Journal of Psychiatric Research

BackgroundWorldwide, common mental disorders such as anxiety and depression are major contributors to disability. However, the role of diet as a risk factor for anxiety and depression remains underexplored. Therefore, we investigated the associations between food groups and major depressive disorder (MDD) and anxiety disorders, following a harmonized protocol to enable integration of studies. MethodsWe analysed data from 1,634 participants in the Netherlands Study of Depression and Anxiety to examine cross-sectional associations between 14 dietary exposures--derived from a 238-item Food Frequency Questionnaire (fruit, vegetables, legumes, whole grains, nuts and seeds, milk, red meat, processed meat, sweet drinks, fibre, calcium, omega-3 fatty acids, polyunsaturated fatty acids, and trans fats)--and anxiety and depressive disorders in the past month (assessed with the Composite International Diagnostic Interview). Secondary outcomes were depressive symptoms (Quick Inventory of Depressive Symptomatology score [&ge;]13 vs. <13) and anxiety symptoms (Beck Anxiety Index score [&ge;]16 vs. <16). Logistic regression analyses were conducted for each dietary exposure, with depression and anxiety measures as outcomes. Results8.7% had MDD and 14.4% had an anxiety disorder in the past month. Higher vegetable intake was associated with lower odds of depression and anxiety disorders. Additionally, higher intakes of omega-3 fatty acids, red meat, whole grains, and fibre were associated with lower odds of depression and anxiety, whereas higher intake of trans fats was associated with increased odds of these disorders. Other dietary exposures were not significantly related to depression or anxiety. DiscussionCertain dietary exposures, particularly vegetables, as well as omega-3 fatty acids, red meat, whole grains, and fibre, were associated with depression and anxiety outcomes. These findings may contribute to integration of results in Global Burden of Diseases initiatives on exploring dietary risk factors of depression and anxiety.

The first publication demonstrating that major depressive disorder (MDD) is associated with alterations in the gut microbiota appeared in 2008 (Maes et al., 2008). The purpose of the present study is to delineate a) the microbiome signature of the phenome of depression, including suicidal behaviours and cognitive deficits; the effects of adverse childhood experiences (ACE) and recurrence of illness index (ROI) on the microbiome; and the microbiome signature of lowered high-density lipoprotein cholesterol (HDLc). We determined isometric log-ratio abundances or prevalence of gut microbiome phyla, genera, and species by analyzing stool samples from 37 healthy Thai controls and 32 MDD patients using 16S rDNA sequencing. Six microbiome taxa accounted for 36% of the variance in the depression phenome, namely Hungatella and Fusicatenibacter (positive associations) and Butyricicoccus, Clostridium, Parabacteroides merdae, and Desulfovibrio piger (inverse association). This profile (labeled enterotype 1) indicates compositional dysbiosis, is strongly predicted by ACE and ROI, and is linked to suicidal behaviours. A second enterotype was developed that predicted a decrease in HDLc and an increase in the atherogenic index of plasma (Bifidobacterium, P. merdae, and Romboutsia were positively associated, while Proteobacteria and Clostridium sensu stricto were negatively associated). Together, enterotypes 1 and 2 explained 40.4% of the variance in the depression phenome, and enterotype 1 in conjunction with HDLc explained 39.9% of the variance in current suicidal behaviours. In conclusion, the microimmuneoxysome is a potential new drug target for the treatment of severe depression and suicidal behaviours, and possibly for the prevention of future episodes.

ObjectiveDepression remains one of the most critical healthcare concerns worldwide. While increasing patient numbers inevitably lead to a greater need for treatment, resources to adequately match this demand are limited. Digital technologies hold promises to complement standard therapeutic approaches such as psychotherapy, thereby alleviating the strain on an increasingly burdened healthcare system. This study aimed at testing a new comprehensive smartwatch-based digital intervention program administered for 12 weeks in depressed patients to aid therapeutic progression and symptom relief. MethodsSeventeen mildly to moderately depressed patients receiving the smartwatch-based intervention were compared to an existing, retrospective control group (35 patients). The intervention program comprised behavioral activation, cognitive-behavioral intervention for insomnia and physical activity interventions. Intervention effects on the reduction of depression severity, measured by the PHQ-9, were investigated using a repeated measure analysis of variance (rmANOVA). ResultsThe rmANOVA showed a significant group x time interaction for the PHQ-9 scores, F(1, 50) = 7.21, p = 0.010, with post-hoc t-tests revealing group differences after but not before the intervention. ConclusionThis study suggests that smartwatch-based interventions are feasible and effective in reducing mild to moderate depressive symptoms and could therefore be a promising stand-alone or complementary intervention to psychotherapy. Further research with a randomized controlled trial is required to validate these results.

