Saffron (Crocus sativus L.) has long been recognized for its mood-enhancing properties. However, the precise contribution and neurobiological mechanisms of its main active compounds, crocins and safranal, remain underexplored, despite their potential to improve the management of mood disorders. This preclinical study compared their antidepressant-like effects alongside their impact on key neurobiological systems involved in mood regulation. Additionally, it assessed safranal's oral bioavailability, which was previously unknown. C57BL/6J mice received an acute oral dose of crocins (250 µg kg-1) or safranal (75 µg kg-1), corresponding to the respective amounts present in the saffron extract Safr'Inside™ at the dose previously used in preclinical studies, 30 min before behavioral assessment. Dopaminergic function was evaluated via quantification of dopamine and its metabolites by HPLC-ECD, combined with RT-qPCR analysis of related receptors and transporters, while kynurenine pathway activation was assessed through mRNA expression of its key enzymes in the prefrontal cortex and striatum. Both compounds reduced depressive-like behavior, albeit with distinct response patterns. Crocins primarily modulated the dopaminergic system, whereas safranal selectively downregulated neurotoxic components of the kynurenine pathway, shifting its neurotoxic/neuroprotective balance to promote neuroprotection. In parallel, serum and brain concentrations of safranal were measured at 15 and 30 min after oral administration of increasing doses, using a newly developed and validated UHPLC-DAD-MS/MS method. This allowed, for the first time, the detection of safranal in both serum and the brain following a single administration using a validated analytical method. Altogether, these findings provide novel and valuable insights into the disposition of safranal following oral administration and the distinct neurobiological mechanisms of saffron bioactives, highlighting their complementary roles and supporting their relevance as functional agents for mood-related disorders.

Neuropsychiatric symptoms are highly prevalent in obesity, and mounting data highlight the key role of adiposity-related inflammation in their etiology. Pro-inflammatory cytokines may disrupt dopamine metabolism and function, contributing to depressive manifestations such as anhedonia, loss of motivation, and fatigue, which are poorly alleviated by standard antidepressants. However, although obesity is characterized by chronic inflammation, not all individuals with obesity develop depression, underscoring an incomplete understanding of this association and the likely contribution of additional vulnerability factors. Our previous findings point to early-life adversity (ELA) as a potential contributor. Inflammation and ELA may converge on the dopamine system by impairing the activity of GTP-cyclohydrolase I (GTP-CH1), a key enzyme in the synthesis of tetrahydrobiopterin, which catalyzes the conversion of phenylalanine to tyrosine, a dopamine precursor. To test this possibility, seventy-two adults with obesity were recruited, and the relationships between systemic inflammation, peripheral markers of GTP-CH1 pathway activity, and neuropsychiatric symptoms were assessed, along the influence of ELA. Results showed that higher levels of inflammation were associated with an increased phenylalanine/tyrosine (PHE/TYR) ratio, consistent with altered tyrosine metabolism. This metabolic alteration was further linked to greater depressive symptoms, particularly anhedonia and reduced motivation. ELA did not significantly interact with inflammation to influence tyrosine metabolism but contributed additively to symptom severity alongside systemic inflammation. Overall, these findings suggest that inflammation-related disruptions in tyrosine metabolism may contribute to hedonic and motivational symptoms in obesity, while ELA may shape a vulnerability context that amplifies symptom expression.

BACKGROUND:Elevated inflammatory biomarkers have been consistently associated with a subset of depressive symptoms, particularly atypical and energy-related features, as well as antidepressant treatment resistance. This evidence has supported the definition of an inflammatory subtype of major depressive disorder (ISMDD), characterized by immune-inflammatory dysregulation and reduced response to first- and second-line antidepressants. However, a lack of consensus on its definition and assessment tools limits research and treatment development. METHODS:Using a Delphi approach, international experts from the ASPIRE consortium (Advanced Stratification of People with Depression based on Inflammation, n = 25) identified ISMDD symptom domains, which were then evaluated by the European College of Neuropsychopharmacology Immuno-Neuropsychiatry Network (INPN-ECNP, n = 12). Using the same consensus structure, the coverage of these domains by depression rating scales was then assessed. People with lived experience (PWLE, n = 11) provided perspectives on the clinical relevance and impact of the emerged symptoms. RESULTS:ASPIRE consensus identified ten ISMDD symptom domains: fatigue/low energy, hypersomnia, increased weight/appetite, cognitive difficulties, lack of motivation, anhedonia, diminished interest, leaden paralysis, psychomotor retardation, and insomnia, with the first five being also confirmed by INPN-ECNP consensus. Except for increased weight/appetite, PWLE identified these domains as negatively affecting quality of life; most of them were also reported as not extensively assessed in clinical care. Among rating scales, the Inventory of Depressive Symptomatology tools, including their Quick versions, were the only instruments covering all or almost all the ISMDD domains. CONCLUSION:These findings support a framework for ISMDD and highlight the importance of symptom assessment to improve clinical evaluation, research, and personalized immunopsychiatric treatment.

