Search Results (281)

Background: Bipolar disorder (BD) is a chronic and disabling psychiatric condition characterized by recurring episodes of mania, hypomania, and depression. Despite the availability of mood stabilizers, antipsychotics, and antidepressants, long-term management remains challenging due to incomplete symptom control, adverse effects, and high relapse rates. Methods: This paper is a narrative review aimed at synthesizing emerging trends and future directions in the pharmacological treatment of BD. Results: Future pharmacotherapy for BD is likely to shift toward precision medicine, leveraging advances in genetics, biomarkers, and neuroimaging to guide personalized treatment strategies. Novel drug development will also target previously underexplored mechanisms, such as inflammation, mitochondrial dysfunction, circadian rhythm disturbances, and glutamatergic dysregulation. Physiological endophenotypes, such as immune-metabolic profiles, circadian rhythms, and stress reactivity, are emerging as promising translational tools for tailoring treatment and reducing associated somatic comorbidity and mortality. Recognition of the heterogeneous longitudinal trajectories of BD, including chronic mixed states, long depressive episodes, or intermittent manic phases, has underscored the value of clinical staging models to inform both pharmacological strategies and biomarker research. Disrupted circadian rhythms and associated chronotypes further support the development of individualized chronotherapeutic interventions. Emerging chronotherapeutic approaches based on individual biological rhythms, along with innovative monitoring strategies such as saliva-based lithium sensors, are reshaping the future landscape. Anti-inflammatory agents, neurosteroids, and compounds modulating oxidative stress are emerging as promising candidates. Additionally, medications targeting specific biological pathways implicated in bipolar pathophysiology, such as N-methyl-D-aspartate (NMDA) receptor modulators, phosphodiesterase inhibitors, and neuropeptides, are under investigation. Conclusions: Advances in pharmacogenomics will enable clinicians to predict individual responses and tolerability, minimizing trial-and-error prescribing. The future landscape may also incorporate digital therapeutics, combining pharmacotherapy with remote monitoring and data-driven adjustments. Ultimately, integrating innovative drug therapies with personalized approaches has the potential to enhance efficacy, reduce adverse effects, and improve long-term outcomes for individuals with bipolar disorder, ushering in a new era of precision psychiatry. 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

Background: The N-methyl-d-aspartate receptor (NMDA-R) is a glutamate ionotropic receptor in the brain that is crucial for synaptic plasticity, which underlies learning and memory formation. Dysfunction of NMDA receptors is implicated in various neurological diseases due to their roles in both normal cognition and excitotoxicity. However, their dynamics are challenging to capture accurately due to their high complexity and non-linear behavior. Methods: This article presents the elaboration and calibration of experimentally constrained computational models of GluN1/GluN2A NMDA-R dynamics: (1) a nine-state kinetic model optimized to replicate experimental data and (2) a computationally efficient look-up table model capable of replicating the dynamics of the nine-state kinetic model with a highly reduced footprint. Determination of the kinetic model’s parameter values was performed using the particle swarm optimization algorithm. The optimized kinetic model was then used to generate a rich input–output dataset to train the look-up table synapse model and estimate its coefficients. Results: Optimization produced a kinetic model capable of accurately reproducing experimentally found results such as frequency-dependent potentiation and the temporal response due to synaptic release of glutamate. Furthermore, the look-up table synapse model was able to closely mimic the dynamics of the optimized kinetic model. Conclusions: The results obtained with both models indicate that they constitute accurate alternatives for faithfully reproducing the dynamics of NMDA-Rs. High computational efficiency is also achieved with the use of the look-up table synapse model, making this implementation an ideal option for inclusion in large-scale neuronal models. Full article