BackgroundCell deformability of all major blood cell types is increased in depressive disorders (DD). Furthermore, impaired glucocorticoid secretion is causally related to DD. Nevertheless, there are no longitudinal studies examining changes in glucocorticoid output and depressive symptoms regarding cell deformability in DD. AimTo investigate, whether changes in depressive symptoms or hair glucocorticoids predict cell deformability in DD. MethodsIn 136 individuals, depressive symptoms (PHQ-9) and hair glucocorticoids (cortisol and cortisone) were measured at timepoint one (T1), while one year later (T2) depressive symptoms and hair glucocorticoids were remeasured and additionally cell deformability of peripheral blood cells was assessed and DD status was determined by clinical interview. ResultsDepression severity at T1 predicted higher cell deformability in monocytes and lymphocytes over the entire sample. Subjects with continuously high depressive symptoms at T1 and T2 showed elevated monocyte deformability as compared to subjects with low depressive symptoms. Depression severity at T1 of subjects with a lifetime persistent depressive disorder (PDD) was associated with elevated monocyte, neutrophil, and granulo-monocyte deformability. Depression severity at T1 of subjects with a 12-month PDD was positively associated with monocyte deformability. Furthermore, increases in glucocorticoid concentrations from T1 to T2 tended to be associated with higher immune cell deformability, while strongest associations emerged for the increase in cortisone with elevated neutrophil and granulo-monocyte deformability in the 12-month PDD group. ConclusionContinuously elevated depressive symptomatology as well as an increase in glucocorticoid levels over one year are associated with higher immune cell deformability, particularly in PDD. These findings suggest, that persistent depressive symptomatology associated with increased glucocorticoid secretion may lead to increased immune cell deformability thereby compromising immune cell function and likely contributing to the perpetuation of PDD.

Meteorological factors affect the serotonergic system, potentially influencing SLC6A4 promoter methylation in seasonal affective disorder (SAD). However, studies on how sunlight impacts methylation and modulates SERT activity in this context remain limited. This study aims to investigate the effect of average daily sunshine duration on SLC6A4 promoter methylation in a cohort consisting of both patients with SAD as well as healthy controls (HC). Methylation data were collected from 28 patients with SAD and 40 healthy controls (HC). Average methylation from four SLC6A4 promoter CpG sites was assessed. Daily sunlight data for Vienna, Austria (mean of 28 days before blood sampling), were obtained from (C)GeoSphere Austria. A general linear model (GLM) analyzed SLC6A4 promoter methylation as the dependent variable, with sunlight hours as the independent variable, and group (SAD, HC), age, sex, and 5-HTTLPR/rs25531 as covariates. Exploratory analyses examined sunlight hours and methylation effects on Beck Depression Inventory (BDI) scores. Sunlight had a significant effect on SLC6A4 promoter methylation (p = 0.03), with more sunlight hours resulting in lower methylation (r = -0.25). However, the interaction between sunlight and group was non-significant, suggesting a rather general effect across both groups. Sunlight also influenced BDI scores (p < 0.01), with fewer sunlight hours leading to higher BDI scores (r = -0.25), which aligns with previous research. SLC6A4 promoter methylation had no significant effect on BDI scores. Our findings suggest that sunlight impacts SLC6A4 promoter methylation, but this effect appears general, not specific to SAD pathophysiology.

