Epilepsy and psychosis are dysfunctions of the nervous system that may occasionally co-occur. The current study was designed to investigate the causes of psychosis with or without epilepsy in Pakistani families. We identified two consanguineous families in which all affected members had treatment-resistant psychosis while three patients also had epilepsy. Every participant was examined by psychiatrists and a psychologist, while epilepsy was diagnosed by neurologists. The doctors confirmed the presence of severe psychosis with or without epilepsy in the patients and their absence in other participants. Exome sequencing identified a biallelic variant c.570G > T; p.Trp190Cys in CLN8 that segregated with the phenotype of epilepsy with psychosis in one family whereas the results for the other family were negative. CLN8 variant affects an amino acid which is conserved in diverse vertebrate orthologues. In-silico analysis indicated that substitution of tryptophan with cysteine resulted in the loss of an intramolecular interaction, which may affect protein folding. This study emphasizes that CLN8-related phenotype can include severe treatment-resistant psychosis and also provides a genotypic extension.
Electroconvulsive therapy (ECT) is a highly effective intervention for treatment-resistant catatonia and severe neuropsychiatric disorders. We present the case of a 67-year-old patient with a long-standing diagnosis of schizophrenia who developed catatonic symptoms in the context of Parkinson disease (PD) and neuroborreliosis. After a medication switch from risperidone to quetiapine the patient rapidly deteriorated, displaying psychotic symptoms, disorganized behavior, and aggression. Multiple pharmacological interventions, including clozapine, high-dose risperidone, and benzodiazepines, were ineffective despite therapeutic plasma levels. The patient required seclusion over 50 times due to persistent agitation. Subsequently, he became increasingly withdrawn, refusing food and fluids, and developed pronounced catatonic features (mutism, echopraxia). After 3 months of unsuccessful pharmacotherapy, bilateral ECT was initiated. Within 6 sessions, the patient showed marked clinical improvement. A total of 18 ECT sessions led to full remission of catatonic and psychotic symptoms, with no further need for coercive measures. The patient was discharged home and continues to receive maintenance ECT. This case highlights the efficacy of ECT in managing complex catatonic states in patients with comorbid neuropsychiatric and neuroinflammatory conditions. It also emphasizes the importance of early ECT consideration when pharmacological approaches fail in multifactorial clinical scenarios.
Treatment-resistant depression (TRD) affects a substantial proportion of patients with major depressive disorder and remains a major therapeutic challenge. Augmentation with second-generation antipsychotics (SGAs) is commonly used; however, comparative evidence regarding their efficacy and safety remains limited. This systematic review aimed to evaluate the augmentative efficacy and tolerability of SGAs in adults with TRD. A systematic search of PubMed/MEDLINE, Embase, Web of Science, Scopus, and the Cochrane Library was conducted for randomized controlled trials published between 2016 and 2025. Eligible studies included adults with TRD receiving SGA augmentation. Two reviewers independently screened studies, extracted data, and assessed risk of bias using the Cochrane RoB 2 tool. Due to clinical heterogeneity across interventions and outcomes, findings were synthesized narratively. Eleven randomized controlled trials including 5,300 participants were analyzed, evaluating brexpiprazole, cariprazine, aripiprazole, and quetiapine XR. Most studies reported greater reductions in depressive symptoms compared with placebo, commonly measured by changes in the Montgomery-Åsberg Depression Rating Scale. Brexpiprazole and the aripiprazole-sertraline combination showed the most consistent improvements, with brexpiprazole augmentation yielding remission rates ranging from 22 to 31% and cariprazine augmentation showing rates of 22-32% across flexible-dose trials. Several agents demonstrated early onset of action within 2-3 weeks. Common adverse events included akathisia, insomnia, restlessness, and weight gain. Discontinuation due to adverse events ranged from 0.4% to 8.6%. Ten studies were assessed as having a low risk of bias. SGA augmentation is an effective treatment strategy for TRD, with brexpiprazole showing particularly consistent benefits. Careful risk-benefit assessment and monitoring for adverse effects are essential. Further head-to-head and long-term studies are needed to guide personalized treatment.
