Cognitive Impairment Associated With Schizophrenia Research Articles

Psychometric evaluation of the patient-reported experience of cognitive impairment in schizophrenia (PRECIS) scale.

Cognitive impairment associated with schizophrenia (CIAS) represents a distinct, persistent, and core group of schizophrenia symptoms. Cognitive symptoms have been shown to have an impact on quality of life. There are several published CIAS measures, but none based on direct patient self-report. It is important to capture the patient's perspective to supplement performancebased outcome measures of cognition to provide a complete picture of the patient's experience. This paper describes additional validation work on the Patient-Reported Experience of Cognitive Impairment in Schizophrenia (PRECIS) instrument. Data from two large, international, pharmaceutical clinical trials in medically and psychiatrically stable English-speaking patients with schizophrenia and 88 healthy controls were analyzed. An exploratory factor analysis (EFA) was conducted in one trial (n = 215), using the original 35-item PRECIS. The factor structure suggested by EFA was further evaluated using item response theory (IRT; Samejima's graded response model), and tested using confirmatory factor analysis (CFA). Both EFA and CFA results were tested in a second trial with similar inclusion/exclusion characteristics (n = 410). Additional statistical properties were evaluated in healthy controls. EFA suggested that the best solution after item reduction suggested a factor structure of 6 factors based on 26 items (memory, communication, self-control, executive function, attention, sharpness of thought), supporting a total score, with an additional 2-item bother score (28 items in all). IRT analysis indicated the items were well-ordered within each domain. The CFA demonstrated excellent model fit, accounting for 69% of the variance. The statistical properties of the 28-item version of the PRECIS were confirmed in the second trial. Evidence for internal consistency and test-retest reliability was robust. Known-groups validity was supported by comparison of healthy controls with patients with schizophrenia. Correlations indicated moderate associations between PRECIS and functioning instruments like the Schizophrenia Cognition Rating Scale (SCoRS), but weak correlations with performance-based outcomes like MATRICS Consensus Cognitive Battery (MCCB). Using two clinical trial samples, we identified a robust factor structure for the PRECIS and were able to replicate it in the second sample. Evaluation of the meaningful score difference (MSD) should be repeated in future studies, as these samples did not show enough change for it to be evaluated. This analysis provides strong evidence for the reliability and validity of the PRECIS, a 28-item, patient-reported instrument to assess cognitive impairment associated with schizophrenia. The correlation with functioning and the weak correlation with performance on cognitive tasks suggests that patient reports of cognitive impairment measure a unique aspect of patient experience.

Pharmacological treatment of Cognitive Impairment Associated with Schizophrenia: state of the art and future perspectives

Abstract 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 an 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.

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.

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).

Challenges of Psychiatry Drug Development and the Role of Human Pharmacology Models in Early Development-A Drug Developer's Perspective.

Psychiatric diseases have the lowest probability of success in clinical drug development. This presents not only an issue to address the unmet medical needs of patients, but also a hurdle for pharmaceutical and biotech industry to continue R&D in this disease area. Fundamental pharmacokinetic and pharmacodynamic principles provide an understanding of the drug exposure, target binding and pharmacological activity at the target site of action for a new drug candidate. Collectively, these principles determine the likelihood of testing the mechanism of action and enhancing the likelihood of candidate survival in Phase 2 clinical development, therefore, they are termed as the “three pillars of survival.” Human Phase 1 pharmacokinetic and pharmacodynamic studies provide evidence of the three pillars. Electroencephalogram (EEG) assessments and cognitive function tests in schizophrenia patients can provide proof of pharmacology and ensure that a pharmacological active regimen will be tested in Phase 2 proof of concept (POC) studies for the treatment of cognitive impairment associated with schizophrenia (CIAS).