BACKGROUND:Chrono-nutrition - when, not only what, one eats relative to circadian timing - is an emerging determinant of mental health. We tested whether Meal Timing Jetlag (MTJL), the workday-to-free-day discordance in eating schedules, is associated with anxiety (primary outcome) and with depressive and insomnia symptoms (secondary), independently of sleep-based circadian misalignment. METHODS:Cross-sectional analysis of the ALIMENTAL 2 French-speaking online cohort (n = 2945). Sleep timing was assessed with the Munich Chronotype Questionnaire and meal timing with a Food Timing Screener. Outcomes were the GAD-7 (anxiety), CES-D (depression) and ISI (insomnia). Multivariable models adjusted for age, sex, BMI, unemployment, financial difficulty and shift work, with dose-response, logistic and BMI-stratified sensitivity analyses. RESULTS:In the primary model (n = 2817), MTJL was independently associated with anxiety (β = +0.47/h, 95% CI [0.14, 0.79], p = 0.005). The relationship was J-shaped (non-linearity p = 0.020; slope above 1 h + 1.03/h, p < 0.001). MTJL was also associated with depressive symptoms (β = +1.81, 95% CI [1.00, 2.61], p < 0.001) and insomnia severity (β = +0.90, 95% CI [0.47, 1.33], p < 0.001). Sleep-based circadian phase and sleep social jetlag were not. The per-hour anxiety effect is modest (≈12% of the GAD-7 minimal clinically important difference). LIMITATIONS:The cross-sectional design cannot establish causality; reverse causation cannot be excluded. The cohort was online and 80% female, limiting generalisability. CONCLUSIONS:Meal-timing regularity may be a candidate behavioural correlate of anxiety, depression and insomnia, warranting longitudinal and interventional confirmation before any clinical recommendation.

Background Previous studies link obesity to neurophysiological changes, however cognitive outcomes in adolescents who are overweight or obese, especially with their eating behavior, require further documentation.Objective To examine the association between body mass index (BMI), eating behavior, and cognitive performance in Mexican adolescents.Method Urban Mexican adolescents completed CANTAB tasks assessing spatial memory (PAL: Paired Associates Learning; SSP: Spatial Span), verbal memory (VRM: Verbal Recognition Memory), and emotional recognition (ERT: Emotion Recognition Task), as well as eating behavior measures. Cognitive performance was compared between normal-weight and overweight and obesity groups. Hierarchical regressions tested BMI and eating disorder symptoms as predictors of cognition.Results The overweight and obesity group showed significantly poorer performance on PAL and SSP. Multivariate analyses revealed BMI, sex, and age predicted PAL, SSP, and VRM performance. Eating behavior differed by weight group, but only eating disorder symptoms predicted cognition. Neither BMI nor eating behavior predicted ERT performance.Conclusions Spatial working memory is weaker in adolescents who are overweight or obese. Higher BMI also relates to poorer verbal memory, expanding known executive function deficits. Overall, these data reinforce the evidence on the negative effects of hyperadiposity on cognitive performance in adolescents.

A growing body of data highlights the key role of adiposity-related inflammation in the development of neuropsychiatric comorbidity in obesity. Nevertheless, despite similar levels of inflammation, only a subgroup of obese subjects is afflicted with neuropsychiatric symptoms, suggesting the contribution of additional vulnerability factors. In light of previous work suggesting the involvement of early life adversity (ELA), this study aims to determine whether ELA promotes the emergence of inflammation-related neuropsychiatric symptoms in a sample of obese subjects. Eighty-two adults afflicted with obesity (BMI > 30 kg/m2) and twenty-one lean individuals (BMI < 25 kg/m2) were recruited. Depressive symptoms, fatigue and neurobehavioral symptoms were assessed through semi-structured interviews and validated self-reports. ELA was measured using the Childhood Trauma Questionnaire (CTQ). Systemic inflammation was determined through serum concentrations of high-sensitivity C-reactive protein (hsCRP). In the whole population under study, hsCRP concentrations were significantly associated with neuropsychiatric symptoms, consistent with the increased prevalence of neuropsychiatric comorbidity in obese subjects. Significant associations were also found between ELA severity and neuropsychiatric symptoms. Although they did not influence hsCRP levels, ELA antecedents in obese subjects were associated with more marked mood, fatigue and cognitive symptoms. Among ELA, sexual abuse was the only significant predictor of the association between hsCRP levels and neuropsychiatric comorbidity in obesity. These findings support the hypothesis that ELA represents a potent vulnerability factor for the development of neuropsychiatric comorbidity in obese subjects with chronic inflammation.

