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Comparison of Paliperidone Palmitate and Risperidone Long-Acting Injection in Schizophrenic Patients

Comparison of Paliperidone Palmitate and Risperidone Long-Acting Injection in Schizophrenic Patients affect and alogia). The course of the disease varies widely, alternating Purpose/Background: The study objective was to compare the impact between periods of remission and relapse, where patients experience of being treated by paliperidone palmitate (PP) or risperidone long-acting unpredictable patterns of symptoms. These symptoms are associated injection (RLAI) on the length of stay on initial hospitalization, rehospital- with isolation, alteration of daily functioning and feelings, as well as ization risk, and treatment duration in schizophrenic patients. disorganized thoughts and behaviors. The public health and financial Methods: We conducted an observational retrospective cohort study in burdens of schizophrenia are considered to be substantial by the French 43 centers in France, including schizophrenic patients who initiated a treat- 1,2 authorities. Indeed, patients affected by schizophrenia are the largest ment by PP or RLAI during initial hospitalization. The follow-up periods 3 group of hospitalized patients for mental disorders in 2011. In France, started in September 2012 for the RLAI group (median follow-up duration, between 300,000 and 600,000 patients are affected by schizophrenia, 233 days) and in June 2013 for the PP group (259 days). Statistical analyses 4–6 with approximately 10,000 new patients per year. were based on Cox regression models, with propensity score weighting to Long-acting injectable (LAI) antipsychotics are recom- account for differences in patients’ characteristics. mended for the maintenance treatment of schizophrenia especially Findings/Results: The analysis included 347 patients: 197 in the PP treat- for the prevention of relapse in noncompliant patients. Also, consen- ment group and 150 in the RLAI group. Compared with patients on RLAI, pa- sus-based guidance recommends using LAIs as first-line therapy in tients on PP were significantly more likely to have nonpsychiatric comorbidities, 7–9 patients who will be treated with antipsychotics over the long term. to have been on previous antipsychotic therapy, or to have been hospitalized for Relapses involve an increase of hospitalizations and disease deteriora- psychiatric care in the previous year. With regard to length of stay on initial hos- tion such as treatment resistance and socialization issues. Compliance pitalization, there was no statistically significant difference between both groups is a key challenge in treatment management, as noncompliance is (hazard ratio, 1.13 [0.97; 1.31]). Being on PP was associated with similar times strongly associated with relapses or hospitalizations. Paliperidone pal- to first rehospitalization compared with RLAI (hazard ratio,0.92 [0.65; 1.30]). mitate (PP) long-acting injection and risperidone long-acting injection Implications/Conclusions: We observed nonsignificant differences in (RLAI) are two long-acting antipsychotics recommended in the pre- initial hospitalization duration and time to rehospitalization between PP and vention of relapses. Paliperidone palmitate long-acting injection is ad- RLAI, potentially due to lack of statistical power. A trend was observed in ministered once monthly, whereas RLAI is administered fortnightly. favor of PP with regard to time to treatment discontinuation, although this Advantages of PP include a quick onset of action, a one-monthly in- result was compromised by patients who switched between RLAI and PP. jection, and the absence of oral supplementation at treatment initia- Key Words: Paliperidone Palmitate, Antipsychotic Agents, schizophrenia, tion. Thus, PP may help patient compliance. Retrospective Study, France To date, several observational studies have been conducted 11–13 assessing the effectiveness of RLAI. One study evaluated (J Clin Psychopharmacol 2018;38: 19–26) the comparative effectiveness of RLAI versus PP in the United chizophrenia is a severe chronic mental disorder characterized States. However there is still a lack of real-life data on patients S by various “positive” symptoms (such as hallucinations and treated with PP in Europe. The Long Acting Outcomes Study in Schizophrenia (LAOS) From the *Assistance Publique-Hôpitaux de Paris (AP-HP), Corentin-Celton was a multicenter observational retrospective cohort study conducted Hospital, Department of Psychiatry, Issy-les-Moulineaux; †Paris Descartes University, in 43 centers in France. It included schizophrenic patients who ini- PRES Sorbonne Paris Cité, Paris; ‡Amaris, Paris; §Axonal, Nanterre; ||Janssen-Cilag, tiated a treatment by PP or RLAI during the initial hospitalization. Issy-les-Moulineaux, France; and }Janssen-Cilag GmbH, Neuss, Germany. Received May 5, 2017; accepted after revision October 24, 2017. The primary objective of the study was to evaluate and com- Reprints: Drifa Belhadi, MSc, Amaris, 28 rue Jacques Ibert, 92300 Levallois pare the impact of being treated by PP or long-acting risperidone Perret, France (e‐mail: drifa.belhadi@amaris.com). injection on the length of stay on initial hospitalization of schizo- This study was funded by Janssen-Cilag, Issy-les-Moulineaux, France. phrenic patients. Secondary objectives included evaluation and Sponsor employees participated in the study design, data interpretation, and writing of the report. The sponsor of the study did not participate in the data comparison of risk of rehospitalization and treatment duration. collection and data analysis. Employees of an independent consulting Our hypothesis is that PP is associated with better patient com- company (Axonal) received funding for contribution to the study design, pliance and reduced disease management costs through a decrease in and employees of another independent consulting company (Amaris) health resource use compared with long-acting risperidone injection. received funding for contribution to the data analyses. Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal’s Web site (www.psychopharmacology.com). MATERIALS AND METHODS Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 LAOS Study (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or Study Objectives used commercially without permission from the journal. This study was designed to assess and compare, in patients ISSN: 0271-0749 DOI: 10.1097/JCP.0000000000000827 with schizophrenia who were hospitalized full-time for symptomatic Journal of Clinical Psychopharmacology � Volume 38, Number 1, February 2018 www.psychopharmacology.com 19 Limosin et al Journal of Clinical Psychopharmacology Volume 38, Number 1, February 2018 decompensation and in whom treatment (with PP or RLAI) was Monitoring Plan initiated during the initial hospitalization period, the duration of Data were directly collected in electronic case report form, maintenance treatments, the duration of the initial hospitalizations with automatic controls and alerts when potential incorrect data periods, and the hospitalization rates and cumulative hospitaliza- were entered (outlier data check), by investigators. To ensure the tion periods for psychiatric reasons during exposure to treatment quality of data collected in this study, on-site monitoring visits (eitherPP orRLAI). were carried out by independent clinical research assistants trained in the study protocol. A first monitoring visit was performed, after the sixth patient, to check that patients were informed by investi- Study Design gators about the collection of their medical data and were not The LAOS study was an observational, retrospective, multi- opposed to it, to control that all required data entered into the elec- center, and national cohort and was carried out in public and private tronic case report form were in accordance with data from medical health care establishments equipped for the full-time hospitalization records and to check that sites performed the study in compliance of patients in psychiatric units. Although the study was retrospec- with the study protocol and current regulations. A total of 60 monitor- tive, monitoring visits equivalent to quality-check visits were con- ing visits were carried out and allowed to monitor 308 patients (75% ducted to ensure optimal quality and completeness of data. of the patients included) by direct access to medical data records or by Psychiatrists were identified