Glycine Transporter I Inhibitor, N-methylglycine (Sarcosine), Added to Clozapine for the Treatment of Schizophrenia

Lane, Hsien‐Yuan; Huang, Chieh-Liang; Wu, Po-Lun; Liu, Yi-Ching; Chang, Yue‐Cune; Lin, Pao‐Yen; Chen, Po‐Wei; Tsai, Guochuan E.

doi:10.1016/j.biopsych.2006.04.005

Cited by 172 publications

(92 citation statements)

References 53 publications

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“…With the exception of one study, negative symptoms were reduced [46]. Treatment with the endogenous glycine transport inhibitor sarcosine has also been reported to reduce negative symptoms, improve cognition and further reduce positive symptoms in schizophrenic patients receiving concurrent antipsychotics [47,48].…”

Section: Nmda Hypofunctionmentioning

confidence: 96%

Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia

Lisman

Coyle

Green

et al. 2008

Trends in Neurosciences

913

824

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Many risk genes interact synergistically to produce schizophrenia and many neurotransmitter interactions have been implicated. We have developed a circuit-based framework for understanding gene and neurotransmitter interactions. NMDAR hypofunction has been implicated in schizophrenia because NMDAR antagonists reproduce symptoms of the disease. One action of antagonists is to reduce the excitation of fast-spiking interneurons, resulting in disinhibition of pyramidal cells. Overactive pyramidal cells, notably those in the hippocampus, can drive a hyperdopaminergic state that produces psychosis. Additional aspects of interneuron function can be understood in this framework, as follows. (i) In animal models, NMDAR antagonists reduce parvalbumin and GAD67, as found in schizophrenia. These changes produce further disinhibition and can be viewed as the aberrant response of a homeostatic system having a faulty activity sensor (the NMDAR). (ii) Disinhibition decreases the power of gamma oscillation and might thereby produce negative and cognitive symptoms. (iii) Nicotine enhances the output of interneurons, and might thereby contribute to its therapeutic effect in schizophrenia.

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Section: Nmda Hypofunctionmentioning

confidence: 96%

Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia

Lisman

Coyle

Green

et al. 2008

Trends in Neurosciences

913

824

View full text Add to dashboard Cite

show abstract

“…Augmentation with DHEA 92 or agonists at glycine sites 93,94 have been reported to improve negative symptoms in schizophrenic patients maintained on antipsychotic drugs, excluding clozapine. 95 Drugs modulating GABA activity can differentially affect working memory performance and brain function in schizophrenia. 96 Further clinical support for the relevance of GABA function for negative symptoms and cognitive functions comes from a study examining the relationship between visuomotor performance, working memory and negative symptoms.…”

Section: Clinical Relevancementioning

confidence: 99%

Multifunctional Pharmacotherapy: What Can We Learn from Study of Selective Serotonin Reuptake Inhibitor Augmentation of Antipsychotics in Negative-Symptom Schizophrenia?

et al. 2009

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Summary: Many patients suffering from major psychiatric disorders do not respond adequately to monotherapy and require additional drugs. To date, there are no objective guidelines for deciding which combination may be effective, and the choice is based on previous clinical experience and on trial and error. Even when combination drugs are effective, the biochemical mechanisms responsible for the value-added effect are unknown. Understanding the mechanism of such synergism may provide a rational basis for choosing drug combinations and for developing more effective drugs. In schizophrenia, negative symptoms respond poorly to antipsychotics, but may improve when these are augmented with selective serotonin reuptake inhibitors (SSRI). This augmenting effect cannot be explained by summating the pharmacological effects of the individual drugs. We proposed that the study of SSRI augmentation can serve as a window to understanding the biochemical mechanisms of clinically effective drug synergism. In a series of studies we identified unique biochemical effects of the combination, different from each individual drug, and proposed that some of these are involved in mediating the clinical effect. Here we review some of the findings and propose that the mechanism of action involves regionally selective modulation of the GABA system. The evidence indicates that the SSRI antidepressant-antipsychotic combination may be a useful paradigm for studying therapeutically effective synergistic drug interactions in schizophrenia. Although as yet limited in scope, the findings of definable molecular targets for synergistic SSRIantipsychotic interaction provide new directions to inform future research and provide novel bio-molecular targets for drug development.

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“…129 Interestingly, a subsequent study with patients on clozapine, found no improvement of symptoms with the addition of sarcosine, a result similar to studies with the NMDA glycine site agonists. 130 These results strongly suggest a role of glycine transport inhibitors in the treatment of schizophrenia, though results of trials with selective, high-potency inhibitors are anticipated.…”

Section: Glycine Transportermentioning

confidence: 99%

The pipeline and future of drug development in schizophrenia

2007

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While the current antipsychotic medications have profoundly impacted the treatment of schizophrenia over the past 50 years, the newer atypical antipsychotics have not fulfilled initial expectations, and enormous challenges remain in long-term treatment of this debilitating disease. In particular, improved treatment of the negative symptoms and cognitive dysfunction in schizophrenia which greatly impact overall morbidity is needed. In this review we will briefly discuss the current pipeline of drugs for schizophrenia, outlining many of the strategies and targets currently under investigation for the development of new schizophrenia drugs. Many of these compounds have great potential as augmenting agents in the treatment of negative symptoms and cognition. In addition, we will highlight the importance of developing new paradigms for drug discovery in schizophrenia and call for an increased role of academic scientists in discovering and validating novel drug targets. Indeed, recent breakthroughs in genetic studies of schizophrenia are allowing for the development of hypothesis-driven approaches for discovering possible disease-modifying drugs for schizophrenia. Thus, this is an exciting and pivotal time for the development of truly novel approaches to drug development and treatment of complex disorders like schizophrenia.

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Glycine Transporter I Inhibitor, N-methylglycine (Sarcosine), Added to Clozapine for the Treatment of Schizophrenia

Cited by 172 publications

References 53 publications

Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia

Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia

Multifunctional Pharmacotherapy: What Can We Learn from Study of Selective Serotonin Reuptake Inhibitor Augmentation of Antipsychotics in Negative-Symptom Schizophrenia?

The pipeline and future of drug development in schizophrenia

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