Search Results (2,289)

Background/Objectives: Major depressive disorder (MDD) remains a leading cause of disability worldwide and exhibits substantial biological heterogeneity that is not adequately captured by current symptom-based diagnostic systems. While the classical monoamine hypothesis has historically guided antidepressant development, it does not fully account for variability in treatment response, delayed therapeutic onset, or the persistence of cognitive and anhedonic symptoms. Converging evidence from molecular, neuroimaging, and translational studies increasingly implicates glutamatergic dysregulation and impaired neuroplasticity as key mechanisms in depressive pathology. This narrative review aims to integrate monoaminergic and glutamatergic perspectives within a dimensional framework that may help explain clinical heterogeneity and inform mechanism-based treatment strategies. Methods: A narrative synthesis of the literature was conducted using major biomedical databases including PubMed, Scopus, and Web of Science. Preclinical studies, neuroimaging investigations, biomarker research, randomized clinical trials, and meta-analyses examining monoaminergic dysfunction, glutamatergic signaling, neuroplasticity pathways, and rapid-acting antidepressants were reviewed and thematically integrated. Results: Evidence indicates that depressive syndromes may reflect varying contributions of monoaminergic dysregulation and glutamatergic–neuroplastic impairment. Monoaminergic disturbances interact with inflammatory and neuroendocrine processes, including cytokine-driven activation of the kynurenine pathway. In parallel, alterations in glutamatergic signaling, glial function, and BDNF–TrkB–mTOR pathways contribute to synaptic atrophy and network dysfunction. Rapid-acting antidepressants such as ketamine, esketamine, and dextromethorphan–bupropion provide clinical proof-of-concept that direct engagement of synaptic plasticity mechanisms can accelerate symptom improvement, particularly in treatment-resistant depression. Conclusions: Integrating monoaminergic and glutamatergic mechanisms within a “monoamine–glutamate continuum” offers a conceptual framework for understanding depressive heterogeneity and treatment response. Multimodal approaches combining clinical phenotyping with inflammatory, neuroimaging, and molecular markers may ultimately support mechanism-informed precision psychiatry strategies in major depressive disorder. 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

Background: Autonomic side effects are a major determinant of tolerability for many psychotherapeutic drugs. While often attributed to receptor-mediated mechanisms, the potential contribution of direct modulation of smooth muscle excitability remains poorly characterized at a comparative pharmacological level. Methods: A systematic comparative pharmacological profiling of a broad panel of psychotherapeutic drugs (antidepressants, antipsychotics, and anxiolytics) was conducted using a standardized ex vivo model. Potassium chloride (KCl, 105 mM) was used to induce depolarization-dependent contraction in three isolated smooth muscle preparations (rat uterus, rat vas deferens, and guinea-pig ileum). Inhibitory potency (IC₅₀), dose-dependency, and tissue consistency were integrated to define functional inhibitory profiles. Results: Psychotherapeutic drugs exhibited marked heterogeneity in their ability to inhibit K⁺-induced smooth muscle contraction. Integrative analysis stratified compounds into four distinct functional profiles: (i) High Inhibitory Liability (e.g., nortriptyline, paroxetine), characterized by low micromolar IC₅₀ values and dose-dependent inhibition across multiple tissues; (ii) Non-Selective Inhibition (e.g., flunarizine, cinnarizine), showing consistent but dose-independent inhibition; (iii) Tissue-Dependent Inhibition (e.g., risperidone, reboxetine); and (iv) Minimal Inhibition (e.g., moclobemide). Agents classified within the High Inhibitory Liability profile correspond to drugs known to carry a higher clinical burden of autonomic adverse effects. Conclusions: This study reveals a previously underrecognized pharmacodynamic dimension of psychotherapeutic drugs and establishes a comparative functional taxonomy based on their direct, non-receptor-mediated inhibition of smooth muscle excitability. The identified profiles provide a mechanism-informed framework for contextualizing autonomic side-effect liability and may support improved safety evaluation in psychotherapeutic drug development. Full article