from exhaustive national list- investigator interview (depending on hospital’s practices on medical ings of practicing physicians by specialty (CEGEDIM OneKey records access). In addition to monitoring, data quality testing based registries; Cegedim, Boulogne-Billancourt, France www. on the comparison of rates of missing data on the monitored variables cegedim.com), where the sponsor (Janssen-Cilag) has a list of and on the number of deviant patients was carried out. e-mail addresses provided by practitioners. On 3,615 contacted French psychiatrists, 193 sites sent a confidentiality agreement Data Collection and received a feasibility questionnaire, notably about their For each patient, a patient case report form was filled retro- patient recruitment potential. On these 193 sites, 89 feasibility spectively by participating psychiatrists, in providing information questionnaires were received and site selection was organized on patient attributes. These related to demographics, type of schizo- (by visit or remote contact). On these 89 sites, 64 sites, with a phrenia, disease history and severity, initial full-time hospitalization potential to take more than 5 patients per treatment group, were (admission and discharge dates, reason having led to hospitaliza- preselected. Psychiatrists did not receive any specific incentive tion, antipsychotic treatment at the time of admission to hospital, to report cases. treatment compliance issues, treatment resistance, treatments re- As psychiatric services are organized per sector (sectors are lated to the disorder prescribed and administered during the hospi- established based on population density) with the sectors essen- tal stay (with start and end dates, dosage, and administration route), tially proposing state-run services (92% of state-run structures: other nonmedical therapeutic measures during hospitalization and general or specialized hospitals, medicopsychological consulta- other concurrent disorders). tion services), to ensure the whole of France was represented in At the end of the initial hospitalization and throughout the the study, the geographic localization of the centers was based follow-up period, were also been collected all the types of hospi- on 7 large French metropolitan areas. talizations, all the consultations as an outpatient, all the visits to On the 64 preselected sites, the study was carried out an emergency unit, taking part in activities organized by part- in 50 selected centers representative of the French centers, time therapeutic reception centers, the number of suicide attempts with sampling being stratifiedper region accordingtothe and forced hospitalizations, all the other nonmedical therapeutic aforementioned distributions. measures and the hospitalization alternatives. Treatments related In each center, the first 6 to 18 patients meeting the inclusion to the disorder prescribed and administered during the hospital criteria were selected and 3 to 9 patients were allocated to each stay, with start and end dates, dosage, and administration route were treatment group. This method of cluster sampling within the centers also collected. Finally, date and circumstances of the last contact, and systematic assessment of the first eligible patients (chronologic initiated treatment (PP or RLAI) continued or discontinued (with selection) with equivalent numbers of patients being selected per discontinuation data and reason). center guarantees representativeness. Patients were informed about the study and were not opposed Patients were eligible for inclusion in the study if they to the use of their data. They also signed a consent form to autho- satisfied the following criteria: at least 18 years of age; with rize the access to their medical data. confirmed schizophrenia according to the criteria of the Inter- The study protocol was approved by an independent scien- national Classification of Diseases (CIM10), except for schi- tific committee and in accordance with French law, the Ethics zoaffective disorders; hospitalized full-time for symptomatic Committee’s approval was not required as the protocol was strictly decompensation (acute psychotic episode, behavior disorders/ observational and usual practice was unchanged. However, the aggressive behavior toward self or others, thymic state, intoxica- study protocol was approved by the Advisory Committee on In- tion with alcohol or other substances, etc.); and in whom the fol- formation Processing in Research in the Field of Health and by lowing treatment was initiated during hospitalization: either RLAI the French Data Protection Authority. from September 1, 2012 (before PP French market access) or PP from June 1, 2013. The LAI prescription was initiated before the Outcome Measures onset of the study. Participants were excluded if they were with schizoaffective The primary outcome was length of stay on initial hospitaliza- disorder or another psychotic disorder, hospitalized full-time chron- tion, which was defined as the number of days between the admis- ically (hospitalized for more than 60 consecutive days) at the time sion to the hospital and the last day of this initial hospitalization. of treatment initiation (RLAI or PP), whose previous treatment in- Secondary outcomes were the time to first rehospitalization after cluded RLAI or PP (in the 6 months preceding treatment initiation the initial hospitalization and the time to treatment discontinuation. with PP or RLAI long-acting injection), who had already been The individual study period started from the beginning of the treated with clozapine or patients participating in another clinical initial hospitalization and ended 30 days after the last injection of trial at the time of the initial hospitalization. treatment or at the date of last contact. If a patient switched from 20 www.psychopharmacology.com © 2017 Wolters Kluwer Health, Inc. All rights reserved. Journal of Clinical Psychopharmacology Volume 38, Number 1, February 2018 Cohort Study in Schizophrenia RLAI to PP (or vice versa), the study period ended at the time of only, a switch from RLAI to PP (and vice versa) was considered the treatment switch. Consequently, each patient was included in a as a censoring event in a sensitivity analysis. single treatment group. A switch from RLAI to PP (and vice Outputs are reported as hazard ratios (HRs) with their corre- versa) was considered to be a treatment withdrawal for the analy- sponding 95% confidence intervals (95% CIs). Statistical analyses sis of time to discontinuation (treatment duration). were conducted using SAS® version 9.4. Patients who deviated from the protocol and patients who never left the initial hospitalization were excluded from the analy- sis in order to minimize bias. Patients from center 69 were also ex- RESULTS cluded from the analysis as the monitoring in this center could not be conducted according to the study protocol. Descriptive Statistics Descriptive data on the baseline characteristics of the study Statistical Analyses population is reported for each treatment group in Table 1 and pa- Time to end of initial hospitalization, time to first rehospi- tient’s characteristics over the follow-up period are described in talization and time to treatment discontinuation were analyzed Table 2. A total of 347 patients were included in the analysis: 197 through Kaplan-Meier survival analyses and Cox regression from the PP treatment group (mean dose of 106.3 mg) and 150 models. In nonrandomized studies, there is a risk that the alloca- from the RLAI treatment group (mean dose of 45.3 mg; Table 1 tion of a treatment may be dependent on patient characteristics. and Fig. 1). Therefore, to control for this potential selection bias, the propen- Both treatment groups were well balanced with regard to sex, sity score weighting method was used to account for differences alcohol addiction, drug addiction, and type of schizophrenia in individual patient’s characteristics. The propensity score corre- (paranoid vs other types of schizophrenia). Compared with pa- sponds to the probability for a patient to receive PP rather than tients on RLAI, patients on PP were significantly more likely to RLAI as a function of patients’ and prescribers’ characteristics. have nonpsychiatric comorbidities (P = 0.007), to have been on The propensity score was estimated with a logistic regression using previous antipsychotic therapy (P = 0.04), or to have been hospi- the following variables (selected based on statistical