Add-on Treatment of Benzoate for Schizophrenia

Lane, Hsien‐Yuan; Lin, Ching‐Hua; Green, Michael F.; Hellemann, Gerhard; Huang, Chih‐Chia; Chen, Po‐Wei; Tun, R. Y. M.; Chang, Y C; Tsai, Guochuan E.

doi:10.1001/jamapsychiatry.2013.2159

Cited by 193 publications

(116 citation statements)

References 71 publications

(71 reference statements)

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“…Sodium benzoate (NaB) is also a modest DAAO inhibitor and has been used as add-on treatment therapy in schizophrenia (24). Locomotor activity was measured after sodium benzoate acute administration (NaB, 400 mg/kg, i.p.).…”

Section: Resultsmentioning

confidence: 99%

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Modulating NMDA Receptor Function with d-Amino Acid Oxidase Inhibitors: Understanding Functional Activity in PCP-Treated Mouse Model

et al. 2016

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Deficits in N-methyl-D-aspartate receptor (NMDAR) function are increasingly linked to persistent negative symptoms and cognitive deficits in schizophrenia. Accordingly, clinical studies have been targeting the modulatory site of the NMDA receptor, based on the decreased function of NMDA receptor, to see whether increasing NMDA function can potentially help treat the negative and cognitive deficits seen in the disease. Glycine and D-serine are endogenous ligands to the NMDA modulatory site, but since high doses are needed to affect brain levels, related compounds are being developed, for example glycine transport (GlyT) inhibitors to potentially elevate brain glycine or targeting enzymes, such as D-amino acid oxidase (DAAO) to slow the breakdown and increase the brain level of D-serine. In the present study we further evaluated the effect of DAAO inhibitors 5-chloro-benzo[d]isoxazol-3-ol (CBIO) and sodium benzoate (NaB) in a phencyclidine (PCP) rodent mouse model to see if the inhibitors affect PCP-induced locomotor activity, alter brain D-serine level, and thereby potentially enhance D-serine responses. D-Serine dose-dependently reduced the PCP-induced locomotor activity at doses above 1000 mg/kg. Acute CBIO (30 mg/kg) did not affect PCP-induced locomotor activity, but appeared to reduce locomotor activity when given with D-serine (600 mg/kg); a dose that by itself did not have an effect. However, the effect was also present when the vehicle (Trappsol®) was tested with D-serine, suggesting that the reduction in locomotor activity was not related to DAAO inhibition, but possibly reflected enhanced bioavailability of D-serine across the blood brain barrier related to the vehicle. With this acute dose of CBIO, D-serine level in brain and plasma were not increased. Another weaker DAAO inhibitor sodium benzoate (NaB) (400 mg/kg), and NaB plus D-serine also significantly reduced PCP-induced locomotor activity, but without affecting plasma or brain D-serine level, arguing against a DAAO-mediated effect. However, NaB reduced plasma L-serine and based on reports that NaB also elevates various plasma metabolites, for example aminoisobutyric acid (AIB), a potential effect via the System A amino acid carrier may be involved in the regulation of synaptic glycine level to modulate NMDAR function needs to be investigated. Acute ascorbic acid (300 mg/kg) also inhibited PCP-induced locomotor activity, which was further attenuated in the presence of D-serine (600 mg/kg). Ascorbic acid may have an action at the dopamine membrane carrier and/or altering redox mechanisms that modulate NMDARs, but this needs to be further investigated. The findings support an effect of D-serine on PCP-induced hyperactivity. They also offer suggestions on an interaction of NaB via an unknown mechanism, other than DAAO inhibition, perhaps through metabolomic changes, and find unexpected synergy between D-serine and ascorbic acid that supports combined NMDA glycine- and redox-site intervention. Although mechanisms of these specific agents need to be det...

