Cognitive Impairment Associated With Schizophrenia Research Articles

Psychiatric and functional correlates of stigma associated with cognitive impairment in schizophrenia

Schizophrenia is the most strongly stigmatized psychiatric diagnosis, with negative stereotypes including assumptions of incompetence and inability to recover. Individuals with cognitive impairment associated with schizophrenia (CIAS) have reported stigma experiences, suggesting that CIAS carries stigma in addition to the stigma associated with schizophrenia as a diagnostic label. While research has established that mental illness stigma more generally is linked with poor psychiatric and functional outcomes, no research has explored correlates of CIAS stigma. This study evaluated cognitive, psychiatric, and functional correlates of CIAS stigma among 54 individuals with schizophrenia spectrum disorders participating in a cognitive remediation trial. Participants with greater estimated cognitive decline reported higher levels of CIAS stigma experiences. Participants who reported higher levels of CIAS stigma also scored higher on a measure of depressive symptom severity. No significant associations were found between CIAS stigma and positive and negative psychosis symptoms or general psychopathology ratings. CIAS stigma was not associated with performance-based functional capacity or ratings of community functioning. Findings suggest that CIAS stigma is linked with the degree of cognitive decline and depressive symptom severity among individuals with schizophrenia spectrum disorders. Additional research is needed to elucidate directionality and the relationship between CIAS stigma and functioning outcomes.

Treatment of Cognitive Impairment Associated with Schizophrenia Spectrum Disorders: New Evidence, Challenges, and Future Perspectives.

Cognitive impairment associated with schizophrenia (CIAS) represents one of the core features of the disorder and has a significant impact on functional and rehabilitation outcomes of people living with schizophrenia spectrum disorders (SSD). The aim of this critical review is to highlight the most recent evidence on effective treatments available for CIAS, to discuss the current challenges in this field, and to present future perspectives that may help to overcome them. Concerning psychopharmacological approaches, among the most indicated strategies for the management and prevention of CIAS is to favor second-generation antipsychotic medications and avoid long-term and high-dose treatments with anticholinergic medications and benzodiazepines. Moreover, non-pharmacological approaches such as cognitive remediation and physical exercise-based programs represent evidence-based interventions in the treatment of CIAS that have shown reliable evidence of effectiveness on both cognitive and functional outcomes. These treatments, however, are still delivered to people accessing mental health services with a diagnosis of CIAS in an uneven manner, even in high-income countries. Academic and clinical partnership and collaboration, as well as advocacy from service users, families, carers, and stakeholders' organizations could help to reduce the bench to bedside gap in the treatment of CIAS. Future perspectives include the development of novel pharmacological agents that could be effective in the treatment of CIAS, the implementation of novel technologies such as telemedicine and virtual reality in the delivery of evidence-based interventions to improve accessibility and engagement, and further research in the field of non-invasive brain stimulation.

Perceived Stigma Toward Cognitive Impairment Among People With Schizophrenia.

Stigma toward schizophrenia spectrum disorders is pervasive and negatively influences service access and delivery. Cognitive impairment associated with schizophrenia (CIAS) is common, but its association with stigma is unknown. In this study, the authors examined whether individuals with CIAS receiving cognitive remediation treatment report experiencing CIAS-related stigma and sought to establish associations between CIAS-related stigma and recovery-relevant outcomes. Data from 48 individuals with schizophrenia spectrum diagnoses were drawn from a larger study evaluating cognitive remediation. Participants completed measures of CIAS-related stigma, internalized mental illness stigma, self-perceived cognitive impairment, cognitive performance, and interviewer-rated quality of life. CIAS-related stigma was commonly reported and significantly positively associated with internalized stigma and self-perceived cognitive impairment. CIAS-related stigma was also significantly negatively associated with motivation to engage in goal-directed behavior and daily activities. CIAS-related stigma exists and warrants additional exploration with regard to implications for psychiatric service delivery.

Measuring Cognitive Impairments Associated With Schizophrenia in Clinical Practice: Overview of Current Challenges and Future Opportunities.