Phase 1 randomized study on the safety, tolerability, and pharmacodynamic cognitive and electrophysiological effects of a dopamine D1 receptor positive allosteric modulator in patients with schizophrenia

ASP4345, a novel dopamine D1 receptor positive allosteric modulator, is being evaluated for the treatment of cognitive impairment associated with schizophrenia (CIAS). This phase 1 multiple ascending-dose study (NCT02720263) assessed the safety, tolerability, and pharmacodynamics of ASP4345 in patients with schizophrenia/schizoaffective disorder. Pharmacodynamic assessments were Cogstate cognitive tests and electrophysiological biomarkers, including gamma-band power and phase synchronization in response to 40-Hz auditory steady-state stimulation, as well as mismatch negativity (MMN) and P3a event-related potentials. The sample size determination was based on standard practice in assessing safety and tolerability of a new chemical entity. Data were summarized by conversion of this data into effect sizes using descriptive and inferential statistics. A total of 36 randomized patients received ASP4345 (3, 15, 50, and 150 mg; n = 9 each dose) and 12 patients received placebo. Patients in the ASP4345 group experienced 73 treatment-emergent adverse events (TEAEs) and 34 TEAEs were reported for the placebo group. The most common TEAEs were headache and somnolence and nearly all TEAEs were mild in severity. No changes in mood or self-reports of suicidal ideation/behavior were observed. Improvements in performance on cognitive tests were noted, which suggests a potential improvement in psychomotor function and visual attention. Furthermore, positive changes in neurophysiological biomarkers (auditory steady-state response [ASSR] and MMN) suggest improvement in information processing. The findings need to be confirmed in studies with a larger patient population. Nonetheless, the trends in safety and pharmacodynamic data support further clinical development of ASP4345 for the treatment of CIAS.

Translation-Focused Approaches to GPCR Drug Discovery for Cognitive Impairments Associated with Schizophrenia.

There are no effective therapeutics for cognitive impairments associated with schizophrenia (CIAS), which includes deficits in executive functions (working memory and cognitive flexibility) and episodic memory. Compounds that have entered clinical trials are inadequate in terms of efficacy and/or tolerability, highlighting a clear translational bottleneck and a need for a cohesive preclinical drug development strategy. In this review we propose hippocampal-prefrontal-cortical (HPC-PFC) circuitry underlying CIAS-relevant cognitive processes across mammalian species as a target source to guide the translation-focused discovery and development of novel, procognitive agents. We highlight several G protein-coupled receptors (GPCRs) enriched within HPC-PFC circuitry as therapeutic targets of interest, including noncanonical approaches (biased agonism and allosteric modulation) to conventional clinical targets, such as dopamine and muscarinic acetylcholine receptors, along with prospective novel targets, including the orphan receptors GPR52 and GPR139. We also describe the translational limitations of popular preclinical cognition tests and suggest touchscreen-based assays that probe cognitive functions reliant on HPC-PFC circuitry and reflect tests used in the clinic, as tests of greater translational relevance. Combining pharmacological and behavioral testing strategies based in HPC-PFC circuit function creates a cohesive, translation-focused approach to preclinical drug development that may improve the translational bottleneck currently hindering the development of treatments for CIAS.

Aerobic exercise improves memory and prevents cognitive deficits of relevance to schizophrenia in an animal model.

Cognitive impairment associated with schizophrenia (CIAS) greatly reduces patients' functionality, and remains an unmet clinical need. The sub-chronic phencyclidine (scPCP) rat model is commonly employed in studying CIAS. We have previously shown that voluntary exercise reverses impairments in novel object recognition (NOR) induced by scPCP. However, there has not been a longitudinal study investigating the potential protective effects of exercise in a model of CIAS. This study aimed to investigate the pro-cognitive and protective effects of exercise on CIAS using the translational NOR and attentional set-shifting tasks (ASST). Female Lister Hooded rats were either exercised (wheel running for one hour per day, five days per week, for six weeks; n=20) or not (n=20) and then tested in a natural-forgetting NOR test. Rats in each group were then administered either PCP (2 mg/kg intraperitoneally (i.p.)) or saline solution (1 mL/kg i.p.) for seven days, followed by seven days washout. Three NOR tests were conducted immediately and two and nine weeks after washout, and a natural-forgetting NOR test was carried out again eight weeks post washout. Rats were trained and tested in ASST from week 6 to week 10 post washout. Non-exercised rats displayed a deficit in both of the natural-forgetting NOR tests, whereas exercised rats did not. The scPCP exercise group did not show the expected deficit in NOR at any time point, and had a significantly ameliorated deficit in the ASST compared to the scPCP control group. Voluntary exercise has long-lasting pro-cognitive and protective effects in two cognitive domains. Exercise improves cognition and could provide protection against CIAS.