significance): talized for psychiatric care in the previous year (P =0.001). High nonpsychiatric comorbidities, number of hospitalizations for psy- rates of involuntary hospitalizations were observed in both groups chiatric care during the last 12 months, monitoring method, admis- (67% in the RLAI group and 69% in the PP group). This may be sion method, prior therapies and compliance, alcohol addiction, associated with the use of injectable antipsychotics, which are fre- concomitant psychotic treatment, psychiatric comorbidities, sex, quently administered in more severe and less compliant patients. age, sex of the investigator, education level, and psychoeducation received (Supplemental Digital Content, Table S1 Results of the Length of Stay on Initial Hospitalization and Time propensity score estimation, http://links.lww.com/JCP/A489). to First Re-Hospitalization Sensitivity analyses were conducted to assess the robustness of the results. Several statistical models were tested (nonadjusted, Results from the base case and sensitivity analyses for both multivariate Cox regressions and use of the propensity score as an the length of stay on initial hospitalization and the time to first re- adjustment variable). Sensitivity analyses excluding patients with hospitalization are reported in Figure 2. extreme propensity scores were conducted. Based on discussions The average length of stay on initial hospitalization was com- with a clinical expert, covariates used for the propensity score parable among PP patients compared with RLAI patients (38 vs estimation were selected based on clinical relevance instead of 42 days). There was no statistically significant difference between statistical significance. For the duration of initial hospitaliza- both treatment groups (hazard ratio [HR], 1.13 [0.97; 1.31]). Con- tion only, a sensitivity analysis including patients still in initial clusions were similar across all sensitivity analyses: no statistically hospitalization at the end of follow-up was conducted. For the significant results were identified across analyses. When including time to first rehospitalization and treatment discontinuation, an patients still in their initial hospitalization at the end of follow-up, analysis was restricted on patients with at least one injection after results remained similar between both treatment groups (HR,1.00 initial hospitalization. For the time to treatment discontinuation [0.86; 1.16]). TABLE 1. Baseline Characteristics of the Study Population Paliperidone Risperidone Long-Acting Palmitate n = 197 Injection n = 150 P Age, mean (SD), yrs 37.8 (12.3) 37.8 (12.1) 0.97* Sex (male), n (%) patients 126 (64%) 107 (71%) 0.15 At least one nonpsychiatric comorbidity, n (%) patients 28 (14%) 8 (5%) 0.01 At least one psychiatric comorbidity, n (%) patients 37 (19%) 29 (19%) 0.90 Alcohol abuse, n (%) patients 37 (19%) 37 (25%) 0.18 Substance abuse (other than nicotine), n (%) patients 64 (32%) 50 (33%) 0.87 Paranoid schizophrenia, n (%) patients 142 (72%) 105 (70%) 0.67 At least one prior antipsychotic therapy, n (%) patients 84 (43%) 48 (32%) 0.04 At least one hospitalization for psychiatric care in the last 12 months, n (%) patients 136 (69%) 77 (51%) 0.001 Involuntary hospitalization, n (%) patients 136 (69%) 101 (67%) 0.74 Psychoeducation received, n (%) patients 88 (45%) 64 (43%) 0.71 † 2 *Wilcoxon test; χ test. © 2017 Wolters Kluwer Health, Inc. All rights reserved. www.psychopharmacology.com 21 Limosin et al Journal of Clinical Psychopharmacology Volume 38, Number 1, February 2018 TABLE 2. Patient’s Characteristics over the Follow-Up Period Paliperidone Risperidone Long-Acting Palmitate n = 197 Injection n = 150 P Treatment dose, mean (SD), mg 106.3 (22.1) 45.3 (8.9) — At least one emergency room visit, n (%) 84 (43%) 61 (41%) 0.71* At least one adverse event, n (%) 25 (13%) 12 (8%) 0.16* Concomitant therapies, n (%) Antipsychotics 80 (41%) 76 (51%) 0.06* Anticholinergic agents 55 (28%) 44 (29%) 0.77* Anxiolytics 59 (30%) 49 (33%) 0.59* Antidepressants 19 (10%) 17 (11%) 0.61* Antiepileptic agents 21 (11%) 16 (11%) 0.99* Hypnotics and sedatives 26 (13%) 20 (13%) 0.97* Other 13 (7%) 3 (2%) 0.04* Length of stay on initial hospitalization, mean (SD), days 38.1 (24.6) 41.6 (38.1) 0.95 No. patients rehospitalized during the study, n (%) 39 (20%) 33 (22%) 0.62* Cumulative duration of rehospitalizations among patients with at least one 42.1 (36.8) 44.4 (30.7) 0.36 rehospitalization, mean (SD) No. rehospitalizations among patients with at least one rehospitalization, mean 1.56 (0.9) 1.4 (0.8) 0.34 (SD) per patient No. patients who discontinued their treatment, n (%) 39 (20%) 67 (45%) <0.001* §, || No. patients who discontinued their treatment during the initial hospitalization, n (%) 14 (7%) 20 (13%) 0.05* No. patients with at least one rehospitalization and who discontinued their 13 (20%) 6 (11%) 0.16* §, ¶ treatment during a rehospitalization, n(%) 2 † ‡ § *χ test; only 2 patients received chlorpromazine as concomitant therapy (100 mg and 300 mg) both in the PP group; Wilcoxon test; considering a || ¶ switch as a treatment withdrawal; 3 missing values; 2 missing values. The percentages of patients being rehospitalized after the ini- in Table 2). The treatment discontinuation rates during a rehospi- tial hospitalization were low and comparable in both treatment talization in patients with at least one rehospitalization were also groups (20% in PP patients and 22% in RLAI patients, as reported comparable in both treatment groups (20% in PP patients and FIGURE 1. Patient’s eligibility for the base case analysis. 22 www.psychopharmacology.com © 2017 Wolters Kluwer Health, Inc. All rights reserved. Journal of Clinical Psychopharmacology Volume 38, Number 1, February 2018 Cohort Study in Schizophrenia FIGURE 2. Base case and sensitivity analyses results for both outcomes: length of stay on initial hospitalization and time to first rehospitalization. For the length of stay on initial hospitalization an HR higher than 1 indicates a shorter duration in favor of PP. For the time to first rehospitalization, an HR lower than 1 indicates a lower risk of rehospitalization in favor of PP. 11% in RLAI patients). Being on PP was associated with similar hospitalization was significantly higher in the RLAI group (13%) times to first rehospitalization compared with being on RLAI than in the PP group (7%). (HR,0.92 [0.65; 1.30]). Conclusions were similar across sensitiv- Results from the base case and sensitivity analyses are re- ity analyses (with HRs ranging from 0.61 to 0.95), except for one ported in Figure 4. When considering a switch as a treatment with- analysis testing a methodological assumption which resulted in an drawal, patients on PP were associated with a 61% risk reduction HR significantly in favor of PP (HR,0.59 [0.35; 0.98]). These dif- in treatment discontinuation compared with patients on RLAI ferences in results across analyses were due to the low number of (HR,0.39 [0.29; 0.52]). However, when a switch was considered patients being rehospitalized after the initial hospitalization (39 in as a censoring event, the results indicated a nonstatistically signifi- the PP group and 33 in the RLAI group). cant trend in favor of PP (HR,0.73 [0.52; 1.02]). All other sensitiv- ity analyses were also associated with significantly longer treatment duration for PP compared with RLAI. When focusing on patients Treatment Duration with at least one injection after the initial hospitalization, the treat- Figure 3 shows the Kaplan-Meier survival curves for time to ment duration remained significantly longer among patients on PP treatment discontinuation, considering a treatment switch as a treat- than among patients on RLAI (HR,0.44 [0.31; 0.61]). ment withdrawal (base case assumption). As reported in Table 2, the percentage of patients who discontinued their treatment was sig- DISCUSSION nificantly higher in the RLAI group (45%) than in the PP group (20%). The probability of remaining on treatment after one year This retrospective observational study assesses PP versus was higher with PP (76%) than with RLAI (53%). The percentage RLAI among schizophrenic patients with regard to length of stay of patients who discontinued their treatment during the initial on initial hospitalization, time to first rehospitalization and time to FIGURE 3. Time to treatment discontinuation: Kaplan-Meier curves. © 2017 Wolters Kluwer Health, Inc. All rights reserved. www.psychopharmacology.com 23 Limosin et al Journal of