Search Results (170)

A naive Bayesian classifier (NBC) combined with principal component analysis (PCA) effectively differentiates the dose-dependent effects of certain groups of psychoactive drugs based on their impact on the amplitude–spectral characteristics of electrocorticograms (ECoG) in rats. This approach has been shown to be useful for pharmacological screening of agents with unknown or poorly understood activity. Despite previously obtained optimistic results, classification determination for some drugs was inaccurate, necessitating the search for possible ways to improve the predictive effectiveness of the proposed algorithm. One possible approach would be to use as input quantitative data not only the impact of the psychoactive drugs studied on the amplitude–spectral characteristics of ECoG but also connectivity changes, including the average coherence power of different pairs of leads. The aim of this study was to compare the accuracy of NBC in classifying the pharmacological mechanism of action of agents with well-known mechanisms (test set) using pharmaco-EEG data on changes in the amplitude–spectral characteristics of ECoG, coherence, and the combined use of two data sets. Materials and methods. Experiments were performed on Wistar rats with chronically implanted ECoG electrodes. The training set, relative to which the effects of the pharmacological agents from the test set were classified, were the matrices of effects of 12 pharmacological agents: the NMDA antagonist dizocilpine, the D2/D3 antagonists haloperidol and sulpiride, the M-anticholinergic tropicamide, the H1/5HT2A receptor blocker hydroxyzine, the acetylcholinesterase inhibitor galantamine, the alpha-2 adrenergic agonist dexmedetomidine, the alpha-2 adrenergic antagonist atipamezole, the adenosine receptor blocker caffeine and the GABA-mimetics aminophenylbutyric acid (phenibut), bromdihydrochlorophenylbenzodiazepine (phenazepam) and 5-ethyl-5-phenyl-2,4,6(1H,3H,5H)-pyrimidinetrione. The test set included various drugs with tropism for the targets of the training set drugs: dopamine receptor antagonists chlorpromazine, droperidol, tiapride and raclopride, H1-histamine blockers diphenhydramine and promethazine, 5-HT2-receptor blockers ritanserin and glemenserin, acetylcholinesterase inhibitor ipidacrine, alpha2-adrenergic receptor antagonist yohimbine, alpha2-adrenergic agonists medetomidine and xylazine, GABA-mimetics 5-ethyl-5-(1-methylbutyl)-2,4,6(1H,3H,5H)-pyrimidinetrione and chloral hydrate. The analysis of the ECoG signal included the calculation of 132 amplitude–spectral characteristics and 75 coherence indicators, which, using the PCA, led to new integrative indicators used for further classification of the NBC. Results and discussion. For each drug in the test set, the median similarity probability with a particular group from the training set was calculated, which was used to assess the classification quality. It was found that, when using the amplitude–spectral characteristics of ECoG, the proposed methodological approach allows for the identification of the ECoG effects of several groups of psychoactive drugs, including D2/D3-dopamine, M-cholinergic, H1-histamine, and 5-HT2-serotonin receptor blockers, AChE inhibitors, GABA-mimetics, and alpha-2-adrenergic receptor agonists and antagonists. This approach enabled the correct classification of 18 of 24 groups in the test set. When using changes in coherence indices as the initial data, the classification accuracy also amounted to 18 of 24 groups. When combining the two data sets, the number of correctly identified NBC groups was 20 of 24 groups. When comparing the classification during training (confusion matrix), it was found that coherence data or adding coherence data to the data based on changes in amplitude–spectral characteristics leads to a statistically significant (p < 0.01 in both cases) increase in accuracy. Conclusions. The obtained data demonstrated high accuracy in classifying the pharmacological activity of the test sample drugs using any of the three compared approaches. Despite the lack of statistically significant differences between them, classification based on the combined dataset demonstrated a higher number of “correct” similarities. This allows us to recommend the approach based on combined data of drug effects on amplitude–spectral characteristics and coherence as the most promising for further studies using pharmaco-EEG screening. Full article

