Real-world use of brexpiprazole during inpatient treatment for schizophrenia: continuation, discontinuation, and concomitant psychotropics

IntroductionIn the treatment of schizophrenia, antipsychotics used during acute inpatient care must control acute symptoms while remaining sufficiently tolerable to support treatment beyond the acute phase. Brexpiprazole, a serotonin-dopamine activity modulator may be one such option; however, its real-world use and short-term continuation in acute inpatient settings remain insufficiently characterized.MethodsWe conducted a retrospective observational study of inpatients with DSM-5 schizophrenia treated with brexpiprazole at a university hospital in Japan between June 2018 and July 2024. The index date (week 0) was defined as the date of brexpiprazole initiation during the index hospitalization. The primary outcome was brexpiprazole continuation at week 8. We compared baseline demographic and treatment-related variables between the continuation and discontinuation groups and summarized reasons for discontinuation from electronic medical records. As a secondary exploratory analysis, we examined longitudinal changes in Clinical Global Impressions–Severity scale (CGI-S) and Brief Psychiatric Rating Scale (BPRS) total scores (weeks 0/4/8) in the continuation group using a linear mixed-effects model including time, concomitant psychotropic medication status, and their interaction.ResultsSixty-seven patients were included. Baseline illness severity was substantial (median CGI-S 5.0 [IQR 5.0–6.0]; mean BPRS total 58.5 ± 9.6). Concomitant psychotropic medications were common. Thirty-six patients continued brexpiprazole to week 8 (53.7%). In unadjusted exploratory comparisons, continuation was associated with the female sex (p = 0.036), lower prior chlorpromazine-equivalent dose (p = 0.015), and shorter duration of untreated psychosis (p = 0.003), with a trend toward shorter duration since onset (p = 0.073). The most frequent reason for discontinuation was adverse events (n = 10, 32.3%), most commonly akathisia (n = 6), followed by insufficient efficacy (n = 9, 29.0%) and patient preference/refusal (n = 7, 22.6%). In exploratory mixed-effects analyses within the continuation group, CGI-S and BPRS total scores decreased over time, with significant group-by-time interactions by concomitant medication status. However, between-group differences should be interpreted cautiously.DiscussionThis study describes 8-week continuation and reasons for discontinuation of brexpiprazole in acute inpatient schizophrenia care. Given the retrospective single-center design and potential selection/information bias and unmeasured confounding, further studies are warranted to clarify its clinical positioning in real-world practice.

Analysis of risk factors for tic disorders in children in Hubei region based on liquid chromatography-tandem mass spectrometry

ObjectiveThis study aims to investigate the correlation between trace element concentrations, 25-hydroxyvitamin D [25(OH)D] levels, and the severity of tic disorders (TD) in children from the Hubei region. Additionally, it seeks to explore the interrelationships among these monitored indicators to provide a reference for the clinical diagnosis and treatment of pediatric TD.MethodsA retrospective review was conducted on the medical records of 237 children diagnosed with TD (TD group) and 137 healthy controls, admitted to the Department of Neurology at Hubei Maternal and Child Health Care Hospital. The TD group was further divided into mild and moderate-to-severe subgroups based on the Yale Global Tic Severity Scale scores. General clinical data were collected, and serum trace element levels were measured using inductively coupled plasma mass spectrometry (ICP-MS), while serum 25(OH)D levels were quantified via liquid chromatography–tandem mass spectrometry (LC–MS/MS). Group comparisons, Spearman correlation analysis, and univariate/multivariate logistic regression analyses were performed.ResultsThe findings indicated that serum 25(OH)D levels were significantly lower in children with TD compared to controls (p < 0.001). Logistic regression analysis demonstrated that 25(OH)D was an independent protective factor against tic disorders.(p < 0.001). Compared to the control group, children with TD exhibited significantly lower levels of calcium and copper (p < 0.001), along with higher levels of iron and cadmium (p < 0.01). These differences were more pronounced in the subgroup of children older than 6 years. An age-stratified subgroup analysis revealed no significant differences in any other indicators except for cadmium between the TD and control groups among children aged 6 years or younger (p > 0.05). Spearman correlation analysis demonstrated that within the TD group, 25(OH)D levels had the most significant correlations with calcium and copper (p < 0.001). No statistically significant differences were observed in the levels of the 10 trace elements or 25(OH)D between the mild and moderate-to-severe TD subgroups (p > 0.05).ConclusionChildren with Tic Disorders in Hubei Province demonstrate a distinctive alteration in their micronutrient profile, primarily characterized by a deficiency in 25(OH)D, alongside reduced levels of calcium and copper, and elevated levels of iron and cadmium. This association is particularly pronounced in male children over the age of six. While 25(OH)D deficiency is identified as an independent risk factor for TD, its concentration does not significantly correlate with the severity of the disorder.