Ionotropic glutamate receptors—including N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainate receptors—play a pivotal role in excitatory signaling in the central nervous system (CNS), which is particularly important for learning and memory processes. Among them, AMPA and kainate receptors (known as ‘non-NMDA’ receptors) have gained increasing attention as therapeutic targets for various CNS disorders. Positive allosteric modulators (PAMs) of these receptors enhance their activity without directly activating them, offering a promising strategy to fine-tune glutamatergic signaling with potentially fewer side effects compared to orthosteric agonists. This review presents a comprehensive overview of recent advances in the development of AMPA and kainate receptor PAMs. We classify the most relevant modulators into main chemotype groups and discuss their binding modes, structure–activity relationships, and efficacy as determined through in vitro and in vivo studies. Additionally, we provide an overview of AMPA receptor PAMs that have entered into clinical trials over the past few decades. The increasing interest in kainate receptor PAMs is also mentioned, underlining their emerging role in future neuropharmacological strategies. 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

Objective:Burning mouth syndrome (BMS) is a chronic, intractable orofacial pain condition characterized by a burning sensation in the oral mucosa without discernible lesions. The syndrome predominantly affects menopausal and postmenopausal women and is considered a form of nociplastic pain, where the processing of pain stimuli is altered. Given the significant sex disparity, it is crucial to consider underlying neurobiological differences that may inform treatment. This review explores potential pharmacological targets by examining the pathological mechanisms of BMS. Method of Research: A narrative review approach was utilized to systematically explore and synthesize literature regarding the pathophysiology of BMS and to identify receptors implicated in the enhancement of sensory transmission and the altered processing of pain stimuli. Results: The mechanism of enhanced sensory transmission points to receptors such as TRPV1, P2X3, and CB2 as potential targets. However, considering the nociplastic nature of BMS and its prevalence in women, mechanisms involving altered central pain processing are paramount. Research indicates significant sex differences in glutamate transmission and plasticity within reward-related brain regions. This suggests that the N-methyl-D-aspartate (NMDA) receptor, a cornerstone of glutamate signaling and synaptic plasticity, is a primary therapeutic target. Furthermore, the altered processing of pain and reward, which is a key feature of chronic pain, implicates the brain’s dopaminergic system. A decrease in dopamine D2 receptor function within this system is believed to contribute to the pathology of BMS. Estrogen receptors are also considered relevant due to the menopausal onset. Conclusions: Based on the evidence, the most promising targets for pharmacotherapy in BMS are likely the NMDA receptor and the dopamine D2 receptor. The high prevalence of BMS in women, coupled with known sex differences in the glutamate and dopamine pathways of the reward system, provides a strong rationale for this focus. Effective treatment strategies should therefore aim to modulate these specific systems, directly or indirectly controlling NMDE receptor hyperactivity and addressing the decreased D2 receptor function. Further research into therapies that specifically target this sex-linked neurobiology is essential for developing effective pharmacotherapy for BMS. Full article

Adolescent binge drinking has lasting behavioral consequences by disrupting the endocannabinoid system (ECS) and depleting brain omega-3. The natural accumulation of omega-3 fatty acids in cell membranes is crucial for maintaining the membrane structure, supporting interactions with the ECS, and restoring synaptic plasticity and cognition impaired by prenatal ethanol (EtOH) exposure. However, it remains unclear whether omega-3 supplementation can mitigate the long-term effects on the ECS, endocannabinoid-dependent synaptic plasticity, and cognition following adolescent binge drinking. Here, we demonstrated that omega-3 supplementation during EtOH withdrawal increases CB1 receptors in hippocampal presynaptic terminals of male mice, along with the recovery of receptor-stimulated [³⁵S]GTPγS binding to Gαi/o proteins. These changes are associated with long-term potentiation (LTP) at excitatory medial perforant path (MPP) synapses in the dentate gyrus (DG), which depends on anandamide (AEA), transient receptor potential vanilloid 1 (TRPV1), and N-methyl-D-aspartate (NMDA) receptors. Finally, omega-3 intake following binge drinking reduced the time and number of errors required to locate the escape box in the Barnes maze test. Collectively, these findings suggest that omega-3 supplementation restores Barnes maze performance to levels comparable to those of control mice after adolescent binge drinking. This recovery is likely mediated by modulation of the hippocampal ECS, enhancing endocannabinoid-dependent excitatory synaptic plasticity. Full article

