Metabolic dysregulation is currently considered a major risk factor for hippocampal pathology. The aim of the present study was to characterize the influence of key metabolic drivers on functional connectivity of the hippocampus in healthy adults.

Insulin resistance was directly quantified by measuring steady-state plasma glucose (SSPG) concentration during the insulin suppression test and fasting levels of insulin, glucose, leptin, and cortisol, and measurements of body mass index and waist circumference were obtained in a sample of healthy cognitively intact adults (n = 104). Resting-state neuroimaging data were also acquired for the quantification of hippocampal functional cohesiveness and integration with the major resting-state networks (RSNs). Data-driven analysis using unsupervised machine learning (k-means clustering) was then employed to identify clusters of individuals based on their metabolic and functional connectivity profiles.

K-means clustering identified two clusters of increasing metabolic deviance evidenced by cluster differences in the plasma levels of leptin (40.36 (29.97) vs. 27.59 (25.58) μg/L) and the degree of insulin resistance (SSPG concentration: 161.63 (65.27) vs. 125.72 (66.81) mg/dL). Individuals in the cluster with higher metabolic deviance showed lower functional cohesiveness within each hippocampus and lower integration of posterior and anterior components of the left and right hippocampus with the major RSNs. The two clusters did not differ in general intellectual ability or episodic memory.

We identified two clusters of individuals differentiated by abnormalities in insulin resistance, leptin levels, and hippocampal connectivity, with one of the clusters showing greater deviance. These findings support the link between metabolic dysregulation and hippocampal function even in nonclinical samples.

There is growing interest in new factors contributing to the genesis of eating disorders (EDs). Research recently focused on the study of microbiota. Dysbiosis, associated with a specific genetic susceptibility, may contribute to the development of anorexia nervosa (AN), bulimia nervosa, or binge eating disorder, and several putative mechanisms have already been identified. Diet seems to have an impact not only on modification of the gut microbiota, facilitating dysbiosis, but also on its recovery in patients with EDs.

This systematic review based on the PICO strategy searching into PubMed, EMBASE, PsychINFO, and Cochrane Library examined the literature on the role of altered microbiota in the pathogenesis and treatment of EDs.

Sixteen studies were included, mostly regarding AN. Alpha diversity and short-chain fatty acid (SCFA) levels were lower in patients with AN, and affective symptoms and ED psychopathology seem related to changes in gut microbiota. Microbiota-derived proteins stimulated the autoimmune system, altering neuroendocrine control of mood and satiety in EDs. Microbial richness increased in AN after weight regain on fecal microbiota transplantation.

Microbiota homeostasis seems essential for a healthy communication network between gut and brain. Dysbiosis may promote intestinal inflammation, alter gut permeability, and trigger immune reactions in the hunger/satiety regulation center contributing to the pathophysiological development of EDs. A restored microbial balance may be a possible treatment target for EDs. A better and more in-depth characterization of gut microbiota and gut–brain crosstalk is required. Future studies may deepen the therapeutic and preventive role of microbiota in EDs.

Changes in inflammatory and metabolic markers are implicated in the pathogenesis in both the development and progression of bipolar disorder (BD). Notwithstanding, these markers have not been investigated in newly diagnosed BD.

We compared high-sensitive C-reactive protein (hs-CRP) and homocysteine (Hcy) levels in 372 patients with newly diagnosed BD, 106 unaffected first-degree relatives (URs), and 201 healthy control persons (HCs). Within the patient group, we also investigated possible associations between hs-CRP and Hcy, respectively, with illness-related characteristics and psychotropic medication.

No statistically significant differences in Hcy and hs-CRP levels were found when comparing BD and URs with HCs. Similarly, there were no differences when comparing only patients in remission or patients with affective symptoms, respectively, with HCs. Hcy levels were found to be 11.9% (95% CI: 1.030–1.219) higher in patients with BD when compared with their URs (p = 0.008), when adjusting for folate and cobalamin status, age, sex, and self-reported activity levels. Hcy levels were significantly associated with folate, cobalamin, gender, and age in all models (p < 0.05).

