NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medication development

@article{Krystal2003NMDARA,
  title={NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medication development},
  author={John H. Krystal and Deepak Cyril D’Souza and Daniel H. Mathalon and Edward B. Perry and Aysenil Belger and Ralph E. Hoffman},
  journal={Psychopharmacology},
  year={2003},
  volume={169},
  pages={215-233}
}
There is an urgent need to improve the pharmacotherapy of schizophrenia despite the introduction of important new medications. New treatment insights may come from appreciating the therapeutic implications of model psychoses. In particular, basic and clinical studies have employed the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, ketamine, as a probe of NMDA receptor contributions to cognition and behavior. These studies illustrate a translational neuroscience approach for probing… Expand
Role of prefrontal cortex in pharmacological models of schizophrenia and antipsychotic action
NMDA receptor (NMDA-R) antagonists are extensively used as schizoph- renia models due to their ability to evoke positive and negative symptoms as well as cog- nitive deficits similar to those of theExpand
Do NMDA receptor antagonist models of schizophrenia predict the clinical efficacy of antipsychotic drugs?
  • C. Large
  • Psychology, Medicine
  • Journal of psychopharmacology
  • 2007
TLDR
The extent to which the different hypotheses that have been proposed to account for the psychotomimetic effects of NMDA receptor antagonist have been validated by the results of these trials is considered. Expand
Brain NMDA Receptors in Schizophrenia and Depression
TLDR
The temporal mechanisms implicated in schizophrenia-like and antidepressant-like effects of NMDA blockade in rats are described, and it is postulate that such effects may indicate that NMDA receptor antagonists induce similar mechanistic effects, and only the basal pre-drug state of the organism delimitates the overall outcome. Expand
Novel Potential Therapeutics for Schizophrenia: Focus on the Modulation of Metabotropic Glutamate Receptor Function
Schizophrenia is the most disabling psychiatric disorder and one of the world's top ten causes of long-term disability, affecting 1% of the population worldwide. The major symptoms of schizophrenia ,Expand
Glutamatergic drugs for schizophrenia treatment.
TLDR
Despite repeated failures, the glutamatergic approach to the treatment of schizophrenia has not been exhausted and all theoretical aspects that relate these complex neurochemical mechanisms with symptoms of schizophrenia should be reviewed until the authors find truly effective molecules with an acceptable side effect profile. Expand
Disruption of thalamocortical activity in schizophrenia models: relevance to antipsychotic drug action.
TLDR
The present experimental model can be successfully used to elucidate the neurobiological basis of schizophrenia symptoms and to examine the potential antipsychotic activity of new drugs in development. Expand
Antipsychotic drugs reverse the disruption in prefrontal cortex function produced by NMDA receptor blockade with phencyclidine
TLDR
Light is shed on the involvement of PFC in the schizomimetic action of NMDA-R antagonists and show that antipsychotic drugs may partly exert their therapeutic effect by normalizing a disrupted PFC activity, an effect that may add to subcortical dopamine receptor blockade. Expand
Targeting glutamate system for novel antipsychotic approaches: relevance for residual psychotic symptoms and treatment resistant schizophrenia.
TLDR
Preclinical results in animal models mimicking the pathophysiology of psychosis, mainly believed to be responsible of negative and cognitive symptoms, and predicting antipsychotic-like activity of these compounds are focused on; and clinical efficacy in open-label and double-blind trials are reviewed. Expand
Targeting metabotropic glutamate receptors for treatment of the cognitive symptoms of schizophrenia
TLDR
Heterogeneous distribution, both at structural and synaptic levels, of at least eight subtypes of mGlu receptors suggests that selective pharmacological manipulation of these receptors may modulate glutamatergic neurotransmission in a regionally and functionally distinct manner. Expand
NMDA antagonist and antipsychotic actions in cortico-subcortical circuits
TLDR
It is reported that PCP induces a marked disruption of the network activity in PFC and that antipsychotic drugs may partly exert their therapeutic effect by normalizing hyperactive cortico-thalamocortical circuits. Expand
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 325 REFERENCES
The NMDA antagonist model for schizophrenia: promise and pitfalls.
TLDR
Subanesthetic doses of ketamine in healthy individuals produce not only paranoia and perceptual alterations but also thought disorder, negative symptoms, cognitive deficits, as well as impairment on a number of electrophysiologic tests known to be abnormal in schizophrenia. Expand
Therapeutic Implications of the Hyperglutamatergic Effects of NMDA Antagonists
Antagonists of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor produce transient effects in healthy human subjects that resemble symptoms observed in some schizophrenic patients. NMDAExpand
NMDA agonists and antagonists as probes of glutamatergic dysfunction and pharmacotherapies in neuropsychiatric disorders.
TLDR
This review will examine pathophysiological and therapeutic hypotheses generated or supported by clinical studies employing NMDA antagonists and glycine-B agonists and partial agonists, and consider ethical issues related to human psychopharmacological studies employing glutamatergic probes. Expand
Glutamate agonist activity: implications for antipsychotic drug action and schizophrenia
TLDR
It is shown that the conventional neuroleptic haloperidol and the atypical antipsychotic clozapine had potent augmenting influences on the NMDA receptor, suggesting that unique action at glutamate receptors may contribute to antipsychotics efficacy and emphasize the potential importance of glutamatergic dysfunction in the etiology of schizophrenia. Expand
The role of N-Methyl-D-Aspartate (NMDA) receptor-mediated neurotransmission in the pathophysiology and therapeutics of psychiatric syndromes
TLDR
Emerging data indicating that alterations of NMDA receptor function may be pivotal to the pathophysiology of four common psychiatric syndromes: schizophrenia, major depression, posttraumatic stress disorder, and alcoholism are reviewed. Expand
Glutamate receptor dysfunction and schizophrenia.
TLDR
It is proposed that since N-methyl-D-aspartate receptor hypofunction can cause psychosis in humans and corticolimbic neurodegenerative changes in the rat brain, and since these changes are prevented by certain antipsychotic drugs, including atypical neuroleptic agents, a better understanding of this mechanism may lead to improved pharmacotherapy in schizophrenia. Expand
The Glutamatergic Dysfunction Hypothesis for Schizophrenia
  • J. Coyle
  • Psychology, Medicine
  • Harvard review of psychiatry
  • 1996
TLDR
Dysregulation of glutamatergic neurotransmission may be particularly relevant to those forms of schizophrenia in which negative symptoms, cognitive deficits, and deterioration are prominent features. Expand
D-serine added to antipsychotics for the treatment of schizophrenia
TLDR
A significant improvement in patients who received D-serine treatment revealed significant improvements in their positive, negative, and cognitive symptoms as well as some performance in Wisconsin Card Sorting Test (WCST). Expand
Schizophrenia and glutamatergic transmission.
  • C. Tamminga
  • Medicine
  • Critical reviews in neurobiology
  • 1998
TLDR
A "working" glutamate hypothesis of schizophrenia is proposed which postulates a diminished glutamatergic transmission in the hippocampal glutamate-mediated efferent pathways and cerebral dysfunction in the hippocampus and its target areas, especially the anterior cingulate cortex. Expand
Efficacy of high-dose glycine in the treatment of enduring negative symptoms of schizophrenia.
TLDR
Glycine-induced augmentation of NMDA receptor-mediated neurotransmission may thus offer a potentially safe and feasible approach for ameliorating persistent negative symptoms of schizophrenia. Expand
...
1
2
3
4
5
...