Performance and interview-based assessments of cognitive change in a randomized, double-blind comparison of lurasidone vs. ziprasidone,☆☆

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Abstract

Background

Improving cognitive functioning in people with schizophrenia is a major treatment goal. In addition, interview-based measures have been developed to supplement performance-based assessments. However, few data are available regarding whether interview-based measures are sensitive to treatment-related changes.

Methods

Adult outpatients who met DSM-IV criteria for schizophrenia or schizoaffective disorder were randomized to 21 days of double-blind treatment with lurasidone 120 mg once daily (N = 150) or ziprasidone 80 mg BID (N = 151). A similar proportion of patients completed the study on lurasidone (67.5%) and ziprasidone (69.3%). Study participants were assessed with the majority of the tests from the MATRICS Consensus Cognitive Battery (MCCB) and an interview-based assessment of cognitive functioning, the Schizophrenia Cognition Rating Scale (SCoRS). SCoRS ratings were based on the interviewer's best judgment, after interviews with the patient and a caregiver when available. The study was conducted from April 2006 to January 2007.

Results

There were no between-group treatment differences in performance on the MCCB or the SCoRS ratings. Lurasidone patients demonstrated significant within group-improvement from baseline on the MCCB composite score (p = 0.026) and on the SCoRS (p < 0.001), but ziprasidone patients did not improve on either the MCCB composite (p = 0.254) or the SCoRS (p = 0.185). At endpoint there was a statistical trend (p = 0.058) for lurasidone to demonstrate greater improvement from baseline in SCoRS ratings. Improvements in interview-based aspects of cognition were not related to MCCB test changes, and had minimal correlations with changes in symptoms.

Conclusions

These data suggest that interview-based cognitive measures such as the SCoRS may be sensitive to changes after 3 weeks of treatment in patients with schizophrenia. Lurasidone is being assessed further in ongoing clinical trials with additional outcome measures.

Introduction

Cognitive impairment is a major determinant of disability in people with schizophrenia (Green et al., 2000). The assessment of cognitive impairment has typically been accomplished with performance-based neuropsychological (NP) tests. These assessments can be lengthy and require specialized expertise for both administration and interpretation. As a result, many people with schizophrenia do not receive these assessments because specialists are not readily available. While there has been considerable debate about the duration of psychological assessment required (Velligan et al., 2004), even abbreviated assessments require interpretive expertise. Relying on the self reports of people with schizophrenia regarding their functioning is problematic. Studies directly examining the convergence between performance on NP tests and patients' self report of their disability have shown minimal-to-no correlations (McKibbin et al., 2004, Bowie et al., 2007, Keefe et al., 2006). In contrast, when case managers or relatives who know the patients well were asked to provide information about their functioning, the reports of these informants were more highly correlated than the patient's own reports with the patients' performance on NP tests (Bowie et al., 2007, Keefe et al., 2006). Furthermore, direct assessments of the ability to perform critical functional skills are quite highly correlated with performance on NP tests (see Leifker et al., 2009).

It has been suggested that cognitive impairment can be inferred from ratings on comprehensive psychiatric rating scales, such as the Positive and Negative Syndrome Scales (PANSS; Kay, 1991). However, the “cognitive” subscales of these instruments are typically less strongly correlated with NP test performance than are ratings of negative symptoms (Good et al., 2004, Harvey et al., 2001). Furthermore, completing the PANSS may take as long as performing an abbreviated NP assessment, so there is little benefit in time required to perform the assessment.

A recent scientific development has been the introduction of structured rating scales aimed at evaluating cognitive impairment (Keefe et al., 2006, Ventura et al., 2008, Ventura et al., 2010). These rating scales are much more abbreviated than the PANSS and do not have practice effects, as they are not performance-based (Goldberg et al., 2010). In addition, these rating scales are already in use in clinical treatment studies aimed at cognition in schizophrenia, where the Food and Drug Administration (FDA) requires the collection of a co-primary functional measure.

We present here the results of a randomized, double-blind, short-term comparative trial of lurasidone and ziprasidone in which structured informant-based rating scales were included as a priori measures. Lurasidone is a novel psychotropic agent with high affinity for D2 and 5-HT2A receptors, and for receptors implicated in cognition (5-HT7, 5-HT1A and α2c; Schmidt et al., 2001, Roth et al., 2004, Meyer et al., 2009). Lurasidone has no affinity for histamine H1 and acetylcholine M1 receptors, which are thought to contribute to side effects such as weight gain, sedation and worsening of cognitive deficits. In preclinical studies lurasidone has been shown to reverse scopolamine- and MK-801-induced impairment in learning and memory in the passive-avoidance test in rats (Ishiyama et al., 2007, Enomoto et al., 2008). The comparator medication in this study, ziprasidone, does not have substantial 5-HT7 affinity, has modest histaminergic activity and no affinity for acetylcholine M1 receptors (Daniel and Copeland, 2000).

