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English Journal
- Predictive validity of a MK-801-induced cognitive impairment model in mice: Implications on the potential limitations and challenges of modeling cognitive impairment associated with schizophrenia preclinically.
- Brown JW1, Rueter LE2, Zhang M2.Author information 1Neuroscience Discovery, AbbVie, 1 North Waukegan Rd., North Chicago, IL 60064, United States. Electronic address: jordan.brown@abbvie.com.2Neuroscience Discovery, AbbVie, 1 North Waukegan Rd., North Chicago, IL 60064, United States.AbstractCognitive impairment associated with schizophrenia (CIAS) is a major and disabling symptom domain of the disease that is generally unresponsive to current pharmacotherapies. Critically important to the discovery of novel therapeutics for CIAS is the utilization of preclinical models with robust predictive validity. We investigated the predictive validity of MK-801-induced memory impairments in mouse inhibitory avoidance (MK-IA) as a preclinical model for CIAS by investigating compounds that have been tested in humans, including antipsychotics, sodium channel blocker mood stabilizers, and putative cognitive enhancers. The atypical antipsychotic clozapine, as well as risperidone and olanzapine (see Brown et al., 2013), had no effect on MK-801-induced memory impairments. For sodium channel blockers, carbamazepine significantly attenuated memory impairments induced by MK-801, whereas lamotrigine had no effect. Nicotine, donepezil, modafinil, and xanomeline all significantly attenuated MK-801-induced memory impairments, but the magnitude of effects and the dose-responses observed varied across compounds. Clinically, only acute administration of nicotine has demonstrated consistent positive effects on CIAS, while inconsistent results have been reported for lamotrigine, donepezil, and modafinil; atypical antipsychotics produce only moderate improvements at best. A positive clinical signal has been observed with xanomeline, but only in a small pilot trial. The results presented here suggest that the MK-IA model lacks robust predictive validity for CIAS as the model is likely permissive and may indicate false positive signals for compounds and mechanisms that lack clear clinical efficacy for CIAS. Our findings also highlight the potential limitations and challenges of using NMDA receptor antagonists in rodents to model CIAS.
- Progress in neuro-psychopharmacology & biological psychiatry.Prog Neuropsychopharmacol Biol Psychiatry.2014 Mar 3;49:53-62. doi: 10.1016/j.pnpbp.2013.11.008. Epub 2013 Nov 19.
- Cognitive impairment associated with schizophrenia (CIAS) is a major and disabling symptom domain of the disease that is generally unresponsive to current pharmacotherapies. Critically important to the discovery of novel therapeutics for CIAS is the utilization of preclinical models with robust pred
- PMID 24269664
- Long-term neurocognitive effects of antipsychotics in schizophrenia: a network meta-analysis.
- Désaméricq G, Schurhoff F, Meary A, Szöke A, Macquin-Mavier I, Bachoud-Lévi AC, Maison P.Author information Inserm, U955, Equipe 01, Créteil, 94000, France.AbstractPURPOSE: Most schizophrenic patients have mild to moderate cognitive impairment in the early stages of schizophrenia. The aim was to compare the long-term effects of various antipsychotic drugs on overall cognition and on specific cognitive domains in patients with schizophrenia or related disorders.
- European journal of clinical pharmacology.Eur J Clin Pharmacol.2014 Feb;70(2):127-34. doi: 10.1007/s00228-013-1600-y. Epub 2013 Oct 22.
- PURPOSE: Most schizophrenic patients have mild to moderate cognitive impairment in the early stages of schizophrenia. The aim was to compare the long-term effects of various antipsychotic drugs on overall cognition and on specific cognitive domains in patients with schizophrenia or related disorders
- PMID 24145817
- Safety profile of iloperidone in the treatment of schizophrenia.
- Dargani NV, Malhotra AK.Author information The Zucker Hillside Hospital, Hofstra North Shore-LIJ School of Medicine , 75-59 263rd Street, Glen Oaks, NY 11004 , USA +1 718 470 8012 ; +1 718 343 1659 ; malhotra@lij.edu.AbstractIntroduction: Iloperidone is a novel antipsychotic medication approved for the treatment of schizophrenia in adults with efficacy similar to its class counterparts. The purpose of this article is to describe the safety profile of iloperidone and its clinical implications. Areas covered: A PubMed search was undertaken on May 10, 2013, using the keyword iloperidone. Of the 121 articles that resulted, those with primary sources of information, along with secondary sources with an emphasis on drug safety, were included in this article. Iloperidone was found to have lower extrapyramidal symptom (EPS) and akathisia rates compared to haloperidol and risperidone. Twelve percent of patients experienced clinically significant weight gain, largely during initiation phase of treatment. No other clinically significant metabolic abnormalities were observed. QTc interval was increased by 10 ms, comparable to the effect observed with ziprasidone. QTc prolongation was heightened under inhibition of CYP2D6 and CYP3A4. Orthostatic hypotension was a common effect seen in the first week of treatment. Expert opinion: The favorable EPS and akathisia profile of iloperidone makes it an attractive choice for patients whose compliance is limited by these effects. However, the slow titration schedule adapted to reduce orthostasis may limit the use of this agent in an acute setting.
- Expert opinion on drug safety.Expert Opin Drug Saf.2014 Feb;13(2):241-6. doi: 10.1517/14740338.2014.854770. Epub 2013 Nov 11.
- Introduction: Iloperidone is a novel antipsychotic medication approved for the treatment of schizophrenia in adults with efficacy similar to its class counterparts. The purpose of this article is to describe the safety profile of iloperidone and its clinical implications. Areas covered: A PubMed sea
- PMID 24206391
Japanese Journal
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