Clinical Psychopharmacology Volume 38, Number 1, February 2018 FIGURE 4. Base case and sensitivity analyses results for the time to treatment discontinuation. *Switch considered as a treatment withdrawal. For the time to treatment discontinuation, an HR lower than 1 indicates a lower risk of treatment discontinuation in favor of PP, that is, a longer treatment duration. treatment discontinuation. Overall, the study population was rep- when considering a switch as a treatment failure. It should be noted resentative of the general French schizophrenic patient popula- that considering a switch as a censoring event changed the conclu- tion. Mean age was 38 years and 67% of patients were male. sion of this analysis (results are no longer statistically significant). This is very comparable to the Cohort for the General study of Little bias was expected on the primary and secondary end Schizophrenia, which included more than 1,500 patients (mean points as the duration of hospitalization, time to rehospitalization, age, 38 years; 68% of male). and time to treatment discontinuation are robust end points, which Length of stay on initial hospitalization was comparable be- are not subject to interpretation. The absence of randomization is tween treatment groups (average duration of 38 days in the PP usually associated with a potential selection bias, which was ad- group and 42 days in the RLAI group). Fewer days of hospitalization justed for by using the propensity score method. This statistical tech- for PP compared to RLAI were expected given that the initiation of nique is recommended in guidelines such as the ones from the RLAI requires an oral supplementation (pretreatment by oral risperi- National Institute for Health and Care Excellence and International 17,18 done during at least 2 weeks followed by a 3-week oral supplementa- Society for Pharmacoeconomics and Outcomes Research. Sev- tion). However, these lengths of stay were not significantly different eral sensitivity analyses were conducted to assess the robustness between treatments potentially owing to a lack of statistical power. In- of the results, accounting for patient selection, differences in out- deed, fewer patients than initially planned wereincluded. In addition come definitions, and for the implementation of different statistical patients with protocol deviations or patients from center 69 were ex- methods. Overall, the results were considered to be robust, as the cluded. This resulted in 347 of the 500 patients initially planned being conduct of these different analyses did not significantly change included in the statistical analyses. the interpretation of the results. There was only a few number of rehospitalization in both Few studies have been published on the association between treatment groups: 39 in the PP group (20% of patients) and 33 long-acting antipsychotic treatments and hospitalization. In par- in the RLAI group (22% of patients). This low number of rehospi- ticular, there is a lack of studies investigating the factors influenc- talization may be because all patients received a treatment (either ing the duration of hospital stay and the consequences on patients’ PP or RLAI) throughout the study and were followed until 30 days outcomes of shorter hospital stays. Nevertheless, some recent after the last injection of treatment or until the date of last contact. studies have been identified. Results from previous observational 9,10 Rehospitalization rates were comparable between PP and RLAI studies indicate that RLAI is associated with lower hospitaliza- groups and results were nonsignificant for most of the analyses tion rates compared to oral antipsychotics. A Hungarian registry- conducted. Those results are consistent with noninferiority results based observational follow-up study including 9,567 schizophrenic with regard to efficacy between PP and RLAI demonstrated in a patients also reported longer time to treatment discontinuations randomized controlled trial. with RLAI than with oral antipsychotics. Moreover, our results The assumption made regarding the switch between PP and are consistent with those obtained in previous studies comparing RLAI (and vice versa) impacted the conclusion of the treatment dis- PP versus RLAI. An American retrospective longitudinal cohort continuation analysis as a total of 30 patients switched from RLAI to study demonstrated that the use of PP was associated with better ad- PP and 2 patients switched from PP to RLAI. Results for the analysis herence, lower discontinuation rates, and longer treatment durations of treatment discontinuations were significantly in favor of PP compared to RLAI. Paliperidone palmitate was also associated with 24 www.psychopharmacology.com © 2017 Wolters Kluwer Health, Inc. All rights reserved. Journal of Clinical Psychopharmacology Volume 38, Number 1, February 2018 Cohort Study in Schizophrenia a lower risk of hospitalization and shorter hospitalization lengths. result is compromised by patients who switched between RLAI A double-blind randomized trial also showed that PP was non- and PP and would need to be confirmed by a dedicated study. inferior to RLAI based on the change in the PANSS total score from baseline and a French retrospective study based on pharmacy AUTHOR DISCLOSURE INFORMATION treatment issuance reported significantly longer treatment duration F Limosin received honorarium from Janssen for his partici- for PP compared with RLAI. pation in the LAOS study design, writing the protocol, data interpre- Our study also has some limitations. For instance, length of tation, and approving the final manuscript. F Limosin received also hospital stay is driven by the diversity of health care institutions honorarium as consultant or board participation from AstraZeneca, in France. In 2011, an IRDES study reported a mean length of stay Euthérapie-Servier, Janssen, Lundbeck, Otsuka Pharmaceuticals of 83 days over 1 year, varying from 75 to 78 days in multidisciplin- France, and Roche. D Belhadi and M Pacou work for Amaris Com- ary public institutions to 85 to 97 in specialized public structures. pany and report no conflict of interest. D Comet works for Axonal- The variety of type of institutions participating in the LAOS study Biostatem Company and reports no conflict of interest. P Guillon, could thus have introduced some heterogeneity in length and fre- S Bouju, and K Van Impe are employees of Janssen-Cilag. quency of hospital stays. Moreover, the study design was also associated with some limitations. 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Guidelines for the use and agement is to maintain patients under treatment in the long term. management of long-acting injectable antipsychotics in serious mental Indeed, it has been demonstrated that lack of adherence is fre- illness. BMC Psychiatry.2013;13:1. quent in the use of antipsychotic medications. Half of patients 21,22 9. Haddad PM, Taylor M, Niaz OS. First-generation antipsychotic long-acting with schizophrenia experience poor adherence, and a previ- injections v. oral antipsychotics in schizophrenia: systematic review of ous Finnish study showed a low adherence to the initial antipsy- randomised controlled trials and observational studies. Br J Psychiatry. chotic treatment during the first 60 days after patient’s first 2009;195:S20–S28. hospitalization for schizophrenia. A lack of adherence to anti- 10. Newton R, Hustig H, Lakshmana R, et al. Practical guidelines on the use of psychotics is often associated with relapses; indeed, it has been paliperidone palmitate in schizophrenia. Curr Med Res Opin.2012;28: shown that the risk of relapse is 5 times higher among patients 559–567. who discontinued their antipsychotic treatment after a first epi- 11. Bitter I, Katona L, Zámbori J, et al. Comparative effectiveness of depot and sode of schizophrenia. Relapses usually lead to hospitalizations oral second generation antipsychotic drugs in schizophrenia: a nationwide and substantial changes in the disease management. As a result, study in Hungary. Eur Neuropsychopharmacol. 2013;23:1383–1390. relapses are associated with a high economic burden. Thus, maintaining schizophrenic patients under treatment for a longer 12. Schreiner A, Svensson A, Wapenaar R, et al. Long-acting injectable period of time may have a positive impact on both clinical out- risperidone and oral antipsychotics in patients with schizophrenia: results comes and the economic burden of schizophrenia. from a prospective, 1-year, non-interventional study (InORS). World J Biol Psychiatry. 