CanJPsychiatry 2014;59(1):5–12
In Review
Neurocognition: Clinical and Functional Outcomes in Schizophrenia Martin Lepage, PhD1; Michael Bodnar, PhD2; Christopher R Bowie, PhD3 1
Professor, Department of Psychiatry, McGill University, Montreal, Quebec. Correspondence: Douglas Mental Health University Institute, Frank B Common Pavilion, 6875 LaSalle Boulevard, Verdun, QC H4H 1R3; [email protected].
2
Research Associate, Douglas Mental Health University Institute, Montreal, Quebec.
3
Associate Professor, Department of Psychology, Queen’s University, Kingston, Ontario.
Key Words: neurocognition, remission, clinical outcome, functional outcome, schizophrenia, impairment Received and accepted June 2013.
Schizophrenia is characterized by significant heterogeneity in outcome. The last decades have witnessed a significant interest in identifying factors that can moderate or influence clinical and functional outcomes in people with schizophrenia. One factor of particular interest is neurocognition, as performance on various measures of cognitive abilities, such as memory, attention, and executive functions, have been consistently related to functional outcome and, to a lesser extent, clinical outcome. This review aims to provide an up-todate description of recent studies examining the association between neurocognition and clinical and (or) functional outcomes. In the first section, studies examining neurocognitive performance in relation to clinical outcome are examined. When clinical outcome is defined dichotomously (for example, comparing remitted and nonremitted), verbal memory performance consistently exhibits a strong association with clinical status, with the poor outcome group showing the largest deficits. In the second section, studies exploring the relation between neurocognition and various dimensions of functional outcome are reviewed. These dimensions include independent living, social functioning, and vocational functioning, among others. Again, a strong link between neurocognitive deficits and impairments in several aspects of functioning clearly emerges from this review. Finally, several measurement issues are discussed that pertain to the need to standardize definitions of clinical and (or) functional outcomes, the importance of defining cognitive domains consistently across studies, and distinguishing between one’s competence to perform tasks and what one actually does in everyday life. Addressing these measurement issues will be key to studies examining the development of effective interventions targeting neurocognitive functions and their impact on clinical and functional outcomes. WWW
Neurocognition : résultats cliniques et fonctionnels en schizophrénie La schizophrénie se caractérise par l’hétérogénéité significative des résultats. Les dernières décennies ont vu naître un intérêt marqué pour l’identification des facteurs qui peuvent modérer ou influencer les résultats cliniques et fonctionnels des personnes souffrant de schizophrénie. Un facteur particulièrement intéressant est la neurocognition, car la performance à diverses mesures des capacités cognitives, comme la mémoire, l’attention et les fonctions exécutives, a été liée de façon constante à un résultat fonctionnel et, dans une moindre mesure, à un résultat clinique. Cette revue entend offrir une description à jour des études récentes qui examinent l’association entre la neurocognition et les résultats cliniques et (ou) fonctionnels. La première section examine les études sur la performance neurocognitive en relation avec les résultats cliniques. Lorsque le résultat clinique est défini dichotomiquement (par exemple, en comparant rémittent et non rémittent), la performance de la mémoire verbale montre de façon constante une forte association avec l’état clinique, et le groupe ayant le moins bon résultat démontre les déficits les plus lourds. À la deuxième section, les études explorant la relation entre neurocognition et diverses dimensions du résultat fonctionnel sont examinées. Ces dimensions sont notamment la vie autonome, le fonctionnement social, et le fonctionnement au travail. Aussi, se dégage de cette revue un fort lien entre incapacités et déficits neurocognitifs dans divers aspects du fonctionnement. Sont finalement discutées plusieurs questions de mesures qui ont trait au besoin de standardiser les définitions des résultats cliniques et (ou) fonctionnels, à l’importance de définir les domaines cognitifs de www.TheCJP.ca
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In Review
façon uniforme dans toutes les études, et à la distinction entre l’habileté d’une personne à exécuter les tâches et ce qu’elle accomplit réellement dans la vie quotidienne. Aborder ces questions de mesures sera essentiel pour les études qui examinent l’élaboration d’interventions efficaces ciblant les fonctions neurocognitives et leur effet sur les résultats cliniques et fonctionnels.
S
chizophrenia is no longer considered a debilitating and deteriorating disorder. Although some studies show recovery rates as low as 28%, others have shown rates to be as high as 77% (recovery as defined by the Bleuler symptom scale).1 However, this variable response among the people affected, along with the current inability to predict an individual response early on,2 has led to a trial-and-error treatment strategy that includes ongoing assessments and the careful monitoring of the clinical response and any adverse side effects.3 Together, this has fuelled one of the great challenges of research in schizophrenia—to better understand the heterogeneity of outcome following an FEP. But what do outcome and recovery actually mean? There are 2 aspects to outcome: functional and clinical. Functional outcome can be defined as (or measured by), for example, quality of life, whether one is employed, the ability to live independently, or the ability to plan and alter basic daily activities.4–6 Alternatively, clinical outcome focuses more on psychopathology and has been defined as, for example, a therapeutic response to neuroleptics,7 persistent positive8,9 or negative symptoms,10,11 or achieving a remitted state.12,13 Taken together, Emsley et al stated, “recovery is both an outcome and a process.”13 p 117 However, there is a lack of consensus and consistency on how recovery is defined but the overall concept includes improving, both clinically and functionally.13,14 Past research has explored markers related to recovery from both the clinical and functional aspects. Briefly, there are numerous markers associated with a poor outcome, which include: being male, having a younger age of onset, poorer insight, longer duration of untreated psychosis, poorer premorbid social adjustment, and higher negative symptoms.15–17 A final marker of outcome, which has recently become a key area of research in schizophrenia, is Abbreviations CNTRICS
Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia
CPT
Continuous Performance Task
FEP
first-episode psychosis
FES
first-episode schizophrenia
MATRICS
Measurement and Treatment Research to Improve Cognition in Schizophrenia
RAVLT
Rey Auditory Verbal Learning Test
TAP
Test of Attentional Performance
TMT
Trail-Making Test
WAIS
Wechsler Adult Intelligence Scale
WCST
Wisconsin Cart Sorting Task
WMS
Wechsler Memory Scale
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Clinical Implications •
Neurocognitive deficits represent a core symptom of schizophrenia, with verbal memory consistently reported as one of the most impaired cognitive domains.
•
Specific neuropsychological measures (for example, the Logical Memory subtest of the WMS or the RAVLT) may be more sensitive in identifying relations with outcome.
•
Neurocognitive deficits in schizophrenia are more responsible than clinical symptoms for the broadly and persistently observed impairments in functioning.
Limitations •
Research studies do not apply consistent definitions for either clinical or functional outcome, making comparisons and conclusions drawn between studies more difficult.
•
Several measurement issues have been highlighted. First, cognitive domains are not consistently created using the same neuropsychological tests, making crossstudy comparisons more difficult. Second, the distinction between one’s competence to perform tasks and what one actually does in everyday life is an important one but has received only scant attention so far.
cognition. Disturbed processing in cognition is considered a fundamental symptom of schizophrenia,18,19 with mild cognitive deficits appearing well before the onset of psychosis, followed by a sharp decline in functioning, at or near the FEP, that remains stable into the chronic stages.19 The importance of cognition in relation to outcome in schizophrenia has been recognized with the formation of the MATRICS20,21 and the CNTRICS22 consensus groups, with foundations based on improving outcome by enhancing cognitive ability. Our review will explore studies that have explored neurocognitive function in relation to both clinical and functional outcome. The identification of specific neurocognitive markers related to outcome will help improve our understanding of the heterogeneity of outcome and, invariably, schizophrenia itself.
