Perspective Chapter - NMDA Treatments for CNS Disorders

The N-methyl-D-aspartate receptor (NMDAR), a glutamate-gated ion channel, mediates various physiological functions, such as synaptic plasticity, learning, and memory. Any homeostatic dysregulation of NMDAR may cause central nervous system (CNS) disorders, such as Alzheimer’s disease, depression, and schizophrenia. The involvement of NMDA dysfunction promotes advanced research on developing NMDAR pharmaceutics for treating CNS disorders. NMDAR enhancers, by direct or indirect potentiating NMDAR functions, have been used to recover NMDAR functions for treating schizophrenia. Interestingly, NMDAR blockers, by direct or indirect inhibiting NMDAR functions, have also been utilized for CNS disorders, such as Alzheimer’s disease and depression. In this chapter, the current strategy of NMDAR modulation for CNS disorders are elaborated on to discern underlying neurophysiological mechanisms of how homeostatic regulation of NMDAR plays a vital role in the normal and pathological states, respectively

MET and AKT Genetic Influence on Facial Emotion Perception

Background: Facial emotion perception is a major social skill, but its molecular signal pathway remains unclear. The MET/ AKT cascade affects neurodevelopment in general populations and face recognition in patients with autism. This study explores the possible role of MET/AKT cascade in facial emotion perception. Methods: One hundred and eighty two unrelated healthy volunteers (82 men and 100 women) were recruited. Four single nucleotide polymorphisms (SNP) of MET (rs2237717, rs41735, rs42336, and rs1858830) and AKT rs1130233 were genotyped and tested for their effects on facial emotion perception. Facial emotion perception was assessed by the face task of Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT). Thorough neurocognitive functions were also assessed. Results: Regarding MET rs2237717, individuals with the CT genotype performed better in facial emotion perception than those with TT (p = 0.016 by ANOVA, 0.018 by general linear regression model [GLM] to control for age, gender, and education duration), and showed no difference with those with CC. Carriers with the most common MET CGA haplotype (frequency = 50.5%) performed better than non-carriers of CGA in facial emotion perception (p = 0.018, df = 1, F = 5.69, p = 0.009 by GLM). In MET rs2237717/AKT rs1130233 interaction, the C carrier/G carrier group showed better facial emotion perception than those with the TT/AA genotype (p = 0.035 by ANOVA, 0.015 by GLM), even when neurocognitive functions were controlled (p = 0.046 by GLM)

D-Alanine Added to Antipsychotics for the Treatment of Schizophrenia

[[abstract]]Background Hypofunction of the N-methyl-d-aspartate (NMDA) subtype glutamate receptor had been implicated in the pathophysiology of schizophrenia. Treatment with D-serine, glycine, endogenous full agonists of the glycine site of the NMDA receptor (NMDA-glycine site), D-cycloserine, a partial agonist, or sarcosine, a glycine transporter-1 inhibitor, improves the symptoms of schizophrenia. D-alanine is another endogenous agonist of the NMDA-glycine site that might have beneficial effects on schizophrenia. Methods Thirty-two schizophrenic patients enrolled in a 6-week double-blind, placebo-controlled trial of D-alanine (100 mg/kg/day), which was added to their stable antipsychotic regimens. Measures of clinical efficacy and side effects were determined every other week. Results Patint who received D-alanine treatment revealed significant reductions in their Clinical Global Impression Scale and Positive and Negative Syndrome Scale (PANSS) total scores. The Scale for the Assessment of Negative Symptoms and PANSS subscores of positive and cognitive symptoms were improved. D-alanine was well tolerated, and no significant side effect was noted. Conclusions The significant improvement with the D-alanine further supports the hypothesis of hypofunction of NMDA neurotransmission in schizophrenia and strengthens the proof of the principle that NMDA-enhancing treatment is a promising approach for the pharmacotherapy of schizophrenia.[[notice]]補正完畢[[incitationindex]]SC

Sarcosine (N-Methylglycine) Treatment for Acute Schizophrenia: A Randomized, Double-Blind Study

[[abstract]]Background Small molecules that enhance the N-methyl-D-aspartate (NMDA) neurotransmission have been shown to be beneficial as adjuvant therapy for schizophrenia. Among these compounds, sarcosine (a glycine transporter-I inhibitor), when added to an existing regimen of antipsychotic drugs, has shown its efficacy for both chronically stable and acutely ill patients. However, the efficacy of these agents as a primary antipsychotic agent has not yet been demonstrated. Methods Twenty acutely symptomatic drug-free patients with schizophrenia were randomly assigned under double-blind conditions to receive a 6-week trial of 2 g or 1 g of sarcosine daily. Results Overall, patients in the 2-g group were more likely to respond as defined by a 20% or more reduction of the Positive and Negative Syndrome Scale total score, particularly among antipsychotic-naïve patients. However, there was no significant between-group difference in the sarcosine dose × time interaction analysis. Both doses were well tolerated with minimal side effects. Conclusions Although patients receiving the 2-g daily dose were more likely to respond, it requires further clarification whether the effect is limited to the antipsychotic-naive population. Future placebo- or active-controlled, larger-sized studies are needed to fully assess sarcosine’s effects.[[journaltype]]國外[[incitationindex]]SCI[[ispeerreviewed]]Y[[booktype]]紙本[[countrycodes]]US

