Schizophrenia Research 120 (2010) 199–203 Contents lists available at ScienceDirect Schizophrenia Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / s c h r e s Effect of aripiprazole versus haloperidol on PANSS Prosocial items in early-episode patients with schizophrenia J.P. Docherty a,⁎, R.A. Baker b, J. Eudicone b, S. Mathew c, R.N. Marcus d, R.D. McQuade e, R. Mankoski b a b c d e Weill-Cornell Medical College, White Plains, NY, USA Bristol-Myers Squibb, Plainsboro, NJ, USA Otsuka America Pharmaceutical Inc., Rockville, MD, USA Bristol-Myers Squibb, Wallingford, CT, USA Otsuka Pharmaceutical Development and Commercialization Inc., Princeton, NJ, USA a r t i c l e i n f o Article history: Received 23 November 2009 Accepted 31 March 2010 Available online 23 May 2010 Keywords: Functioning Social Relationships a b s t r a c t Background and aim: Improving social functioning is critically important in early-episode schizophrenia, if patients are to achieve functional recovery. This post-hoc, pooled analysis of two studies compared the effect of aripiprazole versus haloperidol on social functioning in early-episode schizophrenia. Methods: Data were pooled from two 52 week, randomized (2:1), double-blind, multicenter studies involving 1294 patients with chronic schizophrenia who were in an acute psychotic episode and had a history of positive antipsychotic response during previous episodes. The early-episode group was deﬁned as patients who are ≤ 40 years of age with ≤ 5 years' duration of illness. Social functioning was assessed by mean change from baseline on the PANSS Prosocial subscale (ANCOVA and LOCF), comprising six PANSS items, and the Modiﬁed Prosocial subscale, comprising four PANSS items. Measurements were taken at approximately monthly intervals for up to 1 year. Results: Aripiprazole (n = 237) demonstrated signiﬁcant improvement versus haloperidol (n = 123) as early as Week 18 on both the Prosocial subscale (−4.75 versus − 3.78, p b 0.05) and on the Modiﬁed Prosocial subscale (− 3.16 versus − 2.28, p b 0.05). Patients receiving aripiprazole continued to show similar signiﬁcant improvement versus haloperidol at all remaining timepoints through Week 52 using the Modiﬁed Prosocial subscale, but less consistent improvement with the Prosocial subscale. Signiﬁcant advantage for the aripiprazoletreated patients was observed at Weeks 46 and 52 (endpoint) with both subscales. Conclusion: In patients with early-episode schizophrenia, aripiprazole demonstrates greater improvement than haloperidol on PANSS items related to social functioning. The cognitive and functional implications of these ﬁndings remain to be clariﬁed in future studies. © 2010 Published by Elsevier B.V. 1. Introduction ⁎ Corresponding author. Weill-Cornell Medical College, 21 Bloomingdale Road, White Plains, NY 10605, USA. Tel.: +1 914 843 2541; fax: +1 914 234 7733. E-mail address: [email protected] (J.P. Docherty). 0920-9964/$ – see front matter © 2010 Published by Elsevier B.V. doi:10.1016/j.schres.2010.03.040 Many patients with schizophrenia – up to two-thirds – are unable to perform fundamental social functions, even in the absence of ﬂorid psychosis (Bellack et al., 2007). This social dysfunction in schizophrenia can have devastating consequences, with few patients being successfully married or in regular productive employment (Bellack et al., 2007). Deﬁcits 200 J.P. Docherty et al. / Schizophrenia Research 120 (2010) 199–203 in social function impact negatively on the patient's community and economic status, increasing the risk of isolation, exclusion and poverty (Barrowclough and Tarrier, 1990; Yager and Ehmann, 2006). Importantly, social functioning impairments are already present at the ﬁrst psychotic episode (Grant et al., 2001) and these impairments, if left untreated, pose a progressively increasing barrier to overall functional recovery and become increasingly difﬁcult to remedy. Thus, monitoring and management of social functioning is imperative from an early stage of the illness. A Prosocial subscale of the Positive and Negative Syndrome Scale (PANSS) that reﬂects impairment of interpersonal engagement has been derived by factor analysis (Purnine et al., 2000). It consists of six items (Table 1), four of which reﬂect a lack of social interaction or emotional withdrawal or suspiciousness. In addition, a Modiﬁed Prosocial subscale (Baran and Docherty, 2008) was derived that consists of four PANSS items, including