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The National Institute of Mental Health (NIMH)-Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Project and related efforts have stimulated the initiation of several studies of pharmacologic treatments for cognitive impairment in schizophrenia. 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. However, it is not clear how a cognitive remediation intervention would be employed in multisite clinical trials. A meeting of experts on cognitive remediation and related methodological topics was convened to address the feasibility and study design issues for the development of a multisite trial of cognitive remediation in schizophrenia called the Cognitive Remediation in the Schizophrenia Trials Network study. This report details the findings from this meeting, which included the following 4 conclusions. (1) A multisite trial of a cognitive remediation intervention using a network of diverse research sites would be of great scientific value. (2) Various interventions could be employed for this multisite trial. (3) Programs that do not address key motivational and interpersonal aspects of cognitive remediation may benefit from supplementation with “bridging groups” that allows patients to meet with others and to apply their newly acquired cognitive skills to everyday life. (4) Before a multisite efficacy trial is initiated, a pilot study could demonstrate the feasibility of conducting a trial using a cognitive remediation intervention.
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 table 1). 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.
Several potential cognitive remediation interventions that could be utilized in multisite trials were reviewed at the conference based upon the experience of the attendees. Our aim was not to choose the “best” cognitive remediation strategy but rather to discuss cognitive remediation interventions that could best be implemented in a multisite trial, with the intention that these interventions may eventually be useful for trials that integrate cognitive remediation and pharmacologic interventions. Because a review of available programs is beyond the scope of this article, and has been covered recently in the literature,12 we will not devote space in this journal to describe the programs that were under consideration. There are many programs that could serve as potential interventions for multisite trials.
The following features of a cognitive remediation program were identified as desirable for a multisite trial in schizophrenia:
The group agreed that an active control condition is important for the control for nonspecific elements of treatment.10,11,18 The 2 key factors were controlling for time spent with a trainer or in-group interaction and controlling for total training time. The nature of the control condition should be governed by the hypothesized mechanism of action and what are considered to be nonspecific effects.
The previous experience of the meeting attendees suggested that a variety of training strategies are acceptable depending upon the complexities of the intervention, especially the degree of interpersonal interactions between patient and therapist. Some of the more interpersonally intensive interactions, such as the NEAR program, have been found to benefit from an intensive face-to-face training session using a clinician's training manual19 followed by individual study of the manualized training procedures, pencil-and-paper and role-play certification examinations, review of gold standard videotaped sessions, shadowing of actual training sessions, and supervised live sessions.10 It is best if trials can include an ongoing process of assessing whether the patient-therapist interaction continues to reflect the clinical procedures taught at the beginning of the study, although it will be challenging to implement these so-called “fidelity checks” in multisite trials.33,34
Interventions that rely less upon patient-therapist interaction will obviously require less training. The standard PositScience training and certification system has involved a half-day session, but this approach has not been implemented with trainers conducting multisite schizophrenia trials, and there was some question about whether this would be sufficient for a multisite trial.
National Institute of Mental Health (N01 MH90001).
Additional attendees: Alison Adcock, Duke University; Jeffrey Baker, Abbott Laboratories; Wendy Granberry, GlaxoSmithKline; Matcheri Keshavan, BIDMC and Wayne State University; Eva Kohegyi, Sanofi-aventis; Michael Kraus, Duke University; Martin Lowy, GlaxoSmithKline; Henry Mahncke, PositScience; Wen-Chen Ouyang, Duke University Medical Center; Donna Palumbo, Pfizer Inc; Thomas Patterson, University of California San Diego; David Penn, The University of North Carolina; Diana Perkins, The University of North Carolina; Ingrid Rojas, The University of North Carolina; Jaskaran Singh, Johnson & Johnson PRD, LLC; Joyce Tsai, Forest Research Institute; Claire Vilain, Lundbeck SAS; Trina Walker, Duke University; and Nancy Zucker, Duke University. R.S.E.K. reports that he currently or in the past 12 months has received investigator-initiated research funding support from the National Institute of Mental Health, Allon, GlaxoSmithKline, Novartis, and the Singapore National Medical Research Council and an unrestricted educational grant from Astra-Zeneca. He currently or in the past 12 months has received honoraria, served as a consultant, or advisory board member for Abbott, BiolineRx, BrainCells, CHDI, Dainippon Sumitomo Pharma, Eli Lilly, Lundbeck, Memory Pharmaceuticals, Merck, Neurosearch, Novartis, Orion, Otsuka, Pfizer, Roche, Sanofi/Aventis, Shire, Solvay, Takeda, and Wyeth. In the past, he has received honoraria, served as a consultant, or advisory board member from Acadia, AstraZeneca, Bristol-Myers Squibb, Cortex, Cephalon, Eli Lilly, Johnson & Johnson, Orexigen, Organon, Pfizer, and Xenoport. Also in the past, he has received research funding from AstraZeneca, Eli Lilly, Janssen, Organon, and Pfizer. R.S.E.K. receives royalties from the Brief Assessment of Cognition in Schizophrenia (BACS) testing battery and the MATRICS Battery (BACS Symbol Coding).