Clinical Outcome and Neurocognition Defining Clinical Outcome
Clinical outcome is generally defined using either a per cent reduction in symptom totals (from 20% to more than 50% reduction)23–27 or a minimum cut-off criterion for specific symptoms9,12,28,29 (or sometimes as a mix of the 2 definitions together30,31). This variability in defining clinical outcome, or the lack of any clear definition, has made it extremely difficult to draw cross-study comparisons.32 Recently, this began to change with the introduction of the consensus definition for remission in schizophrenia proposed in 2005.12,32 Although achieving remission is an important, but www.LaRCP.ca
Neurocognition: Clinical and Functional Outcomes in Schizophrenia
Table 1 Definitions used for defining clinical outcome Study (year)
Sample description
Definition
Meesters et al37 (2012)
Chronic; 20 R and 47 NR
Andreasen12; no hospitalization in past 6 months
Yun da et al42 (2011)
Chronic; 26 R and 28 NR
Andreasen12
Hofer et al (2011)
Chronic and FES; 62 R and 78 NR
Andreasen12; no time component
Brissos et al40 (2011)
Chronic; 23 R and 53 NR
Andreasen12; no hospitalization in past 6 months
Bodnar et al (2011)
FES; 42 R and 81 NR
Andreasen12; no time component
Montreuil et al45 (2010)
FEP; 18 good and 27 poor
Mild (≤2) on all global SAPS; moderate (≤3) on all global SANS; no time component
Li et al43 (2010)
Chronic; 33 R and 57 NR
Andreasen12; no time component
Eberhard et al (2009)
Chronic; 36 R and 52 NR
Andreasen12; 12-month time component; no hospitalization in past 12 months
Ciudad et al44 (2009)
Chronic; 441 R and 537 NR (patient-rated); 331 R and 411 NR (caregiver-rated)
Andreasen12; no time component
Bodnar et al34 (2008)
FEP; 73 good and 78 poor
Mild (≤2) on all global SAPS; moderate (≤3) on all global SANS; no time component
Holthausen et al38 (2007)
Chronic; 29 R and 86 NR
Period without any psychotic symptom that would justify a score of moderate (≥4) on the PANSS
Helldin et al35 (2006)
Chronic; 76 R and 135 NR
Andreasen12; no time component
Joober et al (2002)
Chronic; 36 responders and 39 nonresponders
Complete or quasi-complete disappearance of schizophrenic symptoms, based on the clinical evaluation and hospital records
39
36
41
7
NR = nonremitted; PANSS = Positive and Negative Symptoms Scale; R = remitted; SANS = Scale for the Assessment of Negative Symptoms; SAPS = Scale for the Assessment of Positive Symptoms
not necessary, step in the recovery process,12 the following review of neurocognition and clinical outcome will not be limited to studies only investigating remission, per se, but to more recent studies that explicitly compared 2 clinical outcome groups. Table 1 lists the articles included, along with the definition employed. Our focus here is to highlight more recent findings linking outcome to neuropsychological tests associated with the 7 cognitive domains identified by the MATRICS (verbal learning and memory, visual learning and memory, working memory, speed of processing, reasoning and problem solving, attention, and social cognition).20,33
Verbal Learning and Memory
To begin, neuroleptic nonresponders were found to be more impaired on the Logical Memory and Verbal Pairs subtests of the WMS.7 Next, embracing both positive and negative symptoms, patients with FEP with a poorer clinical outcome also showed significant impairments in the Logical Memory subtests.34 Related more to remission, immediate memory, learning, and long-term memory from the RAVLT have been shown to be more compromised in nonremitted people with chronic schizophrenia.35 Moreover, nonremitted FES patients also exhibit significant deficits on the Logical Memory subtests of the WMS.36 Although these findings appear quite robust, 1 study did find a trend-level difference between remitted and nonremitted patients on the RAVLT Learning subtest37 and 3 studies—1 exploring clinical outcome38 and 2 examining remission39,40—did not find significant differences in measures of verbal memory between outcome groups. Interestingly, the 3 studies that www.TheCJP.ca
did not find any group differences all used the California Verbal Learning Test, which differs from other list-learning tasks by including semantically-related words, the encoding of which benefits from executive functioning. This may suggest purer measures of verbal memory that do not include an executive component may be more sensitive in identifying group differences in relation to clinical outcome.
Visual Learning and Memory
Only one study7 revealed nonresponders performed worse on the Rey-Osterreith Complex Figure Test (copy and 30-minute delayed recall). Although a study by Bodnar et al36 did show trend-level poorer performance in the Visual Reproduction subtests of the WMS in patients with nonremitting FES, this trend disappeared when all patients with FEP were included. Moreover, in a previous study from this laboratory,34 no group differences were found in relation to clinical outcome when examining the entire sample with FEP or the subsample of patients with FEP. Finally, people with nonremitted and remitted schizophrenia displayed no differences on the Benton Visual Retention Test.39 Although not related to memory, per se, people with nonremitted schizophrenia were shown to have significant impairments on the Elithorn’s maze test (visuospatial ability)41; yet no group differences in visuospatial ability (picture completion and Block Design subtests of the WAIS) were identified between neuroleptic responders and nonresponders.7
Working Memory
People with nonremitted schizophrenia have been shown to have significant impairments on the Letter–Number The Canadian Journal of Psychiatry, Vol 59, No 1, January 2014 W 7
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Sequencing subtest of the WAIS.35 In support of this finding, patients with poor clinical outcome FEP showed worse performance on the Digit Span subtest of the WAIS and the Spatial Span subtest of the WMS; results were significant for the entire FEP sample and the FES subsample.34 However, in a follow-up report by Bodnar et al,36 only a trend-level difference was reported when examining remission in the entire FEP sample, with no significant differences reported in the FES subsample. Three other studies also revealed no significant deficit in people with nonremitted schizophrenia when using the Digit Span subtest37,40 or the Working Memory subtest of the TAP.39
Speed of Processing
Only one study35 revealed nonremitted people with schizophrenia performed worse in this domain as measured with the TMT-A. The remaining studies found no significant between-group differences when using the TMT-A,37 the TMT-A and mental tracking of the WMS,40 or the TMT-A and Digit Symbol subtest of the WAIS.34,36
Reasoning and Problem Solving
images) and Social Translation (an ability to recognize changes in behavioural meaning) subtests.
Summary: Clinical Outcome
In brief, verbal memory and social cognitive deficits appear as the more robust markers of clinical outcome in schizophrenia; the other 5 domains appear to show a more ambiguous relation with clinical outcome. This is not to say these 5 domains are not related to clinical outcome but perhaps specific tests within each domain may be, as it was apparent for both the verbal memory and social cognition domains. Future outcome studies need to define the cognitive domains more consistently; for example, measure the domains using only CogState Schizophrenia Battery46,47 or the MATRICS Consensus Cognitive Battery48,49 as both batteries show high cross-validity.46 With consistently defined cognitive domains and consistent definitions of clinical outcome, more definitive results would be evident. Finally, the use of a categorical approach (between 2 groups of patients within 1 sample) may be more reliable and more sensitive for detecting markers of outcome as a linear relation is not assumed.
People with nonremitted schizophrenia have been shown to display significant impairments on the TMT-B35,37 and the WCST (categories).35 In contrast, there were 6 studies that did not find any significant between-group differences: 2 using the WCST,7,39 one using the TMT-B,40 one using the Stroop colour test,37 and 2 using the TMT-B and Block Design subtest of the WAIS.34,36 In addition, Yun da et al42 revealed patient groups did not differ on a set-shifting task (Intradimensional–Extradimensional Shift task) of the Cambridge Neuropsychological Test Automated Battery.
Functional Outcome and Neurocognition
Attention
Estimates of medical comorbidities range above 50% among people with schizophrenia50 and contribute to a reduced lifespan of up to 25 years51 Some of these comorbidities are complicated by deficits in self-care. Overall cognitive functioning is robustly associated with poor self-care in late life52,53 and predictive of deteriorating ability to perform routine activities of daily living.54,55 The precise role that cognition plays in self-care and health problems needs to be addressed in future work; this is a relatively understudied area.
People with nonremitted schizophrenia have been shown to display significant deficits in the CPT (levels 1, 2, and 3).35 Interestingly, using the TAP, nonremitted patients displayed significant impairments in optical vigilance but not in phasic alertness.39 Moreover, trend-level poorer performance on the d2 Test of Attention was shown in poor clinical outcome and patients with nonremitted FEP; poorer attention was not apparent when examining the subsample of patients with FES.34,36 Finally, no significant betweengroup differences were found on the CPT and Digit Span of the WAIS7 or on the divided attention and go–no-go tasks of the TAP.43
Social Cognition
Using both a patient- and caregiver-rated measure of social cognition, people with nonremitted schizophrenia display significant impairments on measures of perceived difficulty to manage specific tasks or situations.44 In support of this finding, Montreuil et al45 revealed that patients with poor clinical outcome FEP also display significant difficulties in overall social cognition. As revealed by the authors, their result was driven by the Cartoon Prediction subtest of the Four Factor Social Intelligence test—a test that measures the ability to predict social consequences. They also identified trend-level differences in the Expression Grouping (an ability to abstract common attributes from different expressive 8 W La Revue canadienne de psychiatrie, vol 59, no 1, janvier 2014
The tremendous increase in attention paid to neurocognitive impairments in the past several years is largely driven by the findings that this feature of schizophrenia is more responsible than clinical symptoms for the broadly and persistently observed impairments in functioning.5 Impairments are present in multiple areas, and most have a robust relation with cognition, though sometimes this relation is quite complicated.