BackgroundMajor depressive disorder (MDD) is widely acknowledged as stemming from the dysregulation of neuroimmune, metabolic, and oxidative stress (NIMETOX) pathways. The objective of this study was to examine insulin metabolism in Chinese patients with MDD and to clarify the relationship between insulin resistance and the acute phase protein (APP) response, as shown by the negative APPs albumin and transferrin. MethodsThis investigation utilized a cross-sectional case-control approach, enrolling 125 inpatients with MDD and 40 healthy controls. ResultsPatients with MDD exhibited markedly reduced levels of fasting plasma glucose, insulin, and insulin resistance, and heightened insulin sensitivity, in comparison to healthy controls. The significance of these alterations persisted after controlling for metabolic syndrome, body mass index (BMI), and age, but was nullified with adjustment for both negative APPs. We determined that 41.4% of the variance in insulin resistance was accounted for by elevated levels of BMI, albumin, transferrin, and age. Insulin resistance was significantly and inversely associated with weight loss. We found that 27.7% of the variance in overall depression severity was accounted for by adverse childhood experiences (positive correlation) and insulin resistance (negative correlation). ConclusionsThis work demonstrates that Chinese MDD patients display increased insulin sensitivity and reduced insulin resistance, with these alterations being associated with a modest smoldering inflammatory response. MDD is characterized by a hormetic response that enhances insulin efficacy, hence optimizing glucose consumption to sustain normal organ function. It is incorrect to claim that MDD is intrinsically associated with increased insulin resistance.

BackgroundMood and anxiety disorders are highly prevalent and comorbid worldwide, with variability in symptom severity that fluctuates over time. Digital phenotyping, a growing field that aims to characterize clinical, cognitive and behavioral features via personal digital devices, enables continuous quantification of symptom severity in the real world, and in real-time. MethodsIn this study, N=114 individuals with a mood or anxiety disorder (MA) or healthy controls (HC) were enrolled and completed 30-days of ecological momentary assessments (EMA) of symptom severity. Novel real-world measures of anxiety, distress and depression were developed based on the established Mood and Anxiety Symptom Questionnaire (MASQ). The full MASQ was also completed in the laboratory (in-lab). Additional EMA measures related to extrinsic and intrinsic motivation, and passive activity data were also collected over the same 30-days. Mixed-effects models adjusting for time and individual tested the association between real-world symptom severity EMA and the corresponding full MASQ sub-scores. A graph theory neural network model (DEPNA) was applied to all data to estimate symptom interactions. ResultsThere was overall good adherence over 30-days (MA=69.5%, HC=71.2% completion), with no group difference (t(58)=0.874, p=0.386). Real-world measures of anxiety/distress/depression were associated with their corresponding MASQ measure within the MA group (ts > 2.33, ps < 0.024). Physical activity (steps) was negatively associated with real-world distress and depression (IRRs > 0.93, ps [&le;] 0.05). Both intrinsic and extrinsic motivation were negatively associated with real-world distress/depression (IRRs > 0.82, ps < 0.001). DEPNA revealed that both extrinsic and intrinsic motivation significantly influenced other symptom severity measures to a greater extent in the MA group compared to the HC group (extrinsic/intrinsic motivation: t(46) = 2.62, p < 0.02, q FDR < 0.05, Cohens d = 0.76; t(46) = 2.69, p < 0.01, q FDR < 0.05, Cohens d = 0.78 respectively), and that intrinsic motivation significantly influenced steps (t(46) = 3.24, p < 0.003, q FDR < 0.05, Cohens d = 0.94). ConclusionsNovel real-world measures of anxiety, distress and depression significantly related to their corresponding established in-lab measures of these symptom domains in individuals with mood and anxiety disorders. Novel, exploratory measures of extrinsic and intrinsic motivation also significantly related to real-world mood and anxiety symptoms and had the greatest influencing degree on patients overall symptom profile. This suggests that measures of cognitive constructs related to drive and activity may be useful in characterizing phenotypes in the real-world.

The ongoing war in Ukraine has exposed young adults to sustained psychological stress, elevating their risk of developing post-traumatic stress disorder (PTSD). In a case-control study of 698 individuals, we investigated associations between PTSD, dietary patterns, disordered eating behaviours, and hematological parameters. PTSD was associated with greater adherence to restrictive diets--including ketogenic, low-fat, and intermittent fasting patterns--as well as higher scores for emotional, external, and uncontrolled eating. Conversely, adherence to a Mediterranean diet was associated with a reduced likelihood of PTSD. Hematologically, PTSD was linked to lower hemoglobin and red blood cell counts, along with elevated inflammatory markers, particularly an increased neutrophil-to-lymphocyte ratio (NLR). Using machine learning, we identified NLR, white blood cell count, and hemoglobin concentration as the strongest predictors of PTSD status. War-related trauma appears to disrupt both eating behaviour and immune function, contributing to the emergence of stress-related psychiatric conditions.

