Guochuan E. Tsai

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

BACKGROUNDnSmall 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.nnnMETHODSnTwenty 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.nnnRESULTSnOverall, 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 x time interaction analysis. Both doses were well tolerated with minimal side effects.nnnCONCLUSIONSnAlthough 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 sarcosines effects.

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

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.

Clinical symptoms, mainly negative symptoms, mediate the influence of neurocognition and social cognition on functional outcome of schizophrenia

BACKGROUNDnThe functional outcome of schizophrenia is affected by multiple factors such as cognitive function and clinical symptoms. The complex relationship among cognitive function (both neuro- and social-cognitions), clinical symptoms, and functional outcome remains unclear. The current study employed structural equation modeling (SEM) to examine whether clinical symptoms mediate the relationship between cognitive function and functional outcome in a large cohort of patients with schizophrenia.nnnMETHODnThree hundred and two Han-Chinese patients with chronically stable schizophrenia received evaluation of cognitive function (using the Measurement and Treatment Research to Improve Cognition in Schizophrenia [MATRICS] Consensus Cognitive Battery, including 7 domains covering neurocognition and social cognition), clinical symptoms (including positive, negative and depressive symptoms), and functional outcome as assessed by Global Assessment of Functioning Scale and Quality of Life Scale.nnnRESULTSnSEM identified clinical symptoms as a mediator between cognitive function (including all 7 domains of MATRICS) and functional outcome in schizophrenia. The relationship between cognitive function and functional outcome was significant in the basic model. In the mediation model, the link between cognitive function and functional outcome was mediated by clinical symptoms, mainly negative symptoms.nnnCONCLUSIONnThis study suggests that clinical symptoms, mainly negative symptoms, mediate the influence of neurocognition and social cognition on functional outcome of schizophrenia. Future studies should explore the impact on other functional outcomes in different ethnicities and various illness phases.

Add-on Treatment of Benzoate for Schizophrenia: A Randomized, Double-blind, Placebo-Controlled Trial of d-Amino Acid Oxidase Inhibitor

IMPORTANCEnIn addition to dopaminergic hyperactivity, hypofunction of the N-methyl-d-aspartate receptor (NMDAR) has an important role in the pathophysiology of schizophrenia. Enhancing NMDAR-mediated neurotransmission is considered a novel treatment approach. To date, several trials on adjuvant NMDA-enhancing agents have revealed beneficial, but limited, efficacy for positive and negative symptoms and cognition. Another method to enhance NMDA function is to raise the levels of d-amino acids by blocking their metabolism. Sodium benzoate is a d-amino acid oxidase inhibitor.nnnOBJECTIVEnTo examine the clinical and cognitive efficacy and safety of add-on treatment of sodium benzoate for schizophrenia.nnnDESIGN, SETTING, AND PARTICIPANTSnA randomized, double-blind, placebo-controlled trial in 2 major medical centers in Taiwan composed of 52 patients with chronic schizophrenia who had been stabilized with antipsychotic medications for 3 months or longer.nnnINTERVENTIONSnSix weeks of add-on treatment of 1 g/d of sodium benzoate or placebo.nnnMAIN OUTCOMES AND MEASURESnThe primary outcome measure was the Positive and Negative Syndrome Scale (PANSS) total score. Clinical efficacy and adverse effects were assessed biweekly. Cognitive functions were measured before and after the add-on treatment.nnnRESULTSnBenzoate produced a 21% improvement in PANSS total score and large effect sizes (range, 1.16-1.69) in the PANSS total and subscales, Scales for the Assessment of Negative Symptoms-20 items, Global Assessment of Function, Quality of Life Scale and Clinical Global Impression and improvement in the neurocognition subtests as recommended by the National Institute of Mental Healths Measurement and Treatment Research to Improve Cognition in Schizophrenia initiative, including the domains of processing speed and visual learning. Benzoate was well tolerated without significant adverse effects.nnnCONCLUSIONS AND RELEVANCEnBenzoate adjunctive therapy significantly improved a variety of symptom domains and neurocognition in patients with chronic schizophrenia. The preliminary results show promise for d-amino acid oxidase inhibition as a novel approach for new drug development for schizophrenia.