Our results do not support hs-CRP or Hcy as markers in newly diagnosed BD.

Patients with severe mental illness (SMI), such as schizophrenia or bipolar disorders, are more frequently affected by metabolic syndrome and cardiovascular (CV) diseases than the general population, with a significant reduction in life expectancy. Beyond metabolic syndrome, quantifying the risk of CV morbidity in the long-term may help clinicians to put in place preventive strategies. In this study, we assessed 10-year CV risk in patients with SMI and healthy individuals using an algorithm validated on the Italian general population.

Patients aged 35–69 years diagnosed with SMI were consecutively recruited from psychiatric acute care units. Single CV risk factors were assessed, and 10-year CV risk calculated by means of the CUORE Project 10-year CV risk algorithm, based on the combination of the following risk factors: age, systolic blood pressure, total and high-density lipoprotein cholesterol, diabetes, smoking habit, and hypertensive treatment. Patients’ data were compared with those from the general population. The 10-year CV risk was log-transformed, and multivariable linear regression was used to estimate mean ratios, adjusting for age, and education.

Three hundred patients and 3,052 controls were included in the analysis. Among men, the 10-year CV risk score was very similar between patients with SMI and the general population (mean ratio [MR]: 1.02; 95%CI 0.77–1.37), whereas a 39% increase in 10-year CV risk was observed in women with SMI compared to the general population (MR: 1.39; 95%CI 1.16–1.66).

In our study, women with SMI were consistently more at risk than the general population counterpart, even at younger age.

General population data on associations between mental disorders and total mortality are rare. The aim was to analyze whether the number of mental disorders, single substance use, mood, anxiety, somatoform or eating disorders during the lifetime and whether treatment utilization may predict time to death 20 years later in the general adult population.

We used data from the Composite International Diagnostic Interview, which includes DSM-IV diagnoses for substance use, mood, anxiety, somatoform, and eating disorders, for a sample of 4,075 residents in Germany who were 18–64 years old in 1996. Twenty years later, mortality was ascertained using the public mortality database for 4,028 study participants. Cox proportional hazards models were applied for disorders that existed at any time in life before the interview.

The data revealed increased hazard ratios (HRs) for number of mental disorders (three or more; HR 1.4; 95% confidence interval [CI] 1.1–1.9) and for single disorders (alcohol dependence, dysthymia, panic disorder with agoraphobia, and hypochondriasis), with the reference group being study participants who had not suffered from any of the mental disorders analyzed and with adjustments made for age, sex, and education. Among individuals with any mental disorder during their lifetimes, having been an inpatient in treatment for a mental disorder was related to a higher HR (2.2; CI 1.6–3.0) than was not having been in any treatment for a mental disorder.

In this sample of adults in the general population, three or more mental disorders, alcohol dependence, dysthymia, panic disorder with agoraphobia, and hypochondriasis were related to premature death.

The mechanisms linking cardiovascular disease (CVD) and depression are still not established. We investigated the impact of mental vulnerability on the relationship between CVD and depression.

A total of 19,856 individuals from five cohorts of random samples of the background population in Copenhagen were followed from baseline (1983–2011) until 2017 in Danish registries. Additive hazard and Cox proportional hazard models were used to analyze the effects of confounding by mental vulnerability as well as interactions between mental vulnerability and CVD on the risk of depression.

During follow-up, 15.3% developed CVD, while 18.1% experienced depression. A strong positive association between CVD and depression (hazard ratio: 3.60 [95% confidence intervals (CI): 3.30; 3.92]) corresponding to 35.4 (95% CI: 31.7; 39.1) additional cases per 1,000 person-years was only slightly attenuated after adjustment for mental vulnerability in addition to other confounders. Synergistic interaction between CVD and mental vulnerability was identified in the additive hazard model. Due to interaction between CVD and mental vulnerability, CVD was associated with 50.9 more cases of depression per 1,000 person-years among individuals with high mental vulnerability compared with individuals with low mental vulnerability.

