Search Results (328)

Treatment-resistant depression (TRD) is associated with immune dysregulation. Ketamine, a rapid-acting antidepressant, may exert effects via immunomodulation. The aim was to examine ketamine’s impact on immune markers in TRD, including T-cell subsets, cytokines, and in vitro T-cell responses. Eighteen TRD inpatients received 0.5 mg/kg iv ketamine. Blood was sampled at baseline, 4 h, and 24 h to analyze T-cell phenotypes (CD28, CD69, CD25, CD95, HLA-DR) and serum cytokines (IL-6, IL-8, IL-10, TNF-α, IL-1β, IL-12p70). In vitro, PBMCs from TRD patients and controls were exposed to low (185 ng/mL) and high (300 ng/mL) ketamine doses. Ketamine induced a transient increase in total T cells and CD4⁺CD25⁺ and CD4⁺CD28⁺ subsets at 4 h, followed by a reduction in CD4⁺ and an increase in CD8⁺ T cells at 24 h, decreasing the CD4⁺/CD8⁺ ratio. Activation markers (CD4⁺CD69⁺, CD4⁺HLA-DR⁺, CD8⁺CD25⁺, CD8⁺HLA-DR⁺) declined at 24 h. Serum IL-10 increased, IL-6 decreased, and IL-8 levels—initially elevated—showed a sustained reduction. In vitro, high-dose ketamine enhanced the proliferation of TRD CD4⁺ T cells and dose-dependent IL-8 and IL-6 secretion from activated cells. Ketamine induces rapid, transient immune changes in TRD, including reduced T-cell activation and cytokine modulation. A sustained IL-8 decrease suggests anti-inflammatory effects and potential as a treatment-response biomarker. Full article

Background: Depression that is resistant to two or more adequate treatment trials—treatment-resistant depression (TRD)—is a prevalent clinical challenge. Although psychotherapies have been recommended by clinical guidelines as an alternative or adjunctive treatment strategy, the effectiveness of psychotherapy in individuals with TRD has not yet been evaluated through meta-analytic methods, primarily due to a limited number of trials. This highlights the necessity of personalized research targeting this specific population. This systematic review and meta-analysis aimed to summarize the evidence on psychotherapy in treating TRD. Methods: A systematic search was conducted following the Guidelines from Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Articles were included if they quantitatively examined the efficacy of psychotherapy on depression symptoms in individuals diagnosed with depression who had not responded to at least two prior treatments (i.e., pharmacotherapy and/or psychotherapy). Results: A total of 12 studies were included. The quality of evidence was evaluated as being globally moderate. When pooling all psychotherapies, a small-to-moderate, but significant, effect on depressive symptoms was observed compared to the control group (SMD = −0.49, CI = −0.63; −0.34). The observed effect remained unchanged after removing the outlier (SMD = −0.47, CI = −0.62; −0.32). When examining depressive symptoms by type of psychotherapy, Mindfulness-Based Cognitive Therapy (SMD = −0.51, CI = −0.76; −0.25), Cognitive Behavioral Therapy (SMD = −0.53, CI = −0.92; −0.14), and Cognitive Therapy (SMD = −0.51, CI = −1.01; −0.01) showed a moderately significant effect on depressive symptoms compared to the control group. Conclusions: Although this potentially represents the first meta-analysis in this area, the number of studies specifically addressing this complex population remains limited, and the existing literature is still in its early stages. Research focusing on TRD is notably sparse compared to the broader body of work on depression without treatment resistance. Consequently, it was not possible to conduct meta-analyses by type of psychotherapy across all treatment modalities and by type of control group. Due to several study limitations, there is currently limited evidence available about the effectiveness of psychotherapy for TRD, and further trials are needed. Beyond the treatments usually offered for depression, it is possible that TRD requires a personalized medicine approach. Full article