2014;15:534–545. To conclude, this observational retrospective study indicated nonsignificant differences in duration of initial hospitalization and 13. Grimaldi-Bensouda L, Rouillon F, Astruc B, et al. Does long-acting time to rehospitalization between PP and RLAI, potentially due to injectable risperidone make a difference to the real-life treatment of a lack of statistical power. A trend was observed in favor of PP schizophrenia? Results of the Cohort for the General Study of with regard to time to treatment discontinuation, although this Schizophrenia (CGS). Schizophr Res. 2012;134:187–194. © 2017 Wolters Kluwer Health, Inc. All rights reserved. www.psychopharmacology.com 25 Limosin et al Journal of Clinical Psychopharmacology Volume 38, Number 1, February 2018 14. Joshi K, Pan X, Wang R, et al. Healthcare resource utilization of 19. Capdevielle D, Ritchie K, Villebrun D, et al. Durées d’hospitalization des second-generation long-acting injectable antipsychotics in schizophrenia: patients souffrant de schizophrénie: facteurs cliniques de variations et leurs risperidone versus paliperidone palmitate. Curr Med Res Opin.2016;32: conséquences. Encéphale.2009;35:90–96. 1873–1881. 20. Harmand S, Ansolabehere X, Guillon P. Antipsychotiques injectables à 15. Coldefy M, Lepage J. Les secteurs de psychiatrie générale en 2003. Série action prolongée en pharmacie de ville en France : étude de la persistance et Etudes no. 70, November 2007, Minister of Health, Direction de la des caractéristiques de traitements. 14e congrès de l’encéphale, Paris 2016 Recherche des Etudes de l’Evaluation et des Statistiques (DREESS). PO-387. Available at: http://eposter.europa-organisation.com/2016/encephale/ Available at: http://drees.solidarites-sante.gouv.fr/IMG/pdf/serieetud70. index/slide/abstract/370/search/PO-387. Accessed August 22, 2017. pdf. Accessed August 22, 2017. 21. Lacro JP, Dunn LB, Dolder CR, et al. Prevalence of and risk factors for 16. Pandina G, Lane R, Gopal S, et al. A double-blind study of paliperidone medication nonadherence in patients with schizophrenia: a comprehensive palmitate and risperidone long-acting injectable in adults with review of recent literature. J Clin Psychiatry. 2002;63:892–909. schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35: 22. Gilmer TP, Dolder CR, Lacro JP, et al. Adherence to treatment with 218–226. antipsychotic medication and health care costs among Medicaid 17. Faria R, Hernandez Alava M, Manca A, et al. NICE DSU (National Institute beneficiaries with schizophrenia. Am J Psychiatry. 2004;161:692–699. for Health and Care Excellence, Decision Support Unit) technical support 23. Tiihonen J, Haukka J, Taylor M, et al. A nationwide cohort study of oral and document 17: The use of observational data to inform estimates of depot antipsychotics after first hospitalization for schizophrenia. Am J treatment effectiveness for technology appraisal: methods for comparative Psychiatry. 2011;168:603–609. individual patient data. Sheffield, UK: NICE Decision Support Unit; 2015. 24. Robinson D, Woerner MG, Alvir JM, et al. Predictors of relapse following 18. Johnson ML, Crown W, Martin BC, et al. Good research practices for response from a first episode of schizophrenia or schizoaffective disorder. comparative effectiveness research: analytic methods to improve causal JAMA Psychiatry. 1999;56:241–247. inference from nonrandomized studies of treatment effects using secondary data sources: the ISPOR Good Research Practices for Retrospective 25. Munro J, Osborne S, Dearden L, et al. Hospital treatment and management Database Analysis Task Force Report—part III. Value Health.2009;12: in relapse of schizophrenia in the UK: associated costs. Psychiatrist.2011; 1062–1073. 35:95–100. 26 www.psychopharmacology.com © 2017 Wolters Kluwer Health, Inc. All rights reserved. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Clinical Psychopharmacology Pubmed Central

Comparison of Paliperidone Palmitate and Risperidone Long-Acting Injection in Schizophrenic Patients

Limosin, Frédéric; Belhadi, Drifa; Comet, Denis; Pacou, Maud; Bouju, Sophie; Van Impe, Kristel; Guillon, Pascal
Journal of Clinical Psychopharmacology , Volume 38 (1) – Dec 11, 2017
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Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc.
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0271-0749
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10.1097/JCP.0000000000000827
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Abstract

affect and alogia). The course of the disease varies widely, alternating Purpose/Background: The study objective was to compare the impact between periods of remission and relapse, where patients experience of being treated by paliperidone palmitate (PP) or risperidone long-acting unpredictable patterns of symptoms. These symptoms are associated injection (RLAI) on the length of stay on initial hospitalization, rehospital- with isolation, alteration of daily functioning and feelings, as well as ization risk, and treatment duration in schizophrenic patients. disorganized thoughts and behaviors. The public health and financial Methods: We conducted an observational retrospective cohort study in burdens of schizophrenia are considered to be substantial by the French 43 centers in France, including schizophrenic patients who initiated a treat- 1,2 authorities. Indeed, patients affected by schizophrenia are the largest ment by PP or RLAI during initial hospitalization. The follow-up periods 3 group of hospitalized patients for mental disorders in 2011. In France, started in September 2012 for the RLAI group (median follow-up duration, between 300,000 and 600,000 patients are affected by schizophrenia, 233 days) and in June 2013 for the PP group (259 days). Statistical analyses 4–6 with approximately 10,000 new patients per year. were based on Cox regression models, with propensity score weighting to Long-acting injectable (LAI) antipsychotics are recom- account for differences in patients’ characteristics. mended for the maintenance treatment of schizophrenia especially Findings/Results: The analysis included 347 patients: 197 in the PP treat- for the prevention of relapse in noncompliant patients. Also, consen- ment group and 150 in the RLAI group. Compared with patients on RLAI, pa- sus-based guidance recommends using LAIs as first-line therapy in tients on PP were significantly more likely to have nonpsychiatric comorbidities, 7–9 patients who will be treated with antipsychotics over the long term. to have been on previous antipsychotic therapy, or to have been hospitalized for Relapses involve an increase of hospitalizations and disease deteriora- psychiatric care in the previous year. With regard to length of stay on initial hos- tion such as treatment resistance and socialization issues. Compliance pitalization, there was no statistically significant difference between both groups is a key challenge in treatment management, as noncompliance is (hazard ratio, 1.13 [0.97; 1.31]). Being on PP was associated with similar times strongly associated with relapses or hospitalizations. Paliperidone pal- to first rehospitalization compared with RLAI (hazard ratio,0.92 [0.65; 1.30]). mitate (PP) long-acting injection and risperidone long-acting injection Implications/Conclusions: We observed nonsignificant differences in (RLAI) are two long-acting antipsychotics recommended in the pre- initial hospitalization duration and time to rehospitalization between PP and vention of relapses. Paliperidone palmitate long-acting injection is ad- RLAI, potentially due to lack of statistical power. A trend was observed in ministered once monthly, whereas RLAI is administered fortnightly. favor of PP with regard to time to treatment discontinuation, although this Advantages of PP include a quick onset of action, a one-monthly in- result was compromised by patients who switched between RLAI and PP. jection, and the absence of oral supplementation at treatment initia- Key Words: Paliperidone Palmitate, Antipsychotic Agents, schizophrenia, tion. Thus, PP may help patient compliance. Retrospective Study, France To date, several observational studies have been conducted 11–13 assessing the effectiveness of RLAI. One study evaluated (J Clin Psychopharmacol 2018;38: 19–26) the comparative effectiveness of RLAI versus PP in the United chizophrenia is a severe chronic mental disorder characterized States. However