Abstract
Background
Paliperidone palmitate once-monthly (PP1M) demonstrated symptomatic and functional remission in patients with schizophrenia. This post hoc analysis aimed to identify factors associated with improved clinical outcomes in patients switching to PP1M (75–150 mg eq.).
Methods
The improved patient outcomes were observed as Positive and Negative Symptom Scale (PANSS, symptoms) score <70:66.7% (407/610), Personal and Social Performance (PSP, function) score >70:34.3% (199/581), and Involvement Evaluation Questionnaire (IEQ, caregiver burden) reduction ≥6:50.2% (270/538). Independent variables including demographics, disease duration, employment status, and clinical scores were screened individually using a univariate analysis and subsequently, variables (cutoff p<0.15) were analyzed using a multivariate regression analysis for association with better clinical outcomes at week 13.
Results
The factors significantly associated with favorable clinical outcomes were reduction in PANSS at week 5 (odds ratio [OR]=1.14, 95% CI=1.11–1.17) with symptom reduction; baseline PSP total score (OR=1.07, 95% CI=1.05–1.10), PSP change at week 5 (OR=1.07, 95% CI=1.05–1.10), PANSS reduction at week 5 (OR=1.06, 95% CI=1.03–1.08) with functional improvement, reduction in PANSS at week 5 (OR=1.02, 95% CI=1.01–1.03), and total IEQ score at baseline (OR=1.09, 95% CI=1.07–1.11) with caregiver burden reduction.
Conclusion
Thus, symptom and functional improvements with caregiver burden reduction were observed in patients, and PANSS reduction at week 5 was commonly associated with favorable outcomes.
Introduction
Management of schizophrenia, a chronic debilitating disorder, includes clinically meaningful improvement in symptoms along with improved social functioning.Citation1 Impairments in interpersonal relations and daily living skills, and poor interactions in occupational, social, and community settings that reduce the patients’ quality of life are common features of schizophrenia.Citation2,Citation3 Although most antipsychotics improve the acute symptoms of schizophrenia within a couple of weeks, complete functional improvement requires long-term treatment.Citation4–Citation6 Several factors could contribute as predictors of treatment outcomes in a chronic multidimensional disorder such as schizophrenia. These factors include severity of disease at baseline, employment and financial status, disease duration, hospitalizations, medication dose, and disease- and medication-associated scores (adherence, satisfaction, and preference), and have been analyzed for their potential association with treatment outcomes.Citation7–Citation9
Management of psychotic symptoms along with meeting basic living needs can be an overwhelming burden for the patient and, hence, the need for caregiver assistance arises.Citation10 Routine disturbances, emotional stress, as well as social and financial pressure escalate with severity of the patients’ symptoms and also contribute to reduction in the caregivers’ quality of life.Citation11 This increased caregiver burden may impact treatment adherence as well as long-term outcomes in patients with chronic disease. Previous studies on caregiver burden were descriptive; however, some recent studies have attempted to measure caregiver burden objectively using validated instruments such as an Involvement Evaluation Questionnaire (IEQ), which evaluated factors affecting reduction of caregiver burden.Citation12,Citation13
Long-acting injectables (LAIs) were developed for schizophrenia treatment with the aim to increase adherence among patients by avoiding daily treatment with oral antipsychotics and having the advantage of reduced frequency of doses and administration with physician’s monitoring.Citation14 Relapses within the first 5 years of onset of schizophrenia are a common observation.Citation15 A recent literature review summarizes evidence of LAIs lowering the relapse rates when used in the treatment of first episode psychosis or recent-onset schizophrenia.Citation16 LAIs are also recommended for relapse patients with a history of self-harm, self-neglect, or violence.Citation17 A neuroprotective effect of promoting intra-cortical myelination, essential for delaying chronic disease progression, has been observed within a year of LAI therapy as compared with oral antipsychotics in patients with recent-onset schizophrenia.Citation18
It is thus important for clinicians to not only evaluate whether LAIs could potentially be utilized as first-line therapy in patients with acute schizophrenia but also while switching from oral antipsychotics because of unsatisfactory response. Identification of factors influencing improvement in clinical outcomes might further aid the choice of therapy and facilitate informed decision-making for switching therapy (in the case of ineffective therapy).Citation19
Paliperidone palmitate once-monthly (PP1M) LAI is approved for use globally in many countries and has demonstrated efficacy and safety in acute and long-term, randomized controlled studies.Citation20–Citation25 Additionally, patients switching to PP1M (due to poor adherence to previous oral antipsychotics) remained adherent as reported by follow-up studies carried out in naturalistic settings.Citation26,Citation27 In a primary study in patients with schizophrenia from People’s Republic of China, switching to PP1M from previously unsatisfactory oral antipsychotics demonstrated a reduction in schizophrenia symptoms and improved patient functioning, with a safety comparable to other global short-term studies.Citation22,Citation23,Citation28 In the current post hoc analyses of the primary study, we aimed to explore the factors associated with improvement in clinical outcomes with PP1M therapy.
