Cognitive-Impairment Research Poised to Advance

Two agents targeting cognitive impairment in schizophrenia demonstrated positive benefits in early-stage clinical trials reported at the recent meeting of the American College of Neuropsychopharmacology (ACNP).

But most completed clinical trials of agents targeting cognitive deficits in schizophrenia have been poorly designed to measure effects accurately, according to an analysis of clinical trials to date.

Newer ongoing trials, using larger sample sizes and incorporating standardized outcome measures, may be much more promising, pointing to the success of the MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) project—a joint government/academic/pharmaceutical industry collaborative to develop study protocols and a standardized battery of tests for measuring outcome. The review appears in the November 22, 2011, Schizophrenia Bulletin.

Prior to the MATRICS project there was no agreement on how to conduct these trials, what were the measurable outcomes, how many subjects were needed to detect effects, and what stage of subjects' illness to include in trials. In the absence of that consensus, pharmaceutical companies were reluctant to invest in costly trials of drugs for neurocognition.

For clinicians treating patients with schizophrenia, the Schizophrenia Bulletin review—and the results from the ACNP meeting—suggest hope for the future.

Results from many of the completed trials were not available in the public domain, and in those that existed, there were few positive results. But there are promising lines of research—especially with alpha-7 nicotine agonists.

“In terms of the maturation of this area of research, we are probably still in our adolescence,” lead author Richard Keefe, M.D., told Psychiatric News in an interview. “We know there are agents that have an effect on cognition, and we have developed techniques and outcome measurements for studying them. But in terms of having something that will cure or prevent schizophrenia, we have a long way to go.”

Keefe is a professor of psychiatry and behavioral sciences and psychology at Duke University Medical Center. He is also founder and president of Neurocog Trials, a for-profit company that provides consulting, site screening, rater training and certification, and data-review services to pharmaceutical companies engaging in clinical trials of agents for neurocognition.

Keefe and colleagues searched clinical trials of agents for cognition in schizophrenia on the NIMH-sponsored Web site at www.clinicaltrials.gov using a variety of search terms. They included trials that were conducted in people with schizophrenia, in which the effects of a pharmacologically active substance on cognition were either a primary or secondary outcome.

They identified 118 trials, most (62 percent) using an add-on parallel group design; monotherapy and crossover trials were in the minority. Keefe and colleagues found that the large majority of completed trials were underpowered to detect moderate effect sizes, had less than eight weeks' duration, and were performed in samples of participants with chronic stable schizophrenia.

However, trials still ongoing are longer, have larger sample sizes, and are more likely to use a widely accepted standardized cognitive battery, such as the MATRICS Consensus Cognitive Battery and MATRICS guidelines; a number of the trials are adequately powered to detect moderate effect sizes. Ongoing studies involving subjects with recent-onset schizophrenia may help identify subjects who are most likely to show an effect in cognition, according to the review.

Despite the relatively dismal findings from the literature review, Keefe said there continues to be optimism about finding agents to treat cognitive impairment. And he suggested that such a therapy could potentially be transformative for the course of psychosis generally, noting that there is a consensus that cognitive impairment is a central—possibly a defining—feature of the disorder.

“We know it is at the core of schizophrenia,” he told Psychiatric News. “It precedes the onset of psychosis; it persists throughout the illness and doesnt respond to symptom change.”

He also said that the field has coalesced around established protocols for conducting trials and standards for measuring efficacy, a crucial advance of the MATRICS project.

Keefe spoke with Psychiatric New's immediately after the annual meeting of the ACNP in Honolulu, where he said two positive studies of alpha-7 nicotine agonists were presented. One of those was a phase 2b trial of EVP-6124, manufactured by Envivo, that showed statistically significant effects on cognition and functional symptoms, including global cognitive function, according to a statement released by the company on its Web site at www.envivopharma.com; another alpha-7 nicotine agonist, TC5169, manufactured by Targacept, demonstrated statistical significance on the Scale for Assessment of Negative Symptoms and one measure of executive function in a phase 2 clinical trial, according to Targacept's Web site at www.targacept.com/wt/page/index.

He also expressed optimism about the prospects for computerized brain training to improve cognition, such as that presented by Sophia Vinogradov, M.D., of the University of California San Francisco at APA's Institute on Psychiatric Services in October 2011 (Psychiatric News, December 16, 2011).

“The take-home message is, ‘Watch this space,' ” he said. “There are a lot of trials, and a lot of good research has been precipitated by the MATRICS initiative, which overall has been very successful. The trials themselves have not been so successful. But I do think that based on the most recent work, there is cause for optimism.”