Search Results (287)

Extensive epidemiological evidence links psychosis (PZ)—particularly schizophrenia (SCZ)—with disproportionate periodontal destruction, suggesting shared biological vulnerability. Beyond local tissue damage, periodontitis provides a clinically accessible translational paradigm for systemic redox dysregulation, where sustained inflammatory activation coincides with measurable oxidative injury and exhaustion of antioxidant (AO) defenses across cardiometabolic and neuropsychiatric domains. In this critical narrative review, we argue that the excess periodontal burden in PZ reflects a “pathological confluence” shaped by antipsychotic-associated iatrogenic factors, rapid metabolic deterioration, and chronic oxidative distress. We appraise the thioredoxin-interacting protein (TXNIP)–NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) axis as a metabolic–redox sensor linking dysglycemia to periodontal inflammasome activation and downstream cytokine signaling, and address the advanced glycation end-products (AGEs)–receptor for advanced glycation end-products (RAGE) axis as a key immunometabolic redox pathway. We further discuss mitochondrial dysfunction, impaired mitophagy, and mitochondrial deoxyribonucleic acid (mtDNA) leakage as damage-associated molecular patterns (DAMPs) that can amplify systemic “silent inflammation”. Integrating evidence on periodontal pathogen–host interactions and redox-sensitive neuroimmune pathways (including NADPH oxidase 4 (NOX4)-linked microglial activation), we propose periodontitis as a plausible upstream amplifier that may exacerbate vascular dysfunction and compromise blood–brain barrier (BBB) integrity. Finally, we outline clinically measurable biomarker readouts to operationalize redox-informed integrated care and highlight the need for pragmatic trials targeting clinically meaningful endpoints to improve somatic longevity in PZ-spectrum populations. We acknowledge that current human evidence is largely associative and that the proposed mechanistic links remain hypothesis generating. Full article

Tardive dyskinesia (TD) is a persistent hyperkinetic movement disorder associated with prolonged dopamine D2 receptor blockade, particularly during chronic haloperidol (HP) exposure. Emerging evidence suggests that TD-like pathology is sustained by an interconnected redox–mitochondrial–inflammatory network within striatal circuits; however, the regulatory architecture of this network remains incompletely defined. Hyperoside (HS), a flavonol glycoside with cytoprotective properties, has been implicated in cellular stress-response modulation, yet its role in antipsychotic-induced motor dysfunction remains unclear. In this study, a six-group mechanistic design was employed in which rats received HP (1 mg/kg, i.p., 21 days) to induce TD-like orofacial dyskinesia (OD), quantified by vacuous chewing movements (VCMs) and tongue protrusions (TPs). HS (30 mg/kg, i.p.) was administered alone or in combination with HP, with or without pharmacological inhibition of nuclear factor erythroid 2–related factor 2 (Nrf2) using ML385. HP exposure induced progressive dyskinetic behavior accompanied by oxidative and nitrosative stress, mitochondrial dysfunction, increased pro-inflammatory cytokines, and elevated caspase-3 activity in the striatum. HS significantly attenuated behavioral abnormalities while restoring redox balance, preserving mitochondrial enzyme activities, and reducing inflammatory and apoptotic signaling. Notably, Nrf2 inhibition intensified molecular pathology without proportionally worsening behavioral outcomes, indicating a dissociation between biochemical vulnerability and overt motor expression. Furthermore, ML385 markedly attenuated HS-mediated protection across multiple endpoints. Collectively, these findings support a potential protective role for Nrf2-related regulatory mechanisms in limiting network destabilization in TD-like pathology, while highlighting the importance of integrated stress-response pathways in modulating disease progression. Full article