Self-Care and Medical Comorbidities
Independent Living
Waves of deinstitutionalization have resulted in a reduction of inpatient hospital beds, but these efforts have been followed by insufficient work to promote true independent living for people with schizophrenia.56 The minority of people with schizophrenia live independently and are financially responsible for their residence,57 and many people are now living in long-term community housing that does not sufficiently address their needs.58 Paradoxically, a major driving force behind hospital discharge, reduction of psychotic symptoms, is poorly correlated with independent living skills and status. In clinically stable outpatients, most cognitive domains are predictive of the skills associated with independent living,4,59,60 while verbal memory ability is a strong predictor of independent living among stable outpatients.61 In an interesting study that highlights the www.LaRCP.ca
Neurocognition: Clinical and Functional Outcomes in Schizophrenia
reciprocal nature of the cognition–living status relation, Caplan et al62 found that formerly homeless people demonstrated improved sustained attention and verbal memory on moving to a residence; further, those randomized to supported housing had greater executive function improvement than those randomized to independent apartments. These conclusions are supported by a recent study that found independent living status in outpatients with schizophrenia to moderate the relation between their abilities and their performance in functioning.63 These studies underscore the need to appreciate the dynamic relation between cognition and living status for people transitioning among residential placements and as they acclimate to new settings.
Medication and Illness Management
Closely related to health status and self-care are medication and illness management. Schizophrenia is associated with poor compliance with medication regimens.64 Although cognitive performance is the strongest predictor of poor competence in managing complex medication regiments,65 and, of course, with high rates of polypharmacy and comorbid medical conditions, there is certainly complexity, relations with adherence differ, with some studies finding higher cognitive ability predicting nonadherence.66 Difficulties with recognition or awareness of illness is a hallmark feature of schizophrenia and interacts with medication compliance. Cognitive variables, most notably executive dysfunction, have been associated with poor insight into illness.67,68 People with poorer cognitive abilities, most notably executive functions, are in need of more services,69 yet the clinical reality is complicated because cognitive deficits are associated with poor engagement in services.70 Further, treatment service intensity is preferentially associated with functional improvement during rehabilitation only for people who demonstrate cognitive improvements.71 Thus it appears that cognitive impairments reflect people in most need of services, yet they are associated with the poorest engagement in the services that are most likely to provide benefits to their functioning.
Social and Interpersonal Functioning
As previously mentioned, people with schizophrenia are increasingly living in nonhospital settings, which putatively increases opportunities for social relationships. However, impairment in social functions and relationships remains an issue, with zero or very few friendships as the norm.72 Low marriage and reproductive rates are also observed despite a desire to have relationships.73 Neurocognitive skills are associated with several factors related to successful social outcomes, including impairments in understanding social situations,74 interpersonal problem solving skills,75 communication,76 empathy,77 and aggression.78 Compared with other domains of functioning, the relation of neurocognition to social skills is smaller and more closely associated with negative and depressive symptoms.4 Several investigators are now exploring the many paths to social disability and early evidence suggests that neurocognition has an important indirect role via its influence on social cognitive skills, which appear to be more robust predictors www.TheCJP.ca
of social functions. This is an important area for future study because many people with schizophrenia value friendships,72 and a healthy social network is associated with higher rates of recovery.79
Community Activities and Leisure
Cognitive deficits interfere with the ability of people with schizophrenia to be fully active members of their community by limiting everyday living skills and engagement in activities.80 For many, residence in lessthan-desirable neighbourhoods and restricted financial resources complicate the engagement in community activities. The ability to navigate everyday obstacles and public transportation is limited by cognitive impairments,81 but independent transportation is difficult for people with financial strain and complicated by poorer driving abilities associated with cognitive performance82 and more accidents.83 The ability to plan and execute shopping is also compromised and related to poor executive functions in schizophrenia,84,85 which could have a role in the self-care deficits described above.
Vocational Functioning
Unemployment rates in schizophrenia are exceptionally high, with fewer than 20% returning to work after the FEP.86 On returning to the work force following illness onset, a reduction in status or wages is common.87 Level of productivity at work is diminished and results in increased occupational stress.88 Even people in a supported employment setting are more likely than not to lose their job within the first 6 months of employment.89 Despite this, many reports describe patients who strongly desire work.90 For the many people with chronic mental illness in the previous century, engagement in productive roles was discouraged because of a prevailing philosophy that a return to premorbid role function may increase stress and lead to relapse of clinical symptoms. Indeed, epidemiologic survey research has found that, in the general population, 31% of Canadians considered most days at work to be either “quite a bit stressful” or “extremely stressful.”91 The cognitive impairments of schizophrenia make it important to consider the likelihood of stress resulting from difficulty in effectively processing information and engaging in goaldirected behaviour in the vocational setting. Nevertheless, it is critical to not overlook the stress of being chronically unemployed and appreciate the potential positive effects that work can have when people with schizophrenia are cognitively equipped.92 Work provides a sense of purpose and improves self-esteem.93 Quality of life, sense of satisfaction, self-worth, and self-esteem tend to improve with the commencement of work.94 These intrapersonal experiences associated with work are increasingly recognized as a critical aspect of the recovery process for people experiencing mental illness.95 Objective indicators include reduced rates of hospitalization.96 Among studies that have objectively examined neurocognition and work status, there is consensus for an association between the variables97 and evidence for cognitive functioning as a predictor for later work success.86 Impairments in neurocognition are associated with acute The Canadian Journal of Psychiatry, Vol 59, No 1, January 2014 W 9
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impairments in work at FEP, and these impairments predict long-term disability for most patients. They account for up to 52% of the variance in work outcomes 6 to 9 months after treatment initiation for FEP.98 After 7 years of treatment following the FEP, work outcomes are severely impaired and baseline impairments in processing speed and attention are the strongest predictor of poor work outcomes.99 Importantly, these deficits result in difficulty in acquiring skills in psychosocial rehabilitation, including programs that focus on vocational services.100
functioning have been shown to significantly limit the ability to acquire, retain, or relearn skills necessary for real-world functioning, such as forming relationships and undertaking employment.104 Also, daily problem solving skills have been significantly correlated with processing speed, verbal memory, and working memory.105 To properly understand the link between neurocognition and outcome, more studies need to use similar measures of cognition and outcome to provide reliable and consistent results that can be translated into clinical practice.
Measurement Issues
Acknowledgements
Clearly we have established a strong link between neurocognitive deficits and impairments in several aspects of functioning. As we continue to examine these relations and embark on treatment strategies to improve functioning, several issues related to assessment and design are important to note. A critical measurement issue is the distinction between one’s competence to perform tasks and what one actually does in everyday life. Performance-based assessments, which can be completed in an office or laboratory setting, provide the basis for measuring one’s competence in an environment that is not affected by symptoms, such as depression and motivational impairment, or by extraneous factors, such as lack of opportunity, social networks, or finances. However, these factors do limit the degree to which cognition is associated with real-world functioning.63,80 This distinction between competence and performance is also critical for treatment studies. The long-standing nature of both neurocognitive and functional impairments may make it unreasonable to expect a direct transfer of cognitive change to functional change. In fact, in a recent study,101 treatment effects from cognitive remediation produced significant transfer to functioning when subjects also received supplemental skills training. As we start to examine more opportunities to improve functioning via cognitive rehabilitation methods, performance-based measures of competence, which are proximal to cognition, may be more likely to change in a short trial, but realworld behaviour may require more time and supplemental rehabilitative efforts.
Conclusions
Cognitive deficits represent a core symptom of schizophrenia and are strongly related to not only the illness itself but also eventual recovery. People with schizophrenia display significant cognitive impairments, with deficits in verbal memory consistently reported as one of the most impaired cognitive domains.18,19,102 In addition, as highlighted by this review, verbal memory appears to be one of the strongest markers of outcome. However, all studies on cognition and outcome do not answer the question of whether patients with good outcome display better cognitive functioning, or if patients with a higher level of cognitive performance are more likely to have a better prognosis.17 Nevertheless, improving treatments for cognitive symptoms in schizophrenia is a key area in future research and drug developments efforts, as these symptoms are believed to affect the functional abilities of these patients.103 For example, impairments in working memory and executive 10 W La Revue canadienne de psychiatrie, vol 59, no 1, janvier 2014
Dr Lepage received a grant (68961) in support of this research from the Canadian Institutes for Health Research. Dr Bowie has received funding as a consultant to Abbott Laboratories and AbbVIE, and as a speaker for Janssen Cilag. The Canadian Psychiatric Association proudly supports the In Review series by providing an honorium to the authors.
