Search Results (584)

Bergamot essential oil (BEO) has demonstrated antidepressant potential, but its oral application is limited by poor water solubility and undesirable organoleptic properties. In this study, a BEO-loaded beverage was developed based on a whey protein-stabilized oil-in-water emulsion system. The optimal formulation, determined via single-factor experiments combined with orthogonal optimization, consisted of inulin (0.5 g/50 g), milk powder (2.0 g/50 g), sucralose (0.008 g/50 g), and sodium carboxymethyl cellulose (0.04 g/50 g). The resulting beverage remained stable without visible phase separation during 4 months of storage at 4 °C. In a chronic corticosterone treatment (CCT)-induced mouse model of depression, oral administration of the BEO beverage increased activity in the central area of the open field test and exploratory behavior in the elevated plus maze, while reducing repetitive stereotyped behaviors in the marble burying test. At the molecular level, the BEO beverage was associated with reduced levels of interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and corticosteroid (CORT), and increased levels of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), serotonin (5-HT), dopamine (DA), and norepinephrine (NE). Additionally, the BEO beverage was associated with observed alleviation of neuronal damage in the hippocampal CA3 region, upregulation of brain-derived neurotrophic factor (BDNF), improved gut microbial diversity, and altered host metabolic profiles. Collectively, these findings suggest that the BEO emulsion beverage is a feasible intervention for alleviating depression-like behaviors in the mouse model, and provide initial associative evidence supporting its potential as a functional food for mood management. Full article

Background/Objectives: Based on the central nervous system-related activity potential of 1,3,4-thiadiazole derivatives, novel 1,3,4-thiadiazole compounds were synthesized, and their possible antidepressant-like and anxiolytic-like effects were investigated. Methods: The chemical structures of the compounds were elucidated using several spectroscopic techniques. Antidepressant-like effects of compounds were evaluated using the tail suspension and the modified forced swimming tests, while anxiolytic-like effects were assessed using the hole board, elevated plus maze, and open field tests in male Balb/c mice. Motor activities of the animals were examined using the activity-meter device. Mechanistic and computational in silico studies were also performed. Results: The results demonstrated that compounds 4e–4i exhibited antidepressant-like effects, whereas only compound 4e showed an anxiolytic-like effect. None of the compounds produced significant alterations in motor activities of animals, indicating that the observed behavioral effects were specific. The antidepressant-like effects of compounds 4e–4i were abolished by p-chlorophenylalanine methyl ester (PCPA) and α-methyl-para-tyrosine methyl ester (AMPT) pre-administration indicating that the antidepressant-like effects of these test compounds are related to both serotonergic and catecholaminergic mechanisms. Furthermore, the anxiolytic-like effect of compound 4e was reversed by flumazenil and NAN-190 pre-administrations, indicating the participation of the GABA-A benzodiazepine receptor complex and 5-HT_1A receptors in its pharmacological activity. Computational in silico studies revealed that compounds have good ADME profiles; compounds 4e–4i interact with the serotonin transporter; compound 4e shows affinity for GABA-A and 5-HT_1A receptors; and all interactions remain stable under dynamic conditions. Conclusions: These findings supported the previous papers reporting the antidepressant-like and anxiolytic-like effects of 1,3,4-thiadiazole derivatives. Full article

(1) Background: Clinopodium pulchellum (Kunth) Govaerts (Panizara) is an aromatic Andean medicinal plant traditionally used in Peru to manage nervous disorders, insomnia, and digestive complaints; however, its neuropharmacological properties remain poorly validated. This study aimed to evaluate the anxiolytic- and antidepressant-like effects of C. pulchellum and to characterize its phytochemical profile as supportive evidence. (2) Methods: The essential oil was obtained by hydrodistillation and analyzed using GC–MS and GC–FID. (3) Results: Fifteen volatile compounds were identified based on retention indices and mass spectral data, with β-caryophyllene (22.9%) and linalool (19.1%) as the most representative constituents, while other compounds were tentatively identified. The aqueous extract showed total phenolic and flavonoid contents of 34.15 mg GAE/g and 29.44 mg QE/g, respectively, and moderate antioxidant activity (DPPH = 2.36 mg TE/g; ABTS = 3.33 mg TE/g). In vivo assays revealed that EOCP at 200 mg·kg⁻¹ significantly increased open-arm exploration in the elevated plus maze and reduced immobility time in the CUMS–forced swim test by 37% compared with the stress group, although the effect was lower than that of reference drugs. Molecular docking analysis indicated favorable binding affinities of β-caryophyllene, humulene, and aromandendrene with serotonergic and ion channel targets, while ADMET predictions suggested suitable pharmacokinetic properties. (4) Conclusions: These findings indicate that the observed neuropharmacological effects may be associated with the presence of bioactive terpenoids typical of Lamiaceae, supporting the traditional use of C. pulchellum. However, further studies are required to confirm the identity of uncommon constituents and to elucidate the mechanisms underlying its biological activity. Full article