Oxidative stress is intrinsically linked to mental disorders, involving an imbalance between reactive species and antioxidant defenses, where catalase is an essential, ubiquitous antioxidant enzyme. The pleiotropic effects of antipsychotic drugs, used for schizophrenia and mood disorders, are not fully elucidated at the molecular level. This study characterized the binding of a highly effective but potentially dangerous antipsychotic, clozapine (CLZ), to commercial bovine liver catalase (BLC). Using various spectroscopic methods under simulated physiological conditions, we found a moderate binding affinity of CLZ for BLC (K_a = 1.4 × 10⁻⁵ M⁻¹), subtly influencing the protein’s secondary and tertiary structures and slightly increasing its thermal stability. CLZ efficiently protected BLC against free-radical-induced oxidation and preserved its catalytic activity for decomposing toxic hydrogen peroxide. The effect of CLZ on BLC antioxidant activity was dual: no significant effect at lower, physiologically relevant concentrations, but significant inhibition at saturating, toxic drug concentrations. Molecular docking and molecular dynamics results indicated the presence of two specific binding sites within BLC monomers, one located near its active site. In conclusion, our in vitro results indicate that CLZ’s specific binding to BLC can be both beneficial and potentially harmful, and that this effect is dose-dependent. Full article

Background: Neurodegenerative diseases are a major health problem, and the neuropsychiatric symptoms seen in these diseases adversely impact the lives of patients, families, and caregivers. Inappropriate aggressive behavior is a highly disruptive symptom and a leading cause of institutionalization. There are no approved drugs specifically for the treatment of problematic aggression, and the off-label use of antipsychotics has limited benefit with significant side effects and safety risks. This review discusses dysregulated arginine vasopressin (AVP) signaling in fear–threat circuitry as a key driver of inappropriate aggression. Because the AVP 1a receptor (V1aR) is the dominant subtype in the CNS, the selective antagonism of this receptor represents a well-rationalized target for the treatment of aggression across neurodegenerative, psychiatric, and neurodevelopmental disorders. Objectives: Our goal was to summarize the basis for using V1aR antagonists as a treatment for irritability and aggressive behavior. We describe its discovery, biosynthesis, receptor pharmacology, and CNS distribution, emphasizing V1aR localization in central fear–threat circuits. Translational evidence from animal studies, pharmacological neuroimaging, and lesion network mapping is presented. These data support the suggestion that heightened vasopressinergic tone biases socioemotional information processing toward negative valence, increasing threat sensitivity and the likelihood of inappropriate aggressive responses. Emerging clinical data support this framework. Highly selective, CNS-penetrant V1aR antagonists reduced aggressive behavior and had an excellent safety profile in phase 2 studies in Huntington’s disease and intermittent explosive disorder, with efficacy signals across caregiver-reported, clinician-rated, and incident-based measures. Furthermore, pharmacological neuroimaging showed that V1aR antagonism normalizes AVP-induced alterations in activity within fear–threat circuitry. Conclusions and Future Directions: Preclinical, translational, and clinical findings to date support V1aR antagonism as a promising strategy for treating pathological aggression across disorders. Additional experimental medicine studies and clinical trials are needed to conclusively establish efficacy in various disease populations, and we note the need for improved trial designs and analytical methods as part of the development process. Full article

Background/Objectives: Schizophrenia is a severe psychiatric disorder frequently characterised by sleep and circadian disturbances, which are closely linked to cognitive dysfunction, symptom exacerbation, and poor functional outcomes. A growing body of evidence implicates the orexin (hypocretin) system—an essential regulator of arousal, sleep–wake stability, metabolic processes, and motivated behaviour—in the pathophysiology and treatment response of psychotic disorders. We aimed to investigate the relationships between the orexinergic system and psychoses. Methods: On 3 March 2026, we searched the PubMed, Scopus, PsycInfo/Articles and Cinahl databases for studies dealing with the orexin system and psychotic disorders and treatment response. Results: We found 20 eligible studies reporting variable and inconsistent alterations in orexin signalling in patients with schizophrenia. Studies were mostly cross-sectional and heterogeneous in design. Antipsychotic medications interfere with orexin-dependent pathways, potentially contributing to both therapeutic effects and adverse outcomes such as sleep disruption and metabolic dysregulation. Conclusions: While evidence from preclinical studies could point to an influence of dopaminergic activity through orexinergic mechanisms, with possible attenuation of antipsychotic-induced motor side effects and improvement of attentional deficits associated with NMDA receptor hypofunction, the utility of dual orexin receptor antagonists (DORAs) in psychoses is unclear. Despite the high prevalence of insomnia in schizophrenia, its pharmacological management remains suboptimal, with current treatments often limited by reduced efficacy or tolerability concerns. DORAs, which are currently approved medications for the treatment of insomnia, represent a novel and mechanistically distinct therapeutic option that may improve sleep while modulating arousal- and cognition-related circuits relevant to psychosis. Full article