Mental vulnerability did not explain the strong relationship between CVD and depression. CVD was associated with additional cases of depression among individuals with higher mental vulnerability indicating that this group holds the greatest potential for intervention, for example, in rehabilitation settings.

Although pharmacogenetics for major depressive disorder (MDD) is gaining momentum, the role of genetics in differences in response to antidepressant treatment is controversial, as they depend on multifactorial and polygenic phenotypes. Previous studies focused on the genes of the serotonergic system, leaving apart other pathological factors such as the inflammatory pathway. The main objective of the study was to assess whether treatment response might be associated with specific inflammation-related genetic variants or their methylation status.

41 SNPs in 8 inflammatory genes: interleukin (IL) 1-β, IL2, IL6, IL6R, IL10, IL18, tumor necrosis factor (TNF)-α and interferon (IFN)-γ were genotyped in 153 patients with MDD, who were evaluated with the Mausdley Staging Method to determine treatment response profiles. Pyrosequencing reactions and methylation quantification were performed in a PyroMark Q24 in 5 selected CpG islands of IL1- β, IL6 and IL6R. Linear and logistic regression analyses were conducted, including age and gender as covariates using PLINK 1.07.

Allelic distribution of IL1- β rs1143643 was significantly associated with MSM scores (FDR corrected p = 0.04). Allelic distribution of IL6R rs57569414 showed a trend towards significance with MSM scores (p = 0.002; FDR corrected p = 0.07). Haplotype analyses showed associations between allelic combinations of IL1-β and IL10 with treatment response (FDR corrected p < 0.01). Methylation percentage of treatment responders was only higher in an IL6R CpG island (p < 0.05).

These exploratory findings suggest that IL1-β and, marginally, IL6R polymorphisms may affect treatment response in major depression. If confirmed, these results may account for the heterogeneous phenotypes of major depression that underlie differences in treatment response.

Depression and chronic inflammatory medical conditions have been linked to impaired cognitive ability. However despite frequent comorbidity, their combined association with cognitive ability has rarely been examined.

This study examined associations between self-reported depression and chronic inflammatory diseases and their interaction with cognitive performance in 456,748 participants of the UK Biobank, adjusting for sociodemographic and lifestyle factors. Numbers with available data ranged from 94,899 to 453,208 depending on the cognitive test.

Self-reported depression was associated with poorer performance compared to controls in several cognitive tests (fully adjusted models, reaction time: B = 6.08, 95% CI = 5.09, 7.07; pairs matching: incidence rate ratio = 1.02, 95% CI = 1.02, 1.03; Trail Making Test B: B = 1.37, 95% CI = 0.88, 1.87; Digit Symbol Substitution Test (DSST): B = −0.35, 95% CI = −0.44, −0.27). Self-reported chronic inflammatory conditions were associated with slower reaction time (B = 3.79, 95% CI = 2.81, 4.78) and lower DSST scores (B = −0.21, 95% CI = −0.30, −0.13). No interaction effects were observed.

In this large, population-based study we provide evidence of lower cognitive performance in both depression and a comprehensive category of chronic inflammatory conditions. Results are consistent with additive effects of both types of disorder on cognitive ability. Clinicians should be aware of such effects, particularly as cognitive impairment is linked to poorer disease outcomes and quality of life.

Life expectancy of people with depression is on average 15 years less than that of the general population. This excess of mortality is largely attributed to a deteriorated physical health. Evidence about the association between major depressive disorder (MDD) and physical health is still lacking in some areas. The aim of this study was to explore the association between MDD and physical health-related variables in southern Spain.

The PISMA-ep is a cross-sectional study based on community-dwelling adult population. Our main outcome was current prevalence of MDD. Independent variables explored were: lifetime prevalence of twenty-one chronic physical conditions (CPCs), anthropometric measures (height, weight, body max index, and hip and waist circumferences), general health status, and medication use.

