ObjectivesSchizophrenia is characterized by positive, negative and cognitive symptoms, including different degrees of impairment in several neurocognitive domains, such as executive function, processing speed, learning and memory, which impact a patient´s functioning and quality of life. Cognitive remediation can help restore cognitive functioning through repeated exercises, following at least two possible strategies: a “top-down” approach, focused on training executive functions, or perceptual training, a “bottom-up” approach, aimed at first addressing impairments in perceptual processing. This study aims to clarify whether both approaches have comparable efficacy in improving neurocognitive performance, and to explore the timing of their cognitive and molecular effects. It will also examine the relationship between these approaches and changes in BDNF levels, considered a biomarker of neuroplasticity.Materials and methodsIn order to have a control group, patients will undergo an initial 10-week observation period receiving treatment as usual, followed by randomization into either executive training or perceptual training during the active phase of the trial. Clinical and neurocognitive assessments, as well as blood sampling, will be conducted at the beginning and end of each stage. Finally, assessments will be repeated after a 12-week follow-up period.DiscussionThe study aims to answer these research questions concerning clinical efficacy and molecular mechanisms and expects to identify possible clinical or molecular biomarkers (such as BDNF levels or the Val66Met polymorphism) that could be helpful as predictors of neurocognitive treatment response for each remediation strategy, thereby contributing to a personalized treatment approach. Study registered on clinicaltrials.gov number NCT06482918.
Feasibility Trial of a Parent Peer-Co-Led Caregiver Group for Pediatric Early Onset Schizophrenia Spectrum Disorders
Conditions: Schizophrenia; Psychosis
Interventions: Behavioral: Group Therapy; Other: Treatment as Usual (TAU)
Sponsors: Boston Children’s Hospital
Not yet recruiting
Interventions: Behavioral: Group Therapy; Other: Treatment as Usual (TAU)
Sponsors: Boston Children’s Hospital
Not yet recruiting
Usability of digital medicine systems in patients with schizophrenia or schizoaffective disorder
ObjectiveTo assess the usability and performance of digital medication management systems (DMS) for patients with stable ambulatory schizophrenia and schizoaffective disorder.MethodsThis prospective, interventional study comprised a screening phase (up to 4 weeks), training phase (3 weeks: system use under the support), and independent phase (5 weeks under the minimized support) with a follow-up period of 2 weeks. Based on the DSM-5 criteria, patients with a diagnosis of schizophrenia or schizoaffective disorder, taking an atypical antipsychotic as their primary medication, and having access to a smartphone were included in this study.ResultsA total of 30 patients participated in the study. The main characteristics of the patients were as follows: age, 43.5 ± 11.4 years; male percentage, 40% (n = 12); duration of antipsychotic drug use, 14.2 ± 11.7 years; educational period, 13.3 ± 2.1 years; chlorpromazine (CP) equivalent dose, 369.6 ± 253.6 mg/day; and Brief Psychiatric Rating Scale (BPRS), 23.6 ± 4.8. The patients applied patches with the sensor of the DMS embedded in (hereinafter, a wearable sensors) for 93.2% of the study period. The patients could apply the patch independently and successfully and synchronize it with a smartphone application that allowed them to monitor their medication intake in 15.2 ± 8.1 days (median, 9.0; interquartile range (IQR), 1.0–15.0 days after initiation). Thirty-eight adverse events that were reported in 17 patients were classified as mild or moderate, and were related to wearable sensor use.ConclusionIt was concluded that most patients completed the task for the DMS with minimal assistance early in the study and continued to apply wearable sensors throughout the study period. Moreover, the results confirmed the feasibility of DMS in clinical practical use in stable schizophrenia.
Anti-Inflammatory Drug Target for Alzheimer’s, TBI, and Neurodegenerative Disease Identified
The results of research headed by a team at the University of Birmingham suggest that inflammatory conditions in the brain, including traumatic brain injury (TBI) and degenerative diseases such as Alzheimer’s disease and Parkinson’s disease, could be targeted with an existing developmental drug.
Using live cultures of human brain cells and slices of brain tissue obtained during neurosurgery, the researchers, headed by Nicholas Barnes, PhD, professor at the University of Birmingham College of Medicine and Health, investigated the role of the P2X7 receptor, which is responsible for triggering inflammatory signaling. Their findings revealed that these P2X7 receptors drive the release of cytokines involved in controlling inflammation. By blocking this receptor with a specific antagonist, the team was able to significantly reduce the inflammatory response in human brain tissue.
The team suggests that their results could open the door to treating a wide spectrum of chronic neurological conditions, including TBI, neurodegenerative diseases, and even psychiatric disorders such as depression and psychosis, which are increasingly understood to have a neuroinflammatory component.
