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Original Investigation |

Add-on Treatment of Benzoate for Schizophrenia:  A Randomized, Double-blind, Placebo-Controlled Trial of d-Amino Acid Oxidase Inhibitor

Hsien-Yuan Lane, MD, PhD1,2; Ching-Hua Lin, MD, PhD3; Michael F. Green, PhD4,5; Gerhard Hellemann, PhD4; Chih-Chia Huang, MD, PhD1,2; Po-Wei Chen, MD6; Rene Tun, MD7; Yue-Cung Chang, PhD8; Guochuan E. Tsai, MD, PhD7
[+] Author Affiliations
1Department of Psychiatry, China Medical University Hospital, Taichung, Taiwan
2Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan
3Department of Adult Psychiatry, Kaohsiung Municipal Kai-Syuan Psychiatric Hospital, Kaohsiung, Taiwan
4Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles
5Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California
6Department of Psychiatry, Taichung Chin-Ho Hospital, Taichung, Taiwan
7Department of Psychiatry, Harbor-UCLA Medical Center, Torrance, California
8Department of Mathematics, Tamkang University, Taipei, Taiwan
JAMA Psychiatry. 2013;70(12):1267-1275. doi:10.1001/jamapsychiatry.2013.2159.
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Importance  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 Participants  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.

Interventions  Six weeks of add-on treatment of 1 g/d of sodium benzoate or placebo.

Main Outcomes and Measures  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.

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 Relevance  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.

Trial Registration  clinicaltrials.gov Identifier: NCT00960219

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Patient Progress Through Phases of the Study

Progress through phases of a randomized, double-blind, placebo-controlled trial of the add-on treatment of sodium benzoate for schizophrenia.

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