Retrospective and prospective studies in schizophrenia have identified a period of time, termed the prodromal period, that precedes the first episode of frank psychosis by a variable length of time (days–years) and is characterized by subthreshold psychotic symptoms. Importantly, both the prodromal phase and the early stages of the schizophrenia illness are associated with significant loss in social and intellectual abilities (Yung et al, 2005), as well as gray matter volume (Cahn et al, 2006; Pantelis et al, 2003). In addition, patients' response to antipsychotic medication decreases from first to subsequent episodes (Agid et al, 2011). It has been hypothesized that a neurobiological process might underlie this early progressive deterioration. In order to gain insight into this period, researchers have identified and followed subjects at ‘ultra high risk’, either because of a strong family history of schizophrenia or because of the presence of subthreshold symptoms. In addition, studies of first-episode subjects have become more common, in part because they lack the confounding effect of antipsychotic medication treatment.

In this issue of Neuropsychopharmacology, de la Fuente-Sandoval et al (2011) use 1H magnetic resonance spectroscopy (MRS) to obtain glutamate measurements in the caudate nucleus of antipsychotic-naïve prodromal subjects, antipsychotic-naïve first-episode psychosis subjects, and matched healthy control subjects. These investigators report that the high-risk and first-episode groups showed higher levels of glutamate than controls, without differences between ultra high risk and first episode. These findings are noteworthy for several reasons. Few studies have compared ultra high-risk and first-episode populations cross-sectionally. Because only 15–35% of high-risk subjects transition to psychosis, the interpretation of purely cross-sectional studies is somewhat ambiguous. Yet, in this study, the identification of the same pattern of high glutamate levels in the high-risk and first-episode populations provides stronger support for the relevance of this abnormality. Clearly, prospective studies of ultra high-risk populations are needed to address whether the degree of this early abnormality is predictive of the illness. Nevertheless, this study suggests that high levels of glutamate measured in the precommissural dorsal-caudate nucleus, a region with prominent projections throughout the cortical mantle, could induce cortical neuronal toxicity leading to a progressive functional and intellectual deterioration. Because there is preliminary evidence that stable medicated subjects either do not show a difference or evidence a decrease in glutamate levels compared with normal subjects (de la Fuente-Sandoval et al, 2011; Reid et al, 2010), it is tempting to hypothesize that a time-limited neurotoxic process may characterize the prodromal period and the early stages of the illness. Although more research is needed in this area, this suggests the possibility of curtailing functional deterioration by intervening therapeutically during the early stages. Importantly, this study provides strong clues as to the nature of these interventions, as well as specific targets, that is, glutamate level, to monitor treatment intervention. This study also points towards potential prediction algorithms to identify those who might, or might not, go on to develop the illness.

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