cognitive remediation for schizophrenia: current status, biological correlates and predictors of...

10.1586/ERN.12.71 813ISSN 1473-7175© 2012 Expert Reviews Ltdwww.expert-reviews.com

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Cognitive remediation (CR) for schizophrenia, defined by a recent meeting of the Cognitive Remediation Experts Workshop (Florence, Italy, April 2010), as “a behavioral training based intervention that aims to improve cognitive pro-cesses (attention, memory, executive-function, social cognition or meta-cognition) with the goal of durability and generalization”, has seen a remarkable growth in research interest over the past 40 years. This growth can be seen in the rapidly accelerating cumulative number of controlled trials in the field (Figure 1). Work in this area has been fueled by research showing a substantial and well-replicated link between measures of cognitive skills in schizophrenia and a variety of indices of functioning, including pro-gress in psychosocial rehabilitation programs, community function and role-play measures of social and everyday life skills [1,2]. These links provide support for the possibility that improv-ing cognitive skills may improve outcome in the disorder.

Two recent literature reviews on CR have focused on the relationship between studies of CR efficacy and dissemination of these findings into clinical practice [3] and the mechanisms of

action of CR interventions [4]. While the current review has some overlap with these articles, it is intended to build on this previous work by including sections on the status of prediction of treatment response to CR, and studies of neural correlates of CR effects, as well as more recently published work. For the purposes of this review we divide CR methods into three major categories of interventions:

• Restorative approaches, which target cogni-tive deficits directly through repeated task practice, careful titration of task difficulty and maintenance of high levels of accurate perfor-mance. In these interventions, task practice is typically organized hierarchically, with elemen-tary aspects of sensory processing or attention trained first, followed subsequently by training in higher-order memory and problem-solving skills;

• Strategy-based approaches that focus on the acquisition of techniques for circumventing cognitive difficulties. These interventions typ-ically require the therapist to provide cognitive supports for a task at first; these supports are discussed with the client, and then the client

Matthew M KurtzDepartment of Psychology and Program in Neuroscience and Behavior, Wesleyan University, Judd Hall, 207 High Street, Middletown, CT 06459, USATel.: +1 860 685 2072 Fax: +1 860 685 2761 [email protected]

Cognitive remediation (CR) is an increasingly studied behavioral intervention for improving illness-linked cognitive deficits in schizophrenia, with considerable promise for improving the disease outcome when offered in concert with other therapies. We present findings from a comprehensive, critical review of the extant literature on CR for schizophrenia. Conclusions from six meta-analyses presented to date are summarized, and existing CR interventions are categorized into three major classes: restorative, strategy-based and hybrid approaches. The crucial elements and empirical support for each class are presented. Studies of predictors of treatment response suggest that attention, motivation and clinician expertise, along with the measures of ‘brain reserve’, are key features of a positive treatment response. Lastly, findings from studies of neuroimaging indicate that CR is accompanied by structural and functional neural changes in key frontal and temporal brain regions.

Cognitive remediation for schizophrenia: current status, biological correlates and predictors of responseExpert Rev. Neurother. 12(7), 813–821 (2012)

Keywords: cognition • cognitive remediation • functioning • outcome • psychological treatments • schizophrenia

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is allowed to practice cognitive strategies as the therapist gradu-ally removes these supports. Interventions of this type are often tied directly to cognitive skills used in everyday life function;

• Hybrid approaches – these programs typically involve a mel-ange of both restorative drill-and-practice training and strategy acquisition and include additional elements designed to address deficits in motivation, social cognition (the ability to accurately decode the mental states of others) and/or social skills.

For each class of intervention we describe both the methods used for improving cognitive function and then the empirical basis for intervention efficacy.

Meta-analyses of the efficacy of CR on cognition, function & symptomsTo date, six quantitative meta-analyses have been published, with all but one [5] sup-porting the efficacy of CR for improving cognitive outcomes targeted by these inter-ventions (see Figure 2). More recent meta-analyses have also provided strong support for moderate effect-size improvements in function, and small effects on symptoms as well.