The COVID-19 pandemic has presented a significant challenge to societal mental health. Yet, it remains unknown which factors influence the mental adaptation from lockdown to subsequent relaxation periods, particularly for vulnerable groups. This study used smartphone-based monitoring to explore how 74 individuals with major depression (MDD) and 77 healthy controls (HCs) responded to the transition from lockdown to relaxation during the first wave of the COVID-19 pandemic (March 21 to November 01, 2020) regarding interpersonal interactions, COVID-19-related fear (fear of participants own health, the health of close relatives, and the pandemics economic impact), and the feeling of isolation. Furthermore, we investigated the effect of a diagnosis of MDD and the experience of childhood maltreatment (CM) on adaptive functioning. During the transition from lockdown to relaxation, we observed an increase in direct contacts and a decrease in indirect contacts and self-perceived isolation in the study population. The diagnosis of MDD and the experience of CM moderated a maintenance of COVID-19-related fear: HCs and participants without the experience of CM showed a decrease in fear, while fear of participants with MDD and with an experience of CM did not change significantly. The finding that elevated COVID-19-related fear was sustained in vulnerable groups after lockdown measures were lifted could help guide psychosocial prevention efforts in future pandemic emergencies.

BackgroundMetabolic syndrome (MetS) is highly prevalent among adults and is frequently accompanied by depressive symptoms. While high-sensitivity C-reactive protein (hsCRP) has been proposed as a potential indicator of depression, existing evidence remains inconclusive. ObjectiveThis study aimed to determine whether increased serum hsCRP or other immune-metabolic biomarkers are associated with depressive symptoms in drug-naive individuals with obesity and MetS. MethodsA total of 88 drug-naive patients with obesity and MetS but without coronary-artery disease were enrolled and serum levels of neuro-immune and metabolic biomarkers were assessed. ResultsIn MetS, the severity of depression, as assessed using the von Zerssen Depression Rating (VZDR) scale was significantly associated with interleukin (IL)-6, leukocyte numbers, triglyceride x glucose (Tyg) index, low-density lipoprotein cholesterol, Apolipoprotein B (all positively) and mean platelet volume (MPV), visfatin and adiponectin (all negatively). There were no significant associations between hsCRP and severity of depression. In MetS patients, hsCRP is strongly associated with increased leukocyte numbers, alkaline phosphatase, {gamma}-glutamyl transferase, uric acid, platelet numbers and MPV, thereby shaping a distinct subtype of MetS, which is not related to depression. ConclusionsOur findings indicate that depressive symptoms in MetS patients are associated with immune-metabolic biomarkers indicating immune activation, atherogenicity and insulin resistance, but not with hsCRP. The reason is that hsCRP in MetS is a biomarker of a specific MetS subtype that is characterized by megakaryopoiesis, hepatocyte activation, and uric acid production, which were not associated with depression.

BackgroundMental disorders affect approximately 14% of adolescents worldwide, often leading to persistent cognitive and emotional difficulties and reduced health-related quality of life (HRQoL). Executive functions (EF)--including cognitive flexibility, inhibition, attention, and working memory-- are particularly impaired in many psychiatric conditions. Chess has recently been proposed as a low-cost cognitive remediation training (CRT). This pilot study investigated whether chess-based CRT could enhance EF and HRQoL in adolescents with psychiatric disorders. MethodsA quasi-experimental design was conducted at the Department of Child and Adolescent Psychiatry, Mannheim, Germany (September 2022-April 2024). Participants aged 13-17 years were assigned to either a six-week chess intervention (experimental group, EG) or treatment as usual (control group, CG). Both groups received standard multidisciplinary therapy, while the EG additionally participated in weekly 90-minute chess sessions based on The Kings Plan for Kids. Cognitive flexibility (DCCS), inhibitory control (Stop-Signal Task), sustained attention (d2-R), and working memory (n-back task) were assessed alongside HRQoL (KIDSCREEN-27). Data were analyzed using t-tests. ResultsThirty-three adolescents were included (19 EG, 14 CG; 82% female). While no significant group differences emerged for cognitive flexibility, inhibitory control, or sustained attention, the EG showed significantly faster reaction times in the working memory task (p = .016, d = 0.79), suggesting improved cognitive efficiency. Psychological well-being increased significantly in the EG compared to the CG (p = .035, d = 0.67), whereas physical well-being showed a non-significant upward trend. ConclusionChess-based CRT was associated with enhanced psychological well-being and improved working memory efficiency in adolescents with psychiatric disorders. Although other EF measures did not show significant changes, findings support the feasibility and potential clinical value of chess as an engaging, low-risk adjunct to standard therapy. Larger randomized trials are needed to confirm these preliminary results.