Background: Post-psychotic depression (PPD) is an underestimated but clinically significant affective syndrome that occurs during remission from psychosis, particularly in schizophrenia. Material and Methods: This comprehensive review traces the evolution of this concept over five decades of research, starting from its initial differentiation from primary depression and schizoaffective disorders in the 1970s. Relying on more than thirty studies, we analyze historical definitions, biological and psychosocial mechanisms, diagnostic controversies, and therapeutic implications. Results: Research indicates that PPD develops from multiple contributing factors, including psychological insight, autobiographical disturbances, pharmacological influences, and social losses, rather than simply as a byproduct of psychosis or pharmacological treatment. We discuss the persistence of depressive symptoms after acute remission, their role in suicidal tendencies, and the diagnostic challenges arising from the overlap of negative symptoms and demoralization. Despite its exclusion from current diagnostic standards, PPD continues to affect a significant fraction of patients, particularly those with high insight and early onset. Conclusions: Effective treatment requires a multidimensional, phase-specific approach combining antidepressants, atypical antipsychotics such as lurasidone, and psychological interventions targeting identity, self-esteem, and narrative processing. We argue that PPD should be reintroduced as a distinct clinical unit and incorporated into psychiatric guidelines to reduce diagnostic oversights and improve patient outcomes. Full article

(1) Different classes of antidepressant drugs have been shown to activate lysophosphatidic acid (LPA) receptors, but their effects on the receptor signaling stimulated by LPA have not been fully investigated. In the present study, we examined the effect of the tricyclic antidepressant amitriptyline on the LPA-induced activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and Rho signaling in C6 glioma cells and cultured rat astrocytes. (2) LPA receptor signaling was investigated by using Western blot and microscopic immunofluorescence assays. Rho activation was determined by a pull-down assay. (3) Amitriptyline potentiated the LPA-induced activation of ERK1/2 signaling, as indicated by the more than additive increases in the phosphorylation/activation of key components of this pathway including fibroblast growth factor 1 receptor, MEK1/2, ERK1/2, Elk-1, and cyclic AMP response element binding protein (CREB). Amitriptyline also enhanced the expression of brain-derived neurotrophic factor (BDNF) elicited by LPA. In contrast, the antidepressant failed to mimic the LPA-induced activation of Rho and Rho-dependent responses, such as the reversal of astrocyte stellation, accumulation of stress fibers, and the phosphorylation of focal adhesion kinase and myosin target subunit of myosin phosphatase isoform 1. Moreover, when combined with LPA, amitriptyline curtailed Rho activation and the Rho-mediated cellular responses. (4) These results demonstrate that in astroglial cells, amitriptyline exerts a balanced action on LPA-activated receptors by enhancing the neuroprotective ERK1/2-CREB-BDNF signaling and dampening the potentially detrimental Rho–ROCK pathway, and suggest that this unique property may contribute to the antidepressant activity of the drug. 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

Introduction: Major Depressive Disorder (MDD) has been increasingly associated with inflammatory dysregulation, particularly involving tumor necrosis factor-alpha (TNF-α). Genetic polymorphisms within the TNFA promoter region have been investigated as potential modulators of depressive susceptibility, symptom expression, treatment response, and inflammatory comorbidity. However, findings remain inconsistent across populations and clinical contexts. Methods: This systematic review adhered to PRISMA 2020 guidelines and was registered in PROSPERO (CRD420251242724). Observational and interventional studies evaluating associations between TNFA polymorphisms—specifically rs1800629 (−308 G/A), rs1799724 (−857 C/T), and rs1799964 (−1031 T/C)—and MDD-related outcomes in adults were included. Data extraction and methodological quality assessment were performed independently using an adapted GRIPS framework. Results: Eleven studies met the inclusion criteria, with eight investigating MDD without cardiovascular comorbidity and three assessing cardiovascular populations. Across diverse cohorts, rs1800629 and rs1799724 did not demonstrate consistent associations with MDD susceptibility. Although isolated population-specific findings were reported, genotype and allele distributions were generally comparable between cases and controls. Rs1799724 was associated with symptom dimensions and altered TNF-α expression in two cohorts. Rs1799964 was not linked to disease occurrence but showed potential association with antidepressant response and adverse cardiovascular outcomes in patients with chronic heart failure and comorbid depression. Overall, findings were heterogeneous and influenced by population characteristics, sample size, and clinical context. Conclusions: Current evidence does not support a robust etiological role for TNFA promoter polymorphisms in major depressive disorder. These variants may exert context-dependent modulatory effects on symptom expression, treatment response, or inflammatory-cardiovascular interactions rather than serving as primary susceptibility determinants. Larger, ethnically diverse studies integrating genetic, inflammatory, and clinical data are required to clarify the contribution of inflammatory genetic variability in depressive disorders. Full article