Despite growing evidence supporting the efficacy of LSD-assisted psychotherapy in treating major depressive disorder (MDD), identifying reliable psychopharmacological biomarkers remains necessary. Oxytocin, a neuropeptide implicated in social bonding and flexibility, is a promising candidate due to its release following serotonergic psychedelic administration in healthy individuals; however, its dynamics in psychiatric populations are currently unexplored. This observational pilot study aimed to characterize salivary oxytocin dynamics during a single LSD-assisted psychotherapy session in our patients with treatment-resistant MDD. Participants received 100 or 150 µg LSD, and salivary oxytocin was measured at baseline, 60, 90, and 180 min post-LSD. Concurrently, participants rated subjective drug intensity (0–10 scale) at 60, 90, and 180 min. A linear mixed model revealed significant variation of oxytocin levels over time. Perceived psychedelic intensity also significantly varied over time. This supports oxytocin as a potential biomarker. Larger, controlled trials are warranted to replicate these findings and clarify the mechanistic links between oxytocin dynamics and clinical outcomes, including changes in depressive symptoms and mental flexibility. Full article

Forty per cent of major depression patients are resistant to antidepressant medication. Thus, it is necessary to search for alternative treatments. Melatonin (N-acetyl-5-hydroxytryptamine) enhances neurogenesis and neuronal survival in the adult mouse hippocampal dentate gyrus. Additionally, melatonin stimulates the activity of Ca²⁺/Calmodulin-dependent Kinase II (CaMKII), promoting dendrite formation and neurogenic processes in human olfactory neuronal precursors and rat organotypic cultures. Similarly, ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, modulates CaMKII activity. Importantly, co-treatment of low doses of ketamine (10⁻⁷ M) in combination with melatonin (10⁻⁷ M) produces additive effects on neurogenic responses in olfactory neuronal precursors. Importantly, enhanced neurogenic responses are produced by conventional antidepressants like ISSRs. The goal of this study was to investigate whether hippocampal CaMKII participates in the signaling pathway elicited by combining doses of melatonin with ketamine acutely administered to mice, 30 min before being subjected to the forced swimming test. The results showed that melatonin, in conjunction with ketamine, significantly enhances CaMKII activation and changes its subcellular distribution in the dentate gyrus of the hippocampus. Remarkably, melatonin causes nuclear translocation of the active form of CaMKII. Luzindole, a non-selective MT₁ and MT₂ receptor antagonist, abolished these effects, suggesting that CaMKII is downstream of the melatonin receptor pathway that causes the antidepressant-like effects. These findings provide molecular insights into the combined effects of melatonin and ketamine on neuronal plasticity-related signaling pathways and pave the way for combating depression using combination therapy. Full article

The balance between physiological, psychological, and environmental factors often shapes human experience. In recent years, research has drawn attention to the gut microbiota as a significant contributor to brain function and emotional regulation. This narrative review examines how changes in gut microbiota may relate to depression. We selected studies that explore the link between intestinal dysbiosis and mood, focusing on mechanisms such as inflammation, vagus nerve signaling, HPA axis activation, gut permeability, and neurotransmitter balance. Most of the available data come from animal models, but findings from human studies suggest similar patterns. Findings are somewhat difficult to compare due to differences in measurement procedures and patient groups. However, several microbial shifts have been observed in people with depressive symptoms, and trials with probiotics or fecal microbiota transplant show potential. These results remain limited. We argue that these interventions deserve more attention, especially in cases of treatment-resistant or inflammation-driven depression. Understanding how the gut and brain interact could help define clearer subtypes of depression and guide new treatment approaches. Full article

