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Updated 22 August 2007
Printable version

Forum Discussion: Molecular Targets for Treating Cognitive Dysfunction in Schizophrenia

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In our Forum discussion “journal club” series, the editors of Schizophrenia Bulletin provide access to the full text of a new article. A short introduction by a journal editor, below, gets us started, and then it's up to our readers to share their ideas and insights, questions and reactions to the selected paper. So read on…

Gray JA, Roth BL. Molecular Targets for Treating Cognitive Dysfunction in Schizophrenia. Schizophr Bull. 2007 Jul 7; [Epub ahead of print]

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Amresh Shrivastava — Posted 17 September 2007

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By Gunvant Thaker, Maryland Psychiatric Research Center, and Associate Editor, Schizophrenia Bulletin

Improving the effectiveness of the existing drug treatments in schizophrenia is much to be desired, as they work only against the positive symptoms without improving negative symptoms and cognitive function. Consequently, functional impairments are common even in optimally treated persons with schizophrenia. In the past half century, the drug discovery process mostly focused on targeting of D2 dopamine receptors following the serendipitous discovery of antipsychotic effects of chlorpromazine in 1950s, and more recently, mimicking clozapine's actions. Identifying therapy of cognitive impairment as an unmet need, the NIMH initiated the MATRICS project, with the focus on improving cognition in schizophrenia. The project identified measurable cognitive targets as outcomes measures and molecular targets for drug development.

The paper by Gray and Roth in the upcoming issue of Schizophrenia Bulletin reviews potential molecular targets for drug development to treat specific cognitive deficits of schizophrenia, or nonspecifically enhance cognition. These targets were identified based on the known effects of manipulating the target molecules in animal models or on the known roles of the molecules in cognition or in cognitive disorders. This is a fairly comprehensive review that includes a list of potential compounds as well as a summary of findings from the proof-of-concept studies in humans.

To start off the discussion, one may point out some of the challenges associated with the strategy adopted by the MATRICS initiative. The cognitive phenotype of schizophrenia is likely to be complex, caused by various combinations of etiological factors and causal pathways. More than one molecular pathway may lead to the same cognitive deficit, and a drug targeting a given molecular pathway may be effective only in a subgroup of subjects. This reduces the power of the proof-of-concept studies, risking false negatives. Thus, identifying physiological impairments that underlie the cognitive deficits and index abnormalities along different molecular pathways has a critical role in drug development.

Comments on Online Discussion
Comment by:  Amresh Shrivastava
Submitted 17 September 2007 Posted 17 September 2007

Molecular targets for cognitive improvement are a...  Read more

View all comments by Amresh Shrivastava
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