Luvadaxistat: A Novel Potent and Selective D-Amino Acid Oxidase Inhibitor Improves Cognitive and Social Deficits in Rodent Models for Schizophrenia.

N-methyl-D-aspartate (NMDA) receptor hypofunctionality is a well-studied hypothesis for schizophrenia pathophysiology, and daily dosing of the NMDA receptor co-agonist, D-serine, in clinical trials has shown positive effects in patients. Therefore, inhibition of D-amino acid oxidase (DAAO) has the potential to be a new therapeutic approach for the treatment of schizophrenia. TAK-831 (luvadaxistat), a novel, highly potent inhibitor of DAAO, significantly increases D-serine levels in the rodent brain, plasma, and cerebrospinal fluid. This study shows luvadaxistat to be efficacious in animal tests of cognition and in a translational animal model for cognitive impairment in schizophrenia. This is demonstrated when luvadaxistat is dosed alone and in conjunction with a typical antipsychotic. When dosed chronically, there is a suggestion of change in synaptic plasticity as seen by a leftward shift in the maximum efficacious dose in several studies. This is suggestive of enhanced activation of NMDA receptors in the brain and confirmed by modulation of long-term potentiation after chronic dosing. DAAO is highly expressed in the cerebellum, an area of increasing interest for schizophrenia, and luvadaxistat was shown to be efficacious in a cerebellar-dependent associative learning task. While luvadaxistat ameliorated the deficit seen in sociability in two different negative symptom tests of social interaction, it failed to show an effect in endpoints of negative symptoms in clinical trials. These results suggest that luvadaxistat potentially could be used to improve cognitive impairment in patients with schizophrenia, which is not well addressed with current antipsychotic medications.

The oDGal Mouse: A Novel, Physiologically Relevant Rodent Model of Sporadic Alzheimer's Disease.

Sporadic Alzheimer's disease (sAD) represents a serious and growing worldwide economic and healthcare burden. Almost 95% of current AD patients are associated with sAD as opposed to patients presenting with well-characterized genetic mutations that lead to AD predisposition, i.e., familial AD (fAD). Presently, the use of transgenic (Tg) animals overexpressing human versions of these causative fAD genes represents the dominant research model for AD therapeutic development. As significant differences in etiology exist between sAD and fAD, it is perhaps more appropriate to develop novel, more sAD-reminiscent experimental models that would expedite the discovery of effective therapies for the majority of AD patients. Here we present the oDGal mouse model, a novel model of sAD that displays a range of AD-like pathologies as well as multiple cognitive deficits reminiscent of AD symptomology. Hippocampal cognitive impairment and pathology were delayed with N-acetyl-cysteine (NaC) treatment, which strongly suggests that reactive oxygen species (ROS) are the drivers of downstream pathologies such as elevated amyloid beta and hyperphosphorylated tau. These features demonstrate a desired pathophenotype that distinguishes our model from current transgenic rodent AD models. A preclinical model that presents a phenotype of non-genetic AD-like pathologies and cognitive deficits would benefit the sAD field, particularly when translating therapeutics from the preclinical to the clinical phase.

The efficacy of cariprazine on cognition: a post hoc analysis from phase II/III clinical trials in bipolar mania, bipolar depression, and schizophrenia.

OBJECTIVE: To investigate the effect of cariprazine on cognitive symptom change across bipolar I disorder and schizophrenia. METHODS: Post hoc analyses of 3- to 8-week pivotal studies in bipolar I depression and mania were conducted; one schizophrenia trial including the Cognitive Drug Research System attention battery was also analyzed. Outcomes of interest: Montgomery-Åsberg Depression Rating Scale [MADRS], Functioning Assessment Short Test [FAST], Positive and Negative Syndrome Scale [PANSS]). LSMDs in change from baseline to end of study were reported in the overall intent-to-treat population and in patient subsets with specified levels of baseline cognitive symptoms or performance. RESULTS: In patients with bipolar depression and at least mild cognitive symptoms, LSMDs were statistically significant for cariprazine vs placebo on MADRS item 6 (3 studies; 1.5 mg=-0.5 [P<.001]; 3 mg/d=-0.2 [P<.05]) and on the FAST Cognitive subscale (1 study; 1.5 mg/d=-1.4; P=.0039). In patients with bipolar mania and at least mild cognitive symptoms, the LSMD in PANSS Cognitive subscale score was statistically significant for cariprazine vs placebo (3 studies; -2.1; P=.001). In patients with schizophrenia and high cognitive impairment, improvement in power of attention was observed for cariprazine 3 mg/d vs placebo (P=.0080), but not for cariprazine 6 mg/d; improvement in continuity of attention was observed for cariprazine 3 mg/d (P=.0012) and 6 mg/d (P=.0073). CONCLUSION: These post hoc analyses provide preliminary evidence of greater improvements for cariprazine vs placebo across cognitive measures in patients with bipolar I depression and mania, and schizophrenia, suggesting potential benefits for cariprazine in treating cognitive symptoms.

