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☆
Introduction
Cognitive dysfunction is a common and functionally relevant impairment in schizophrenia. Impairments in cognitive functioning are correlated with impaired functional capacity (Leifker et al., 2011), which are important for successful real-world functioning (Bowie et al., 2006). Therefore, reduction of cognitive impairment has been recognized for years as a major goal in the treatment of schizophrenia (Davidson and Keefe, 1995, Keefe et al., 1999, Harvey and Keefe, 2001). A number of large-scale trials finding little cognitive improvement associated with various drug treatments have dampened the initial enthusiasm about the potential cognitive enhancing effects of atypical antipsychotic medications (Keefe et al., 2013). In some studies the benefits of atypical medications are consistent with the practice effects that would be expected from simple retesting (Goldberg et al., 2010). However, a number of previous studies aimed at showing cognitive enhancement with atypical medications have had substantial methodological limitations. These have included inappropriate dosing of comparators, lack of placebo or active controls (rendering the assessment of practice effects impossible), and lack of blinding to reduce bias (Keefe et al., 2013). There have also been studies that have reported long-term functional benefits of atypical medications (Harvey et al., 2007, Harvey et al., 2011a, Harvey et al., 2011b, Stahl et al., 2010). These studies have focused on patients who manifested a positive initial response to treatment and who sustained adherence over long time periods.
Systematic procedures are now established to examine the cognitive enhancing effects of pharmacological compounds (Buchanan et al., 2005, Buchanan et al., 2010). These include a standardized cognitive performance assessment battery, the utilization of a co-primary measure of functioning (typically a performance-based assessment of functional capacity or an interview-based measure), and several other methodological recommendations to ensure the reliability of study results. Despite this standardization, there have been no pharmacological studies to date where both the neuropsychological primary outcome and the co-primary measure were both improved. Two studies have found improvements in a co-primary measure of functional capacity, but not the neuropsychological assessment (Javitt et al., 2012, Harvey et al., 2011a, Harvey et al., 2011b). The UCSD Performance-Based Skills assessment (UPSA) improved in an add-on therapy study of the neuroprotective peptide davunetide, although the MATRICS consensus cognitive battery (MCCB) did not improve significantly in the somewhat small sample (Javitt et al., 2012). In another study, an interview-based assessment of cognitive functioning, the Schizophrenia Cognition Rating Scale (SCoRS) improved with treatment with lurasidone, although the overall treatment effect for an abbreviated version of the MCCB was not significant (Harvey et al., 2011a, Harvey et al., 2011b). Although this study was not controlled for practice effects, the SCoRS is an interview based measure and practice effects are not relevant to this assessment modality (Harvey et al., 2011a, Harvey et al., 2011b).
We report here the results of a study that has several key design features that distinguish it from previous studies of the effects of a pharmacological intervention on neurocognitive impairment in schizophrenia. This study included an initial acute treatment period that was placebo-controlled, with subjects randomized to two fixed doses of lurasidone and an active control, quetiapine XR (at an approved dose). In addition to facilitating a rigorous evaluation of treatment effects, the inclusion of placebo allowed for an assessment of the extent to which practice effects might contribute to improvement in cognition. Cognitive performance was examined with a widely used computerized assessment battery (Pietrzak et al. 2009) and a performance-based co-primary measure of functional capacity (Mausbach et al., 2007) was employed. A double-blind extension study allowed for examination of cognitive treatment effects for up to 6 months after the acute study period.
Lurasidone is a novel benzisothiazol derivative with potent binding affinity for D2, 5-HT2A and 5HT7 receptors (antagonist effect), moderate affinity for 5HT1A (partial agonist effect) and α2C receptors (antagonist effect), and no appreciable affinity for H1 and M1 receptors (Ishibashi et al., 2010). Preclinical studies support the potential for procognitive effects (Ishibashi et al., 2007, Enomoto et al., 2008, Horisawa et al., 2011); these have received preliminary support in earlier clinical studies without the extensive methodological refinements of the current study (Harvey et al., 2011a, Harvey et al., 2011b). This is the first study to evaluate both short and longer-term effects of lurasidone on cognitive performance in schizophrenia, utilizing a double-blind design and both active and placebo controls.
Section snippets
Design
The results reported here are derived from a multicenter, randomized, 6-week, double-blind study (http://clinicaltrials.gov/, trial number: NCT00790192), followed by a double-blind extension study that continued up to 1 year (http://clinicaltrials.gov/, trial number: NCT00789698). Overall study design and methods have been described in detail elsewhere (Loebel et al., 2013a, Loebel et al., 2013b) and are briefly summarized here. Subjects with a primary diagnosis of schizophrenia, who had been
Disposition of patients and characteristics
Figure 1 depicts the disposition of subjects and analysis populations. A total of 488 subjects were randomized in the acute phase study, of which 353 subjects (72%) completed the 6-week acute phase and 140 subjects (48% of the subjects enrolled in the extension phase) completed the 6-month extension phase. In all, 7753 cognitive task assessments on 481 subjects were performed at pre-treatment baseline or week 6 during the acute phase; 1355 (17.5%) cognitive task assessments failed the
Discussion
This study evaluated neurocognitive performance in patients with acute schizophrenia treated with atypical antipsychotic medications across a short-term placebo and active-controlled treatment period, followed by a 6 month double-blind extension. In the all subjects population (including subjects who did not meet prespecified cognitive testing data integrity criteria), no statistically significant differences were found at week 6 in neurocognitive composite score performance for either
Role of funding source
This study was sponsored by Sunovion Pharmaceuticals Inc. The sponsor was involved in the study design and collection of data.
Contributors
All authors contributed to the design of the study. Drs. Harvey, Siu and Hsu undertook the statistical analysis. Drs. Harvey and Siu prepared the first draft of the manuscript. All authors contributed to and approved the final manuscript. No medical writers worked on this manuscript.
Conflict of interest
Dr. Harvey has contract funding from Genentech. He also serves as a consultant/advisory board member for Abbott Labs, Amgen, Boeheringer Ingelheim, Forest Labs, Genentech, Otsuka America, Shire, Sunovion, and Takeda.
Dr. Siu has received payments for consulting from Pfizer Inc., Sunovion Pharmaceuticals Inc. and the Center for Addiction and Mental Health at the University of Toronto.
Dr. Maruff is a full-time employee of CogState Ltd.
Drs. Cucchiaro, Hsu, and Loebel are employees of Sunovion
Acknowledgments
All contributors to this paper are listed as authors.
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ClinicalTrials.gov Identifier: NCT00790192; ClinicalTrials.gov Identifier: NCT00789698.