Amyloid-β (Aβ) aggregates are considered as the important factors of Alzheimer’s disease (AD). Multifunctional materials have shown significant effects in the diagnosis and treatment of AD by modulating the aggregation of Aβ and production of reactive oxygen species (ROS). Compared to traditional surgical treatment and radiotherapy, phototherapy has the advantages, including short response time, significant efficacy, and minimal side effects in disease diagnosis and treatment. Recent studies have shown that local thermal energy or singlet oxygen generated by irradiating certain organic molecules or nanomaterials with specific laser wavelengths can effectively degrade Aβ aggregates and depress the generation of ROS, promoting progress in AD diagnosis and therapy. Herein, we outline the development of photothermal therapy (PTT) and photodynamic therapy (PDT) strategies for the diagnosis and therapy of AD by modulating Aβ aggregation. The materials mainly include organic photothermal agents or photosensitizers, polymer materials, metal nanoparticles, quantum dots, carbon-based nanomaterials, etc. In addition, compared to traditional fluorescent dyes, aggregation-induced emission (AIE) molecules have the advantages of good stability, low background signals, and strong resistance to photobleaching for bioimaging. Some AIE-based materials exhibit excellent photothermal and photodynamic effects, showing broad application prospects in the diagnosis and therapy of AD. We further summarize the advances in the detection of Aβ aggregates and phototherapy of AD using AIE-based materials. Full article

Objectives: (R)-ketamine hydrochloride injection is a novel, rapid-acting antidepressant for the treatment of treatment-resistant depression. The aim of this study was to assess the pharmacokinetics, safety, and tolerability of (R)-ketamine hydrochloride injection in healthy Chinese subjects following ascending single intravenous doses ranging from 10.0 mg to 180 mg. Methods: This randomized, double-blind, placebo-controlled study was conducted in 50 healthy male and female Chinese subjects after single ascending doses of (R)-ketamine hydrochloride injection (10.0, 30.0, 60.0, 120, and 180 mg). Ten subjects (including two subjects treated with a placebo) were included in each dose cohort. Pharmacokinetic characteristics, safety, and tolerability profiles of the study drug were evaluated. Results: After the intravenous doses administered from 10.0 mg to 180 mg of (R)-ketamine hydrochloride injection to the subjects, the C_max and AUC values for both (R)-ketamine and its metabolite (R)-norketamine in the subjects increased approximately proportionally to the doses. The average peak plasma concentration levels at the five dose cohorts ranged from 56.0 to 1424 ng/mL and 27.7 to 491 ng/mL for (R)-ketamine and (R)-norketamine, respectively. The adverse events of (R)-ketamine hydrochloride injection were temporary and recovered spontaneously without treatment. Conclusions: In summary, (R)-ketamine hydrochloride injection was safe and well tolerated in healthy Chinese subjects. The clinical study results laid a foundation for the further clinical studies of (R)-ketamine hydrochloride injection in patients. Full article

Background: Insomnia, as one of the most common sleep disorders, is a significant health problem, especially among patients suffering from drug-resistant depression. Problems related to the quality of sleep in that population can significantly affect the effectiveness of treatment and quality of life, which is why it is necessary to search for effective therapeutic interventions in this area. Objective: The aim of this study was to compare the effectiveness of esketamine and other standard antidepressants in improving sleep quality in patients with drug-resistant depression. The main research question is whether and to what extent esketamine improves sleep parameters compared with other antidepressants. Methods: This study involves the analysis of data collected from 50 patients divided into two groups: those using esketamine in combination with other antidepressants and those using other antidepressants. The analysis of the results focuses on the assessment of differences in AIS scores between the groups assessed using the Athens Insomnia Scale (AIS). Results: Insomnia occurs much less frequently among people using esketamine than among people not using this drug. With the increase in the time of using esketamine and with the increase in the dose, the level of insomnia decreases. Conclusions: Esketamine brings about a rapid improvement in sleep quality, which is a significant advance in the treatment of drug-resistant depression. The obtained results not only confirm the effectiveness of esketamine but also show its advantage over traditional treatment methods in improving sleep quality. Full article

