Clozapine treatment increases serum glutamate and aspartate compared to conventional neuroleptics

Evins, A. Eden; Amico, E. T.; Shih, Vivian E.; Goff, Donald C.

doi:10.1007/bf01291892

Cited by 65 publications

(40 citation statements)

References 17 publications

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“…Recently, clozapine has recently been shown to block glycine and glutamine transport mediated by SNAT2-like synaptosomal transporters, providing a potential mechanism for both the differential therapeutic effects of clozapine and the differential effects of NMDAR modulators in the presence of clozapine vs other antipsychotics. 29 This finding may also account for the reported ability of clozapine to increase serum glutamate levels, 100 and downregulate central glutamate transport. 101,102 Glycine transport inhibitors Both glycine and D-serine appear to be effective when used in treatment resistant schizophrenia.…”

Section: Glutamatergicmentioning

confidence: 67%

Glutamate as a therapeutic target in psychiatric disorders

2004

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Glutamate is the primary excitatory neurotransmitter in the mammalian brain. Glutamatergic neurotransmission may be modulated at multiple levels, only a minority of which are currently being exploited for pharmaceutical development. Ionotropic receptors for glutamate are divided into N-methyl-D-aspartate receptor (NMDAR) and AMPA receptor subtypes. NMDAR have been implicated in the pathophysiology of schizophrenia. The glycine modulatory site of the NMDAR is currently a favored therapeutic target, with several modulatory agents currently undergoing clinical development. Of these, the full agonists glycine and D-serine have both shown to induce significant, large effect size reductions in persistent negative and cognitive symptoms when added to traditional or newer atypical antipsychotics in double-blind, placebo-controlled clinical studies. Glycine (GLYT1) and small neutral amino-acid (SNAT) transporters, which regulate glycine levels, represent additional targets for drug development, and may represent a site of action of clozapine. Brain transporters for D-serine have recently been described. Metabotropic glutamate receptors are positively (Group I) or negatively (Groups II and III) coupled to glutamatergic neurotransmission. Metabotropic modulators are currently under preclinical development for neuropsychiatric conditions, including schizophrenia, depression and anxiety disorders. Other conditions for which glutamate modulators may prove effective include stroke, epilepsy, Alzheimer disease and PTSD. Glutamate is the primary excitatory neurotransmitter in the mammalian brain. Approximately 60% of neurons in the brain, including all cortical pyramidal neurons and thalamic relay neurons, utilize glutamate as their primary neurotransmitter. 1 As a result, virtually all thalamocortical, corticocortical and corticofugal neurotransmission in the brain is mediated by glutamate. Glutamate is released from presynaptic terminals in response to neuronal depolarization, and is recycled by excitatory amino acid (EAA) transporters located on both neurons and glia. 2 Within glia, glutamate is converted to glutamine and released into extracellular fluid from which it is reabsorbed into presynaptic terminals and converted back to glutamate via action of neuronal glutaminase. Up to 2/3 of brain energy metabolism is related to reuptake and recycling of glutamate. 3 As such, functional imaging modalities, such as PET and fMRI, indexing activity primarily of brain glutamatergic systems. 4 The exchange of glutamine from glia to neurons is accomplished by coordinated actions of two transport systems, systems N and A, both of which are members of sodium-dependent neutral amino acid (SNAT) family of transporters. 5 These transport systems also transport precursors for cysteine and glycine, which are precursors to glutathione synthesis. 6 As these transporters are electrogenic, glutamate transporters may also participate in cellular signaling. 7 As with glutamate and GABA transporters, these recycling systems may constitute interesti...

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Section: Glutamatergicmentioning

confidence: 67%

Glutamate as a therapeutic target in psychiatric disorders

2004

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“…Chronic treatment with conventional antipsychotic drugs inhibits the glutamate transporter (De Souza et al, 1999) and increases the basal concentration of extracellular glutamate (Meshul et al, 1996;Yamamoto & Cooperman, 1994). Likewise, atypical antipsychotic drugs increase the release of glutamate (Arvanov et al, 1997;Daly & Moghaddam, 1993;Evins et al, 1997) and of glycine (Chapman & See, 1996). However, the direct effects of antipsychotic drugs on the glutamate system are far less robust than their effects on other systems such as the dopamine system.…”

Section: Direct Interaction Of Antipsychotic Drugs With the Glutamatementioning

confidence: 99%

Molecular aspects of glutamate dysregulation: implications for schizophrenia and its treatment

Konradi

Heckers

2003

Pharmacology & Therapeutics

296

165

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The glutamate system is involved in many aspects of neuronal synaptic strength and function during development and throughout life. Synapse formation in early brain development, synapse maintenance, and synaptic plasticity are all influenced by the glutamate system. The number of neurons and the number of their connections are determined by the activity of the glutamate system and its receptors. Malfunctions of the glutamate system affect neuroplasticity and can cause neuronal toxicity. In schizophrenia, many glutamate-regulated processes seem to be perturbed. Abnormal neuronal development, abnormal synaptic plasticity, and neurodegeneration have been proposed to be causal or contributing factors in schizophrenia. Interestingly, it seems that the glutamate system is dysregulated and that N-methyl-D-aspartate receptors operate at reduced activity. Here we discuss how the molecular aspects of glutamate malfunction can explain some of the neuropathology observed in schizophrenia, and how the available treatment intervenes through the glutamate system.

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“…Studies have shown that atypical antipsychotics increase serum glutamate levels in subjects with schizophrenia (Goff et al, 2002, Evins et al, 1997. In addition to atypical antipsychotics increasing serum glutamate levels, Goff et al demonstrated that the atypical antipsychotic olanzapine increased the ACC Glx to creatine ratio (Glx/Cr) in subjects for whom olanzapine significantly improved negative symptoms (Goff et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Mania, glutamate/glutamine and risperidone in pediatric bipolar disorder: A proton magnetic resonance spectroscopy study of the anterior cingulate cortex

Moore

Biederman

Wozniak

et al. 2007

Journal of Affective Disorders

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Background-The purpose of this study was to investigate the anterior cingulate cortex (ACC) Glutamate/Glutamine (Glx) to creatine ratio (Glx/Cr) in two groups of children with bipolar disorder (BPD): those exhibiting manic symptoms requiring treatment and those being stably treated with the atypical antipsychotic risperidone. Atypical antipsychotics have been shown to increase serum glutamate levels and ACC Glx/Cr in subjects with schizophrenia. In this study, we hypothesized that the children with BPD in need of treatment would have lower Glx/Cr compared with the children with BPD being stably treated with risperidone.

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Clozapine treatment increases serum glutamate and aspartate compared to conventional neuroleptics

Cited by 65 publications

References 17 publications

Glutamate as a therapeutic target in psychiatric disorders

Glutamate as a therapeutic target in psychiatric disorders

Molecular aspects of glutamate dysregulation: implications for schizophrenia and its treatment

Mania, glutamate/glutamine and risperidone in pediatric bipolar disorder: A proton magnetic resonance spectroscopy study of the anterior cingulate cortex

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