Chronic idiopathic urticaria is a challenging condition that may require advanced therapies, such as omalizumab. Its association with malignancy, particularly papillary thyroid carcinoma, remains unclear and is rarely reported. A 31-year-old Omani woman, with treatment-resistant idiopathic chronic urticaria requiring omalizumab for symptom control was subsequently diagnosed with papillary thyroid carcinoma. The patient underwent total thyroidectomy, after which she experienced partial remission of urticaria symptoms, including the longest symptom-free interval since disease onset. This case highlights a potential association between papillary thyroid carcinoma and chronic idiopathic urticaria, suggesting that evaluation for underlying malignancy may be considered in refractory cases.
Various dominant disease phenotypes are caused by germline variants of ATP1A1, the gene for the ubiquitously expressed Na+,K+-ATPase (NKA) α1 subunit. What characteristics link specific variants to a particular disease phenotype remains unclear. We used heterologous expression in mammalian cells and Xenopus oocytes to evaluate the characteristics of α1 variants causing hypomagnesemia with treatment-resistant seizures: L302R, G303R, M859R, and W931R. Cell survival in the presence of micromolar ouabain was reduced in cells expressing ouabain-resistant versions of these variants, indicating defective function of the variants relative to WT. Fluorescently tagged WT-α1 expressed in HEK293 cells showed plasmalemma localization, while all variants displayed increased cytosolic signal. In variant-expressing oocytes under voltage clamp, each variant showed passive "leak" currents, which were unaffected by ouabain in L302R and M859R, partially inhibited by ouabain in G303R and enhanced by ouabain in W931R. Na+ and Cl‒ permeate through G303R and W931R. M859R and W931R presented small K+-activated ouabain-inhibitable NKA currents that were absent in L302R and G303R. Growth of cells in ouabain and enzymatic studies demonstrated Na+/K+-dependent active transport for W931R, albeit with reduced Na+ affinity. We solved the cryo-EM structure of W931R-α1β1 with bound ouabain at 3 Å resolution. The structure showed a distorted transmembrane segment M9, which causes a concavity in the detergent micelle, suggesting that similar distortions may provide a leak pathway at the protein-lipid interface. Our results demonstrate that besides a loss of NKA function, all four variants carry an aberrant leak current that probably underlies the seizures and the hypomagnesemia characterizing this phenotype.
Major depressive disorder (MDD) in adolescents remains a significant public health challenge. Treatment-resistant depression (TRD) affects a substantial proportion of cases and is associated with chronic symptoms, comorbidities, and elevated suicide risk. Standard treatments frequently show limited success, leading to off-label consideration of atypical antipsychotics as augmentation agents. Risperidone has shown promise in adults, but data in adolescents are limited. This retrospective study evaluates clinical outcomes of risperidone augmentation in adolescent TRD, complemented by in silico modeling of potential molecular interactions. Retrospective data from 50 adolescents (aged 12-18) with DSM-5 MDD and TRD (non-response to ≥2 antidepressants) were analyzed. Risperidone (0.25-2 mg/day) was added to ongoing antidepressants for ≥8 weeks. Efficacy was assessed via changes in CDRS-R and HAM-D scores, response (≥50% reduction), and remission rates. Adverse events were documented. In silico molecular docking and 200 ns MD simulations explored risperidone's interactions with selected targets (DRD2, 5-HT2AR, SERT, and NMDA) using available PDB structures. Mean age was 15.4 years; 56% female. Depression scores improved: CDRS-R decreased from 64.3 to 38.9 (mean change -25.4 points), HAM-D from 23.6 to 12.1 (mean change -11.5 points). Response rates were 64% (CDRS-R) and 60% (HAM-D); remission rates were 40% and 36%, respectively. Baseline severity was associated with response (OR 1.22, p = 0.01). Common adverse events (mostly mild-moderate) included weight gain (24%), sedation (16%), and EPS (12%). Docking and MD simulations suggested favorable binding, particularly to DRD2 and 5-HT2AR. In this retrospective cohort, risperidone augmentation was associated with symptom improvement in adolescents with TRD and showed an acceptable short-term safety profile. In silico analyses suggest potential interactions with monoaminergic receptors that may contribute to its effects. These findings are hypothesis-generating and require confirmation in prospective randomized controlled trials.
Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia. However, evidence regarding whether adverse effects are related to the clozapine concentration is insufficient. Patients treated with clozapine for at least 6 weeks and maintained on a fixed dose for > 1 week were included (n = 47). Adverse effects were assessed using the self-rated Glasgow Antipsychotic Side-effects Scale for Clozapine (GASS-C). Plasma concentrations of clozapine and norclozapine were measured, and the relationship between the GASS-C score and clozapine concentration was analyzed. Clozapine concentration was significantly associated with both the GASS-C score (rs = 0.435, p = 0.002) and norclozapine concentration (rs = 0.363 p = 0.012). In addition, significant correlations with large effect sizes were found for GASS-C sub-items such as hypersalivation and anticholinergic symptoms. Multiple regression indicated that the GASS-C total score was associated with both clozapine (β = 0.374, p = 0.012) and norclozapine (β = 0.404, p = 0.005) concentrations. Adverse effects, including subjective ones, of clozapine may be concentration-related and clinically important. However, monitoring clozapine levels may only have a supplementary role in managing its subjective adverse effects because subjective GASS-C scores could be influenced by psychological factors and patient perception, which may not always correlate linearly with pharmacokinetic data.
Early detection of treatment-resistant schizophrenia (TRS) is of substantial clinical importance. While TRS is heritable, the associated genetic variants have been difficult to identify. Cigarette smoking is associated with non-response to antipsychotics, and smoking behavior and schizophrenia have a shared genetic basis. Thus, TRS may also have a shared genetic basis with smoking behavior. Here we aim to identify genetic variants associated with TRS, by leveraging overlapping genetic variants with smoking initiation to increase statistical power. We analyzed genome-wide data for TRS and smoking initiation with the conditional/conjunctional false discovery rate (cond/conjFDR) to identify shared loci, and LD score regression to determine genetic correlations. To investigate potential causal effects of shared loci, we performed Mendelian randomization (MR) analyses. Shared loci were mapped to genes, which were further investigated for enrichment of drug target genes. We observed a significant positive genetic correlation between TRS and smoking initiation (rg = 0.47 p = 0.0002). Leveraging the genetic overlap between TRS and smoking initiation, we identified four novel loci jointly associated with TRS and smoking initiation. The condFDR results improved polygenic prediction of TRS. MR indicates putative evidence for a causal effect of genetic liability to TRS on smoking initiation. The functional genetic analyses suggest that alpha-1-adrenergic receptors may be involved in the pathophysiology of TRS and possibly related to the efficacy of clozapine versus other antipsychotic drugs. In conclusion, our results show that shared genetic mechanisms influence both TRS and smoking behavior, which provide new insights into the biological underpinnings of TRS.
Major depressive disorder (MDD) is a heterogeneous, debilitating disorder. A distinct subgroup within the MDD spectrum is identified to have treatment-resistant depression (TRD). There is an impetus to find alternative treatments for TRD to reduce disease burden and improve quality of life. Psychedelics have been used in the treatment of various psychiatric disorders since the 1950s, with potential benefits in TRD. Aiming to summarize the evidence of using psychedelics for TRD by exploring mechanisms and potential benefits, we conducted a literature search on different psychedelics with their mechanisms from clinical and preclinical evidence. Psychedelics have been examined in many preclinical studies for efficacy and mechanisms with fewer clinical studies on patients with TRD. Besides serotonergic agonism, glutamate surge and monoamine release, psychedelics promote neuroplasticity, corticolimbic function, and epigenetic changes. Psilocybin, ketamine, and esketamine are the most researched agents of psychedelics in the context of TRD. Psilocybin-assisted therapy has been shown to induce short-term improvement in symptoms that can persist for weeks and months, with some meta-analyses consolidating such findings. Ketamine, as an atypical psychedelic, in many clinical trials of intravenous, subcutaneous, and oral forms, had rapid and robust effects in reducing depressive symptoms and relapses without decreasing cognitive function. Similarly, esketamine induced early and clinically meaningful improvements in function and productivity. Ayahuasca also showed