In this issue, Bowie et al. (1) report on a randomized comparison of cognitive remediation therapy versus functional adaptation skills training alone and in combination to improve cognition, functional competence, and real-world outcomes in a sample of 96 persons with schizophrenia. The intervention period spanned 24 weeks, including 12 weeks of either cognitive remediation therapy or functional adaptation skills training followed by a 12-week durability assessment period for the single treatment groups and a sequence of 12 weeks of cognitive remediation therapy followed by 12 weeks of functional adaptation skills training for the combination group. The major findings include the following: 1) cognition improved with cognitive remediation therapy whether or not combined with functional adaptation skills training, but not with functional adaptation skills training alone; 2) social competence improved with functional adaptation skills training whether or not combined with cognitive remediation therapy, but not with cognitive remediation therapy alone; 3) enduring functional competence was achieved with combined treatment, but not with either treatment alone; 4) real-world social functioning did not improve; 5) real-world community and work functioning improved more with combined treatment than with either cognitive remediation therapy or functional adaptation skills training. In summary, cognitive remediation therapy and functional adaptation skills training each produced the expected proximal outcome improvements, but the combined treatment showed further advantages in real-world behaviors. These findings support the notion that achievement of improvements in real-world outcomes is more likely to occur when both cognitive impairments and skills impairments are addressed (2). Failure to provide some combination diminishes the yield from single interventions.

This study is notable from a number of perspectives. First, it illustrates the increasing sophistication of psychosocial interventions for persons with schizophrenia, in this case comparing and sequencing two well-developed and standardized interventions that target related but distinct proximal outcomes—cognition and functional competence. Second, it demonstrates the complexities of discerning whether an intervention really makes a difference along a continuum of outcomes. Cognition was assessed using a standardized battery of cognitive tests, social and functional competence were measured by observed role play performances on standardized tasks simulating everyday skills, and real-world performance was gleaned from ratings by case workers who knew the subjects well. We see in this range of outcomes the tensions between, on the one hand, the precision of outcomes proximal to the mechanisms of action of an intervention and, on the other hand, the associated loss of precision of measurement in assessing more distal outcomes of real-world relevance (3). This tension arose as well in the Clinical Antipsychotic Trials of Intervention Effectiveness study (4), which compared several antipsychotic medications and focused on all-cause medication discontinuation as the real-world outcome over more standardized proximal outcome measures of symptoms or side effects. Third, the study demonstrates the potential value of rationally sequencing interventions to achieve greater effects. Cognitive remediation therapy and functional adaptation skills training alone had significantly less impact than when they were combined sequentially, first addressing cognitive impairments and then addressing functional skills deficits. This study does not tell us whether this particular sequence is critical. The study also does not report on the pharmacotherapy the patients received, but we can probably assume that this too was part of the treatment cascade. Hence we see a complex illness addressed in a multifaceted manner such that the whole of the treatment regimen is greater than the sum of its parts.

Yet even with this level of sophistication in treatment regimen, the effects of treatments on real-world functioning of persons with schizophrenia are often modest. It would be incorrect to argue that, overall, the treatment and the well-being of most persons with schizophrenia have not improved substantially over the past half century. We have better medications and a much broader and well developed array of psychosocial treatment options and services (5). Most persons with this disorder no longer live in institutions. Still, it does feel at times as if we have hit barriers in enabling persons with schizophrenia to fully recover or to avoid the perils of the illness in the first place. The fact that even our most advanced treatments, including that exemplified by Bowie et al., do not return individuals to full real-world functioning raises serious challenges for advocacy and compels us to greater innovation.

No doubt we can do better with what we already know. The vast majority of patients do not receive optimal combinations of psychosocial treatments and pharmacotherapy, especially the type of carefully crafted and sequenced treatments studied by Bowie et al. However, moving forward, we need new directions—and we see glimpses of that elsewhere in this issue. Apud et al. (6) provide intriguing clues to the refinement of the choice of antipsychotic agents using pharmacogenetics. Such personalized approaches to treatment, in combination with other optimized and sequenced psychosocial treatments, may advance the cause of making a difference. It is easy to imagine a time when our treatments are much more precise and personalized. It is also daunting to witness the scientific challenges required to get us there. In a lecture at the 2010 APA annual meeting, Snyder discussed the challenges in translating advances in basic neuroscience into meaningful therapeutics, citing as an example the many years that have elapsed since the discovery of the gene for Huntington's disease and the continuing elusiveness of treatments for the disorder (S.H. Snyder, unpublished 2010 lecture).

Finally, no current discussion about making a difference can be complete without mention of health care reform policies to promote access to the most effective treatments. Even as more evidence-based treatments become available and as we see growing sophistication in our capacity to construct sequenced treatment, as exemplified in the Bowie et al. study, the common failure to make even one evidence-based treatment available in many communities underscores the challenges. It is not at all clear how proposed changes in health care law and policy will promote the implementation of personalized, sophisticated treatment regimens (7). The resources needed to implement the interventions examined by Bowie et al. seem modest but include computers and software for cognitive training, doctoral-level therapists to conduct both cognitive remediation therapy and functional adaptation skills training, and training and ongoing monitoring for staff to implement and maintain fidelity of the interventions. Such innovation requires a commitment from agency leaders to prioritize these approaches. This type of “retooling” of rehabilitation programs requires considerable perseverance, especially if existing resources need to be redirected. How would outcomes improve, for example, if we combined the personalized approach to pharmacotherapy envisioned by Apud et al. with the sequenced psychosocial regimen presented by Bowie et al. among young persons experiencing the early phases of schizophrenia? How much would it cost to achieve this? How much does it cost not to do this? Costs may at times dominate the national debate on mental health coverage, but this is all the more reason to have evidence that treatments can make a meaningful difference. As we move forward, we have to be concerned that the types of treatments presented by Bowie et al. may be vulnerable under new insurance plans that will likely emphasize core medical services and leave rehabilitation services increasingly vulnerable to mightily challenged state and local budgets (8). Pardes pointed out some years ago (9) that as technologies advance to improve the outcomes for a given medical condition, costs to treat that condition typically rise, at least until a cure is found. To make a difference in the real-world outcomes for persons with schizophrenia, we will need to invest smartly and to argue persuasively for greater parity based on the evidence.