Depression represents one of the most prevalent mental health challenges globally, affecting individuals across diverse populations and settings. Based on the neurogenesis-informed hypothesis that stair use may likely elevate brain-derived neurotrophic factor (BDNF) in humans that in turn may have an antidepressant effect, this study takes residential buildings as a controlled environment to test whether there is a difference in depression symptoms based on single- or multi-storey housing. This study examined associations between staying at home and depression symptoms using the Public Health Questionnaire-8 (PHQ-8) data from 128 adults in England who spend most of their time at home. Residents in single-storey flats in apartment buildings had significantly higher overall depression scores than multi-storey house residents. Among the PHQ-8 items, only Item 8, psychomotor agitation/retardation (moving or speaking too slowly, or restlessly moving around more than usual), approached but did not reach statistical significance after Bonferroni correction (p = 0.056). After adjusting for gender, age, number of residents, activity level, and income, apartment living (vs. multi-storey houses) (β = −0.362, p < 0.001) and loneliness (β = 0.221, p = 0.016) were significant independent predictors of psychomotor agitation/retardation. Future research is needed to explore this relationship using a larger sample size and to explore whether the use of stairs explains this potential relationship through a change in BDNF. Full article

Background: Cang-ai volatile oil (CAVO) is a traditional Chinese medicine with properties that soothe the liver and alleviate depression. CAVO is widely utilized in the field of antidepressant research and has surfaced as a possible treatment for depression. Depression is a common affective disorder and effective treatment methods are still limited. CAVO is effective in treating depression; however, the exact mechanism is still unclear. This study aimed to explore the likely mechanism by which CAVO reduces symptoms of depression in rats exposed to chronic unpredictable mild stress (CUMS). Methods: We established a CUMS model in Sprague–Dawley rats and administered CAVO via nebulization to evaluate its therapeutic effect. Behavioral and histology tests were conducted to evaluate brain tissue damage. We utilized metabolomics combined with proteomics to analyze the effects of CAVO. We then assessed molecular validation to further clarify the molecular mechanism of its activity. Results: In CUMS model rats, inhaling aerosolized CAVO reduced brain pathology and depression-like behaviors. CAVO changed serum levels of inflammatory cytokines and neurotrophic factors. Biomarkers linked to CAVO’s antidepressant effects were found via metabolomics. Functional analyses highlighted key molecular players such as TrkB, and CREB, and a close association with the antidepressant action of CAVO was confirmed. Conclusions: This study reveals that CAVO reduces depression-like behaviors in CUMS rats by regulating the NT/Trk signaling pathway. These results demonstrate CAVO’s therapeutic potential and lay the groundwork for future studies and the creation of depressive treatments. Full article

Depression is a complex mental and neurological disorder and has become one of the most serious public health issues in modern society. Trihexyphenidyl (THY) is a traditional drug used to treat Parkinson’s disease. Recent studies have suggested that it may play a role in regulating neurotransmitters and protecting neurons, but its potential for treating depression has not been fully explored, and how it works remains unclear. Therefore, we examined the effects of THY on depression-like behaviors in zebrafish caused by chronic unpredictable stress (CUS). Our results showed that THY significantly attenuated the CUS-induced decrease in exploratory behavior and shortened the CUS-induced increase in latency time. At the tissue level, THY effectively attenuated the thinning of the optic tectum and the loss of Nissl bodies caused by CUS. In addition, THY reversed the CUS-induced increase in stress hormone levels and reduction in neurotransmitter content. Through network pharmacology and transcriptome sequencing analysis, we found that the mechanisms underlying depression-like behaviors and the antidepressant effects of THY might be related to the MAPK signaling pathway. Further experiments showed that THY regulated the CUS-induced activation of the MAPK signaling pathway, improved the abnormal activation of microglia and damage to astrocytes, and reduced the expression of pro-inflammatory factors, thereby easing neuroinflammation and improving depression-like behaviors. In summary, this study explored the potential mechanism of THY ameliorating depressive-like behaviors and provided basic theoretical evidence. Full article