Cantharidin (CANT) and sodium fluoride inhibit serine/threonine phosphatase (PP) 1 and PP2A in the heart. We hypothesized that Cant and sodium fluoride could weaken the reduction in force by carbachol in the presence of serotonin in human right atrial preparations (HAP). We measured contractility in HAP, and for comparison, in left atria from wild type mice (CD1, WT), mice with human 5-HT₄-serotonin receptor cardiac overexpression (5-HT₄-TG), or in mice with human H₂-histamine receptor cardiac overexpression (H₂-TG). Isoprenaline (1 µM), histamine (1 µM), and serotonin (1 µM) raised contraction in HAP. Likewise, isoprenaline (1 µM), histamine (1 µM), and serotonin (1 µM) raised contractility in the left atria of WT, H₂-TG, and 5-HT₄-TG. Carbachol (1 µM), a muscarinic cholinoceptor agonist, diminished the force of contraction in a time-dependent manner after prior stimulation of force by serotonin, isoprenaline, or histamine in HAP but also in left atria from 5-HT₄-TG, WT, and H₂-TG. These anti-β-adrenergic, anti-serotoninergic and anti-histaminergic effects of carbachol on force of contraction were attenuated by 100 µM or 30 µM cantharidin or 3 mM sodium fluoride in HAP and in left atrial preparations from WT, H₂-TG, and 5-HT₄-TG, respectively. We conclude that muscarinic cholinoceptor activation may exert a negative inotropic effect in the HAP by stimulating PP1 and/or PP2A, which had previously been inhibited by isoprenaline or histamine or serotonin. Full article

Background/Objectives: The study sought to investigate the neurotoxicity of NBOHs, which are a class of new psychoactive substances (NPSs) that act as agonists of serotonin 5-HT2A and 5-HT2C receptors, resulting in hallucinogenic effects similar to those of LSD, often found in paper blotters. Methods: Differentiated SH-SY5Y cells were incubated for 24 h with 0.5, 1.0, 3.5, 5 and 10 nM of the derivatives 25I-NBOH, 25E-NBOH and 25B-NBOH. Cell viability was assessed by MTT reduction and neutral red uptake assays. Mitochondrial membrane potential and production of free radicals were also evaluated. In addition, Drosophila melanogaster flies were exposed to 5, 10 and 50 nM of each NBOH derivative for 4 h. Negative geotaxis, CAT, and AChE enzymatic activities were evaluated. Results: Both 25E-NBOH and 25B-NBOH decreased cell viability. Furthermore, mitochondrial hyperpolarization of cells and an increase in oxidative species were observed in response to higher concentrations of 25E-NBOH and 25B-NBOH. In D. melanogaster, 25B-NBOH increased climbing time and both 25E-NBOH and 25B-NBOH increased CAT and AChE activities at 50 nM. Conclusions: These findings indicate greater toxicity of the 25E- and 25B-NBOH compared to 25I-NBOH, suggesting metabolic activity or mitochondrial signaling, oxidative stress, and cholinergic dysregulation as a potential mechanism related to NBOH neurotoxicity. Full article

Recent evidence reveals that several psychotropic compounds exert significant biological effects on the skin through neurochemical and immunomodulatory pathways. Cannabinoids such as tetrahydrocannabinol (THC) show potent anti-inflammatory, antipruritic, and anti-aging properties when applied topically, and may hold therapeutic potential. Antidepressants, particularly fluoxetine (Prozac), have been shown to regulate the expression of pro-inflammatory cytokines in keratinocytes, suggesting benefits applied in allergic pathologies. Additionally, fluoxetine promotes wound healing and cell regeneration, indicating broader dermatological applications. Psychedelics, acting as serotonin receptor agonists (5-HTR), may influence cellular aging and immune modulation via the serotonergic system. Studies report that 5-HT receptor agonists can prevent UV-induced photocarcinogenesis, while psilocybin has been observed to reduce aging markers in human fibroblasts. Furthermore, recent data suggests that psilocin may alleviate acute itch involving the kynurenine pathway. These findings highlight the emerging relevance of psychoactive compounds in cutaneous biology, bridging neuropharmacology and dermatology toward novel therapeutic strategies. Full article