BackgroundEnvironmental heat exposure can negatively impact mental health. Evidence for its effect on mood disorder symptoms is inconsistent. Current studies are limited by poor temporal and geographical resolution. MethodsWe used ecological momentary assessment (EMA) data from the smartphone app juli to investigate the association between real-time mean and maximum ambient temperature collected from smartphone geolocation, and depressive and manic symptom scales, every two weeks, in adults with depression and bipolar disorder. We used negative binomial mixed-effects regression models, controlled for demographic and weather variables, and stratified by season. ResultsWe analysed data from 4,000 participants with depressive symptom scores and 2,132 with manic symptom scores, between 2021 and 2023. We found that each 1{degrees}C increase in mean daily temperature in the preceding two weeks was associated with a 0.2% reduction in depressive symptom scores (coeff 0.998, 95%CI 0.997-0.999) and a 0.4% increase in manic symptom scores (coeff 1.004, 95%CI 1.001-1.007). Associations between maximum temperature and symptom scores followed a similar pattern. LimitationsWe were unable to capture several socio-demographic covariates, had limited geographical information due to privacy regulations, and included a non-random sample. ConclusionsWe found evidence that higher temperatures were associated with increased manic symptoms and decreased depressive symptoms, indicating an important relationship between temperature and the mood disorder continuum. With global heating, there is a need to understand the impact of temperature on mood symptoms, to provide targeted clinical prevention and support. This study demonstrates potential for EMA methods to inform our understanding of these links.

Background: Generalized anxiety disorder (GAD) is associated with substantial psychological burden, autonomic dysregulation, and limitations of existing pharmacological and psychotherapeutic treatments. Transcutaneous auricular vagus nerve stimulation (taVNS) has emerged as a promising non-invasive neuromodulation approach, but evidence regarding home-based application in GAD remains limited. Objective: To evaluate the feasibility, safety, and preliminary clinical and physiological outcomes of a home-based taVNS intervention in adults with psychologist-confirmed moderate-to-severe GAD. Methods: In this prospective single-arm feasibility study, 48 participants initiated a 4-week home-based taVNS intervention consisting of two daily stimulation sessions performed five days per week. Clinical assessments were conducted at baseline, Week 2, Week 4, and follow-up visits at Weeks 6 and 8. Ambulatory electrocardiographic monitoring was performed before treatment initiation, at Week 2, and at the end of treatment to assess heart rate variability (HRV) using the root mean square of successive differences (RMSSD). Primary outcomes included feasibility, safety, adherence, and change in clinician-rated anxiety severity (HAM-A). Results: Thirty-four participants completed the study and were included in the primary analyses. HAM-A scores decreased significantly from baseline to Week 4 ([EMD] -6.9, 95% CI -10.4 to -3.4, p = 0.001), with partial maintenance during follow-up. Improvements were also observed in Beck Anxiety Inventory scores, whereas changes in GAD-7, perceived stress, depressive symptoms, and sleep quality were not statistically significant. RMSSD increased significantly from baseline to Week 4 (EMD 6.7 ms, 95% CI 2.1-11.3, p = 0.009). Greater increases in RMSSD were associated with larger reductions in HAM-A (R^2 = 0.18, p = 0.031) and BAI scores (R^2 = 0.21, p = 0.019). No serious adverse events occurred. Mean adherence was 79.8%, and 73.5% of participants completed at least 70% of prescribed stimulation sessions. Conclusions: Home-based taVNS was feasible and generally well tolerated in adults with moderate-to-severe GAD. Preliminary improvements in clinician-rated anxiety severity and autonomic physiological measures were observed; however, the single-arm design precludes causal inference. These findings support further evaluation of home-based taVNS in adequately powered randomized sham-controlled trials.

