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. 2016 Oct 14;7(2):59–65. doi: 10.1177/2045125316673012

The effect of long-acting paliperidone palmitate once-monthly on negative and depressive symptoms in patients with schizophrenia switched from previous unsuccessful treatment with oral aripiprazole

Andreas Schreiner 1,✉, Paul Bergmans 2, Pierre Cherubin 3, Ludger Hargarter 4
PMCID: PMC5315228  PMID: 28255435

Abstract

Background:

The negative symptoms of schizophrenia are generally harder to recognize, more difficult to treat than positive symptoms, and have a significant impact on patient functioning and overall outcomes. Treatment with aripiprazole may be associated with benefits on negative symptoms and functioning given its partial agonism to the dopamine D2 receptor. The aim of this subanalysis was to explore the impact of flexibly dosed, long-acting paliperidone palmitate once monthly (PP1M) on negative and depressive symptoms, disorganized thoughts, anxiety, extrapyramidal symptoms, and patient functioning in nonacute adult patients with schizophrenia previously unsuccessfully treated with oral aripiprazole monotherapy.

Methods:

Post-hoc subanalysis of 46 nonacute but symptomatic patients enrolled in a prospective, interventional, single-arm, multicenter, open-label 6-month study.

Results:

At endpoint, improvements of ⩾ 20% and ⩾ 50% in the Positive and Negative Syndrome Scale (PANSS) total score were observed in 52.2% and 21.7% of patients, respectively. Significant and clinically relevant improvements were observed at endpoint in mean (standard deviation [SD]) PANSS negative subscale score (−3.0 (5.0); p < 0.0001) and in the PANSS Marder factor scores for negative symptoms (−2.9 (5.4); p = 0.0006), disorganized thoughts (−2.8 (4.3); p < 0.0001) and anxiety/depression (−1.8 (3.9); p = 0.0031). Patient functioning assessed by mean (SD) Personal and Social Performance scale score (3.9 (13.2); p = 0.0409), Mini International Classification of Functioning rating for Activity and Participation Disorders in Psychological Illnesses total scores (−2.9 (7.1); p = 0.0079), and Extrapyramidal Symptom Rating Scale scores (−0.6 (3.4); p = 0.0456) improved significantly at endpoint. PP1M was well tolerated with no new safety signals.

Conclusions:

Six-month treatment with flexibly dosed PP1M was associated with significant and clinically relevant improvements in negative and depressive symptoms, disorganized thoughts, functioning, and extrapyramidal symptoms in nonacute but symptomatic patients with schizophrenia previously unsuccessfully treated with oral aripiprazole.

Keywords: negative symptoms, schizophrenia, paliperidone palmitate, functioning

Introduction

Schizophrenia is a chronic and often debilitating disorder that develops long before the symptomatic onset of illness and is often marked by psychotic relapses, treatment failure, and incomplete remission and recovery along the treatment pathway [Lieberman et al. 2001]. The full onset of schizophrenia is marked by the presence of positive, negative, and cognitive symptoms [National Institutes of Health, 2009], and most patients require long-term treatment. Antipsychotic (AP) monotherapy is the preferred treatment option for relapse prevention and for reducing symptoms over the longer term [Hasan et al. 2013].

Negative symptoms of schizophrenia include affective flattening, poverty of speech, lack of social engagement, withdrawal, avolition, and anhedonia, among others [Schooler, 2006; National Institutes of Health, 2009], and can be harder to recognize and more difficult to treat. Prominent negative symptoms and clinically relevant cognitive impairment affect approximately 40% and 80% of people with schizophrenia, respectively [Carbon and Correll, 2014]. Moreover, negative and cognitive symptoms are closely related to functional outcomes, such as social and vocational skills and independent living [Harvey and Strassnig, 2012], and contribute substantially to the overall illness burden [Carbon and Correll, 2014]. Improvements in relevant outcomes, such as cognition, health-related quality of life, and social functioning, are recognized as important indices of treatment success that may reflect on the patient’s ability to function on a day-to-day basis [Huang et al. 2012]. However, the heterogeneous and often chronic nature of negative symptoms presents a challenge for pharmacological and nonpharmacological interventions [Galderisi et al. 2013]. Therefore, approaches to describe, measure, and manage these symptom domains are relevant [Carbon and Correll, 2014]. It has been suggested that treatment with aripiprazole, a partial agonist of the dopamine D2 receptor and the 5-hydroxytryptamine 5-HT1A receptor may be associated with benefits on negative symptoms and functioning in patients with schizophrenia [Stip and Tourjman, 2010]. However, a recent meta-analysis concluded that long-term data were sparse and that available information comparing the efficacy of aripiprazole with other atypical APs was inadequate [Khanna et al. 2014].

