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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.

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Comment by:  Amresh Shrivastava
Submitted 17 September 2007
Posted 17 September 2007

Molecular targets for cognitive improvement are a desirable context. This may lead to some improvement in a few dimensions of outcome in schizophrenia, assuming that cognitive deficits are a key component in its pathology, However we need not forget that they are neither universal nor unchallenged. It has been rightly pointed out that cognitive deficits may be the final result of many complex causations and pathways. No doubt succeeding in developing a molecule for working on molecular targets may give some benefit.

This entire research effort needs much appreciation. However, it opens other vistas of debate as well. E.g., cognition is a complex bio-behavioral psychological function. Believing that there are exclusive molecular targets suggests that ‘Cognitive deficits have molecular pathology.' That they are driven by dopaminergic, cholinergic, and glutaminergic neurotransmitter systems. Available data only shows association of dysfunction of these systems of neurotransmission in various areas of brain with cognitive deficits. It does not indicate what preceded and what is the causal relationship. In that sense it would be quite premature to assume that molecular target medication development will provide any significant change in the scenario of outcome.

While the research attempt is commendable, it does not solve the problem of outcome in schizophrenia. E.g. Why do the patients having deficits and no deficits both go through a chronic deteriorating course? If cognition is a trait domain of schizophrenia, how is it that deficits will be reversed? Do we know the biological determinants of disability and dysfunction, and which is the main outcome concern? Is cognition anyway related to disability and dysfunction in schizophrenia?

Not speaking much about biology of memory, information processing, retention and learning in schizophrenia, the assumption discussed in the review seems itself premature. One would wonder if more architectural pharmacotherapies add to the basket of drugs or bring value to the patients.

View all comments by Amresh Shrivastava