SH-SY5Y neuroblastoma cells can be effectively differentiated into a neuronal phenotype using retinoic acid (RA) and brain-derived neurotrophic factor (BDNF), making them a valuable in vitro model for studying neuronal differentiation. This study aimed to investigate the electrophysiological properties of SH-SY5Y cells following prolonged differentiation, with a focus on membrane characteristics, evoked action potentials, and the functionality of cellular components such as N-methyl-D-aspartate (NMDA) receptor. Whole-cell patch-clamp recordings were employed to evaluate ionic currents and action potentials in embryonic mouse cortical neurons (mCNs) and in both differentiated and undifferentiated SH-SY5Y neuroblastoma cells. Differentiated SH-SY5Y cells exhibited neurite outgrowth, evoked action potential firing, and functional NMDA receptor-mediated currents. Notably, atorvastatin significantly modulated the duration and firing of action potentials as well as NMDA receptor-mediated currents in differentiated SH-SY5Y cells. These findings highlight that neuronally differentiated SH-SY5Y cells expressing functional NMDA receptor-mediated currents serve as a robust and convenient model for investigating the molecular mechanisms of NMDA receptor function and for screening pharmacological agents targeting these receptors. Full article

Antibodies against the NR1 or NR2 subunits of the NMDA receptor are linked to anti-N-methyl-D-aspartate (NMDA) receptor encephalitis, a type of encephalitis that mainly affects women. Clinicians who treat patients of all ages should be aware of this type of encephalitis since it may be a treatable differential for symptoms and indicators observed in neurology and psychiatric clinics. Auditory and visual hallucinations, delusions, altered behavior (often accompanied by agitation), reduced consciousness, motor disruption (from dyskinesia to catatonia), seizures, and autonomic dysfunction are typical clinical characteristics. In recent years, the incidence of autoimmune encephalitis diagnoses has markedly risen among adults, children, and adolescents. This fact is unequivocally connected to the dynamic evolution of novel diagnostic techniques and the advancement of medical knowledge. A specific variant of this illness is anti-NMDA receptor encephalitis. Psychiatrists frequently serve as the initial specialists to treat patients with this diagnosis, owing to the manifestation of psychiatric symptoms associated with the condition. The differential diagnosis is quite challenging and predominantly relies on the patient’s history and the manifestation of characteristic clinical signs. Given its high prevalence, anti-NMDA receptor encephalitis should be included in the differential diagnosis in routine psychiatric treatment. We provide an overview of the research on the condition, covering its prognosis, management, epidemiology, differential diagnosis, and clinical presentation. Full article

In animal models, ketamine, a non-competitive N-methyl-D-aspartate (NMDA) antagonist, induces schizophrenia-like symptoms, such as positive and negative symptoms, as well as cognitive deficits. In the present study, we evaluated the behavioral responses and the number of EODs (electric organ discharges) of the weakly electric fish Gnathonemus petersii using the novel object recognition task (NORT). We aimed to investigate whether pharmacological modulation of the glutamatergic system would impair cognitive functions by administering the NMDA receptor antagonist ketamine, and whether these impairments could be suppressed by the administration of typical (first-generation) and atypical (second-generation) antipsychotics—clozapine and haloperidol, respectively. G. petersii preferred the familiar object over the novel object in the NORT paradigm. Although no significant differences were observed when exploring the two identical objects during the training session, the fish spent less time, moved a shorter distance, and emitted fewer EODs in the testing phase with the novel object. No direct relationship was detected between the EODs and behavioral responses to the administration of ketamine and typical antipsychotics. Ketamine administered with atypical antipsychotic clozapine disrupted the perception of the original object, where one of the objects was preferred. In the novel object trial, the time spent on the original and new objects was attenuated to the same level. Full article

