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Pathophysiologically based treatment interventions in schizophrenia

Abstract

Identifying the molecular alterations that underlie the pathophysiology of critical clinical features of schizophrenia is an essential step in the rational development of new therapeutic interventions for this devastating illness. Cognitive deficits, such as the impairments in working memory that arise from dysfunction of the dorsolateral prefrontal cortex, are a major determinant of functional outcome in schizophrenia. Here we consider the contributions of disturbances in glutamate, dopamine and GABA neurotransmission to the pathophysiology of working memory impairments in schizophrenia, suggest a cascade of molecular events that might link these disturbances, and argue that the molecular alterations most proximal to the pathophysiology of prefrontal dysfunction offer the most promise as targets for new drug development.

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Figure 1: Potential routes to NMDA receptor hypofunction in schizophrenia.
Figure 2: Summary of the postulated causes and consequences of altered DA signaling in the DLPFC in schizophrenia.
Figure 3: Hypothetical model illustrating a cascade of molecular alterations in neurotransmitter signaling in DLPFC circuitry that converge on impaired working memory in schizophrenia.

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Acknowledgements

Work by the authors cited in this manuscript was supported by US National Institutes of Health grants MH 045156, MH 051234 and MH 043784.

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David A. Lewis has received research grants and/or consulting fees from Lilly, Merck, Pfizer, Sepracor and the BMS Foundation.

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Lewis, D., Gonzalez-Burgos, G. Pathophysiologically based treatment interventions in schizophrenia. Nat Med 12, 1016–1022 (2006). https://doi.org/10.1038/nm1478

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