MDD was significantly associated with any CPC (OR = 2.60; 95% CI: 2.01–3.35; p < 0.001). Increases in BMI were associated with MDD in women (OR=1.08; 95% CI: 1.05–1.11; p < 0.001), but not in men (OR=0.99; 95% CI: 0.95–1.05; p = 0.916). Variables associated with MDD in the multivariate model were: female gender, obesity, general health status, cancer, peptic ulcer, tinnitus and vertigo. 21.4% of participants with MDD received antidepressant treatment.

MDD is associated with CPCs, obesity, and increased use of medication. The high rates of comorbidity between MDD and CPCs call for a more holistic management of patients in the clinical practice. The low rate of antidepressant use may be indicating underdiagnosis. Anthropometric variables were differently associated with MDD depending on gender, suggesting a strong influence of psychosocial factors.

Birth dimensions have been associated with increased risk of both, severe mental illness and type 2 diabetes in adulthood, however, any influence on their co-occurrence has never been examined. This cohort study examine whether birth weight/ponderal index explain or modify the later association between severe mental illness and risk of type 2 diabetes.

The Metropolit cohort included 10,863 Danish men born in 1953 with information from age at conscription (between1971-84) until February 15th, 2018. Severe mental illness was defined as the exposure and information was retrieved from the national Danish health registries. Information on type 2 diabetes diagnosis or oral antidiabetic prescriptions was also obtained, as they were the outcome of interest. Information on birth weight/ponderal index was available from birth certificates. Cox proportional hazards regression models were used to estimate the associations and interactions were tested.

After 47.1 years of follow-up, 848 (7.8%) and 1320 (12.2%) men developed a severe mental illness or diabetes, respectively. Men with severe mental illness presented higher risk of subsequent diabetes (HR = 1.92; 95%CI, 1.61–2.30). This association was stronger in severe mental ill men with low birth weight (HR = 3.58; 95%CI, 2.11–6.07), than in those normal birth weight (HR = 1.79; 95%CI, 1.45–2.20). This effect modification was most evident for men diagnosed with schizophrenia.

Birth information on birth weight/ponderal index could be of interest in diabetes screening on severe mental ill populations (especially in schizophrenia) since they might play a critical role in the increased risk of type 2 diabetes following severe mental illness.

Early life adversity is associated with both metabolic impairment and depression in adulthood, as well as with poorer responses to antidepressant medications. It is not yet known whether individual differences in sensitivity to antidiabetic medications could also be related to early life adversity. We examined whether a history of early life adversity affected the observed changes in metabolic function and depressive symptoms in a randomized trial of pioglitazone for augmentation of standard treatments for depression.

Early life adversity is associated with both metabolic impairment and depression in adulthood, as well as with poorer responses to antidepressant medications. It is not yet known whether individual differences in sensitivity to antidiabetic medications could also be related to early life adversity. We examined whether a history of early life adversity affected the observed changes in metabolic function and depressive symptoms in a randomized trial of pioglitazone for augmentation of standard treatments for depression.

We found that early life adversity significantly impaired the metabolic response to pioglitazone. Effects on depressive symptoms did not reach significance, but nonetheless suggested that pioglitazone could mitigate the depressant effects of childhood adversity, only among those insulin resistant at baseline.

We conclude that a history of early life adversity may impair the body’s ability to respond to insulin sensitizing pharmacotherapy, and furthermore that its contribution to resistant depression may function in part via the generation of an insulin resistant phenotype.

Metabolic syndrome and impaired insulin sensitivity may occur as side effects of atypical antipsychotic drugs. However, studies of peripheral insulin resistance using the homeostatic model assessment of insulin resistance (HOMA-IR) or oral glucose tolerance tests (OGTT) suggest that abnormal glucose metabolism is already present in drug-naive first-episode schizophrenia (DNFES). We hypothesized impairments of neuronal insulin signaling in DNFES.