Glucagon-like peptide-1 (GLP-1) and dual GIP/GLP-1 receptor agonists, originally introduced for the management of type 2 diabetes mellitus and obesity, are increasingly recognized for their broader actions within the central nervous system, with emerging implications in neuropsychiatry and neurodegeneration. This review integrates current preclinical and clinical evidence, emphasizing their pharmacodynamic profile, central receptor distribution, and the molecular pathways linking metabolic signaling to neural function. Evidence suggests that GLP-1 receptor activation across key brain regions involved in energy balance and reward modulates multiple neurotransmitter systems, including dopamine and serotonin, as well as glutamatergic and GABAergic transmission, thereby influencing behavior, affective processes, and cognitive function. In parallel, these agents exhibit neuroprotective properties through improved neuronal insulin sensitivity, attenuation of neuroinflammatory pathways, and support of neuroplasticity, alongside effects on limiting pathological protein aggregation. Dual GIP/GLP-1 agonism may further potentiate these central actions through complementary metabolic and synaptic mechanisms. Although pharmacovigilance data have identified isolated neuropsychiatric adverse events, current clinical evidence does not support a consistent causal association. Collectively, incretin-based therapies represent a promising translational approach at the interface of metabolic and neuropsychiatric disorders, warranting further investigation into their long-term central safety, therapeutic efficacy, and clinical relevance. Full article

Obsessive-compulsive disorder (OCD) is a chronic mental disorder characterized by distressing thoughts and repetitive behaviors that significantly impair daily functioning and quality of life. Many patients fail to achieve sufficient symptom relief with first-line treatments, such as cognitive-behavioral therapy (CBT) or selective serotonin reuptake inhibitors (SSRIs). Dopaminergic dysregulation has been implicated in the pathophysiology of OCD, providing a rationale for pharmacological augmentation strategies. This article presents a narrative review of the evidence regarding the efficacy, safety, and clinical applicability of antipsychotic agents and emerging pharmacological augmentation approaches, including extended-release methylphenidate (MPH-ER), in SSRI-resistant OCD. A literature search was conducted using PubMed, EBSCO, and Embase databases, with an additional search of Google Scholar, focusing on studies examining pharmacological augmentation in treatment-resistant OCD. Overall, the evidence base is limited by small sample sizes, short follow-up durations, heterogeneous response criteria, and a lack of head-to-head comparisons versus CBT augmentation, which constrains the generalizability of conclusions. Dopamine receptor antagonists, particularly risperidone, as well as the partial agonist aripiprazole, remain the most consistently supported augmentation strategies, while olanzapine and quetiapine may be considered in selected cases. Evidence for MPH-ER is currently limited—supported by one small RCT and two recent case series—and may be considered in carefully selected adults with comorbid ADHD or marked executive dysfunction, although larger controlled studies and long-term safety data are required before firm clinical recommendations can be made. Full article

In recent years, psychopharmacology has experienced a significant challenge, highlighting a renewed and strong scientific interest in psychedelics as breakthrough therapies for mental disorders. Psychedelics can influence cognitive and emotional processes, showing solid therapeutic potential, particularly in treatment-resistant psychiatric disorders. Amongst the most promising compounds, ayahuasca and its main psychoactive component, N,N-dimethyltryptamine (DMT), have received considerable attention. Ayahuasca is a psychoactive brew traditionally prepared from the liana Banisteriopsis caapi and the leaves of Psychotria viridis. Its psychoactive properties derive mainly from DMT, while β-carbolines, which act as monoamine oxidase-A (MAO-A) inhibitors, prevent the metabolic degradation of DMT, enhancing its bioavailability and allowing oral administration. In contrast, in monotherapy, DMT or its analog 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is generally administered via alternative routes, like inhalation, intranasal, or intravenous delivery. DMT is primarily a serotonin (5-HT)2A receptor partial agonist, whereas 5-MeO-DMT has a higher affinity for the 5-HT1A receptor compared to 5-HT2A, though other receptor targets are engaged, fostering neuroplasticity and a reorganization of brain networks involved in perception, cognition, and mood regulation. Despite limited clinical trials, current evidence offers an optimistic outlook on DMT and 5-MeO-DMT efficacy for treatment-resistant depression (TRD) and major depressive disorder (MDD), whereas evidence for other mental disorders studies is still preliminary. There are four phase II studies with 5-MeO-DMT and one with DMT for TRD, while there are two phase II studies with DMT fumarate for MDD. Beyond their therapeutic potential, psychedelics also represent powerful tools for exploring the human mind, offering valuable insights into brain function and mental health. Full article