Background: Different patterns of food consumption may be associated with a differential risk of depression. Differences in dietary patterns between men and women and across different age groups have been reported, but their influence on the risk of depression has not been fully explored. Objectives: To investigate the associations between dietary patterns and risk of depression across sex and age groups to identify vulnerable subpopulations, which may inform targeted prevention and intervention strategies. Methods: The ALIMENTAL study was a cross-sectional, online international survey conducted between 2021 and 2023. Dietary data were collected using a validated food frequency questionnaire; depression data were collected using a self-reported validated questionnaire. Principal component analysis (PCA) was applied to identify distinct food consumption patterns. Multivariate analyses were then conducted to assess the associations between these patterns and depression, adjusting for multiple potential confounders. Results: Among 15,262 participants without chronic diseases or current psychotropic treatments, 4923 (32.2%) were classified in the depression group. Among those aged 18–34, the PCA-derived factor of ultra-processed foods consumption was significantly associated with increased risk of depression in both sexes with similar odds ratios (women 1.21, 95% confidence interval (CI): (1.15; 1.27), men 1.21, 95% CI: (1.07–1.18)). In women aged 18–34, the PCA factors for sodas (aOR 1.10, 95% CI: (1.06; 1.95) and canned and frozen foods (aOR 1.10, 95% CI: (1.04; 1.15) were associated with an increased risk of depression. In participants aged 35–54 years, the association between ultra-processed foods and depression was only observed in women (35–54 years: aOR 1.30, 95% CI: (1.20; 1.42), ≥55 years: 1.41, 95% CI: (1.11; 1.79)), with a significant association between a higher adherence to the PCA-derived “healthy diet” factor (e.g., fruits, nuts, green vegetables) and a lower risk of depression (35–54 years: aOR 0.82, 95% CI: (0.75; 0.89), ≥55 years: aOR 0.79, 95% CI: (0.64; 0.97)). Conclusions: These results show significant differences between men and women and between age groups regarding associations between dietary patterns and the risk of depression. These findings can help better target public health interventions.

BACKGROUND:Subclinical depressive symptoms, including low mood, fatigue and anxiety, refer to clinically relevant depressive manifestations that do not meet the criteria for major depressive disorder. These symptoms affect quality of life and can lead to chronic mental health issues. Nutritional interventions, such as saffron extract supplementation, may help modulate mood and inflammation, potentially alleviating these symptoms. OBJECTIVES:This study evaluated the efficacy of a 6-wk saffron extract supplementation on mood in healthy individuals with subclinical neuropsychiatric symptoms and explored the underlying mechanisms. METHODS:This randomized, double-blind, placebo-controlled study involved 51 adult healthy individuals who received oral administration of either saffron extract or a placebo for 6 wk. The primary outcome was a composite z-score averaging standardized scores of depression (Beck Depression Inventory-II), anxiety (State-Trait Anxiety Inventory-YA), and fatigue (Multidimensional Fatigue Inventory 20). Secondary outcomes included neuropsychiatric scores, quality of life, inflammatory markers, and hypothalamic-pituitary-adrenal axis reactivity. Amino acid derivatives were analyzed in blood samples. RESULTS:Saffron extract did not significantly affect the primary outcome of combined depressive, anxiety, and fatigue symptoms (z-score) nor individual symptoms. However, it improved autoperceived mental health, as reflected in increased mental health scores over time on the Medical Outcome Study Short-Form 12 questionnaire, compared with placebo (mean at 6 wk: 53.8 ± 12.7 vs 44.6 ± 11.4 for placebo and saffron group, respectively; time × treatment, P = 0.04). There were no significant effects on inflammatory parameters or hypothalamic-pituitary-adrenal axis reactivity. Metabolomic analysis revealed that saffron extract significantly modulated N-acetyl-phenylalanine. CONCLUSIONS:Saffron extract supplementation do not affect subclinical depressive symptoms, either as a composite score or individual symptom categories. A potential effect on improved mental health outcomes cannot be excluded but requires further replication in future well-powered trials. This trial (Saffromfood study) is registered at clinicaltrial.gov as NCT05690126 (https://clinicaltrials.gov/study/NCT05690126?term=NCT05690126&rank=1).

