Cognitive functioning in first-episode schizophrenia: MATRICS Consensus Cognitive Battery (MCCB) Profile of Impairment
Introduction
Marked cognitive impairment is a core, enduring feature of schizophrenia, prompting some researchers to posit that the illness can be conceptualized as primarily a disorder of cognition (Rund, 1998, Green and Nuechterlein, 1999). Among patients with chronic schizophrenia (CSz), cognitive impairment is diffuse and pervasive, with deficits typically 1 to 2 standard deviations below non-psychiatric control samples across various cognitive domains (Heinrichs and Zakzanis, 1998, Gold, 2004, Green, 2006). Cognitive impairment appears to be a relatively stable feature of schizophrenia (Hoff et al., 2005, Barder et al., 2013b), even across acute vs. remitted states (Nuechterlein et al., 1992), with limited response to antipsychotic treatment (Rund, 1998, Keefe et al., 2007). Cognitive impairment is present in first-episode schizophrenia (FESz; Gold et al., 1999, Hoff et al., 1999, Mohamed et al., 1999, Addington and Addington, 2002, Barder et al., 2013a), and likely precedes the onset of illness in an attenuated form (Cornblatt et al., 1999, Hawkins et al., 2004, Lencz et al., 2006, Simon et al., 2007, Seidman et al., 2010, Lewandowski et al., 2011). However, the findings have been mixed regarding the magnitude of cognitive impairment in FESz compared to CSz, with some studies reporting negligible differences between FESz and CSz (e.g., Hoff et al., 1992), and others reporting less impairment in FESz relative to CSz, at least on some cognitive tests (e.g., Saykin et al., 1994, Albus et al., 1996, Addington and Addington, 2002, Townsend and Norman, 2004, Braw et al., 2008). Hence, the pattern and severity of impairment in FESz across cognitive domains remain unclear.
A meta-analysis of 43 studies of cognition in FESz (Mesholam-Gately et al., 2009) provided strong evidence for notable impairment across all cognitive domains, with medium to large mean effect sizes on par with those reported in CSz (Heinrichs and Zakzanis, 1998). Impairment was most pronounced in immediate verbal memory and processing speed, in addition to the global impairment observed in schizophrenia. Indeed, a selective deficit of verbal memory and processing speed has been reported elsewhere in the schizophrenia literature (e.g., Dickinson et al., 2008, Gonzalez-Blanch et al., 2010). The meta-analysis noted significant heterogeneity of effect sizes within cognitive domains and between studies, likely due to methodological variations across studies, such as differences in the operational definition of FESz, properties of the patient samples (e.g., diagnoses, demographic variables), medications, and possible cohort effects. Inconsistency in cognitive test batteries across studies provides an additional source of variability in that tests may differ substantially in reliability, which impacts estimates of effect size (Baugh, 2002). Moreover, given that the various tests were not normed on the same sample, it is difficult to directly compare differences in effect sizes across tests/domains (Russell et al., 2005).
The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB; Nuechterlein and Green, 2006) is a compilation of independently owned and published tests that initially had normative data from non-overlapping samples. The MCCB has the advantage of being co-normed (i.e., normative data for each test collected from the same sample) on the non-psychiatric (NP) community sample from the MATRICS Psychometric and Standardization Study (MATRICS PASS; Kern et al., 2008). The MCCB includes seven cognitive domains: speed of processing, attention/vigilance, working memory, verbal learning, visual learning, reasoning and problem solving, and social cognition. A brief description of the 10 tests comprising the MCCB can be found in Table 1. Five MCCB domains are assessed with one test each, thus the T-score and percentile for those domains are based on those individual tests. The speed of processing and working memory domains are assessed with multiple tests, and these domain scores are based on a composite of the included tests. In addition to the seven domain scores, the MCCB also provides an Overall Composite score, an index of cognitive functioning across domains. The Overall Composite score is derived through equal weighting of the seven MCCB domain scores (Nuechterlein and Green, 2006).
The profile of MCCB impairment for a CSz sample was previously reported (Kern et al., 2011). Compared to the NP sample, CSz patients were impaired across all MCCB domains, with greater relative impairment in speed of processing and working memory, and less relative impairment in reasoning and problem solving compared to their average performance across the remaining MCCB domains.