Barnes said, “This exciting discovery marks a major step toward repurposing existing therapeutics to combat neuroinflammation at its source. The identification of this receptor could have far-reaching implications for some of the most debilitating and widespread brain disorders such as Alzheimer’s disease, Parkinson’s, and multiple sclerosis, or inflammation-linked psychiatric conditions like schizophrenia and depression.”
Barnes is senior and corresponding author of the team’s published paper in Brain, titled “P2X7 receptor-mediated IL-1β release by human brain tissue: the impact of CNS-penetrant potential therapeutics,” in which they concluded “Our findings provide direct relevant evidence for the use of P2X7R antagonism to inhibit human microglia-mediated inflammation, with arising potential benefits for patients with TBI and other neuroinflammatory diseases.”
TBI is a major cause of death globally, and there are currently there are no approved therapeutic drugs to improve clinical outcomes, “… emphasizing the clear unmet substantial clinical need,” the authors wrote.
The mechanical damage associated with TBI drives a neuroinflammatory response. “The purinergic P2X7 receptor (P2X7R) is a key driver of neuroinflammation in a range of animal models of traumatic brain injury,” the team continued. P2X7R is expressed by microglia, the resident immune cells in the CNS that are involved in many developmental, homeostatic and pathological roles. “It is well recognized that microglial activation and the hostile neuroinflammatory response arising after the initial insult provide a therapeutic window for pharmacological intervention,” the investigators further stated.
For their reported study investigating how brain cells respond to and manage inflammation, the team developed a way of turning a type of white blood cell into microglia, replicating a normal cellular transformation that has recently been identified to occur in the brain as a natural part of human aging. These microglia are the central coordinators of the immune system in the brain.
Using readily accessible human peripheral monocytes taken from blood samples, the researchers converted them into microglia-like cells—human monocyte-derived microglia (hMDM)—that were used to see how microglia are likely to respond to the inflammation signals. “This enabled us to demonstrate the ability of clinically relevant P2X7R antagonists, including brain-penetrant molecules, to curtail pro-inflammatory cytokine release,” they wrote.
The team showed that administering a P2X7 receptor antagonist interrupted the triggers that these microglia give off as they are damaged and die. Barnes said, “Studying human microglia has long been a major challenge: once removed from their native brain environment, they rapidly lose their defining characteristics, likely due to the absence of critical regulatory signals. Our approach involved the use of monocyte-derived microglia which provide a powerful, scalable, and virtually unlimited platform for studying human microglial biology with unprecedented precision.”
The team confirmed their results using adult human precision-cut brain slices that had been generated subsequent to neurosurgical resections. “Having identified the response in the human monocyte-derived microglia, this provided the impetus to translate these findings with human brain obtained following neurosurgical procedures, Barnes continued. “This successful translation means the next stage for this research is the development of clinical trials in patients with neurodegenerative conditions and patients with TBI where there are no effective pharmacological treatments to reduce the neuroinflammation and arising damage.”
In their paper the authors concluded, “The present study provides direct translational evidence from human cellular and brain tissue models to support the clinical use of P2X7R antagonists to limit secondary ATP-driven neuroinflammatory events, such as those that occur in TBI, and thus might improve the clinical outcomes for patients.”
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Circulating miR-1260a as a potential biomarker for First-Episode of Psychosis: a replication study in a treatment-Naïve Romanian cohort
The diagnosis of first-episode psychosis (FEP) in adolescents and young adults remains primarily clinical, often complicated by symptom overlap and the heterogeneity of psychiatric presentations. There is a critical need for non-invasive, objective biomarkers to support early diagnosis and patient stratification. This study aimed to replicate a panel of 10 candidate microRNAs (miRNAs) identified in a previous exploratory study within a larger, independent cohort of treatment-naïve Romanian adolescents and young adults. This cross-sectional study included 50 participants (22 drug-naïve FEP patients and 28 age- and sex-matched controls). Total RNA was isolated from plasma, and the levels of miRNAs were measured using qRT-PCR. Clinical symptoms were assessed using standardized psychiatric scales (PANSS, HDRS, YMRS). We successfully replicated miR-1260a as significantly modified in the plasma of treatment-naïve FEP patients compared to controls (FDR Adj. p = 0.04). ROC analysis for miR-1260a yielded an AUC of 0.741 (p = 0.004). Furthermore, exploratory correlation analyses conducted exclusively within the FEP patient group indicated a negative correlation between miR-1260a levels and the positive PANSS score (p = 0.017, rho = -0.503), which did not retain statistical significance after FDR correction (FDR Adj. p = 0.102). Our results corroborate and enhance our prior exploratory research, highlighting miR-1260a as a prominent candidate among circulating biomarkers for early psychosis. Future longitudinal studies are necessary to evaluate the diagnostic, prognostic, and clinical monitoring efficacy of this miRNA.
