The efficacy of sodium benzoate as an adjunctive treatment in early psychosis - CADENCE-BZ: study protocol for a randomized controlled trial

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Abstract

Background

Psychotic disorders affect up to 3% of the population and are often chronic and disabling. Innovation in the pharmacological treatment of psychosis has remained stagnant in recent decades. In order to improve outcomes for those with psychotic disorders, we present a protocol for the trial of a common food preservative, sodium benzoate, as an adjunctive treatment in early psychosis.

Methods

Persons experiencing early psychosis (n = 160) will be recruited through hospitals and community mental health services in Queensland, Australia. Patients will be randomized to receive either 12-week treatment with 1000 mg (500 mg twice daily (BD)) sodium benzoate or placebo. Patients will undergo fortnightly outcome assessments, in addition to weekly ongoing capacity to consent, drug compliance and safety assessments. The primary outcome measure is the Positive and Negative Syndrome Scale (PANSS) total score. Secondary outcomes are Global Assessment of Function (GAF), Assessment of Quality of Life Scale (AQOL), the Activity and Participation Questionnaire (APQ6), International Physical Activity Questionnaires (IPAQ), Simple Physical Activity Questionnaire (SIMPAQ), Physical Activity Questionnaire, Clinical Global Impression (CGI), Hamilton Depression rating Scale-17 items (HDRS), Opiate Treatment Index (OTI) and the Patients’ Global Impression of Improvement (PGI-I). As a tertiary objective, changes from baseline to endpoint in to serum markers related to D-alanine, L-alanine, D-serine, L-serine, glycine and glutamate will be investigated.

Discussion

Consumers and clinicians are keen to help develop better treatments for those with psychosis. This study, part of the wider Cadence clinical trials platform will examine if a safe and accessible food preservative can help optimize outcomes in those with psychosis.

Trial Registration

Australian New Zealand Clinical Trials registry (ANZCTR), ACTRN12615000187549. Registered on 26 February 2015.

Electronic supplementary material

The online version of this article (doi:10.1186/s13063-017-1908-5) contains supplementary material, which is available to authorized users.

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Most cited references 27

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Add-on treatment of benzoate for schizophrenia: a randomized, double-blind, placebo-controlled trial of D-amino acid oxidase inhibitor.

Hsien-Yuan Lane, Ching-Hua Lin, Michael Green … (2013)

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. To examine the clinical and cognitive efficacy and safety of add-on treatment of sodium benzoate for schizophrenia. A 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. Six weeks of add-on treatment of 1 g/d of sodium benzoate or placebo. The 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. 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. Benzoate 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.

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Benzoate, a D-amino acid oxidase inhibitor, for the treatment of early-phase Alzheimer disease: a randomized, double-blind, placebo-controlled trial.

Chieh-Hsin Lin, Ping-Kun Chen, Yue-Cune Chang … (2014)

N-methyl-D-aspartate receptor (NMDAR)-mediated neurotransmission is vital for learning and memory. Hypofunction of NMDAR has been reported to play a role in the pathophysiology of Alzheimer disease (AD), particularly in the early phase. Enhancing NMDAR activation might be a novel treatment approach. One of the methods to enhance NMDAR activity is to raise the levels of NMDA coagonists by blocking their metabolism. This study examined the efficacy and safety of sodium benzoate, a D-amino acid oxidase inhibitor, for the treatment of amnestic mild cognitive impairment and mild AD. We conducted a randomized, double-blind, placebo-controlled trial in four major medical centers in Taiwan. Sixty patients with amnestic mild cognitive impairment or mild AD were treated with 250-750 mg/day of sodium benzoate or placebo for 24 weeks. Alzheimer's Disease Assessment Scale-cognitive subscale (the primary outcome) and global function (assessed by Clinician Interview Based Impression of Change plus Caregiver Input) were measured every 8 weeks. Additional cognition composite was measured at baseline and endpoint. Sodium benzoate produced a better improvement than placebo in Alzheimer's Disease Assessment Scale-cognitive subscale (p = .0021, .0116, and .0031 at week 16, week 24, and endpoint, respectively), additional cognition composite (p = .007 at endpoint) and Clinician Interview Based Impression of Change plus Caregiver Input (p = .015, .016, and .012 at week 16, week 24, and endpoint, respectively). Sodium benzoate was well-tolerated without evident side-effects. Sodium benzoate substantially improved cognitive and overall functions in patients with early-phase AD. The preliminary results show promise for D-amino acid oxidase inhibition as a novel approach for early dementing processes. Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

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Targeting of NMDA receptors in new treatments for schizophrenia.