Social isolation strongly affects our emotions, behavior and interactions. Worldwide, individuals experienced prolonged periods of isolation during the first wave of the COVID-19 pandemic when authorities imposed restrictions to reduce the spread of the virus. In this study, we investigated the effects of social isolation on emotional and behavioral outcomes in young adults from Lombardy, Italy, a global hotspot of COVID-19. We leverage baseline (pre-social isolation) and follow-up (mid-or post isolation) data collected from young adults enrolled in the ongoing, longitudinal Public Health Impact of Metals Exposure (PHIME) study. At baseline, 167 participants completed the ASEBA questionnaires (ASR/YSR) by weblink or in person; 65 completed the ASR between 12-18 weeks after the onset of restrictions. Using the sign test and multiple linear regression models, we examined differences in ASR scores between baseline and follow-up adjusting for sex, age, pre-pandemic IQ (Kaufman Brief Intelligence Tests; K-BIT 2), and time with social restrictions (weeks). Further, we examined interactions between sex and time in social isolation. Participants completed the ASR after spending an average of 14 weeks in social isolation (range 12-18 weeks). Thought Problems increased between baseline and follow-up (median difference 1.0; 1st., 3rd quartile: -1.0, 4.0; p=0.049). Among males, a longer time with social isolation ([&ge;] 14 weeks) was associated with increased rule-breaking behaviors of 2.8 points. These results suggest the social isolation related to COVID-19 adversely impacted mental health. In particular, males seem to externalize their condition. These findings might help future interventions and treatment to minimize the consequences of social isolation experience in young adults.

ObjectiveMajor depressive disorder (MDD) in adolescence is frequently accompanied by emotion regulation (ER) deficits, particularly in socially stressful contexts. However, how comorbid social anxiety disorder (SAD) modulates ER during social exclusion in depressed adolescents the behavioral and neural level remains poorly understood. MethodSixty-two adolescents (30 with MDD, 32 healthy controls; aged 12-18) completed a social-exclusion-stimuli task during electroencephalogram (EEG) recording. Using EEG in combination with a dedicated paradigm showing social exclusion (versus neutral situations), ER ability was assessed via cognitive reappraisal performance, negative affect ratings, EEG and prefrontal-limbic functional connectivity. The Adolescent-MDD group was further stratified by SAD comorbidity status. ResultsCompared to healthy peers, adolescents with MDD showed reduced cognitive reappraisal use and heightened negative affect during social exclusion, reflecting impaired top-down control. Neurally, they showed increased LPP amplitudes and greater left prefrontal theta-band activity during reappraisal, alongside weakened prefrontal-limbic functional coupling. Critically, youth with comorbid SAD demonstrated more pronounced ER impairments and fronto-limbic dysconnectivity, suggesting SAD amplifies neural inefficiency and social withdrawal in depression. ConclusionDisrupted prefrontal-limbic connectivity may underlie ER impairments in depressed adolescents, particularly those with comorbid SAD. These findings identify a potential neurophysiological target for early intervention and offer mechanistic insight into the interaction of depression, social anxiety, and ER during adolescence.

BackgroundThere are strong associations between major depressive disorder (MDD), metabolic syndrome (MetS) and cardiovascular disorder, which may be explained by increased atherogenicity and the microimmuneoxysome (Maes et al., 1994; 2011). The present study was conducted to determine if MDD, the severity of depression, suicidal behaviors, and neuroticism are associated with increased pro-atherogenic versus anti-atherogenic indices (PRO/ANTI-AI) and a reverse cholesterol transport (RCT) index. MethodsThis study included 34 healthy controls, 33 participants with MetS, and MDD patients with (n=31) and without (n=35) MetS, and measured total (TC) and free (FC) cholesterol, high (HDLc) and low (LDLc) density lipoprotein cholesterol, triglycerides (TG), apolipoprotein (ApoA), ApoB, cholesterol esterification rate (CER) and a composite (based on HDLc, ApoA and CER), reflecting RCT. ResultsIn the combined MDD + MetS study group, no associations between MDD and lipids were detected. After the exclusion of all MetS participants, MDD is strongly associated with (a) increased FC, TG, ApoB, Castelli risk index 1, ApoB/ApoA, and (b) decreased HDLc, ApoA and the RCT index. In participants without MetS, there are significant associations between severity of depression, suicidal behaviors, and neuroticism and ApoB/ApoA, Castelli risk, and RCT indices. ConclusionsStudies linking lipids to depressive subtypes can only be interpreted after MetS patients are excluded. The depression phenome, suicidal behaviors, and neuroticism are associated with a lowered RCT and increased atherogenicity, which are likely involved in the microimmuneoxidative pathophysiology of MDD. The RCT is a new drug target to treat and prevent MDD, neuroticism, and suicidal behaviors.

