Rational and Translational Implications of D-Amino Acids for Treatment-Resistant Schizophrenia: From Neurobiology to the Clinics
Schizophrenia has been conceptualized as a neurodevelopmental disorder with synaptic alterations and aberrant cortical–subcortical connections. Antipsychotics are the mainstay of schizophrenia treatment and nearly all share the common feature of dopamine D2 receptor occupancy, whereas glutamatergic...
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MDPI AG
2022-06-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/12/7/909 |
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| author | Andrea de Bartolomeis Licia Vellucci Mark C. Austin Giuseppe De Simone Annarita Barone |
| author_facet | Andrea de Bartolomeis Licia Vellucci Mark C. Austin Giuseppe De Simone Annarita Barone |
| author_sort | Andrea de Bartolomeis |
| collection | DOAJ |
| description | Schizophrenia has been conceptualized as a neurodevelopmental disorder with synaptic alterations and aberrant cortical–subcortical 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 30–40% 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’ 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. |
| first_indexed | 2024-03-09T03:39:24Z |
| format | Article |
| id | doaj.art-6580b4addbe947e988d945dcb1842a83 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-09T03:39:24Z |
| publishDate | 2022-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-6580b4addbe947e988d945dcb1842a832023-12-03T14:43:19ZengMDPI AGBiomolecules2218-273X2022-06-0112790910.3390/biom12070909Rational and Translational Implications of D-Amino Acids for Treatment-Resistant Schizophrenia: From Neurobiology to the ClinicsAndrea de Bartolomeis0Licia Vellucci1Mark C. Austin2Giuseppe De Simone3Annarita Barone4Laboratory 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, ItalyLaboratory 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, ItalyClinical Psychopharmacology Program, College of Pharmacy, Idaho State University, Pocatello, ID 83209, USALaboratory 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, ItalyLaboratory 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, ItalySchizophrenia has been conceptualized as a neurodevelopmental disorder with synaptic alterations and aberrant cortical–subcortical 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 30–40% 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’ 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.https://www.mdpi.com/2218-273X/12/7/909antipsychoticstreatment-resistant schizophreniaNMDAdopamineglutamateD-serine |
| spellingShingle | Andrea de Bartolomeis Licia Vellucci Mark C. Austin Giuseppe De Simone Annarita Barone Rational and Translational Implications of D-Amino Acids for Treatment-Resistant Schizophrenia: From Neurobiology to the Clinics Biomolecules antipsychotics treatment-resistant schizophrenia NMDA dopamine glutamate D-serine |
| title | Rational and Translational Implications of D-Amino Acids for Treatment-Resistant Schizophrenia: From Neurobiology to the Clinics |
| title_full | Rational and Translational Implications of D-Amino Acids for Treatment-Resistant Schizophrenia: From Neurobiology to the Clinics |
| title_fullStr | Rational and Translational Implications of D-Amino Acids for Treatment-Resistant Schizophrenia: From Neurobiology to the Clinics |
| title_full_unstemmed | Rational and Translational Implications of D-Amino Acids for Treatment-Resistant Schizophrenia: From Neurobiology to the Clinics |
| title_short | Rational and Translational Implications of D-Amino Acids for Treatment-Resistant Schizophrenia: From Neurobiology to the Clinics |
| title_sort | rational and translational implications of d amino acids for treatment resistant schizophrenia from neurobiology to the clinics |
| topic | antipsychotics treatment-resistant schizophrenia NMDA dopamine glutamate D-serine |
| url | https://www.mdpi.com/2218-273X/12/7/909 |
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