Methods
The current post hoc analyses are part of a multicenter, single-arm, open-label, prospective Phase IV study conducted in patients with schizophrenia. The methodology for this study has been described previously and is reviewed here briefly.Citation28,Citation29 The protocol of the current study was reviewed and approved by the Independent Ethics Committee of Peking University Sixth Hospital.
Patients
Adult patients from People’s Republic of China (18–65 years, inclusive), meeting Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria for schizophrenia; with Positive and Negative Symptom Scale (PANSS) score 70–120 (inclusive) at baseline and screening; with stable disease and unsatisfactory response to previous oral antipsychotics, were enrolled. The major exclusion criteria were DSM-IV-TR Axis I diagnosis; severely suicidal or violent behavior (12 months before screening); history of paliperidone or risperidone allergy or resistance, and presence of any serious or unstable systemic disease.
The study protocol was approved by the local Institutional Review Board and the study was conducted in accordance with the ethical principles that originated in the Declaration of Helsinki, the International Conference on Harmonization and Good Clinical Practice guidelines, and applicable regulatory requirements. All participants provided written informed consent to participate in the study.
Study drug
The PP1M doses are expressed as milligram equivalent (mg eq.) wherein pharmacologically active paliperidone of 75, 100, and 150 mg eq. correspond to 117, 156, and 234 mg of paliperidone palmitate, respectively. PP1M was supplied as a suspension in a prefilled syringe.
Study design
This open-label study was conducted at 22 sites in the People’s Republic of China from October, 2012 to November, 2013. It consisted of three phases: screening phase (up to 7 days), acute treatment phase (13 weeks), and follow-up phase (1 year). Patients received the following treatment with PP1M: day 1, 150 mg eq.; day 8, 100 mg eq.; and later once-monthly flexible dosing of 75–150 mg eq.Citation20
Study outcomes
The current post hoc analyses evaluated clinical improvement by PANSS total scores, psychosocial functioning by Personal and Social Performance (PSP) score, and caregiver burden by IEQ reduction. Better clinical outcomes were defined as PANSS total score <70, PSP total score >70, and IEQ reduction ≥6 after 13 weeks of treatment. The PANSS total score ≤60 (mildly ill condition) and PANSS ≤75 (moderately ill condition) were considered as a “gold-standard” in a study assessing symptomatic remission.Citation30,Citation31 The current study utilizes PANSS <70 (a score midway between the previously used scores) as representative of symptomatic reduction (mild-to-moderate severity). The rationale for utilizing PSP total score >70 was based on a previous study wherein this cutoff was indicative of good overall functioning corresponding to functional remission.Citation7 IEQ reduction in total score of ≥6 was considered a reasonable estimate of lowering caregiver burden. The following factors influencing these outcomes were analyzed:
Demographics and other factors – sex, age, employment status (full, temporary, or unemployed), monthly incomes, disease duration (classified as ≤3 or >3 years, >5 or ≤5 years),Citation32,Citation33 and dose of third injection (75, 100, or 150 mg eq.).