BackgroundAdolescence and youth are periods of significant maturational changes which seem to involve greater susceptibility to disruptive events in the brain such as binge drinking (BD). This pattern -characterized by repeated alcohol intoxications- is of special concern, as it has been associated with significant alterations in the young brain. Recent research indicates that alcohol may also induce changes in gut microbiota composition and that these disturbances can lead to impairments in the brain and behaviour. Additionally, there is evidence suggesting that microbiota-targeted interventions (psychobiotics) may have a beneficial impact on mitigating alcohol-induced damage in chronic alcoholics, while also potentially influencing cognitive/brain functioning. However, this triadic relationship between BD, gut microbiota, and brain structure/functioning as well as the therapeutic potential of gut microbiota-targeted interventions in youths with a BD pattern remains largely unexplored. MethodThis double-blind, parallel, randomized controlled study (registered in the clinical trials database; NCT05946083) aims to evaluate whether a BD pattern may disrupt gut microbiota balance in young college students. Furthermore, it seeks to determine whether alcohol-induced alterations in the microbial composition and functions are associated with immune, cognitive, neurostructural, and neurofunctional impairments. For this purpose, 82 college students (36 non/low drinkers and 46 binge drinkers [BDs]), matched for age and gender, will be recruited. During the pre-intervention phase, all participants will undergo comprehensive assessments, including microbiota and inflammatory profiling, neuropsychological testing, and evaluations of brain structure and function using magnetic resonance imaging. Subsequently, only BDs will proceed to the intervention phase, which involves a 6-week regimen of either a prebiotic (inulin) or placebo (maltodextrin). Following the intervention, the baseline variables will be re-evaluated and, over the subsequent 3 months, levels of craving and alcohol consumption will be monitored. DiscussionThis will, to our knowledge, be the first study to assess the potential relationship between gut microbiota and neurocognitive functioning in young BDs. The administration of psychobiotics is expected to promote the restoration of gut microbiota, thereby decreasing pro-inflammatory responses and mitigating alcohol-induced brain disruptions. This reduction in the detrimental effects of alcohol is anticipated to lead to cognitive enhancements and neurofunctional changes. Collectively, these findings might have major implications for understanding and treating alcohol misuse, potentially leading to new therapeutic strategies targeting the gut-brain axis to alleviate some of the detrimental effects associated with excessive alcohol use. Clinical Trial registrationClinicalTrials.gov, ID: NCT05946083. Strengths and LimitationsThe present protocol has several notable strengths such as: O_LINovel insights into the influence of alcohol on the microbiota-gut-brain axis. This study is the first to date to examine the interaction between binge drinking, gut microbiota, and brain function. C_LIO_LIBreakthrough therapeutic impact. This is a double-blind, parallel, randomized controlled trial focuses on a relevant population group -young college students- who are particularly vulnerable to harmful alcohol consumption patterns. By exploring prebiotic interventions, the study introduces innovative strategies to mitigate the neurotoxic effects of alcohol, opening new ways for therapeutic approaches in mental health and preventive medicine. C_LIO_LIMultidisciplinary approach. By integrating analyses of gut microbiota, inflammatory profile, and neuropsychological and neurostructural assessments, this study offers a comprehensive investigation of the impact of binge drinking on the microbiota-gut-brain axis. C_LI However, there are limitations to consider, including: O_LIPotential for low adherence: Young binge drinkers may have low adherence to a six-week intervention, which could compromise data validity. C_LIO_LIUncontrolled external factors: Factors such as diet, exercise, sleep, and stress, which can affect both microbiota and brain function, are not fully controlled. This could hinder the interpretation of the results and mask the effects of the intervention. C_LI

