{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T22:53:49Z","timestamp":1788908029610,"version":"build-2803163510"},"reference-count":423,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,6,29]],"date-time":"2022-06-29T00:00:00Z","timestamp":1656460800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Schizophrenia has been conceptualized as a neurodevelopmental disorder with synaptic alterations and aberrant cortical\u2013subcortical connections. Antipsychotics are the mainstay of schizophrenia treatment and nearly all share the common feature of dopamine D2 receptor occupancy, whereas glutamatergic abnormalities are not targeted by the presently available therapies. D-amino acids, acting as N-methyl-D-aspartate receptor (NMDAR) modulators, have emerged in the last few years as a potential augmentation strategy in those cases of schizophrenia that do not respond well to antipsychotics, a condition defined as treatment-resistant schizophrenia (TRS), affecting almost 30\u201340% of patients, and characterized by serious cognitive deficits and functional impairment. In the present systematic review, we address with a direct and reverse translational perspective the efficacy of D-amino acids, including D-serine, D-aspartate, and D-alanine, in poor responders. The impact of these molecules on the synaptic architecture is also considered in the light of dendritic spine changes reported in schizophrenia and antipsychotics\u2019 effect on postsynaptic density proteins. Moreover, we describe compounds targeting D-amino acid oxidase and D-aspartate oxidase enzymes. Finally, other drugs acting at NMDAR and proxy of D-amino acids function, such as D-cycloserine, sarcosine, and glycine, are considered in the light of the clinical burden of TRS, together with other emerging molecules.<\/jats:p>","DOI":"10.3390\/biom12070909","type":"journal-article","created":{"date-parts":[[2022,6,29]],"date-time":"2022-06-29T03:26:37Z","timestamp":1656473197000},"page":"909","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Rational and Translational Implications of D-Amino Acids for Treatment-Resistant Schizophrenia: From Neurobiology to the Clinics"],"prefix":"10.3390","volume":"12","author":[{"given":"Andrea","family":"de Bartolomeis","sequence":"first","affiliation":[{"name":"Laboratory of Translational and Molecular Psychiatry and Unit of Treatment-Resistant Psychosis, Section of Psychiatry, Department of Neuroscience, Reproductive Sciences and Dentistry, University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Licia","family":"Vellucci","sequence":"additional","affiliation":[{"name":"Laboratory of Translational and Molecular Psychiatry and Unit of Treatment-Resistant Psychosis, Section of Psychiatry, Department of Neuroscience, Reproductive Sciences and Dentistry, University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark C.","family":"Austin","sequence":"additional","affiliation":[{"name":"Clinical Psychopharmacology Program, College of Pharmacy, Idaho State University, Pocatello, ID 83209, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0422-3415","authenticated-orcid":false,"given":"Giuseppe","family":"De Simone","sequence":"additional","affiliation":[{"name":"Laboratory of Translational and Molecular Psychiatry and Unit of Treatment-Resistant Psychosis, Section of Psychiatry, Department of Neuroscience, Reproductive Sciences and Dentistry, University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2751-5683","authenticated-orcid":false,"given":"Annarita","family":"Barone","sequence":"additional","affiliation":[{"name":"Laboratory of Translational and Molecular Psychiatry and Unit of Treatment-Resistant Psychosis, Section of Psychiatry, Department of Neuroscience, Reproductive Sciences and Dentistry, University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1001\/jamapsychiatry.2019.3360","article-title":"Schizophrenia-An Overview","volume":"77","author":"McCutcheon","year":"2020","journal-title":"JAMA Psychiatry"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Correll, C.U., and Howes, O.D. 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