The Paliperidone Palmitate Flexible Dosing in Schizophrenia (PALMFlexS) trial was a prospective, pragmatic 6-month study designed specifically to mimic real-world clinical situations involving acute and nonacute patients who had been unsuccessfully treated with previous oral or long-acting injectable APs, and who were switched to long-acting paliperidone palmitate once monthly (PP1M) [Schreiner et al. 2014, 2015a; Hargarter et al. 2015]. The aim of the present analysis was to explore the impact of flexibly dosed PP1M on negative and depressive symptoms, disorganized thoughts, anxiety, extrapyramidal symptoms, and patient functioning, specifically in a subgroup of nonacute adult patients with schizophrenia previously unsuccessfully treated with oral aripiprazole.

Materials and methods

Study design

This study was a prospective, interventional, single-arm, international, multicenter 6-month study performed in patients with schizophrenia (Clinicaltrials.gov number: NCT01281527). Trial participants were recruited from 160 centers across Austria, Belgium, Croatia, Denmark, Estonia, France, Germany, Greece, Hungary, Israel, Italy, Latvia, Lithuania, The Netherlands, Portugal, Spain, Sweden, Switzerland, Turkey, Ukraine, and the United Kingdom.

Before trial initiation, the protocol was reviewed and approved by an independent ethics committee in all participating countries. The trial was performed in accordance with the Declaration of Helsinki and was consistent with the good clinical practice guideline of the International Conference on Harmonization and applicable regulatory requirements. Before any trial-related activities commenced, patients provided informed written consent. Full details of the study methodology have been published elsewhere [Schreiner et al. 2014, 2015b].

Briefly, the study consisted of a 7-day screening and a 6-month prospective study period. The screening period included a 2-day oral tolerability test with daily paliperidone extended-release (ER) tablets for patients without source documentation of previous risperidone or paliperidone exposure. Eligible participants were male and female non-acute but symptomatic patients with schizophrenia (Diagnostic and Statistical Manual of Mental Disorder IV) aged 18 years or older, who were switched to PP1M from previous unsuccessful oral AP treatment with a change in Clinical Global Impression–Severity score of ⩽ 1 in the 4 weeks before enrollment. PP1M was initiated in line with its prescribing information using 150 mg Eq. on day 1 and 100 mg Eq. on day 8, both administered in the deltoid muscle. Subsequently, the flexible paliperidone palmitate maintenance dose (50–150 mg Eq.) was given once monthly (± 7 days) in either the deltoid or gluteal muscle at the discretion of the treating physician. The present analysis evaluated patients with previous unsuccessful treatment with a therapeutic dose of oral aripiprazole monotherapy. At initiation of PP1M, previous oral aripiprazole was tapered off at the discretion of the treating physician, preferably within a maximum of 4 weeks.

Objectives and efficacy assessments

The primary study objectives were to explore the tolerability, safety, and treatment response of a switch to flexibly dosed PP1M. The primary statistical endpoint was change from baseline in Positive and Negative Syndrome Scale (PANSS) score. Efficacy assessments included mean change from baseline to endpoint in various symptom assessments and quality-of-life scales, including: PANSS negative symptoms subscale [Kay et al. 1987], PANSS Marder factor scores [Marder et al. 1997], Personal and Social Performance scale (PSP) total and domain scores [Morosini et al. 2000], and Mini International Classification of Functioning rating for Activity and Participation Disorders in Psychological Illnesses (Mini-ICF-APP) [Linden and Baron, 2005; Molodynski et al. 2013].