Timing of exercise differentially modulates fear memory and hippocampal neurotransmitters in male rats

Exercise promotes neurogenesis and enhances memory consolidation while reducing the retention of aversive memories and anxiety-like behaviors. While our previous work found that acute exercise alters neurotransmitter concentrations, including dopamine and serotonin, in a time-of-day-dependent manner, the long-term effects of chronically timed exercise on neurotransmitter dynamics and behavioral phenotypes remain unclear. To examine whether the daily timing of a chronic exercise intervention modulates its impact on neurotransmitter profiles and fear responses, male rats were conditioned using a Pavlovian contextual fear approach, then assigned to a 4-week treadmill exercise intervention performed during the early (ZT14) or late (ZT22) active phase or a time-matched sham-exercise control group. One day after completing training, rats underwent a context retrieval test in the middle of active phase (ZT18), and hippocampal neurotransmitters were quantified using UPLC–MRM/MS. Rats subjected to sham-exercise at ZT22 exhibited higher freezing than sham-exercised rats at ZT14, whereas exercise interventions at ZT22 selectively attenuated freezing. Histamine, acetylcholine, and GABA exhibited significant exercise × time interactions. Direct neurotransmitter–freezing correlations were weak after false discovery rate control, consistent with a network-level reorganization rather than a single transmitter driver. These findings suggest that vulnerability to aversive memory expression can be buffered by exercise, if timed appropriately, and that exercise reshapes hippocampal neuromodulatory tone in a circadian–phase–dependent manner, supporting the potential of exercise timing as a chronotherapeutic strategy to enhance stress resilience and mental wellbeing.

Current Landscape of Mental Health Conversational Agents From a Trauma-Informed Care Lens: Scoping Review

Background: Conversational agents (CAs) are increasingly used in mental health care to enhance access and engagement. However, their safe, ethical, and user-sensitive design remains a challenge. Despite growing attention to trauma-informed approaches in human-computer interaction, there is limited work on how the trauma-informed care (TIC) framework could be applied in the design of mental health CAs and no comprehensive synthesis to date. Objective: Guided by the Substance Abuse and Mental Health Services Administration’s TIC framework, this scoping review explored how TIC principles (safety; trustworthiness and transparency; collaboration and mutuality; empowerment, voice, and choice; peer support; and cultural, historical, and gender issues) are currently represented in the design and evaluation of mental health conversational agents (MHCAs) and identified gaps and opportunities to promote more trauma-informed design practices. Methods: Online databases, as well as a secondary survey of citation lists from an initial search, were used to identify English-language journal articles and conference proceedings from 2000 to 2024 that empirically evaluated an independent, web- or app-based, unassisted CA used for mental health and included concepts from TIC. Results: Our analysis included 38 publications (n=28, 73.7%, published in 2020 or later) covering 28 distinct MHCAs. Most studies used experimental methods (n=23, 60.6%) or user studies (n=11, 28.9%), with samples skewed toward female (men: mean 34.92%, SD 18.64%), young in age (mean 32.52, SD 14.6 y), and predominantly nonclinical (n=29, 76.3%). MHCAs were largely rule-based prototypes. No studies explicitly referenced the TIC framework as a guiding lens for MHCA design or evaluation. A total of 26 studies referenced terminology from TIC core principles but rarely defined them, while all 38 included language that could be linked to one or more principles. Overall, TIC-related concepts appeared most often within intervention design descriptions, qualitative assessments, or as items embedded in questionnaires evaluating broader constructs. Trustworthiness and transparency, safety, empowerment, voice and choice, and collaboration and mutuality were comparatively well addressed, while peer support and cultural, historical, and gender issues were largely absent. Design recommendations, where present, were relatively broad and emphasized secure, customizable, reliable, human-like, and context-sensitive MHCAs that offered multimodal interaction, goal setting and tracking, and transparency. Conclusions: Studies did not self-identify as using Substance Abuse and Mental Health Services Administration’s framework for TIC, making it more difficult to identify its elements. The fragmented terms, disciplines, and metrics used make it difficult to draw more systematic conclusions about the current research landscape related to TIC, but our analysis indicates TIC to be a descriptive and potentially unifying framework and provides a starting point for the explicit trauma-informed MHCA research and design.
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Combinatorial effects of multi-site stimulation on depression-related brain regions: clinical data analysis and predictive modeling