difﬁculty with abstract thinking, an item that is not contained in the Prosocial subscale but one that is empirically demonstrated as a prominent residual symptom following resolution of an acute psychotic episode (Table 1). A high score on the Prosocial or Modiﬁed Prosocial subscales reﬂects emotional withdrawal and a lack of social interaction. Aripiprazole is an atypical antipsychotic with a novel mechanism of action, exerting partial agonist activity at dopamine D2 and D3 (Burris et al., 2002; Shapiro et al., 2003; Tadori et al., 2005, 2008) and serotonin 5-HT1A receptors, and antagonist activity at 5-HT2A receptors (Jordan et al., 2002, 2004). In addition to efﬁcacy for the treatment of primary positive and negative symptoms of schizophrenia (Kane et al., 2002; Kasper et al., 2003; Pigott et al., 2003; Potkin et al., 2003), aripiprazole has shown beneﬁts on quality of life outcomes in patients with schizophrenia (Kane et al., 2007; Kerwin et al., 2007; Wolf et al., 2007). In addition, patients switched from either olanzapine or risperidone to aripiprazole manifested improvements in subjective well-being (Mizrahi et al., 2009). Although improvement in social functioning is an important treatment goal, limited data exist on the effect of antipsychotics on social functioning outcomes. This paper presents the results of a post-hoc pooled analysis of two 52 week studies of aripiprazole versus haloperidol in patients with early-episode schizophrenia. The aim of these analyses was to assess the comparative effect of aripiprazole compared with haloperidol on the PANSS Prosocial items in patients with early-episode schizophrenia, given the importance of minimizing the impact of these symptoms early in the course of illness. Table 1 PANSS items associated with social functioning. Prosocial items Purnine et al. (2000) Modiﬁed Prosocial items Baran and Docherty (2008) G16: Active social avoidance N2: Emotional withdrawal N4: Passive social withdrawal N7: Stereotyped thinking P3: Hallucinatory behavior P6: Suspiciousness/persecution G16: Active social avoidance N2: Emotional withdrawal N4: Passive/apathetic social withdrawal N5: Difﬁculty in abstract thinking PANSS, Positive and Negative Syndrome Scale. 2. Methods 2.1. Study design Data from two 52 week, double-blind, randomized, controlled trials comparing aripiprazole with haloperidol in the treatment of schizophrenia were pooled for post-hoc analysis (31-98-217 and 31-98-304). The primary study results and associated methodology have previously been described (Kasper et al., 2003). 2.2. Patients The parent studies included males and females, aged 18– 65 years with a DSM-IV diagnosis of schizophrenia, who were experiencing an acute relapse—deﬁned as PANSS score ≥60, and a score of ≥4 on at least two of four PANSS psychotic items. For inclusion in this analysis, patients also had to meet criteria for early episode: ≤40 years of age and ≤5 years duration of illness. 2.3. Dosing Patients were randomly assigned in a 2:1 ratio to aripiprazole (30 mg) or haloperidol (5 mg, Days 1–3; 10 mg, Day 4 onwards). The study medication was administered orally once-daily after breakfast. After completion of the ﬁrst week of the double-blind acute treatment phase, a one-time dose reduction was permitted as determined by clinical judgement (20 mg for aripiprazole or 7 mg for haloperidol). Thus, patients in the two studies received either 20–30 mg/day of aripiprazole or 5–10 mg/day of haloperidol. 2.4. Assessments Efﬁcacy for the treatment of positive and negative symptoms was evaluated by the mean change in PANSS Total score from baseline to Week 52 and those results have been reported elsewhere (Girgis et al., submitted for publication; Kim et al., 2007). Social functioning was assessed by the mean change in the PANSS Prosocial subscale (Purnine et al., 2000) and the Modiﬁed Prosocial subscale (Baran and Docherty, 2008). The items included in the Prosocial and Modiﬁed Prosocial scale are shown in Table 1. The “stereotyped thinking” item is assigned an opposite sign in the scale, as it had an opposite signed factor-loading. Safety and tolerability were evaluated by reports of adverse events (AEs), serious adverse events (SAEs), discontinuations from study due to AEs, change in weight and clinical laboratory tests. 