fast and sustained effects with higher remission rates and good safety. Psychedelics have significant potential in TRD with superior mechanisms over traditional antidepressants. Despite the encouraging findings of the existing studies, large, well-designed studies are needed to extend their use as part of standard recommendations. ZWECK: Die Major-Depression (MDD) ist eine heterogene, stark beeinträchtigende Erkrankung. Eine bestimmte Untergruppe innerhalb des MDD-Spektrums wird als therapieresistente Depression (TRD) bezeichnet. Es besteht ein dringender Bedarf an alternativen Behandlungsmethoden für die TRD, um die Krankheitslast zu verringern und die Lebensqualität zu verbessern. Psychedelika werden seit den 1950er Jahren zur Behandlung verschiedener psychiatrischer Störungen eingesetzt und bieten potenzielle Vorteile bei der TRD. Mit dem Ziel, die Evidenz zur Anwendung von Psychedelika bei TRD durch die Untersuchung von Wirkmechanismen und potenziellen Vorteilen zusammenzufassen, führten wir eine Literaturrecherche zu verschiedenen Psychedelika und deren Wirkungsweise anhand klinischer und präklinischer Erkenntnisse durch. Psychedelika wurden in vielen präklinischen Studien auf ihre Wirksamkeit und Mechanismen untersucht, während es nur wenige klinische Studien an Patienten mit TRD gibt. Neben serotonergem Agonismus, Glutamat-Anstieg und Monoamin-Freisetzung fördern Psychedelika die Neuroplastizität, die kortikolimbische Funktion und epigenetische Veränderungen. Psilocybin, Ketamin und Esketamin sind die am besten erforschten Psychedelika im Zusammenhang mit TRD. Es hat sich gezeigt, dass die Psilocybin-unterstützte Therapie eine kurzfristige Verbesserung der Symptome bewirkt, die über Wochen und Monate anhalten kann, wobei einige Metaanalysen diese Ergebnisse bestätigen. Ketamin zeigte als atypisches Psychedelikum in vielen klinischen Studien mit intravenösen, subkutanen und oralen Darreichungsformen schnelle und robuste Wirkungen bei der Verringerung depressiver Symptome und Rückfälle, ohne die kognitiven Funktionen zu beeinträchtigen. In ähnlicher Weise führte Esketamin zu frühen und klinisch bedeutsamen Verbesserungen der Funktionsfähigkeit und Produktivität. Auch Ayahuasca zeigte schnelle und anhaltende Wirkungen mit höheren Remissionsraten und guter Verträglichkeit. Psychedelika verfügen bei therapieresistenter Depression über ein erhebliches Potenzial und weisen im Vergleich zu herkömmlichen Antidepressiva überlegene Wirkmechanismen auf. Trotz der vielversprechenden Ergebnisse der bisherigen Studien sind groß angelegte, gut konzipierte Studien erforderlich, um ihren Einsatz als Teil der Standardempfehlungen auszuweiten.
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Treatment options for severe self-injurious behavior (SIB) in autism spectrum disorder (ASD) with comorbid intellectual disability (ID) are limited. A 24-year-old man with ASD and severe ID presented with treatment-refractory SIB (an 11-year history; baseline frequency of 5-6 hand-biting episodes per day during pre-modified electroconvulsive therapy (MECT) hospitalization observation), despite multiple pharmacotherapy trials. On Day 27, baseline assessments and pre-MECT demonstrated a Violence Risk Assessment Scale (VRAS) score of 18, a Brief Psychiatric Rating Scale (BPRS) score of 74, an Activities of Daily Living (ADL) score of 46, and 4-5 h of nocturnal sleep each night. After 12 sessions of MECT administered over 7 weeks, the primary outcome, that is, SIB frequency, completely resolved (no hand-biting episodes each day). Additionally, secondary outcome measures showed marked improvement, including a VRAS score of 7 (a 61.1% reduction), a BPRS score of 47 (a 36.5% reduction), an ADL score of 34 (a 26.1% improvement in functional independence), and 5-6 h of nocturnal sleep each night. At 30 days post-MECT (Day 106, during continued hospitalization), therapeutic gains were sustained and further enhanced: the VRAS score persisted at 7, the BPRS score decreased to 35 (a 52.7% reduction from baseline), and the ADL score improved to 30 (a 34.8% improvement in functional independence from baseline), with complete resolution of SIB (self-directed harmful acts) and aggressive behavior (other-directed harmful acts). The patient scored zero on the VRAS. No serious adverse events were observed during hospitalization. Based on controlled nursing frequency counts, mental assessment scales, and photographic wound records, this case provides preliminary observational evidence that MECT may reduce treatment-refractory SIB in patients with ASD and severe ID. Further controlled studies using standardized SIB outcome measures are warranted, given the lack of validated SIB-specific instruments and the limitations inherent to a single-case design.