BackgroundDespite growing evidence supporting deep brain stimulation (DBS) for treatment- resistant depression (TRD), how stimulation delivered across hemispheres or across multiple targets interact to shape large-scale network activity remains poorly characterized.ObjectiveUsing a unique opportunity to simultaneously stimulate the subcallosal cingulate (SCC) and ventral capsule/ventral striatum (VC/VS) in subjects with TRD while recording neural activity across putative prefrontal networks underlying depression via intracranial electrodes, we investigated whether bilateral or multi-target stimulation has additive, synergistic/super-additive, or antagonistic/sub-additive effects on power modulation across depression-related brain networks.MethodsFour DBS leads, and ten stereo-electroencephalography (sEEG) leads were implanted in depression-related prefrontal brain regions in three subjects with TRD. Power modulation in response to unilateral and bilateral stimulation, as well as interaction classes of combinatorial stimulations, were evaluated across various combinations of frequency bands and region of interests (ROI) using marginal predictions from a linear mixed-effects model which were then used as input for machine learning classifiers to predict the additive interaction class of combinatorial stimulations.ResultsBilateral and multi-target stimulation produced additive or sub-additive interactions in most cases. A decision tree classifier identified ROI as the most important feature for predicting interaction class, followed by stimulation target and spectral frequency band.

‘Type’ Casting: Flagship-Founded Serif Modifying DNA into New Therapy Class

What happens when the scalability and redosability of messenger RNA (mRNA) is combined with the durability and programmability of gene therapy?

According to Serif Biomedicines, a five-year-old startup that emerged from stealth mode this month, the result is “modified DNA,” a new class of therapeutics designed to be programmable, durable, scalable, and redosable—while minimizing the drawbacks of both mRNA and gene therapy.

Modified DNA builds upon generative protein and mRNA platforms created by Flagship Pioneering, the venture capital giant which founded Serif in 2021. On April 21, Flagship formally launched Serif with an initial commitment of $50 million in financing—capital that Serif intends to use toward developing its scalable platform for optimizing and manufacturing Modified DNA treatments, aided by artificial intelligence (AI), and advancing its first drug discovery programs.

“The reason we’re bringing the company out of stealth mode now is we think we have made progress. We’ve made real progress that we’re excited to share with the world, that we’re excited to get feedback from the broader scientific community on, and we want to tell that story more broadly,” Jacob (Jake) Rubens, PhD, Serif’s co-founder and CEO, and an Orig­i­na­tion Part­ner at Flag­ship Pio­neer­ing, told GEN.

“It’s been on our minds for a long time: What might be possible when DNA becomes an engineerable biotechnology for the first time?”

It’s a question pursued by numerous researchers and companies over the years as they sought to capitalize on DNA’s qualities of being a durably expressing molecule capable of coding for any gene, producing proteins or RNAs in a cell-specific way, as well as being scalable to manufacture and capable of re-dosing for patients.

“Those are, I think, the key differentiating attributes of theoretical DNA medicines. So the question for us became not, would this be valuable if we could do it, but why hasn’t anyone done it yet?” Rubens explained. “We’ve known about the centrality of DNA in biology, the central information molecule in DNA. We’ve known this for 75 years since Watson and Crick’s seminal discoveries around how the structure of DNA enabled it to function as an information molecule.”