2.5. Statistical analysis Analysis of covariance (ANCOVA) was used to analyze the least squares mean change from baseline for the earlyepisode population in both treatment groups, with treatment and protocol as the main effects and baseline score as covariate with last observation carried forward (LOCF) for the PANSS Total score and the two subscales — Prosocial and Modiﬁed Prosocial. An observed case (OC) analysis was also conducted. J.P. Docherty et al. / Schizophrenia Research 120 (2010) 199–203 3. Results 3.1. Patients The mean age of this population of early-episode patients was 27.5 years in the haloperidol group and 27.0 years in the aripiprazole group. The majority of patients in both groups were Caucasian males. Baseline PANSS Total scores were similar in both groups: haloperidol, 92.5; aripiprazole, 95.2. The full demographics of this population have been published previously (Girgis et al., submitted for publication; Kim et al., 2007). A greater proportion of patients with early-episode schizophrenia treated with aripiprazole versus haloperidol completed double-blind treatment (48% versus 28%, p b 0.01) (Table 2). Signiﬁcantly fewer patients discontinued due to AEs unrelated to worsening schizophrenia from the aripiprazole versus haloperidol groups (11% versus 29%, p b 0.01) (Table 2). 3.2. Dosing The mean daily dose of aripiprazole was 28.1 (SD = 3.1) mg/day and that of haloperidol was 8.9 (SD = 1.3) mg/day for those subjects with early-episode schizophrenia. 3.3. Efﬁcacy results Mean change in PANSS Total score at Week 52 was signiﬁcantly greater in patients receiving aripiprazole versus haloperidol (−21.8 versus −15.3; p = 0.02). 3.4. Social functioning results Aripiprazole demonstrated signiﬁcant improvements versus haloperidol as early as Week 18 on both the Prosocial subscale (−4.75 versus − 3.78, LOCF, p b 0.05) (Fig. 1A) and on the Modiﬁed Prosocial subscale (−3.16 versus −2.28, LOCF, p b 0.05) (Fig. 1B). Using the LCOF analysis, patients showed similar signiﬁcant improvements over time at all remaining testing intervals through Week 52 using the Modiﬁed Prosocial subscale, but less consistent improvement over time with the Prosocial subscale. Similar signiﬁcant improvements at Weeks 46 and 52 (endpoint) were observed with both subscales (LOCF). Using an OC analysis, the direction of change in both scales was consistent. However, Table 2 Disposition of patients with early-episode schizophrenia. Reason for discontinuation Efﬁcacy sample Discontinued double-blind treatment Lost to follow-up Withdrawal of consent Insufﬁcient clinical response Adverse event (worsening schizophrenia) Other adverse event Non-compliance Protocol violation Patient met withdrawal criteria Completed double-blind treatment *pb 0.01 versus haloperidol, Chi-square test. Haloperidol Aripiprazole 123 89 (72) 4 (3) 20 (16) 8 (7) 15 (12) 36 (29) 4 (3) 1 (1) 1 (1) 34 (28) 237 123 (52) 6 (3) 42 (18) 20 (8) 23 (10) 25 (11)* 6 (3) 1 (0) 0 114 (48)* 201 the magnitude of the treatment differences at Week 34 and beyond was approximately two-thirds that of the LOCF analyses, and not large enough for a statistically signiﬁcant difference to be observed except at Week 34, with a trend toward signiﬁcance (p b 0.10) at Week 52. 3.5. Safety results The tolerability proﬁle of aripiprazole in this subgroup of patients with early-episode schizophrenia was generally similar to the overall population. The most common AEs in the aripiprazole group were insomnia, anxiety and akathisia. The three most common AEs in the haloperidol group were extrapyramidal syndrome (EPS), akathisia and insomnia. 4. Discussion These data suggest that aripiprazole is superior to haloperidol for the reduction of social functioning impairment in earlyepisode schizophrenia patients, as measured by the PANSS Prosocial and Modiﬁed Prosocial subscales. Such an effect may provide an important advantage for patients in the early phase of their illness in the achievement of a greater degree of overall functional recovery. The efﬁcacy of aripiprazole in improving social functioning is in addition to the known efﬁcacy in treating a broad range of other symptoms (Janicak et al., 2009). Further analysis of the dataset presented herein conﬁrmed that aripiprazole provides signiﬁcantly greater improvement than haloperidol on the PANSS Total score, even when the Prosocial (−17.3 versus −12.2, p = 0.03) or Modiﬁed Prosocial items (−18.7 versus −13.5, p = 0.03) are excluded, conﬁrming that efﬁcacy is not restricted to those items. However, an evaluation of all timepoints and effect sizes suggests that the items from the