Butyrate, a short-chain fatty acid derived from the gut microbiota, has been linked to depression through correlational studies; however, whether it might act as a sufficient downstream mediator of the antidepressant effects of a probiotic remains poorly understood. To explore this, a chronic unpredictable mild stress (CUMS) rat model was established to evaluate the potential antidepressant effects of Weizmannia coagulans BC99. Behavioral assessments included the sucrose preference test (SPT), forced swim test (FST), tail suspension test (TST), and open field test (OFT). In addition, 16S rRNA sequencing, serum metabolomics, and short-chain fatty acid (SCFA) profiling were performed. Levels of inflammatory cytokines (IL-1β, IL-6, IL-4, and LPS) and brain-derived neurotrophic factor (BDNF) were measured in serum, hippocampus, and colon by ELISA. An independent sodium butyrate supplementation experiment was conducted to test functional sufficiency, and hippocampal BDNF/TrkB/CREB signaling was assessed by Western blotting. Treatment with BC99 was associated with alleviation of CUMS-induced depressive-like behaviors, increased butyrate levels, reduced neuroinflammation (IL-1β, IL-6, LPS, and IL-4), and restored hippocampal BDNF levels. BC99 also enriched butyrate-producing bacterial taxa (e.g., Lactobacillus, Bifidobacterium, Faecalibaculum) and normalized tryptophan and sphingolipid metabolism. Notably, sodium butyrate alone recapitulated several of the behavioral and anti-inflammatory effects observed with BC99 and, as shown by Western blot, partially restored hippocampal BDNF/TrkB/CREB signaling, which was impaired in CUMS rats. Together, these findings suggest that butyrate may be associated with the antidepressant effects of W. coagulans BC99, potentially acting through suppression of neuroinflammation and activation of the BDNF pathway. Our results support further investigation of butyrate-enhancing strategies as a nutritional approach for depression. Full article

A pair of enantiomeric stilbene–lignan hybrids, (−)- and (+)-dracaenolignan A (1), and four new flavonoid derivatives, xuejieins F–I (2–5), were isolated from Dracaena cochinchinensis exudates. Compound 1 features an unprecedented carbon skeleton with a 6/6/5/6-fused ring system and four consecutive chiral carbons. Their structures were clarified by spectroscopic data, theoretical NMR calculations, and ECD calculations. Furthermore, a potential biogenetic pathway for 1 is put forward. Biological evaluations inspired by the chemical defense of D. cochinchinensis revealed that (−)-1 significantly alleviates LPS-induced neuroinflammation and depression-like behaviors, suggesting potential antidepressant lead structure. Full article

Background: Histamine H3 receptor-targeting compounds modulate histaminergic tone and downstream monoaminergic/arousal circuits and have been proposed to exert potential antidepressant-like effects in preclinical models. Methods: We conducted a systematic review and meta-analysis of rodent studies evaluating H3-related interventions on depression-like behavior. We screened 60 records, assessed 12 studies qualitatively (four CORE, eight sensitivity), and included nine studies in random-effects meta-analyses (REML). Primary outcomes were the forced swim test (FST) and tail suspension test (TST); effect sizes were summarized as Hedges’ g (positive values indicate reduced immobility). Results: In the primary ALL analysis, H3-related interventions improved FST outcomes (g = 1.40, 95% CI 0.83–1.97; k = 7) and were also associated with improved TST outcomes, albeit with substantial heterogeneity (g = 2.27, 95% CI 0.80–3.73; k = 5). CORE-only analyses were directionally consistent but less precise (FST: g = 1.11, 95% CI −0.06–2.27; k = 3; TST: g = 2.95, 95% CI 0.87–5.02; k = 2). Sucrose preference was reported in one study and indicated improvement (g = 1.61, 95% CI 0.29–2.92). Conclusions: H3-related interventions show an antidepressant-like signal in rodent FST and TST, with greater heterogeneity for TST, highlighting the need for more standardized and adequately powered preclinical studies. Full article

Mushroom use dates back to ancient times, and it currently remains significant among indigenous and urban populations as a medicinal option. Psilocybe species are suggested to modify emotions when administered in macro- or microdose form for the treatment of anxiety and depression, both often affected by a delayed onset and adverse effects of current pharmacological therapy. The objective of this study was to evaluate the anxiolytic and/or antidepressant-like effects of P. cubensis mushroom aqueous extract (PcAE) microdosing in mice using open-field and rota-rod tests, followed by plus-maze or forced swimming tests. We also evaluated changes in neuronal activity and dendritic maturation using electrocorticography (ECoG) and immunohistochemical techniques. The outcomes were compared with an effective macrodose of PcAE and antidepressant fluoxetine (FLX). For this study, mice were grouped as follows: (1) vehicle, (2) acute, and (3) repeated (10 days) PcAE microdosing (1 µg/kg); (4) single PcAE macrodose (1 g/kg); and (5) acute and (6) repeated reference drug fluoxetine (FLX, 10 mg/kg).The anxiolytic and antidepressant-like effects using microdosing were similar to those observed with macrodoses of PcAE and FLX; significant dose- and/or time-dependent changes in the ECoG and dendritic maturation of hippocampus neurons were also observed, in addition to altered corticosterone levels. To conclude, P. cubensis mushroom promotes brain effects in mice after micro- and macrodosing, supporting its potential as a therapeutic alternative for mental health. Full article