The first meta-analysis of CR was con-ducted by our group [6] to investigate the effi-cacy of a variety of remediation strategies for improving performance on the Wisconsin Card Sorting Test (WCST), a measure of rule-learning and cognitive flexibility. In this test, patients sort cards from a deck and are asked to match each card to one of four

‘key cards’. Cards can be matched to the key cards on one of three dimensions such as color, form or number, and participants learn the correct sorting rule through corrective feedback to their responses. At the time of this review, the WCST had been the most consistently studied outcome measure in cognitive training studies in schizo-phrenia. Work in this area was driven by a report [7] that even after providing information on the nature of the categories in the task, the occurrence of shifts in set and card-by-card instructions on how to do the task, chronically hospitalized patients with schizophrenia were still unable to improve their performance. The authors con-cluded from their work that deficits in performance on the WCST were linked to structural neural impairments in the dorsolateral prefrontal cortex (PFC) that rendered training strategies useless.

In response to the potential treatment implications of this report, a range of studies aimed to replicate the lack of training effect and evaluate whether alternative strategies might be more successful. The instructional techniques used in these studies included task explanation and card-by-card instruction similar to that employed by Goldberg et al. [7], errorless learning methods, in which the WCST is broken down into smaller elements and each element is trained individually with minimal opportunity for error, and self-monitoring interventions, in which patients are asked to simply verbalize their sorting strategy on the WCST. The meta-analytic results of these studies revealed mean weighted effect sizes in for categories solved, preservative errors and conceptual level responses for the WCST all in the large range (Cohen’s d effect sizes = 1.08, 0.93 and 0.90, respectively). The limitations of the analysis included the very limited scope of the cognitive interventions studied (typically one-session interventions), and that these studies included testing, training and testing on the same outcome instrument. Thus, there was a

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Figure 2. Effects of cognitive remediation on cognition, function and symptoms in schizophrenia: results from meta-analyses.

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lack of assessment of generalization of treatment effects to other cognitive measures or functioning. Despite these limitations of the review, the finding that cognitive deficits in schizophrenia are malleable in response to behavioral interventions has been nearly unequivocally supported in studies conducted since.

Subsequent meta-analyses [8,9] have revealed that in 40 controlled studies of CR to date, consisting of 2104 participants, CR pro-duces moderate effect-size improvements in cognitive outcomes (d = 0.45) and function (d = 0.42). The Wykes et al. review was particularly important, as the authors were the first to evaluate the impact of methodological rigor of CR studies on observed findings [9]. Treatment factors such as duration, computer presenta-tion, adjunctive psychiatric rehabilitation and whether training was largely restorative or strategy-based were also evaluated. Results were computed by comparing cognitive test performance, and/or measures of functioning and symptoms in patients treated with an experimental CR intervention against a control condition at the termination of the CR intervention. Effects on function were found to be much larger when CR was administered as one ele-ment of a more general rehabilitation program, and there was some evidence for an advantage of strategy over restorative interventions on functioning, but not cognitive outcomes. There was some evi-dence that having more symptoms led to weaker treatment effects, however even clients with high levels of symptoms showed some benefit. Other illness, demographic variables and treatment factors did not influence treatment response, and the quality of the design methodology had no impact on the observed treatment effects.

Methods of CRRestorative CR trainingTwo of the most commonly studied approaches to restorative CR have been neurocognitive enhancement therapy (NET), and the PositScience Brain Fitness program. NET uses Bracy’s PSS CogRehab software (Psychological Software Services, Inc., IN, USA) [10], along with a weekly group discussion for social informa-tion-processing, and has been merged with work therapy programs. The cognitive training consists of a series of computer-assisted cognitive exercises that first focused on sustained attention, then on divided and shifting attention, and then followed by exercises in working and episodic memory as well as problem-solving. Exercises are started at individually determined levels of difficulty at which each client is successful, (e.g., 80% accuracy). Task difficulty is increased as performance improves. Several large sample studies have shown that NET in combination with work therapy produces improvements in working memory, executive function and affect recognition [11] that generalize to improved work performance as measured by hours worked and wages earned [12].

