Innovations In Clinical Neuroscience

NOV-DEC 2017

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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24 ICNS INNOVATIONS IN CLINICAL NEUROSCIENCE November-December 2017 • Volume 14 • Number 11–12 O R I G I N A L R E S E A R C H treatment-related data, on the longitudinal relationships between improved insight and neurocognitive performance, functional capacity, quality of well-being, and depressive symptoms over time. The objective of this post-hoc analysis was to evaluate the short-term and long-term effects of lurasidone and quetiapine extended release (XR) on clinically rated insight and judgment in a six-month, double-blind, continuation period that followed an acute six-week trial. We also evaluated the extent to which treatment- related changes in insight were associated with improvements in cognition, functional capacity, quality of well-being, and depressive symptoms in patients followed for up to six months in the continuation study. METHODS We conducted a post-hoc analysis based on data from a previously reported randomized, double-blind, six-week, placebo- and active- controlled acute study, 22 followed by a one-year, double-blind continuation study. 23 Study conduct was consistent with the Declaration of Helsinki and in accordance with Good Clinical Practices as required by the International Conference on Harmonization guidelines. All patients provided written informed consent prior to study enrollment. Subjects and study treatment. This multiregional study, conducted in the United States and five other countries, enrolled patients with a primary diagnosis of schizophrenia who had recently been hospitalized for an acute exacerbation of psychotic symptoms. Patients who met entry criteria were randomized to receive six weeks of double-blind treatment with once-daily doses of lurasidone (80mg/d or 160mg/d), quetiapine XR (600mg/d), or placebo. Upon completion of the initial six- week study, patients were eligible to receive continued treatment with either flexible-dose lurasidone 40 to 160mg/d (the lurasidone-to- lurasidone cohort) (LUR-LUR) or flexible dose quetiapine XR 200-800mg/d (the quetiapine XR-to-quetiapine XR cohort) (QXR-QXR) in the one-year, double-blind continuation study. Subjects who had been treated with placebo in the initial six-week study were switched in blinded fashion to flexible-dose lurasidone 40 to 160mg/d treatment (the placebo-to-lurasidone cohort) (PBO-LUR). All study medications were taken once daily, in the evening, with food. Statistical methods. This post-hoc analysis was based on the intent-to-treat sample, which consisted of all patients who received at least one dose of study medication, and had at least one postbaseline PANSS assessment during the 6 weeks in the core study followed by the 6 months in the extension study. The effect of treatment on change in outcome measure from baseline (week 0 in acute phase) was evaluated using Mixed Model for Repeated Measures (MMRM) (33), with fixed effects terms for treatment, baseline score, visit, treatment-by- visit, and study site. Longitudinal relationships between improvement in insight and changes in outcome measures from acute baseline (week 0) to week 6 (end of acute phase) and week 32 (month 6 of extension phase) were assessed based on the regression coefficient (slope) of change score in insight in a mixed-effects longitudinal data analysis (LDA) model.(33) The sign of change in PANSS-item G12 (where higher score indicates greater symptom severity) was reversed so that positive values of change scores represented improvement from baseline, when examining its longitudinal association with improvement of both cognition, UPSA-B and QWB-SA scores (where higher scores indicate better functioning and quality of well- being). For purposes of categorical analysis, an item score of > 4 (moderate severity) was set as the threshold for impaired insight. RESULTS Figure 1 depicts the disposition of subjects who were randomized and completed both treatment periods. Among the 482 subjects FIGURE 1. Disposition of subjects (*6-month extension phase in a 12-month, double-blind continuation study) *

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