Glutamate signaling in the pathophysiology and therapy of schizophrenia

Glutamatergic neurotransmission, particularly through the N-methyl-d-aspartate (NMDA) receptor, has drawn attention for its role in the pathophysiology of schizophrenia. This paper reviews the neurodevelopmental origin and genetic susceptibility of schizophrenia relevant to NMDA neurotransmission, and discusses the relationship between NMDA hypofunction and different domains of symptom in schizophrenia as well as putative treatment modality for the disorder. A series of clinical trials and a meta-analysis which compared currently available NMDA-enhancing agents suggests that glycine, d-serine, and sarcosine are more efficacious than d-cycloserine in improving the overall psychopathology of schizophrenia without side effect or safety concern. In addition, enhancing glutamatergic neurotransmission via activating the AMPA receptor, metabotropic glutamate receptor or inhibition of d-amino acid oxidase (DAO) is also reviewed. More studies are needed to determine the NMDA vulnerability in schizophrenia and to confirm the long-term efficacy, functional outcome, and safety of these NMDA-enhancing agents in schizophrenic patients, particularly those with refractory negative and cognitive symptoms, or serious adverse effects while taking the existing antipsychotic agents.

Benzoate, a D-Amino Acid Oxidase Inhibitor, for the Treatment of Early-Phase Alzheimer Disease: A Randomized, Double-Blind, Placebo-Controlled Trial

BACKGROUNDnN-methyl-D-aspartate receptor (NMDAR)-mediated neurotransmission is vital for learning and memory. Hypofunction of NMDAR has been reported to play a role in the pathophysiology of Alzheimer disease (AD), particularly in the early phase. Enhancing NMDAR activation might be a novel treatment approach. One of the methods to enhance NMDAR activity is to raise the levels of NMDA coagonists by blocking their metabolism. This study examined the efficacy and safety of sodium benzoate, a D-amino acid oxidase inhibitor, for the treatment of amnestic mild cognitive impairment and mild AD.nnnMETHODSnWe conducted a randomized, double-blind, placebo-controlled trial in four major medical centers in Taiwan. Sixty patients with amnestic mild cognitive impairment or mild AD were treated with 250-750 mg/day of sodium benzoate or placebo for 24 weeks. Alzheimers Disease Assessment Scale-cognitive subscale (the primary outcome) and global function (assessed by Clinician Interview Based Impression of Change plus Caregiver Input) were measured every 8 weeks. Additional cognition composite was measured at baseline and endpoint.nnnRESULTSnSodium benzoate produced a better improvement than placebo in Alzheimers Disease Assessment Scale-cognitive subscale (p = .0021, .0116, and .0031 at week 16, week 24, and endpoint, respectively), additional cognition composite (p = .007 at endpoint) and Clinician Interview Based Impression of Change plus Caregiver Input (p = .015, .016, and .012 at week 16, week 24, and endpoint, respectively). Sodium benzoate was well-tolerated without evident side-effects.nnnCONCLUSIONSnSodium benzoate substantially improved cognitive and overall functions in patients with early-phase AD. The preliminary results show promise for D-amino acid oxidase inhibition as a novel approach for early dementing processes.

RGS4 polymorphisms predict clinical manifestations and responses to risperidone treatment in patients with schizophrenia.

Objective: Polymorphisms of the gene encoding the regulator of G-protein signaling subtype 4 (RGS4) are associated with schizophrenia. This study aims to investigate the association of 4 RGS4 polymorphisms (single nucleotide polymorphisms [SNPs] 1, 4, 7, and 18), implicated in previous studies, with baseline symptoms and treatment response to risperidone in patients with schizophrenia. Methods: One hundred twenty patients with acutely exacerbated schizophrenia who had never been treated by atypical antipsychotics were recruited. They received optimal treatment of risperidone for up to 42 days in the inpatient research unit. Patients social functions were monitored by Nurses Observation Scale for Inpatients Evaluation and clinical manifestations, by Positive and Negative Syndrome Scale. Results: At baseline status, the A/A genotype at SNP7 of RGS4 was associated with poorer social function when compared with the G/G genotype. After risperidone treatment, the A/A genotype at SNP1 was associated with greater improvement at social function, and the A/A genotype at SNP18 was associated with greater improvement at social function, Positive and Negative Syndrome Scale total score, and positive- and negative-symptom subscale. Conclusions: These findings suggest that RGS4 variances influence clinical manifestations of schizophrenia as well as the treatment response to risperidone, suggesting that RGS4 plays a role in the fundamental process of disease pathophysiology.

