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Forum Discussion: Unmet Therapeutic Indications in Schizophrenia—New Standards Based on Recent Experience


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In our Forum discussion “journal club” series, the editors of Schizophrenia Bulletin provide access to the full text of a recent article. An introduction to this discussion by journal editor Will Carpenter gets us started, and then it's up to our readers to share their ideas and insights, questions and reactions to these papers. So read on….

Send in your comments now! The papers under discussion:

Keefe RS, Buchanan RW, Marder SR, Schooler NR, Dugar A, Zivkov M, Stewart M. Clinical Trials of Potential Cognitive-Enhancing Drugs in Schizophrenia: What Have We Learned So Far? Schizophr Bull . 2011 Nov 22. Abstract

Buchanan RW, Keefe RS, Umbricht D, Green MF, Laughren T, Marder SR. The FDA-NIMH-MATRICS guidelines for clinical trial design of cognitive-enhancing drugs: what do we know 5 years later? Schizophr Bull . 2011 Nov 1 ; 37(6):1209-17. Abstract



Background Text
By William Carpenter

There is a general consensus in the field that impaired cognition and negative symptoms represent the two most important unmet therapeutic needs in schizophrenia. As an aspect of the NIMH MATRICS process, academic, government, and industry scientists developed clinical trial methodology recommendations that would support testing of efficacy hypotheses for each of these pathology domains (Buchanan et al., 2005; Kirkpatrick and Fischer. 2006). Most critical was addressing pseudospecificity, a term used by the FDA to indicate that superiority of the experimental treatment to the control condition may be secondary rather than a direct therapeutic effect. For example, an experimental drug might beat haloperidol on cognition measures based on adverse effects of haloperidol rather than true efficacy for cognition, or a subject becoming much less psychotic may become a better test-taker and better scores on cognitive tests may be the result. This and other issues were addressed with specific methodology recommendations in a manner that FDA representatives believed would enable consideration of an indication for cognition or for negative symptoms (Buchanan et al., 2005; Kirkpatrick and Fischer. 2006).

Clinical trials in the five years following the cognition paper (Buchanan et al., 2005) provide data on which Buchanan et al. modify guidelines for clinical trial design of cognition-enhancing drugs (Buchanan et al., 2011). Keefe et al. (Keefe et al., 2011) identified 118 trials for cognition in schizophrenia, report results, and critique significant problems associated with almost all the trials. They add additional recommendations regarding clinical trial design for future studies. The field needs to address the identified problems to prevent the next generation of trials from being uninformative, as was the case with the vast majority of reports to date.

We invite readers to address the following questions, and to raise others:

1. Is the issue of "pseudospecificity" adequately addressed by the recommended methods?

2. Can the consensus clinical trials methodology for cognition efficacy be integrated with the NIMH Research Domain Criteria (RDoC) initiative? If so, which behavioral constructs have a compelling relationship with impaired cognition measured with neuropsychological tests?

3. Are novel therapies for impaired cognition in schizophrenia likely to address pathophysiology? Or common final pathway phenomena? Or enhance compensatory mechanisms?

References:
Buchanan RW, Davis M, Goff D, Green MF, Keefe RS, Leon AC, Nuechterlein KH, Laughren T, Levin R, Stover E, Fenton W, Marder SR. A summary of the FDA-NIMH-MATRICS workshop on clinical trial design for neurocognitive drugs for schizophrenia. Schizophr Bull . 2005 Jan 1 ; 31(1):5-19. Abstract

Kirkpatrick B, Fischer B. Subdomains within the negative symptoms of schizophrenia: commentary. Schizophr Bull . 2006 Apr 1 ; 32(2):246-9. Abstract

Buchanan RW, Keefe RS, Umbricht D, Green MF, Laughren T, Marder SR. The FDA-NIMH-MATRICS guidelines for clinical trial design of cognitive-enhancing drugs: what do we know 5 years later? Schizophr Bull . 2011 Nov 1 ; 37(6):1209-17. Abstract

Keefe RS, Buchanan RW, Marder SR, Schooler NR, Dugar A, Zivkov M, Stewart M. Clinical Trials of Potential Cognitive-Enhancing Drugs in Schizophrenia: What Have We Learned So Far? Schizophr Bull . 2011 Nov 22. Abstract