Cognitive impairment associated with schizophrenia (CIAS) negatively impacts daily functioning, quality of life, and recovery, yet effective pharmacotherapies and practical assessments for clinical practice are lacking. Despite the pivotal progress made with establishment of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) for clinical research, implementation of the full MCCB is too time-consuming and cost-ineffective for most clinicians in clinical practice. Here we discuss current assessments in relation to delivery format (interview-based and performance-based), validity, ease of use for clinicians and patients, reliability/reproducibility, cost-effectiveness, and suitability for clinical implementation. Key challenges and future opportunities for improving cognitive assessments are also presented. Current assessments that require 30min to complete would have value in clinical settings, but the associated staff training and time required might preclude their application in most clinical settings. Initial profiling of cognitive deficits may require about 30min to assist in the selection of evidence-based treatments; follow-up monitoring with brief assessments (10-15min in duration) to detect treatment-related effects on global cognition may complement this approach. Guidance on validated brief cognitive tests for the strategic monitoring of treatment effects on CIAS is necessary. With increased advancements in technology-based and remote assessments, development of validated formats of remote and in-person assessment, and the necessary training models and infrastructure required for implementation, are likely to be of increasing clinical relevance for future clinical practice.

New clues for the role of cerebellum in schizophrenia and the associated cognitive impairment.

Schizophrenia (SZ) is a complex neuropsychiatric disorder associated with severe cognitive dysfunction. Although research has mainly focused on forebrain abnormalities, emerging results support the involvement of the cerebellum in SZ physiopathology, particularly in Cognitive Impairment Associated with SZ (CIAS). Besides its role in motor learning and control, the cerebellum is implicated in cognition and emotion. Recent research suggests that structural and functional changes in the cerebellum are linked to deficits in various cognitive domains including attention, working memory, and decision-making. Moreover, cerebellar dysfunction is related to altered cerebellar circuit activities and connectivity with brain regions associated with cognitive processing. This review delves into the role of the cerebellum in CIAS. We initially consider the major forebrain alterations in CIAS, addressing impairments in neurotransmitter systems, synaptic plasticity, and connectivity. We then focus on recent findings showing that several mechanisms are also altered in the cerebellum and that cerebellar communication with the forebrain is impaired. This evidence implicates the cerebellum as a key component of circuits underpinning CIAS physiopathology. Further studies addressing cerebellar involvement in SZ and CIAS are warranted and might open new perspectives toward understanding the physiopathology and effective treatment of these disorders.

Novel α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) potentiator LT-102: A promising therapeutic agent for treating cognitive impairment associated with schizophrenia.

We aimed to evaluate the potential of a novel selective α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) potentiator, LT-102, in treating cognitive impairments associated with schizophrenia (CIAS) and elucidating its mechanism of action. The activity of LT-102 was examined by Ca2+ influx assays and patch-clamp in rat primary hippocampal neurons. The structure of the complex was determined by X-ray crystallography. The selectivity of LT-102 was evaluated by hERG tail current recording and kinase-inhibition assays. The electrophysiological characterization of LT-102 was characterized by patch-clamp recording in mouse hippocampal slices. The expression and phosphorylation levels of proteins were examined by Western blotting. Cognitive function was assessed using the Morris water maze and novel object recognition tests. LT-102 is a novel and selective AMPAR potentiator with little agonistic effect, which binds to the allosteric site formed by the intradimer interface of AMPAR's GluA2 subunit. Treatment with LT-102 facilitated long-term potentiation in mouse hippocampal slices and reversed cognitive deficits in a phencyclidine-induced mouse model. Additionally, LT-102 treatment increased the protein level of brain-derived neurotrophic factor and the phosphorylation of GluA1 in primary neurons and hippocampal tissues. We conclude that LT-102 ameliorates cognitive impairments in a phencyclidine-induced model of schizophrenia by enhancing synaptic function, which could make it a potential therapeutic candidate for CIAS.

Management of cognitive symptoms in schizophrenia.