Modiﬁed Prosocial subscale have slightly more effect than other PANSS items in determining differences in efﬁcacy between aripiprazole and haloperidol (data not shown). Social functioning deﬁcits in schizophrenia are already present early in the course of illness (Grant et al., 2001), and improvement in such domains is of essential clinical value. Social withdrawal and social exclusion are more likely among patients with social functioning impairments, as these patients often have problems holding an appropriate conversation, conveying their needs and feelings, or developing close personal relationships (Bellack et al., 2007). One strength of this analysis is the duration of the studies from which the data is derived, an important consideration since improvements in social functioning can only be meaningful if they endure. This study demonstrated that the beneﬁcial effect of aripiprazole, once achieved, was maintained for up to one year. Another strength is the use of PANSS-derived measures of social function. The broad use of the PANSS in clinical studies makes a large number of studies accessible to post-hoc analyses regarding social functioning. A primary limitation of this paper is the post-hoc nature of the analysis. In addition, the dose of haloperidol (5–10 mg/day) used in this study, although within a range commonly seen both in clinical practice and in other published studies, may be considered to exceed optimal levels and may account for the observed differences. It is important to note, however, that lower doses of haloperidol may be accompanied by an increased risk of relapse (Csernansky et al., 2002; Marder et 202 J.P. Docherty et al. / Schizophrenia Research 120 (2010) 199–203 Fig. 1. A. Mean change from baseline in PANSS Prosocial subscale (LOCF, efﬁcacy sample) (*p b 0.05 versus haloperidol). B. Mean change from baseline in PANSS Modiﬁed Prosocial subscale (LOCF, efﬁcacy sample) (*p b 0.05 versus haloperidol). al., 2003; Potkin et al., 2009). Post-hoc subgroup analyses raise the potential for a Type I error. There are also limitations to the speculation that functional recovery may be positively inﬂuenced by improvement in the Prosocial items. Overall functional recovery is inﬂuenced by many variables, and the effect of an improvement in a PANSS-derived measure of social functioning on overall functional recovery still needs to be empirically assessed. Finally, consideration must be given to the fact that the treatment differences observed in the OC analyses were less robust than those seen in the LOCF analyses, although the sample sizes in the former were considerably smaller. In conclusion, however, these data do suggest that for patients with early-episode schizophrenia, aripiprazole treatment may have an important enduring beneﬁt over haloperidol in providing improvement in social function. Role of funding source This study was supported by Bristol-Myers Squibb(Princeton, NJ) and Otsuka Pharmaceutical Co., Ltd. (Tokyo, Japan). Bristol-Myers Squibb had a role in the study design, analysis interpretation of the data, writing of report and decision to submit the paper for publication. Editorial support for the preparation of this manuscript was provided by Ogilvy Healthworld Medical Education; funding was provided by Bristol-Myers Squibb. Contributors J.P. Docherty developed one of the subscales used in these post-hoc evaluations; independently proposed the idea for the analyses; and was involved in directing the analysis and interpretation of the ﬁndings and drafting, reviewing and approving the manuscript. R.A. Baker, S. Mathew, R.N. Marcus, R.D. McQuade, and R. Mankoski played a critical role in designing the post-hoc analyses, analysis and interpretation of data, literature searches and analyses, or drafting, reviewing and approving the manuscript. J. Eudicone undertook the statistical analysis and was involved in reviewing and approving the manuscript. Conﬂict of interest Dr John Docherty has been on the Advisory Boards, Speakers Bureau or has received grants from: Bristol-Myers Squibb, AstraZeneca, Janssen, and Forest, Pﬁzer, and Merck. Ross A Baker, James Eudicone, Ronald N. Marcus, and Raymond Mankoski are employees of Bristol-Myers Squibb. Suja Mathew is an employee of Otsuka America Pharmaceutical Inc., Rockville, MD, USA. Robert D. McQuade is an employee of Otsuka Pharmaceutical Development & Commercialization, Inc. J.P. 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