Schizophrenia is a severe mental disorder associated with a characteristic constellation of symptoms and neurocognitive deficits. At present, etiological mechanisms remain relatively unknown, although multiple points of convergence have been identified over recent years. One of the primary convergence points is dysfunction of N-methyl-D-aspartate (NMDAR)-type glutamate receptors. Antagonists of NMDAR produce a clinical syndrome that closely resembles, and uniquely incorporates negative and cognitive symptoms of schizophrenia, along with the specific pattern of neurocognitive dysfunction seen in schizophrenia. Genetic polymorphisms involving NMDAR subunits, particularly the GRIN2B subunit have been described. In addition, polymorphisms have been described in modulatory systems involving the NMDAR, including the enzymes serine racemase and D-amino acid oxidase/G72 that regulate brain D-serine synthesis. Reductions in plasma and brain glycine, D-serine and glutathione levels have been described as well, providing potential mechanisms underlying NMDAR dysfunction. Unique characteristics of the NMDAR are described that may explain the characteristic pattern of symptoms and neurocognitive deficits observed in schizophrenia. Finally, the NMDAR complex represents a convergence point for potential new treatment approaches in schizophrenia aimed at correcting underlying abnormalities in synthesis and regulation of allosteric modulators, as well as more general potentiation of pre-and post-synaptic glutamatergic and NMDAR function. KeywordsSchizophrenia; glutamate; NMDA receptor; glycine; D-serine; visual; auditory; review The glutamate hypofunction model of schizophrenia was first proposed over two decades ago, based upon the observation that phencyclidine (PCP), ketamine and similarly acting psychotomimetic compounds induced their unique behavioral effects by blocking neurotransmission at N-methyl-D-aspartate-type glutamate receptors (NMDAR) [60]. The ability of these compounds to transiently reproduce key symptoms of schizophrenia by Address correspondence to: Daniel C. Javitt, M.D., Ph,D., Director, Schizophrenia Research Center, Nathan Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, Orangeburg, New York, 10962 USA. Tel: +1-845-398-6534, Fax: +1-845-398-6545, Javitt@nki.rfmh.org. Conflict of interest: Dr. Javitt holds intellectual property rights for use of glycine, D-serine and glycine transport inhibitors in treatment of schizophrenia and related disorders.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. blocking NMDAR led to the concept that symptoms...

Scientists have long sought to characterize the pathophysiologic basis of schizophrenia and develop biomarkers that could identify the illness. Extensive postmortem and in vivo neuroimaging research has described the early involvement of the hippocampus in the pathophysiology of schizophrenia. In this context, we have developed a hypothesis that describes the evolution of schizophrenia-from the premorbid through the prodromal stages to syndromal psychosis-and posits dysregulation of glutamate neurotransmission beginning in the CA1 region of the hippocampus as inducing attenuated psychotic symptoms and initiating the transition to syndromal psychosis. As the illness progresses, this pathological process expands to other regions of the hippocampal circuit and projection fields in other anatomic areas including the frontal cortex, and induces an atrophic process in which hippocampal neuropil is reduced and interneurons are lost. This paper will describe the studies of our group and other investigators supporting this pathophysiological hypothesis, as well as its implications for early detection and therapeutic intervention.

Background D-serine is an allosteric modulator of the brain N-methyl-D-aspartate (NMDA) receptor and a potential novel treatment of schizophrenia. Double-blind studies have been performed at 30 mg/kg/day (~2 g/day) with encouraging results, but no formal dose escalation studies have been performed. We describe the first evaluation of the efficacy and safety of D-serine at doses >30 mg/kg/day; a 4-week, open-label trial of adjunctive D-serine (30, 60 or 120 mg/kg/day). Methods 42 antipsychotic-stabilized patients with schizophrenia or schizoaffective disorder participated. PANSS was obtained bi-weekly and neuropsychological (MATRICS) was obtained pre- and post medication phase. The pharmacokinetics/pharmacodynamics (PK/PD), and safety of doses ≥30 mg/kg was also evaluated. Results Significant improvement in symptoms and neuropsychological measures was noted across doses. On the PANSS, improvement was observed for positive (p=0.006;d=0.46), negative (p<0.001;d=0.68), general (p=0.001;d=0.53), and total (p<0.0001;d=0.74) symptoms. On MATRICS, while only non-significant improvement was noted at 30 mg/kg, highly significant, large effect size improvement was noted on the composite score (p<0.01;d=1.0) for doses ≥60 mg/kg, leading to a significant dose-by-time interaction (p<0.01). In PK analyses, significant dose-dependent increases in plasma D-serine levels were seen during the study, predictive of significantly increased brain levels. Furthermore, increases in plasma levels correlated with improved symptomatic and neuropsychological function. Discussion These findings support double-blind investigation of D-serine at doses ≥60 mg/kg/d, and suggest effectiveness in treatment of both persistent symptoms and neurocognitive dysfunction.

Currently, all treatments for schizophrenia (SCZ) function primarily by blocking D(2)-type dopamine receptors. Given the limitations of these medications, substantial efforts have been made to identify alternative neurochemical targets for treatment development in SCZ. One such target is brain glutamate. The objective of this article is to review and synthesize the proton magnetic resonance spectroscopy ((1)H MRS) and positron emission tomography (PET)/single-photon emission computed tomography (SPECT) investigations that have examined glutamatergic indices in SCZ, including those of modulatory compounds such as glutathione (GSH) and glycine, as well as data from ketamine challenge studies. The reviewed (1)H MRS and PET/SPECT studies support the theory of hypofunction of the N-methyl-D-aspartate receptor (NMDAR) in SCZ, as well as the convergence between the dopamine and glutamate models of SCZ. We also review several advances in MRS and PET technologies that have opened the door for new opportunities to investigate the glutamate system in SCZ and discuss some ways in which these imaging tools can be used to facilitate a greater understanding of the glutamate system in SCZ and the successful and efficient development of new glutamate-based treatments for SCZ.

The last fifteen years have seen a great increase in our understanding of the role of glutamate in schizophrenia (SCZ). The glutamate hypothesis focuses on disturbances in brain glutamatergic pathways and impairment in signaling at glutamate receptors. Proton Magnetic Resonance Spectroscopy (1H-MRS) is an MR-based technique that affords investigators the ability to study glutamate function by measuring in vivo glutamatergic indices in the brains of individuals with SCZ. 1H-MRS studies have been performed comparing glutamatergic levels of individuals with SCZ and healthy control subjects or studying the effect of antipsychotic medications on glutamatergic levels. In this article we summarize the results of these studies by brain region. We will review the contribution of 1H-MRS studies to our knowledge about glutamatergic abnormalities in the brains of individuals with SCZ and discuss the implications for future research and clinical care.