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.

Adverse effects of psychedelics: From anecdotes and misinformation to systematic science.

Background: Despite an increasing body of research highlighting their efficacy to treat a broad range of medical conditions, psychedelic drugs remain a controversial issue among the public and politicians, tainted by previous stigmatisation and perceptions of risk and danger.

Objective: This narrative review examines the evidence for potential harms of the classic psychedelics by separating anecdotes and misinformation from systematic research.

Methods: Taking a high-level perspective, we address both psychological and psychiatric risks, such as abuse liability and potential for dependence, as well as medical harms, including toxicity and overdose.

Effects of cariprazine, a novel antipsychotic, on cognitive deficit and negative symptoms in a rodent model of schizophrenia symptomatology.

Negative symptoms and cognitive impairment associated with schizophrenia are strongly associated with poor functional outcome and reduced quality of life and remain an unmet clinical need. Cariprazine is a dopamine D3/D2 receptor partial agonist with preferential binding to D3 receptors, recently approved by the FDA for the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder. The aim of this study is to evaluate effects of cariprazine in an animal model of cognitive deficit and negative symptoms of schizophrenia.

Nicotinic α7 and α4β2 agonists enhance the formation and retrieval of recognition memory: Potential mechanisms for cognitive performance enhancement in neurological and psychiatric disorders.

Cholinergic dysfunction has been shown to be central to the pathophysiology of Alzheimer's disease and has also been postulated to contribute to cognitive dysfunction observed in various psychiatric disorders, including schizophrenia. Deficits are found across a number of cognitive domains and in spite of several attempts to develop new therapies, these remain an unmet clinical need. In the current study we investigated the efficacy of donepezil, risperidone and selective nicotinic α7 and α4β2 receptor agonists to reverse a delay-induced deficit in recognition memory.

A systematic review and meta-analysis of cognitive remediation in early schizophrenia.

Neurocognitive impairment predicts disability in schizophrenia, making intervention theoretically attractive as a means to minimise chronic disability. Many trials confirm that cognitive remediation (CR) produces meaningful, durable improvements in cognition and functioning but fewer focus on the early stages. We systematically reviewed CR trials in early schizophrenia to determine its efficacy on global cognition, functioning and symptoms.

Impaired limbic cortico-striatal structure and sustained visual attention in a rodent model of schizophrenia.

Background: N-methyl-d-aspartate receptor (NMDAR) dysfunction is thought to contribute to the pathophysiology of schizophrenia. Accordingly, NMDAR antagonists such as phencyclidine (PCP) are used widely in experimental animals to model cognitive impairment associated with this disorder. However, it is unclear whether PCP disrupts the structural integrity of brain areas relevant to the profile of cognitive impairment in schizophrenia.

First episode psychosis patients show impaired cognitive function--a study of a South Asian population in the UK.

Background: Cognitive deficits are a core symptom of schizophrenia, severely debilitating and untreated by current medication. However, to date there is limited research focusing on the precise nature of the cognitive disturbances at first episode in ethnic populations. Improved understanding of this will allow improved approaches to therapy.

The preclinical profile of asenapine: clinical relevance for the treatment of schizophrenia and bipolar mania.

Introduction: Asenapine is a novel antipsychotic drug approved for the treatment of acute schizophrenia, manic, or mixed episodes associated with bipolar I disorder, as a maintenance treatment of schizophrenia and as an adjunctive therapy with lithium or valproate for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults.

Areas Covered: This review focuses on the preclinical profile of asenapine. It analyzes the pharmacological, neurochemical, behavioral, and molecular mechanisms of asenapine and their contribution to the beneficial therapeutic advantages of the drug as reported in published preclinical and clinical studies, product labels, and poster presentations.

PNU-120596, a positive allosteric modulator of α7 nicotinic acetylcholine receptors, reverses a sub-chronic phencyclidine-induced cognitive deficit in the attentional set-shifting task in female rats.

The α7 nicotinic acetylcholine receptors (nAChRs) have been highlighted as a target for cognitive enhancement in schizophrenia. Adult female hooded Lister rats received sub-chronic phencyclidine (PCP) (2 mg/kg) or vehicle i.p.

D₁ receptor activation improves vigilance in rats as measured by the 5-choice continuous performance test.

Rationale: Impaired attention/vigilance is putatively core to schizophrenia. The dopaminergic D(1) receptor system has been reported as one of the most promising targets for improving cognition in patients with schizophrenia, with some evidence suggesting D(1) activation may improve sustained attention.

Objectives: The purpose of this study was twofold: firstly assessing the applicability of using rats in the 5-Choice Continuous Performance Test (5 C-CPT), recently validated in mice.

Rats tested after a washout period from sub-chronic PCP administration exhibited impaired performance in the 5-Choice Continuous Performance Test (5C-CPT) when the attentional load was increased.