IntroductionCognitive impairment is the frequent symptom occurring in nonelderly patients with schizophrenia or other neurodegenerative disorders. Cognitive dysfunction in patients with schizophrenia was described by Kraepelin more than a century ago. Increased awareness and advancements in the area of neuropsychological assessment and neuroimaging techniques have now rendered cognitive impairment an important focus of theories on the etiology and treatment of schizophrenia. Cognitive enhancement still remains a clinically unresolved challenge. Till date, there is no effective treatment available for enhancing cognitive function in patients with schizophreniaObjectivesThis e-poster aimed to summarize evidence regarding clinical data on the nonpharmacologic and pharmacologic management of cognitive symptoms of schizophrenia, also known as cognitive impairment associated with schizophrenia (CIAS), and highlight the selection of appropriate treatment options.MethodsA bibliopgraphical review was performed using PubMed platform. All relevant articles were found using the keywords: schizophrenia, cognitive symptoms, menagement.ResultsMany different drug targets and strategies for drug development have been employed for enhancement of cognition in schizophrenia. Receptor targets have been identified on the basis of pharmacologic challenges that mimic schizophrenia (e.g., dopamine agonists and NMDA receptor antagonists), receptor abnormalities found on postmortem analysis of schizophrenia brain, and genetic linkage studies. Treatment with a D1 agonist was shown to “sensitize” D1 receptors and improve memory in both aged and antipsychotic-treated monkeys. Clinical trials of D1 agonists in schizophrenia have been delayed due to poor tolerability related to orthostatic hypotension and nausea. The glycine-site agonists, glycine, D-serine, and D-alanine, produced improvement in negative symptoms in small trials and some improvement in measures of cognition, although formal cognitive testing was not performed.ConclusionsAlthough the evidence supporting cognitive remediation has not yet achieved the level necessary to merit inclusion in evidence-based treatment guidelines, this approach, combined with other psychosocial interventions, is promising. Several pharmacologic approaches are currently under study to facilitate neuroplasticity.Disclosure of InterestNone Declared

Pharmacological Treatment of Cognitive Impairment Associated With Schizophrenia: State of the Art and Future Perspectives.

Cognitive Impairment Associated with Schizophrenia (CIAS) represents one of the core dimensions of Schizophrenia Spectrum Disorders (SSD), with an important negative impact on real-world functional outcomes of people living with SSD. Treatment of CIAS represents a therapeutic goal of considerable importance, and while cognition-oriented evidence-based psychosocial interventions are available, effective pharmacological treatment could represent a game-changer in the lives of people with SSD. The present critical review reports and discusses the evidence regarding the effects of several pharmacological agents that are available in clinical practice or are under study, commenting on both current and future perspectives of CIAS treatment. In particular, the effects on CIAS of antipsychotic medications, anticholinergic medications, benzodiazepines, which are currently commonly used in the treatment of SSD, and of iclepertin, d-serine, luvadaxistat, xanomeline-trospium, ulotaront, anti-inflammatory molecules, and oxytocin, which are undergoing regulatory trials or can be considered as experimental agents, will be reported and discussed. Currently, available pharmacological agents do not appear to provide substantial benefits on CIAS, but accurate management of antipsychotic medications and avoiding treatments that can further exacerbate CIAS represent important strategies. Some molecules that are currently being investigated in Phase 2 and Phase 3 trials have provided very promising preliminary results, but more information is currently required to assess their effectiveness in real-world contexts and to provide clear recommendations regarding their use in clinical practice. The results of ongoing and future studies will reveal whether any of these molecules represents the awaited pharmacological game-changer in the treatment of CIAS.

The potential of muscarinic M1 and M4 receptor activators for the treatment of cognitive impairment associated with schizophrenia.

Cognitive impairment is a core symptom of schizophrenia and a major determinant of poor long-term functional outcomes. Despite considerable efforts, we do not yet have any approved pharmacological treatments for cognitive impairment associated with schizophrenia (CIAS). A combination of advances in pre-clinical research and recent clinical trial findings have led to a resurgence of interest in the cognition-enhancing potential of novel muscarinic acetylcholine receptor (mAChR) agonists in schizophrenia. This article provides an overview of the scientific rationale for targeting M1 and M4 mAChRs. We describe the evolution of neuroscience research on these receptors since early drug discovery efforts focused on the mAChR agonist xanomeline. This work has revealed that M1 and M4 mAChRs are highly expressed in brain regions that are implicated in cognition. The functional significance of M1 and M4 mAChRs has been extensively characterized in animal models via use of selective receptor subtype compounds through neuronal and non-neuronal mechanisms. Recent clinical trials of a dual M1/M4 mAChR agonist show promising, replicable evidence of potential pro-cognitive effects in schizophrenia, with several other mAChR agonists in clinical development.

