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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan; Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Chieh-Hsin
CH
Lin
Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan; Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan; Department of Neurology, Lin-Shin Hospital, Taichung, Taiwan.
Ping-Kun
PK
Chen
Department of Mathematics, Tamkang University, Taipei, Taiwan.
Yue-Cune
YC
Chang
Department of Psychiatry, Taichung Veterans General Hospital, Taichung, Taiwan.
Liang-Jen
LJ
Chuo
Department of Mathematics, Tamkang University, Taipei, Taiwan; Department of Psychiatry, China Medical University Hospital, Taichung, Taiwan.
Yan-Syun
YS
Chen
Department of Psychiatry, Harbor-UCLA Medical Center, Torrance, California.
Guochuan E
GE
Tsai
Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan; Department of Psychiatry, China Medical University Hospital, Taichung, Taiwan. Electronic address: hylane@gmail.com.
Hsien-Yuan
HY
Lane
D000368:Aged; D000544:Alzheimer Disease / Q000188:drug therapy*; D003071:Cognition / Q000187:drug effects; D060825:Cognitive Dysfunction / Q000188:drug therapy*; D003605:D-Amino-Acid Oxidase / Q000037:antagonists & inhibitors; D018450:Disease Progression; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D018697:Nootropic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D012720:Severity of Illness Index; D020160:Sodium Benzoate / Q000009:adverse effects / Q000627:therapeutic use*; D013624:Taiwan; D013997:Time Factors; D016896:Treatment Outcome
D004791:Enzyme Inhibitors; D018697:Nootropic Agents; D003605:D-Amino-Acid Oxidase; D020160:Sodium Benzoate
Alzheimer disease; D-amino acids oxidase (DAAO) inhibitor; N-methyl-D-aspartate; clinical trial; mild cognitive impairment; sodium benzoate