Background/Objectives: Burning mouth syndrome (BMS) is a chronic idiopathic orofacial pain disorder characterized by persistent intraoral burning in the absence of detectable mucosal alterations. Diagnosis is challenging due to the lack of specific biomarkers and the need to exclude numerous systemic and local conditions that can mimic oral burning. This literature review aims to summarize current and emerging therapeutic strategies for BMS. Methods: A structured and filtered search of PubMed, Scopus, and Web of Science identified studies evaluating pharmacological, phytotherapeutic, and non-pharmacological interventions. Results: Various antidepressants, anticonvulsants, benzodiazepines, H2 receptor antagonists, and low-dose naltrexone have demonstrated varying degrees of symptom reduction, while alpha lipoic acid (ALA) and phytomedicines such as capsaicin, Hypericum perforatum, Catuama, lycopene, crocin, and melatonin show mixed clinical benefits. Non-pharmacological approaches, including photobiomodulation (PBM), oral cryotherapy, neuromodulation techniques, and cognitive behavioral therapy, also provide meaningful symptom improvement in many patients. Conclusions: Across all modalities, therapeutic responses remain heterogeneous and generally incomplete, underscoring the absence of a universally effective treatment. Current evidence supports an individualized and multidisciplinary approach that integrates pharmacological, psychological, and adjunctive therapies to address the multifactorial nature of BMS. Full article

Background: Depression is highly prevalent among individuals with chronic pain and strongly impacts pain intensity, psychological functioning, and health-related quality of life. Self-efficacy has emerged as a potentially modifiable resilience factor within this interplay, yet large-scale real-world evidence integrating self-efficacy into multidimensional pain–depression models remains limited. Methods: This cross-sectional registry-based analysis evaluated standardized patient-reported measures from chronic pain patients enrolled in the German Pain e-Registry. All variables were directionally harmonized and transformed into standardized deviation scores (hSDSs) relative to patients without depression. Group-level hSDS profiles for five DASS-21 depression severity strata (none, mild, moderate, severe, extreme) were compared across pain intensity, disability, psychological well-being, affective pain processing, quality of life, neuropathic pain features, and pain-related self-efficacy (PSEQ). Correlations and exploratory principal component analysis (PCA) were used to assess multivariate structure. PCA-informed path models were estimated to evaluate directional relationships between pain, function, depression, and self-efficacy. All directional and mediation models represent exploratory, theory-informed statistical frameworks and do not imply causal or mechanistic relationships. Results: Across all domains, hSDS values increased monotonically with depression severity, while self-efficacy showed the strongest inverse gradient. Exploratory PCA revealed a dominant severity component explaining most variance and a secondary affective–self-efficacy axis, supporting the conceptual separation between functional–physical and psychological–affective symptom clusters. In the bottom-up path model (pain → function → self-efficacy → depression), self-efficacy showed the largest indirect statistical contribution within the proposed path models, and the model explained 55% of depression variance (R² = 0.55). In the top-down model (depression → affective pain → self-efficacy → pain), 45% of pain intensity variance was explained (R² = 0.45), again with self-efficacy as a central mediating construct. Associations remained robust after adjustment for age, sex, and BMI, as well as during sensitivity analyses. Conclusions: This large real-world cohort demonstrates a highly coherent pattern of associations across biopsychosocial domains and highlights pain-related self-efficacy as a central statistical construct linking pain, functional impairment, and depressive symptom burden within the applied exploratory models. The findings suggest that self-efficacy occupies a key position in the interplay between pain and mood, and that pharmacological and non-pharmacological treatments traditionally used in chronic pain management may be associated with changes in this construct. Importantly, all directional and mediation analyses are exploratory and do not imply causal or mechanistic relationships. Therapeutic strategies aimed at enhancing self-efficacy may therefore represent promising targets for future research within multimodal pain management frameworks. 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

Frailty is a multifactorial geriatric syndrome marked by reduced physiological reserves and increased vulnerability to adverse outcomes. This multicenter observational study adopted a One Health approach to examine the association between frailty and biological sex, denture use, and antidepressant medication, as well as their impact on bite force, in two transnational cohorts of physically active older adults. The sample included 499 individuals aged ≥60 years (295 from Brazil and 204 from Portugal), all with functional dentition and regular physical activity. Frailty was assessed using the adapted Fried phenotype and classified as non-frail (G0), pre-frail (G1), or frail (G2). Oral health, depressive symptoms (CES-D), bite force, and self-reported use of dentures and antidepressants were analyzed. Frailty was significantly associated with biological sex (p < 0.001), with higher prevalence among women, especially in G2. Antidepressant use was associated with frailty in the Portuguese cohort (p < 0.001) and in the total sample (p = 0.005), but not in Brazil. No significant association was observed between denture use and frailty. However, Brazilian participants without dentures showed significantly higher bite force (p < 0.001), indicating a functional oral health effect. Frailty was associated with female sex and antidepressant use, while bite force emerged as a complementary functional marker for geriatric assessment. 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