The neuropharmacology of psychedelics has traditionally focused on serotonergic mechanisms, particularly 5-HT2A receptor activation. However, this paradigm incompletely explains the diversity of neurobiological and therapeutic effects observed across psychedelic compounds. Non-classical psychedelics such as salvinorin A, the primary active constituent of Salvia divinorum, challenge this framework through direct kappa opioid receptor (KOR) agonism, representing a serotonin-independent pathway to altered consciousness. This review systematically examines the role of the endogenous opioid system in mediating psychedelic effects, with emphasis on salvinorin A’s unique KOR-dependent mechanisms. We synthesized preclinical and clinical evidence from in vitro studies, genetically modified animal models, optogenetic circuit dissection, and human neuroimaging trials. Salvinorin A’s selective KOR activation is characterized by pronounced β-arrestin-biased signaling, distinguishing it from endogenous dynorphins and classical KOR agonists. This produces rapid receptor desensitization, transient functional plasticity, and profound dissociative effects mediated through thalamocortical disruption, mesolimbic dopaminergic suppression, and fragmentation of large-scale brain networks. Classical serotonergic psychedelics indirectly engage opioid systems through downstream 5-HT2A signaling, contributing to analgesic and mood-regulatory effects via secondary MOR/DOR modulation. Despite being a potent opioid agonist, salvinorin A exhibits low abuse potential due to aversive phenomenology, dopaminergic suppression, and absence of positive reinforcement in animal models. Incorporating opioid receptor pharmacology into psychedelic neuroscience expands mechanistic understanding beyond serotonin-centric models, revealing multiple neurochemical pathways capable of inducing therapeutically relevant altered states. This framework enables rational development of biased KOR ligands and establishes salvinorin A as a paradigmatic model for non-serotonergic psychedelia with applications in treatment-resistant depression, addiction, and chronic pain. Full article

Background/Objectives: Fluvoxamine (FLU) is a selective serotonin reuptake inhibitor and one of the most potent agonists of the sigma-1 receptor. Emerging evidence shows that FLU exerts protective effects in multiple organs, making it a promising candidate for topical ocular therapy. Developing an FLU eyedrop for glaucoma can address a significant treatment gap with potentially fewer side effects compared with conventional therapies. To optimise formulation development, precise quantification of FLU in ocular compartments such as aqueous humour, as well as systemic circulation, is essential to characterise drug absorption, ocular bioavailability, and safety. Methods: We developed and validated a UHPLC-MS method for FLU detection in aqueous humour and serum using simple sample preparation steps. Results: The 11-min-long reverse phase chromatography followed by SRM-based mass spectrometry detection provides a highly selective and sensitive FLU detection method. Our method was proved to be linear in the 0.0625–1.5 µg/mL range and was validated according to the EMA guidelines. Conclusions: The simplicity of sample preparation, the tolerable matrix effects, and the favourable detection parameters provide a robust tool for preclinical pharmacokinetic and pharmacodynamic studies of FLU’s ocular protective effects. Full article