Background: Schizophrenia is a heterogeneous disorder, and treatment-resistant schizophrenia (TRS) affects 20–30% of patients, yet objective biomarkers for its identification remain limited. Routine electroencephalography (EEG) offers a non-invasive window into cortical network dynamics, with previous studies reporting paroxysmal epileptiform activity and background slowing in a subset of patients. However, the biological significance of these findings—whether purely pathological or potentially compensatory—remains unclear. This study aimed to compare EEG abnormalities between TRS patients and those in clinical remission and to propose an integrative neurobiological interpretation. Methods: In a cross-sectional design, 89 patients with schizophrenia (39 TRS, 50 in remission) underwent routine EEG recordings using the international 10–20 system. TRS was defined according to TRRIP consensus criteria, requiring <20% symptom reduction after adequate antipsychotic trials. EEG analysis focused on the prevalence of interictal epileptiform discharges (IEDs) and the severity of background slowing, assessed on a 4-point ordinal scale. Results: IEDs were more than twice as prevalent in TRS patients compared to those in remission. Background slowing was significantly more severe in the TRS group, with the majority showing moderate-to-severe abnormalities versus predominantly normal-to-mild patterns in remission patients. Focal EEG abnormalities also followed this pattern. Multivariate analysis confirmed that both IEDs and background severity were independent predictors of TRS. Conclusions: EEG abnormalities, particularly IEDs and background slowing, are potential neurophysiological signatures associated with treatment resistance. We propose an integrative hypothesis suggesting that IEDs may originate as a failed compensatory mechanism—the brain’s attempt to restore network homeostasis. In chronic TRS these discharges become maladaptive, contributing to excitotoxicity and network dysfunction. This framework opens avenues for EEG-based stratification and novel therapeutic strategies targeting cortical excitability. Full article

Background: Schizophrenia spectrum disorders (SSD) affect females differently than males, yet there is limited research on Physical Activity (PA) levels and sex differences in patients with SSD. This study aimed at comparing PA levels between female and male SSD patients and controls. Methods: Altogether, 132 SSD residents and outpatients (48 females and 84 males) and 113 controls (46 females and 67 males) were assessed using standardised clinical tools. PA was monitored for seven consecutive days using a tri-axial ActiGraph GT9X accelerometer and quantified using the Euclidean Norm Minus One (ENMO) as an index of overall movement intensity. Descriptive and regression analyses were conducted. Results: Most patients were unemployed and overweight; males were less educated, less often divorced, smoking more, and using more antipsychotics than females (p < 0.05). Patients were less likely to be married, educated, employed, and had higher BMI and smoking rates than controls. Among patients, there were no significant sex differences in daily PA levels. In the control group, males showed slightly higher PA levels than females, although this difference did not reach statistical significance. Objective PA levels were not significantly associated with clinical outcomes in either female or male patients with SSD. Conclusions: Patients with SSD exhibited similarly low levels of objectively measured PA regardless of sex, suggesting a “flattening” phenomenon of sex differences in PA. These findings highlight the need for interventions aimed at promoting PA in individuals with SSD and support further research to identify factors influencing PA engagement across sexes. Full article

