Effects of low-dose d-serine on recognition and working memory in mice

Bado, Patricia; Madeira, Caroline; Vargas-Lopes, Charles; Moulin, Thiago C.; Wasilewska-Sampaio, Ana Paula; Maretti, Luise; Oliveira, Ricardo Vígolo de; Amaral, Olavo B.; Panizzutti, Rogério

doi:10.1007/s00213-011-2330-4

Cited by 73 publications

(51 citation statements)

References 61 publications

(81 reference statements)

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“…8 Consistently, NMDA-enhancing agents can benefit cognitive function in animal models of schizophrenia. 63 In the current study, benzoate treatment improved neurocognition in general and specifically in processing speed and visual memory ( weeks of adjunctive treatment with high-dose D-serine improved MATRICS scores. Currently, no cognition enhancer has been approved for the treatment of schizophrenia.…”

Section: Discussionmentioning

confidence: 52%

Add-on Treatment of Benzoate for Schizophrenia

et al. 2013

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In addition to dopaminergic hyperactivity, hypofunction of the N-methyl-D-aspartate receptor (NMDAR) has an important role in the pathophysiology of schizophrenia. Enhancing NMDAR-mediated neurotransmission is considered a novel treatment approach. To date, several trials on adjuvant NMDA-enhancing agents have revealed beneficial, but limited, efficacy for positive and negative symptoms and cognition. Another method to enhance NMDA function is to raise the levels of D-amino acids by blocking their metabolism. Sodium benzoate is a D-amino acid oxidase inhibitor.OBJECTIVE To examine the clinical and cognitive efficacy and safety of add-on treatment of sodium benzoate for schizophrenia. DESIGN, SETTING, AND PARTICIPANTSA randomized, double-blind, placebo-controlled trial in 2 major medical centers in Taiwan composed of 52 patients with chronic schizophrenia who had been stabilized with antipsychotic medications for 3 months or longer.INTERVENTIONS Six weeks of add-on treatment of 1 g/d of sodium benzoate or placebo. MAIN OUTCOMES AND MEASURESThe primary outcome measure was the Positive and Negative Syndrome Scale (PANSS) total score. Clinical efficacy and adverse effects were assessed biweekly. Cognitive functions were measured before and after the add-on treatment.RESULTS Benzoate produced a 21% improvement in PANSS total score and large effect sizes (range, 1.16-1.69) in the PANSS total and subscales, Scales for the Assessment of Negative Symptoms-20 items, Global Assessment of Function, Quality of Life Scale and Clinical Global Impression and improvement in the neurocognition subtests as recommended by the National Institute of Mental Health's Measurement and Treatment Research to Improve Cognition in Schizophrenia initiative, including the domains of processing speed and visual learning. Benzoate was well tolerated without significant adverse effects. CONCLUSIONS AND RELEVANCEBenzoate adjunctive therapy significantly improved a variety of symptom domains and neurocognition in patients with chronic schizophrenia. The preliminary results show promise for D-amino acid oxidase inhibition as a novel approach for new drug development for schizophrenia. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT 00960219

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Section: Discussionmentioning

confidence: 52%

Add-on Treatment of Benzoate for Schizophrenia

et al. 2013

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“…Declarative memory in rodents is markedly impaired by sc treatment with each of the three most frequently studied NMDAR antagonists, PCP, MK-801 and ketamine (Ennaceur and Delacour, 1988;Nabeshima et al, 2006;Karasawa et al, 2008;Young et al, 2009;Snigdha et al, 2010;Horiguchi et al, 2011a,b,c;see Neill et al, 2010;Meltzer et al, 2011 for review). Deficits in executive function and working memory have also been shown to result from 7-10 d consecutive treatment with an NMDAR antagonist Bado et al, 2011;Li et al, 2011). The doses of PCP, ketamine and MK-801 needed to establish these deficits are in the same range as those that increase locomotor activity, a surrogate for their psychotomimetic effects .…”

Section: The Scnmdar Antagonist Model Of Cognitive Impairment In Schimentioning

confidence: 99%

Translating the N-methyl-d-aspartate receptor antagonist model of schizophrenia to treatments for cognitive impairment in schizophrenia

Meltzer

Rajagopal

Huang

et al. 2013

International Journal of Neuropsychopharmacology

105

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The N-methyl-D-aspartate receptor (NMDAR) antagonists, phencyclidine (PCP), dizocilpine (MK-801), or ketamine, given subchronically (sc) to rodents and primates, produce prolonged deficits in cognitive function, including novel object recognition (NOR), an analog of human declarative memory, one of the cognitive domains impaired in schizophrenia. Atypical antipsychotic drugs (AAPDs) have been reported to improve declarative memory in some patients with schizophrenia, as well as to ameliorate and prevent the NOR deficit in rodents following scNMDAR antagonist treatment. While the efficacy of AAPDs to improve cognitive impairment in schizophrenia (CIS) is limited, at best, and controversial, single doses of all currently available AAPDs so far tested transiently restore NOR in rodents following scNMDAR antagonist treatment. Typical antipsychotic drugs (APDs), e.g. haloperidol and perphenazine, are ineffective in this rodent model, and may be less effective as treatments of some domains of CIS. Serotonergic mechanisms, including, but not limited to serotonin (5-HT)2A and 5-HT7 antagonism, 5-HT(1A), and GABA(A) agonism, contribute to the efficacy of the AAPDs in the scNMDAR antagonist rodent models, which are relevant to the loss of GABA interneuron/hyperglutamate hypothesis of the etiology of CIS. The ability of sub-effective doses of the atypical APDs to ameliorate NOR in the scNMDAR-treated rodents can be restored by the addition of a sub-effective dose of the 5-HT(1A) partial agonist, tandospirone, or the 5-HT7 antagonist, SB269970. The mGluR2/3 agonist, LY379268, which itself is unable to restore NOR in the scNMDAR-treated rodents, can also restore NOR when given with lurasidone, an AAPD. Enhancing cortical and hippocampal dopamine and acetylcholine efflux, or both, may contribute to the restoration of NOR by the atypical APDs. Importantly, co-administration of lurasidone, tandospirone, or SB269970, with PCP, to rodents, at doses 5-10 fold greater than those acutely effective to restore NOR following scNMDAR treatment, prevents the effect of scPCP to produce an enduring deficit in NOR. This difference in dosage may be relevant to utilizing AAPDs to prevent the onset of CIS in individuals at high risk for developing schizophrenia. The scNMDAR paradigm may be useful for identifying possible means to treat and prevent CIS.

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“…Moreover, in contrast to GLY, DSR may preferentially act at synaptic NMDARs (Papouin et al, 2012) which are involved in signal transduction of cell survival pathways (Hardingham and Bading, 2010). In animal models, DSR was shown to have procognitive (Bado et al, 2011;Kew et al, 2000;Ballard et al, 2002) and antidepressant/anxiolytic (Malkesman et al, 2012) effects and reduced DSR serum and cerebrospinal fluid levels were documented in schizophrenia (Hashimoto et al, 2003(Hashimoto et al, , 2005.…”

Section: Introductionmentioning

confidence: 99%