The histamine system and cognitive function: An in vivo H3 receptor PET imaging study in healthy volunteers and patients with schizophrenia.

The histamine-3 receptor (H3R) is an auto- and heteroreceptor that inhibits the release of histamine and other neurotransmitters. Post-mortem evidence has found altered H3R expression in patients with psychotic disorders, which may underlie cognitive impairment associated with schizophrenia (CIAS). We used positron emission tomography (PET) imaging to compare brain uptake of an H3R selective tracer between patients with schizophrenia and matched controls (healthy individuals). Regions of interest included the dorsolateral prefrontal cortex (DLPFC) and striatum. We explored correlations between tracer uptake and symptoms, including cognitive domains. A total of 12 patients and 12 matched controls were recruited to the study and were assessed with psychiatric and cognitive rating scales. They received a PET scan using the H3R-specific radioligand [11C]MK-8278 to determine H3R availability. There was no statistically significant difference in tracer uptake between patients and controls in the DLPFC (t19 = 0.79, p = 0.44) or striatum (t21 = 1.18, p = 0.25). An exploratory analysis found evidence for lower volume of distribution in the left cuneus (pFWE-corrected = 0.01). DLPFC tracer uptake was strongly correlated with cognition in controls (trail making test (TMT) A: r = 0.77, p = 0.006; TMT B: rho = 0.74, p = 0.01), but not in patients (TMT A: r = -0.18, p = 0.62; TMT B: rho = -0.06, p = 0.81). These findings indicate H3R in the DLPFC might play a role in executive function and this is disrupted in schizophrenia in the absence of major alterations in H3R availability as assessed using a selective radiotracer for H3R. This provides further evidence for the role of H3R in CIAS.

A Patient-Clinician Discussion of Current Challenges in Schizophrenia Part 1: Addressing Daily Functioning and Cognitive Impairments Associated with Schizophrenia [Podcast

Dr John M. Kane discusses cognitive impairments in schizophrenia with fellow expert Dr Philip D. Harvey and patient advocate and mental health clinician, Mr Carlos A. Larrauri, who was diagnosed with schizophrenia. The podcast aims to raise awareness of the unmet need to address cognitive impairments associated with schizophrenia (CIAS) as well as the challenges/opportunities faced by patients and clinicians regarding assessments and treatments. The authors emphasize the importance of a treatment focus on daily functioning, in parallel with cognitive symptoms, to mitigate impairments and improve overall outcomes. Mr Larrauri presents the patient perspective and shares his experiences of how psychosocial support and cognitive training can benefit recovery and help patients achieve their goals.

Combining Iclepertin (BI 425809) With Computerized Cognitive Training in Patients With Schizophrenia: Baseline Data From an Ongoing Phase II Trial