Background/Objective: A substantial proportion of patients with obsessive–compulsive disorder (OCD) does not respond adequately to first-line treatments such as selective serotonin reuptake inhibitors and cognitive-behavioral therapy. OCD has traditionally been conceptualized as a serotonergic disorder. However, emerging evidence suggests that glutamatergic dysfunction plays an important role. Ketamine and esketamine are NMDA receptor antagonists with rapid antidepressant effects and have therefore attracted interest as potential treatments for OCD. This scoping review aims to map and synthesize the existing preclinical and clinical evidence regarding the therapeutic potential of ketamine and esketamine in OCD. Methods: A scoping review methodology based on the Arksey and O’Malley framework and Joanna Briggs Institute guidance was applied. Searches were conducted in PubMed, Scopus, and Web of Science. Studies that examined ketamine or esketamine in OCD populations or relevant experimental models were included. Results: Twenty-one studies met the inclusion criteria, of which five were preclinical studies and sixteen were clinical investigations. Preclinical evidence suggests that ketamine and esketamine improve compulsive-like behaviors. Clinical studies suggest that ketamine can produce rapid reductions in obsessive symptoms, though results remain inconsistent. Most trials evaluated single administrations, while limited evidence suggests that repeated dosing strategies may provide greater clinical benefit. Conclusions: Ketamine and esketamine show promise as rapid acting interventions for OCD, particularly in treatment refractory cases. However, current evidence remains preliminary and heterogeneous. Future research should prioritize adequately powered randomized trials and investigation of repeated administration protocols with longer follow-up periods to determine efficacy and optimal clinical implementation. Full article

Background/Objectives: Hypothyroidism, including subclinical hypothyroidism, may affect mental health in children and adolescents through disturbances of neurotransmission and dysregulation of the hypothalamic–pituitary–thyroid and stress axes. Anxiety disorders are common in this population and frequently coexist with somatic symptoms overlapping those of hypothyroidism, complicating diagnosis and treatment. This study aimed to evaluate the association between levothyroxine treatment for hypothyroidism and the need for psychiatric interventions in children and adolescents with anxiety disorders. Methods: A retrospective cohort study was performed using data from the TriNetX global research network. Patients aged 5–18 years with diagnoses of hypothyroidism (ICD-10: E03) and anxiety disorders (ICD-10: F41) were included. Two propensity score–matched cohorts were analysed: patients treated with levothyroxine (n = 1861) and untreated patients (n = 1861). Outcomes included psychiatric hospitalisations, use of selective serotonin reuptake inhibitors and tricyclic-like antidepressants, frequency of psychiatric and psychotherapeutic consultations, and the occurrence of suicidal ideation and self-harm. Results: Levothyroxine treatment was associated with lower odds of SSRI use (OR = 0.58; p < 0.001), fewer psychiatric consultations (OR = 0.48; p < 0.001), and lower recorded use of psychotherapy (OR = 0.75; p = 0.029). Suicidal ideation and self-harm were recorded less frequently in the treated group (OR = 0.53; p = 0.001). No significant differences were observed in psychiatric hospitalisation rates. Use of tricyclic-like antidepressants was uncommon and did not differ significantly between groups. Conclusions: Among children and adolescents with comorbid anxiety disorders, levothyroxine treatment for hypothyroidism is associated with lower recorded utilization of certain psychiatric services and lower recorded rates of suicidal ideation and self-harm. Due to the retrospective design, causal inferences cannot be made, and the findings should be considered hypothesis-generating, requiring confirmation in prospective studies with standardised psychiatric outcome measures. Full article