The Brain Fitness program consists of repeated drill-and-practice of exercises that place a much greater emphasis on sensory process-ing than the Bracy exercises [13]. In this program the first part of the training program focuses on training in distinctions between frequency modulation sweeps of auditory stimuli, increasing or decreasing in frequency as the sweeps become faster and are sepa-rated by briefer interstimulus intervals. Subsequent exercises train processing of difficult-to-distinguish phonemes using synthesized

speech. Later exercises focus on accurate identification of increasing long lists of syllables in spatial and sequential contexts or ask the par-ticipant to listen to a series of verbal instructions and carry them out. Thus, first exercises target elementary auditory sensory processing, while subsequent exercises target working and verbal memory. The conceptual model guiding the approach is that by improving the speed and accuracy of auditory information processing, the men-tal representations that encoding and rehearsal processes operate upon will be strengthened, leading to improved cognitive function. Preliminary findings from this intervention have been very strong. Fisher et al. reported large effect-size improvement in verbal episodic learning and memory (Cohen’s d = 0.86 and 0.89, respectively) in a sample of clients with schizophrenia randomly assigned to the Brain Fitness program [13]. Effects persisted at a 6-month follow-up [14].

Strategy-based CR trainingTo date, the most well-studied strategy-based remediation inter-vention has been cognitive remediation therapy (CRT) [15,16]. The therapy is based on three general principles: teaching new effi-cient information-processing strategies, individualizing therapy and aiding the transfer of cognitive gains to the real world. The program consists of three modules: cognitive flexibility, work-ing memory and planning. In each module there are a series of exercises graded from ‘extremely easy’ to ‘easy’, to minimize task-related errors and promote errorless learning. In the cognitive flexi bility module, clients are given practice in engagement, dis-engagement and re-engagement for a particular cognitive set or between two sets, while the working memory module requires the person to maintain two sets of information simultaneously and to carry out cognitive operations on this retained set of information. The planning module consists of tasks in which the participant has to plan a series of moves to reach a goal. The emphasis in this module is to organize information and to create and use subgoals. In each task, within each module, information-processing strate-gies are incorporated into the task at first (e.g., performance speed on a task may be regulated by the therapist by pointing to each test item at a fixed rate), the information-processing strategy is then discussed, and then the client practices the strategy with the therapist (e.g., slowing down performance speed), first overtly and then covertly. CRT has shown effectiveness in both early-phase [17] and later-stage illness [18], with evidence that the intervention effects persist over time [19]. A newer development in this area is the development of variants of CRT (e.g., RECOS) that tailor strategy-based CR to the specific pattern of deficit of the partici-pants, accounting for the heterogeneity in cognitive deficits in schizophrenia. This intervention has shown feasibility [20].

Although still in its pilot phase, Twamley et al. have developed a manualized intervention consisting of a series of modules in which both internal (use of acronyms and visual imagery) and external supports (writing down lists, placing lists in a convenient and visible location in the home environment) are utilized to support a variety of instrumental everyday life tasks identified as important by both consumers, their family members and health-care professionals [21]. These skills are grouped into four general domains of prospective memory, attention and vigilance, learning



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and memory, and executive function that are taught sequentially. Examples of everyday tasks include remembering to go to work or school (prospective memory unit), maintaining attention in class (attention and vigilance), learning and remembering names of supervisors (learning and memory), and self-monitoring performance at work (executive-function). Pilot testing has indicated that this intervention produces a medium effect-size improvement on verbal learning and executive-function measures, and a large effect-size improvement in passive auditory attention at a 6-month follow-up after cessation of treatment. Findings also indicate generalization of effects to such treatment-resistant facets of the illness as negative symptoms and quality of life.

Hybrid CR programsNeuropsychological Education & RehabilitationThe Neuropsychological Education and Rehabilitation (NEAR) manualized CR program developed by Medalia et al. [22] places the emphasis of cognitive training on the learning process required for acquisition of cognitive skills. According to this model, the central stumbling blocks for acquisition of novel cognitive skills in schizo-phrenia are deficits in motivation and volition, which are both a central feature of the negative symptoms in the disorder, as well as a consequence of repeated failure experiences from adolescence and beyond secondary to cognitive and social impairments associ-ated with the disease process. Thus, according to this view, for CR to have an impact on cognitive skills in schizophrenia, it must be driven by factors that enhance motivation; these include patient choice in CR exercises, exercises that are engaging and intrinsically rewarding, and they must be contextualized for the client. The key factor for these exercises, according to the NEAR model, is that they promote independence, self-efficacy and persistence. The treatment is most often offered in groups of up to ten clients in which clients meet two to three times per week in 45-min sessions, progressing on computerized exercises at their own pace. While a range of different computerized interventions have been used in this approach, exer-cises are typically ‘top down’ in that they train a range of cognitive skills within the same task. For example, with respect to problem-solving training, these researchers have studied the ‘Where in the USA is Carmen San Diego’ software. In this task, participants are asked to solve a crime through planning, organization and deduc-tions based on clues offered by the program on how to identify and track a criminal. Participants travel around the USA conducting interviews to support the issue of a warrant for the suspect. Thus, the program provides practice on problem-solving skills, as well as more basic skills in attention, memory and concentration.