AbstractIntroductionThere are currently no approved pharmacotherapies to treat cognitive impairment associated with schizophrenia (CIAS). Iclepertin (BI 425809) is a novel glycine transporter-1 inhibitor under development for treatment of CIAS. A previous study demonstrated pro-cognitive effects of iclepertin in patients with schizophrenia; however, concurrent cognitive stimulation could in theory enhance any pro-cognitive pharmacological effects on neuroplasticity. We present preliminary demographics and baseline data from a trial exploring the efficacy of iclepertin together with at-home computerized cognitive training (CCT).MethodsThis is an ongoing Phase II, double-blind, placebo-controlled, parallel-group trial in patients with schizophrenia on stable antipsychotic therapy across ~58 centers in 6 countries. Patients aged 18–50 years, compliant with CCT during the run-in period (completing ≥2 hours/week for 2 weeks), were randomized (1:1) to receive once-daily iclepertin 10 mg or placebo together with CCT for 12 weeks. Thereafter, minimum compliance for at-home CCT is 1 hour/week, with a target of ~30 hours across 3–5 sessions totaling 2.5 hours/week. Patients have been stratified to balance potential effects of age (18–40; 41–50 years). Primary endpoint is change from baseline (CfB) in neurocognitive composite T-score of the MATRICS Consensus Cognitive Battery (MCCB) at Week 12. Secondary endpoints include CfB in the Schizophrenia Cognition Rating Scale (SCoRS) total score, MCCB overall composite T-score, and Positive and Negative Syndrome Scale (PANSS) total scores. Novel exploratory endpoints include the Virtual Reality Functional Capacity Assessment Tool to assess daily functioning and the Balloon Effort Task to assess motivation in cognitive performance.ResultsOf the planned sample of 200 randomized patients, the overall treated population currently includes 183: 67% (n=122) are male; mean (standard deviation [SD]) age and time since first diagnosis are 38.2 (7.9) years and 13.5 (8.5) years. Overall, 49% (n=89) are White and 43% (n=79) are Black or African American; 80% (n=147) are from North America, 15% (n=28) from Europe, and 4% (n=8) from Australia/New Zealand. Mean (SD) baseline MCCB neurocognitive composite and overall T-scores (n=178) are 33.7 (11.9) and 32.5 (12.6). Mean (SD) baseline SCoRS total score (n=167) is 35.2 (8.7). Mean (SD) baseline PANSS total and negative symptom scale scores (n=183) are 64.7 (14.6) and 17.3 (5.4). Median (Q1, Q3) CCT compliance over the on-treatment period for patients who have completed or discontinued early is 2.00 (1.21, 2.51) hours/week.ConclusionThis trial is, to our knowledge, the largest of its kind combining daily pharmacotherapy for CIAS with at-home CCT. It will indicate whether iclepertin together with concurrent cognitive stimulation provides enhanced cognitive benefit, and whether any improvements in neurocognition can translate into improved measures of daily functioning in patients.FundingBoehringer Ingelheim International GmbH (NCT03859973/1346-0038)

Handling prevents and reverses cognitive deficits induced by sub-chronic phencyclidine in a model for schizophrenia in rats

Treatments for schizophrenia are not effective in ameliorating cognitive deficits. Therefore, novel therapies are needed to treat cognitive impairments associated with schizophrenia (CIAS), which are modelled in rats through administration of sub-chronic phencyclidine (scPCP). We have previously shown that enrichment via voluntary exercise prevents and reverses impairments in novel object recognition (NOR) in this model.The present study aimed to investigate if handling could prevent delay-induced NOR deficits and prevent and reverse scPCP-induced NOR deficits.Two cohorts of adult female Lister Hooded rats were used. In experiment one, handling (five minutes/day, five days/week for two weeks), took place before scPCP administration (2 mg/kg, i.p. twice-daily for seven days). NOR tests were conducted at two, four, and seven weeks post-handling with a one-minute inter-trial interval (ITI) and at five weeks post-dosing with a six-hour ITI. In experiment two, rats were handled after scPCP administration and tested immediately in the one-minute ITI NOR task and again at two weeks post-handling.In both handling regimens, the scPCP control groups failed to discriminate novelty, conversely the scPCP handled groups significantly discriminated in this task. In the 6 h ITI test, vehicle control and scPCP control failed to discriminate novelty; however, the vehicle handled and scPCP handled groups did significantly discriminate.Handling rats prevented and reversed scPCP-induced deficits and prevented delay-induced NOR deficits. These findings add to evidence that environmental enrichment is a viable treatment for cognitive deficits in rodent tests and models of relevance to schizophrenia, with potential to translate into effective treatments for CIAS.

Qualitative Analysis of the Content Validity of the Virtual Reality Functional Capacity Assessment Tool (VRFCAT) in Schizophrenia: A Multi-Stakeholder Perspective.

The US Food and Drug Agency (FDA) requires clinical trials targeting cognitive impairment associated with schizophrenia (CIAS) to demonstrate the functional relevance of cognitive improvements by employing a functional co-primary measure. Although quantitative evidence supports the suitability of the Virtual Reality Functional Capacity Assessment Tool (VRFCAT) for this purpose, FDA guidelines for qualification of clinical outcome assessments require evidence of content validity, defined as qualitative evidence that key stakeholders view the measure as relevant and important. To collect this important qualitative data, semi-structured interviews were conducted with outpatients with schizophrenia (n = 24), caregivers (n = 12), and professional peer support specialists (n = 12) to elicit their views about the definition and importance of functional independence, the importance of the functional domains assessed by the VRFCAT (meal planning, using transportation, handling money, shopping), and the relevance of the VRFCAT tasks to these domains. Qualitative thematic analyses revealed consistent themes across groups in defining functional independence, including performing instrumental self-care, financial, and social tasks; making decisions autonomously; and not depending on others to carry out daily activities. There were, however, notable differences in their views regarding the importance of and barriers to functional independence. All groups viewed the VRFCAT as assessing skill domains that are central to independent functioning and, with some minor differences, the VRFCAT tasks were viewed as relevant and meaningful examples of the domains. These qualitative results provide converging evidence that key stakeholders view the VRFCAT as a content-valid measure.