Clinical scores – Medication Adherence Rating Scale (MARS) total score at baseline; Medication Preferences Questionnaire (MPQ) status at baseline with the first question analyzed – tablet or injection favored; Medication Satisfaction Questionnaire (MSQ) score at baseline (MSQ score of both patients and caregivers); Clinical Global Impression (CGI) score at baseline; IEQ total score at baseline; PSP total score at baseline, PSP change at week 5 and 13 as compared with baseline; PANSS total score at baseline and PANSS change at week 1, 5, and 13 from baseline.
Statistical analysis
The post hoc analyses were conducted on the full analysis set, comprising all patients who had at least one dose of PP1M and had at least one post-baseline efficacy assessment. As the last dose of PP1M was administered at week 13, the assessments conducted at this time were included. The outcomes were analyzed descriptively. For all the clinical scores, mean (SD) or median (range) values and for categorical data, number, percentage, or ratios were summarized. The hypothesis was two-sided with p<0.05 considered to be significant. Odds ratio (OR) and p-values were calculated to determine the association of different factors with clinical outcomes.
Symptoms (PANSS), functionality (PSP), and caregiver burden (IEQ) scores
The PANSS score was analyzed at baseline, weeks 1, 5, 9, and 13; PSP was analyzed at baseline, weeks 5 and 13; and IEQ was analyzed at baseline and week 13. The data were summarized based on better clinical outcomes using the last observation carried forward approach.
Better clinical outcomes
The factors were summarized descriptively. Comparison among groups (PANSS <70 vs ≥70, PSP >70 vs ≤70 and IEQ reduction ≥6 vs <6) for demographics and other factors was done using chi-square test or Fisher’s exact probability test. For clinical scores, comparisons were done using analysis of covariance or by Wilcoxon rank sum test.
Factors associated with better clinical outcomes
The factors were considered as single independent variables and were evaluated for better clinical outcomes as response variables. Initially, a univariate analysis screen was applied and independent variables with p<0.15 as candidate variables were tested in the multivariate logistic regression analyses model (– and Box S1). A multivariate logistic regression analysis was performed using the backward elimination method to determine the variables associated with the response. The 95% CIs along with the p-values were also calculated.
Results
Patient disposition and characteristics
Detailed efficacy and safety analysis of PP1M in this study has been published previously.Citation28,Citation29 Of the 616 patients from People’s Republic of China enrolled in the study, 610 were part of the full analysis set. The proportion of men (55.1%) was higher than women (44.9%). The mean (SD) age was 31.5 (10.85) years and body mass index was 23.22 (3.77) kg/m2.
Better clinical outcomes
During the course of treatment, PANSS scores on average displayed improvement with a gradual decrease toward <70 from baseline (mean [SD], 91.83 [12.54]) to week 13 (60.88 [19.74]). At week 13, 407 of the 610 patients presented with PANSS score <70 (66.7%) and PANSS reduction rate of ≥30% (73.4%). The PSP scores improved from baseline (44.92 [13.65]) to week 13 (64.11 [13.63]) with PSP total score >70 in 34.3% of the patients (199/581) and PSP change of ≥10% in 69.7% patients. The IEQ scores improved from baseline (44.92 [13.65]) to week 13 (23.72 [12.75]). In total, 50.2% patients (270/538) had a reduction in the IEQ score (≥6) ().
Table 1 Total scores in PANSS, PSP and IEQ from baseline to week 13 (last observation carried forward)
Factors influencing improvements in symptoms, function, and caregiver burden
Factors affecting clinical symptoms
At week 13, there was a significant difference between the patient group with PANSS <70 vs PANSS ≥70 with regard to factors such as disease duration (p=0.0123), disease duration ≤3 years vs >3 years (p=0.0228), dose of third injection (p=0.0008), MSQ score of patients (p=0.0261), CGI score (p=0.0008), PSP total score of patients (p=0.0080), PSP change at week 5 (p<0.0001), PANSS total score (p<0.0001), and PANSS change at weeks 1 and 5 (both p<0.0001) (). Though many factors were significantly different between the two groups, further multiple regression analysis revealed that only PANSS reduction at week 5 associated with PANSS score <70 (OR=1.14, 95% CI=1.11–1.17, p<0.0001). PANSS total score at baseline and disease duration (>3 years vs ≤3 years) associated with less probability of PANSS score <70 ().
