Background/Objective Methamphetamine is a potent psychostimulant associated with severe neurotoxicity mediated by oxidative stress, neuroinflammation, metabolic dysfunction, and neuronal apoptosis. Vitamin D₃ has been reported to possess antioxidant and anti-inflammatory properties that may provide neuroprotective effects. This study evaluated the potential protective effects of vitamin D₃ against methamphetamine-induced neurotoxicity in rat brain tissue. Methods Twenty male Wistar rats were randomly divided into four groups (n = 5): control, methamphetamine-treated (10mg/kg), vitamin D₃-treated (0.1μg/kg), and methamphetamine plus vitamin D₃. Treatments were administered orally for 56 days. At the end of the experimental period, brain tissues were harvested for biochemical analyses, including oxidative stress markers, antioxidant defense parameters, neurotransmitter levels, metabolic enzymes, inflammatory markers, apoptotic indicators, and histopathological examination. Results Methamphetamine administration significantly increased oxidative stress markers and inflammatory mediators while reducing antioxidant defenses, neurotransmitter levels, and metabolic enzyme activities in brain homogenates. Caspase-3 activity was significantly elevated, indicating enhanced apoptotic signaling. Histopathological examination revealed vascular congestion and structural alterations in methamphetamine-treated animals. Co-administration of vitamin D₃ attenuated several of these biochemical alterations by reducing oxidative stress and inflammatory responses and improving antioxidant status and neurotransmitter levels, although some histological changes persisted. Conclusions Methamphetamine induces neurotoxicity through mechanisms involving oxidative stress, neuroinflammation, metabolic disruption, and apoptosis in brain tissue. Vitamin D₃ supplementation partially mitigates these adverse effects, suggesting its potential role as a neuroprotective agent against methamphetamine-induced neuronal damage.
Purpose We investigated the expression of inflammation-related lncRNAs—RMRP, CTC 487M23.5, FOXD3-AS1, and DGCR5—in children with autism. The aim was to explore their potential as biomarkers in autism. Materials and Methods Expression levels of lncRNAs were assessed in the peripheral blood of 30 autistic children and 41 controls using real-time PCR. Results Significant downregulation of RMRP, CTC 487M23.5, and FOXD3-AS1 was observed in the peripheral blood of autistic children compared to healthy controls. No significant modification in the levels of DGCR5 was detected. The areas under the ROC curve for RMRP, CTC 487M23.5, and FOXD3-AS1 were 0.64, 0.71, and 0.65, respectively. A significant correlation was found between age and the expression levels of RMRP and DGCR5 in autistic children, while the expression levels of CTC 487M23.5 correlated significantly with the age of healthy children. DGCR5 was associated with CTC 487M23.5 and FOXD3-AS1 in both autistic and healthy children, and a significant direct correlation was observed between CTC 487M23.5 and FOXD3-AS1 in the autistic group. Conclusion Dysregulation of these lncRNAs in the peripheral blood of autistic children may reflect systemic inflammation, a process also implicated in CNS pathology. However, direct evidence of CNS involvement requires further investigation in brain tissue or relevant models. Given the modest sample size and the neurobiological heterogeneity of autism, these results should be interpreted as hypothesis-generating. CTC‑487M23.5 and RMRP showed promising but preliminary discriminatory potential, warranting further validation in larger, independent cohorts before any clinical application can be considered.
