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To the Editor: In the June 2016 issue of the Journal, Kantrowitz et al reported that "the change from prestabilization was statistically significant for MCCB composite score" for patients who were randomized and completed at least 1 cognitive remediation therapy (CRT) vs video game control session, with d = 0.42 and P < .001 based on 1-sample paired t test across the 2 randomized groups (see the abstract and the Results under "Cognitive remediation period" heading). This methodology is fundamentally flawed in that (a) the 2 randomized groups should not be pooled, as this is in conflict with the design of the study and reduces interpretability of the study results; (b) the significant reported differences between the groups at randomization baseline add to the difficulty in pooling these groups; (c) the assessment of the true effect of CRT (vs nonspecific control) in this study would require estimation of change in MATRICS Consensus Cognitive Battery (MCCB) scores from the randomization baseline (week 8), not the prestabilization baseline (week 0) as reported by Kantrowitz et al; and (d) the application of a 1-sample paired t test to 2 independent samples in a randomized controlled design violates the basic statistical analysis principle that the choice of statistical test should be governed by the study design.
It can be shown that the effect size d = 0.42 for change from prestabilization [= C – A] as reported by Kantrowitz et al is the sum of 2 components (C – B) + (B – A): (1) the effect of lurasidone monotherapy on MCCB composite score compared with prestabilization baseline [= B – A, dlurasidone = (32.3 – 29)/11.3 = 3.3/11.3 = 0.29, P < .001] (Tables 1 and 2 in the article) and (2) the effect of CRT or video game control combined with lurasidone treatment on MCCB composite score compared with the randomization baseline [= C – B, dCRT or video game = (33.8 – 32.3)/11.3 = 1.5/11.3 = 0.13] (Table 2).
See reply by Kantrowitz et al and article by Kantrowitz et al
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Efficacy of Auditory Processing-Focused Cognitive Remediation Therapy
To the Editor: In the June 2016 issue of the Journal, Kantrowitz et al1 reported that "the change from prestabilization was statistically significant for MCCB composite score"1(p799) for patients who were randomized and completed at least 1 cognitive remediation therapy (CRT) vs video game control session, with d = 0.42 and P < .001 based on 1-sample paired t test across the 2 randomized groups (see the abstract and the Results under "Cognitive remediation period" heading). This methodology is fundamentally flawed in that (a) the 2 randomized groups should not be pooled, as this is in conflict with the design of the study and reduces interpretability of the study results; (b) the significant reported differences between the groups at randomization baseline add to the difficulty in pooling these groups; (c) the assessment of the true effect of CRT (vs nonspecific control) in this study would require estimation of change in MATRICS Consensus Cognitive Battery (MCCB) scores from the randomization baseline (week 8), not the prestabilization baseline (week 0) as reported by Kantrowitz et al1; and (d) the application of a 1-sample paired t test to 2 independent samples in a randomized controlled design violates the basic statistical analysis principle that the choice of statistical test should be governed by the study design.
It can be shown that the effect size d = 0.42 for change from prestabilization [= C – A] as reported by Kantrowitz et al1 is the sum of 2 components (C – B) + (B – A): (1) the effect of lurasidone monotherapy on MCCB composite score compared with prestabilization baseline [= B – A, dlurasidone = (32.3 – 29)/11.3 = 3.3/11.3 = 0.29, P < .001] (Tables 1 and 2 in the article)1 and (2) the effect of CRT or video game control combined with lurasidone treatment on MCCB composite score compared with the randomization baseline [= C – B, dCRT or video game = (33.8 – 32.3)/11.3 = 1.5/11.3 = 0.13] (Table 2).1 Therefore, nearly 70% of the effect size for MCCB composite score (d = 0.42) was associated with lurasidone treatment before randomization, which is consistent with the observed effect size of 0.37 at week 6 for lurasidone versus placebo in Harvey et al.2 The remaining 30% (dCRT or video game = 0.13) was associated with cognitive remediation or video game sessions in combination with lurasidone treatment in the period after randomization. Attribution of the change in MCCB score to the relevant study treatment intervention is obscured by reporting the change from prestabilization baseline to study endpoint without regard to study phase or specific treatment within each phase.
In addition, Kantrowitz et al1 noted that the CRT group had significantly better MCCB domain scores (for visual learning and reasoning and problem solving) at randomization baseline compared to the video game control group. The between-group difference at randomization trended toward significance for MCCB composite score favoring the CRT group (P = .08). These randomization baseline differences can only have resulted from randomization failure (not "retrospective" differences in randomized group change during the stabilization phase); this can arise due to site-based randomization with many incomplete blocks for sites with few subjects. The significant trend and the small-to-moderate effect sizes reported for MCCB domains favoring the CRT group at midpoint and/or study completion are misleading because of the bias due to the presence of significant baseline differences at randomization.
Figure 1 in Kantrowitz et al1 shows parallel and continued improvement from randomization baseline in MCCB composite score during both CRT and video game control sessions combined with lurasidone treatment, indicating that this combined treatment strategy was able to maintain the cognitive benefits achieved in the early lurasidone stabilization phase, perhaps in part by engaging and motivating patients, which in itself may provide cognitive benefit.3 The authors should acknowledge the significant improvement in MCCB score associated with lurasidone treatment in the stabilization phase, the randomization failure, and the lack of significant between-group differences (comparing CRT vs nonspecific video game control) at study completion in the abstract and the article.
References
1. Kantrowitz JT, Sharif Z, Medalia A, et al. A multicenter, rater-blinded, randomized controlled study of auditory processing-focused cognitive remediation combined with open-label lurasidone in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry. 2016;77(6):799-806. PubMed doi:10.4088/JCP.15m09998
2. Harvey PD, Siu CO, Hsu J, et al. Effect of lurasidone on neurocognitive performance in patients with schizophrenia: a short-term placebo- and active-controlled study followed by a 6-month double-blind extension. Eur Neuropsychopharmacol. 2013;23(11):1373-1382. PubMed doi:10.1016/j.euroneuro.2013.08.003
3. Saperstein AM, Medalia A. The role of motivation in cognitive remediation for people with schizophrenia. Curr Top Behav Neurosci. 2015;27:533-546. PubMed doi:10.1007/7854_2015_373
aCOS and Associates Ltd, Central, Hong Kong
bCentre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada
Potential conflicts of interest: Dr Siu has received consulting fees within the last 12 months from Sunovion, Pfizer, Sumitomo Dainippon, Hong Kong Health and Medical Research Grant, and the Chinese University of Hong Kong. Dr Agid has received consulting fees or served on advisory boards for Janssen-Ortho (Johnson & Johnson), Sepracor, Sunovion, Roche, Novartis, BMS, Otsuka, Lundbeck, Eli Lilly & Company US, Eli Lilly Canada, and Sumitomo Dainippon Pharma (DSP); participated in speaking engagements for Janssen-Ortho (Johnson & Johnson), Novartis, Sepracor Inc, US, Sunovion, Lundbeck, Eli Lilly & Company US, Eli Lilly Canada, Mylan, and Otsuka; and received research contracts from Pfizer Inc, Janssen-Ortho (Johnson & Johnson), Otsuka, Boehringer Ingelheim, Neurocrine Biosciences, and Sunovion.
Funding/support: None.
J Clin Psychiatry 2016;77(10):e1352
dx.doi.org/10.4088/JCP.16lr10887
© Copyright 2016 Physicians Postgraduate Press, Inc.
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