To gain insight into neuronal insulin-signaling in vivo, we analyzed peripheral blood extracellular vesicles enriched for neuronal origin (nEVs). Phosphorylated insulin signal transduction serine-threonine kinases pS312-IRS-1, pY-IRS-1, pS473-AKT, pS9-GSK3β, pS2448-mTOR, pT389-p70S6K and respective total protein levels were determined in plasma nEVs from 48 DNFES patients and healthy matched controls after overnight fasting.

Upstream pS312-IRS-1 was reduced at trend level (p = 0.071; this condition may amplify IRS-1 signaling). Exploratory omnibus analysis of downstream serine-threonine kinases (AKT, GSK3β, mTOR, p70S6K) revealed lower phosphorylated/total protein ratios in DNFES vs. controls (p = 0.013), confirming decreased pathway activation. Post-hoc-tests indicated in particular a reduced phosphorylation ratio of mTOR (p = 0.027). Phosphorylation ratios of p70S6K (p = 0.029), GSK3β (p = 0.039), and at trend level AKT (p = 0.061), showed diagnosis-dependent statistical interactions with insulin blood levels. The phosphorylation ratio of AKT correlated inversely with PANSS-G and PANSS-total scores, and other ratios showed similar trends.

These findings support the hypothesis of neuronal insulin resistance in DNFES, small sample sizes notwithstanding. The counterintuitive trend towards reduced pS312-IRS-1 in DNFES may result from adaptive feedback mechanisms. The observed changes in insulin signaling could be clinically meaningful as suggested by their association with higher PANSS scores.

There is an increasing focus on lifestyle as a factor in the pathogenesis of mental health disorders; however, this has been relatively underexplored in child populations. This study aimed to assess the relationships between behavioural lifestyle factors and emotional functioning in a large, population-representative sample of schoolchildren in Greece.

A representative sample of 2,240 schoolchildren, aged 9–13 years, participated in the Healthy Growth Study during 2007–2010. Emotional functioning was measured using the Dartmouth COOP Functional Health Assessment charts/World Organization of Family Doctors Charts. A score of 3 or higher out of 5 indicated poorer emotional functioning. Participants self-reported dietary intake via three 24-h dietary recalls; fruit, vegetable and soft drink consumption were the dietary variables of interest. Participants’ self-reported daily time spent in moderate to vigorous physical activity, and watching TV or playing video games were used to assess physical activity and sedentary behaviour.

In fully adjusted models, females were at a greater risk of experiencing impaired emotional functioning compared to males (OR 1.76, 95%CI 1.44, 2.15, p < 0.01). Overweight/obesity compared to normal body weight (OR 1.52, 95%CI 1.31, 1.77, p < 0.01) was associated with poorer emotional functioning. Three hours or more of daily average physical activity compared to less than one hour (OR 0.59, 95%CI 0.40, 0.86, p < 0.01) was associated with improved emotional functioning. Consuming soft drinks compared to non-consumption (OR 1.24, 95%CI 1.02, 1.51) was associated with poorer emotional functioning; this became non-significant after corrections for multiple comparisons were made. Clustering of municipalities was accounted for in all models.

Whilst findings were cross-sectional and causality cannot be inferred, this study highlights the interdependence of emotional and physical functioning in schoolchildren. This points to the potential for targeting shared risk factors for both physical chronic diseases and emotional and mental health conditions among children. Further longitudinal evidence will identify the potential for such shared intervention targets. Adopting a comprehensive, integrated approach to children’s emotional, mental, and physical health is warranted.

Lifestyles are involved in the pathogenesis of depression and many of these factors can be modified for the potential prevention of depression. Our aim was to assess the association between a healthy-lifestyle score, that includes some less-studied lifestyle indicators, and the risk of depression.