Two key problems

Jacob (Jake) Rubens, PhD, Serif Biomedicines co-founder and CEO

“And when we looked at this space,” he continued, “we saw that there were two key problems: The first is that DNA is a highly inflammatory molecule. The second is that DNA needs to be delivered not just into a cell, but into the nucleus, the center of the cell.”

To create Mod­i­fied DNA, Serif alters the struc­tur­al and chem­i­cal form of DNA in order to min­i­mize innate immuno­genic­i­ty as lipid nanoparticles drop off the DNA not in the nucleus, but in the cytoplasm of the cell.

Once inside the cell nucleus, Mod­i­fied DNA reverts to unmod­i­fied DNA, enabling tran­scrip­tion into ther­a­peu­tic RNA and proteins. The resulting treatments are designed to last longer, be giv­en more than once, and be pro­grammed for cell-spe­cif­ic expres­sion. To enhance durability, Serif delivers with its Mod­i­fied DNA proteins which help the DNA access the nucleus. The proteins, called mRNA co-fac­tors, are designed to tran­sient­ly express pro­teins that enhance entry into the nucleus and gene expression.

Pending an announcement it expects to make later this year, Serif isn’t revealing specifics of its initial drug discovery programs, except to say that they focus on rare diseases and immune programming.

“This is not meant to be a limited list of where we could go but the areas that we think we’re going to go first, which are likely in addressing protein deficiencies in genetic diseases,” Rubens said.

Modified DNA has shown itself to be disease agnostic, he added, reflecting DNA’s qualities as a general, programmable information molecule: “One of the reasons we’re so excited about, the future of modified DNA as a new biotechnology akin to RNA, akin to protein, is its centrality in biology. It is the fundamental information molecule inside of all of us, inside of every living thing on this planet. So that is really the existence proof that it is generalizable.”

Tolerability and sustained expression

Also later this year, Serif plans to present data at an as-yet-unspecified scientific conference that will show modified DNA’s tolerability in non-human primates, as well as sustained gene expression with therapeutic effects in preclinical models following intravenous (IV) administration.

Serif aims to transform Modified DNA into treatments as effectively and commercially successfully as Amgen, Genentech (now a member of the Roche Group), and later Regeneron did with engineered proteins, as Alnylam Pharmaceuticals did with small interfering RNA (siRNA), and as Moderna more recently accomplished with mRNA—most notably in developing its SpikeVax® COVID-19 vaccine, which the FDA authorized for emergency use in 2020 and fully approved in 2022.

Flagship launched Moderna in 2010; the company went public in 2018 by raising $604 million, the largest-ever U.S. biotech initial public offering (IPO) until Kailera Therapeutics raised $625 million earlier this month.

At Flagship, Rubens is a sci­en­tist entre­pre­neur who leads the firm’s Pio­neer­ing Busi­ness Unit, which establishes and grows com­pa­nies based on new biotechnology. In addition to Serif, Rubens co-founded Quo­tient Ther­a­peu­tics, which develops therapies based on its somatic genomics platform; Tessera Ther­a­peu­tics, which writes therapeutic messages into the genome through a genome engineering approach called GeneWriting™; and Sana Biotech­nol­o­gy, a developer of treatments based on engineered cells. He also launched Kalei­do Bio­sciences, a microbiome therapeutics company that ceased operations in 2022.

Before join­ing Flagship, Jake received his PhD in micro­bi­ol­o­gy from MIT, work­ing with Tim Lu, MD, PhD, a core member of the Synthetic Biology Center, through the sup­port of a Nation­al Sci­ence Foun­da­tion Grad­u­ate Research Fel­low­ship. At MIT, Jake helped enable ​“intel­li­gent” cell therapies by invent­ing gene cir­cuits that allow engi­neered cells to do nov­el ana­log, dig­i­tal, and hybrid com­pu­ta­tions.

Based in Cambridge, MA, Serif employs about 50 people and as of Wednesday was disclosing five open positions on its website in its three areas of focus: Chemistry (associate scientist and senior scientist, both specializing in LNP formulations), Molecular Biology (research associate and senior scientist), and Research/Discovery (scientist specializing in bioanalytical assays).

“I’m not at this point going to provide any guidance on how much more we will or won’t grow,” Rubens said. “We’re quite agile and responsive to the company’s needs.”

