Rational and Translational Implications of D-Amino Acids for Treatment-Resistant Schizophrenia: From Neurobiology to the Clinics

Abstract

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.

Antipsychotics-Induced Changes in Synaptic Architecture and Functional Connectivity: Translational Implications for Treatment Response and Resistance

“…In the same experimental setting, the mGlu2/3R agonist LY379268 differentially modified the network oscillatory activity, reducing the power of high-frequency gamma bands in control Wistar but not in Han Wistar rats [ 144 ]. In addition, regulators of the NMDAR have been experimented in clinical trials and may account for beneficial antipsychotic effects also by modulating brain connectivity [ 6 ]. Specifically, SSR504734, an inhibitor of the glycine transporter-1 (GlyT1) could enhance the NMDAR-mediated glutamatergic neurotransmission by increasing extracellular glycine levels and was shown to significantly reduce the ketamine-induced increase of brain metabolic activity in the PFC, cingulate cortex, hippocampus, nucleus accumbens, and anteroventral thalamic nucleus [ 145 ].…”

“…Most antipsychotics, albeit with individual differences, share the common feature of occupying the dopamine D2 receptor (D2R), which is considered the main mechanism responsible for their therapeutic effect [ 3 ]. Despite the relevance of dopamine-related action, atypical antipsychotics and novel compounds in experimental trials modulate other neurotransmitter pathways, including the serotonergic, glutamatergic, and adrenergic ones with a putative beneficial effect on psychotic symptoms [ 4 , 5 , 6 ]. Mounting evidence suggests that antipsychotics can lead to morphological and synaptic changes in the brain through the modulation of processes that regulate synaptic plasticity, dendritic spine architecture, and postsynaptic density [ 5 , 7 ].…”

Canonical and Non-Canonical Antipsychotics’ Dopamine-Related Mechanisms of Present and Next Generation Molecules: A Systematic Review on Translational Highlights for Treatment Response and Treatment-Resistant Schizophrenia

“…However, no cumulative evidence of significant clinically beneficial differences was shown, except for improvement in negative symptoms with memantine and minocycline [ 220 ]. It is possible that the use of additional glutamatergic agents in patients receiving clozapine may have little effect, possibly due to a putative ceiling effect on the NMDAR transmission enhancement already exerted by clozapine [ 221 ]. Strategies based on the potentiation of glutamatergic signaling by glycinergic agents (e.g., glycine and D-serine), glycine transporter 1 (GlyT1) inhibitors (e.g., bitopertin and BI 425809), and other glutamate allosteric NMDAR modulators (e.g., CNS4) have been tested.…”

The Role of D-Serine and D-Aspartate in the Pathogenesis and Therapy of Treatment-Resistant Schizophrenia

“…Preclinical studies in an animal model of Sch have demonstrated that a decrease in the level of D-Ser in the CNS due to a decrease in SR activity can cause Sch symptoms, including stereotypy, cognitive impairment, impaired prepulse inhibition (a measure of sensorimotor gating), persistent latent inhibition (a measure of inhibition of learning and cognitive flexibility) and a lack of social interaction [ 38 , 96 , 97 ].…”

“…Various studies in animal models and humans have demonstrated that D-amino acids, in particular D-Ser and D-Asp ( Table 1 ) [ 38 ], are able to modulate various NMDAR-dependent processes, including synaptic plasticity, brain development, cognition and aging brain [ 39 ]. Dysfunctional NMDAR activity is associated with the etiology and pathophysiology of a wide range of psychiatric and neurological disorders, including Sch [ 40 ].…”