A revised excitotoxic hypothesis of schizophrenia: Therapeutic implications

A revision of an "excitotoxic hypothesis" of schizophrenia is summarized. T he hypothesis suggests that in, at least, a subtype of patients with schizo phrenia, progressive excitotoxic neuronal cell death in hippocampal and cor tical areas occurs via "disinhibition" of glutamatergic projections to thes e areas. Patients who have excitotoxic damage would be expected to have poo r outcomes characterized, perhaps, by anatomic evidence of progressive neur odegeneration, pronounced negative symptoms and cognitive deficits, and pro found psychosocial deterioration. Disinhibited glutamatergic activity could result from inhibition of N-methyl-D-aspartate (NMDA) receptor-mediated ne urotransmission and a consequent failure to stimulate inhibitory gamma-amin obutyric acid(GABA) ergic interneurons, and/or anatomic degeneration of inh ibitory GABAergic interneurons. The result of these hypothesized mechanisms is excessive stimulation of the alpha-amino-3-hydroxy-5-methylisoxazole-4- propionic acid (AMPA)/kainate class of glutamate receptor complexes. In tur n, this excessive stimulation of AMPA/kainate receptors could lead to disru ption of ionic gradients, depletion of energy reserves expended in an attem pt to restore and maintain the ionic disequilibrium across neuronal membran es, generation of reactive oxygen species, and cell death from apoptotic an d other mechanisms. The postulated existence of disinhibited glutamatergic neurotransmission and the subsequent cascade of excitotoxic events resultin g from NMDA receptor hypofunction (NRH), anatomic degeneration of inhibitor y GABAergic interneurons, or a combination of the two has suggested a diver se variety of experimental therapeutic interventions For schizophrenia. The se interventions include facilitation of NMDA receptor-mediated neurotransm ission, potentiation of GABAergic neurotransmission, antagonism of AMPA/kai nate receptors, and "quenching" of locally generated reactive oxygen specie s. In fact, several of these approaches have already been pursued or are pr oposed as part of a systematic clinical investigation of the revised excito toxic hypothesis of schizophrenia.