Table 2 Comparison of factors between PANSS subgroups (<70 and ≥70 groups) affecting better clinical outcomes (week 13, LOCF)
Table 3 Factors associated with better clinical outcomes: PANSS <70, PSP >70, and IEQ reduction ≥6 (week 13, LOCF, multivariate logistic regression analysisTable Footnote*)
Factors affecting psychosocial function
Disease duration (p=0.0129), dose of third injection (p=0.0011), CGI score (p=0.0334), IEQ total score (p=0.0438), PSP total score (p=0.0049), PSP change at week 5 (p<0.0001), PANSS total score (p=0.0051), and its change at weeks 1 and 5 (both p<0.0001) were significantly different between the PSP >70 and PSP ≤70 groups at week 13 (). Multiple regression analyses of factors influencing PSP >70 demonstrate that PSP total score at baseline (OR=1.07, 95% CI=1.05–1.10, p<0.0001), its change at week 5 (OR=1.07, 95% CI=1.05–1.10, p<0.0001), and PANSS reduction at week 5 (OR=1.06, 95% CI=1.03–1.08, p<0.0001) associated with PSP >70. PANSS total score at baseline had no effect on the PSP outcome ().
Table 4 Comparison of factors between PSP subgroups (>70 and ≤70) affecting better clinical outcomes (week 13, LOCF)
Factors affecting caregiver burden
Factors such as disease duration (p=0.0460), disease duration >3 years vs ≤3 years (p=0.0366), CGI score (p=0.0099), IEQ total score (p<0.0001), PSP change at week 13 (p=0.0001), and PANSS change at week 1 (p=0.0061) and week 5 (p=0.0027) were significantly different between the groups with IEQ reduction (five-classification data) ≥6 and <6 (). Factors significantly associated with reduction of IEQ ≥6 based on multiple regression analysis include the total IEQ score at baseline (OR=1.09, 95% CI=1.07–1.11, p<0.0001) and PANSS reduction at week 5 (OR=1.02, 95% CI=1.01–1.03, p=0.0056) ().
Table 5 Comparison of factors between IEQ reduction subgroups (≥6 and <6) affecting better clinical outcomes (week 13, LOCF)
Discussion
The current post hoc analyses were aimed at determining the factors associated with better clinical outcomes of symptoms (PANSS <70), psychosocial function (PSP >70), and caregiver burden (IEQ reduction ≥6) in patients with schizophrenia from People’s Republic of China switching from oral antipsychotics to PP1M. Overall, the analyses demonstrated an improvement in all of these outcomes at week 13. Factors such as disease duration, CGI score, and PANSS change at weeks 1 and 5 differed significantly between the patient groups (PANSS <70 vs ≥70, PSP >70 vs ≤70, IEQ reduction ≥6 vs <6; p<0.05 for all). There was a significant difference between PANSS <70 vs ≥70 and PSP >70 vs ≤70 patient groups with respect to the factor of dose of the third injection (PP1M monthly maintenance dose, p<0.05 for all) probably as the lower dose of the third injection was administered in patients with less severity of disease. A significant difference between PANSS <70 vs ≥70 and IEQ reduction ≥6 vs <6 patient groups was also observed with respect to the factor of disease duration >3 years vs ≤3 years (p<0.05 for all). Multivariate regression analyses indicate that factors such as shorter disease duration (≤3 years), PSP total score at baseline, PSP change at week 5, IEQ total score at baseline, and PANSS reduction at week 5 are all associated with good clinical outcomes. Specifically, PANSS reduction at week 5 was the only common factor associated with favorable response in clinical outcomes of symptoms, function, and caregiver burden.