Does resilience protect everyone equally? Tannous Haddad, Barel, and Tzischinsky (2026) answer with a striking finding: resilience buffers anxiety only among Arab citizens of Israel, not among Jewish participants. This discovery dismantles universal assumptions about resilience and demands a culturally grounded rethinking. We extend this pivotal insight to the Philippines, where Muslim Filipino and Indigenous Lumad communities endure a conflict landscape defined not only by violence but also by deep seated historical injustice, marginalization, and fractured state relations. Anchored in the socioecological model of resilience (Ungar, 2011), we argue that the original study’s distinction between anxiety as a “temporally diffused emotional state” and stress as an acute emergency response (Daviu et al., 2019) holds the key to understanding differential distress across ethnic lines. For marginalized minorities, anxiety is chronic, shaped by generations of exclusion and uncertainty. For majority populations, stress is acute, triggered by immediate threat. This distinction reframes war related mental health: interventions that treat anxiety as a universal condition risk failure where structural vulnerability goes unaddressed. We translate these findings into actionable policy grounded in the Philippine Mental Health Act (Republic Act No. 11036, 2018), calling for culturally congruent assessment, community embedded interventions codesigned with Imams, Datus, and traditional healers, and investment in local culture brokers who bridge trust gaps between communities and formal mental health systems. Resilience is not a trait to be built. It is a resource that communities already possess, waiting to be recognized and supported on their own cultural terms.
Type 2 diabetes mellitus (T2DM) is associated with an elevated risk of dementia, prompting interest into the concept of brain-specific insulin resistance. However, the brain's reliance on insulin-independent glucose transporters complicates attempts to measure in vivo brain insulin resistance using the definition of system-wide insulin resistance, which is based on glucose-insulin interactions. In this review, we explore three available biomarkers for evaluating in vivo brain-specific insulin resistance in humans: (1) correlating systemic insulin resistance with brain function, (2) examining functional brain changes after the administration of intranasal insulin, and (3) quantifying insulin signalling proteins in neuronally enriched blood-derived extracellular vesicles. Integrating evidence from these three approaches tentatively suggests for the first time that a comprehensive assessment of the brain's default mode network (DMN), combining these methodologies within a single study, may offer a useful biomarker to quantify in vivo brain-specific insulin resistance in humans. Correlating DMN responses to concentrations of pY-IRS-1 in blood-derived extracellular vesicles would corroborate evidence for a brain-specific biomarker and provide a scalable approach to detecting brain-specific insulin resistance in humans. This advancement would enable in vivo evaluations of insulin resistance in the central nervous system, akin to the precise measurements of systemic insulin resistance seen in T2DM. An established and clearly defined biomarker of in vivo brain insulin resistance in humans would permit further investigation into the links between diabetes and dementia, ultimately bolstering support for secondary dementia prevention by identifying those at higher risk for cognitive decline.
The Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium categorized individuals with psychosis into 3 biologically distinct Biotypes (B1, B2, B3) based on cognitive and EEG measures. Deficient verbal episodic memory (VEM, a contributor to Biotype determination), is strongly associated with poor clinical outcome. Hippocampal glutamatergic circuits support VEM. Furthermore, glutamatergic mechanisms, implicated in cognitive and psychotic symptoms, are proposed as novel treatment targets. We used MRS to measure hippocampus glutamate and N-acetyl-aspartate (NAA) concentrations (non-contributors to Biotype) in psychosis vs. healthy-controls (HC). We examined VEM vs. glutamate relationships across DSM-IV diagnoses and Biotypes. We compared fits of linear and quadratic regression models. Glutamate was non-significantly lower in B1, higher in B2, and similar in B3 vs. HC. NAA did not differ. Quadratic models with Biotype-based groups provided best fits using the adjusted R2 and AIC criteria. In B1, reduced glutamate tended to associate with deficient VEM, suggesting reduced excitatory glutamatergic signaling, which could be compensated by glutamate enhancing treatments, increasing production of synaptic glutamate or NMDAR mediated currents. In B2, higher glutamate and the accentuated inverted-U shaped VEM vs. glutamate relationship suggest high levels of dysregulated glutamatergic activity possibly related to deficient inhibitory GABAergic control. In B3, the independence of VEM and glutamate suggests that, in contrast to B1 and B2, B3 may be more sensitive to non-glutamatergic or GABAergic neurotransmitter system-targeted compounds to maintain healthy memory function. Because of the limited sample size, the interpretation of results is of a tentative nature. Results help explain the role of hippocampal glutamatergic neurotransmission in VEM deficits in psychotic disorders and motivate distinct treatment strategies for individuals with psychosis stratified by Biotype.