In support of these ideas, these researchers have manipulated personalization, choice and contextualization and found that these factors together influenced the degree to which patients with schizophrenia acquired arithmetic skills from an arithme-tic training task, as well as generalization of this training to a measure of attention [23]. To date, this approach has received additional empirical support from other randomized controlled trials (RCTs), with evidence of improvement on neuropsycho-logical measures distinct from those trained and that persist for 4 weeks after the cessation of treatment [24,25].

Cognitive enhancement therapyDeveloped by Hogarty et al., this intervention consists of 75 h of training in elementary attention function using software develop by Yehuda Ben-Yishay for head injury, along with 56 group social cognitive treatment sessions focused on increas-ing mental stamina, promoting active rather than passive social information processing and learning to abstract ‘gistful’ rather than concrete processing of social relationships [26]. Group exer-cises, influenced by Brenner’s integrated psychological therapy (IPT) model, are focused on understanding social cues, includ-ing recognizing affect in others, making effective attributions about others mental states and regulating one’s own emotions. Results have revealed that the intervention produces improve-ments in composite neurocognitive measures, as well as a specific index of processing speed, and behavioral measures of social cognition, cognitive style and social adjustment relative to an active, enriched supportive therapy condition in which clients acquired skills in illness management through psychoeducation and stress management. Larger effects of treatment were evident after a second year of treatment, and effects of treatment on the composite measure of cognition, along with cognitive style, social cognition and adjustment, were evident even 1 year after cessation of therapy [26,27].

Integrated psychological therapyThe most well-studied group approach to CR is IPT, as developed and studied by Roder et al. in Europe [28], as well as Spaulding et al., at the University of Nebraska (NE, USA) [29]. IPT integrates neurocognitive, social cognitive and psychosocial rehabilitation into a comprehensive treatment program consisting of five modules – the first training module, in which cognitive differentiation is targeted specifically at remediating cognitive deficits in schizophrenia, with the next two modules targeting cognition in a social context (social perception and verbal communication), and the last two modules training social skills (social skill and interpersonal problem-solving). Training is typically conducted in 30–60 min sessions two-to-three times per week in groups of five to seven patients. In certain respects, cognitive training in IPT is similar to computer-assisted restorative CR in that training is targeted at specific cognitive deficits that are impaired in schizophrenia. It can be differentiated from this approach in that training in cognition is accomplished through a group interactive format, and shares elements with strategy CR in that strategies are practiced for achieving goals, and the tasks used are more directly integrated into the acquisition of social skills. The cognitive differentiation subprogram includes group exercises designed to enhance cognitive flexibility, such as sorting objects of different color, size and shape. The social perception subprogram trains cognitive skills involved in social perception and includes exercises targeted at a detailed examination of pictures of people in social situations, while the verbal communication subprogram includes training in cognitive skills directly relevant to verbal interaction, such as training sustained auditory vigilance and memory, by asking participants to process and repeat a conversation. A recent meta-analysis including 29 studies of IPT yielded several

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interesting findings [28]. Effect sizes for measures of neurocognition were moderate-to-large (d = 0.61) and, importantly, effects were also evident, albeit in a slightly attenuated form, on measures of psychosocial functioning (d = 0.41).

Predictors of response to CRThree studies have investigated the relationship between base-line demographic, illness and cognitive factors in response to CR interventions. The relationship of demographic, symptom, process and neurocognitive variables to the probability of show-ing normalized performance (improvement to within 1 standard deviation [SD] of healthy control performance) after training on a memory task was evaluated in a study by Fiszdon et al. [30]. They studied a task that served as a part of a computer-assisted, drill-and-practice remediation program. Results revealed that sustained visual vigilance, immediate verbal memory, time between termination of intervention and follow-up assessment, and measures of hostility accounted for 70% of the chance of normalization on the selected memory task.