Ketamine is a fast-acting intervention for treatment-resistant depression (TRD), yet only a subset of patients show robust clinical response, and the underlying neural mechanisms remain unclear. High-order interactions (HOI) derived from multivariate information theory provide a framework for examining nonlinear dependencies among brain regions beyond pairwise connectivity. One such metric, the O-information, captures the balance between synergistic and redundant interactions across three or more variables. In this secondary analysis of a randomized, double-blind, midazolam-controlled trial (NCT02556606), we examined EEG-derived HOI in 30 late-life veterans with TRD following a single 40-minute intravenous infusion of ketamine (0.1, 0.25, 0.5 mg/kg; n = 18) or midazolam (0.03 mg/kg; n = 12). Resting state and mismatch negativity data were analyzed at baseline, 1 h, 24 h, and 7 d post-infusion. Ketamine induced temporally dynamic alterations in redundancy-dominant O-info, with maximal effects in the alpha-band at 1 h (Cohen's d = 2.57), attenuation at 24 h that shifted toward the theta-band, and partial resurgence in beta and gamma by Day 7. Linear mixed-effects modeling identified significant group effects across most band x metric families, with the strongest effects in alpha, beta, and gamma redundancy. Greater increases in 24-hour alpha-band redundancy were associated with greater improvement in depressive symptoms at Day 7 (β = 69.31, q = 0.05). HOI metrics also tracked acute dissociative states, with several 24-hour alpha and beta features remaining positively associated with symptom severity after correction. These findings extend prior HOI work in healthy samples to a controlled TRD cohort and suggest that ketamine induces temporally structured reorganization of higher-order brain interactions, with exploratory associations to clinical outcomes.
Nitrous oxide is being investigated as a treatment for therapy-resistant depression, yet its environmental implications as a potent greenhouse gas are largely unaddressed. A single 1 h treatment generates ∼150 kg CO2-equivalents, rising to ∼7.8 t per patient-year, highlighting the need to incorporate environmental externalities into evaluation.
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Interactions between the nervous and immune systems play a central role in depression, yet the mechanisms integrating neuroimmune signaling remain poorly understood. Here, we investigated the regulation of immune checkpoints in three mechanistically distinct models of depressive-like behavior: treatment-resistant Wistar Kyoto rats, Wistar rats exposed to chronic restraint stress, and Porphyromonas gingivalis-infected C57BL/6 mice. Using integrated molecular analyses that combine targeted gene and protein measurements with transcriptional profiling, we identified alterations in immune checkpoint signaling within the CD28 superfamily that were associated with the severity of depressive-like phenotypes across selected models. Across all models, immune signaling showed concurrent costimulatory activation (CD28, ICOS) alongside alterations in the PD-1/PD-L1 axis, including increased PD-1 levels in peripheral blood and changes in PD-L1 expression in the brain. Transcriptional alterations in CD28-superfamily regulators and related immune modulators further indicated the coexistence of immune activation and partial exhaustion signatures, consistent with chronic immune dysregulation rather than a uniform inflammatory response. Among the investigated immune checkpoints, reduced PD-L1 expression in the WKY model represented the most consistent finding across targeted and transcriptomic analyses. Despite model-specific transcriptional differences, the expression levels of selected immune checkpoint-related genes were associated with performance in the novel object recognition test. Together, these findings suggest that alterations in the CD28 immune checkpoint (PD-1/PD-L1, CD28/CD80, ICOS/ICOSL) network accompany depressive-like phenotypes and suggest that impaired immune checkpoint control may contribute to cognitive dysfunction in depressive disorders. Targeting immune checkpoint pathways may therefore represent a promising direction for future therapeutic strategies in treatment-resistant depression.