NMDA Neurotransmission Dysfunction in Behavioral and Psychological Symptoms of Alzheimer’s Disease

Dementia has become an all-important disease because the population is aging rapidly and the cost of health care associated with dementia is ever increasing. In addition to cognitive function impairment, associated behavioral and psychological symptoms of dementia (BPSD) worsen patient’s quality of life and increase caregiver’s burden. Alzheimer’s disease is the most common type of dementia and both behavioral disturbance and cognitive impairment of Alzheimer’s disease are thought to be associated with the N-methyl-D-aspartate (NMDA) dysfunction as increasing evidence of dysfunctional glutamatergic neurotransmission had been reported in behavioral changes and cognitive decline in Alzheimer’s disease. We review the literature regarding dementia (especially Alzheimer’s disease), BPSD and relevant findings on glutamatergic and NMDA neurotransmission, including the effects of memantine, a NMDA receptor antagonist, and NMDA-enhancing agents, such as D-serine and D-cycloserine. Literatures suggest that behavioral disturbance and cognitive impairment of Alzheimer’s disease may be associated with excitatory neurotoxic effects which result in impairment of neuronal plasticity and degenerative processes. Memantine shows benefits in improving cognition, function, agitation/aggression and delusion in Alzheimer’s disease. On the other hand, some NMDA modulators which enhance NMDA function through the co-agonist binding site can also improve cognitive function and psychotic symptoms. We propose that modulating NMDA neurotransmission is effective in treating behavioral and psychological symptoms of Alzheimer’s disease. Prospective study using NMDA enhancers in patients with Alzheimer’s disease and associated behavioral disturbance is needed to verify this hypothesis.

Attention Deficit Hyperactivity Disorder and N-methyl-D-aspartate (NMDA) Dysregulation

Attention deficit hyperactivity disorder (ADHD) is a long recognized and common childhood disorder. ADHD adolescents tend to encounter more difficulties in school and peer relationships, whereas ADHD adults have more occupational and interpersonal difficulties. However, with the treatment of central nervous system (CNS) stimulants, 10-20 % of the patients still remain poor responders to treatment. Among hypotheses for ADHD, dysfunction of N-methyl-D-aspartate (NMDA)-type glutamate receptors has recently been suggested by accumulating genetic and animal studies. This article systemically reviews evidence supporting NMDA dysfunction as a potential ADHD pathogenesis from perspectives of neurodevelopment, attentional circuitry, and impulse inhibition. The review also addresses the development of novel treatments for ADHD via modulation of glutamatergic system, particularly the NMDA/glycine site. These so-called NMDA enhancers may provide a new treatment option for patients with ADHD.

Assessing Gene-Gene Interactions in Pharmacogenomics

In pharmacogenomics studies, gene-gene interactions play an important role in characterizing a trait that involves complex pharmacokinetic and pharmacodynamic mechanisms, particularly when each involved feature only demonstrates a minor effect. In addition to the candidate gene approach, genome-wide association studies (GWAS) are widely utilized to identify common variants that are associated with treatment response. In the wake of recent advances in scientific research, a paradigm shift from GWAS to whole-genome sequencing is expected, because of the reduced cost and the increased throughput of next-generation sequencing technologies. This review first outlines several promising methods for addressing gene-gene interactions in pharmacogenomics studies. We then summarize some candidate gene studies for various treatments with consideration of gene-gene interactions. Furthermore, we give a brief overview for the pharmacogenomics studies with the GWAS approach and describe the limitations of these GWAS in terms of gene-gene interactions. Future research in translational medicine promises to lead to mechanistic findings related to drug responsiveness in light of complex gene-gene interactions and will probably make major contributions to individualized medicine and therapeutic decision-making.