In an analysis of a variety of patient- and treatment-related variables designed to evaluate what promotes a ‘good response’ to CR, Medalia and Richardson have reported that motivation, as indexed by voluntary participation in CR sessions (treatment intensity), work style and clinician experience were the most important predictors of a positive response to CR treatment [31]. Sustained attention was the only cognitive measure related to improvement across three mixed samples of psychiatric in- and out-patients. Improvement in the study was measured by neuro-cognitive outcome measures that were distinct in content from the NEAR treatment program employed in the study. Patients were classified as ‘improved’ if they increased performance on any measure of neurocognitive function in a manner that could have occurred by chance only 5% of the time.

In a related study, Kurtz et al. studied the relationship between crystallized verbal ability, auditory sustained attention and work-ing memory, verbal learning and memory and problem-solving, positive and negative symptoms from the Positive and Negative Syndrome Scale, and remediation treatment intensity and dura-tion, to change on a performance-based measure of everyday life skills after a year of computer-assisted CR [31]. This reme-diation was offered as part of intensive outpatient rehabilitation treatment for 36 patients with schizophrenia or schizo affective disorder. Results revealed that auditory attention and working memory predicted change in measures of everyday life skills after cognitive training, even when all other neurocognitive variables in the model were controlled.

In the first study of its kind, Keshavan et al. investigated the relationship of the concept of ‘brain reserve’ to treatment outcome in 50 patients with schizophrenia randomly assigned to cognitive enhancement therapy (CET) or enriched support-ive therapy [32]. Pretreatment cortical areas were measured by cortical gray matter volumes and surface area (GM/CS) and cognitive/social cognitive outcome was measured over a 2-year period in patients in an early phase of illness. Structures hypoth-esized to be more closely linked to the disease process (temporal

and frontal volumes) were hypothesized to play a larger role in predicting response to treatment. The results revealed several interesting findings. First, GM/CS measures at baseline were linked to improved social cognitive task performance, but not cognitive task performance. Second, there were large differences in response to treatment between low GM/CS patients and high GM/CS patients at a 1-year assessment, but both groups were similar in the magnitude of their treatment response to CET by the second year of treatment. Importantly, all relationships were specific, with GM/CS measures predicting response to the active intervention when compared directly to the predictive value of these measurements for change in the control training condition. While there was evidence that specific regions of the temporal lobe, including the amygdala, hippocampus, insula and other regions were linked to first-year improvement in CET, these effects became nonsignificant when adjusting for overall brain volumes.

Neuroimaging studies of CRTo date four studies have investigated the effects of cognitive training on neurobiological indices as measured by structural and functional neuroimaging. Wexler et al. trained eight stabilized outpatients on restorative verbal working memory exercises over a period of 10 weeks [33]. Improvement on cognitive outcome measures in the study was specific, with observed improvement on verbal, but not nonverbal, memory measures distinct from those trained. Substantial improvement was evident in three patients, with little change in the other five. Improvement on verbal mem-ory measures was associated with increased left inferior frontal activation. Additional training in one participant produced addi-tional gains in verbal working memory performance that persisted for 6 weeks after the cessation of training and that were associated with normalized left frontal lobe activity.

Wykes et al. used functional MRI to assess activation in response to a working memory task, the n-back, a task in which the partici-pant has to decide whether a visually presented item has appeared before [34]. In six patients treated with an extended program of CRT compared with six patients treated with intensive occupa-tional therapy and six healthy controls assessed at identical time intervals, the results revealed that the CRT-treated patients showed an increase in activation in right inferior frontal gyrus, as well as both right and left occipital lobe, relative to healthy controls, who showed reductions in activation in these same regions during second exposure to the n-back task. In support of the link between reported brain function and the targeted effects of the intervention, the three patients with the largest improvement in out-of-scanner memory test performance after the CRT intervention showed the greatest increases in neural activation.

The largest functional neuroimaging study to date has investigated the relationship between changes in reality monitoring, defined as the ability to distinguish the source of self-generated experience from outside reality, and changes in activation in medial PFC in a group of chronic outpatients with schizophrenia [35]. Patients were randomly assigned to either the cognitive training condition consisting of a hybrid program of Posit Science exercises targeted



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at elementary sensory discrimination tasks, along with training in facial affect identification and theory-of-mind exercises, or a computer games control condition that controlled for interaction with a computer and experimenter contact. Results from 16 patients in the CR condition and 15 patients in the computer games control condition revealed that: CR-treated participants showed improved performance on a measure of reality monitoring that was distinct from the skills taught in the intervention; there was a significant increase in medial PFC activity during performance of the task after the CR training; there was a significant association between the level of medial PFC activity and task performance; and greater activation levels in the medial PFC at the termination of training were linked to better social functioning as measured 6 months after the cessation of training in the CR group, but not the control group.