We followed 14,908 participants initially free of any history of depression in the “Seguimiento Universidad de Navarra” (SUN) cohort. Information was collected biennially from 1999 to December 2016. We calculated a healthy-lifestyle score (0–10 points), previously associated with cardioprotection, by giving one point to each of the following components: never smoking, physical activity (> 20 METs-h/week), Mediterranean diet adherence (≥ 4 points), healthy body mass index (≤ 22 kg/m2), moderate alcohol consumption (women 0.1–5 g/d; men 0.1–10 g/d of ethanol), avoidance of binge drinking (never more than 5 alcoholic drinks in a row), low television exposure (≤ 2 h/d), short afternoon nap (≤ 30 min/day), time spent with friends (>1 h/d) and working at least 40 h/week.

During a median follow-up of 10.4 years, we observed 774 new cases of major depression among participants initially free of depression. The highest category (8–10 factors) showed a significant inverse association with a 32% relative risk reduction for depression compared to the lowest category (0–3 factors) (multivariable-adjusted hazard ratio: 0.68; 95% CI:0.49-0.95) (p for trend = 0.010).

Adopting a healthy-lifestyle was associated with a lower risk of incident depression in the SUN cohort. This index, including ten simple healthy lifestyle habits, may be useful for a more integrative approach to depression prevention.

Although neurocognitive dysfunction and physical performance are known to be impaired in patients with schizophrenia, evidence regarding the relationship between these two domains remains insufficient. Thus, we aimed to investigate the relationship between various physical performance domains and cognitive domains in individuals with schizophrenia, while considering other disorder-related clinical symptoms.

Sixty patients with schizophrenia participated in the study. Cardiorespiratory fitness and functional mobility were evaluated using the step test and supine-to-standing (STS) test, respectively. Executive function and working memory were assessed using the Stroop task and Sternberg working memory (SWM) task, respectively. Clinical symptoms were evaluated using the Brief Psychiatric Rating Scale, Beck Depression Inventory, and State-Trait Anxiety Inventory. Multivariate analyses were performed to adjust for relevant covariates and identify predictive factors associated with neurocognition.

Multiple regression analysis revealed that the step test index was most strongly associated with reaction time in the Stroop task (β = 0.434, p = 0.001) and SWM task (β = 0.331, p = 0.026), while STS test time was most strongly associated with accuracy on the Stoop task (β=−0.418, p = 0.001) and SWM task (β=−0.383, p = 0.007). Total cholesterol levels were positively associated with Stroop task accuracy (β=−0.307, p = 0.018) after controlling for other clinical correlates. However, clinical symptoms were not associated with any variables in Stroop or SWM task.

The present findings demonstrate the relationship between physical performance and neurocognition in patients with schizophrenia. Considering that these factors are modifiable, exercise intervention may help to improve cognitive symptoms in patients with schizophrenia, thereby leading to improvements in function and prognosis.

Activation of the immune-inflammatory response system (IRS) and the compensatory immune-regulatory system (CIRS) and aberrations in endogenous opioids play a role in the pathophysiology of major depressive disorder (MDD). There are no studies which examined the associations between both systems in MDD. The aim of the present study was to examine the relation between β-Endorphin (β-EP), Endomorphin-2, and their mu-opioid receptor (MOR) as well as interleukin (IL)-6 and IL-10, an anti-inflammatory cytokine, in MDD patients.

The study included 60 depressed drug-free male patients and 30 matched controls. Serum β-EP, Endomorphin-2, MOR, IL-6 and IL-10 levels were measured using ELISA techniques.

The results revealed a significant increase in serum β-EP, MOR, IL-6 and IL-10 in MDD patients versus healthy controls. MOR levels were strongly associated with IL-10 levels. There were no significant correlations between endogenous opioids and IL-6 and IL-10.

The results show that MOR levels may function as a possible component of the CIRS whilst there is no evidence that β-EP and EM-2 may modify the IRS. The significant correlation between MOR levels and IL-10 may be explained through central activation of the HPA-axis and increased B-cell numbers expressing MOR as a response to cytokine over-secretion in MDD.