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In recent years, there has been much attention and effort in schizophrenia research devoted to understanding the active processes taking place in early stages of schizophrenia. There is emerging evidence that multiple structural and functional abnormalities develop in the brain during the prodrome and the years following a schizophrenia diagnosis, and that these are accompanied by progressive cognitive impairment and decline in community functioning. Indeed, outcomes in schizophrenia may improve significantly if we can prevent emerging morbidity at these early stages as opposed to reversing it once established (1). Which are the most relevant physiological changes and appropriate targets for future intervention in early schizophrenia? One leading hypothesis states that schizophrenia is associated with abnormal glutamatergic neurotransmission. There is strong evidence for NMDA receptor hypofunction, which in turn is associated with neurodegenerative features such as dendritic dysgenesis and reduced spine density. Glutamatergic abnormalities may also play a role in neurodevelopmental alterations and lead to GABAergic dysfunction in schizophrenia. Although it is not clear exactly how these abnormalities evolve in the course of schizophrenia, recent evidence from 1 H magnetic resonance spectroscopy (1 H MRS) studies is instructive in this regard. The increasing availability of glutamate-modulating agents makes early intervention in glutamate signaling an even more attractive target in schizophrenia research. High field 1 H MRS provides separate measures of glutamine (Gln) and glutamate (Glu) in specific brain regions and the Gln/Glu ratio is considered one index of glutamatergic neurotransmission for reasons described in greater detail below. In 1 H MRS studies, elevations and reductions in Gln/Glu have been interpreted as reflecting increased and decreased glutamatergic neurotransmission, respectively (2). Studies of never-or minimally-treated first-episode schizophrenia patients consistently find evidence of Gln/Glu elevation, possibly reflecting accelerated glutamate signaling (3,4). Gln/Glu is reduced with disease progression, possibly crossing below normal levels in chronic disease, suggesting an impoverishment in glutamatergic synapses over time (5). Thus, in vivo neuroimaging studies indicate an active glutamatergic process in first episode schizophrenia which " burns out " with transition to chronic disease. This pattern is temporally consistent with the emergence of other changes (possibly downstream from glutamate signaling) such as cortical thinning and cognitive impairment which are present but stable in chronic disease. The Glu-Gln cycling that underlies glutamate signaling is an energy-intensive process supported by

Glutamate and bioenergetic abnormalities in the emergence and evolution of schizophrenia