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Neurocognition: Clinical and Functional Outcomes in Schizophrenia 17. Lambert M, Karow A, Leucht S, et al. Remission in schizophrenia: validity, frequency, predictors, and patients’ perspective 5 years later. Dialogues Clin Neurosci. 2010;12(3):393–407. 18. Heinrichs RW, Zakzanis KK. Neurocognitive deficit in schizophrenia: a quantitative review of the evidence. Neuropsychology. 1998;12(3):426–445. 19. Mesholam-Gately RI, Giuliano AJ, Goff KP, et al. Neurocognition in first-episode schizophrenia: a meta-analytic review. Neuropsychology. 2009;23(3):315–336. 20. Marder SR, Fenton W. Measurement and Treatment Research to Improve Cognition in Schizophrenia: NIMH MATRICS initiative to support the development of agents for improving cognition in schizophrenia. Schizophr Res. 2004;72(1):5–9. 21. Green MF, Nuechterlein KH, Gold JM, et al. Approaching a consensus cognitive battery for clinical trials in schizophrenia: the NIMH-MATRICS conference to select cognitive domains and test criteria. Biol Psychiatry. 2004;56(5):301–307. 22. Ranganath C, Minzenberg MJ, Ragland JD. The cognitive neuroscience of memory function and dysfunction in schizophrenia. Biol Psychiatry. 2008;64(1):18–25. 23. Szymanski S, Masiar S, Mayerhoff D, et al. Clozapine response in treatment-refractory first-episode schizophrenia. Biol Psychiatry. 1994;35(4):278–280. 24. Kopala LC, Fredrikson D, Good KP, et al. Symptoms in neurolepticnaive, first-episode schizophrenia: response to risperidone. Biol Psychiatry. 1996;39(4):296–298. 25. Sanger TM, Lieberman JA, Tohen M, et al. Olanzapine versus haloperidol treatment in first-episode psychosis. Am J Psychiatry. 1999;156(1):79–87. 26. Emsley RA. Risperidone in the treatment of first-episode psychotic patients: a double-blind multicenter study. Risperidone Working Group. Schizophr Bull. 1999;25(4):721–729. 27. Yap HL, Mahendran R, Lim D, et al. Risperidone in the treatment of first episode psychosis. Singapore Med J. 2001;42(4):170–173. 28. Amminger GP, Resch F, Mutschlechner R, et al. Premorbid adjustment and remission of positive symptoms in first-episode psychosis. Eur Child Adolesc Psychiatry. 1997;6(4):212–218. 29. Liberman R, Kopelowicz A, Venture J, et al. Operational criteria and factors related to recovery from schizophrenia. Int Rev Psychiatry. 2002;14:256–272. 30. Manchanda R, Malla A, Harricharan R, et al. EEG abnormalities and outcome in first-episode psychosis. Can J Psychiatry. 2003;48(11):722–726. 31. Lieberman JA, Phillips M, Gu H, et al. Atypical and conventional antipsychotic drugs in treatment-naive first-episode schizophrenia: a 52-week randomized trial of clozapine vs chlorpromazine. Neuropsychopharmacology. 2003;28(5):995–1003. 32. Gorwood P, Peuskens J. Setting new standards in schizophrenia outcomes: symptomatic remission 3 years before versus after the Andreasen criteria. Eur Psychiatry. 2012;27(3):170–175. 33. Nuechterlein KH, Barch DM, Gold JM, et al. Identification of separable cognitive factors in schizophrenia. Schizophr Res. 2004;72(1):29–39. 34. Bodnar M, Malla A, Joober R, et al. Cognitive markers of shortterm clinical outcome in first-episode psychosis. Br J Psychiatry. 2008;193(4):297–304. 35. Helldin L, Kane JM, Karilampi U, et al. Remission and cognitive ability in a cohort of patients with schizophrenia. J Psychiatr Res. 2006;40(8):738–345. 36. Bodnar M, Harvey P-O, Malla A, et al. The parahippocampal gyrus as a neural marker of early remission in first-episode psychosis: a voxel-based morphometry study. Clin Schizophr Relat Psychoses. 2011;4(4):217–228. 37. Meesters PD, Schouws S, Stek M, et al. Cognitive impairment in late life schizophrenia and bipolar I disorder. Int J Geriatr Psychiatry. 2013;28(1):82–90; Epub 2012 Mar 12. 38. Holthausen EA, Wiersma D, Cahn W, et al. Predictive value of cognition for different domains of outcome in recent-onset schizophrenia. Psychiatry Res. 2007;149(1–3):71–80. 39. Hofer A, Bodner T, Kaufmann A, et al. Symptomatic remission and neurocognitive functioning in patients with schizophrenia. Psychol Med. 2011;41(10):2131–2139. www.TheCJP.ca
40. Brissos S, Dias VV, Balanza-Martinez V, et al. Symptomatic remission in schizophrenia patients: relationship with social functioning, quality of life, and neurocognitive performance. Schizophr Res. 2011;129(2–3):133–136. 41. Eberhard J, Levander S, Lindstrom E. Remission in schizophrenia: analysis in a naturalistic setting. Compr Psychiatry. 2009;50(3):200–208. 42. Yun da Y, Hwang SS, Kim Y, et al. Impairments in executive functioning in patients with remitted and non-remitted schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(4):1148–1154. 43. Li CT, Su TP, Chou YH, et al. Symptomatic resolution among Chinese patients with schizophrenia and associated factors. J Formos Med Assoc. 2010;109(5):378–388. 44. Ciudad A, Alvarez E, Bobes J, et al. Remission in schizophrenia: results from a 1-year follow-up observational study. Schizophr Res. 2009;108(1–3):214–222. 45. Montreuil T, Bodnar M, Bertrand MC, et al. Social cognitive markers of short-term clinical outcome in first-episode psychosis. Clin Schizophr Relat Psychoses. 2010;4(2):105–114. 46. Pietrzak RH, Olver J, Norman T, et al. A comparison of the CogState Schizophrenia Battery and the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Battery in assessing cognitive impairment in chronic schizophrenia. J Clin Exp Neuropsychol. 2009;31(7):848–859. 47. Maruff P, Thomas E, Cysique L, et al. Validity of the CogState brief battery: relationship to standardized tests and sensitivity to cognitive impairment in mild traumatic brain injury, schizophrenia, and AIDS dementia complex. Arch Clin Neuropsychol. 2009;24(2):165–178. 48. Nuechterlein KH, Green MF, Kern RS, et al. The MATRICS Consensus Cognitive Battery, part 1: test selection, reliability, and validity. Am J Psychiatry. 2008;165(2):203–213. 49. Kern RS, Nuechterlein KH, Green MF, et al. The MATRICS Consensus Cognitive Battery, part 2: co-norming and standardization. Am J Psychiatry. 2008;165(2):214–220. 50. Chwastiak LA, Rosenheck RA, McEvoy JP, et al. Interrelationships of psychiatric symptom severity, medical comorbidity, and functioning in schizophrenia. Psychiatr Serv. 2006;57(8):1102–1109. 51. Tiihonen J, Lonnqvist J, Wahlbeck K, et al. 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study). Lancet. 2009;374(9690):620–627. 52. Evans JD, Heaton RK, Paulsen JS, et al. The relationship of neuropsychological abilities to specific domains of functional capacity in older schizophrenia patients. Biol Psychiatry. 2003;53(5):422–430. 53. Harvey PD, Sukhodolsky D, Parrella M, et al. The association between adaptive and cognitive deficits in geriatric chronic schizophrenic patients. Schizophr Res. 1997;27(2–3):211–228. 54. Velligan DI, Bow-Thomas CC, Mahurin RK, et al. Do specific neurocognitive deficits predict specific domains of community function in schizophrenia? J Nerv Ment Dis. 2000;188(8):518–524. 55. Friedman JI, Harvey PD, Coleman T, et al. Six-year follow-up study of cognitive and functional status across the lifespan in schizophrenia: a comparison with Alzheimer’s disease and normal aging. Am J Psychiatry. 2001;158(9):1441–1448. 56. Hegarty JD, Baldessarini RJ, Tohen M, et al. One hundred years of schizophrenia: a meta-analysis of the outcome literature. Am J Psychiatry. 1994;151(10):1409–1416. 57. Mausbach BT, Harvey PD, Goldman SR, et al. Development of a brief scale of everyday functioning in persons with serious mental illness. Schizophr Bull. 2007;33(6):1364–1372. 58. Bowie CR, Fallon C, Harvey PD. Convergence of clinical staff ratings and research ratings to assess patients with schizophrenia in nursing homes. Psychiatr Serv. 2006;57(6):838–843. 59. Keefe RS, Poe M, Walker TM, et al. The relationship of the Brief Assessment of Cognition in Schizophrenia (BACS) to functional capacity and real-world functional outcome. J Clin Exp Neuropsychol. 2006;28(2):260–269. 60. Heinrichs RW, Ammari N, Miles AA, et al. Cognitive performance and functional competence as predictors of community independence in schizophrenia. Schizophr Bull. 2010;36(2):381–387. 61. Shamsi S, Lau A, Lencz T, et al. Cognitive and symptomatic predictors of functional disability in schizophrenia. Schizophr Res. 2011;126(1–3):257–264. The Canadian Journal of Psychiatry, Vol 59, No 1, January 2014 W 11
