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 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.

Automated summary

Schizophrenia is a neurodevelopmental disorder characterized by synaptic alterations and abnormal cortical-subcortical connections. Current treatment options mainly focus on dopamine D2 receptor occupancy, while glutamatergic abnormalities remain untargeted. In recent years, D-amino acids acting as NMDAR modulators have emerged as potential augmentation strategies for treatment-resistant schizophrenia (TRS), which affects around 30-40% of patients and is characterized by cognitive deficits and functional impairment. This systematic review explores the efficacy of D-amino acids and their impact on synaptic architecture, as well as compounds targeting D-amino acid oxidase and D-aspartate oxidase enzymes.