hoc tailored interventions and for preventing the development of full-blown mental disorders in large scale.

COVID-19 pandemic and its related containment measures have been associated with increased levels of stress, anxiety and depression in the general population. While the use of digital media has been greatly promoted by national governments and international authorities to maintain social contacts and healthy lifestyle behaviors, its increased access may also bear the risk of inappropriate or excessive use of internet-related resources. The present study, part of the COVID Mental hEalth Trial (COMET) study, aims at investigating the possible relationship between social isolation, the use of digital resources and the development of their problematic use. A cross sectional survey was carried out to explore the prevalence of internet addiction, excessive use of social media, problematic video gaming and binge watching, during Italian phase II (May–June 2020) and III (June–September 2020) of the pandemic in 1385 individuals (62.5% female, mean age 32.5 ± 12.9) mainly living in Central Italy (52.4%). Data were stratified according to phase II/III and three groups of Italian regions (northern, central and southern). Compared to the larger COMET study, most participants exhibited significant higher levels of severe-to-extremely-severe depressive symptoms (46.3% vs. 12.4%; p < 0.01) and extremely severe anxiety symptoms (77.8% vs. 7.5%; p < 0.01). We also observed a rise in problematic internet use and excessive gaming over time. Mediation analyses revealed that COVID-19-related general psychopathology, stress, anxiety, depression and social isolation play a significant role in the emergence of problematic internet use, social media addiction and problematic video gaming. Professional gamers and younger subjects emerged as sub-populations particularly at risk of developing digital addictions. If confirmed in larger and more homogenous samples, our findings may help in shedding light on possible preventive and treatment strategies for digital addictions.

Predicting disease trajectories in patients with major depressive disorder (MDD) can allow designing personalized therapeutic strategies. In this study, we aimed to show that measuring patients’ plasticity – that is the susceptibility to modify the mental state – identifies at baseline who will recover, anticipating the time to transition to wellbeing. We conducted a secondary analysis in two randomized clinical trials, STAR*D and CO-MED. Symptom severity was assessed using the Quick Inventory of Depressive Symptomatology while the context was measured at enrollment with the Quality-of-Life Enjoyment and Satisfaction Questionnaire. Patients were retrospectively grouped based on both their time to response or remission and their plasticity levels at baseline assessed through a network-based mathematical approach that operationalizes plasticity as the inverse of the symptom network connectivity strength. The results show that plasticity levels at baseline anticipate time to response and time to remission. Connectivity strength among symptoms is significantly lower – and thus plasticity higher – in patients experiencing a fast recovery. When the interplay between plasticity and context is considered, plasticity levels are predictive of disease trajectories only in subjects experiencing a favorable context, confirming that plasticity magnifies the influence of the context on mood. In conclusion, the assessment of plasticity levels at baseline holds promise for predicting MDD trajectories, potentially informing the design of personalized treatments and interventions. The combination of high plasticity and the experience of a favorable context emerges as critical to achieve recovery.

Antidepressants represent the standard treatment for major depression. However, their efficacy is variable and incomplete. A growing number of studies suggest that the environment plays a major role in determining the efficacy of these drugs, specifically of selective serotonin reuptake inhibitors (SSRI). A recent hypothesis posits that the increase in serotonin levels induced by SSRI may not affect mood per se, but enhances neural plasticity and, consequently, renders the individual more susceptible to the influence of the environment. Thus, SSRI administration in a favorable environment would lead to a reduction of symptoms, while in a stressful environment might lead to a worse prognosis. To test this hypothesis, we treated C57BL/6 adult male mice with chronic fluoxetine while exposing them to either (i) an enriched environment, after exposure to a chronic stress period aimed at inducing a depression-like phenotype, or (ii) a stressful environment. Anhedonia, brain BDNF and circulating corticosterone levels, considered endophenotypes of depression, were investigated. Mice treated with fluoxetine in an enriched condition improved their depression-like phenotype compared to controls, displaying higher saccharin preference, higher brain BDNF levels and reduced corticosterone levels. By contrast, when chronic fluoxetine administration occurred in a stressful condition, mice showed a more distinct worsening of the depression-like profile, displaying a faster decrease of saccharin preference, lower brain BDNF levels and increased corticosterone levels. Our findings suggest that the effect of SSRI on depression-like phenotypes in mice is not determined by the drug per se but is induced by the drug and driven by the environment. These findings may be helpful to explain variable effects of SSRI found in clinical practice and to device strategies aimed at enhancing their efficacy by means of controlling environmental conditions.

Maternal obesity has been recognized as a stressor affecting the developing fetal brain, leading to long-term negative outcomes comparable to those resulting from maternal psychological stress, although the mechanisms have not been completely elucidated. In this study, we tested the hypothesis that adverse prenatal conditions as diverse as maternal stress and maternal obesity might affect emotional regulation and stress response in the offspring through common pathways, with a main focus on oxidative stress and neuroplasticity. We contrasted and compared adolescent male and female offspring in two mouse models of maternal psychophysical stress (restraint during pregnancy - PNS) and maternal obesity (high-fat diet before and during gestation - mHFD) by combining behavioral assays, evaluation of the hypothalamic–pituitary–adrenal (HPA) axis reactivity, immunohistochemistry and gene expression analysis of selected markers of neuronal function and neuroinflammation in the hippocampus, a key region involved in stress appraisal. Prenatal administration of the antioxidant N-acetyl-cysteine (NAC) was used as a strategy to protect fetal neurodevelopment from the negative effects of PNS and mHFD. Our findings show that these two stressors produce overlapping effects, reducing brain anti-oxidant defenses (Nrf-2) and leading to sex-dependent impairments of hippocampal Bdnf expression and alterations of the emotional behavior and HPA axis functionality. Prenatal NAC administration, by restoring the redox balance, was able to exert long-term protective effects on brain development, suggesting that the modulation of redox pathways might be an effective strategy to target common shared mechanisms between different adverse prenatal conditions.

The serotonin-transporter-linked promoter region (5-HTTLPR) has been widely investigated as contributing to depression vulnerability. Nevertheless, empirical research provides wide contrasting findings regarding its involvement in the etiopathogenesis of the disorder. Our hypothesis was that such discrepancy can be explained considering time as moderating factor. We explored this 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. The effect of the 5-HTTLPR x stress interaction on depression risk was found to be moderated by the following temporal factors: the duration of stress (i.e. chronic vs. acute) and the time interval between end of stress and assessment of depression (i.e. within 1 year vs. more than 1 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, with a significant subgroup difference ( p  = 0.004). The stratification according to time interval revealed a significant interaction only for intervals within 1 year, 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 1 year and a significant subgroup difference was found ( p  = 0.01). These 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, that results in a three-way interaction: gene x environment x time.