Can we incorporate psychosocial treatment interventions into psychopharmacology clinical trials

T article by Richard Keefe and colleagues1 in this month’s Journal has substantial value to researchers who face an important methodological question in clinical trials of cognitive-enhancing medications in schizophrenia. Do patients in pharmacologic intervention trials need to exercise their cognitive “muscles” for a drug that increases cognitive “muscle mass” to work? This is the analogy offered by these authors. Exercise is defined as some form of training in cognitive skills, such as cognitive remediation. Often, discussion of this question is side-tracked by a procedural question, namely, can introducing a cognitive remediation intervention into large, multicenter randomized clinical trials (RCTs) of medication be feasible? First, there is the concern that staff at the clinical sites where trials are conducted will not be able to implement the procedures, and, second, there is concern that patients who enroll in these trials will not actually participate adequately in cognitive remediation activities involving multiple training sessions per week over several months. The study reported by Keefe et al1 was formally designed to address these 2 feasibility questions and to provide some information about the efficacy of cognitive remediation training as a stand-alone intervention in this patient population. There was no cognitive-enhancing medication in the trial; therefore, the important substantive question of whether introducing a cognitive remediation or other cognitive-enhancing platform to a study of drug effects would potentiate the drug effect remains an important question to be addressed by future studies. Keefe and colleagues1 conducted a small RCT (N = 53) comparing a specific cognitive remediation approach, Posit Science Brain Fitness auditory training2 and the Neuropsychological and Educational Approach to Remediation (NEAR),3 to an attention control at 9 sites, 7 of which had no formal prior research experience with cognitive remediation. The cognitive remediation intervention involved individual computer-based auditory training (up to 40 sessions over 12 weeks) and weekly groups designed to provide a link to day-to-day activities and boost self-esteem. The study methods were meticulous, and the authors answer the procedural question of feasibility with a resounding yes. The sites met very rapid enrollment goals: 6 subjects recruited in a 3-month period. Clinicians were centrally trained and monitored, there was no clinician turnover, and subjects participated adequately in the interventions. The majority of subjects completed 40 sessions: 59% in the cognitive remediation group and 57% in the attention control group. The criterion for intervention completion was 24 sessions (60%), which was met by 77% of the study subjects. The investigators provide data to show that acoustic discrimination (a focus of the individual cognitive remediation training) was significantly improved over the full course of treatment. Data also showed that the MATRICS Consensus Cognitive Battery composite score improved more in the cognitive remediation group than in the attention control group after 20 sessions.1 Were the methods sound? The answer is yes, but. . . . The inclusion criteria for subjects in the study yielded a study sample that “looks” much like samples in recent RCTs in schizophrenia, which has clinical implications as noted below. The only novel inclusion criterion compared to criteria in medication trials was that subjects had to be able to “state specific goals relevant to the intervention that they would like to achieve.”1 There is no information on whether this inclusion criterion excluded many subjects. From the CONSORT flowchart, it appears that only 4 subjects were excluded after entering screening for inclusion criteria, suggesting that having goals and other inclusion criteria were assessed informally before potential subjects entered the formal screening process. Although 7 of the 9 sites had no prior cognitive remediation experience, these were all academic sites with investigators and staff that have vast experience in treating and conducting research with schizophrenia patients. Most had participated in the Clinical Antipsychotic Trials of Intervention Effectiveness,4 and, because they were among the more successful sites in that study, they were part of the National Institute of Mental Health Schizophrenia Trials Network. So the question remains whether these sites are representative of the clinical trial sites where most studies of cognitive-enhancing medications will be conducted and, by implication, whether the fact that a cognitive remediation intervention can be implemented at these 9 sites provides adequate evidence of feasibility in the hands of less committed investigators and staff. Second, the study assessment model of Keefe et al1 followed the usual procedures in cognitive remediation studies: assessments were completed at time points defined by number of completed sessions—in this study, at baseline and after 20 and 40 sessions (or the last session completed). Randomized clinical trials to assess medication effects have assessment schedules tied to study week, eg, at baseline and 6 and 12 weeks. The present study does not allow us to determine how many sessions had been completed at the 6-week time point, Submitted: April 2, 2012; accepted April 3, 2012. Corresponding author: Nina R. Schooler, PhD, Department of Psychiatry and Behavioral Sciences, SUNY Downstate Medical Center, 450 Clarkson Ave, Box 1203, Brooklyn, NY 11203 (nina.schooler@googlemail.com).