Safety assessments

Adverse events and treatment-emergent adverse events (TEAEs) were monitored throughout the study. Extrapyramidal motor symptoms were assessed using the Extrapyramidal Symptom Rating Scale (ESRS) [Chouinard and Margolese, 2005].

Data analysis

The intent-to-treat population comprised all patients who received at least one dose of PP1M. Actual values and changes from baseline were summarized descriptively at each assessment time point and at endpoint. Endpoint analysis using the last observation carried forward method was performed in addition to observed-case analysis. Categorical variables were summarized with frequency and percentage. Quantitative differences between subgroups by reason for switching were tested by means of the Wilcoxon two-sample test and within-group changes from baseline were tested by means of the Wilcoxon signed-rank test. There were no adjustments for multiple comparisons, thus all p values are nominal.

Results

Disposition and demographic characteristics

Patient disposition is summarized in Supplementary Figure 1. Of patients who initiated PP1M treatment, 28.3% (n = 13/46) were switched for lack of efficacy with previous oral aripiprazole and 71.7% (n = 33/46) were switched for other reasons (Supplementary Figure 1). Baseline demographic characteristics are summarized in Supplementary Table 1. Patients had an average age of 34.4 ± 9.4 years, and were predominately male (73.9%). The majority of patients had more than one previous psychiatric hospitalization (71.7%) and at baseline received a mean daily dose of oral aripiprazole of 22.7 ± 10.7 mg (Supplementary Table 1).

Efficacy outcomes

There was a statistically significant and clinically relevant improvement with PP1M treatment in mean PANSS total scores (standard deviation [SD]) from baseline to endpoint (74.7 [14.9] versus 62.6 [16.5]) with a change (SD) from baseline of −12.2 (16.7) (95% confidence interval [CI], −17.1–7.2; p < 0.0001). Statistically significant improvements in PANSS negative subscale score were observed beginning at month 1 and were maintained through to endpoint (Figure 1). Improvements of ⩾ 20% and ⩾ 50% on PANSS total score at endpoint were observed in 52.2% (n = 24/46) and 21.7% (n = 10/46) of patients, respectively.

Figure 1.

Figure 1.

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Change in PANSS negative subscale score over time.

*p < 0.05 versus baseline; **p < 0.0001 versus baseline, Wilcoxon signed-rank test. Error bars represent standard deviation.

BL, baseline; PANSS, Positive and Negative Syndrome Scale; PP1M, paliperidone palmitate once-monthly.

Significant improvements were observed in the negative, disorganized thoughts, and anxiety/depression PANSS Marder factor scores (Figure 2). For negative symptoms, mean Marder factor scores (SD) were significantly reduced from 19.5 (5.8) at baseline to 16.7 (5.1) at month 2 (p < 0.0001), and remained significantly lower through to endpoint: 16.6 (5.9) (p = 0.0006). Scores for disorganized thoughts (SD) were significantly reduced from 17.0 (4.6) at baseline to 15.4 (4.1) at day 8 (p < 0.0001), and remained significantly reduced through to endpoint: 14.3 (4.5) (p < 0.0001). Similarly, mean Marder factor scores for anxiety/depression (SD) were significantly reduced from 10.3 (3.6) at baseline to 9.2 (3.4) at day 8 (p = 0.0063), and remained significantly reduced at endpoint: 8.5 (2.9) (p = 0.0031).

Figure 2.

Figure 2.

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PANSS Marder factor scores: (a) negative symptoms; (b) disorganized thoughts; (c) anxiety/depression.

*p < 0.01 versus baseline; **p < 0.001 versus baseline; ***p ⩽ 0.0001 versus baseline, Wilcoxon signed-rank test. Error bars represent standard deviation.

†Blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, lack of spontaneity (items 1, 2, 3, 4, and 6 of the negative subscale), motor retardation, active social avoidance (items 7 and 16 of the general psychopathology subscale). ‡Conceptual disorganization (item 2 of the positive subscale), difficulty in abstract thinking (item 5 of the negative subscale), mannerisms and posturing, disorientation, poor attention, disturbance of volition, preoccupation (items 5, 10, 11, 13, and 15 of the general psychopathology subscale). §Anxiety, guilt feelings, tension, depression (items 2, 3, 4, and 6 of the general psychopathology subscale).

