Drugs Based on NMDAR Hypofunction Hypothesis in Schizophrenia

Abstract

Treatments for negative symptoms and cognitive dysfunction in schizophrenia remain issues that psychiatrists around the world are trying to solve. Their mechanisms may be associated with N-methyl-D-aspartate receptors (NMDARs). The NMDAR hypofunction hypothesis for schizophrenia was brought to the fore mainly based on the clinical effects of NMDAR antagonists and anti-NMDAR encephalitis pathology. Drugs targeted at augmenting NMDAR function in the brain seem to be promising in improving negative symptoms and cognitive dysfunction in patients with schizophrenia. In this review, we list NMDAR-targeted drugs and report on related clinical studies. We then summarize their effects on negative symptoms and cognitive dysfunction and analyze the unsatisfactory outcomes of these clinical studies according to the improved glutamate hypothesis that has been revealed in animal models. We aimed to provide perspectives for scientists who sought therapeutic strategies for negative symptoms and cognitive dysfunction in schizophrenia based on the NMDAR hypofunction hypothesis.

Caught in vicious circles: a perspective on dynamic feed-forward loops driving oxidative stress in schizophrenia

“…MitoQ), and positive modulators of NMDAR-mediated signaling (e.g. D-serine, sarcosine, benzoate, glycine transporter inhibitors) [ 217 ]. The efficacy of these different compound categories may however differ from patients to patients, according to the timing of initiation during neurodevelopment of the vicious feedforward processes that are primarily triggered and the disease stages (prodrome, first episode or chronic).…”

“…b MitoQ and other mitochondria-targeted antioxidants could support compromised energy metabolism and mitochondria function [ 116 ]. c For NMDAR hypofunction, several strategies using compounds (e.g., D-serine, sarcosine, glycine transporter inhibitor and benzoate) that modulate NMDAR activity have been tried in schizophrenia patients with mixed success [ 217 , 223 – 229 ]. d In terms of neuro-inflammation, estrogens, minocycline and NAC showed efficacy, with greater beneficial results on symptom severity in first-episode psychosis patients or during early-phase of schizophrenia [ 216 ].…”

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

“…Conversely, NMDAR antagonists may exacerbate Sch symptoms, and NMDARs hypofunction causes psychosis. NMDAR antagonists modulate dopaminergic activity in nucleus accumbens and different subregions of the prefrontal cortex and this modulation is related to positive symptoms, negative symptoms and cognitive deficits, respectively [ 75 , 76 ]. D-Asp has an effect on synaptic plasticity [ 34 ]; its condensate has been found in synaptic vesicles of axon terminals in the developing brain, further supporting the suggestion that D-Asp is an important neurotransmitter involved in CNS development [ 77 ].…”

A Mini-Review Regarding the Modalities to Study Neurodevelopmental Disorders-Like Impairments in Zebrafish—Focussing on Neurobehavioural and Psychological Responses

“…However, the NMDA receptors inactivation leads to impaired socio-affective behavior, delayed learning, but normal sensitivity to feedback, as seen in the traditional NDDs (a mice model of inactivation of NMDA receptors on dopaminergic neurons) [ 20 ], while the loss of NMDA receptive neurons via autoimmune reaction initially mimics schizophrenia symptomatology (despite that this mechanism was not previously described in schizophrenic patients) [ 21 ]. In this context, many of the pharmacological solutions for schizophrenia management are based on the NMDA receptors deficiency (as seen in the traditional NDDs) rescue which can be successfully achieved in the adult brain together with schizophrenia-associated symptomatology remission [ 22 , 23 ].…”