Chronic inflammatory conditions, such as obesity, are frequently associated with a high prevalence of mood disorders and a reduced response to conventional antidepressants. Therefore, identifying the biological substrates underlying these comorbidities is crucial, as it could help uncover new therapeutic strategies to improve current treatments. Growing evidence implicates inflammation-driven dysregulation of tryptophan breakdown along the kynurenine pathway (KP) as a key contributor, although the specific roles of its various metabolites remain unclear. Additionally, the involvement of the gut-derived indole pathway (IP) of tryptophan metabolism is still poorly understood, despite increasing evidence linking gut microbiota metabolites to mood regulation. To address these questions, we assessed depressive-like and anxiety-like behaviors in C57BL/6J mice chronically exposed to high-fat diet (HFD), a reliable preclinical model of inflammatory depression. We also measured plasma and brain (hippocampus, frontal cortex, striatum) levels of a broad panel of KP and IP metabolites. HFD increased emotional behaviors and altered plasma and brain levels of tryptophan metabolites. Notably, it promoted a systemic neurotoxic-neuroprotective KP imbalance favoring neurotoxicity. It also drastically reduced indole production, with significant repercussions on brain indole-3 sulfate levels. Importantly, these metabolomic changes correlated with the severity of emotional alterations, with distinct metabolite-behavior relationships depending on the specific neuropsychiatric symptom dimensions assessed. In conclusion, this study offers valuable novel insights into the role of KP- and IP-derived tryptophan metabolites as key mediators between obesity and depression, and thus potential new promising therapeutic targets to improve neuropsychiatric comorbidities of obesity.

Major depressive disorder (MDD) and obesity are significant global health concerns with a strong bidirectional relationship. Gut microbiota dysbiosis has been implicated in both MDD and obesity, characterized by alterations in microbial diversity and its metabolites. Omega-3 polyunsaturated fatty acids (PUFAs), mainly eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) have shown promise in alleviating depressive symptoms and improving metabolic health. Diet plays a crucial role in shaping gut microbiota, with omega-3 PUFAs emerging as a potential therapeutic target. By modulating gut microbiota, reducing inflammation, and influencing neurotransmitter systems, omega-3 PUFAs may offer a novel approach to treating MDD and obesity. This article will investigate the potential role of omega-3 PUFAs in the relationship between depression and obesity via modulating the gut microbiome and reducing inflammation. Further investigation is needed to establish the optimal dosage of supplementation for individuals with MDD and comorbid obesity. [ Psychiatr Ann . 2025;55(2):e34–e39.]

BackgroundMultimorbidity, known as the co-occurrence of at least two chronic conditions, has become of increasing concern in the current context of ageing populations, though it affects all ages. Early life risk factors of multimorbidity include adverse childhood experiences (ACEs), particularly associated with psychological conditions and weight problems. Few studies have considered related mechanisms and focus on old age participants. We are interested in estimating, from young adulthood, the risk of overweight-depression comorbidity related to ACEs while adjusting for early life confounders and intermediate variables.MethodsWe used data from the 1958 National Child Development Study, a prospective birth cohort study (N = 18 558). A four-category outcome (no condition, overweight only, depression only and, overweight-depression comorbidity) was constructed at 23, 33, and 42 years. Multinomial logistic regression models adjusting for intermediate variables co-occurring with this outcome were created. ACEs and sex interaction on comorbidity risk was tested.ResultsIn our study sample (N = 7762), we found that ACEs were associated with overweight-depression comorbidity risk throughout adulthood (RRR [95% CI] at 23y = 3.80 [2.10-6.88]) though less overtime. Comorbidity risk was larger than risk of separate conditions. Intermediate variables explained part of the association. After full-adjustment, an association remained (RRR [95% CI] at 23y = 2.00 [1.08-3.72]). Comorbidity risk related to ACEs differed by sex at 42.ConclusionOur study provides evidence on the link and potential mechanisms between ACEs and the co-occurrence of mental and physical diseases throughout the life-course. We suggest addressing ACEs in intervention strategies and public policies to go beyond single disease prevention.