Socioeconomic (SES) and ethno-racial factors may tilt psychosis diagnoses for persons from different backgrounds. Clinical diagnoses depend on patient and informant reports and are suspected of being susceptible to unintended bias. Diagnoses using laboratory tests are thought to be objective. Social disadvantages, however, alter brain functions related to psychosis. Race and class bias in laboratory medical diagnostics is an area of concern. To probe these issues for psychosis diagnoses, we describe relationships of SES, race/ethnicity, and ancestral genetic background to 11 integrated laboratory bio-factors that are associated with DSM categories and distinguish B-SNIP Biotypes. A series of analyses evaluated relationships of social factors and ancestry-related genetic background to those bio-factors: (i) canonical correlation revealed that SES and race (a social construct) are strongly associated (r2=.305) with cognitive performance and measures of brain physiology (prominently ERP magnitudes); genetic background neither significantly added to nor altered the structure of those associations; (ii) regression models illustrated that cognitive performance, intrinsic brain activity, and ERP magnitudes are substantially to modestly predicted by SES/race/genetic background, with SES/race accounting for the most variance on cognitive performance (approximately 25 %); (iii) regardless of including SES/race in differential diagnosis models, group differences between psychosis Biotypes were largely (85 %) preserved on bio-factor scores. For DSM diagnoses, less than 11 % of psychosis group differences were preserved. These outcomes illustrate that social factors are associated with psychosis-related laboratory tests. Nevertheless, SES/race did not substantially modify differential diagnosis of psychosis Biotypes. Using laboratory tests for psychosis differential diagnosis may facilitate the usefulness of stratification approaches, aid investigations of psychosis neurobiology and environmental risk, and improve treatment selections and approaches for all persons suffering with idiopathic psychosis.
This editorial serves as an introduction to the Special Issue ''Biomarkers of Trans-Nosological Functional Domains'', offering an overview of its central themes and contributions.
Schizophrenia is a complex psychiatric disorder characterized by debilitating positive, negative, and cognitive symptoms, whose etiology is traditionally attributed to dopamine dysregulation. While dopamine receptor antagonists effectively alleviate positive symptoms, they fail to address the persistent cognitive and negative symptom domains of disease. Growing evidence supports a broader neurobiological framework in which cortical excitation-inhibition (E/I) imbalance acts as an upstream contributor to dopaminergic dysregulation in schizophrenia, with the neurotransmitters gamma-aminobutyric acid (GABA) and glutamate playing a critical role in this homeostasis. Herein, we summarize such evidence, including preclinical findings from animal models of schizophrenia that support the role of GABAergic dysfunction in disease pathophysiology and validate the GABAA receptor as a promising therapeutic target. We review the potential of subtype-selective GABAA receptor modulators to restore E/I balance and improve symptoms currently resistant to antidopaminergic agents. Key challenges and considerations for the future development of these therapeutics are also discussed, emphasizing the importance of targeting E/I imbalance to better understand and treat the network-level dysfunction underlying schizophrenia.
Objective: We examined the effect of delirium and catatonia on psychosis symptom presentation in trauma intensive care unit (TICU) patients without previous history of serious psychiatric illness. Design: Prospective observational cohort study at a single academic medical center TICU, enrolling adult patients with critical illness secondary to traumatic injury excluding patients with significant psychiatric history. ICU patients received once-daily DSM-5 delirium and catatonia evaluations, and Clinician-Related Dimensions of Psychosis Severity Scale (CRDPSS) assessment. Patients were grouped by delirium and/or catatonia diagnosis with Kruskal-Wallis and Pearson’s Chi-square testing of differences between groups in CRDPSS scores. Main Results: 74 patients were sorted into delirium and/or catatonia groups for the dimensions of psychosis analysis. Catatonia was common in this critically ill trauma population with 26 % prevalence. Patients with delirium and/or catatonia diagnoses had differing severities of psychosis symptoms from those with neither condition. CRDPSS total scores were significantly different between the groups (p = 0.011). Conclusions: Further investigation is needed to explore commonalities in the mechanisms underpinning ICU psychosis and to identify specific psychotic symptom manifestations suggestive of delirium versus catatonia.