Low-grade serous ovarian carcinoma (LGSOC) is a rare ovarian cancer subtype with limited sensitivity to chemotherapy and modest benefit from endocrine and MEK-directed therapy. New therapeutic targets are needed. We evaluated trophoblast cell-surface antigen 2 (TROP2) expression in LGSOC and the activity of datopotamab deruxtecan (Dato-DXd), a TROP2-directed antibody-drug conjugate, in an LGSOC patient-derived xenograft (PDX) model. TROP2 expression was assessed by immunohistochemistry in a retrospective single-center cohort of 29 LGSOC cases treated at Yale University. Antitumor activity of Dato-DXd was evaluated in a TROP2-expressing PDX model derived from a heavily pretreated patient with LGSOC resistant to chemotherapy, aromatase inhibitors, and MEK inhibitors. TROP2 expression was detected in 29 of 29 cases, and 23 tumors showed moderate-to-strong expression. In vivo, Dato-DXd significantly inhibited tumor growth versus vehicle/saline control in a treatment-resistant LGSOC PDX model (p < 0.0001) without relevant toxicity. Median survival was 22 days in control animals and was not reached by day 50 in the Dato-DXd group. TROP2 is frequently expressed in LGSOC and may represent a therapeutically relevant target. Dato-DXd showed marked antitumor activity in a treatment-resistant LGSOC PDX model. Clinical evaluation in patients with recurrent LGSOC is warranted.
Approximately 25% of patients with bipolar disorder are reported to have treatment-resistant bipolar depression (TRBD). Accelerated intermittent Theta Burst Stimulation (aiTBS) is an innovative form of repetitive transcranial magnetic stimulation (rTMS), delivering bursts of stimulation at theta wave frequencies, which are believed to enhance synaptic plasticity. This pilot study aimed to explore the safety, tolerability, and preliminary efficacy of aiTBS in individuals with treatment-resistant bipolar depression (TRBD). This open-label pilot study (registered at Overview of Medical Research in the Netherlands (OMON), NL-OMON53634), conducted between July 2023 and September 2024, included patients aged 43-64 years who were diagnosed with bipolar I or II and were experiencing a current moderate-to-severe depressive episode. Patients were required to have treatment-refractory symptoms according to the Hidalgo-Mazzei criteria. All patients were receiving antidepressant medication. Patients received eight daily sessions of intermittent Theta Burst Stimulation (iTBS) over five consecutive days, with 50-min intervals between sessions. Stimulation targeted the left dorsolateral prefrontal cortex (DLPFC) using the BeamF3 targeting method. Outcomes included safety, tolerability, and efficacy and were assessed at day 3, day 5, week 2, week 4 and week 12 post-treatment. Safety was assessed by documentation of serious adverse events (SAEs) and adverse events (AEs); tolerability was evaluated based on reported side effects. Efficacy was measured by the mean reduction in depression symptoms using the 17-item Hamilton Depression Rating Scale (HDRS-17). Eight patients were recruited, all of whom completed the treatment course. aiTBS was well tolerated and no SAEs occurred during the treatment week or during follow-up. The most frequently reported AEs were discomfort at the stimulation site and fatigue (87.5%). Although one patient experienced hypomanic symptoms (YMRS = 13) at the 3-month follow-up visit, this was considered unrelated to the study treatment due to the timing of onset, and because several significant psychosocial stressors were identified in the patient's life during that period. Mean HDRS scores decreased from 22.9 (SD = 4.4) at baseline to 16.6 (SD = 4.2) on day 3 of treatment (difference = 6.3 (95% CI, 1.6-10.9); 27.3% improvement, p = 0.01), 12.8 (SD = 4.1) on day 5 (difference = 10.1 (95% CI, 2.2-18.1); 44.3%, p = 0.02), 11.1 (SD = 3.8) at week 2 (difference = 11.8 (95% CI, 4.5-19.0); 51.4%, p = 0.004) and 13.5 (SD = 3.9) at week 4 (difference = 9.4 (95% CI, 1.0-17.7); 41.0% improvement, p = 0.03). At month 3, the mean HDRS score was 13.7 (SD = 6.9, difference compared to baseline = 9.1 (95% CI, -3.0 to 21.3); 40.0% improvement, p = 0.2). This pilot study extends prior evidence suggesting the antidepressant effects, safety, and tolerability of aiTBS in patients with TRBD; however, its durability may be limited. We recommend that future RCTs investigate relapse prevention following acute aiTBS and determine the optimal strategy for maintaining antidepressant effects.
