Background SEP-363856 is a novel trace amine associated receptor-1 (TAAR1)/5-HT1A agonist with no dopamine-D2/5-HT2A antagonist activity. SEP-363856 showed significant antipsychotic efficacy in patients with schizophrenia, and a safety and tolerability profile similar to placebo and consistent with a non-D2 mechanism of action. Here, we examined measures of cognition and social functioning in schizophrenia patients receiving SEP-363856. Methods Patients aged 18–40 years with an acute exacerbation of schizophrenia were randomized, double-blind (DB), to 4-weeks of flexible-dose treatment with once daily SEP-363856 (N=120; 50 or 75 mg) or placebo (N=125). Patients (N=156) entering a subsequent 26-week open-label (OL) extension study were evaluated utilizing the Cogstate Brief Battery, administered at DB baseline and week 4, and OL baseline and weeks 12 and 26. Standardized z-scores were calculated for the Cogstate composite and subscale tasks (Detection task, Identification task, One Card Learning task, One Back task). The University of California San Diego Performance Based Skills Assessment (UPSA-B) scale was assessed at the same time-points, as were the following psychiatric scales: Positive and Negative Syndrome Scale (PANSS), the Brief Negative Symptom Scale (BNSS), the Montgomery–Åsberg Depression Rating Scale (MADRS), the Clinical Global Impression Scale, severity scale (CGI-S), and the Pittsburgh Sleep Quality Index global score (PSQI-global). Pearson correlation analyses were performed between DB baseline to Week 26 change in Cogstate composite and subscale scores and Week 26 change in the psychiatric scale scores. Results Small improvements, from DB baseline to Week 26, were observed in standardized scores on the Cogstate composite (+0.29), Identification task (+0.19), Detection task (+0.28); One Card learning task (+0.33); and One Back task (+0.33). Improvement from OL baseline at Week 26 was also observed on the mean [SD] UPSA-B total score (+6.2 [11.6]). At DB baseline, there were no correlations between CogState composite score and individual test scores with any of the psychiatric scales. Week 26 improvement in the following Cogstate composite and subscale tasks were correlated with Week 26 improvement in the following psychiatric scale scores: Cogstate composite score (PANSS total, r=-0.26; BNSS total, r=-0.31; CGI-S, r=-0.30; MADRS total, r=-0.23; PSQI-global, r=-0.23); Identification task (PANSS total, r=-0.30; BNSS total, r=-0.30), Detection task (BNSS total, r=-0.30; CGI-S, r=-0.28; PSQI-global, r=-0.23); One Card learning task (MADRS total, r=-0.29); and One Back task (PANSS total, r=-0.26). Discussion During 6-months of open-label extension treatment with SEP-363856, improvement in overall functioning was observed on the UPSA-B scale; and small but consistent improvement in cognition was noted in the Cogstate composite and subscale task scores. Endpoint reduction in the severity of schizophrenia-related symptomatology (eg, on the PANSS, BNSS, MADRS, insomnia) were associated with modest correlations, in the range of 0.2 to 0.3, in cognitive performance as measured by the Cogstate composite and subscale task scores.
BackgroundInterpretation of the efficacy of antipsychotic agents in treating schizophrenia using standard (Marder) Positive and Negative Syndrome Scale (PANSS) factors is confounded by moderate-to-high between-factor correlations. In previous pooled analyses of short-term, placebo-controlled lurasidone clinical trials, clustering and factor analysis identified an uncorrelated PANSS score matrix (UPSM) that generated transformed PANSS factor scores with high face validity (good correlation with standard [Marder] PANSS factors), and high specificity/orthogonality (low levels of between-factor correlation) at both baseline, and when measuring change during short-term treatment. In a validation analysis using 12 separate clinical trials, we previously confirmed that the weighted UPSM coefficients had generalizable utility, yielding transformed PANSS factors with high specificity while retaining good levels of correlation with standard PANSS factors. The aim of the current analysis was to determine whether distinct clinical subtypes of schizophrenia could be empirically derived from the transformed PANSS factor scores at baseline.MethodsIn a new analysis of a pooled sample of 5 placebo-controlled trials (N=1,710 patients), K-means clustering of baseline UPSM factor scores in MATLAB was used to identify whether clinical sub-groups could be empirically derived that were characterized by predominant symptom severity in one or more of the transformed PANSS factor domains. For each empirically derived domain thus identified, key demographic and clinical variables were examined, including baseline transformed PANSS factor severity scores [note: the weighted UPSM coefficient yields factor scores with numerical values that are much smaller than are observed with standard Marder factor scores]; and Montgomery-Åsberg Depression Rating Scale (MADRS) and Negative Symptom Assessment Scale (NSA) scores.ResultsCluster analysis using the UPSM transformed PANSS Factor scores identified 5 distinct clinical subtypes defined by the severity of the UPSM Factor score relative to the mean score for all patients on the respective transformed PANSS factors. For the predominant positive cluster, the mean transformed PANSS positive factor score was 3.9 (vs. a mean score of 2.9 ± 0.9 SD for all patients); for the predominant hostile cluster, the hostility factor score was 2.6 (vs. a mean score of 1.4 ± 1.1); for the predominant disorganized cluster, the disorganized factor score was 3.0 (vs. 2.5 ± 1.0); for the affective cluster, the anxiety and depression factors, respectively, were 2.3 (vs. 1.8 ± 0.9) and 2.7 (vs. 1.7 ± 1.0); and for the predominant negative cluster, the apathy/avolition and deficit of expression factors, respectively, were 3.1 (vs. 2.5 ± 0.9) and 2.5 (vs. 1.8 ± 0.9). Patients in the predominant negative cluster had the highest NSA score (61 vs. a mean score overall of 53); and patients in the predominant affective cluster had the highest MADRS score (16 vs. a mean score overall of 11).DiscussionThese results provide e...
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