Progress and Pitfalls in Developing Agents to Treat Neurocognitive Deficits Associated with Schizophrenia.

Cognitive impairments associated with schizophrenia (CIAS) represent a central element of the symptomatology of this severe mental disorder. CIAS substantially determine the disease prognosis and hardly, if at all, respond to treatment with currently available antipsychotics. Remarkably, all drugs presently approved for the treatment of schizophrenia are, to varying degrees, dopamine D2/D3 receptor blockers. In turn, rapidly growing evidence suggests the immense significance of systems other than the dopaminergic system in the genesis of CIAS. Accordingly, current efforts addressing the unmet needs of patients with schizophrenia are primarily based on interventions in other non-dopaminergic systems. In this review article, we provide a brief overview of the available evidence on the importance of specific systems in the development of CIAS. In addition, we describe the promising targets for the development of new drugs that have been used so far. In doing so, we present the most important candidates that have been investigated in the field of the specific systems in recent years and present a summary of the results available at the time of drafting this review (May 2022), as well as the currently ongoing studies.

Effects of the Glycine Transporter-1 Inhibitor Iclepertin (BI 425809) on Sensory Processing, Neural Network Function, and Cognition in Animal Models Related to Schizophrenia.

N-methyl-D-aspartate (NMDA) receptor hypofunction leading to neural network dysfunction is thought to play an important role in the pathophysiology of cognitive impairment associated with schizophrenia (CIAS). Increasing extracellular concentrations of the NMDA receptor co-agonist glycine through inhibition of glycine transporter-1 (GlyT1) has the potential to treat CIAS by improving cortical network function through enhanced glutamatergic signaling. Indeed, the novel GlyT1 inhibitor iclepertin (BI 425809) improved cognition in a recent clinical study in patients with schizophrenia. The present study tested the ability of iclepertin to reverse deficits in auditory sensory processing and cortical network function induced by the uncompetetive NMDA receptor antagonist, MK-801, using electroencephalography (EEG) to measure auditory event-related potentials (AERPs) and 40 Hz auditory steady-state response (ASSR). In addition, improvements in memory performance with iclepertin were evaluated using the T-maze spontaneous alternation test in MK-801-treated mice and the social recognition test in naïve rats. Iclepertin reversed MK-801-induced deficits in the AERP readouts N1 amplitude and N1 gating, as well as reversing deficits in 40 Hz ASSR power and intertrial coherence. Additionally, iclepertin significantly attenuated an MK-801-induced increase in basal gamma power. Furthermore, iclepertin reversed MK-801-induced working memory deficits in mice and improved social recognition memory performance in rats. Overall, this study demonstrates that inhibition of GlyT1 is sufficient to attenuate MK-801-induced deficits in translatable EEG parameters relevant to schizophrenia. Moreover, iclepertin showed memory-enhancing effects in rodent cognition tasks, further demonstrating the potential for GlyT1 inhibition to treat CIAS. SIGNIFICANCE STATEMENT: Despite the significant patient burden caused by cognitive impairment associated with schizophrenia, there are currently no approved pharmacotherapies. In this preclinical study, the novel glycine transporter inhibitor iclepertin (BI 425809) reversed sensory processing deficits and neural network dysfunction evoked by inhibition of N-methyl-D-aspartate receptors and enhanced working memory performance and social recognition in rodents. These findings support previous clinical evidence for the procognitive effects of iclepertin.

Multiparameter Optimization of Naphthyridine Derivatives as Selective α5-GABAA Receptor Negative Allosteric Modulators.