Clozapine has been used for treatment-resistant aggression across a range of psychiatric diagnoses. We aimed to comprehensively review the effectiveness of clozapine in the management of aggression. We searched PubMed, Web of Science, Cochrane Library, PsycINFO, and MEDLINE up to 8 June 2025. Full-text articles examining the effects of clozapine on aggression and violence in psychotic and non-psychotic disorders were included. In total, 75 papers were included; 49 papers focused on patients with schizophrenia and consisted of randomised controlled trials (n = 9), registry studies (n = 3), prospective pre-post studies (n = 8), prospective comparative studies (n = 6), retrospective studies (n = 21), and case series (n = 2). The remaining 26 papers primarily consisted of case series and focused on patients with non-psychotic disorders, including autism spectrum disorder (n = 4), conduct disorder (n = 3), intellectual disability (n = 5), personality disorders (n = 6), dementia (n = 6), and mixed diagnoses (n = 2). All studies showed reductions in violence and aggression associated with clozapine, particularly in treatment-resistant cases. Clozapine may also offer benefits in selected non-psychotic conditions. Further research is needed to clarify the role of clozapine as a transdiagnostic treatment for aggressive behaviour associated with mental illness.
Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD). Neutrophil extracellular traps (NETs) have been recognized as contributing to UC progression. This study aimed to identify key genes driving NET formation in UC and evaluate their potential as biomarkers. Gene expression profiles from colon biopsies of UC patients and healthy controls were obtained from the GSE224758 dataset. Differentially expressed genes (DEGs) were identified using the GEO2R tool. Hub genes involved in NET formation, including FCGR3B, AQP9, FPR1, FPR2, and NCF2, were validated through reverse transcription-quantitative polymerase chain reaction (RT-qPCR) using colon biopsy samples from healthy controls (n=20), newly diagnosed UC (n=20), and treatment-resistant UC patients (n=20) collected between November 8, 2022, and February 2, 2025, at Tohid Hospital, Kurdistan University of Medical Sciences, Sanandaj, Iran. Data normality was assessed using the Shapiro-Wilk test; Kruskal-Wallis test and Dunn's post hoc test were applied for group comparisons. ROC analysis was applied to determine the potential of genes for the differentiation of healthy people from patients. RT-qPCR validation confirmed significantly increased expression of AQP9 (P <0.0001), FPR1, and FPR2 (P=0.03 and P=0.02) genes in patients with UC and those with refractory UC compared to healthy controls. Among these, AQP9 exhibited the most significant differential expression, demonstrating high sensitivity and specificity in distinguishing newly diagnosed and treatment-resistant UC patients from healthy individuals (sensitivity 83.49% and 80.98%, and specificity 67.77% and 64.24%, respectively), indicating its potential as a diagnostic biomarker. This study identifies NET-associated genes, particularly AQP9, FPR1, and FPR2, as candidate tissue biomarkers for UC, with AQP9 exhibiting the strongest ability to distinguish patients from healthy controls. These findings support the utility of NET-related genes as tissue biomarkers for UC, while emphasizing that any therapeutic targeting of these molecules lies beyond the scope of the present work and will require additional functional and in vivo validation.
Breast cancer remains a highly heterogeneous malignancy in which metastasis and therapeutic resistance represent the primary drivers of patient mortality. Berberine (BBR), a natural isoquinoline alkaloid, has emerged as a promising pleiotropic agent capable of simultaneously targeting multiple oncogenic vulnerabilities. In this Review, we systematically outline the multifaceted molecular mechanisms underlying the anti-tumor efficacy of BBR in breast cancer. We detail how BBR disrupts core intracellular signaling networks-specifically the PI3K/AKT/mTOR, MAPK/ERK, and Wnt/β-catenin pathways-and modulates the m6A RNA epitranscriptome via the METTL3/IGF2BP3 axis to induce apoptosis, enforce cell cycle arrest, and suppress the epithelial-mesenchymal transition (EMT). Beyond direct cytotoxicity, we highlight BBR's capacity to remodel the tumor microenvironment (TME) by suppressing cancer-associated fibroblasts (CAFs) and tumor angiogenesis, while simultaneously targeting treatment-resistant cancer stem cells (CSCs) through the epigenetic restoration of tumor-suppressive microRNAs. Furthermore, we discuss the role of BBR as a potent chemosensitizer capable of reversing multidrug resistance to augment conventional chemotherapeutic and endocrine regimens. Finally, we address the inherent pharmacokinetic bottlenecks that limit BBR's clinical translation and examine how cutting-edge nanomedicine platforms can circumvent these barriers, offering a comprehensive translational roadmap for integrating BBR into next-generation oncology therapeutics.