there is still a lack of real-life data on patients S by various “positive” symptoms (such as hallucinations and treated with PP in Europe. The Long Acting Outcomes Study in Schizophrenia (LAOS) From the *Assistance Publique-Hôpitaux de Paris (AP-HP), Corentin-Celton was a multicenter observational retrospective cohort study conducted Hospital, Department of Psychiatry, Issy-les-Moulineaux; †Paris Descartes University, in 43 centers in France. It included schizophrenic patients who ini- PRES Sorbonne Paris Cité, Paris; ‡Amaris, Paris; §Axonal, Nanterre; ||Janssen-Cilag, tiated a treatment by PP or RLAI during the initial hospitalization. Issy-les-Moulineaux, France; and }Janssen-Cilag GmbH, Neuss, Germany. Received May 5, 2017; accepted after revision October 24, 2017. The primary objective of the study was to evaluate and com- Reprints: Drifa Belhadi, MSc, Amaris, 28 rue Jacques Ibert, 92300 Levallois pare the impact of being treated by PP or long-acting risperidone Perret, France (e‐mail: drifa.belhadi@amaris.com). injection on the length of stay on initial hospitalization of schizo- This study was funded by Janssen-Cilag, Issy-les-Moulineaux, France. phrenic patients. Secondary objectives included evaluation and Sponsor employees participated in the study design, data interpretation, and writing of the report. The sponsor of the study did not participate in the data comparison of risk of rehospitalization and treatment duration. collection and data analysis. Employees of an independent consulting Our hypothesis is that PP is associated with better patient com- company (Axonal) received funding for contribution to the study design, pliance and reduced disease management costs through a decrease in and employees of another independent consulting company (Amaris) health resource use compared with long-acting risperidone injection. received funding for contribution to the data analyses. Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal’s Web site (www.psychopharmacology.com). MATERIALS AND METHODS Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 LAOS Study (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or Study Objectives used commercially without permission from the journal. This study was designed to assess and compare, in patients ISSN: 0271-0749 DOI: 10.1097/JCP.0000000000000827 with schizophrenia who were hospitalized full-time for symptomatic Journal of Clinical Psychopharmacology � Volume 38, Number 1, February 2018 www.psychopharmacology.com 19 Limosin et al Journal of Clinical Psychopharmacology Volume 38, Number 1, February 2018 decompensation and in whom treatment (with PP or RLAI) was Monitoring Plan initiated during the initial hospitalization period, the duration of Data were directly collected in electronic case report form, maintenance treatments, the duration of the initial hospitalizations with automatic controls and alerts when potential incorrect data periods, and the hospitalization rates and cumulative hospitaliza- were entered (outlier data check), by investigators. To ensure the tion periods for psychiatric reasons during exposure to treatment quality of data collected in this study, on-site monitoring visits (eitherPP orRLAI). were carried out by independent clinical research assistants trained in the study protocol. A first monitoring visit was performed, after the sixth patient, to check that patients were informed by investi- Study Design gators about the collection of their medical data and were not The LAOS study was an observational, retrospective, multi- opposed to it, to control that all required data entered into the elec- center, and national cohort and was carried out in public and private tronic case report form were in accordance with data from medical health care establishments equipped for the full-time hospitalization records and to check that sites performed the study in compliance of patients in psychiatric units. Although the study was retrospec- with the study protocol and current regulations. A total of 60 monitor- tive, monitoring visits equivalent to quality-check visits were con- ing visits were carried out and allowed to monitor 308 patients (75% ducted to ensure optimal quality and completeness of data. of the patients included) by direct access to medical data records or by Psychiatrists were identified from exhaustive national list- investigator interview (depending on hospital’s practices on medical ings of practicing physicians by specialty (CEGEDIM OneKey records access). In addition to monitoring, data quality testing based registries; Cegedim, Boulogne-Billancourt, France www. on the comparison of rates of missing data on the monitored variables cegedim.com), where the sponsor (Janssen-Cilag) has a list of and on the number of deviant patients was carried out. e-mail addresses provided by practitioners. On 3,615 contacted French psychiatrists, 193 sites sent a confidentiality agreement Data Collection and received a feasibility questionnaire, notably about their For each patient, a patient case report form was filled retro- patient recruitment potential. On these 193 sites, 89 feasibility spectively by participating psychiatrists, in providing information questionnaires were received and site selection was organized on patient attributes. These related to demographics, type of schizo- (by visit or remote contact). On these 89 sites, 64 sites, with a phrenia, disease history and severity, initial full-time hospitalization potential to take more than 5 patients per treatment group, were (admission and discharge dates, reason having led to hospitaliza- preselected. Psychiatrists did not receive any specific incentive tion, antipsychotic treatment at the time of admission to hospital, to report cases. treatment compliance issues, treatment resistance, treatments re- As psychiatric services are organized per sector (sectors are lated to the disorder prescribed and administered during the hospi- established based on population density) with the sectors essen- tal stay (with start and end dates, dosage, and administration route), tially proposing state-run services (92% of state-run structures: other nonmedical therapeutic measures during hospitalization and general or specialized hospitals, medicopsychological consulta- other concurrent disorders). tion services), to ensure the whole of France was represented in At the end of the initial hospitalization and throughout the the study, the geographic localization of the centers was based follow-up period, were also been collected all the types of hospi- on 7 large French metropolitan areas. talizations, all the consultations as an outpatient, all the visits to On the 64 preselected sites, the study was carried out an emergency unit, taking part in activities organized by part- in 50 selected centers representative of the French centers, time therapeutic reception centers, the number of suicide attempts with sampling being stratifiedper region accordingtothe and forced hospitalizations, all the other nonmedical therapeutic aforementioned distributions. measures and the hospitalization alternatives. Treatments related In each center, the first 6 to 18 patients meeting the inclusion to the disorder prescribed and administered during the hospital criteria were selected and 3 to 9 patients were allocated to each stay, with start and end dates, dosage, and administration route were treatment group. This method of cluster sampling within the centers also collected. Finally, date and circumstances of the last contact, and systematic assessment of the first eligible patients (chronologic initiated treatment (PP or RLAI) continued or discontinued (with selection) with equivalent numbers of patients being selected per discontinuation data and reason). center guarantees representativeness. Patients were informed about the study and were not opposed Patients were eligible for inclusion in the study if they to the use of their data. They also signed a consent form to autho- satisfied the following criteria: at least 18 years of age; with rize the access to their medical data. confirmed schizophrenia according to the criteria of the Inter- The study protocol was approved by an independent scien- national Classification of Diseases (CIM10), except for schi- tific committee and in accordance with French law, the Ethics zoaffective disorders; hospitalized full-time for symptomatic Committee’s approval was not required as the protocol was strictly decompensation (acute psychotic episode, behavior