Ketamine infusion therapy has gained recognition as an innovative treatment for treatment-resistant depression (TRD), demonstrating rapid and robust antidepressant effects. Its therapeutic promise is increasingly understood to involve molecular and neurobiological processes that promote neural plasticity and cognitive flexibility. These changes may create a unique window for psychotherapeutic interventions to take deeper effect. This retrospective chart review examined the clinical outcomes of individuals with TRD who received either single or repeated ketamine infusion(s), with or without weekly psychotherapy. Depression severity, measured by Beck Depression Inventory scores, was assessed pre-treatment and 30 days post-infusion(s). The results showed significant symptom reduction across all groups, with the most pronounced effects observed in those who received concurrent psychotherapy. While infusion number did not significantly alter outcomes, the integration of ketamine with psychotherapy appeared to enhance treatment response. Full article

Ketamine, originally developed as an anesthetic, is gaining increasing attention due to its multifaceted pharmacological properties. In addition to its use in anesthesia, ketamine exerts potent analgesic effects via N-methyl-D-aspartate (NMDA) receptor antagonism, modulating pain perception and reducing central sensitization, particularly in chronic and neuropathic pain conditions. Emerging evidence also supports ketamine’s potential in the treatment of substance use disorder, where it may disrupt maladaptive reward-related memories and promote neuroplasticity which facilitates behavioral change. Moreover, in recent years, S-ketamine has shown rapid and potent antidepressant effects, especially in treatment-resistant depression (TRD), probably due to increased glutamatergic signaling, synaptic plasticity and the release of neurotrophic factors. This heterogeneous therapeutic profile positions ketamine as a unique agent at the interface of anesthesia, pain management, addiction medicine and psychiatry, warranting further exploration into its mechanism and long-term effectiveness. Full article

The oral microbiome, a highly diverse and intricate ecosystem of microorganisms, plays a pivotal role in the maintenance of systemic health. With the oral cavity housing over 700 different bacterial species, the body’s second most diverse microbial community, periodontal pathogens often lead to the dysregulation of immune responses and consequently, neuropsychiatric disorders. Emerging evidence suggests a significant link between the dysbiosis of oral taxa and the progression of neurogenic disorders such as depression, schizophrenia, bipolar disorders, and more. In this paper, we show the relationship between mental health conditions and shifts in the oral microbiome by highlighting inflammatory responses and neuroactive pathways. The connection between the central nervous system and the oral cavity highlights its role as a modulator of mental health. Clinically, these findings have significant importance as dysbiosis could compromise quality of life. The weight of mental health is often compounded with treatment resistance, non-adherence, and relapse, causing a further need for treatment development. This review seeks to underscore the crucial role of the proposed oral–brain axis in hopes of increasing its presence in future intervention strategies and mental health therapies. Full article

Ketamine and esketamine are two closely related compounds with fast-acting antidepressant properties that have reshaped the treatment landscape for individuals with treatment-resistant depression (TRD). Originally developed as anesthetic agents, both have since demonstrated rapid and robust antidepressant effects in patients who have not responded to conventional treatments such as selective serotonin reuptake inhibitors (SSRIs) or cognitive behavioral therapy. This narrative review synthesizes evidence on their pharmacology, mechanisms of action, clinical efficacy, safety profiles, and regulatory considerations, with a particular focus on their neuroplastic effects. While ketamine is a racemic mixture composed of equal parts R- and S-enantiomers, esketamine consists solely of the S-enantiomer and has been approved for intranasal use by the FDA and EMA for TRD. These agents have been shown to produce symptom relief within hours of administration—an unprecedented effect in psychiatric pharmacology. This rapid onset is particularly valuable in managing suicidal ideation, offering potential lifesaving benefits in acute settings. Furthermore, ketamine and esketamine’s influence on synaptic plasticity, brain-derived neurotrophic factor (BDNF), and glutamate transmission provides insights into novel therapeutic targets beyond monoaminergic systems. This review incorporates recent real-world findings and peer-reviewed literature to contextualize the clinical use of these agents in modern psychiatry, bridging experimental research with practical application. Full article