The discovery and characterization of novel naphthyridine derivatives with selective α5-GABAAR negative allosteric modulator (NAM) activity are disclosed. Utilizing a scaffold-hopping strategy, fused [6 + 6] bicyclic scaffolds were designed and synthesized. Among these, 1,6-naphthyridinones were identified as potent and selective α5-GABAAR NAMs with metabolic stability, cardiac safety, and beneficial intellectual property (IP) issues. Relocation of the oxo acceptor function and subsequent modulation of the physicochemical properties resulted in novel 1,6-naphthyridines with improved profile, combining good potency, selectivity, ADME, and safety properties. Besides this, compound 20, having the most balanced profile, provided in vivo proof of concept (POC) for the new scaffold in two animal models of cognitive impairment associated with schizophrenia (CIAS).

An Update on Treatment of Cognitive Impairment Associated with Schizophrenia.

Cognitive impairment associated with schizophrenia (CIAS) is widely regarded as a critically important treatment target for schizophrenia. Despite major efforts and a number of promising findings, we do not yet have an approved drug for CIAS. Similarly, promising cognitive remediation approaches are limited in their ability to help patients achieve real-world functional gains on a wide scale. This article provides an update and critical evaluation of recent treatment development activities for CIAS. First, we provide update on pharmacological approaches, which include a glutamatergic drug that is currently in Phase III trials for CIAS, and discuss factors that may have impacted past efforts to identify efficacious drugs. Second, we review positive findings, limitations, and current trends involving cognitive remediation approaches. Third, we consider newer transdiagnostic approaches aimed at looking beyond, or identifying more homogenous subgroups within, the diagnostic category schizophrenia to advance treatment development. Despite its many challenges, treatment development for CIAS remains a major public health issue and research continues to push forward on several encouraging fronts.

High-Dose Betahistine Improves Cognitive Function in Patients With Schizophrenia: A Randomized Double-Blind Placebo-Controlled Trial.

Background: There is currently no effective treatment for cognitive impairment associated with schizophrenia (CIAS). Recent studies have shown that increased histamine levels in the brain may help to improve CIAS symptoms. Betahistine is an H1-receptor agonist and H3-receptor antagonist. This study evaluated the effect of high-dose betahistine on cognitive function as well as its safety in Chinese Han patients with schizophrenia.Methods: This randomized double-blind, placebo-controlled trial enrolled 89 patients with schizophrenia who were randomly administered betahistine (72 mg/d) or placebo for 12 weeks. At baseline and at 4, 8, and 12 weeks after commencing the intervention, we measured changes in cognitive function and clinical symptoms using the MATRICS Consensus Cognitive Battery (MCCB) and Positive and Negative Syndrome Scale (PANSS), respectively. Furthermore, we used the Treatment Emergent Symptom Scale (TESS) to assess the adverse effects of the patients' medications.Results: Compared to the placebo group, the betahistine group showed significant improvements in the MCCB composite score after 12 weeks of treatment (p = 0.003) as well as improvements in MCCB verbal learning (p = 0.02) and visual learning (p = 0.001) domain scores. However, there were no significant improvements in the PANSS total scores or subscores (p > 0.05). Generally, high-dose betahistine treatment was considered safe in patients with schizophrenia.Conclusions: Additional use of high-dose betahistine can effectively improve cognitive function but not psychiatric symptoms in patients with schizophrenia. Betahistine (72 mg/d) is well tolerated by Chinese Han patients with schizophrenia.Trial Registration: chictr.org.cn, identifier: ChiCTR1900021078. http://www.chictr.org.cn/edit.aspx?pid=35484&htm=4

Identification of CVN058, a Novel Brain Penetrant, Selective 5-HT3 Receptor Antagonist That Shows Efficacy in Pre-Clinical Cognition Models

Maintaining excitatory/inhibitory balance is essential for the synchronised signalling required for cognitive function and is impaired in schizophrenia. Evidence from clinical and pre-clinical research have implicated GABAergic interneuronsin this synchronised signalling. Therefore, modulating interneuron activity has therapeutic potential for improving cognitive function. The 5-HT3 receptor (5-HTR3) is expressed on a subset of interneurons in the cortex and existing antagonists of this receptor have been shown to modulate cortical function, but have poor CNS drug-like characteristics and unsuitable pharmacokinetic or off-target activity, precluding use for schizophrenia. Here we describe the development of CVN058, a 5-HTR3 antagonist with good CNS properties and potential for the treatment of cognitive impairment associated with schizophrenia (CIAS).