Systemic hypotheses for generalized cognitive deficits in schizophrenia: a new take on an old problem.

The schizophrenia research community, including government, industry, and academia, has made development of procognitive treatment strategies a priority. Much current research is directed at dividing broad impairments in cognition into more delineated components that might correspond to relatively specific neural systems and serve as targets for intervention. Sometimes overlooked in this ambitious agenda is the substantial neuropsychological literature that signals a more broadly generalized dysfunction in higher order cognitive functions in this illness. In this article, we argue that a generalized cognitive deficit is at the core of the disorder, is not a methodological artifact, and deserves more focused consideration from cognitive specialists in the field. Further, we weigh evidence that this broad deficit may have systemic biological underpinnings. At the level of the central nervous system, examples of findings that might help to account for broad cognitive impairment include gray and white matter irregularities, poor signal integration by neurons and neural networks, and abnormalities in glutamate and gamma-aminobutyric acid neurotransmission. Other, more speculative hypotheses focus on even broader somatic systems, including energy metabolism and inflammatory processes. Treatment implications of systemic conceptualizations of schizophrenia are also considered.