The post ‘Type’ Casting: Flagship-Founded Serif Modifying DNA into New Therapy Class appeared first on GEN – Genetic Engineering and Biotechnology News.

Medication Treatment for Tics and Tourette’s

There are several kinds of medication than can help kids with Tourette’s or another tic disorder. But it’s important to note that not all kids who develop tics need treatment. Tics are very common. They often go away on their own, and they tend to bother parents more than they do the children experiencing them. Drawing attention to them can make them worse. So doing nothing can be the best strategy — at least initially.

Treatment comes into play if tics are upsetting your child, giving them pain, or making it hard for them to function in everyday life — say they’re disrupting class or getting bullied because of their tics.

The first recommended step in treatment is a specialized form of therapy called comprehensive behavioral intervention for tics (CBIT). CBIT is centered on habit reversal training, in which the child learns to recognize when they have an urge to tic and substitute a competing response — an easier, more comfortable, or less noticeable action or behavior that makes the tic impossible. For instance, if a child’s tic is jerking their head to the side, the strategy might be to put their chin down instead.

But if therapy isn’t effective in reducing a child’s tics, medication can help.

Guanfacine and clonidine for tics

First-line medications for Tourette’s and other tic disorders are a class of drugs called alpha-2 agonists, explains Paul Mitrani, MD, PhD, a child and adolescent psychiatrist at the Child Mind Institute. Alpha agonists decrease the release of a neurotransmitter called norepinephrine, which stimulates the nervous system. Alpha agonists serve as a kind of dimmer switch — by calming down the system, they make the urge to tic less frequent, less intense, and by extension, easier to control.

The two alpha-2 agonists usually prescribed for tics are guanfacine and clonidine. Dr. Mitrani reports that he usually starts by prescribing guanfacine because it comes in a longer-acting form (Intuniv), which reduces symptoms for a full 24 hours. Clonidine’s long-acting form (Kapvay) is effective for 12 hours.

Dr. Mitrani adds that there is a new liquid form of clonidine called Onyda XR that lasts 24 hours, but there isn’t yet a strong body of evidence regarding its effectiveness for tics. Onyda XR is FDA-approved for ADHD, as are Kapvay and Intuniv.

While no alpha agonist medications are FDA-approved specifically for tics, Kapvay and Intuniv are frequently used off-label for them. There is ample research on their effectiveness for tics, and they are recommended by clinical practice guidelines.

Some children respond better to several doses of short-acting guanfacine or clonidine, Dr. Mitrani notes, rather than a smoother dose of a long-acting medication. This may be because medication can be timed to peak at times when kids need tic suppression most, such as at school.

Alpha agonists are the preferred first line medications for tic disorders because their side-effects, including drowsiness and low blood pressure, are relatively mild.

Antipsychotics for tics

If alpha agonists aren’t helping, the next step would be to try an antipsychotic medication, which can be more effective for treating tics, Dr. Mitrani notes, but their side effects are potentially more difficult to tolerate.

Aripiprazole (Abilify), which is FDA-approved for tics, is often Dr. Mitrani’s first choice among the antipsychotic medications. Abilify is a second-generation, or atypical, antipsychotic, a group of medications that have fewer side effects than older antipsychotics. Side effects of Abilify can include restlessness, agitation and weight gain.

Haloperidol (Haldol) is also effective for tics, but it’s an older antipsychotic with more side effect concerns, Dr. Mitrani notes. “I’ve only had one patient ever on Haldol, and he tolerated it well and it really helped with his tics when other things did not.”

Risperidone (Risperdal) is another atypical antipsychotic that can help, but its side effects tend to be worse than Abilify. Risperidone can cause more concerning weight gain and metabolic, neurological, and hormonal changes that can be harmful. Sometimes other medications are used to manage the weight gain from antipsychotics.

When kids with tics also have ADHD

More than three-quarters of kids diagnosed with a tic disorder also have another disorder. When a child has multiple disorders, a clinician will want to evaluate which is causing the child the most difficulty and prioritize treating that.

The most common co-occurring disorder with tics is ADHD. “If tics are the bigger problem, we would start with treating them,” says Dr. Mitrani. “If the ADHD is the bigger problem, which it typically is, we usually treat that first.”

