Innovations In Clinical Neuroscience

NOV-DEC 2017

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

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54 ICNS INNOVATIONS IN CLINICAL NEUROSCIENCE November-December 2017 • Volume 14 • Number 11–12 R E V I E W S Schizophrenia is a chronic remitting and relapsing disorder characterized by a wide range of psychological, behavioral and cognitive symptoms. Over more than half a century, dozens of antipsychotics have received regulatory approval, in the United States and internationally, for the treatment of schizophrenia. In 1987, Kay, Fishbein, and Opler 1 introduced the Positive and Negative Syndrome Scale (PANSS) as an "operationalized, drug- sensitive instrument that provides balanced representation of positive and negative symptoms and gauges their relationship to one another and to global psychopathology". Since its introduction, the PANSS has been the most widely used measure of efficacy in clinical trials in patients with schizophrenia. The original validation article has been cited in more than 14,000 published articles. The PANSS was developed by combining items from the Brief Psychiatric Rating Scale 2 and the Psychopathology Rating Schedule, 3 and enhancing the psychometric properties of the resulting instrument by clearly operationalizing item definitions and severity anchor points. The aim was to provide a reliable and valid measure of the two-factor (positive and negative) classification of schizophrenic symptoms that had been proposed by Crow in 1980. 4 The reliability and validity of the PANSS as a measure of outcome was demonstrated for the original positive, negative, and general psychopathology subscales. 5 In the decade after its introduction, it became clear that the two-factor model of psychopathology (or three-factor, including general psychopathology) was not optimal to fully characterize key symptom dimensions of schizophrenia or outcome in response to treatment. Factor and principal component analyses of the PANSS have consistently identified five factors that map to the diagnostic criteria of positive symptoms, negative symptoms, disorganized thinking, and the associated symptoms of hostility/excitement and depression/anxiety. 6–10 For the past two decades, the PANSS total score and the five so-called "Marder Factor" scores have been standard metrics for assessing efficacy in schizophrenia clinical trials. PANSS FACTORS AND ASSESSMENT OF EFFICAC Y: THE CHALLENGE OF PSEUDOSPECIFICIT Y For the standard (Marder) PANSS factors at baseline, the shared variance between A B S T R A C T The Positive and Negative Syndrome Scale (PANSS) is the most widely used efficacy measure in acute treatment studies of schizophrenia. However, interpretation of the efficacy of antipsychotics in improving specific symptom domains is confounded by moderate-to-high correlations among standard (Marder) PANSS factors. The authors review the results of an uncorrelated PANSS score matrix (UPSM) transform designed to reduce pseudospecificity in assessment of symptom change in patients with schizophrenia. Based on a factor analysis of five pooled, placebo-controlled lurasidone clinical trials (N=1,710 patients), a UPSM transform was identified that generated PANSS factors with high face validity (good correlation with standard Marder PANSS factors), and high specificity/ orthogonality (low levels of between-factor correlation measuring change during treatment). Between-factor correlations were low at baseline for both standard (Marder) PANSS factors and transformed PANSS factors. However, when measured change in symptom severity was measured during treatment (in a pooled 5-study analysis), there was a notable difference for standard PANSS factors, where changes across factors were found to be highly correlated (factors exhibited pseudospecificity), compared to transformed PANSS factors, where factor change scores exhibited the same low levels of between-factor correlation observed at baseline. At Week 6-endpoint, correlations among PANSS factor severity scores were moderate-to-high for standard factors (0.34–0.68), but continued to be low for the transformed factors (-0.22–0.20). As an additional validity check, we analyzed data from one of the original five pooled clinical trials that included other well-validated assessment scales (MADRS, Negative Symptom Assessment scale [NSA]). In this baseline analysis, UPSM-transformed PANSS factor severity scores (negative and depression factors) were found to correlate well with the MADRS and NSA. The availability of transformed PANSS factors with a high degree of orthogonality/specificity, but which retain a high degree of concurrent and face validity, can reduce pseudospecificity as a measurement confound, and should facilitate the drug development process, permitting a more accurate characterization of the efficacy of putative new agents in targeting specific symptom domains in patients with psychotic illness. KEYWORDS: Schizophrenia, antipsychotic agents, factor analysis, efficacy, clinical, clinical trials Understanding Antipsychotic Drug Treatment Effects: A Novel Method to Reduce Pseudospecificity of the Positive and Negative Syndrome Scale (PANSS) Factors by SETH C. HOPKINS, PhD; A JAY OGIRALA, PhD, ANTONY LOEBEL, MD; and KENNETH S. KOBLAN, PhD Drs. Hopkins, Ogirala, Loebel, and Koblan are with Sunovion Pharmaceuticals Inc, Marlborough, Massachusetts. Innov Clin Neurosci. 2017;14(11–12):54–58 FUNDING: Funding was provided by Sunovion Pharmaceuticals Inc. DISCLOSURES: The authors are employees of Sunovion Pharmaceuticals Inc. CORRESPONDENCE: Kenneth S. Koblan; Email: kenneth.koblan@sunovion.com.

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