In Review 62. Caplan B, Schutt RK, Turner WM, et al. Change in neurocognition by housing type and substance abuse among formerly homeless seriously mentally ill persons. Schizophr Res. 2006;83(1):77–86. 63. Gupta M, Bassett E, Iftene F, et al. Functional outcomes in schizophrenia: understanding the competence-performance discrepancy. J Psychiatr Res. 2012;46(2):205–211. 64. Velligan DI, Weiden PJ, Sajatovic M, et al. The expert consensus guideline series: adherence problems in patients with serious and persistent mental illness. J Clin Psychiatry. 2009;70(Suppl 4):1–46; quiz 47–48. 65. Heinrichs RW, Goldberg JO, Miles AA, et al. Predictors of medication competence in schizophrenia patients. Psychiatry Res. 2008;157(1–3):47–52. 66. Perkins DO, Gu H, Weiden PJ, et al. Predictors of treatment discontinuation and medication nonadherence in patients recovering from a first episode of schizophrenia, schizophreniform disorder, or schizoaffective disorder: a randomized, double-blind, flexible-dose, multicenter study. J Clin Psychiatry. 2008;69(1):106–113. 67. Smith TE, Hull JW, Israel LM, et al. Insight, symptoms, and neurocognition in schizophrenia and schizoaffective disorder. Schizophr Bull. 2000;26(1):193–200. 68. Kurtz MM, Tolman A. Neurocognition, insight into illness and subjective quality-of-life in schizophrenia: what is their relationship? Schizophr Res. 2011;127(1–3):157–162. 69. McGurk SR, Mueser KT, Walling D, et al. Cognitive functioning predicts outpatient service utilization in schizophrenia. Ment Health Serv Res. 2004;6(3):185–188. 70. Johansen R, Hestad K, Iversen VC, et al. Cognitive and clinical factors are associated with service engagement in earlyphase schizophrenia spectrum disorders. J Nerv Ment Dis. 2011;199(3):176–182. 71. Brekke JS, Hoe M, Green MF. Neurocognitive change, functional change and service intensity during community-based psychosocial rehabilitation for schizophrenia. Psychol Med. 2009;39(10):1637–1647. 72. Harley EW, Boardman J, Craig T. Friendship in people with schizophrenia: a survey. Soc Psychiatry Psychiatr Epidemiol. 2012;47(8):1291–1299; Epub 2011 Oct 8. 73. MacCabe JH, Koupil I, Leon DA. Lifetime reproductive output over two generations in patients with psychosis and their unaffected siblings: the Uppsala 1915–1929 Birth Cohort Multigenerational Study. Psychol Med. 2009;39(10):1667–1676. 74. Corrigan PW, Nelson DR. Factors that affect social cue recognition in schizophrenia. Psychiatry Res. 1998;78(3):189–196. 75. Zanello A, Perrig L, Huguelet P. Cognitive functions related to interpersonal problem-solving skills in schizophrenic patients compared with healthy subjects. Psychiatry Res. 2006;142(1):67–78. 76. Docherty NM. Cognitive impairments and disordered speech in schizophrenia: thought disorder, disorganization, and communication failure perspectives. J Abnorm Psychol. 2005;114(2):269–278. 77. Shamay-Tsoory SG, Shur S, Harari H, et al. Neurocognitive basis of impaired empathy in schizophrenia. Neuropsychology. 2007;21(4):431–438. 78. Serper M, Beech DR, Harvey PD, et al. Neuropsychological and symptom predictors of aggression on the psychiatric inpatient service. J Clin Exp Neuropsychol. 2008;30(6):700–709. 79. Schon UK, Denhov A, Topor A. Social relationships as a decisive factor in recovering from severe mental illness. Int J Soc Psychiatry. 2009;55(4):336–347. 80. Bowie CR, Reichenberg A, Patterson TL, et al. Determinants of real-world functional performance in schizophrenia subjects: correlations with cognition, functional capacity, and symptoms. Am J Psychiatry. 2006;163(3):418–425. 81. McClure MM, Bowie CR, Patterson TL, et al. Correlations of functional capacity and neuropsychological performance in older patients with schizophrenia: evidence for specificity of relationships? Schizophr Res. 2007;89(1–3):330–338. 82. St Germain SA, Kurtz MM, Pearlson GD, et al. Driving simulator performance in schizophrenia. Schizophr Res. 2005;74(1):121–122. 83. Edlund MJ, Conrad C, Morris P. Accidents among schizophrenic outpatients. Compr Psychiatry. 1989;30(6):522–526.
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84. Laroi F, Canlaire J, Mourad H, et al. Relations between a computerized shopping task and cognitive tests in a group of persons diagnosed with schizophrenia compared with healthy controls. J Int Neuropsychol Soc. 2010;16(1):180–189. 85. Rempfer MV, Hamera EK, Brown CE, et al. The relations between cognition and the independent living skill of shopping in people with schizophrenia. Psychiatry Res. 2003;117(2):103–112. 86. Mueser KT, Becker DR, Wolfe R. Supported employment, job preferences, and job tenure and satisfaction. J Ment Health. 2001;10:411–417. 87. Johnstone EC, Macmillan JF, Frith CD, et al. Further investigation of the predictors of outcome following first schizophrenic episodes. Br J Psychiatry. 1990;157:182–189. 88. Bond GR, Drake RE, Mueser KT, et al. An update on supported employment for people with severe mental illness. Psychiatr Serv. 1997;48(3):335–346. 89. Bond G, Dietzen L, McGrew J, et al. Accelerating entry into supported employment for persons with severe psychiatric disabilities. Rehabil Psychol. 1995;40:91–111. 90. Lehman A. Vocational rehabilitation in schizophrenia. Schizophr Bull. 1995;21:645–656. 91. Statistics Canada. Canadian Community Mental Health Survey: mental health and well-being. Ottawa (ON): Statistics Canada; 2003. 92. McGurk SR, Mueser KT, Pascaris A. Cognitive training and supported employment for persons with severe mental illness: one-year results from a randomized controlled trial. Schizophr Bull. 2005;31(4):898–909. 93. Torrey WC, Mueser KT, McHugo GH, et al. Self-esteem as an outcome measure in studies of vocational rehabilitation for adults with severe mental illness. Psychiatr Serv. 2000;51(2):229–233. 94. Arns PG, Linney JA. Work, self, and life satisfaction for persons with severe and persistent mental disorders. Psychosoc Rehabil J. 1993;17:63–79. 95. Krupa T. Interventions to improve employment outcomes for workers who experience mental illness. Can J Psychiatry. 2007;52(6):339–345. 96. Mueser KT, Becker DR, Torrey WC, et al. Work and nonvocational domains of functioning in persons with severe mental illness: a longitudinal analysis. J Nerv Ment Dis. 1997;185(7):419–426. 97. Hoffmann H, Kupper Z, Zbinden M, et al. Predicting vocational functioning and outcome in schizophrenia outpatients attending a vocational rehabilitation program. Soc Psychiatry Psychiatr Epidemiol. 2003;38(2):76–82. 98. Nuechterlein KH, Subotnik KL, Green MF, et al. Neurocognitive predictors of work outcome in recent-onset schizophrenia. Schizophr Bull. 2011;37(Suppl 2):S33–S40. 99. Sanchez P, Ojeda N, Pena J, et al. Predictors of longitudinal changes in schizophrenia: the role of processing speed. J Clin Psychiatry. 2009;70(6):888–896. 100. Milev P, Ho BC, Arndt S, et al. Predictive values of neurocognition and negative symptoms on functional outcome in schizophrenia: a longitudinal first-episode study with 7-year follow-up. Am J Psychiatry. 2005;162(3):495–506. 101. Bowie CR, McGurk SR, Mausbach B, et al. Combined cognitive remediation and functional skills training for schizophrenia: effects on cognition, functional competence, and real-world behavior. Am J Psychiatry. 2012;169(7):710–718. doi: 10.1176/ appi.ajp.2012.11091337. 102. Toulopoulou T, Murray RM. Verbal memory deficit in patients with schizophrenia: an important future target for treatment. Expert Rev Neurother. 2004;4(1):43–52. 103. Bradford DW, Perkins DO, Lieberman JA. Pharmacological management of first-episode schizophrenia and related nonaffective psychoses. Drugs. 2003;63(21):2265–2283. 104. Lasser RA, Nasrallah H, Helldin L, et al. Remission in schizophrenia: applying recent consensus criteria to refine the concept. Schizophr Res. 2007;96(1–3):223–231. 105. Revheim N, Schechter I, Kim D, et al. Neurocognitive and symptom correlates of daily problem-solving skills in schizophrenia. Schizophr Res. 2006;83(2–3):237–245.
www.LaRCP.ca
In Review
Neurocognition: Clinical and Functional Outcomes in Schizophrenia Martin Lepage, PhD1; Michael Bodnar, PhD2; Christopher R Bowie, PhD3 1
Professor, Department of Psychiatry, McGill University, Montreal, Quebec. Correspondence: Douglas Mental Health University Institute, Frank B Common Pavilion, 6875 LaSalle Boulevard, Verdun, QC H4H 1R3; [email protected].