The role of the endocannabinoid system (ECS) in the development of depression and anxiety is being actively studied, with evidence suggesting that elevation of ECS signaling can have anxiolytic and antidepressant properties. The current study explored the therapeutic potential of Oleoyl Serine (OS), an endocannabinoid-like lipid, and HU-910, a synthetic selective Cannabinoid type 2 (CB2) receptors agonist, in depression and anxiety, using both sexes of the depressive-like genetic model: Wistar Kyoto (WKY) rats. The aim was to investigate behavioral and molecular mechanisms associated with acute and sub-chronic intraperitoneal administration of these compounds. We showed that, in females, acutely administered OS yielded antidepressant-like and anxiolytic-like effects in the Forced Swim Test (FST) and Open Field Test (OFT), respectively. In males, OS yielded acute and sub-chronic anxiolytic-like effects. HU-910 yielded an acute anxiolytic-like effect in females and an acute antidepressant-like effect in males. Sub-chronic administration of imipramine (IMI), used as a positive control, yielded an antidepressant-like effect in both sexes but an anxiogenic-like effect in females. Sub-chronic administration of all the treatments increased hippocampal Cannabinoid Receptor 1 (CNR1) mRNA expression (but not Fatty Acid Amide Hydrolase (FAAH)) in males. Exploratory in silico absorption, distribution, metabolism, and excretion (ADME) profiling suggests that sex-dependent pharmacokinetic variability may partly underlie the observed behavioral differences, in addition to possible pharmacodynamic factors. Our study provides a lead towards unraveling the putative sex differences in response to both conventional antidepressants (e.g., IMI) and emerging pharmacological agents (e.g., OS, HU-910). Further, our study helps advance the field of neuropharmacology by elucidating the anxiolytic-like and antidepressant-like effects of OS and HU-910. Full article

Objectives. The aim of our study was to track changes in ODQ scores in adolescents with depressive episodes taking sertraline, depending on CYP2C19 polymorphisms. Methods. This study included 88 adolescents (88% were female) aged 12–17 who were prescribed sertraline. Emotional blunting was assessed using the Oxford Depression Questionnaire (ODQ) scale when the antidepressant was prescribed, after one, three, and 8 weeks, taking into account other medications used. Part 3 of the ODQ scale assessed the changes that occurred after the prescription of an antidepressant. All patients were genotyped for CYP2C19*2, *3, and *17. Based on genotypes, the phenotypes of the CYP2C19 isoenzyme were determined. Results. The ODQ score at the time of enrollment was higher (65[50;79] points) compared with after 8 weeks (38.5[32.5;56.5] points). Part 3 of the ODQ-26 questionnaire remained approximately the same for 8 weeks. Patients with higher ODQ-26 values at enrollment (73[56;83] vs. 59[44;71] points) were more likely to be prescribed antipsychotics. Differences in ODQ scores remained significant up to 3 weeks after enrollment (50.5[41.5;68] vs. 45.5[36;54] points). The comparison of ODQ scores and their dynamics did not show significant differences depending on CYP2C19*2 or *17 polymorphisms, or the type of CYP2C19 metabolism. Conclusions. There was no increase in emotional blunting according to the ODQ score among adolescents with depression who took sertraline for eight weeks. No significant correlations were found between the carrier status of CYP2C19 gene variants and the development of apathy induced by antidepressants. Full article

Major depressive disorder (MDD) is a highly prevalent psychiatric illness for which rapid-acting antidepressants such as ketamine provide only transient benefit. Because κ-opioid receptor (KOR) signaling contributes to stress-related dysphoria and impaired neuroplasticity, we examined whether KOR antagonism could prolong ketamine’s antidepressant-like effects in a mouse model of adolescent chronic unpredictable stress (CUS). Male C57BL/6J mice (n = 10 per group for behavioral analyses) were exposed to CUS during adolescence and developed persistent depression-like behavior in adulthood. Mice with depressive-like behavior received a single injection of ketamine, the selective KOR antagonist norbinaltorphimine (nBNI), or their combination. Behavioral testing showed that all treatments reduced immobility in the tail suspension test (TST) 24 h post-administration; however, only the combined ketamine/nBNI treatment maintained antidepressant-like effects one week post-treatment. Molecular analyses (n = 4–8 per group) were conducted at this single time point, one week post-treatment, to characterize region-specific signaling states in the prefrontal cortex, hippocampus, and striatum, focusing on ERK, AKT, JNK, mTOR, and BDNF pathways. These molecular findings represent correlates of sustained behavioral effects rather than evidence of causal mechanisms. Together, the data indicate that concurrent KOR antagonism is associated with prolonged antidepressant response to ketamine in stress-exposed male mice and with distinct region-dependent signaling profiles at one week post-treatment. Further studies are needed to establish mechanistic causality and confirm the possible applicability of these findings. Full article