It is well documented that schizophrenia patients exhibit dysfunction in various cognitive domains, including attention/vigilance, as demonstrated by impaired performance in the myriad of Continuous Performance Tests (CPTs). NMDA receptor antagonists provide a pharmacological model in animals of the cognitive disruption presented in the disorder. We therefore examined the effects of a sub-chronic PCP treatment regimen (5.

The efficacy of sodium channel blockers to prevent phencyclidine-induced cognitive dysfunction in the rat: potential for novel treatments for schizophrenia.

Sodium channel inhibition is a well precedented mechanism used to treat epilepsy and other hyperexcitability disorders. The established sodium channel blocker and broad-spectrum anticonvulsant lamotrigine is also effective in the treatment of bipolar disorder and has been evaluated in patients with schizophrenia. Double-blind placebo-controlled clinical trials found that the drug has potential to reduce cognitive symptoms of the disorder.

Asenapine improves phencyclidine-induced object recognition deficits in the rat: evidence for engagement of a dopamine D1 receptor mechanism.

Rationale: Cognitive deficits are common in schizophrenia. Asenapine is an atypical antipsychotic approved by the US Food and Drug Administration in adults for treatment of schizophrenia or acute treatment, as monotherapy or adjunct therapy to lithium or valproate, of manic or mixed episodes of bipolar I disorder.

Objectives: Based on the receptor pharmacology of asenapine, the current study assessed the efficacy and mechanism of action of asenapine to improve a subchronic phencyclidine (PCP)-induced deficit in visual recognition memory using the novel object recognition (NOR) paradigm in the rat, a paradigm of relevance to cognition in schizophrenia.

Extrasynaptic GABAA receptor activation reverses recognition memory deficits in an animal model of schizophrenia.

Rationale: Schizophrenia is a complex psychiatric disorder comprised of three main classes of symptoms: positive, negative and cognitive symptoms. Currently, no approved treatment exists for the cognitive symptoms. There is thus a great need for research aiming at identifying novel targets for treatment of this indication.

Activation of α7 nicotinic receptors improves phencyclidine-induced deficits in cognitive tasks in rats: implications for therapy of cognitive dysfunction in schizophrenia.

Rationale: Nicotinic α7 acetylcholine receptors (nAChRs) have been highlighted as a target for cognitive enhancement in schizophrenia.

Aim: To investigate whether the deficits induced by sub-chronic phencyclidine (PCP) in reversal learning and novel object recognition could be attenuated by the selective α7 nAChR full agonist, PNU-282987.

Methods: Adult female hooded-Lister rats received sub-chronic PCP (2mg/kg) or vehicle i.

Effects of asenapine, olanzapine, and risperidone on psychotomimetic-induced reversal-learning deficits in the rat.

Background: Asenapine is a new pharmacological agent for the acute treatment of schizophrenia and bipolar disorder. It has relatively higher affinity for serotonergic and alpha(2)-adrenergic than dopaminergic D(2) receptors. We evaluated the effects of asenapine, risperidone, and olanzapine on acute and subchronic psychotomimetic-induced disruption of cued reversal learning in rats.

Positive modulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors reverses sub-chronic PCP-induced deficits in the novel object recognition task in rats.

Cognitive deficits are a major clinical unmet need in schizophrenia. The psychotomimetic drug phencyclidine (PCP) is widely applied in rodents to mimic symptoms of schizophrenia, including cognitive deficits. Previous studies have shown that sub-chronic PCP induces an enduring episodic memory deficit in female Lister Hooded rats in the novel object recognition (NOR) task.

Comparison of the efficacy of two anticonvulsants, phenytoin and valproate to improve PCP and d-amphetamine induced deficits in a reversal learning task in the rat.

Recent studies in our laboratory have shown that PCP (phencyclidine) and d-amphetamine induce a cognitive deficit in rats, in a paradigm of potential relevance for the pathology of schizophrenia. Atypical, but not classical antipsychotics and the anticonvulsant, lamotrigine have been shown to prevent a selective reversal learning deficit induced by PCP. In contrast, only haloperidol reversed the d-amphetamine-induced deficit.

Subchronic effects of phencyclidine on dopamine and serotonin receptors: implications for schizophrenia.

Changes in representative dopamine (D(1), D(2), and D(4)) and serotonin (5-HT(1A) and 5-HT(2A)) receptors that have been implicated in the pathophysiology and treatment of schizophrenia were autoradiographically quantified after subchronic phencyclidine (PCP) treatment (2 mg/kg for 7 days, bi-daily followed by 7 days drug free). This treatment has consistently induced robust and long-lasting cognitive deficits in adult rats, although the molecular mechanisms contributing to PCP-induced cognitive deficits remain undefined. Repeated PCP treatment significantly decreased labeling of D(1) receptors in the medial and lateral caudate-putamen (22% and 23%, respectively) and increased 5HT(1A) receptor binding in the medial-prefrontal (26%) and dorsolateral-frontal cortex (30%).