Previous pharmacokinetic studies demonstrated that PP1M achieves therapeutic, steady-state plasma levels rapidly on initiation without the necessity of oral supplementation.Citation34 Early symptomatic improvement (within a few days) observed with PP1M therapy may be attributed to its unique pharmacokinetics, though the complete therapeutic effect requires several weeks (eg, longer time to relapse with PP1M compared to oral antipsychotics).Citation24,Citation35–Citation38 These results are consistent with the association of PANSS reduction at week 5 on better symptomatic outcomes observed in the current study. An analysis of 12 studies also identified early symptomatic improvement as one of the predictors of symptomatic remission, thus corroborating the findings of the current study.Citation39 The current analyses also demonstrated that PANSS reduction at week 5 was associated with an improvement in the mean PSP score >70. The correlation between clinical and functional improvement was consistent with findings from other studies, wherein PANSS total score was established as the best predictor of improved functioningCitation7 and PANSS subscores were a contributing factor in PSP total score improvements in patients switching from oral antipsychotics to risperidone LAI.Citation40
The role of the caregiver is important in chronic diseases; however, of the many studies in patients with schizophrenia, relatively few focus on the influence of caregiver burden on therapy.Citation12 The analyses in this study demonstrated that caregiver burden is reduced at week 13 and is associated with reduction in PANSS score at week 5. Consistent results were observed in a study from People’s Republic of China, which reported that patient functioning and PANSS score were good predictors of caregiver burden, in patients with schizophrenia.Citation41 Thus, PANSS reduction at week 5 has a significant association with symptoms, function, and caregiver burden in a short period of 13 weeks with PP1M therapy. Hence, it becomes increasingly important that short-term efficacy of all LAIs be investigated for their consideration as first-line therapy in patients with schizophrenia.
Studies have revealed that the initial few years, post– schizophrenia diagnosis, are crucial for therapeutic intervention to achieve desirable long-term outcomes, as beyond this period, schizophrenia symptoms are refractory.Citation42,Citation43 Therefore, previous studies applied a 5-year cutoff to distinguish between recent and chronic schizophrenia. However, recently, studies have utilized a 3-year cutoff period to analyze efficacy of LAIs.Citation32 This cutoff was based on a 15-year study following the natural course of schizophrenia in patients, which revealed that disease chronicity increases gradually up to four episodes (after which the disease is established as chronic)Citation44 and the characterization of these patients revealed an average illness duration of 3 years.Citation33 The current study utilized both these cutoff periods (3 years and 5 years) for the analysis to identify the time period influencing better clinical outcomes on PP1M therapy. Multivariate regression analysis revealed that the duration of disease ≤3 years has a significant association with symptomatic remission, thus corroborating the data from the other studies.Citation45,Citation46
Clinical outcome reporting routinely focuses on improvement rates from a specific baseline to the end of treatment.Citation23,Citation47,Citation48 However, in the real-world setting, variability in the baseline of individual patients limits the evaluation of achievement of these clinical goals based on improvement rate. Instead, threshold values of scales depicting current patient status as used in this study are considered more appropriate. However, the short duration of this study also restricts its predictive value for long-term therapy to assess symptoms, functional, and caregiver burden improvement. Schizophrenia management can be complex because various factors such as age, employment, disease duration, disease severity at baseline, medication adherence, and medication preference may affect disease prognosis. Based on the limited evidence available in published literature, clinical outcomes were selected for the current analysis;Citation7,Citation30,Citation31 however, there is a lack of consensus on clinical scores most appropriate for the identification of better clinical outcomes.Citation49,Citation50 The cutoff for better clinical outcomes identified in the current study requires further statistical validation in other studies. Additionally, the current study is restricted only to PP1M therapy and, hence, the findings cannot be extrapolated for comparison with other antipsychotics.
Recent evidence and guidelines suggest that LAIs must also be considered earlier in therapy.Citation51,Citation52 The current study adds to this body of growing evidence for the consideration of PP1M therapy in the acute phase, as early improvement in symptomatic and functional outcomes were demonstrated. To the best of our knowledge, there are no previous reports wherein factors associated with clinical outcomes and caregiver burden were analyzed in patients switching over to PP1M from oral antipsychotics.
Conclusions
The findings of these analyses reveal that significant improvements in symptoms, functionality, and caregiver burden were observed with PP1M treatment in patients with schizophrenia from People’s Republic of China switching from oral antipsychotics. Demographic factors, dose of third injection, and MARS, MSQ, and MPQ scores were not significantly associated with the better clinical outcomes discussed here. The PANSS reduction at week 5 was commonly associated with all favorable outcomes in these patients.