Longitudinal white matter network reorganization after rTMS in first-episode schizophrenia: associations with sleep improvement
BackgroundSleep disturbances are highly prevalent in first-episode schizophrenia and are associated with poor clinical and functional outcomes. Although repetitive transcranial magnetic stimulation (rTMS) has shown therapeutic potential for insomnia and schizophrenia, its efficacy for sleep disturbances in first-episode schizophrenia remains insufficiently characterized, and the underlying white matter network mechanisms remain unclear. This study aimed to determine whether active rTMS improves sleep quality compared with sham stimulation and whether longitudinal white matter network reorganization is associated with treatment-related sleep improvement.MethodsOne hundred patients with first-episode schizophrenia were included in the final analysis and randomly assigned to receive active rTMS or sham stimulation over an 8-week intervention period. Subjective sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI), and objective sleep parameters were measured using wrist actigraphy. Diffusion tensor imaging was acquired at baseline and after treatment to construct individual white matter structural networks. Graph-theoretical metrics, nodal efficiency, and rich-club organization were examined. Linear mixed-effects models were used to evaluate group-by-time interaction effects, and correlation analyses were performed to examine associations between network changes and sleep improvement.ResultsCompared with sham stimulation, active rTMS produced greater improvements in subjective and objective sleep outcomes, including reduced PSQI scores, increased sleep efficiency, and decreased wake after sleep onset and sleep latency. Active rTMS was also associated with greater longitudinal increases in global efficiency, local efficiency, clustering coefficient, and nodal efficiency in prefrontal, default-mode, temporal, and salience-related regions. Rich-club connectivity increased more strongly after active rTMS than after sham stimulation, whereas feeder connectivity, normalized rich-club coefficient, and local connectivity did not show significant group-by-time interaction effects after FDR correction. In the active rTMS group, increases in rich-club connectivity were positively associated with improvements in actigraphy-derived sleep efficiency (r = 0.43, P = 0.002).ConclusionsActive rTMS improved sleep quality more effectively than sham stimulation in patients with first-episode schizophrenia and was accompanied by longitudinal changes in DTI-derived white matter network organization. The association between increased rich-club connectivity and improved sleep efficiency suggests that hub-related network reorganization may represent a network-level correlate of rTMS-related sleep improvement.
Timely outpatient follow-up and readmission risk in schizophrenia
Timely outpatient follow-up after psychiatric hospitalization has been proposed as a key strategy to reduce readmission; however, evidence in patients with first-admission schizophrenia remains limited. Using the Korean National Health Insurance Claims Database, we conducted a nationwide retrospective cohort study of 1,961 patients with first-admission schizophrenia, defined as having no psychiatric service utilization during the preceding three years. We examined whether outpatient follow-up within 30 days after discharge was associated with the risk of readmission within 365 days. Adjusted Cox proportional hazards models were used to estimate hazard ratios across multiple cumulative follow-up periods (60, 90, 120, 150, 180, and 365 days), controlling for sociodemographic and clinical factors. Kaplan–Meier analysis was used to assess differences in readmission-free survival. Among the study population, 53.2% received outpatient follow-up within 30 days after discharge. When evaluated across progressively longer cumulative follow-up periods, outpatient follow-up was associated with a significantly lower risk of readmission at 60 days (aHR = 0.52, 95% CI: 0.29–0.95), 90 days (aHR = 0.55, 95% CI: 0.35–0.88), 120 days (aHR = 0.63, 95% CI: 0.43–0.94), 150 days (aHR = 0.66, 95% CI: 0.46–0.95), and 180 days (aHR = 0.70, 95% CI: 0.51–0.98), but not at 365 days (aHR = 0.79, 95% CI: 0.61–1.02). Kaplan–Meier analysis showed longer readmission-free survival in the follow-up group, although the difference was more pronounced over shorter follow-up durations. Timely outpatient follow-up was associated with reduced readmission risk over shorter cumulative follow-up periods, with attenuation of the association as the follow-up duration increased.