For a long time, D-amino acids remained unexplored in mammalian physiology. The technological advances in enantioseparation over the past 50 years have revealed that D-amino acids not only exist in human tissues and fluids but also play important roles in neurotransmission, immune regulation, and cellular proliferation. The present review provides a comprehensive assessment of the role of D-amino acids in cancer, including their endogenous and exogenous production pathways, along with the analytical methodologies used for detection and quantification, from liquid chromatography to biosensors. These methods have underlined how altered levels of D-amino acids can be helpful in early detection, progression, or response to treatment in several malignancies, including gastric, hepatic, colorectal, or breast cancer. The present review also explores how manipulation of D-amino acids can regulate cell proliferation, their mechanisms in cancer regulation, including the modulation of N-methyl-D-aspartate (NMDA) receptors and the production of hydrogen sulphide (H₂S), and the role of specific D-amino acids in cancer onset, immune defence, and protection against chemotherapy-induced toxicity. Finally, several underexplored research directions are outlined, such as potential correlations with gut microbiota composition, the impact of processed food consumption, and the integration of multiomics strategies. Full article

Schizophrenia is a complex neuropsychiatric disorder composed of primary cluster-positive symptoms, negative symptoms, disorganization, neurocognitive deficits, and social cognitive impairments. While traditional antipsychotics primarily target dopamine pathways, they provide limited efficacy against cognitive deficits and negative symptoms. Growing evidence implicates glutamatergic dysregulation, particularly N-methyl-D-aspartate receptor (NMDA-R) hypofunction, in the pathophysiology of schizophrenia, making glutamate modulation a promising therapeutic approach. This review explores emerging glutamate-based treatment strategies, including NMDA receptor modulators, metabotropic glutamate receptor (mGluR) agents, glutamate transporter regulators, and kynurenine pathway inhibitors. We summarize preclinical and clinical findings on NMDA co-agonists (D-serine and glycine), glycine transporter inhibitors, D-amino acid oxidase inhibitors, and mGluR-targeted therapies, highlighting their mechanisms, efficacy, and limitations. In addition, we discuss novel interventions aimed at restoring glutamate homeostasis, including neuroinflammatory modulation and synaptic plasticity enhancers. Despite promising results, many glutamate-targeting therapies have yielded inconsistent clinical outcomes, underscoring the need for biomarker-driven patient selection and optimized treatment protocols. We propose that integrating glutamate modulators with existing antipsychotic regimens may enhance therapeutic response while minimizing side effects. Future research should focus on refining glutamate-based interventions, identifying predictive biomarkers, and addressing the heterogeneity in schizophrenia pathology. With continued advancements, glutamate modulation has the potential to transform schizophrenia treatment, particularly for cognitive and negative symptoms that remain largely unaddressed by current therapies. Full article

Metabotropic glutamate receptor 5 (mGlu₅) plays a fundamental role in synaptic plasticity, potentially serving as a therapeutic target for various neurodevelopmental and psychiatric disorders. Previously, we have shown that mGlu₅ can also signal from intracellular membranes in the cortex, hippocampus, and striatum. Using cytoplasmic Ca²⁺ indicators, we showed that activated cell surface mGlu₅ induced a transient Ca²⁺ increase, whereas the activation of intracellular mGlu₅ mediated a sustained Ca²⁺ elevation in striatal neurons. Here, we used the newly designed ER-targeted Ca²⁺ sensor, ER-GCaMP6-150, as a robust, specific approach to directly monitor mGlu₅-mediated changes in ER Ca²⁺ itself. Using this sensor, we found that the activation of cell surface mGlu₅ led to small declines in ER Ca²⁺, whereas the activation of ER-localized mGlu₅ resulted in rapid, more pronounced changes. The latter could be blocked by the Gq inhibitor FR9000359, the PLC inhibitor U73122, as well as IP₃ and ryanodine receptor blockers. These data demonstrate that like cell surface and nuclear mGlu₅, ER-localized receptors play a pivotal role in generating and shaping intracellular Ca²⁺ signals. Full article