S31. ENHANCEMENT OF SYNAPTIC PLASTICITY BY COMBINATION OF PDE2 AND PDE9 INHIBITION PRESUMABLY VIA PRE- AND POST-SYNAPTIC MECHANISMS

BackgroundEvidence from clinical and preclinical studies has led to the hypothesis that impaired glutamatergic transmission and NMDA receptor hypofunction play an important role in cognitive impairment associated with schizophrenia (CIAS). Second messenger pathways depending on cAMP and/or cGMP are key regulators of glutamatergic transmission and NMDA receptor related pathways. Therefore, the specific cyclic nucleotide phosphodiesterases (PDEs) PDE2 and PDE9, expressed in cognition relevant brain regions such as cortex and hippocampus, are putative targets for cognition enhancement in neuropsychiatric disorders (Dorner-Ciossek et al., 2017; Zhang et al., 2017). In fact, it has previously been shown that either PDE2 or PDE9 inhibition increases synaptic plasticity, as determined by hippocampal long-term potentiation (LTP), and improves memory performance in animal cognition tasks. However, the exact sub-cellular localization of PDE2 and PDE9 enzymes in neurons is not fully established. Thus, in the present study, co-localization studies of PDE2 and PDE9 with pre- and post-synaptic markers were performed by double immunofluorescence staining. Moreover, the PDE2 inhibitor PF-05180999 (Helal et al., 2018) was characterized regarding enhancement of hippocampal LTP and further investigated in combination with the PDE9 inhibitor Bay 73–6691 (Wunder et al., 2005) for potential synergistic effects on LTP.MethodsBrains of adult rats were fixed with formalin and sliced for double immunofluorescence staining of PDE2 or PDE9 enzymes with pre-/post-synaptic markers. Analysis of staining was performed by confocal microscopy. Effects of the PDE2 inhibitor PF-05180999 alone and in combination with the PDE9 inhibitor Bay 73–6691 on synaptic plasticity were evaluated in rat hippocampal slices by using a protein-synthesis independent early LTP paradigm.ResultsDouble immunofluorescence analysis revealed co-localization of PDE2 predominantly with pre-synaptic, but not post-synaptic, markers and mainly in glutamatergic neurons. In contrast, PDE9 showed co-localization with post-synaptic markers. Inhibition of PDE2 by PF-05180999 led to a concentration-dependent enhancement of early LTP. Combination of PF-05180999 with a subthreshold concentration of the PDE9 inhibitor Bay 73–6691 caused a transformation from early LTP into protein-synthesis dependent late LTP.DiscussionImmunofluorescence staining suggests that PDE2 is localized pre-synaptically in glutamatergic neurons. This might indicate an involvement of PDE2 in neurotransmitter release via regulating cGMP/cAMP levels at pre-synaptic terminals, whereas PDE9 is located post-synaptically presumably involved in the NMDA receptor signaling cascade via regulation of cGMP. Corroborating previous findings, PDE2 inhibition improves synaptic plasticity as shown by enhanced LTP. Moreover, for the first time, we could show that the combination of a PDE2 with a PDE9 inhibitor acts synergistically on improvement of synaptic plasticity as demonstrated by the shift from early into late LTP, which is considered to be a crucial mechanism for memory formation.ReferencesDorner-Ciossek et al. (2017), Adv. Neurobiol. 17, 231–254.Helal et al. (2018), J. Med. Chem. 61, 1001–1018.Wunder et al. (2005), Mol.Pharmacol. 68, 1775–1781.Zhang et al. (2017), Adv. Neurobiol. 17, 307–347.