2
Research Associate, Douglas Mental Health University Institute, Montreal, Quebec.
3
Associate Professor, Department of Psychology, Queen’s University, Kingston, Ontario.
Key Words: neurocognition, remission, clinical outcome, functional outcome, schizophrenia, impairment Received and accepted June 2013.
Schizophrenia is characterized by significant heterogeneity in outcome. The last decades have witnessed a significant interest in identifying factors that can moderate or influence clinical and functional outcomes in people with schizophrenia. One factor of particular interest is neurocognition, as performance on various measures of cognitive abilities, such as memory, attention, and executive functions, have been consistently related to functional outcome and, to a lesser extent, clinical outcome. This review aims to provide an up-todate description of recent studies examining the association between neurocognition and clinical and (or) functional outcomes. In the first section, studies examining neurocognitive performance in relation to clinical outcome are examined. When clinical outcome is defined dichotomously (for example, comparing remitted and nonremitted), verbal memory performance consistently exhibits a strong association with clinical status, with the poor outcome group showing the largest deficits. In the second section, studies exploring the relation between neurocognition and various dimensions of functional outcome are reviewed. These dimensions include independent living, social functioning, and vocational functioning, among others. Again, a strong link between neurocognitive deficits and impairments in several aspects of functioning clearly emerges from this review. Finally, several measurement issues are discussed that pertain to the need to standardize definitions of clinical and (or) functional outcomes, the importance of defining cognitive domains consistently across studies, and distinguishing between one’s competence to perform tasks and what one actually does in everyday life. Addressing these measurement issues will be key to studies examining the development of effective interventions targeting neurocognitive functions and their impact on clinical and functional outcomes. WWW
Neurocognition : résultats cliniques et fonctionnels en schizophrénie La schizophrénie se caractérise par l’hétérogénéité significative des résultats. Les dernières décennies ont vu naître un intérêt marqué pour l’identification des facteurs qui peuvent modérer ou influencer les résultats cliniques et fonctionnels des personnes souffrant de schizophrénie. Un facteur particulièrement intéressant est la neurocognition, car la performance à diverses mesures des capacités cognitives, comme la mémoire, l’attention et les fonctions exécutives, a été liée de façon constante à un résultat fonctionnel et, dans une moindre mesure, à un résultat clinique. Cette revue entend offrir une description à jour des études récentes qui examinent l’association entre la neurocognition et les résultats cliniques et (ou) fonctionnels. La première section examine les études sur la performance neurocognitive en relation avec les résultats cliniques. Lorsque le résultat clinique est défini dichotomiquement (par exemple, en comparant rémittent et non rémittent), la performance de la mémoire verbale montre de façon constante une forte association avec l’état clinique, et le groupe ayant le moins bon résultat démontre les déficits les plus lourds. À la deuxième section, les études explorant la relation entre neurocognition et diverses dimensions du résultat fonctionnel sont examinées. Ces dimensions sont notamment la vie autonome, le fonctionnement social, et le fonctionnement au travail. Aussi, se dégage de cette revue un fort lien entre incapacités et déficits neurocognitifs dans divers aspects du fonctionnement. Sont finalement discutées plusieurs questions de mesures qui ont trait au besoin de standardiser les définitions des résultats cliniques et (ou) fonctionnels, à l’importance de définir les domaines cognitifs de www.TheCJP.ca
The Canadian Journal of Psychiatry, Vol 59, No 1, January 2014 W 5
In Review
façon uniforme dans toutes les études, et à la distinction entre l’habileté d’une personne à exécuter les tâches et ce qu’elle accomplit réellement dans la vie quotidienne. Aborder ces questions de mesures sera essentiel pour les études qui examinent l’élaboration d’interventions efficaces ciblant les fonctions neurocognitives et leur effet sur les résultats cliniques et fonctionnels.
S
chizophrenia is no longer considered a debilitating and deteriorating disorder. Although some studies show recovery rates as low as 28%, others have shown rates to be as high as 77% (recovery as defined by the Bleuler symptom scale).1 However, this variable response among the people affected, along with the current inability to predict an individual response early on,2 has led to a trial-and-error treatment strategy that includes ongoing assessments and the careful monitoring of the clinical response and any adverse side effects.3 Together, this has fuelled one of the great challenges of research in schizophrenia—to better understand the heterogeneity of outcome following an FEP. But what do outcome and recovery actually mean? There are 2 aspects to outcome: functional and clinical. Functional outcome can be defined as (or measured by), for example, quality of life, whether one is employed, the ability to live independently, or the ability to plan and alter basic daily activities.4–6 Alternatively, clinical outcome focuses more on psychopathology and has been defined as, for example, a therapeutic response to neuroleptics,7 persistent positive8,9 or negative symptoms,10,11 or achieving a remitted state.12,13 Taken together, Emsley et al stated, “recovery is both an outcome and a process.”13 p 117 However, there is a lack of consensus and consistency on how recovery is defined but the overall concept includes improving, both clinically and functionally.13,14 Past research has explored markers related to recovery from both the clinical and functional aspects. Briefly, there are numerous markers associated with a poor outcome, which include: being male, having a younger age of onset, poorer insight, longer duration of untreated psychosis, poorer premorbid social adjustment, and higher negative symptoms.15–17 A final marker of outcome, which has recently become a key area of research in schizophrenia, is Abbreviations CNTRICS
Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia
CPT
Continuous Performance Task
FEP
first-episode psychosis
FES
first-episode schizophrenia
MATRICS
Measurement and Treatment Research to Improve Cognition in Schizophrenia
RAVLT
Rey Auditory Verbal Learning Test
TAP
Test of Attentional Performance
TMT
Trail-Making Test
WAIS
Wechsler Adult Intelligence Scale
WCST
Wisconsin Cart Sorting Task
WMS
Wechsler Memory Scale
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Clinical Implications •
Neurocognitive deficits represent a core symptom of schizophrenia, with verbal memory consistently reported as one of the most impaired cognitive domains.
•
Specific neuropsychological measures (for example, the Logical Memory subtest of the WMS or the RAVLT) may be more sensitive in identifying relations with outcome.
•
Neurocognitive deficits in schizophrenia are more responsible than clinical symptoms for the broadly and persistently observed impairments in functioning.
Limitations •
Research studies do not apply consistent definitions for either clinical or functional outcome, making comparisons and conclusions drawn between studies more difficult.
•
Several measurement issues have been highlighted. First, cognitive domains are not consistently created using the same neuropsychological tests, making crossstudy comparisons more difficult. Second, the distinction between one’s competence to perform tasks and what one actually does in everyday life is an important one but has received only scant attention so far.
cognition. Disturbed processing in cognition is considered a fundamental symptom of schizophrenia,18,19 with mild cognitive deficits appearing well before the onset of psychosis, followed by a sharp decline in functioning, at or near the FEP, that remains stable into the chronic stages.19 The importance of cognition in relation to outcome in schizophrenia has been recognized with the formation of the MATRICS20,21 and the CNTRICS22 consensus groups, with foundations based on improving outcome by enhancing cognitive ability. Our review will explore studies that have explored neurocognitive function in relation to both clinical and functional outcome. The identification of specific neurocognitive markers related to outcome will help improve our understanding of the heterogeneity of outcome and, invariably, schizophrenia itself.