Fabrication of nanocrystal forms of ᴅ-cycloserine and their application for transdermal and enteric drug delivery systems

ᴅ-cycloserine (DCS), an FDA-approved medicine for the treatment of tuberculosis, is also a partial agonist at the glycine recognition site of N-methyl-ᴅ-aspartate (NMDA) receptor and has shown significant treatment efficacy for central nervous system (CNS) disorders including depression, schizophrenia, Alzheimer’s disease, and post-traumatic stress disorder. The physicochemical properties of DCS, however, limit the options of formulation and medicinal applications of DCS, and warrants further investigation for the development of CNS therapeutics. Nanocrystals play an important role in pharmaceutic design and development. The properties of nanocrystals are remarkably different from their bulk material counterpart, attributed to the large surface-area-to-volume ratio which can improve the bioavailability. In this study, for the first time, DCS, a highly water-soluble compound, has formed nanocrystals and this was confirmed by scanning electronic microscopy and X-ray powder diffraction. Furthermore, DCS nanocrystals were applied to several formulations to test their stability and then to the in vitro Franz diffusion test with reservoir patch formulation as well as in vivo pharmacokinetics study with enteric capsules. We tested these formulations regarding their nanocrystal physical properties, size effect, and dissolution rate, respectively. We found that DCS nanocrystals showed good performance in the Franz diffusion test and rodent pharmacokinetic studies due to the nanoparticle size and faster dissolution as compared with the commercial DCS powder. These DCS nanocrystal formulations could offer a new approach for the development of an advanced drug delivery system for the treatment of CNS disorders

Sarcosine (N-methylglycine) or D-serine add-on treatment for acute exacerbation of schizophrenia: a randomized, double-blind, placebo-controlled study

[[abstract]]Background: Small molecules that enhance the N-methyl-D-aspartate (NMDA) neurotransmission have been shown to be beneficial as adjuvant therapy for schizophrenia. Among these compounds, sarcosine (a glycine transporter-I inhibitor), when added to an existing regimen of antipsychotic drugs, has shown its efficacy for both chronically stable and acutely ill patients. However, the efficacy of these agents as a primary antipsychotic agent has not yet been demonstrated. Methods: Twenty acutely symptomatic drug-free patients with schizophrenia were randomly assigned under double-blind conditions to receive a 6-week trial of 2 g or 1 g of sarcosine daily. Results: Overall, patients in the 2-g group were more likely to respond as defined by a 20% or more reduction of the Positive and Negative Syndrome Scale total score, particularly among antipsychotic-naïve patients. However, there was no significant between-group difference in the sarcosine dose time interaction analysis. Both doses were well tolerated with minimal side effects. Conclusions: Although patients receiving the 2-g daily dose were more likely to respond, it requires further clarification whether the effect is limited to the antipsychotic-naive population. Future placebo- or active-controlled, larger-sized studies are needed to fully assess sarcosine’s effects.[[notice]]補正完畢[[journaltype]]國外[[incitationindex]]SC

A randomized, double-blind, placebo-controlled comparison study of sarcosine (N-methylglycine) and D-serine add-on treatment for schizophrenia

[[abstract]]Recent evidence indicates that enhancing N-methyl-D-aspartate (NMDA) neurotransmission with the treatment of NMDA/glycine site agonists, such as D-serine, or a glycine transporter-1 (GlyT-1) antagonist, N-methylglycine (sarcosine), can improve symptoms of schizophrenia. To compare these two novel approaches, 60 patients with chronic schizophrenia were enrolled into a 6-wk double-blind, placebo-controlled trial of add-on treatments at the reported effective dosages (2 g/d). Clinical assessments were conducted every other week. Treatment group x treatment duration interaction analysis by multiple linear regression showed that sarcosine was superior to placebo at all four outcome measures of Positive and Negative Syndrome Scale (PANSS) total (p=0.005), Scale for the Assessment of Negative Symptoms (SANS) (p=0.021), Quality of Life (QOL) (p=0.025), and Global Assessment of Functioning (GAF) (p=0.042). However, d-serine did not differ significantly from placebo in any measure. Sarcosine treatment was better than d-serine in effect sizes for all outcome measures. Sarcosine also surpassed placebo in most of the measures of five PANSS factors and five SANS subscales. All treatments were well tolerated. These findings suggest that the GlyT-1 inhibitor is more efficacious than the NMDA/glycine site agonist in treatment for schizophrenia, including life quality and global function, at the dosages tested.[[journaltype]]國外[[incitationindex]]SCI[[ispeerreviewed]]Y[[booktype]]紙本[[countrycodes]]GB