BL, baseline; PANSS, Positive and Negative Syndrome Scale; PP1M, paliperidone palmitate once monthly.

There were significant functional improvements in patients’ personal and social performance as assessed by the PSP total score (SD), which improved by 3.9 (13.2) points from baseline to endpoint (p = 0.0409), and the Mini-ICF-APP score (SD), which improved by 2.9 (7.1) points from baseline to endpoint (p = 0.0079) (Table 1). Significant improvements were also observed in the PSP subdomains of socially useful activities, including work and study, personal and social relationships, and self-care (Supplementary Table 2), as well as in the Mini-ICF-APP subdomains of flexibility, self-assertion, and contact with others (Supplementary Table 3).

Table 1.

Patient functioning (efficacy intent-to-treat population; n = 46).*

Mean score Baseline Endpoint Mean change from baseline to endpoint 95% confidence interval p value‡
PSP total score, SD (n = 44) 58.9 (13.4) 62.9 (15.2) 3.9 (13.2) −0.1, 8.0 0.0409
Mini-ICF-APP total score,$ SD (n = 43) 19.0 (7.8) 16.1 (9.8) −2.9 (7.1) −5.1, −0.7 0.0079
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*

Only patients with a baseline measurement and at least one follow-up assessment were included.

$

A lower Mini-ICF-APP total score denotes improved participation and activation.

‡

Wilcoxon signed-rank test.

Mini-ICF-APP, Mini International Classification of Functioning rating for Activity and Participation Disorders in Psychological Illnesses; PSP, Personal and Social Performance; SD, standard deviation.

Safety outcomes

Two-thirds of patients (69.6%; n = 32/46) had at least one TEAE, most of which (93.3%) were rated as mild or moderate in intensity. The most common TEAE (possibly, probably or very likely related to PP1M treatment was akathisia (8.7%; n = 4/46). Akathisia was reported in one patient during the first week of treatment and during or after the third week in the other three patients. Other TEAEs related to PP1M with an incidence of 5% or more were injection-site pain, weight increase, and abnormal weight gain in 6.5% of patients each (n = 3/46) (Supplementary Table 4). Mean weight change (SD) from baseline to endpoint was 3.5 (6.3) kg (95% CI, 1.5–5.4). Extrapyramidal symptoms significantly improved with a mean change in the ESRS total score (SD) from baseline to endpoint of −0.6 (3.4), p = 0.0456 (Supplementary Figure 2). Increased blood prolactin plasma levels were spontaneously reported in two patients (4.3%).

Discussion

The pragmatic and flexible-dose study design of the PALMFlexS study provides a clinically relevant setting to assess treatment options in daily practice, allowing physicians to adjust, alter, and optimize treatment according to their patients’ needs [Schreiner et al. 2014]. The current analysis showed that treatment with PP1M was associated with significant and clinically relevant improvements in negative, depressive, and anxiety symptoms as well as disorganized thoughts in nonacute patients with schizophrenia after unsuccessful treatment with oral aripiprazole. Such observation is of clinical relevance because patients were considered stable before switching, and were receiving a therapeutic dose of oral aripiprazole with no relevant changes in disease severity for at least 1 month. Patients’ personal and social performance, their capabilities for participation and activation, as well as ESRS total score also improved significantly following treatment with PP1M.

Persistent negative symptoms are important contributors to adherence problems in patients with schizophrenia, as they can impact both the willingness and the ability to take medication. A patient may become apathetic and minimize the benefits of taking medication, or may lack the motivation to follow through with their treatment regimen [Velligan et al. 2009]. Aripiprazole’s mechanism of action, in particular the partial D2 and 5-HT1A receptor agonism [De Bartolomeis et al. 2015], has been proposed to be associated with benefits on negative symptoms and functioning in patients with schizophrenia [Stip and Tourjman, 2010]. The present study not only supports results from previous studies in acute and nonacute patients with schizophrenia who demonstrated relevant improvements in functioning when switching to PP1M [Pandina et al. 2011, Schreiner et al. 2014, 2015a; Hargarter et al. 2015], but also supports available evidence that clinically relevant improvements can be observed in difficult-to-treat symptom domains such as negative symptoms.