The outcome measures used in the current study included a performance-based cognitive assessment battery that consisted of the majority of the tests from the MATRICS Consensus Cognitive Battery (MCCB; Nuechterlein et al., 2008), and an interviewer-rated measure of cognitive functioning, the Schizophrenia Cognition Rating Scale (SCoRS; Keefe et al., 2006). This structured rating scale is completed based on a standardized, 20-question interview with both the patient and an informant (when available, see below). We were interested in the sensitivity to cognitive improvement during short-term treatment with an atypical antipsychotic agent of both the performance-based and interview-based ratings (MCCB and SCoRS). We also performed analyses to evaluate whether any changes in the performance- or interview-based measures of cognitive change were correlated with changes in clinical symptoms, which might indicate “pseudospecificity” in the outcome measures.

Section snippets

Participants

Research participants were community dwelling patients with schizophrenia or schizoaffective disorder who had never received treatment with ziprasidone or lurasidone. Adult outpatients, ages 18–70 years old, who met DSM-IV criteria for schizophrenia or schizoaffective disorder that was chronic (at least 6 months duration), and stable, with no hospitalization or acute exacerbation of psychosis in the previous 3 months, were recruited. Exclusion criteria included a history of head trauma with loss

Data analyses

We used between-group t-tests to compare the change scores across the two treatments for the cognitive composite variable, each individual cognitive measure, and the SCoRS total score at the final observation for each patient. We also used within-sample t-tests to compare changes in these variables from baseline to endpoint within each treatment. Finally, we correlated the change scores for the individual and global cognitive performance items and the SCoRS total score and changes in PANSS

Results

A similar proportion of patients completed the study on lurasidone and ziprasidone [67.5% (n = 123) vs. 69.3% (n = 111)]. Demographic characteristics of the sample are presented in Table 2. There were no between-group differences in any baseline characteristics. Table 3 presents the baseline scores for the individual tests of the MCCB and for the SCoRS global score. T-tests found that none of the variables differed at baseline between the two treatments. The lack of differences between the two

Discussion

The results of this study indicate that clinician ratings of cognition, based on multiple sources of information in most cases, may be sensitive to the effects of antipsychotic treatment in schizophrenia. There were no differences between treatments on the MCCB; however, clinician interview-based ratings appeared to have some sensitivity to change for both of the treatments studied. Since the SCoRS ratings are not performance-based, these changes cannot be attributed to a practice effect,

Role of funding source

This study was funded by Merck and Company and Dainippon Sumitomo Pharma America (now known as Sunovion). The sponsor of this study provided the data to Dr. Harvey, who performed the statistical analyses. Three of the authors are also employed by Sunovion, but they served only as equally contributing authors for the submitted version of this paper. Lurasidone is approved for the acute treatment of schizophrenia by the US FDA now, but was not at the time this study was conducted.

Contributors

Drs. Harvey and Keefe consulted on the initial design of this study. Dr. Harvey analyzed the data and prepared the first draft of the paper and graphics. Dr. Keefe contributed to the writing of the paper. Dr. Ogassa edited the graphics and contributed to the writing of the paper. Drs. Loebel and Cucchiaro contributed to the writing of the paper.

Conflict of interest

During the past year Dr. Harvey has served as a consultant or advisor to Abbott Labs, Dainippon Sumitomo Pharma America (now known as Sunovion), Merck and Company, Cypress BioScience, Teva Pharma, and Shire Pharma. He had a research grant from Astra-Zeneca Pharma. He receives royalties from the Brief Assessment of Cognition in Schizophrenia (BACS) testing battery and the MATRICS Battery (BACS Symbol Coding).

Dr. Keefe reports that he currently or in the past 12 months has received

Acknowledgments

This study was designed by research scientists from Merck and Company while working in a previous collaborative effort with Dainippon Sumitomo Pharma America. These scientists were not involved in the analyses of these data or the writing of the paper. All individuals who contributed to this paper are listed as authors. No professional medical writer was involved in any portion of the preparation of the manuscripts.

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    Presented in part at the International Congress on Schizophrenia Research, San Diego, CA, 2009.

    ☆☆

    This study (Study D1050254) was supported by funding from Merck and Sunovion.

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