Background Suicide among adolescents and young adults is an alarming public health issue globally. Though studies suggest the link between genetic factors and suicidal behavior, there is a paucity of studies of specific genetic variants in adolescents and young adults. Hence this study explored the genetic predictors for attempted suicide among adolescents and young adults, by studying the genetic basis of serotonin and dopamine synthesis, transport, and degradation machinery. Methods A Case-control association study was conducted comprising individuals with attempted suicide (cases n = 80), 13–29 years of age, belonging to Malayalam speaking Dravidian population, and attending a tertiary care center in South India. Age, sex, and ethnicity matched controls (n = 267) with no history of attempted suicide were also considered from the same ethnic population. Genotyping was performed for functionally critical SNP in serotonin receptor, Tryptophan hydroxylase, Tyrosine hydroxylase, and Catechol-o-methyl transferase. Statistical significance for allelic and genotypic comparisons and their odds ratios were computed. Results The Tyrosine Hydroxylase THrs2070762 and Tryptophan Hydroxylase TPH1rs211105 genetic variants showed a statistically significant association with attempted suicide phenotype. Conclusion The study suggests that the genetic variants in Tyrosine Hydroxylase and Tryptophan Hydroxylase are predictive of attempted suicide among adolescents and young adults. Understanding the genetic variations will help in identifying and managing high-risk individuals.
First-line treatments for major depressive disorder include medication and cognitive behavioral therapy. While effective, pharmacotherapy often takes time to start demonstrating efficacy in symptomatic improvement and may be accompanied by adverse effects, indicating an ongoing need for new therapeutic approaches. A recently emerging somatic antidepressant intervention is whole-body hyperthermia, in which subjects are temporarily exposed to heat and then allowed to cool down. Recent studies employing hyperthermia-based strategies appear to show mood improvements both immediately and several weeks after the conclusion of treatment. However, published studies are often limited by their sample sizes and by their selection criteria. In this article, we review the literature on this novel approach and propose ideas regarding the possible physiological basis of this novel intervention and how it may be used in the future as adjunctive therapy with the current standard of care.
The aim of this review is to analyze the potential of the inducible form of 70-kDa heat shock protein (i.e. HSP72) as a biomarker for neuropsychiatric diseases, focusing on both animal and clinical studies. We first discuss findings from animal studies where HSP72 has already revealed its reliability as a sensitive marker of neuronal vulnerability, especially research investigating NMDAR antagonists-induced neurotoxicity, cerebral ischemia, epilepsy, behavioral stress, and effects of psychoactive and/or addictive substances. Next, we summarized human studies providing evidence for the involvement of HSP72 in the pathology of neuropsychiatric disorders like major depression, bipolar disorder, schizophrenia, attention deficit hyperactivity disorder, autism spectrum disorder, and neurodegenerative disorders. Finally, we discuss potential future research approaches needed to further investigate and possibly validate HSP72 as a biomarker in clinical psychiatry.
This study aimed to investigate the associations between inflammatory cytokines and cognitive performance in individuals with depression compared to healthy controls, while accounting for variables, such as perceived fatigue, BMI, and age. Individuals diagnosed with depression (n = 23) and healthy controls (n = 31) were included in the study. A 15-minute sustained attention task (subtest of the Test Battery for Attention, version 2.3.1) was administered with concurrent electroencephalographic recordings to evaluate P300 amplitude and latency. Peripheral inflammation was assessed by measuring IL-6, IL-1β, and TNF-α levels. Perceived fatigue was assessed using the German version of the Fatigue Impact Scale. Generalized linear models (GLM) were used to evaluate the main aims of the study. Results indicated that depression was associated with reduced P300 amplitudes (p = 0.011), and age significantly affected P300 amplitude, with older participants showing reductions (p = 0.016). However, no significant effects of inflammatory markers on P300 components were found. While no group differences were observed in the total number of hits, both perceived fatigue (p = 0.033) and TNF-α (p = 0.007) significantly affected hit accuracy. A post-hoc mediation analysis explored that perceived fatigue mediates the relationship between depression and number of hits. These findings suggest that low-grade inflammation may not directly influence P300 components, though inflammation and fatigue appear linked to accuracy deficits. Finally, the impact of depression on the number of hits is primarily mediated by perceived fatigue, suggesting that fatigue is a crucial factor in how depression affects cognition.