The rate of akathisia in the present analysis was somewhat higher (8.7%) compared with patients switched from other oral atypical AP monotherapies (range, 2.6–5.7%) in the parent study [Schreiner et al. 2014]. Although limited patient numbers may prevent firm conclusions, the high affinity of aripiprazole for dopamine D2 receptors [Shapiro et al. 2003], and the long half-life of aripiprazole (75 h) and its active metabolite (dehydro-aripiprazole, 94 h) [De Bartolomeis et al. 2015], may have contributed to the occurrence of akathisia. Therefore, it may be clinically advisable to monitor and, if needed, temporarily treat patients for akathisia when switching from aripiprazole to PP1M.

The proportion of patients with clinically relevant weight gain (⩾ 7%) was greater in patients switched from oral aripiprazole to PP1M (27.9%) compared with those switched from other atypical APs to PP1M in the parent study (range, 10.3–26.8%) [Schreiner et al. 2016]. In this context, it is important to note that the baseline body mass index of patients switched from oral aripiprazole was 30.4 kg/m2 and differed for each of the other subgroups (olanzapine, 27.4 kg/m2; paliperidone ER, 26.9 kg/m2; quetiapine, 28.2 kg/m2; risperidone, 27.2 kg/m2); thus patient selection may have contributed to the observed differences in weight gain. However, in a recent randomized controlled 2-year study, the rate of clinically relevant weight gain was lower for PP1M compared with oral aripiprazole (20.6% versus 23.5%, respectively) [Schreiner et al. 2015b]. It is well known that patients in the earlier stages of schizophrenia have a higher risk of clinically relevant weight gain (with up to 85% of weight gain occurring within the first year of AP treatment) [Perez-Iglesias et al. 2014]. In our study, patients switched from oral aripiprazole were somewhat younger (mean age 34.4 years compared with 36.8–40.8 years for patients switched from other atypical APs) and therefore may have been exposed less to medications causing weight gain [Schreiner et al. 2016]. Therefore, it may also be advisable to educate patients on potential weight gain specifically when switching from aripiprazole to other atypical APs, including PP1M.

Nevertheless, the observed benefits in negative symptoms, symptoms of anxiety and depression, and patient functioning when switching stable patients unsuccessfully treated with oral aripiprazole to PP1M, should outweigh potential side effects, especially when these are well managed.

Study limitations included the limited patient number, the single-arm, non-randomized design, the lack of an active comparator group, and the post-hoc nature of the analysis, all of which limit any conclusions drawn on the efficacy and safety of this drug. The data do, however, suggest that suboptimal treatment with an oral AP medication does not predict failure with other AP agents, including PP1M.

Conclusion

Six-month treatment with flexible doses of PP1M was associated with significant and clinically relevant improvements of negative and depressive symptoms and disorganized thoughts in nonacute but symptomatic patients with schizophrenia previously unsuccessfully treated with oral aripiprazole. The current subanalysis supports results from randomized controlled trials and pragmatic studies in acute and nonacute patients with schizophrenia who demonstrated improvements in functioning when switching to PP1M.

Supplementary Material

Supplementary material

Acknowledgments

This work was previously presented as a Poster at the 23rd Meeting of the European Congress of Psychiatry, 28–31 March 2015, Vienna, Austria.

Footnotes

Funding: Medical writing support was provided by ApotheCom, London, UK and funded by Janssen Cilag. This study was funded by Janssen Cilag.

Conflict of interest statement: The authors are employees of Janssen Cilag.

Contributor Information

Andreas Schreiner, Medical and Scientific Affairs, Janssen Cilag EMEA, Johnson & Johnson Platz 1, Neuss, 41470, Germany.

Paul Bergmans, Biometrics, Janssen Cilag Benelux, Tilburg, The Netherlands.

Pierre Cherubin, EMEA Medical Affairs, Janssen Cilag, Issy-les-Moulineaux, France.

Ludger Hargarter, EMEA Medical Affairs, Janssen Cilag, Neuss, Germany.

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