BackgroundMajor depressive disorder (MDD) involves disturbances in neuroimmune-metabolic and oxidative stress (NIMETOX) pathways. However, oxidized HDL (OxHDL) and oxidized LDL (OxLDL) have not been examined together. MethodsSerum OxHDL, OxLDL, and a panel of oxidative, antioxidant, and acute phase inflammatory (API) biomarkers were measured in 125 Chinese MDD patients and 40 healthy controls using ELISA and spectrophotometry. ResultsMDD patients showed increased OxHDL, reduced OxLDL, and markedly lowered antioxidant defenses, while classical lipid peroxidation markers remained unchanged. These alterations were independent of metabolic syndrome. The acute phase response was closely linked to reductions in HDL-related antioxidants and OxLDL. A combined biomarker model including the HDL/OxHDL ratio, apolipoprotein (ApoA)1, OxHDL, OxLDL, lipid hydroperoxides, and API index achieved an area under the ROC curve of 0.915 (SE=0.023) and a cross-validated sensitivity of 83.1% with 84.6% specificity. The variance in overall severity of depression, physiosomatic symptoms and recurrence of illness was to a large extent explained by oxidative/antioxidant biomarkers. The top-most important biomarkers were OxHDL/OxLDL (increased) and antioxidant (decreased) levels. ConclusionIncreased OxHDL is a key component of MDD, indicating structural and dysfunctional HDL particles and oxidative damage to its major structural protein (ApoA1). HDL particles rather than LDL particles and other lipids are the most vulnerable sites to be attacked by oxidative stress and inflammatory processes in MDD. These data support the view that increased oxidative damage to HDL particles is a key process in MDD. Preventing HDL particle oxidation is a major new drug target in MDD.

Neuroticism, a personality trait, can predict major depressive disorder (MDD). The current study aims to determine whether a) neuroticism is a feature of the acute state of MDD, including suicidal behaviors (SB); and b) adverse childhood experiences (ACEs) are associated with neuroticism in MDD. This study included 133 participants, 67 normal controls and 66 MDD patients, and assessed the Big 5 Inventory (BFI), ACEs using the ACE Questionnaire, and the phenome of depression using the Hamilton Depression (HAMD) Rating Scale (HAMD), Beck Depression Inventory (BDI), The State-Trait Anxiety Inventory (STAI) and Columbia Suicide Severity Rating Scale (C-SSRS) scores to assess current SB. Neuroticism was significantly higher in MDD than controls, and it explained 64.9% of the variance in the depression phenome (a latent vector extracted from HAMD, BDI, STAI, and current SB scores). The other BFI domains had much less (extraversion, agreeableness) or no effect (openness, conscientiousness). One latent vector could be extracted from the phenome, lifetime dysthymia, lifetime anxiety disorders and neuroticism scores. Neglect (physical and emotional) and abuse (physical, neglect and sexual) account for approximately 30% of the variance in this latent vector. Partial Least Squares analysis showed that the effects of neglect on the phenome were partially mediated by neuroticism, whereas the effects of abuse were completely mediated by neuroticism. Neuroticism (trait) and the MDD phenome (state) are both manifestations of the same latent core, with neuroticism being a less severe manifestation of major depression, which in fact is a multiplicative manifestation of neuroticism.

Background: Aberrations in neuro-immune, metabolic, and oxidative stress (NIMETOX) pathways are implicated in major depressive disorder (MDD). First-episode simple dysmood disorder (FE-SDMD) without metabolic syndrome offers a unique model to investigate early lipid alterations underlying NIMETOX pathophysiology. Methods: Plasma samples were collected from 88 university students (44 FE-SDMD, 44 healthy controls). Participants underwent comprehensive psychiatric and psychological assessments, including adverse childhood experiences (ACEs), negative life events (NLEs), depression, anxiety, suicidal behaviors, and insomnia. Untargeted lipid profiling was performed using LC-QTOF-MS, while indices of oxidative and nitrosative stress (ONS) and lecithin-cholesterol acyltransferase (LCAT) activity were assessed. Data was analyzed using machine learning approaches with recursive feature elimination and cross-validation. Results: FE-SDMD was characterized by increased ceramides (CER), diacylglycerides (DAG), triacylglycerides (TG), sphingomyelins (SM), bis-monoacylglycerol phosphates (BMP), cholestone, and fatty-acyl amino acids (FAAA). DAG, CER, and BMP were the strongest predictors of depression severity and physiosomatic symptoms, whereas cholestone, CER, and SM predicted suicidal behaviors. These lipid modules, together with lowered LCAT and increased ONS, explained substantial variance in depression severity (46.4%), physiosomatic symptoms (42.4%), cognitive-affective symptoms (37.9%), suicidal behaviors (30.1%), insomnia (32%), and anxiety (19.5%). ACEs and NLEs were strongly associated with CER (p<0.001), DAG (p<0.01), and cholestone (p<0.01). Conclusion: Early-stage MDD is characterized by distinct lipid dysregulations linked to psychosocial stress exposure, oxidative and nitrosative stress, and an indicant of impaired reverse cholesterol transport. These lipid modules may serve as early biomarkers and therapeutic targets in vulnerable populations.