Author contributions
YF and TMS were involved in study design and NL, TMS, and YF were the lead scientists for the study, contributing to analysis of samples and data interpretation. YF, TMS, HFL, LLZ, and SLC were clinical leads for the study, and were also involved in data interpretation. JMZ and NL were the project statisticians. All authors had access to the study data, contributed to the data interpretation for the results, provided direction and comments on the manuscript, made the final decision about where to publish these data, and approved submission to the journal.
Acknowledgments
Dr Sonia Philipose (SIRO Clinpharm Pvt. Ltd.) provided writing assistance and Dr Ellen Baum (Janssen Research and Development, LLC) provided additional editorial support for this manuscript. The authors also thank the study participants, without whom this study would never have been accomplished, and the investigators for their participation in this study. This study was supported by funding from Janssen Research and Development, People’s Republic of China.
Supplementary materials
The following variables were included in the multivariate logistic regression analysis for PANSS<70
Disease duration (>3 years vs ≤3 years)
Dose of the third injection (75 mg eq.(1), 100 mg eq.(2), 150 mg eq.(3)) (Dummy variables in which “150 mg eq.” was considered as reference)
MARS total score at baseline
MSQ score of patients at baseline
CGI score at baseline
PSP total score at baseline
PSP change at week 5 LOCF
PANSS total score at baseline
PANSS reduction at week 5 LOCF
The following variables were included in the multivariate logistic regression analysis for PSP>70
Employed status (full employment(1), temporarily employed(2), unemployed/almost unemployed(3)) (Dummy variables in which full employment was considered as reference)
Disease duration (>3 years vs ≤3 years)
Dose of the third injection (75 mg eq.(1), 100 mg eq.(2), 150 mg eq.(3)) (Dummy variables in which “150 mg eq.” was considered as reference)
CGI score at baseline
IEQ total score at baseline
PSP total score at baseline
PSP change at week 5 LOCF
PANSS total score at baseline
PANSS reduction at week 5 LOCF
The following variables were included in the multivariate logistic regression analysis for IEQ reduction ≥6 (five classification data)
Disease duration (>3 years vs ≤3 years)
MARS total score at baseline
CGI score at baseline
IEQ total score at baseline
PSP total score at baseline
PANSS total score at baseline
PANSS reduction at week 5 LOCF
Abbreviations: CGI, Clinical Global Impression Scale; IEQ, Involvement Evaluation Questionnaire; LOCF, last observation carried forward; MARS, Medication Adherence Rating Scale; MSQ, Medication Satisfaction Questionnaire; PANSS, Positive and Negative Symptom Scale; PSP, Personal and Social Performance.
Table S1 Factors associated with better clinical outcome: PANSS score <70 (weeks 13, LOCF, univariate logistic regression analysis)
Table S2 Factors associated with better clinical outcome: PSP total score >70 (week 13, LOCF, univariate logistic regression analysis)
Table S3 Factors associated with better clinical outcome: IEQ reduction ≥6 (week 13, LOCF, univariate logistic regression analysis)
Disclosure
Nan Li has been a consultant and/or advisor to Janssen Research and Development (Beijing), Lundbeck, Astellas, Sanofi, Merck Serono, and Hisun Pfizer. He received honoraria and/or grant support from Janssen Research and Development (Beijing), Lundbeck, Astellas, Sanofi, Merck Serono, and Hisun Pfizer. Tianmei Si has been a consultant and/or advisor to Janssen Research and Development (Beijing); Pfizer, Lundbeck, and Otsuka. She received honoraria and/ or grant support from Janssen Research and Development (Beijing), Lundbeck, Pfizer, and Otsuka. Jianmin Zhuo is from Janssen Research and Development, Shanghai, People’s Republic of China. Feng Yu, Zhang Lili, and Huafei Lu are from Janssen Research and Development, Beijing, People’s Republic of China. Shang Li Cai was an employee of Janssen Research and Development, Beijing, People’s Republic of China at the time of this analysis. The authors report no other conflicts of interest in this work.
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