D-Cycloserine Improves Difficult Discriminations in a Pattern Separation Task in Alzheimer's Disease Patients with Dementia.

Recent fMRI studies in human identified that pattern separation ability is associated with increased activity in the hippocampal dentate gyrus (DG), whereas no such DG changes are seen during pattern completion. Disruption to neurogenesis in the DG has been associated with Alzheimer's disease (AD). In a post-hoc analysis of two large unsuccessful AD clinical trials, we examined the effect of D-cycloserine (DCS) on a specific object pattern separation measure, a component of the picture recognition task from the Cognitive Drug Research (CDR) system. This task yields a measure of pattern separation and a measure of pattern completion. Study data were available for 756 AD patients with dementia, randomized to several doses of DCS. Data were available at week 2, 6, 14, and 26 for 732, 707, 653, and 559 patients, respectively. None of the DCS doses had a statistically significant benefit over placebo on pattern completion. However, the DCS 15 mg BID dose significantly increased accuracy over placebo on the pattern separation measure by 5.1%. Further, the magnitude of the benefit of DCS 15 mg BID over placebo was almost doubled relative to the whole study population in a subset of patients whose pattern separation scores were≥2 standard deviations poorer than the CDR norm of age-matched healthy individuals at baseline. These post-hoc analyses suggest a potential value of the pattern separation task for evaluating compounds promoting neurogenesis. Further, the use of a restrictive pattern separation eligibility criterion might facilitate signal detection.

Spatial recognition test: A novel cognition task for assessing topographical memory in mice.

Dysfunction in topographical memory is a core feature of several neurological disorders. There is a large unmet medical need to address learning and memory deficits as a whole in central nervous system disease. There are considerable efforts to identify pro-cognitive compounds but current methods are either lengthy or labour intensive. Our test used a two chamber apparatus and is based on the preference of rodents to explore novel environments. It was used firstly to assess topographical memory in mice at different retention intervals (RI) and secondly to investigate the effect of three drugs reported to be beneficial for cognitive decline associated with Alzheimer's disease, namely: donepezil, memantine and levetiracetam. Animals show good memory performance at all RIs tested under four hours. At the four-hour RI, animals show a significantly poorer memory performance which can be rescued using donepezil, memantine and levetiracetam. Using this test we established and validated a spatial recognition paradigm to address topographical memory in mice by showing a decremental time-induced forgetting response and reversing this decrease in performance using pharmacological tools. The spatial recognition test differs from more commonly used visuospatial laboratory tests in both throughput capability and potentially neuroanatomical substrate. This test has the potential to be used to assess cognitive performance in transgenic animals, disease models and to screen putative cognitive enhancers or depressors.

True alignment of preclinical and clinical research to enhance success in CNS drug development: a review of the current evidence.

Central nervous system pharmacological research and development has reached a critical turning point. Patients suffering from disorders afflicting the central nervous system are numerous and command significant attention from the pharmaceutical industry. However, given the numerous failures of promising drugs, many companies are no longer investing in or, indeed, are divesting from this therapeutic area. Central nervous system drug development must change in order to develop effective therapies to treat these patients. Preclinical research is a cornerstone of drug development; however, it is frequently criticised for its lack of predictive validity. Animal models and assays can be shown to be more predictive than reported and, on many occasions, the lack of thorough preclinical testing is potentially to blame for some of the clinical failures. Important factors such as translational aspects, nature of animal models, variances in acute versus chronic dosing, development of add-on therapies and understanding of the full dose-response relationship are too often neglected. Reducing the attrition rate in central nervous system drug development could be achieved by addressing these important questions before novel compounds enter the clinical phase. This review illustrates the relevance of employing these criteria to translational central nervous system research, better to ensure success in developing new drugs in this therapeutic area.

The attentional set-shifting test paradigm in rats for the screening of novel pro-cognitive compounds with relevance for cognitive deficits in schizophrenia.

Cognition deficits in schizophrenia remain an untreated area, and one in which R&D investment by pharmaceutical companies is high. However, whilst many preclinical assays demonstrate pro-cognitive activity with new drugs, in the main, they have not yet been translated successfully to the clinic. In an attempt to address this and reduce the high attrition rate for drugs in the clinic, selected preclinical researchers are re-focusing their efforts on the development and validation of more translational assays. The attentional setshifting task is an example of such an assay, which has been back-translated from the clinic to a preclinical setting. Here we review its application in schizophrenia research across humans and animals, specifically with regards to the neural basis underlying cognitive performance, the various disease-like or symptom models employed in rodents to mimic cognitive dysfunction in schizophrenia, and the resulting impact of drug treatment on executive function. Using the attentional set-shifting task, we highlight the potential promise a more translational approach can bring, whilst demonstrating the need for closer alignment in the validation and integration of this task to fully realize this promise.

Erythropoietin reverses the attentional set-shifting impairment in a rodent schizophrenia disease-like model.