disorders/ observational and usual practice was unchanged. However, the aggressive behavior toward self or others, thymic state, intoxica- study protocol was approved by the Advisory Committee on In- tion with alcohol or other substances, etc.); and in whom the fol- formation Processing in Research in the Field of Health and by lowing treatment was initiated during hospitalization: either RLAI the French Data Protection Authority. from September 1, 2012 (before PP French market access) or PP from June 1, 2013. The LAI prescription was initiated before the Outcome Measures onset of the study. Participants were excluded if they were with schizoaffective The primary outcome was length of stay on initial hospitaliza- disorder or another psychotic disorder, hospitalized full-time chron- tion, which was defined as the number of days between the admis- ically (hospitalized for more than 60 consecutive days) at the time sion to the hospital and the last day of this initial hospitalization. of treatment initiation (RLAI or PP), whose previous treatment in- Secondary outcomes were the time to first rehospitalization after cluded RLAI or PP (in the 6 months preceding treatment initiation the initial hospitalization and the time to treatment discontinuation. with PP or RLAI long-acting injection), who had already been The individual study period started from the beginning of the treated with clozapine or patients participating in another clinical initial hospitalization and ended 30 days after the last injection of trial at the time of the initial hospitalization. treatment or at the date of last contact. If a patient switched from 20 www.psychopharmacology.com © 2017 Wolters Kluwer Health, Inc. All rights reserved. Journal of Clinical Psychopharmacology Volume 38, Number 1, February 2018 Cohort Study in Schizophrenia RLAI to PP (or vice versa), the study period ended at the time of only, a switch from RLAI to PP (and vice versa) was considered the treatment switch. Consequently, each patient was included in a as a censoring event in a sensitivity analysis. single treatment group. A switch from RLAI to PP (and vice Outputs are reported as hazard ratios (HRs) with their corre- versa) was considered to be a treatment withdrawal for the analy- sponding 95% confidence intervals (95% CIs). Statistical analyses sis of time to discontinuation (treatment duration). were conducted using SAS® version 9.4. Patients who deviated from the protocol and patients who never left the initial hospitalization were excluded from the analy- sis in order to minimize bias. Patients from center 69 were also ex- RESULTS cluded from the analysis as the monitoring in this center could not be conducted according to the study protocol. Descriptive Statistics Descriptive data on the baseline characteristics of the study Statistical Analyses population is reported for each treatment group in Table 1 and pa- Time to end of initial hospitalization, time to first rehospi- tient’s characteristics over the follow-up period are described in talization and time to treatment discontinuation were analyzed Table 2. A total of 347 patients were included in the analysis: 197 through Kaplan-Meier survival analyses and Cox regression from the PP treatment group (mean dose of 106.3 mg) and 150 models. In nonrandomized studies, there is a risk that the alloca- from the RLAI treatment group (mean dose of 45.3 mg; Table 1 tion of a treatment may be dependent on patient characteristics. and Fig. 1). Therefore, to control for this potential selection bias, the propen- Both treatment groups were well balanced with regard to sex, sity score weighting method was used to account for differences alcohol addiction, drug addiction, and type of schizophrenia in individual patient’s characteristics. The propensity score corre- (paranoid vs other types of schizophrenia). Compared with pa- sponds to the probability for a patient to receive PP rather than tients on RLAI, patients on PP were significantly more likely to RLAI as a function of patients’ and prescribers’ characteristics. have nonpsychiatric comorbidities (P = 0.007), to have been on The propensity score was estimated with a logistic regression using previous antipsychotic therapy (P = 0.04), or to have been hospi- the following variables (selected based on statistical significance): talized for psychiatric care in the previous year (P =0.001). High nonpsychiatric comorbidities, number of hospitalizations for psy- rates of involuntary hospitalizations were observed in both groups chiatric care during the last 12 months, monitoring method, admis- (67% in the RLAI group and 69% in the PP group). This may be sion method, prior therapies and compliance, alcohol addiction, associated with the use of injectable antipsychotics, which are fre- concomitant psychotic treatment, psychiatric comorbidities, sex, quently administered in more severe and less compliant patients. age, sex of the investigator, education level, and psychoeducation received (Supplemental Digital Content, Table S1 Results of the Length of Stay on Initial Hospitalization and Time propensity score estimation, http://links.lww.com/JCP/A489). to First Re-Hospitalization Sensitivity analyses were conducted to assess the robustness of the results. Several statistical models were tested (nonadjusted, Results from the base case and sensitivity analyses for both multivariate Cox regressions and use of the propensity score as an the length of stay on initial hospitalization and the time to first re- adjustment variable). Sensitivity analyses excluding patients with hospitalization are reported in Figure 2. extreme propensity scores were conducted. Based on discussions The average length of stay on initial hospitalization was com- with a clinical expert, covariates used for the propensity score parable among PP patients compared with RLAI patients (38 vs estimation were selected based on clinical relevance instead of 42 days). There was no statistically significant difference between statistical significance. For the duration of initial hospitaliza- both treatment groups (hazard ratio [HR], 1.13 [0.97; 1.31]). Con- tion only, a sensitivity analysis including patients still in initial clusions were similar across all sensitivity analyses: no statistically hospitalization at the end of follow-up was conducted. For the significant results were identified across analyses. When including time to first rehospitalization and treatment discontinuation, an patients still in their initial hospitalization at the end of follow-up, analysis was restricted on patients with at least one injection after results remained similar between both treatment groups (HR,1.00 initial hospitalization. For the time to treatment discontinuation [0.86; 1.16]). TABLE 1. Baseline Characteristics of the Study Population Paliperidone Risperidone Long-Acting Palmitate n = 197 Injection n = 150 P Age, mean (SD), yrs 37.8 (12.3) 37.8 (12.1) 0.97* Sex (male), n (%) patients 126 (64%) 107 (71%) 0.15 At least one nonpsychiatric comorbidity, n (%) patients 28 (14%) 8 (5%) 0.01 At least one psychiatric comorbidity, n (%) patients 37 (19%) 29 (19%) 0.90 Alcohol abuse, n (%) patients 37 (19%) 37 (25%) 0.18 Substance abuse (other than nicotine), n (%) patients 64 (32%) 50 (33%) 0.87 Paranoid schizophrenia, n (%) patients 142 (72%) 105 (70%) 0.67 At least one prior antipsychotic therapy, n (%) patients 84 (43%) 48 (32%) 0.04 At least one hospitalization for psychiatric care in the last 12 months, n (%) patients 136 (69%) 77 (51%) 0.001 Involuntary hospitalization, n (%) patients 136 (69%) 101 (67%) 0.74 Psychoeducation received, n (%) patients 88 (45%) 64 (43%) 0.71 † 2 *Wilcoxon test; χ test. © 2017 Wolters Kluwer Health, Inc. All rights reserved. www.psychopharmacology.com 21 Limosin et al Journal of Clinical Psychopharmacology Volume 38, Number 1, February 2018 TABLE 2. Patient’s Characteristics over the Follow-Up Period Paliperidone Risperidone Long-Acting Palmitate n = 197 Injection n = 150 P Treatment dose, mean (SD), mg 106.3 (22.1) 45.3 (8.9) — At least one emergency room visit, n (%) 84 (43%) 61 (41%) 0.71* At least one adverse event, n (%) 25 (13%) 12 (8%) 0.16* Concomitant therapies, n (%) Antipsychotics 80 (41%) 76 (51%) 0.06* Anticholinergic agents 55 (28%) 44 (29%) 0.77* Anxiolytics 59 (30%) 49 (33%) 0.59* Antidepressants 19 (10%) 17 (11%) 0.61* Antiepileptic agents 21 (11%) 16 (11%) 0.99* Hypnotics and sedatives 26 (13%) 20 (13%) 0.97* Other 13 (7%) 3 (2%) 0.04* Length of stay on initial