Adoption of the MCCB as a neuropsychological test battery in schizophrenia research is on the rise. At the time of this writing, ClinicalTrials.gov, an online registry of clinical trials across the globe maintained by the National Institutes of Health and National Library of Medicine, lists over 50 studies that employ the MCCB. The aim of this paper was to examine the overall magnitude and profile of cognitive impairment in FESz using the MCCB. Specifically, we compared MCCB domain scores for a FESz sample to data from CSz and NP participants in MATRICS PASS (Nuechterlein et al., 2008, Kern et al., 2011). Four hypotheses were tested: 1) that FESz patients would show significant impairment averaged across MCCB domains compared to NP; 2) that FESz patients would show similar magnitude of impairment as CSz patients; 3) consistent with the Mesholam-Gately meta-analysis (Mesholam-Gately et al., 2009), that FESz patients would exhibit particular weakness in speed of processing and verbal learning relative to performance in the remaining MCCB domains; and 4) finally, that the proportion of participants from each patient group who exhibit clinically-significant global cognitive impairment will not differ.
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Participants
Three samples of participants provided data for these analyses. The FESz sample included 105 patients from the UCLA Aftercare Research Program, an outpatient research clinic for FESz. Inclusion criteria were: 1) onset of a first psychotic episode within 24 months of program entry, 2) fulfillment of DSM-IV (American Psychiatric Association, 1994) criteria for schizophrenia, schizoaffective disorder, depressed type, or schizophreniform disorder, 3) age of 18 to 45 years, and 4) sufficient fluency
Descriptive statistics
Age and gender corrected T-scores for each MCCB subtest and domain by group are presented in Table 3. Missing data were minimal (3.5% of data points). The mixed model analyses use all available data. Calculation of the MCCB Overall Composite score was completed for subjects with complete data; the sample sizes for the MCCB Overall Composite score chi-square analysis were 99 FESz, 167 CSz, and 289 NP.
Mixed model analysis
The MCCB profiles for each group are presented in Fig. 1. A mixed model was fit to the data,
Discussion
Utilizing the MCCB, a cognitive battery co-normed on a non-psychiatric (NP) community sample, we provide a profile analysis of cognitive impairment in first-episode schizophrenia. Our analyses demonstrate that the overall magnitude and pattern of cognitive impairment in FESz are similar to that observed in CSz. Both FESz and CSz evidence marked impairment across MCCB domains compared to NP. Despite the similarity of MCCB performance profiles in FESz and CSz, subtle differences were observed.
Contributors
K.H. Nuechterlein, J. Ventura, K.L. Subotnik, and D. Gretchen-Doorly designed the study and wrote the FESz protocol, while M.F. Green, K.H. Nuechterlein, and R.S. Kern designed the MATRICS PASS protocol. A. McCleery and K.H. Nuechterlein managed the literature searches and analyses. A. McCleery and G.S. Hellemann undertook the statistical analysis, and A. McCleery wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript.
Author disclosure
A. McCleery is supported by the Canadian Institutes of Health Research fellowship award (MFE-120919). FESz subject recruitment and data collection were supported by NIMH research grant MH037705 (K.H. Nuechterlein, PI) and Center grant MH066086 (K.H. Nuechterlein, PI). CSz and NP subject recruitment and data collection were supported by Contract N01MH22006 from the NIMH to the University of California, Los Angeles (S. Marder, PI; M.F. Green, Co-PI; W. Fenton, Project Officer).
Conflict of interest
M.F. Green and K.H. Nuechterlein are officers within MATRICS Assessment, Inc., the publisher of the MCCB, but do not receive any financial remuneration for their respective roles. R.S. Kern is an officer for MATRICS Assessment, Inc. and receives financial compensation for his role within the non-profit organization. K.H. Nuechterlein has received unrelated research grants from Janssen Scientific Affairs (R092670SCH4005; RIS-NAP-4009), Genentech (ML28264), and Posit Science (BPI-1000-11) and has
Acknowledgments
We thank the patients and community comparison subjects for their participation in this study. We gratefully acknowledge the assistance of the UCLA Aftercare Research Program research assistants Jacqueline Hayata, B.A., Robin Kite, M.A., and Lilian Medina, B.A., and clinic staff Laurie Casaus, M.D., John Luo, M.D., Kimberly Baldwin, M.F.T., Rosemary Collier, M.A., Nicole R. DeTore, M.A., Yurika Sturdevant, Psy.D., and Luana Turner, Psy.D. We also thank MATRICS PASS site PIs Lyle E. Baade,
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