Harnessing Data Warehousing for Precision in Off-Label Prescription Detection in Psychiatry (PSYHAMM): Retrospective Proof-of-Concept Evaluation Study
Background: Off-label drug prescribing is prevalent across medicine, including psychiatry, often due to unmet therapeutic needs and inadequate responses to standard treatments. The PSYHAMM (Psychotropes Hors Autorisation de Mise sur le Marché) project, funded by the French Research Agency, investigates these practices. To support this research, a clinical data warehouse (CDW) with advanced data analysis tools was developed and deployed. This system integrates both structured and unstructured data from electronic health records, facilitating comprehensive data analysis. The goal is to improve understanding, regulation, and safety of off-label drug use in psychiatry by providing insights into prescribing patterns and their impacts, ultimately contributing to better clinical guidelines and patient care. Objective: This study aimed to evaluate the precision (positive predictive value) of a CDW in identifying candidate off-label prescriptions in psychiatry among the cases automatically flagged by the system, rather than its overall accuracy, sensitivity, or specificity. Methods: The PSYHAMM data analysis involved a retrospective study of pathology-medication pairs to evaluate the precision of a computerized system among system-flagged cases. This system was compared with manual checks performed by a psychiatrist. The evaluation process included verifying if the condition identified by PSYHAMM was documented in the medical record, assessing diagnostic agreement with tolerance for schizoaffective disorders, and ensuring the identified treatment was current or prescribed in the past. Precision was measured as the number of relevant documents retrieved divided by the total number of documents proposed and was computed for the precise diagnosis, the broad diagnosis, and the identified treatment among the flagged cases. Results: The study analyzed 197 records, identifying 14 unique drug-pathology combinations. Bipolar disorder treated with sodium valproate represented the most cases (108/197, 54.8%), followed by schizophrenia treated with sodium valproate (37/197, 18.8%). The overall precision for detecting off-label situations was 51.3% (101/197). The precise diagnosis achieved a precision of 75.6% (149/197), while the broad diagnosis showed a higher precision of 84.8% (167/197). The identified treatment had a precision of 61.4% (121/197). The primary challenge was temporal discrepancies, such as distinguishing between acute and chronic conditions, which accounted for most of the 48.7% (96/197) of cases that were incorrectly classified. Conclusions: As a single-center, proof-of-concept evaluation, the PSYHAMM project demonstrates the potential of automated systems to support the identification of off-label prescriptions in psychiatry as a sensitive prescreening step requiring expert validation. The relatively high false-positive rate was driven mainly by temporal discrepancies (drugs prescribed before the index stay, discontinued during the stay, or only hypothetically mentioned) rather than by semantic errors. Future research should focus on integrating real-time data analytics and expanding to multiple institutions to improve the utility of off-label detection systems.
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Beyond dopamine: KarXT and emerging mechanism-based therapies in schizophrenia
KarXT (marketed as Cobenfy™), a fixed-dose combination of xanomeline and trospium chloride, represents the first new mechanism of action of an antipsychotic used for adult schizophrenia approved by the US Food and Drug Administration (FDA) in over 30 years. While mainstream drugs (e.g. haloperidol, chlorpromazine, risperidone, olanzapine, quetiapine, aripiprazole) mainly antagonize dopamine D2 or serotonin 5-HT2A receptors, KarXT acts through transient activation of muscarinic M1 and M4 receptors. M4 stimulation influences the functioning of mesolimbic dopaminergic pathways, providing an indirect means of regulating dopamine release that bypasses D2 blockade. Trospium, a peripherally acting muscarinic receptor antagonist, was used to reduce anticholinergic adverse effects (AEs). It does not cross the blood–brain barrier and therefore minimizes central adverse events. In a series of randomized placebo-controlled phase 2 and 3 studies, the KarXT significantly and clinically meaningfully reduced Positive and Negative Syndrome Scale (PANSS) total scores. The effect sizes were moderate to large with few extrapyramidal symptoms (EPS), minimal metabolic disturbances and no significant prolactin level increases. In this narrative review, we discuss in detail the pharmacological mechanism, basis of preclinical development, and clinical outcomes of KarXT. We also contextualize this drug within the development of a new wave of non-D2 antipsychotics, highlighting cholinergic dysfunction as one important mechanistic pathway within the broader multidimensional neurobiology of schizophrenia.
Methamphetamine-withdrawal catatonia resolved with mixed amphetamine salts: a case report
Catatonia is a well-recognized psychiatric emergency with an evolving understanding of its underlying pathophysiology. However, withdrawal-associated catatonia remains poorly characterized. Here we describe a 32-year-old man with symptoms consistent with methamphetamine-withdrawal catatonia, a previously undescribed etiology, which resolved only after treatment with mixed amphetamine salts. The patient remained catatonic (Bush-Francis Catatonia Rating Scale [BFCRS] >10) for four months despite 38 sessions of electroconvulsive therapy, lorazepam up to 24 mg daily, and multiple augmentation strategies. An extensive medical and neurologic workup excluded alternative causes. Following initiation of mixed amphetamine salts, his BFCRS decreased from 15 to 6 within 48 hours, with sustained resolution and no recurrence of psychosis despite discontinuation of antipsychotics. This case suggests that methamphetamine withdrawal may represent an underrecognized cause of catatonia and that dopaminergic augmentation may have a therapeutic role in refractory cases.