To date, just one study has investigated the impact of cogni-tive training procedures on reduction in loss of gray matter that occurs as a function of the disease process. In this study, Eack et al. evaluated 53 stabilized outpatients with schizophrenia or schizo- affective disorder within 8 years of psychotic symptom onset (mean = 3.22 years) [36]. Participants were randomly assigned to either the CET intervention selected for this study or an active supportive therapy control and were scanned on an annual basis. Voxel-based morphometric analyses using mixed-effects modeling showed three primary rates of differential gray matter change between patients who received CET versus those who were assigned to the control condition: patients in the control condi-tion showed loss of gray matter volume in the parahippocampal and fusiform gyrus, patients in the CET showed preservation of volumes in this area across the 2-year follow-up period, and even a differential increase in gray matter in the left amygdala gray matter volume. These effects were greatest at the 2-year follow-up assessment and cognitive improvements were associated with struc-tural changes. Neurobiological findings mediated the relationship between the experimental intervention and cognitive measures, and effects were maintained even after controlling for key variables such as medication adherence, and demographic and illness factors. Importantly, some neural regions thought to be crucial in terms of the neurobiological basis of cognitive deficits in schizophrenia (dorsolateral PFC) did not show a differential effect of tissue loss in the two groups.

Expert commentaryTo date, a wide range of cognitive interventions have been devel-oped to address deficits in neurocognition in schizophrenia that are thought to be rate-limiting with respect to successful commu-nity function. These methods differ in terms of whether they place a focus on restorative, drill-and-practice training, teach strategies that circumvent cognitive deficits, or represent hybrid programs that consist of a mix of these approaches and that may also include accompanying training in more molar social cognitive and social skills. Results have revealed strong support for moderate (approxi-mately 0.5 SD) [9] improvements on measures of neurocognitive function distinct from the tasks trained as part of specific remedia-tion protocols, and that these effects generalize to function. These

findings are important in that they suggest that these training protocols are producing improvements in the underlying neuro-cognitive skills necessary to successfully complete neurocognitive tasks, rather than teaching skills for each specific test, and that these skills are being effectively implemented in everyday life tasks. These findings are also remarkable given the wide differ-ences in patient sample composition, method of remediation, and duration and intensity of intervention administration in studies in this research area.

However, there are several areas of concern that the field needs to address to be accepted as a front-line evidence-based prac-tice. First, the multitude of different strategies that have been used to intervene with cognitive deficits make it unclear which inter-ventions are most effective. These differences in methods in the CR literature have been identified by opinion leaders in the field as a crucial limitation of this treatment research area to date. Indeed, the most recent Patient Outcomes Research Team psychosocial treatment recommendations, conducted in consulta-tion with an expert mental health psychosocial advisory board, concluded that, “…while the literature to date provides a founda-tion for further research, more work is needed before a concrete recommendation for cognitive remediation can be offered to the field. There are … principal considerations underlying this conclusion ... that the variation among cognitive remediation models and programs is too great to allow identification of key elements of the intervention…” [38].

Second, we note that the specificity of these reported effects remain unclear. Two studies in which CR interventions were com-pared with tightly matched control conditions including similar levels of supportive clinician contact, and in which study patients were administered an array of rehabilitation services, reduced the advantage of CR over control treatment substantially [38,39]. However, other studies that have compared effects of CR with control conditions consisting of active rehabilitation inter-ventions such as supported employment [39], enhanced supportive therapy [25] and work therapy [11] have not shown these types of nonspecific effects.

Third, while there has been an undeniable growth in work in this area over the past 5 years, a continued limitation in the field is the still small number of studies assessing the generalization of cognitive training effects to outcome measures distal from the locus of the remediation intervention. In the Wykes et al. meta-analysis [9], 18 studies included functional outcome measures and these measures varied widely in terms of whether they were clinician-rated, performance-based (based on a laboratory assessment of life or social skills) or global ratings of function. It seems highly unlikely that CR interventions would produce equivalent effects on such a variety of outcome measures that probably bear such different relationships to neurocognitive functioning. To enhance our understanding of mechanisms of action of remediation interventions, future studies could benefit from utilizing a variety of outcome measures that vary systematically in terms of their putative proximity to the site of the remediation intervention. An example of one classification system of outcome measures is presented in Figure 3.