Glutamate metabotropic receptors (mGluRs) and their molecular partners at the postsynaptic density (PSD) represent a highly dynamic molecular hub that integrates multiple neurotransmitter signals and regulates synaptic plasticity and metaplasticity, which are putatively involved in the pathophysiology of psychiatric illnesses, including schizophrenia. Group I mGluRs (mGluR1 and mGluR5) interact with PSD adaptor and scaffolding proteins, such as Homer, Shank, Norbin, and PICK1, as well as intracellular downstream effectors, creating a molecular network that resembles a Lego-like structure, where modular protein interactions fine-tune glutamatergic transmission. Evidence from preclinical research indicates that dysregulation of mGluR expression and function, along with disrupted PSD protein expression, may contribute to the pathophysiology of schizophrenia by altering glutamatergic neurotransmission and synaptic stability. Antipsychotic mechanisms of action may involve, at least in part, the modulation of mGluR activity mediated through PSD proteins. Notably, novel agents that enhance spinogenesis by acting at the level of PSD proteins, such as SPG302, may open promising avenues for therapeutics aimed at restoring synaptic integrity. While Group I mGluRs dominate postsynaptic regulation, Group II (mGluR2/3) and III (mGluR4/6/7/8) receptors -primarily presynaptic- inhibit neurotransmitter release and plasticity, offering complementary therapeutic avenues. Emerging strategies, such as allosteric modulators of mGluRs, aim to rebalance synaptic signaling in treatment-resistant schizophrenia. This review synthesizes how PSD proteins and mGluRs interact in schizophrenia, exploring their potential as druggable targets for novel therapies. Full article

Background: Cancer progression is driven by coordinated dysregulation of intracellular transport, proteostasis, and extracellular matrix remodeling. Therapeutic strategies targeting a single pathway often fail due to tumor adaptability and resistance. Drug repurposing offers a promising approach to identify multi-target anticancer agents with established safety profiles. Pimozide, an FDA-approved antipsychotic drug, has recently emerged as a candidate with potential anticancer activity, although its molecular mechanisms remain incompletely understood. Objectives: This study aimed to investigate the anticancer effects of pimozide across breast, colorectal, and pancreatic cancer models, with a specific focus on its modulation of Ran GTPase signaling, Skp1–Cullin–F-box (SCF) ubiquitin ligase components, and matrix metalloproteinase-2–mediated extracellular matrix remodeling. Methods: Cell viability was assessed using MTT assays in MDA-MB-231, MCF-7, HT-29, and PanC-1 cell lines. Quantitative real-time polymerase chain reaction was employed to evaluate the expression of Ran, MMP2, Cullin1, Rbx1, SKP2, and FBXW10 following pimozide treatment. Molecular docking and MMGBSA analyses were performed to characterize binding interactions between pimozide and selected target proteins. Results: Pimozide induced concentration-dependent cytotoxicity in all tested cell lines with variable IC₅₀ values. Treatment resulted in consistent downregulation of Ran and MMP-2 across cancer types, alongside context-dependent modulation of SCF complex components. Notably, FBXW10 exhibited the strongest binding affinity to pimozide in silico, suggesting functional disruption of ubiquitin-mediated proteostasis. Conclusions: Pimozide exerts anticancer effects through coordinated disruption of nucleocytoplasmic transport, proteostasis regulation, and matrix remodeling. These findings support the repositioning of pimozide as a multi-target anticancer agent and provide a mechanistic foundation for further translational investigation. Full article