There is growing evidence that in utero imbalance immune activity plays a role in the development of neurodevelopmental and psychiatric disorders in children. Mood dysregulation (MD) is a debilitating transnosographic syndrome whose underlying pathophysiological mechanisms could be revealed by studying its biomarkers using the Research Domain Criteria (RDoC) model. Our aim was to study the association between the network of cord serum cytokines, and mood dysregulation trajectories in offsprings between 3 and 8 years of age. We used the data of a study nested in the French birth cohort EDEN that took place from 2003 to 2014 and followed motherchild dyads from the second trimester of pregnancy until the children were 8 years of age. The 2002 mother -child dyads were recruited from the general population through their pregnancy follow-up in two French university hospitals. 871 of them were included in the nested cohort and cord serum cytokine levels were measured at birth. Children 's mood dysregulation symptoms were assessed with the Strengths and Difficulties Questionnaire Dysregulation Profile at the ages 3, 5 and 8 years in order to model their mood dysregulation trajectories. Out of the 871 participating dyads, 53% of the children were male. 2.1% of the children presented a high mood dysregulation trajectory whereas the others were considered as physiological variations. We found a significant negative association between TNF- alpha cord serum levels and a high mood dysregulation trajectory when considering confounding factors such as maternal depression during pregnancy (adjusted Odds Ratio (aOR) = 0.35, 95% Confidence Interval (CI) [0.18 -0.67]). Immune imbalance at birth could play a role in the onset of mood dysregulation symptoms. Our findings throw new light on putative immune mechanisms implicated in the development of mood dysregulation and should lead to future animal and epidemiological studies.

OBJECTIVE:The early consumption of calorie-rich diet disrupts circadian rhythms and has adverse effects on memory, yet the effects of time-restricted feeding (TRF) and the underlying molecular mechanisms are unknown. Here, we set out to identify the behavioral and molecular circadian rhythms disruptions generated by juvenile obesogenic diet consumption and their restoration by TRF in male mice. METHODS:Metabolic rhythms were measured by indirect calorimetry and memory performances by behavioral tasks. Hippocampal translatome (pS6_TRAP), enrichment and co-regulated gene network analyses were conducted to identify the molecular pathways involved in memory impairments and their restoration by TRF. Differential exon usage analyses, mass spectrometry and pharmacological intervention were used to confirm thyroid hormone signaling involvement. RESULTS:We show that four weeks of TRF restore the rhythmicity of metabolic parameters and prevents memory impairments in mice fed a high fat-high sucrose (HFS) diet since weaning, independently of body fat levels. Hippocampal translatome and differential exon usage analyses indicate that impaired memory of mice under ad libitum HFS diet is accompanied by reduced thyroid hormone signaling and altered expression of astrocytic genes regulating glutamate neurotransmission. TRF restored the diurnal expression variation of part of these genes and intra-hippocampal infusion of T3, the active form of thyroid hormone, rescues memory performances and astrocytic gene expression of ad libitum HFS diet-fed mice. CONCLUSIONS:Thus, thyroid hormones contribute to the TRF positive effects on both metabolism and memory in mice fed an obesogenic diet, highlighting this nutritional approach as a powerful tool in addressing obesity brain comorbidities and paving the way for further mechanistic studies on hippocampal thyroid signaling.

According to animal studies, saffron and its main volatile compound safranal may reduce biological and behavioral signs of acute stress. However, little is known about its impact in humans. This study investigated the acute effect of a saffron extract and safranal on the biological and psychological stress responses in healthy men experiencing a laboratory stress procedure. In this double-blind, placebo-controlled, randomized, cross-over study, 19 volunteers aged 18–25 received a single dose of 30 mg saffron extract (Safr’InsideTM), 0.06 mg synthetic safranal, or a placebo on three visits separated by a 28-day washout. Thirteen minutes after administration, participants were exposed to the Maastricht acute stress test (MAST). Salivary cortisol and cortisone were collected from 15 min before the MAST (and pre-dose), 3 min before the MAST, and then 15, 30, 45, 60, and 75 min after the MAST, and stress and anxiety were measured using visual analogic scales. Compared to the placebo, stress and anxiety were significantly toned down after Safranal and Safr’InsideTM administration and coupled with a delay in the times to peak salivary cortisol and cortisone concentrations (p < 0.05). Safr’InsideTM and its volatile compound seem to improve psychological stress response in healthy men after exposure to a lab-based stressor and may modulate the biological stress response.