Major depressive disorder is increasingly recognized as a metabolic–immune disorder in which chronic inflammation diverts tryptophan (Trp) metabolism toward the kynurenine pathway (KP), reducing serotonin synthesis and producing neurotoxic metabolites such as quinolinic acid (QA). Elevated kynurenine (KYN)/Trp ratios and an altered QA/kynurenic acid (KYNA) balance have been consistently reported in depressed individuals, implicating the KP as a key therapeutic target. Exercise provides a unique, translationally relevant intervention: unlike pharmacological agents acting directly on neurotransmission, contracting skeletal muscle acts as a “kynurenine sink” by inducing kynurenine aminotransferases that convert circulating KYN into neuroprotective KYNA, thereby reducing brain KYN uptake and mitigating excitotoxicity. Clinical studies and meta-analyses confirm that aerobic, resistance, and high-intensity training produce antidepressant effects comparable to pharmacotherapy, while also improving cognition, fatigue tolerance, and cardiometabolic function. Beyond KP remodeling, exercise-induced myokines (irisin, IL-6, BDNF, apelin, FGF21) and adipokines (adiponectin, leptin modulators) coordinate systemic anti-inflammatory and neurotrophic adaptations that enhance resilience and brain plasticity. Furthermore, pharmacological “exercise mimetics” and metabolic modulators, such as PPAR agonists, AMPK activators, NAD⁺ boosters, meldonium, trimetazidine, and adiponectin receptor agonists, may be promising adjuncts for patients with low exercise capacity or metabolic comorbidities. This review provides a novel concept, positioning exercise as a systemic antidepressant that breaks the kynurenine lock of depression. Through proper interpretation of skeletal muscle as an endocrine organ of resilience, we integrate molecular, clinical, and translational findings to show how exercise remodels Trp–KYN metabolism and inflammatory signaling and how pharmacological mimetics may extend these benefits. This perspective consolidates scattered mechanistic and clinical data and outlines a forward-looking therapeutic framework that links exercise and lifestyle, metabolism, and drug discovery. We highlight that re-consideration of our understanding of depression, as a whole-body disorder, should provide new opportunities for precision interventions. Full article

Background/Objectives: Thermoregulation is essential for survival, with the hypothalamic preoptic area integrating peripheral signals to maintain core body temperature. While fever enhances immune responses, excessive hyperthermia causes cellular damage. Previous work has shown that central glucagon-like peptide-1 (GLP-1) receptor antagonism intensifies lipopolysaccharide (LPS)-induced fever, suggesting a role for GLP-1 signaling in temperature regulation. However, the direct effects of GLP-1 receptor agonists on fever remained unexplored. This study investigated the effects of liraglutide (LIRA), a GLP-1 analog used to treat diabetes and obesity, on temperature regulation and fever in rats, with a focus on sex-dependent mechanisms. Methods: Male and female Wistar rats received lipopolysaccharide (LPS, i.p.) to induce fever, followed by LIRA treatment (0.3 mg/kg, i.p.) one hour later. Body temperature was monitored for up to six hours post-LPS injection. Results: LIRA reduced body temperature in both euthermic and febrile rats of both sexes. LPS increased PGE₂ concentration in both sexes, with males showing a twofold increase compared to females. LIRA treatment reduced PGE₂ levels in LPS-challenged males (62%, p < 0.01) but not in female rats. LPS elevated interleukin (IL)-6 levels in both sexes, while LIRA treatment decreased IL-6 only in females (45%, p < 0.05). In males, LPS reduced hypothalamic serotonin (5-HT) levels, and LIRA further decreased 5-HT in saline-treated animals. In females, LIRA increased 5-HT levels (84%, p < 0.01) in LPS-challenged animals. Additionally, LIRA exhibited sex-specific effects on hypothalamic JNK phosphorylation, increasing activation in LPS-treated males and reducing it in LPS-treated females. Conclusions: LIRA demonstrates antipyretic properties through distinct, sex-specific mechanisms. In males, temperature reduction correlates with decreased hypothalamic PGE₂, whereas in females, antipyretic effects are associated with reduced IL-6, decreased JNK phosphorylation, and increased 5-HT. These findings reveal sexually dimorphic GLP-1R-mediated thermoregulatory pathways during inflammation. However, the causal relationships between these molecular changes and temperature regulation require further investigation, particularly regarding whether observed biochemical alterations represent primary mechanisms or secondary consequences of temperature modulation. Future studies should investigate the functional significance of the apparent contradiction in serotonergic responses between sexes. Full article

