Glutaminergic hypothesis of schizophrenia:
clinical research studies with ketamine

Mechri A, Saoud M, Khiari G,
d'Amato T, Dalery J, Gaha L.
Service de Psychiatrie, EPS de Monastir,
5019 Monastir, Tunisie.
Encephale. 2001 Jan-Feb;27(1):53-9.


Several lines of evidence suggest that the glutamatergic N-methyl-D-aspartate (NMDA) receptor is involved in schizophrenia pathophysiology. Post-mortem studies have revealed a lower density of glutamatergic receptors in patients with schizophrenia. Other studies of cerebrospinal fluid reported lower levels of glutamate in patients with schizophrenia in healthy comparison subjects. The most compelling evidence is provided by the psychomimetic effects of the NMDA antagonists phencyclidine and ketamine. Recently, much interest has been given to the study related to the role of NMDA receptor in pathophysiology of schizophrenia by administration of sub-anesthetic doses of ketamine. A phencyclidine hydrochloride derivate, ketamine, is a dissociative anesthetic and a non competitive antagonist of the NMDA receptor. In healthy subjects, ketamine produces: 1) positive symptoms of psychosis, such as illusions, thought disorder and delusions; 2) negative symptoms similar to those associated with schizophrenia including blunted emotional responses, emotional detachment, and psychomotor retardation; 3) cognitive impairments, in particular impairments on tests of frontal cortical function including increased distractibility, reduced verbal fluency and poorer performance on the Wisconsin Card Sorting Test. During smooth pursuit eye tracking, ketamine induces nystagmus as well as abnormalities which are among the characteristics of schizophrenia. In patients with schizophrenia, the administration of ketamine produces an activation of their psychotic symptoms, which have striking similarities to symptoms of their usual psychotic episodes. Ketamine effects on memory and other cognitive functions in schizophrenic patients are controversial. The psychomimetic effects of ketamine are transitional, reversible and influenced by time, dose and administration conditions. Susceptibility to the psychotomimetic effects of ketamine is minimal or absent in children and becomes maximal in early adulthood. The similarity between ketamine effects and endogenous psychoses created interest in the capacity of antipsychotic medications to block ketamine effects. Haloperidol failed to block this ketamine-induced psychomimetic effects in healthy subjects and in schizophrenic patients. However, clozapine, the prototype of atypical antipsychotic agents significantly reduced the ketamine-induced increase in positive symptoms in schizophrenic patients. Recently, lamotrigine significantly decreased ketamine-induced positive and negative symptoms in healthy subjects. Brain regions responsible for NMDA-mediated psychosis have not been established. Using positron emission tomography and [18F] fluorodeoxyglucose, the sub-anesthetic ketamine administration produces bilateral increases in metabolic activity in the prefrontal cortex. In a [15O] H2O positron emission tomography study, ketamine selectively increases cerebral blood flow in the anterior cingulate cortex and reduces cerebral blood flow in the hippocampus and primary visual cortex. The mechanism of neuropsychiatric effects of sub-anesthetic ketamine is not clear. A dysfunction in glutamate-dopaminergic interactions has been suggested as a mechanism for these effects of ketamine. Ketamine has been reported to primarily block NMDA receptor complex giving support to a glutamate deficiency hypothesis in schizophrenia. In addition, ketamine caused increases in cortical and striatal synaptic dopamine concentrations. The effects of NMDA receptor antagonist administration are argued to support a neurobiological hypothesis of schizophrenia, which includes pathophysiology within several neurotransmitter systems, manifested in behavioral pathology. Pharmacological modulation of the effects of NMDA receptor antagonists, such as ketamine, may lead to development of novel therapeutic agents for psychiatric illnesses such as schizophrenia.

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