Neurocognitive impairment, a core component of schizophrenia, is increasingly under investigation as a potential treatment target. Such impairment, which affects almost all patients with schizophrenia,1
ranges from moderate to severe2–4
and is strongly correlated with functional outcomes.5
Antipsychotics provide minimal neurocognitive improvement6
consistent with practice effects7
in chronic patients treated with conventional or second-generation antipsychotics. Treatment intervention is sorely needed. The National Institute of Mental Health (NIMH)-Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Project and related efforts have stimulated interest from government and industry, and several studies are underway to explore new pharmacologic treatments for cognitive impairment in schizophrenia (www.clinicialtrials.gov
, accessed November 19, 2009), although no pharmacologic approaches to improve cognition have yet received regulatory approval.
While broad efforts are underway to refine and harness pharmacologic mechanisms that could contribute to enhanced cognitive functioning in schizophrenia, one unaddressed area of work is the relatively impoverished cognitive lives of patients who enroll in these pharmacologic enhancement studies. It is possible that the cognitive benefit of these experimental pharmacologic interventions is minimized when patients are studied in the context of the low level of cognitive, behavioral, and environmental stimulation that is typical in patients with schizophrenia. Thus, analogous to the need for physical exercise in an individual who takes steroids to increase muscle mass, schizophrenia patients in cognitive enhancement trials may require learning contexts sufficient to “exercise” any newfound cognitive potential that they may have acquired from the drug under study.
Cognitive remediation may provide an excellent platform for the provision of new learning opportunities and the acquisition of new skills for patients who are engaged in pharmacologic trials to improve cognition. As defined by McGurk et al,8
cognitive remediation programs developed for schizophrenia seek to address cognitive impairment through a variety of methods such as drill and practice exercises, compensatory strategies, and group discussions. Such programs may be computer based, may rely on interactions with trained instructors, and/or be classroom based.
Recent work on the effects of cognitive remediation suggests that this approach may demonstrate moderate efficacy in improving cognition in schizophrenia. A meta-analysis of 26 randomized controlled trials involving a total of 1151 patients concluded that cognitive remediation produces moderate improvements in cognitive performance and, when combined with psychiatric rehabilitation, also improves functional outcomes.8
Additionally, these programs are quite popular with patients and have even been linked with increases in participant self-esteem.9
Ongoing treatment with cognitive remediation may thus provide schizophrenia patients with the necessary cognitive enrichment and motivation to demonstrate the true potential of effective cognitive enhancement from pharmacologic agents.
However, there are clear challenges to progress. First, results from individual studies remain mixed.10,11
Remediation programs vary in terms of underlying conceptual foundations and intervention modalities, and the field has yet to reach consensus about the essential elements of the intervention. Second, methodological challenges are considerable. It is not clear how a cognitive remediation intervention would be employed in multisite clinical trials, especially in industry trials that may include a number of nonacademic sites with little cognitive remediation experience. Most of the cognitive remediation trials in patients with schizophrenia have been implemented at single sites with highly trained academic research personnel and methods developed at those sites; thus, the generalizability of these methods is not well known. Furthermore, as with drugs in the pharmaceutical industry, the ability of the developers of cognitive remediation programs to evaluate the efficacy of their own programs without bias may be questioned.
The feasibility of completing a study with both pharmacologic and behavioral interventions in schizophrenia may be particularly challenging. It is not clear what percentage of patients would be able to meet medical screening criteria for an experimental drug and would also be able to devote the time necessary to complete a behavioral regimen. Furthermore, because pharmaceutical company trials are increasingly conducted outside of North America, the feasibility of these interventions to be conducted internationally will also need to be determined. One of the crucial next steps is to determine the feasibility of conducting a multisite trial of cognitive remediation in patients with schizophrenia in a circumscribed geographical region that may facilitate maximal benefit.
We convened a meeting of North American–based experts on cognitive remediation and related topics to address several study design issues for the development of a multisite trial of cognitive remediation in schizophrenia (see ). The eventual goal for this project will be to test the efficacy of a combined pharmacologic and cognitive remediation treatment program. The immediate goal is to determine the feasibility of implementing a cognitive remediation program in a network of sites that do not specialize in this area of research. This study, called the Cognitive Remediation in the Schizophrenia Trials Network study, will determine the feasibility of multisite cognitive remediation projects both as solo behavioral interventions and as platforms for pharmacologic cognitive enhancement trials. This article is a report of the methodological issues that were addressed during the course of this working group conference.
Design Issues for Multisite Trials of Cognitive Remediation in Schizophrenia