Aggression among group-housed male laboratory mice poses significant challenges for animal welfare and scientific outcomes. Semiochemicals, such as mammalian appeasing pheromones, have shown potential in modulating social behaviors in various species. This study aimed to evaluate the effects of a synthetic Common Trunk (CT) of mammalian appeasing pheromone on social behavior, aggression, and welfare indicators in adult male mice. Specific Pathogen Free (SPF) male RjOrl:SWISS mice (8–12 weeks old) were housed in open-top cages and exposed via environmental passive diffusion to either a 2% synthetic CT pheromone formulation or a placebo (excipient only). Behavioral tests included the Elevated Plus Maze (EPM) and the Resident–Intruder (RI) test. Clinical welfare assessments and hematobiochemical analyses were also performed. Behavioral testing revealed minimal differences between groups, except for—in animals exposed to the CT—significantly fewer unsupported rearings, both in number (p = 0.0284) and duration (p = 0.0184), suggesting reduced vigilance (EPM Test) and shorter upright posture durations (p = 0.0031), a behavior linked to social signaling during conflict (RI test). Welfare assessments and risk-based analyses indicated that mice exposed to the CT of the appeasing pheromone displayed more agonistic but less violent confrontations, with fewer visible lesions. The protective effect was most pronounced during early group housing of unfamiliar adult males, with significantly fewer injuries in treated mice during the first (p = 0.0215) and second week (p = 0.0329). Treated mice also showed higher serotonin levels (p = 0.0295), suggesting reduced aggressiveness in line with observed behavioral outcomes. Exposure to the CT appeared to improve social dynamics and reduce escalation of aggression in male mice, supporting its potential as a refinement tool in laboratory housing practices. Full article

Background: Burning Mouth Syndrome (BMS) is a nociplastic pain condition characterized by altered central nervous system pain processing, significantly impacting patient quality of life. Pharmacological management often involves amitriptyline (monotherapy) and aripiprazole (for refractory cases) in Japan. However, the therapeutic efficacy of these drugs in BMS frequently exhibits a non-sigmoid (U-shaped or bell-shaped) dose–response relationship, indicating a clinically effective dose that is often considerably lower than those used for their primary indications and challenging conventional pharmacological assumptions. Method: This paper synthesizes existing pharmacological knowledge to elucidate the mechanisms underlying the non-dose-dependent actions of amitriptyline and aripiprazole in BMS. It focuses on their specific interactions with key neurotransmitter systems and receptors, particularly N-methyl-D-aspartate (NMDA) receptors and dopamine D2 receptors, to explain the observed non-linear dose–response and the importance of identifying a personalized therapeutic window. Result: Amitriptyline demonstrates efficacy in BMS at low doses (e.g., 25 mg), primarily through its action as an NMDA receptor antagonist via calcium-dependent desensitization and open-channel block, addressing central sensitization. Its effects are distinct from its antidepressant actions, and the “serotonin paradox” highlights the complexity of serotonin’s role in pain. Aripiprazole, utilized for refractory BMS, acts as a dopamine D2 receptor partial agonist, leading to a non-linear dose–response where sustained therapeutic effect is observed at specific low doses (e.g., 1.7–1.8 mg/day). This non-linearity is attributed to partial agonism, alongside interactions with serotonin 5-HT1A and 5-HT2A receptors. The general non-dose-dependency for both drugs is further explained by phenomena such as multiple binding sites with differing affinities, receptor desensitization/downregulation, activation of counter-regulatory mechanisms, and hormesis. Discussion: The observed non-linear dose–response curves for amitriptyline and aripiprazole in BMS underscore the inadequacy of a “one-size-fits-all” treatment approach. This necessitates a shift towards personalized medicine, which considers individual patient factors including pharmacogenomics, comorbidities, age, organ function, and psychological/social profiles. The true “personalized therapeutic window” is a balance between achieving significant pain relief and minimizing adverse effects, emphasizing careful titration and patient-centered care. Conclusions: The pharmacological actions of amitriptyline and aripiprazole in BMS are not linearly dose-dependent, but rather exhibit a personalized therapeutic window driven by complex interactions with NMDA and D2 receptors and adaptive physiological responses. This intricate pharmacological landscape mandates a personalized medicine approach to optimize treatment outcomes, improve patient adherence, and enhance the quality of life for individuals suffering from this challenging nociplastic pain condition. Full article

