Optimism Grows About Potential to Aid Schizophrenia Cognition

A “total treatment effect” that combines cognitive remediation therapy (CRT) with vocational rehabilitation and other psychosocial interventions—as well as, possibly, psychopharmacology—may be the key to enhancing cognition and improving “real-world” functioning in schizophrenia patients.

That’s what Philip Harvey, Ph.D., the Leonard M. Miller Professor of Psychiatry and Behavioral Sciences at the University of Miami Miller School of Medicine, said at the International Congress of Schizophrenia Research in Orlando, Fla., last month.

Harvey described a trend toward using cognitive remediation in combination with other psychosocial interventions—especially vocational rehabilitation—that can produce robust effects even in a relatively short period, suggesting the importance of a multimodal strategy with a “total dose effect” that may be as important as the duration of treatment.

“When I look at these data, what I see is that there seems to be this total dose treatment effect,” Harvey said. “If you give people 100 sessions of CRT and nothing else, or 20 sessions of CRT plus vocational rehabilitation, you get the same outcome.”

Impaired Cognition: “A Bad Guest”

Harvey provided an overview of a field that has garnered increasing interest among schizophrenia researchers: the effort to address cognitive impairments, which have been shown to be more crucial to long-term functional outcome—and more stubbornly resistant to treatment—than positive symptoms of psychosis.

“Cognitive impairment in schizophrenia is like a bad guest,” Harvey said. “It shows up early, it is present before the onset of other symptomatology, and it sticks around over the lifespan. It leads to a variety of adverse outcomes, limits vocational functioning, and it leads our patients to be socially isolated and to live in substandard conditions.”

Along with increasing research interest, there has been a proliferation of commercial “brain training” products and Web sites, not all of which are reliable, he said. Additionally, it has become increasingly clear that improvements in cognition—as measured by standardized tests—may have little importance for treatment without corresponding improvements in real-world functions such as the ability to hold a job and to interact with peers socially.

“Is cognition on its own important above and beyond everyday functioning? My argument is that cognition may be the path to disturbances in everyday outcome,” he said. “One of the things that becomes challenging is that the relationship between cognitive function and real world outcome is not a perfect relationship and there may be other factors involved.”

Mediating Variables May Affect Outcome

He noted, for instance, that research now suggests a number of mediating variables—such as intrinsic motivation, therapeutic alliance, and self-efficacy—may be influential in whether CRT works. Interventions that fail to increase self-efficacy—the patient’s sense of mastery and ability to succeed without help—may negate whatever improvements in neurocognition may be seen, Harvey said.

And what appears to be emerging is a strategy that emphasizes multiple interventions aimed at multiple brain systems: cognitive remediation, skills training, social cognition training, and supported employment. Several researchers at the congress described cognitive remediation efforts that are embedded within vocational rehabilitation programs.

And a prominent theme in discussion about cognition at the congress was the idea of “bridging,” which requires the involvement of a clinician. “Bridging is the process of teaching patients how to employ their newly acquired cognitive skills,” Harvey explained. “So, you do scenarios that postulate real-world situations and talk about how you would solve a problem.”

In a study published by Harvey and colleagues last year in the American Journal of Psychiatry, they found that in a short intervention, cognitive remediation combined with skills training produced robust improvements in neurocognition and real-world functional improvements. In that study, 107 outpatients with schizophrenia were randomly assigned to cognitive remediation alone, functional adaptation skills training, or a combination of the two. With the combined intervention, statistically significant improvements from baseline were seen in community or household activities and work skills after just 12 weeks.

Adding to the excitement about the possible success of cognitive enhancement in schizophrenia patients is evidence indicating that improvements in cognition and functioning are correlated with changes in the brain. Harvey presented evidence showing that serum brain-derived neurotrophic factor (BDNF) levels in schizophrenia subjects participating in 50 hours of computerized auditory training were comparable to those of age-, sex-, and education-matched healthy comparison subjects. (BDNF is involved in a variety of trophic and neuromodulatory effects that include an important role in the development and survival of dopaminergic and serotonergic neurons, and BDNF levels have been found to be increased in the hippocampus and anterior cingulate cortex of schizophrenia brains.)

Finally, Harvey presented data on experiments with pharmacologic agents that might be used as adjunctive treatments along with CRT. While some of these have been disappointing, he emphasized that many of the studies have been underpowered, requiring very large effect sizes to be statistically significant. And there have been some tentative successes, in particular with davunetide, a neuropeptide that promotes neurite growth, and EVP-6124-009, an alpha-7 partial agonist.

Overall, Harvey said there is reason to be optimistic that CRT in combination with other interventions can produce improvements in cognition and functioning in a short period of time. “Things look promising in certain areas,” he said. “If you give people combined therapies and add up the total dose of the intervention, it tends to correlate with outcome. It’s very encouraging to review data on cognitive enhancement therapies that not only make your cognition better, but make it look like you are doing better in the world in a short time period.” ■