Efficacy of iloperidone in schizophrenia: A PANSS five-factor analysis

Abstract

Background

The Positive and Negative Syndrome Scale (PANSS) total score is widely used to assess antipsychotic efficacy, however schizophrenia is a multi-dimensional disorder. We conducted a 5-factor analysis for evaluating the efficacy of iloperidone vs. placebo across these different domains in the treatment of schizophrenia.

Method

The 5-factor model was determined from pooled data from 7 clinical trials (4 placebo- and active-controlled and 3 non-inferiority active-comparator trials of iloperidone) in schizophrenia (N = 3580).Five factors were derived (excitement/hostility [P4,P7,G8,G14], depression/anxiety [G1,G2,G3,G4,G6], cognition [P2,N5,N7,G5,G10,G11,G12,G13,G15], positive [P1,P3,P5,P6,G9], and negative [N1,N2,N3,N4,N6,G7,G16]) from a factor analysis on the covariance matrix of 30 baseline PANSS items using a varimax rotation; factors retained had eigenvalues of ≥ 0.5. These newly derived 5 factors differ only slightly from other 5-factor analyses published by others using different datasets. The analysis of covariance model was then applied to assess these efficacy outcomes from the 4–6 week double-blind placebo and active controlled clinical trials of iloperidone.

Results

Based on the placebo-controlled trials, iloperidone improvements from baseline (least squared mean change ± standard error) were as follows: excitement/hostility, 0.4 ± 0.21 for 10–16 mg, 0.6 ± 0.43 for 20–24 mg vs. −1.0 ± 0.23 for placebo; P < 0.001 for both iloperidone doses vs. placebo; depression/anxiety, 1.9 ± 0.21 for 10–16 mg, 1.9 ± 0.41 for 20–24 mg vs. 1.1 ± 0.22 for placebo; P < 0.05 for 10–16 mg dose vs. placebo; cognition, 2.8 ± 0.35 for 10–16 mg, 3.9 ± 0.69 for 20–24 mg vs. 1.6 ± 0.38 for placebo; P < 0.05 for both iloperidone doses vs. placebo; positive, 3.7 ± 0.26 for 10–16 mg, 4.1 ± 0.53 for 20–24 mg vs. 2.7 ± 0.29 for placebo; P < 0.05 for both iloperidone doses vs. placebo; and negative, 2.2 ± 0.29 for 10–16 mg, 2.5 ± 0.58 for 20–24 mg vs. 1.3 ± 0.32 for placebo; P < 0.05 for 10–16 mg vs. placebo. Active controls validated iloperidone efficacy.

Conclusions

Iloperidone demonstrated positive treatment effects on these newly derived PANSS factors. The 10–16 mg and 20–24 mg dose groups had similar efficacy on the PANSS factors, with the exception of the depression/anxiety and negative factors, on which the 10–16 mg dose group showed statistical separation from placebo and the 20–24 mg dose group did not. At 6 weeks, the lack of separation from placebo for the higher dose group may have been due to the much smaller sample size in that group.

Introduction

The 30-item Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987)is commonly used in clinical trials to assess the psychopathology associated with schizophrenia. Although the PANSS has 3 subscales – positive symptoms, negative symptoms, and general psychopathology – some of the items assigned to one subscale may perhaps be better conceptualized as belonging to another symptom construct such as “mood” or “cognitive”. This, together with the growing understanding that schizophrenia is a multidimensional disorder with core psychotic, negative, mood, and cognitive components has led to the development of multiple-factor models of the PANSS (Lindenmayer et al., 1994, White et al., 1997, Marder et al., 1997, Van den Oord et al., 2006; see review by Lehoux et al., 2009). These can be used to describe the outcomes of clinical trials for the treatment of schizophrenia and discern differences in efficacy based on symptom dimensions (Lindenmayer et al., 2004).

Iloperidone is a second-generation antipsychotic that in 2009 received US Food and Drug Administration approval and has a current indication for the treatment of schizophrenia in adults (Citrome, 2009, Citrome, 2010, Novartis Pharmaceuticals Corporation, 2011). A pooled analysis was conducted to identify 5 PANSS factors using baseline ratings of 3580 subjects with schizophrenia (excluding schizoaffective disorder) across 7 studies (3 non-inferiority active-controlled and 4 placebo- and active-controlled Phase III studies involving iloperidone). After deriving these 5 PANSS factors, the panels were then used to evaluate the efficacy of iloperidone in subjects with schizophrenia from 4 pooled, placebo- and active-controlled clinical trials of 4 or 6 weeks’ duration.