RATIONALE: Executive function impairment, as classically assessed using the Wisconsin Card Sort Test or intradimensional/extradimensional tests, is a key feature of schizophrenia but remains inadequately treated by existing therapies. Recently, however, erythropoietin has been shown to improve attentional set-shifting performance in schizophrenic patients. OBJECTIVE: The present study utilized the rat intradimensional/extradimensional task to investigate the potential of erythropoietin to reverse a phencyclidine-induced extradimensional shift impairment when given alone or in combination with subchronic haloperidol treatment. METHODS: Rats were subjected to a subchronic systemic administration (7 days, b.i.d) of either saline vehicle or phencyclidine (5 mg/kg) followed by a 7-day washout period during which haloperidol was given. Subsequently, rats were trained to dig in baited bowls for a food reward and to discriminate on the basis of digging media or bowl odor. In experiment 1, rats performed a series of discriminations following acute administration of vehicle, erythropoietin, or modafinil. In a second experiment, rats receiving either haloperidol in the drinking water or just normal drinking water were run in the attentional set-shifting task after acute administration of erythropoietin (1,000 or 10,000 IU/ml i.p., selected from experiment 1). RESULTS: The subchronic phencyclidine-induced extradimensional deficit was ameliorated by both erythropoietin and modafinil. When combined with subchronic haloperidol, the higher dose of erythropoietin tested was able to reverse the extradimensional shift impairment. CONCLUSIONS: Overall, these findings further support the use of erythropoietin as an adjunct to antipsychotic therapy in order to address, at least part of, the cognitive dysfunction associated with schizophrenia.

Chronic infusion of PCP via osmotic mini-pumps: a new rodent model of cognitive deficit in schizophrenia characterized by impaired attentional set-shifting (ID/ED) performance.

The identification of animal disease-like models for cognitive symptoms in schizophrenia is of central importance to the successful development of pharmacological therapies for psychosis resulting in a functional outcome in patients. Executive function is one of the most severely affected cognitive domains in schizophrenia that remains inadequately treated by existing therapies. The rat attentional set-shifting (or intra-dimensional-extra-dimensional (ID/ED)) task has been developed to test executive function in rodents and successful translation of pre-clinical data into the clinical setting now depends on the identification of a predictive animal disease-like model. The present study investigates whether a continuous 14-day mini-pump infusion of the non-competitive NMDA receptor antagonist phencyclidine (PCP) leads to a deficit in the ID/ED task, and subsequently evaluates the effect of modafinil in this model. Lister hooded rats were implanted subcutaneously with osmotic mini-pumps containing saline or PCP (15 mg/kg/day) for 14 days followed by a 7-day drug-free recovery phase. Rats were then tested in the ID/ED task following an acute injection of either vehicle or modafinil. PCP-treated animals displayed a selective deficit at the ED shift stage resembling that observed in schizophrenic patients. This deficit was reversed by an acute injection of modafinil. The PCP-induced impairment and its reinstatement by modafinil are quantitatively and qualitatively similar to that described earlier by our group following sub-chronic intraperitoneal PCP administration, indicative that sub-chronic PCP infusion via osmotic mini-pumps may represent an attractive alternative to the systemic administration protocols generally employed to date.

Comparison of haloperidol, risperidone, sertindole, and modafinil to reverse an attentional set-shifting impairment following subchronic PCP administration in the rat--a back translational study.

RATIONALE: Selective cognitive impairments, including those of executive function as assessed using the Wisconsin Card Sort Test or intradimensional-extradimensional (ID-ED) tests, are a key feature of schizophrenia but remain inadequately treated by existing therapies. Recently, however, modafinil has been shown to improve attentional set-shifting performance in patients with schizophrenia. OBJECTIVE: The present study evaluated the recently described analogous rat ID-ED attentional set-shifting task by investigating the effects of various pharmacological challenges to a phencyclidine (PCP)-induced ED shift impairment, namely, haloperidol, risperidone, sertindole, and modafinil. MATERIALS AND METHODS: Rats were subjected to a subchronic systemic administration of either saline vehicle or PCP (5 mg/kg i.p. b.i.d. for 7 days) followed by a 7-day washout period. During this period, rats were trained to dig in baited bowls for a food reward and to discriminate based on odor or digging media. In a single test session conducted the day after the washout period (day 8), rats performed a series of discriminations following acute administration of either vehicle, or haloperidol (0.1 mg/kg s.c.), or risperidone (0.2 mg/kg i.p.), or sertindole (1.25 mg/kg p.o.) or modafinil (64 mg/kg p.o.). RESULTS: The subchronic PCP-induced ED deficit was ameliorated by sertindole and modafinil but not by haloperidol or risperidone. CONCLUSIONS: Overall, these findings further support that the rat ID-ED test in subchronic PCP-treated rats has utility and validity as a preclinical model of the cognitive symptoms of schizophrenia and demonstrates back-translational potential.