In the past, it was recommended that children with tics and ADHD avoid stimulant medication, based on research that showed it made tics worse. But newer studies counter that finding, Dr. Mitrani notes, concluding that the old research was based on very high doses of amphetamine-based medications. To lower the risk of exacerbating tics, he recommends starting kids with ADHD and tics on methylphenidate-based medication.

“If your child is starting a stimulant,” he adds, “and you see worsening of tics — and it’s clearly related to when the stimulant is in their system — the best approach might be a lower dose of stimulant combined with guanfacine or clonidine.”

One advantage to that combination, he notes, is that kids with ADHD who have behavior problems can benefit from the guanfacine or clonidine being active in the mornings before the stimulant starts working and in the evenings when it’s out of their system.

Kids with other co-occurring disorders

When children with tics have other co-occurring disorders, such as anxiety, OCD, or depression, treating them with medication needs to be done very carefully, Dr. Mitrani says. Since children are typically not bothered by the tics themselves, it’s almost always the other disorder that is more problematic for them.  And, he adds, when the other problems cause distress, it can make the tics worse.

For anxiety, OCD, and depression, the first-line medication treatment is an antidepressant. Antidepressants can actually help alleviate tics indirectly, since they reduce anxiety. “Stress increases tics, so if there is significant anxiety and you treat the anxiety, the tics may get better,” Dr. Mitrani says. “And then maybe you don’t need the guanfacine or clonidine. But again, it depends on what the co-occurring disorders are and what’s the bigger problem for the child.”

Monitoring medication for tics

Due to the waxing and waning nature of tics, it can be challenging to see the full effect of medication and other interventions. It is important to give medication enough time to work, Dr. Mitrani notes, typically a few weeks, to see if the overall pattern, frequency, and severity of tics has improved. And children who are being treated should continue to be monitored regularly for any changes, as tics can recur or worsen, especially when a child is excited, tired, or experiencing more stress.

Most children with tics see a natural improvement or even resolution of tics as they progress through adolescence. If there seems to be a long-standing improvement, it is appropriate to consider reducing or stopping medication, especially if the child is experiencing side effects, Dr. Mitrani notes. If tics continue and are causing distress, it is important to keep treating them.

A child going off any of these medications — alpha agonists or antipsychotics — should do so gradually, by having their dose reduced over weeks or even longer, to avoid unpleasant or dangerous side effects of sudden withdrawal.

The post Medication Treatment for Tics and Tourette’s appeared first on Child Mind Institute.

GABA-Based Target for Alzheimer’s Therapy Identified

Researchers at the University of Galway have found evidence that targeting inhibitory signaling in the brain may help address cognitive dysfunction in Alzheimer’s disease (AD), a finding that runs counter to current therapeutic approaches that focus on influencing excitatory pathways. The research, published in Neuropharmacology, identifies how modulation of gamma-aminobutyric acid (GABA) signaling can restore disrupted neural balance and improve memory-related function in AD disease models.

“Given the ever-increasing burden of Alzheimer’s disease, the urgent need for the identification of novel targets for the development of disease-modifying therapy is clear,” said senior author Andrea Kwakowsky, PhD, associate professor of pharmacology and lead researcher at the School of Medicine, University of Galway.

Alzheimer’s disease is characterized by progressive cognitive impairment and is associated with hallmark pathological features including β-amyloid (Aβ) plaques and neurofibrillary tangles. In addition to these, disruption of the brain’s excitatory/inhibitory (E/I) balance has gained traction as a central mechanism contributing to memory loss. Today, most approved therapies for AD target excitatory neurotransmitter systems such as cholinergic and glutamatergic pathways, but “the symptomatic relief provided by these therapies is only marginal, and the progression or underlying causes of the disease are not addressed,” the researchers noted.

For their work, the University of Galway team instead focused on the inhibitory side of this balance, specifically the role of gamma-aminobutyric acid (GABA), the brain’s main inhibitory neurotransmitter. GABA regulates neuronal activity and is essential for maintaining stable network function and memory processes. In AD, however, E/I balance becomes dysregulated with increased extracellular GABA—triggered in part by Aβ—leading to overactivation of certain GABA receptors, particularly α5-containing GABA type A receptors (α5-GABA ARs), which are abundant in the hippocampus. The result is a dampening of neuronal signaling and which impairs learning and memory.