Scopolamine, also known as hyoscine, is a naturally occurring tropane alkaloid derived from plants of the Solanaceae family. Clinically, the compound has long been used for the prevention of motion sickness and postoperative nausea and vomiting, as well as for ophthalmological procedures requiring mydriasis and cycloplegia. However, beyond these established indications, increasing attention has been directed toward its broader neuropharmacological actions. This narrative review aims to summarise current knowledge regarding the pharmacological properties of scopolamine, with particular emphasis on its mechanisms of action and emerging implications in neuroscience and neuropsychiatric disorders. Scopolamine acts as a non-selective antagonist of muscarinic receptor subtypes M1–M5, interfering with cholinergic neurotransmission. Experimental and clinical studies demonstrate that scopolamine induces transient cognitive impairment. This property has led to its widespread use as a pharmacological model of Alzheimer’s disease, enabling investigation of cholinergic contributions to cognitive decline. More recently, several early clinical studies suggested that intravenous administration may produce rapid reductions in depressive symptoms, possibly through modulation of glutamatergic neurotransmission and activation of mTORC1-dependent synaptic plasticity pathways in the prefrontal cortex. Nevertheless, subsequent trials have yielded inconsistent results, and the therapeutic relevance of these findings remains uncertain. Current evidence indicates that scopolamine’s neuropsychiatric effects likely arise from complex interactions between cholinergic, glutamatergic, and neurotrophic signalling systems. Taken together, scopolamine represents both a valuable experimental tool for studying cholinergic function and a mechanistic framework for the development of novel therapeutics targeting rapid neuroplastic processes in neuropsychiatric disorders. Full article

Serotonin is a critical morphogen in early development, yet the mechanisms regulating its homeostasis in the preimplantation embryo remain unclear, particularly under conditions of maternal antidepressant exposure. Here, we investigated embryonic serotonergic autonomy using mouse models of pharmacological transport blockade (maternal fluoxetine treatment) and in vitro treatment with the monoamine oxidase inhibitor pargyline. We employed immunofluorescence, RT-qPCR, and live-cell imaging to assess metabolic flux, gene expression, and physiological health. We demonstrate that monoamine oxidase functions as a metabolic firewall, progressively maturing from zygote to blastocyst to degrade excess amines. Paradoxically, maternal serotonin transporter blockade triggered significant intracellular serotonin hyper-accumulation in blastocysts, associated with a trend toward a compensatory upregulation of the biosynthetic gene Ddc. While this serotonin overload did not compromise morphology, mitochondrial function, or pluripotency marker expression, it induced a robust epigenetic response. Excess serotonin promoted elevated H3Q5ser immunoreactivity in both nuclear and cytoplasmic compartments via a transglutaminase-dependent mechanism. These findings reveal that the preimplantation embryo possesses a resilient, autonomous serotonergic system capable of compensatory synthesis. However, environmental fluctuations are chemically recorded via transglutaminase-mediated serotonylation, representing an epigenetic mark that warrants further long-term study within the Developmental Origins of Health and Disease (DOHaD) framework. Full article

Depression is notable for high rates of disability. The medical model typically characterizes depression as a physiological dysfunction or psychological disorder. However, both views fail to appreciate the phenomenology of depressed experience. Drawing on the existential phenomenology of Merleau-Ponty, this article contends that the lived experience of chronic depression is marked by a disturbance between the body-subject and the world. More specifically, the experience of depression is characterized by alienation from the world, self and others. While anti-depressants have long been the first line of treatment of depression, many governments subsidize cognitive behavioral therapy (CBT) as an adjunct treatment. CBT is said to be the gold standard psychotherapeutic treatment given that it is evidence-based, cost-effective, and short in duration. However, not only are these justifications questionable, but the theoretical underpinnings of CBT have ideological significance. Rather than approaching depressed persons as body-subjects, CBT casts service users as neo-liberal subjects, insofar as depression is characterized as disordered thinking that is independent of a person’s situated life. The emphasis on quickly returning people to work to reduce strain on welfare systems, while a valid economic concern, is not a valid therapeutic concern. The limited choice of subsidized psychotherapeutic options fails to recognize that depression is a heterogenous phenomenon, meaning that the CBT model of disordered thinking is not necessarily representative of the way in which depression manifests. Full article