Background: Clozapine (CLZ) is an atypical antipsychotic mainly prescribed for treatment-resistant schizophrenia. Beyond psychotic symptoms, patients often exhibit persistent cognitive impairments across domains such as attention, learning, and memory. The mechanisms by which CLZ may influence cognition and provide neuroprotection are not fully elucidated. Accordingly, this study examined how CLZ modulates lipopolysaccharide (LPS)-induced neurotoxicity in rats. Method: Rats were administered LPS to induce cognitive impairment and subsequently treated with CLZ. Behavioral assessments were performed using maze tests (elevated plus-maze (EPM), novel object recognition (NOR), and Y-maze). Biochemical analyses included cholinergic function (acetylcholine (ACh)), neurodegeneration-associated enzymes (glycogen synthase kinase-3 beta (GSK-3β), β-site amyloid precursor protein cleaving enzyme-1 (BACE-1), and dipeptidyl peptidase-4 (DPP-4)), oxidative stress markers (lipid Peroxidation (LPO), catalase, and reduced glutathione (GSH)), and apoptotic proteins (B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), and cleaved Caspase-3 (c-Caspase-3)). Results: CLZ treatment markedly improved performance in EPM, NOR, and Y-maze tasks, indicating recovery of cognitive function in LPS-exposed rats. At the molecular level, CLZ enhanced ACh levels, upregulated the anti-apoptotic protein Bcl-2, and restored antioxidant defenses (catalase and GSH). Conversely, CLZ reduced LPS-induced neurotoxicity by lowering GSK-3β activity, LPO, and pro-apoptotic markers (Bax and c-Caspase-3). Conclusion: The findings demonstrate that CLZ exerts neuroprotective effects in an LPS-induced rat model, improving cognition through modulation of cholinergic transmission, oxidative stress, and apoptosis pathways. These results clarify key mechanistic pathways through which CLZ may exert cognitive benefits and highlight its potential relevance for improving schizophrenia-related cognitive dysfunction. Further molecular studies are warranted to confirm and extend these observations toward clinical translation. Full article

The metabolism of the four major substances—glucose, lipids, amino acids, and nucleotides—constitutes the most prominent metabolic phenotype of schizophrenia. The pathological axis shared by these substances involves energy pathway imbalances, redox stress, immune-inflammatory activation, and abnormalities in neurotransmitter synthesis/degradation. Existing research confirms that key metabolites within these pathways hold potential as biomarkers for diagnosis or progression monitoring. In recent years, electroconvulsive therapy (ECT) has been shown to improve psychotic symptoms while exerting broad regulatory effects on neurogenesis, immune homeostasis, and the hypothalamic–pituitary–target gland axis, though its precise mechanisms remain unclear. Recent studies indicate that ECT treatment can also regulate changes in brain and peripheral metabolism. We propose an integrated “metabolism-immunity-neuroendocrine” hypothesis to systematically elucidate how metabolic reprogramming during ECT treatment cascades sequentially to the immune, neural, and endocrine systems, thereby revealing the molecular basis of its antipsychotic effects. Furthermore, we conduct a comparative analysis of the effects of antipsychotic drugs on the same metabolic network and explore the universality and specificity of metabolic regulation in other physical therapies (such as rTMS, tDCS) and psychiatric disorders like depression and bipolar disorder. This research aims to provide novel biomarkers and intervention targets for the precision diagnosis and treatment of schizophrenia. Full article

Background/Objectives: Cariprazine (CAR), an atypical antipsychotic drug, exhibits potent anticancer activity; however, its mechanism of action remains unclear. Methods: We conducted a comparison of CAR-induced cell death mechanism in HeLa and HCT116 cancer cells and explored its potential role as a Qi-site inhibitor of cytochrome bc1 reductase (complex III). Results: CAR induced a dose-dependent cytotoxic effect and triggered apoptosis in both cell lines; however, the mitochondrial responses were distinctively different. HeLa cells exhibited significant mitochondrial membrane depolarization, significant cytochrome c release, a strong increase in the Bax/Bcl-2 ratio, elevated caspase-3 activation, and notable S phase arrest along with autophagy induction, indicating that mitochondria-driven apoptosis occurred rapidly. In contrast, HCT116 cells showed moderate mitochondrial dysfunction, moderate cytochrome c release, enhanced suppression of Akt signaling, and significant G0/G1 phase arrest, which are consistent with a slower and mixed apoptotic response. The findings from molecular docking studies predicted that CAR had stable binding at the Qi site and showed interactions at the Qi site that were comparable to those of antimycin A, thereby suggesting its possible inhibitory effect on complex III. Conclusions: The results from our study indicate the engagement of CAR-activated apoptotic pathways that are specific to different types of cancer cells, and hence suggest that CAR may act as a new anticancer drug by potentially directing its action towards the mitochondrial Qi-sites of complex III. Full article