Artificial intelligence approaches have tremendous potential to advance our understanding of biological and other processes contributing to mental illness risk. An important question is how such approaches can be tailored to support transdiagnostic investigations that are considered central for gaining deeper insight into etiological processes and psychopathology that may not align well with categorical illness delineations. Here, we present the so-called “knowledge graphs” that could be leveraged in analytic approaches to synthesize multimodal data of transdiagnostic relevance, identify important latent structures and biomarkers, and support the evaluation of existing transdiagnostic frameworks.
Alzheimer's disease (AD) is a heterogeneous neurodegenerative disease, with no standard biomarker(s) to detect or confirm its risk at an early stage. The prevalence of AD increases exponentially worldwide in people of ages over 65 and older. Current improvements have unveiled the disease's pathophysiology and clinical diagnostic tests, targeting the neurological changes (neurodegeneration, amyloid precursor protein metabolism and tangle pathology) with precise PET/MRI imaging and xMAP/SIMOA (Multiplex simultaneous detection/single molecule array) to identify and quantify β-amyloids (Aβ40, Aβ42), total tau (T-tau) and phosphorylated tau (P-tau) proteins in the brain and cerebrospinal fluid (CSF) of patients. However, their utility for diagnosis in routine clinical practice is still challenging because of cost, accessibility, standardization, procedural limitation, and regulatory approval. Further research is needed to establish affordable, patient-friendly, easy, quick, and robust biomarkers for early AD detection, progression, and therapeutic management. Research on blood-based preclinical diagnosis and clinical practice for AD has advanced significantly in the last decade. Emerging literature supports the importance of new molecular biomarkers and signature genes from blood to detect and predict AD in advance. This review examines the potential applications of these blood-based target biomarkers for early disease detection, co-morbid condition risk prediction, and treatment management of AD.
This study aimed to assess the naturally occurring variation in plasma fatty acids in healthy subjects and Parkinson’s disease (PD) patients. Alpha-synuclein (aSyn) plays a major role in Parkinson’s disease. Inhibition of stearoyl-CoA desaturase (SCD) reduces levels of mono-unsaturated C16 and C18 fatty acids, which are involved in aSyn toxicity in vitro and in vivo. The ratio of mono-unsaturated to saturated fatty acids (fatty acid desaturase index (FA-DI)) in plasma after SCD-inhibition correlates with effects on brain FA-DI. However, the FA-DI normal values and the inter- and intra-day variation in PD-patients and healthy subjects is unknown. Ten PD-patients (54 –73 years) and ten age-matched healthy subjects were included. On three consecutive days, fatty acids fractions and concentrations were measured throughout the day. Outcomes are expressed as estimated mean, and the coefficient of variation (CV%) in percentage. For C16 FA-DI, the inter-subject CV% was 20.7 % in healthy subjects, and 37.7 % in PD-patients. The intra-subject CV% over days was 14.0 % in healthy subjects, and 14.2 % in PD-patients, and within days 5.1 % in healthy subjects, and 5.9 % in PD-patients. For C18 FA-DI, the inter-subject CV% was 14.8 % in healthy subjects, and 16.0 % in PD-patients. The intra-subject CV% over days was 11.0 % in healthy subjects, and 8.6 % in PD-patients, and within days 8.4 % in healthy subjects, and 6.7 % in PD-patients. The observed extent of variability in healthy subjects and PD-patients support C16 and C18 FA-DI as suitable biomarkers to demonstrate target engagement in plasma, of for example SCD-inhibitors, in both healthy subjects and PD-patients.