Background: Terahertz (THz) waves, lying between millimeter waves and infrared light, may interact with biomolecules due to their unique energy characteristics. However, whether THz waves are neurally regulated remains controversial, and the underlying mechanism is elusive. Methods: Mouse brain slices were exposed to 1.94 THz waves for 1 h. Synaptic plasticity was evaluated via transmission electron microscopy (TEM), long-term potentiation (LTP), and neuronal class III β-tubulin (Tuj1) and synaptophysin (SYN) expression. Immunofluorescence (IF) and electrophysiology were used to identify neurons sensitive to THz waves. The calcium activity of excitatory neurons, glutamate receptor currents, and glutamate neuron marker expression was also assessed using calcium imaging, a patch clamp, and Western blotting (WB). Optogenetics and chemogenetics were used to determine the role of excitatory neurons in synaptic plasticity impairment after THz wave exposure. NMDA receptor 2B (GluN2B) was overexpressed in the ventral hippocampal CA1 (vCA1) by a lentivirus to clarify the role of GluN2B in THz wave-induced synaptic plasticity impairment. Results: Exposure to 1.94 THz waves increased postsynaptic density (PSD) thickness and reduced the field excitatory postsynaptic potential (fEPSP) slope and Tuj1 and SYN expression. THz waves diminished vCA1 glutamatergic neuron activity and excitability, neural electrical activity, and glutamate transporter function. THz waves reduced N-methyl-D-aspartate receptor (NMDAR) current amplitudes and NMDAR subunit expression. Activating vCA1 glutamatergic neurons through optogenetics and chemogenetics mitigated THz wave-induced synaptic plasticity impairment. GluN2B subunit overexpression improved synaptic plasticity marker expression, synaptic ultrastructure, and the fEPSP slope. Conclusions: Exposure to 1.94 THz waves decreased synaptic plasticity, glutamatergic neuron excitability, and glutamatergic synaptic transmission in the vCA1. Glutamatergic neuron activation and GluN2B overexpression alleviated THz wave-induced synaptic plasticity impairment; thus, neuromodulation could be a promising therapeutic strategy to mitigate the adverse effects of THz radiation. Full article

Background/Objectives: Remifentanil-based anesthesia is linked to opioid-induced hyperalgesia (OIH), increasing postoperative pain and analgesic requirements. Magnesium, an N-methyl-D-aspartate (NMDA) receptor antagonist, might alleviate OIH. We aimed to assess whether intravenous magnesium reduces postoperative pain, analgesic requirements, and hyperalgesia in adults receiving remifentanil-based anesthesia. Methods: We searched PubMed, Embase, the Cochrane Library, and Web of Science (1 December 2024) for randomized controlled trials (RCTs) comparing intravenous magnesium vs. placebo. Risk of bias was evaluated with the Cochrane RoB 2 tool, and random-effects meta-analyses were conducted. GRADE was used to assess evidence quality. Primary outcomes were postoperative analgesic requirements and pain scores; secondary outcomes included intraoperative remifentanil consumption, shivering, postoperative nausea/vomiting (PONV), extubation time, hypotension, and bradycardia. PROSPERO registration: CRD42024609911. Results: Twenty-two RCTs (n = 1362) met eligibility. Magnesium significantly decreased 24 h analgesic requirements (standardized mean difference [SMD] −1.51; 95% confidence interval [CI] −2.15 to −0.87; p < 0.0001) and pain scores (SMD −0.61; 95% CI −0.90 to −0.32; p < 0.0001), with benefits persisting up to 48 h. It also reduced intraoperative remifentanil use (SMD −0.52), shivering (odds ratio [OR] 0.25), and PONV (OR 0.66), without prolonging extubation or increasing hypotension/bradycardia risk. High heterogeneity, potential publication bias, and moderate-to-very-low evidence certainty warrant caution. Conclusions: Intravenous magnesium appears beneficial in remifentanil-based anesthesia, but further large-scale, methodologically robust trials are needed to confirm optimal and clarify safety profiles across diverse surgical populations. Full article