Background: Aripiprazole is an atypical antipsychotic that acts as a partial agonist on the dopamine receptor D2 while also displaying agonistic activity on the 5-HT1A and antagonistic activity on the 5-HT2A receptors. As a partial agonist, aripiprazole stabilizes the activity of the D2 receptor, preventing overactivation. Case presentation: Within our deprescribing activity, we came across the case of a 30-year-old antipsychotic-naïve patient treated with the depot formulation of aripiprazole for bipolar disorder and acute mania, possibly developing hypersexuality due to an overdose that impacted negatively and heavily on his personal life. Results: The patient developed a peculiar subset of hypersexuality, changing his sexual orientation. Of interest, one month after discontinuing aripiprazole and switching to paliperidone, all the sexual-related symptoms and impulse control disorders resolved. Conclusions: We suggest stronger communication among the clinical teams involved in the patient’s care and screening patients for impulse control disorder prior to the administration of aripiprazole and monitoring them during treatment. Full article

Background/Objectives: Obsessive–compulsive disorder (OCD) is a chronic psychiatric illness with intrusive obsessions and compulsive behaviors severely impacting daily functioning and quality of life. The purpose of this narrative review is to present an updated summary of available evidence on third-generation antipsychotics (TGAs) as augmentation strategies for SRI-refractory OCD. Methods: The literature was reviewed using the PubMed database to recognize studies on the use of TGAs in treatment-resistant OCD. Only articles in the English language and on human participants were included. Results: We included nine reports in our review. More numerous (five reports) and higher evidence-level reports were retrieved for aripiprazole, which consistently shows high response rates compared to placebo and other antipsychotics. Two cohort studies were included on brexpiprazole, with no active or placebo comparator. These showed varying but high response rates. One cohort study reported a response rate of 61.5% to cariprazine. Only one paper reported on the efficacy of lumateperone in OCD. This was a single-case report on an adolescent patient with refractory OCD responding to lumateperone monotherapy. Conclusions: The current state of evidence supports the clinical utility of TGAs, particularly aripiprazole, in augmenting SRI treatment in patients with refractory OCD. Evidence regarding cariprazine and lumateperone is scarce, but still contributes to the discussion on the use of TGAs in OCD. Full article

Substance use disorder (SUD) is a chronic and clinically complex condition, frequently complicated by significant organic and psychiatric comorbidities. Most patients are polymedicated and require opioid substitution programs (OSPs). This complexity is further exacerbated by drug–drug interactions, therapeutic duplication, and fragmentation of the healthcare system. This retrospective observational study analyses the prevalence of polypharmacy and associated pharmacotherapeutic risks in a cohort of 1050 patients with SUD treated at Drug Care Units (DCUs) in Tenerife (Canary Islands, Spain). Prescriptions were dominated by methadone (62%), antidepressants, and antipsychotics, often in combination with benzodiazepines. Significant polypharmacy (>10 active prescriptions) was observed in 2.3% of patients, while 8.1% received 6–10 medications and 37.2% were using 2–5 medications. Women showed a higher pharmacological burden, with 3.5% experiencing significant polypharmacy (>10 different prescriptions) compared with 1.1% of men. Overall, 31% of patients received antidepressants, 31% were treated with antipsychotics—frequently with concurrent use of multiple agents—and 6.4% received opioids outside the OSP. Therapeutic duplication was observed in 15.6% of patients for psycholeptics, 14.2% for psychoanaleptics, and 3.2% for antiepileptics. Additionally, 25.2% of patients reported self-medication, predominantly with benzodiazepines. These findings underscore the need for integrated pharmaceutical care programs incorporating individualized therapeutic review and deprescribing strategies to enhance the safety and efficacy of SUD treatment. Full article