Electroconvulsive therapy (ECT) remains one of the most effective interventions for treatment-resistant psychiatric disorders, particularly major depressive disorder and bipolar disorder. Despite extensive clinical and preclinical investigations, the precise neurobiological mechanisms underlying ECT’s therapeutic effects are not fully understood. This review explores the molecular and cellular pathways involved in ECT, emphasizing its impact on neurotrophic signaling, oxidative stress, apoptosis, and neuroplasticity. Evidence suggests that ECT modulates brain-derived neurotrophic factor and other neurotrophic factors, promoting synaptic plasticity and neuronal survival. Additionally, ECT influences the hypothalamic–pituitary–adrenal axis, reduces neuroinflammation, and alters neurotransmitter systems, contributing to its antidepressant effects. Recent findings also highlight the role of mitochondrial function and oxidative stress regulation in ECT-induced neural adaptation. By synthesizing current molecular insights, this review provides a comprehensive perspective on the neurobiological mechanisms of ECT, offering potential directions for future research and therapeutic advancements in brain stimulation. Full article

Anxiety disorders, as common neurological diseases in clinical practice, often coexist with depression. Epidemiological surveys indicate that approximately 85% of patients with depression exhibit significant anxiety symptoms. This comorbid state not only exacerbates clinical symptoms but also leads to treatment resistance and prolonged disease duration. This study innovatively developed a compound aromatic plant essential oil (EO) formulation with remarkable anxiolytic and antidepressant effects and systematically elucidated its mechanism of action. The study found that the essential oil formulation, administered via inhalation, could significantly improve behavioral abnormalities in animals subjected to the chronic unpredictable mild stress (CUMS) model, specifically manifesting as (1) the reversal of stress-induced weight gain retardation; (2) a significant increase in sucrose preference; (3) an increase in the total distance of spontaneous activity; and (4) the prolongation of exploration time in the open arms of the elevated plus maze. Neuropathological examinations confirmed that the formulation could effectively protect the structural integrity of hippocampal neurons and alleviate CUMS-induced neural damage. In terms of mechanism of action, the study revealed that the formulation regulates the neurotransmitter system through multiple targets: (1) the upregulation of serotonin (5-HT) and γ-aminobutyric acid (GABA) levels; (2) the downregulation of glutamate (GLU) concentration; and (3) key targets identified via network pharmacological analysis, such as ESR1, STAT3, and PPARG. These findings provide molecular-level evidence for understanding the neuromodulatory effects of aromatic essential oils. Pharmaceutical formulation studies showed that the oil-in-water (O/W) type compound essential oil microemulsion, prepared using microemulsification technology, has a uniform particle size and excellent stability, maintaining stable physicochemical properties at room temperature for an extended period, thus laying a foundation for its clinical application. This study not only validates the practical value of traditional medicine but also provides new ideas for the development of novel anxiolytic and antidepressant drugs, achieving an organic integration of traditional experience and modern technology. Full article

Psychiatric neurosurgery is undergoing a profound transformation, propelled by advances in neurotechnology, connectomics, and personalized medicine. Once controversial, surgical interventions are now guided by detailed functional brain mapping and precise neuromodulation techniques, such as deep brain stimulation (DBS), which offer therapeutic options for patients with severe, treatment-resistant psychiatric disorders. This manuscript reviews the current techniques, including lesion-based procedures and DBS, and explores their mechanisms of action, from synaptic plasticity to large-scale network modulation. It highlights recent progress in neuroimaging, connectomic targeting, and artificial intelligence applications for surgical planning and the prediction of treatment responses. Ethical considerations—including informed consent, identity, and long-term follow-up—are critically examined in light of these advances. Furthermore, the growing role of minimally invasive procedures and wearable integrated neurotechnologies is discussed as part of a shift toward dynamic and adaptive interventions. Although still investigational, psychiatric neurosurgery is emerging as a technologically sophisticated field that demands rigorous clinical evaluation, ethical accountability, and an individualized approach to restoring function and autonomy in some of the most disabling mental illnesses. Full article