Gepirone, a selective 5-hydroxytryptamine (serotonin) 1A (5-HT_1A) receptor agonist, offers a promising strategy for treating mood and anxiety disorders. The therapeutic importance of 5-HT_1A modulation is well established, as these receptors regulate serotonergic neurotransmission both presynaptically, in the somatodendritic regions of raphe neurons, and postsynaptically, in structures including the hippocampus, neocortex, septum, amygdala, and hypothalamus. Gepirone exhibits a distinctive pharmacological profile, acting as a full agonist at presynaptic autoreceptors and a partial agonist at postsynaptic receptors, with high affinity for 5-HT_1A and much lower affinity for 5-HT_2A receptors. Its effects on serotonergic signaling are time-dependent. Acute administration suppresses serotonergic firing through autoreceptor activation, while chronic treatment induces autoreceptor desensitization, leading to enhanced 5-HT release in projection areas. This process is complemented by partial agonism at postsynaptic 5-HT_1A receptors, which further supports long-term neuromodulation. This article provides an integrated overview of gepirone’s mechanism of action, bridging receptor pharmacology, neurophysiological adaptations, and therapeutic implications. Particular emphasis is placed on the compound’s unique dual role in regulating serotonergic tone over time, a feature that differentiates it from other 5-HT_1A-targeting agents. By linking molecular mechanisms to clinical outcomes, we highlight gepirone’s potential advantages in efficacy, safety, and tolerability compared with conventional antidepressants. This comprehensive perspective underscores gepirone as a paradigmatic example of selective 5-HT_1A modulation and offers novel insights into the development of targeted treatments for depression and anxiety. Full article

Depressive disorder is the most prevalent mental illness, and increasing evidence suggests its potential bidirectional relationship with metabolic disorders. Given the limited efficacy of conventional antidepressants (including Selective Serotonin Reuptake Inhibitors; SSRIs) and the growing prevalence of treatment-resistant depression, there is a significant need to identify alternative molecular pathways underlying the pathophysiology of depressive disorder, which may represent novel therapeutic targets for other agents. Emerging evidence indicates that metabolic dysfunction and depressive disorder share a common pathophysiological molecular mechanism and increase each other’s risk. Targeting peripheral metabolic pathways and their interactions with the central nervous system may alleviate depressive symptoms. Glucagon-Like Peptide-1 agonists (GLP-1 RAs) and Sodium–Glucose Cotransporter-2 (SGLT2) inhibitors, widely used in the treatment of type 2 diabetes and obesity, exhibit neurotrophic and anti-inflammatory effects, ameliorate oxidative stress, and enhance mitochondrial function, collectively contributing to the antidepressant-like effects observed in preclinical studies. Peroxisome Proliferator-Activated Receptor (PPAR) α agonists primarily regulate lipid and glucose metabolism, which may potentially improve neuronal plasticity and mood regulation. Moreover, agents such as Angiotensin Receptor Blockers (ARBs) and Angiotensin Receptor-Neprilysin Inhibitors (ARNIs), used in hypertension treatment, exert central anti-inflammatory and neuroprotective effects via the modulation of the renin–angiotensin–aldosterone system (RAAS), implicated in affective disorders. Nevertheless, long-term, head-to-head trials are required to establish their efficacy, safety, and therapeutic positioning within current treatment paradigms. The aim of this review is to summarize current evidence on metabolic modulators as potential antidepressant strategies, focusing on their molecular mechanisms, preclinical and clinical findings, and prospects for integration into future therapies for depression. Full article