Clinical Outcome and Neurocognition Defining Clinical Outcome
Clinical outcome is generally defined using either a per cent reduction in symptom totals (from 20% to more than 50% reduction)23–27 or a minimum cut-off criterion for specific symptoms9,12,28,29 (or sometimes as a mix of the 2 definitions together30,31). This variability in defining clinical outcome, or the lack of any clear definition, has made it extremely difficult to draw cross-study comparisons.32 Recently, this began to change with the introduction of the consensus definition for remission in schizophrenia proposed in 2005.12,32 Although achieving remission is an important, but www.LaRCP.ca
Neurocognition: Clinical and Functional Outcomes in Schizophrenia
Table 1 Definitions used for defining clinical outcome Study (year)
Sample description
Definition
Meesters et al37 (2012)
Chronic; 20 R and 47 NR
Andreasen12; no hospitalization in past 6 months
Yun da et al42 (2011)
Chronic; 26 R and 28 NR
Andreasen12
Hofer et al (2011)
Chronic and FES; 62 R and 78 NR
Andreasen12; no time component
Brissos et al40 (2011)
Chronic; 23 R and 53 NR
Andreasen12; no hospitalization in past 6 months
Bodnar et al (2011)
FES; 42 R and 81 NR
Andreasen12; no time component
Montreuil et al45 (2010)
FEP; 18 good and 27 poor
Mild (≤2) on all global SAPS; moderate (≤3) on all global SANS; no time component
Li et al43 (2010)
Chronic; 33 R and 57 NR
Andreasen12; no time component
Eberhard et al (2009)
Chronic; 36 R and 52 NR
Andreasen12; 12-month time component; no hospitalization in past 12 months
Ciudad et al44 (2009)
Chronic; 441 R and 537 NR (patient-rated); 331 R and 411 NR (caregiver-rated)
Andreasen12; no time component
Bodnar et al34 (2008)
FEP; 73 good and 78 poor
Mild (≤2) on all global SAPS; moderate (≤3) on all global SANS; no time component
Holthausen et al38 (2007)
Chronic; 29 R and 86 NR
Period without any psychotic symptom that would justify a score of moderate (≥4) on the PANSS
Helldin et al35 (2006)
Chronic; 76 R and 135 NR
Andreasen12; no time component
Joober et al (2002)
Chronic; 36 responders and 39 nonresponders
Complete or quasi-complete disappearance of schizophrenic symptoms, based on the clinical evaluation and hospital records
39
36
41
7
NR = nonremitted; PANSS = Positive and Negative Symptoms Scale; R = remitted; SANS = Scale for the Assessment of Negative Symptoms; SAPS = Scale for the Assessment of Positive Symptoms
not necessary, step in the recovery process,12 the following review of neurocognition and clinical outcome will not be limited to studies only investigating remission, per se, but to more recent studies that explicitly compared 2 clinical outcome groups. Table 1 lists the articles included, along with the definition employed. Our focus here is to highlight more recent findings linking outcome to neuropsychological tests associated with the 7 cognitive domains identified by the MATRICS (verbal learning and memory, visual learning and memory, working memory, speed of processing, reasoning and problem solving, attention, and social cognition).20,33
Verbal Learning and Memory
To begin, neuroleptic nonresponders were found to be more impaired on the Logical Memory and Verbal Pairs subtests of the WMS.7 Next, embracing both positive and negative symptoms, patients with FEP with a poorer clinical outcome also showed significant impairments in the Logical Memory subtests.34 Related more to remission, immediate memory, learning, and long-term memory from the RAVLT have been shown to be more compromised in nonremitted people with chronic schizophrenia.35 Moreover, nonremitted FES patients also exhibit significant deficits on the Logical Memory subtests of the WMS.36 Although these findings appear quite robust, 1 study did find a trend-level difference between remitted and nonremitted patients on the RAVLT Learning subtest37 and 3 studies—1 exploring clinical outcome38 and 2 examining remission39,40—did not find significant differences in measures of verbal memory between outcome groups. Interestingly, the 3 studies that www.TheCJP.ca
did not find any group differences all used the California Verbal Learning Test, which differs from other list-learning tasks by including semantically-related words, the encoding of which benefits from executive functioning. This may suggest purer measures of verbal memory that do not include an executive component may be more sensitive in identifying group differences in relation to clinical outcome.
Visual Learning and Memory
Only one study7 revealed nonresponders performed worse on the Rey-Osterreith Complex Figure Test (copy and 30-minute delayed recall). Although a study by Bodnar et al36 did show trend-level poorer performance in the Visual Reproduction subtests of the WMS in patients with nonremitting FES, this trend disappeared when all patients with FEP were included. Moreover, in a previous study from this laboratory,34 no group differences were found in relation to clinical outcome when examining the entire sample with FEP or the subsample of patients with FEP. Finally, people with nonremitted and remitted schizophrenia displayed no differences on the Benton Visual Retention Test.39 Although not related to memory, per se, people with nonremitted schizophrenia were shown to have significant impairments on the Elithorn’s maze test (visuospatial ability)41; yet no group differences in visuospatial ability (picture completion and Block Design subtests of the WAIS) were identified between neuroleptic responders and nonresponders.7
Working Memory
People with nonremitted schizophrenia have been shown to have significant impairments on the Letter–Number The Canadian Journal of Psychiatry, Vol 59, No 1, January 2014 W 7
In Review
Sequencing subtest of the WAIS.35 In support of this finding, patients with poor clinical outcome FEP showed worse performance on the Digit Span subtest of the WAIS and the Spatial Span subtest of the WMS; results were significant for the entire FEP sample and the FES subsample.34 However, in a follow-up report by Bodnar et al,36 only a trend-level difference was reported when examining remission in the entire FEP sample, with no significant differences reported in the FES subsample. Three other studies also revealed no significant deficit in people with nonremitted schizophrenia when using the Digit Span subtest37,40 or the Working Memory subtest of the TAP.39
Speed of Processing
Only one study35 revealed nonremitted people with schizophrenia performed worse in this domain as measured with the TMT-A. The remaining studies found no significant between-group differences when using the TMT-A,37 the TMT-A and mental tracking of the WMS,40 or the TMT-A and Digit Symbol subtest of the WAIS.34,36
Reasoning and Problem Solving
images) and Social Translation (an ability to recognize changes in behavioural meaning) subtests.
Summary: Clinical Outcome
In brief, verbal memory and social cognitive deficits appear as the more robust markers of clinical outcome in schizophrenia; the other 5 domains appear to show a more ambiguous relation with clinical outcome. This is not to say these 5 domains are not related to clinical outcome but perhaps specific tests within each domain may be, as it was apparent for both the verbal memory and social cognition domains. Future outcome studies need to define the cognitive domains more consistently; for example, measure the domains using only CogState Schizophrenia Battery46,47 or the MATRICS Consensus Cognitive Battery48,49 as both batteries show high cross-validity.46 With consistently defined cognitive domains and consistent definitions of clinical outcome, more definitive results would be evident. Finally, the use of a categorical approach (between 2 groups of patients within 1 sample) may be more reliable and more sensitive for detecting markers of outcome as a linear relation is not assumed.
People with nonremitted schizophrenia have been shown to display significant impairments on the TMT-B35,37 and the WCST (categories).35 In contrast, there were 6 studies that did not find any significant between-group differences: 2 using the WCST,7,39 one using the TMT-B,40 one using the Stroop colour test,37 and 2 using the TMT-B and Block Design subtest of the WAIS.34,36 In addition, Yun da et al42 revealed patient groups did not differ on a set-shifting task (Intradimensional–Extradimensional Shift task) of the Cambridge Neuropsychological Test Automated Battery.
Functional Outcome and Neurocognition
Attention
Estimates of medical comorbidities range above 50% among people with schizophrenia50 and contribute to a reduced lifespan of up to 25 years51 Some of these comorbidities are complicated by deficits in self-care. Overall cognitive functioning is robustly associated with poor self-care in late life52,53 and predictive of deteriorating ability to perform routine activities of daily living.54,55 The precise role that cognition plays in self-care and health problems needs to be addressed in future work; this is a relatively understudied area.
People with nonremitted schizophrenia have been shown to display significant deficits in the CPT (levels 1, 2, and 3).35 Interestingly, using the TAP, nonremitted patients displayed significant impairments in optical vigilance but not in phasic alertness.39 Moreover, trend-level poorer performance on the d2 Test of Attention was shown in poor clinical outcome and patients with nonremitted FEP; poorer attention was not apparent when examining the subsample of patients with FES.34,36 Finally, no significant betweengroup differences were found on the CPT and Digit Span of the WAIS7 or on the divided attention and go–no-go tasks of the TAP.43
Social Cognition
Using both a patient- and caregiver-rated measure of social cognition, people with nonremitted schizophrenia display significant impairments on measures of perceived difficulty to manage specific tasks or situations.44 In support of this finding, Montreuil et al45 revealed that patients with poor clinical outcome FEP also display significant difficulties in overall social cognition. As revealed by the authors, their result was driven by the Cartoon Prediction subtest of the Four Factor Social Intelligence test—a test that measures the ability to predict social consequences. They also identified trend-level differences in the Expression Grouping (an ability to abstract common attributes from different expressive 8 W La Revue canadienne de psychiatrie, vol 59, no 1, janvier 2014
The tremendous increase in attention paid to neurocognitive impairments in the past several years is largely driven by the findings that this feature of schizophrenia is more responsible than clinical symptoms for the broadly and persistently observed impairments in functioning.5 Impairments are present in multiple areas, and most have a robust relation with cognition, though sometimes this relation is quite complicated.