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As can be seen, in this model, performance-based measures of everyday life and social skill that are administered in a labora-tory could be viewed as intermediary measures, influenced less by cognitive interventions than standardized neuropsychologi-cal measures, but that are more likely to show treatment effects than clinician-rated measures of community function or negative symptoms, which are likely to be influenced by a broader array of social factors. Importantly, this model does not include meas-ures of self-reported life satisfaction and self-esteem as treatment end points, as the relationship between these measures, and changes in performance-based and clinician-rated measures of functional status after rehabilitation interventions remain unclear and even paradoxical in some studies [40]. The effects of CR on self-reported quality of life remain largely unknown and should be an important focus of future studies.

Five-year viewOver the next 5 years, a crucial goal for the field will be to gain better insight into the source of differences in response to CR in schizophrenia, and to use this insight to build more efficacious CR interventions. While current data suggest that attention, moti-vation, clinician skill and ‘brain reserve’ play a role in treatment response, the specific parameters within which these factors affect treatment remain ill-understood and, with the exception of ‘brain reserve’, it remains unclear to what extent these factors are specific

to CR. The role of phase of illness will be a crucial area of future inquiry. Initial reports regarding the neuroprotective effects of CR are all derived from patients in an early-phase illness and it remains unclear whether effects are evident in patients with a chronic illness course. The relationship between neuroscience (specifically neuro-imaging methods and research on brain plasticity) and CR has been highly profitable to date, and will be expected to grow in the next 5 years. Lastly, given the observed overlap in CR strategies in the complex interventions discussed in this paper, examining elements within each of these CR interventions to determine the most ‘active’ ingredients of these interventions will be essential for construction of the next generation of CR interventions for producing the most efficacious treatments for the largest number of patients. These research findings will also help to support the establishment of CR as an evidence-based practice for broad use in schizophrenia.

Financial & competing interests disclosureThis work was supported by grants K08 MH-69888 from the National Institute of Mental Health (NIMH), R01 DA-030819 (Lerman and Loughead, PIs) from the National Institute of Drug Abuse, and a NARSAD Young Investigator Award. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Outcome measures

Cognitive remediation training tasks

Cognitive measures distinct from trainingtasks

Social cognitivemeasures (e.g.,facial affect recognition,theory-of-mind andattributional bias)

Capacity measures of interpersonal and daily living skill

Psychosocial function measures and negativesymptoms

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Figure 3. A proposed organization for outcome measures in studies of cognitive remediation to help provide insight into the mechanisms of action of treatment.

Key issues

• Cognitive remediation (CR) in schizophrenia produces 0.5 standard deviation (SD) improvements in measures of cognition.

• CR also produces nearly 0.5 SD improvements on measures of function.

• The effects of CR on function are greater when CR is offered as part of broader psychosocial rehabilitation interventions.

• There are many approaches to CR that can be grouped broadly into the following groups of methods with a focus on: restoration of cognitive function through task practice; teaching strategies for bypassing cognitive deficits; and hybrid interventions that offer a combination of these approaches and/or offer these approaches in concert with social cognitive and/or social skills training.

• Studies of prediction of response to CR suggest that attention and verbal memory, along with motivation, are most closely related to positive outcomes. In the early phase of illness, there is some evidence that temporal and frontal brain volumes predict response to social cognitive outcome measures during CR, but only at shorter test–retest intervals.

• Increases in brain activation have been reported in the inferior frontal and occipital regions during working memory tasks in patients showing the greatest benefit from CR.

• Increases in medial prefrontal region activation have been reported on social cognitive probe tasks after CR training.

• In early-phase schizophrenia, temporal lobe volume loss may be mitigated by the effects of CR.



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ReferencesPapers of special note have been highlighted as:•ofinterest••ofconsiderableinterest

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2 Green MF, Kern RS, Heaton RK. Longitudinal studies of cognition and functional outcome in schizophrenia: implications for MATRICS. Schizophr. Res. 72(1), 41–51 (2004).

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• Anexcellentexampleofalarge-scaletrialofahybridCRprogramthatincludesbothCRandsocialcognitivetrainingelements.

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