“Our research is significant in that it demonstrates that if we block this GABA receptor activity in nerve cells we can reverse Alzheimer-like effects caused by amyloid beta and improve cognitive performance,” Kwakowsky said.

To test whether blocking a5-GGABA A could help restore E/I balance, the team investigated α5IA, an α5-GABA AR-selective inverse agonist. α5IA works by reducing the activity of α5-GABA ARs, which decreases excess tonic inhibition. The data showed that in experimental models of AD, the compound improved long-term potentiation (LTP), a mechanism of synaptic plasticity and memory, reduced abnormal inhibitory conductance, and restored spatial memory performance.

Mechanistically, α5IA appears to act by restoring physiological levels of inhibition in the hippocampus which is critical for memory formation. By reducing excessive tonic inhibition, it rebalances E/I signaling, which allows neuronal circuits to function more effectively. “The data presented here suggest that in both ex vivo and in vivo AD models, α5IA improves cognitive function by restoring CA1 tonic inhibition, thereby re-establishing E/I balance and ameliorating the abnormal hippocampal network activity induced by Aβ1-42,” the researchers wrote.

This new study is the latest to indicate that targeting inhibitory neurotransmission could be an effective treatment approach for AD. Earlier research has shown that α5-GABA AR modulation enhances memory and reduces inhibitory signaling in both animal models and humans. But most of these studies have not directly examined the effect of α5IA in chronic neurodegenerative disease models.

The researchers noted there are some limitations to their work, pointing out that while α5IA improved cognitive outcomes, it did not reverse neuronal loss in vivo, suggesting that its effects may be primarily functional rather than neuroprotective at later stages of AD. Also, variability in drug exposure and timing may influence outcomes. Finally long-term use of α5IA has also been associated with safety concerns at high doses, including renal toxicity, so further research is needed to determine toxicity and dosing regimens and limits.

Nonetheless, the implications of this research indicate there is potential to develop new AD therapies that directly target network dysfunction rather than focusing solely on amyloid accumulation or excitatory signaling. By restoring E/I balance, this approach shows the potential to improve cognitive function even when AD pathology has taken root. The findings could also benefit diagnostic methods, as biomarkers of inhibitory dysfunction or altered GABA signaling could help identify patients who would benefit an approach that rebalances E/I signaling.

The post GABA-Based Target for Alzheimer’s Therapy Identified appeared first on Inside Precision Medicine.

Altered static and dynamic regional homogeneity in basal ganglia–thalamocortical circuits and their association with neuropsychiatric manifestations in Wilson’s disease

PurposeWilson’s disease (WD) is an autosomal recessive disorder caused by ATP7B mutations, resulting in impaired copper metabolism and progressive neuropsychiatric manifestations. This study investigated spatiotemporal alterations in regional brain activity using static and dynamic resting-state fMRI with regional homogeneity (ReHo), and their relationships with clinical features.MethodsResting-state fMRI data were acquired from WD patients and healthy controls (HCs). Static and dynamic ReHo analyses were performed to characterize local synchronization strength and temporal variability of spontaneous neural activity. Group differences were assessed across the basal ganglia, thalamus, cerebellum, and cortical regions. Associations between altered ReHo metrics and clinical measures were evaluated with FDR correction for multiple comparisons.ResultsCompared with HCs, WD patients exhibited widespread ReHo abnormalities involving the basal ganglia (putamen and globus pallidus), thalamus, cerebellum, and cortical regions. Static ReHo in the left putamen and globus pallidus was positively associated with anxiety severity, while right putaminal ReHo was negatively associated with neurological severity and positively associated with disease duration. Dynamic ReHo in the left middle frontal gyrus showed negative associations with depression severity and disease duration. All brain–behavior correlations survived FDR correction, indicating robust effects.ConclusionWD is characterized by disrupted spatiotemporal organization of local functional synchronization within cerebellar and basal ganglia–thalamo–cortical circuits. These findings support a network-level dysfunction model involving subcortical synchronization deficits and cortical temporal instability, which together underpin neuropsychiatric manifestations and disease progression.