Self-Care and Medical Comorbidities
Independent Living
Waves of deinstitutionalization have resulted in a reduction of inpatient hospital beds, but these efforts have been followed by insufficient work to promote true independent living for people with schizophrenia.56 The minority of people with schizophrenia live independently and are financially responsible for their residence,57 and many people are now living in long-term community housing that does not sufficiently address their needs.58 Paradoxically, a major driving force behind hospital discharge, reduction of psychotic symptoms, is poorly correlated with independent living skills and status. In clinically stable outpatients, most cognitive domains are predictive of the skills associated with independent living,4,59,60 while verbal memory ability is a strong predictor of independent living among stable outpatients.61 In an interesting study that highlights the www.LaRCP.ca
Neurocognition: Clinical and Functional Outcomes in Schizophrenia
reciprocal nature of the cognition–living status relation, Caplan et al62 found that formerly homeless people demonstrated improved sustained attention and verbal memory on moving to a residence; further, those randomized to supported housing had greater executive function improvement than those randomized to independent apartments. These conclusions are supported by a recent study that found independent living status in outpatients with schizophrenia to moderate the relation between their abilities and their performance in functioning.63 These studies underscore the need to appreciate the dynamic relation between cognition and living status for people transitioning among residential placements and as they acclimate to new settings.
Medication and Illness Management
Closely related to health status and self-care are medication and illness management. Schizophrenia is associated with poor compliance with medication regimens.64 Although cognitive performance is the strongest predictor of poor competence in managing complex medication regiments,65 and, of course, with high rates of polypharmacy and comorbid medical conditions, there is certainly complexity, relations with adherence differ, with some studies finding higher cognitive ability predicting nonadherence.66 Difficulties with recognition or awareness of illness is a hallmark feature of schizophrenia and interacts with medication compliance. Cognitive variables, most notably executive dysfunction, have been associated with poor insight into illness.67,68 People with poorer cognitive abilities, most notably executive functions, are in need of more services,69 yet the clinical reality is complicated because cognitive deficits are associated with poor engagement in services.70 Further, treatment service intensity is preferentially associated with functional improvement during rehabilitation only for people who demonstrate cognitive improvements.71 Thus it appears that cognitive impairments reflect people in most need of services, yet they are associated with the poorest engagement in the services that are most likely to provide benefits to their functioning.
Social and Interpersonal Functioning
As previously mentioned, people with schizophrenia are increasingly living in nonhospital settings, which putatively increases opportunities for social relationships. However, impairment in social functions and relationships remains an issue, with zero or very few friendships as the norm.72 Low marriage and reproductive rates are also observed despite a desire to have relationships.73 Neurocognitive skills are associated with several factors related to successful social outcomes, including impairments in understanding social situations,74 interpersonal problem solving skills,75 communication,76 empathy,77 and aggression.78 Compared with other domains of functioning, the relation of neurocognition to social skills is smaller and more closely associated with negative and depressive symptoms.4 Several investigators are now exploring the many paths to social disability and early evidence suggests that neurocognition has an important indirect role via its influence on social cognitive skills, which appear to be more robust predictors www.TheCJP.ca
of social functions. This is an important area for future study because many people with schizophrenia value friendships,72 and a healthy social network is associated with higher rates of recovery.79
Community Activities and Leisure
Cognitive deficits interfere with the ability of people with schizophrenia to be fully active members of their community by limiting everyday living skills and engagement in activities.80 For many, residence in lessthan-desirable neighbourhoods and restricted financial resources complicate the engagement in community activities. The ability to navigate everyday obstacles and public transportation is limited by cognitive impairments,81 but independent transportation is difficult for people with financial strain and complicated by poorer driving abilities associated with cognitive performance82 and more accidents.83 The ability to plan and execute shopping is also compromised and related to poor executive functions in schizophrenia,84,85 which could have a role in the self-care deficits described above.
Vocational Functioning
Unemployment rates in schizophrenia are exceptionally high, with fewer than 20% returning to work after the FEP.86 On returning to the work force following illness onset, a reduction in status or wages is common.87 Level of productivity at work is diminished and results in increased occupational stress.88 Even people in a supported employment setting are more likely than not to lose their job within the first 6 months of employment.89 Despite this, many reports describe patients who strongly desire work.90 For the many people with chronic mental illness in the previous century, engagement in productive roles was discouraged because of a prevailing philosophy that a return to premorbid role function may increase stress and lead to relapse of clinical symptoms. Indeed, epidemiologic survey research has found that, in the general population, 31% of Canadians considered most days at work to be either “quite a bit stressful” or “extremely stressful.”91 The cognitive impairments of schizophrenia make it important to consider the likelihood of stress resulting from difficulty in effectively processing information and engaging in goaldirected behaviour in the vocational setting. Nevertheless, it is critical to not overlook the stress of being chronically unemployed and appreciate the potential positive effects that work can have when people with schizophrenia are cognitively equipped.92 Work provides a sense of purpose and improves self-esteem.93 Quality of life, sense of satisfaction, self-worth, and self-esteem tend to improve with the commencement of work.94 These intrapersonal experiences associated with work are increasingly recognized as a critical aspect of the recovery process for people experiencing mental illness.95 Objective indicators include reduced rates of hospitalization.96 Among studies that have objectively examined neurocognition and work status, there is consensus for an association between the variables97 and evidence for cognitive functioning as a predictor for later work success.86 Impairments in neurocognition are associated with acute The Canadian Journal of Psychiatry, Vol 59, No 1, January 2014 W 9
In Review
impairments in work at FEP, and these impairments predict long-term disability for most patients. They account for up to 52% of the variance in work outcomes 6 to 9 months after treatment initiation for FEP.98 After 7 years of treatment following the FEP, work outcomes are severely impaired and baseline impairments in processing speed and attention are the strongest predictor of poor work outcomes.99 Importantly, these deficits result in difficulty in acquiring skills in psychosocial rehabilitation, including programs that focus on vocational services.100
functioning have been shown to significantly limit the ability to acquire, retain, or relearn skills necessary for real-world functioning, such as forming relationships and undertaking employment.104 Also, daily problem solving skills have been significantly correlated with processing speed, verbal memory, and working memory.105 To properly understand the link between neurocognition and outcome, more studies need to use similar measures of cognition and outcome to provide reliable and consistent results that can be translated into clinical practice.
Measurement Issues
Acknowledgements
Clearly we have established a strong link between neurocognitive deficits and impairments in several aspects of functioning. As we continue to examine these relations and embark on treatment strategies to improve functioning, several issues related to assessment and design are important to note. A critical measurement issue is the distinction between one’s competence to perform tasks and what one actually does in everyday life. Performance-based assessments, which can be completed in an office or laboratory setting, provide the basis for measuring one’s competence in an environment that is not affected by symptoms, such as depression and motivational impairment, or by extraneous factors, such as lack of opportunity, social networks, or finances. However, these factors do limit the degree to which cognition is associated with real-world functioning.63,80 This distinction between competence and performance is also critical for treatment studies. The long-standing nature of both neurocognitive and functional impairments may make it unreasonable to expect a direct transfer of cognitive change to functional change. In fact, in a recent study,101 treatment effects from cognitive remediation produced significant transfer to functioning when subjects also received supplemental skills training. As we start to examine more opportunities to improve functioning via cognitive rehabilitation methods, performance-based measures of competence, which are proximal to cognition, may be more likely to change in a short trial, but realworld behaviour may require more time and supplemental rehabilitative efforts.
Conclusions
Cognitive deficits represent a core symptom of schizophrenia and are strongly related to not only the illness itself but also eventual recovery. People with schizophrenia display significant cognitive impairments, with deficits in verbal memory consistently reported as one of the most impaired cognitive domains.18,19,102 In addition, as highlighted by this review, verbal memory appears to be one of the strongest markers of outcome. However, all studies on cognition and outcome do not answer the question of whether patients with good outcome display better cognitive functioning, or if patients with a higher level of cognitive performance are more likely to have a better prognosis.17 Nevertheless, improving treatments for cognitive symptoms in schizophrenia is a key area in future research and drug developments efforts, as these symptoms are believed to affect the functional abilities of these patients.103 For example, impairments in working memory and executive 10 W La Revue canadienne de psychiatrie, vol 59, no 1, janvier 2014
Dr Lepage received a grant (68961) in support of this research from the Canadian Institutes for Health Research. Dr Bowie has received funding as a consultant to Abbott Laboratories and AbbVIE, and as a speaker for Janssen Cilag. The Canadian Psychiatric Association proudly supports the In Review series by providing an honorium to the authors.
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