Over the last half century, optimistic predictions of revolutionary advances in the treatment of mental disorders like schizophrenia have failed to materialize. The crude reality is: most people suffering from mental illness are still left with debilitating social and functional deficits. A focus on cognition and functional recovery has led to a hypothesis of schizophrenia as a “glutamate/NMDA (N-methyl-D-aspartate) disorder.” Glutamate is the predominant excitatory neurotransmitter of mammalian CNS. Among the glutamatergic receptor, the NMDA receptor-mediated neurotransmission plays a critical role in regulating a variety of cortical circuitries and functions. NMDA system is the cornerstone for neurodevelopment, plasticity, cognition and memory as well as experience-dependent learning. Although developing novel CNS drugs faces great challenge, the glutamatergic system is gaining attention recently as multiple novel targets surrounding the glutamatergic system had been identified and explored. Engaging these novel targets, agents modulating the NMDA receptor had been shown to be potentially efficacious for a variety of mental disorders. We had explored the molecular subtlety of NMDA system and exploited its novel regulatory mechanisms to pioneer one of the next generation psychotropic classes of drug.
D-serine, a coagonist for the NMDA receptor, exists in the mammalian CNS. D-serine, acting at the “glycine” site, antagonizes the psychotomimetic effects of NMDA antagonists and dopamine agonists and is present at high contents with a NMDA receptor-like distribution. We learn that D-serine and glycine are regulated by serine racemase, D-amino acid oxidase (DAAO) and glycine transporter-1 (GlyT-1) by gene knockout and molecular studies. As a DAAO inhibitor, benzoate improves working memory and prepulse inhibition (PPI). DAAO inhibitor can further potentiate the efficacy of D-serine in attenuating PPI.

　　We have validated three novel drug targets of action: the coagonist site, GlyT-1, and DAAO (see figure). The lead compounds of agonists include D-serine, D-cycloserine and D-alanine. Another strategy to enhance NMDA function is blocking glycine reuptake through GlyT-1. Sarcosine is a prototype Gly-T1 inhibitor. Our clinical trials demonstrate that sarcosine therapy improved all symptom domains of schizophrenia. Recent studies further suggest that sarcosine is superior to D-serine in improving negative symptoms. Interim analysis also shows that a high dose of sarcosine is efficacious in improving the symptoms and function of super-resistant clozapine-treated patients. In a double-blind, placebo-controlled trial, benzoate therapy safely improves neurocognition and behavior symptoms of schizophrenia with large effect size.

　　Since NMDA system is the main regulator of synaptic function in neocortex, we predict the efficacy of NMDA drugs is beyond schizophrenia. In fact, illnesses including autism, attention deficit hyperactivity disorder, depression, obsessive compulsive disorder (OCD), substance abuse, Parkinson’s disorder, dementia and mild cognitive impairment (MCI) also can be accounted for, at least partly, by NMDA dysfunction. Based upon this unifying hypothesis, we discovered that sarcosine is more efficacious than citalopram in the treatment of major depressive disorder. Sarcosine also benefits patients with OCD. Benzoate is a potent cognitive enhancer for MCI and D-cycloserine is beneficial for Alzheimer’s disease.

　　Overall, our findings elucidate the cellular and molecular regulatory mechanisms underlying the D-serine signaling, which plays a critical role in NMDA system. We prove of principle several novel possibilities to regulate the grand regulator of CNS, the NMDA system. These NMDA agents can address the deficits in not only the symptoms, but the cognition and function of several CNS disorders. Molecular simulation, animal model and neuroimaging advancement can further facilitate the discovery and development of novel compounds based upon the hypothesis that dysregulation of the regulators of NMDA system, like G72, DAAO, serine racemase and GlyT-1 may contribute to a variety of CNS disorders. This type of out-of-box strategies is desperately needed to develop new CNS therapeutics.