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Section: Resultsmentioning

confidence: 99%

“…An alternative compound, sodium benzoate (NaB) has also recently been tested in both preclinical (23) and clinical (19, 24) studies with encouraging results. Nevertheless, the affinity of this compound for DAAO is low, so the degree to which effects were mediated by DAAO inhibition remains uncertain.…”

Section: Introductionmentioning

confidence: 99%

Modulating NMDA Receptor Function with d-Amino Acid Oxidase Inhibitors: Understanding Functional Activity in PCP-Treated Mouse Model

et al. 2016

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“…The case is supported by findings that patients have increased DAO activity and expression (Kapoor et al, 2006; Verrall et al, 2007; Burnet et al, 2008a; Madeira et al, 2008), complemented by equivocal evidence for lower D-serine levels (Hashimoto et al, 2003; Bendikov et al, 2007; Brouwer et al, 2013) and initial findings that novel DAO inhibitors show efficacy in preclinical models of schizophrenia (Adage et al, 2008) and, for sodium benzoate, in the disorder itself (Lane et al, 2013). …”

Section: Discussionmentioning

confidence: 99%

“…Evidence that DAO contributes to the glutamatergic dysfunction in schizophrenia is threefold (Verrall et al, 2010; Labrie et al, 2012; Sacchi et al, 2013): it may be a susceptibility gene (Chumakov et al, 2002; Allen et al, 2008; Shi et al, 2008; Sun et al, 2008); DAO expression and activity are increased (Kapoor et al, 2006; Verrall et al, 2007; Burnet et al, 2008a; Madeira et al, 2008); and DAO inhibitors show preliminary preclinical (Adage et al, 2008) and clinical (Lane et al, 2013) evidence for therapeutic efficacy.…”

Section: Introductionmentioning

confidence: 99%

D-amino acid oxidase is expressed in the ventral tegmental area and modulates cortical dopamine

Betts

Schweimer

Burnham

et al. 2014

Front. Synaptic Neurosci.

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D-amino acid oxidase (DAO, DAAO) degrades the NMDA receptor co-agonist D-serine, modulating D-serine levels and thence NMDA receptor function. DAO inhibitors are under development as a therapy for schizophrenia, a disorder involving both NMDA receptor and dopaminergic dysfunction. However, a direct role for DAO in dopamine regulation has not been demonstrated. Here, we address this question in two ways. First, using in situ hybridization and immunohistochemistry, we show that DAO mRNA and immunoreactivity are present in the ventral tegmental area (VTA) of the rat, in tyrosine hydroxylase (TH)-positive and -negative neurons, and in glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes. Second, we show that injection into the VTA of sodium benzoate, a DAO inhibitor, increases frontal cortex extracellular dopamine, as measured by in vivo microdialysis and high performance liquid chromatography. Combining sodium benzoate and D-serine did not enhance this effect, and injection of D-serine alone affected dopamine metabolites but not dopamine. These data show that DAO is expressed in the VTA, and suggest that it impacts on the mesocortical dopamine system. The mechanism by which the observed effects occur, and the implications of these findings for schizophrenia therapy, require further study.

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“…Benzoate, a compound that inhibits D-amino acid oxidase, is reported to be therapeutically beneficial [79]…”

Section: Emerging Treatmentmentioning

confidence: 99%

Current and Emergent Treatments for Symptoms and Neurocognitive Impairment in Schizophrenia

Javitt

2014

Curr Treat Options Psych

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Add-on Treatment of Benzoate for Schizophrenia

Cited by 193 publications

References 71 publications

Modulating NMDA Receptor Function with d-Amino Acid Oxidase Inhibitors: Understanding Functional Activity in PCP-Treated Mouse Model

Modulating NMDA Receptor Function with d-Amino Acid Oxidase Inhibitors: Understanding Functional Activity in PCP-Treated Mouse Model

D-amino acid oxidase is expressed in the ventral tegmental area and modulates cortical dopamine

Current and Emergent Treatments for Symptoms and Neurocognitive Impairment in Schizophrenia

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