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Targeting d-Amino Acid Oxidase (DAAO) for the Treatment of Schizophrenia: Rationale and Current Status of Research

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Abstract

In the brain, d-amino acid oxidase (DAAO) is a peroxisomal flavoenzyme. Through oxidative deamination by DAAO, d-serine, the main coagonist of synaptic N-methyl-d-aspartate receptors (NMDARs), is degraded into α-keto acids and ammonia; flavin adenine dinucleotide (FAD) is simultaneously reduced to dihydroflavine-adenine dinucleotide (FADH2), which is subsequently reoxidized to FAD, with hydrogen peroxide produced as a byproduct. NMDAR hypofunction is implicated in the pathogenesis of schizophrenia. In previous studies, compared with control subjects, patients with schizophrenia had lower d-serine levels in peripheral blood and cerebrospinal fluid but higher DAAO expression and activity in the brain. Inhibiting DAAO activity and slowing d-serine degradation by using DAAO inhibitors to enhance NMDAR function may be a new strategy for use in the treatment of schizophrenia. The aim of this leading article is to review the current research in DAAO inhibitors.

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  1. Department of Psychiatry, China Medical University Hospital, No. 2, Yude Rd., North Dist., Taichung City, 404327, Taiwan, ROC

    Chien-Yi Kuo & Hsien-Yuan Lane

  2. Graduate Institute of Biomedical Sciences, China Medical University, No. 91, Xueshi Rd., North Dis., Taichung City, 404333, Taiwan, ROC

    Chien-Yi Kuo, Chieh-Hsin Lin & Hsien-Yuan Lane

  3. Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital, No. 123, Dapi Rd., Niaosong Dist., Kaohsiung City, 83301, Taiwan, ROC

    Chieh-Hsin Lin

  4. School of Medicine, Chang Gung University, No. 259, Wenhua 1st Rd., Guishan Dist., Taoyuan City, 33302, Taiwan, ROC

    Chieh-Hsin Lin

  5. Department of Psychology, College of Medical and Health Sciences, Asia University, No. 500, Lioufeng Rd., Wufeng Dist., Taichung City, 413305, Taiwan, ROC

    Hsien-Yuan Lane

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This work was supported by National Health Research Institutes, Taiwan (NHRI-EX111-11133NI), Ministry of Science and Technology, Taiwan (109-2314-B-039-039-MY3; MOST 111-2622-B-039-002) and China Medical University Hospital, Taiwan (DMR-111-243, DMR-HHC-111-9).

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Kuo, CY., Lin, CH. & Lane, HY. Targeting d-Amino Acid Oxidase (DAAO) for the Treatment of Schizophrenia: Rationale and Current Status of Research. CNS Drugs 36, 1143–1153 (2022). https://doi.org/10.1007/s40263-022-00959-5

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