Kenji Hashimoto (2014)

Abnormalities in glutamatergic neurotransmission mediated by N-methyl-d-aspartate (NMDA) are implicated in the pathophysiology of schizophrenia, although the precise mechanisms are unknown. The author examines the role of the NMDA receptor in schizophrenia, focusing on results from preclinical and clinical studies that support the NMDA receptor hypothesis of schizophrenia. The author first reviewed papers detailing alterations in the levels of endogenous substances such as glutamine, glutamate, d-serine, l-serine, kynurenic acid and glutathione (GSH), all of which can affect NMDA receptor function. Next, the author reviewed clinical findings for glycine, d-serine, d-cycloserine, d-amino acid oxidase inhibitors (e.g., sodium benzoate) and glycine transporter-1 inhibitors (e.g., sarcosine, bitopertin), as potential therapeutic drugs. In addition, the author outlined how oxidative stress associated with decreased levels of the endogenous antioxidant GSH may play a role in the pathophysiology of schizophrenia. Finally, the author reviewed N-acetylcysteine (NAC), a precursor of GSH and an activator of the cystine-glutamate antiporter, as a potential therapeutic drug. Given the NMDA receptor hypothesis of schizophrenia, the glycine modulatory site on NMDA receptors is the most attractive therapeutic target for this disease. In addition, both the kynurenine pathway and cystine-glutamate antiporter represent credible potential therapeutic targets for schizophrenia.

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Author and article information

Contributors

Alex Ryan: a.ryan5@uq.edu.au

Andrea Baker: andrea_baker@qcmhr.uq.edu

Frances Dark: frances.dark@health.qld.gov.au

Sharon Foley: Sharon.foley@health.qld.gov.au

Anne Gordon: Anne.Gordon@health.qld.gov.au

Sean Hatherill: sean.hatherill@health.qld.gov.au

Stephen Stathis: Stephen.Stathis@health.qld.gov.au

Sukanta Saha: Sukanta_saha@qcmhr.uq.edu.au

George Bruxner: George.Bruxner@health.qld.gov.au

Martin Beckman: Martin.Beckmann@health.qld.gov.au

Drew Richardson: Drew.Richardson@health.qld.gov.au

Michael Berk: michael.berk@deakin.edu.au

Olivia Dean: olivia.dean@barwonhealth.org.au

John McGrath: j.mcgrath@uq.edu.au

James Scott: +61 7 3636 8111 , james.scott@health.qld.gov.au

Journal

Journal ID (nlm-ta): Trials

Journal ID (iso-abbrev): Trials

Title: Trials

Publisher: BioMed Central (London )

ISSN (Electronic): 1745-6215

Publication date (Electronic): 7 April 2017

Publication date PMC-release: 7 April 2017

Publication date Collection: 2017

Volume: 18

Electronic Location Identifier: 165

Affiliations

[1 ]GRID grid.417162.7, , Queensland Centre for Mental Health Research, The Park Centre for Mental Health, ; Wacol, QLD Australia

[2 ]GRID grid.1003.2, , University of Queensland Centre for Clinical Research, University of Queensland, ; Herston, QLD Australia

[3 ]Metro South Mental Health, 519 Kessels Road, MacGregor, QLD 4109 Australia

[4 ]GRID grid.416100.2, Metro North Mental Health, , Royal Brisbane and Women’s Hospital, ; Level 3 UQCCR, RBWH, Herston, QLD 4029 Australia

[5 ]GRID grid.460757.7, , Logan Hospital, ; Armstrong Rd and Loganlea Rd, Meadowbrook, QLD 4131 Australia

[6 ]GRID grid.240562.7, , Lady Cilento Children’s Hospital, ; Raymond Terrace, South Brisbane, QLD 4101 Australia

[7 ]GRID grid.1003.2, , Queensland Brain Institute, University of Queensland, ; St Lucia, QLD Australia

[8 ]Metro North Mental Health, Caboolture and Redcliffe Hospitals, Caboolture, QLD Australia

[9 ]Specialist Child and Adolescent Psychiatrist, Evolve Therapeutic Services Logan, Child and Youth Mental Health Services Logan, Academic Clinical Unit Logan, Metro South Hospital and Health Services, Logan, QLD Australia

[10 ]GRID grid.415184.d, , Prince Charles Hospital, ; Chermside, Rode Rd, Chermside, QLD 4032 Australia

[11 ]IMPACT Strategic Research Centre, Deakin University, School of Medicine, Barwon Health, P.O. Box 291, Geelong, 3220 Australia

[12 ]Department of Psychiatry, University of Melbourne, Royal Melbourne Hospital, Level 1 North, Main Block, Parkville, 3052 Australia

Article

Publisher ID: 1908

DOI: 10.1186/s13063-017-1908-5

PMC ID: 5383965

PubMed ID: 28388932

SO-VID: ec0a8895-521f-48c9-a7a3-f44a17b7e8ff

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 30 November 2016

Date accepted : 16 March 2017

Custom metadata

ScienceOpen disciplines: Medicine

Keywords: adjuvant,sodium benzoate,early psychosis,schizophrenia,intervention,rct,clinical trial,panss

Data availability:

ScienceOpen disciplines: Medicine

Keywords: adjuvant, sodium benzoate, early psychosis, schizophrenia, intervention, rct, clinical trial, panss

The efficacy of sodium benzoate as an adjunctive treatment in early psychosis - CADENCE-BZ: study protocol for a randomized controlled trial

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Abstract

Background

Methods

Discussion

Trial Registration

Electronic supplementary material

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Herbal Medicines Journal (Herb Med J)

Most cited references 27

Add-on treatment of benzoate for schizophrenia: a randomized, double-blind, placebo-controlled trial of D-amino acid oxidase inhibitor.

Benzoate, a D-amino acid oxidase inhibitor, for the treatment of early-phase Alzheimer disease: a randomized, double-blind, placebo-controlled trial.

Targeting of NMDA receptors in new treatments for schizophrenia.

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