hospitalization, mean (SD), days 38.1 (24.6) 41.6 (38.1) 0.95 No. patients rehospitalized during the study, n (%) 39 (20%) 33 (22%) 0.62* Cumulative duration of rehospitalizations among patients with at least one 42.1 (36.8) 44.4 (30.7) 0.36 rehospitalization, mean (SD) No. rehospitalizations among patients with at least one rehospitalization, mean 1.56 (0.9) 1.4 (0.8) 0.34 (SD) per patient No. patients who discontinued their treatment, n (%) 39 (20%) 67 (45%) <0.001* §, || No. patients who discontinued their treatment during the initial hospitalization, n (%) 14 (7%) 20 (13%) 0.05* No. patients with at least one rehospitalization and who discontinued their 13 (20%) 6 (11%) 0.16* §, ¶ treatment during a rehospitalization, n(%) 2 † ‡ § *χ test; only 2 patients received chlorpromazine as concomitant therapy (100 mg and 300 mg) both in the PP group; Wilcoxon test; considering a || ¶ switch as a treatment withdrawal; 3 missing values; 2 missing values. The percentages of patients being rehospitalized after the ini- in Table 2). The treatment discontinuation rates during a rehospi- tial hospitalization were low and comparable in both treatment talization in patients with at least one rehospitalization were also groups (20% in PP patients and 22% in RLAI patients, as reported comparable in both treatment groups (20% in PP patients and FIGURE 1. Patient’s eligibility for the base case analysis. 22 www.psychopharmacology.com © 2017 Wolters Kluwer Health, Inc. All rights reserved. Journal of Clinical Psychopharmacology Volume 38, Number 1, February 2018 Cohort Study in Schizophrenia FIGURE 2. Base case and sensitivity analyses results for both outcomes: length of stay on initial hospitalization and time to first rehospitalization. For the length of stay on initial hospitalization an HR higher than 1 indicates a shorter duration in favor of PP. For the time to first rehospitalization, an HR lower than 1 indicates a lower risk of rehospitalization in favor of PP. 11% in RLAI patients). Being on PP was associated with similar hospitalization was significantly higher in the RLAI group (13%) times to first rehospitalization compared with being on RLAI than in the PP group (7%). (HR,0.92 [0.65; 1.30]). Conclusions were similar across sensitiv- Results from the base case and sensitivity analyses are re- ity analyses (with HRs ranging from 0.61 to 0.95), except for one ported in Figure 4. When considering a switch as a treatment with- analysis testing a methodological assumption which resulted in an drawal, patients on PP were associated with a 61% risk reduction HR significantly in favor of PP (HR,0.59 [0.35; 0.98]). These dif- in treatment discontinuation compared with patients on RLAI ferences in results across analyses were due to the low number of (HR,0.39 [0.29; 0.52]). However, when a switch was considered patients being rehospitalized after the initial hospitalization (39 in as a censoring event, the results indicated a nonstatistically signifi- the PP group and 33 in the RLAI group). cant trend in favor of PP (HR,0.73 [0.52; 1.02]). All other sensitiv- ity analyses were also associated with significantly longer treatment duration for PP compared with RLAI. When focusing on patients Treatment Duration with at least one injection after the initial hospitalization, the treat- Figure 3 shows the Kaplan-Meier survival curves for time to ment duration remained significantly longer among patients on PP treatment discontinuation, considering a treatment switch as a treat- than among patients on RLAI (HR,0.44 [0.31; 0.61]). ment withdrawal (base case assumption). As reported in Table 2, the percentage of patients who discontinued their treatment was sig- DISCUSSION nificantly higher in the RLAI group (45%) than in the PP group (20%). The probability of remaining on treatment after one year This retrospective observational study assesses PP versus was higher with PP (76%) than with RLAI (53%). The percentage RLAI among schizophrenic patients with regard to length of stay of patients who discontinued their treatment during the initial on initial hospitalization, time to first rehospitalization and time to FIGURE 3. Time to treatment discontinuation: Kaplan-Meier curves. © 2017 Wolters Kluwer Health, Inc. All rights reserved. www.psychopharmacology.com 23 Limosin et al Journal of Clinical Psychopharmacology Volume 38, Number 1, February 2018 FIGURE 4. Base case and sensitivity analyses results for the time to treatment discontinuation. *Switch considered as a treatment withdrawal. For the time to treatment discontinuation, an HR lower than 1 indicates a lower risk of treatment discontinuation in favor of PP, that is, a longer treatment duration. treatment discontinuation. Overall, the study population was rep- when considering a switch as a treatment failure. It should be noted resentative of the general French schizophrenic patient popula- that considering a switch as a censoring event changed the conclu- tion. Mean age was 38 years and 67% of patients were male. sion of this analysis (results are no longer statistically significant). This is very comparable to the Cohort for the General study of Little bias was expected on the primary and secondary end Schizophrenia, which included more than 1,500 patients (mean points as the duration of hospitalization, time to rehospitalization, age, 38 years; 68% of male). and time to treatment discontinuation are robust end points, which Length of stay on initial hospitalization was comparable be- are not subject to interpretation. The absence of randomization is tween treatment groups (average duration of 38 days in the PP usually associated with a potential selection bias, which was ad- group and 42 days in the RLAI group). Fewer days of hospitalization justed for by using the propensity score method. This statistical tech- for PP compared to RLAI were expected given that the initiation of nique is recommended in guidelines such as the ones from the RLAI requires an oral supplementation (pretreatment by oral risperi- National Institute for Health and Care Excellence and International 17,18 done during at least 2 weeks followed by a 3-week oral supplementa- Society for Pharmacoeconomics and Outcomes Research. Sev- tion). However, these lengths of stay were not significantly different eral sensitivity analyses were conducted to assess the robustness between treatments potentially owing to a lack of statistical power. In- of the results, accounting for patient selection, differences in out- deed, fewer patients than initially planned wereincluded. In addition come definitions, and for the implementation of different statistical patients with protocol deviations or patients from center 69 were ex- methods. Overall, the results were considered to be robust, as the cluded. This resulted in 347 of the 500 patients initially planned being conduct of these different analyses did not significantly change included in the statistical analyses. the interpretation of the results. There was only a few number of rehospitalization in both Few studies have been published on the association between treatment groups: 39 in the PP group (20% of patients) and 33 long-acting antipsychotic treatments and hospitalization. In par- in the RLAI group (22% of patients). This low number of rehospi- ticular, there is a lack of studies investigating the factors influenc- talization may be because all patients received a treatment (either ing the duration of hospital stay and the consequences on patients’ PP or RLAI) throughout the study and were followed until 30 days outcomes of shorter hospital stays. Nevertheless, some recent after the last injection of treatment or until the date of last contact. studies have been identified. Results from previous observational 9,10 Rehospitalization rates were comparable between PP and RLAI studies indicate that RLAI is associated with lower hospitaliza- groups and results were nonsignificant for most of the analyses tion rates compared to oral antipsychotics. A Hungarian registry- conducted. Those results are consistent with noninferiority results based observational follow-up study including 9,567 schizophrenic with regard to efficacy between PP and RLAI demonstrated in a patients also reported longer time to treatment discontinuations randomized controlled trial. with RLAI than with oral antipsychotics. Moreover, our results The assumption made regarding the switch between PP and are consistent with those obtained in previous studies comparing RLAI (and vice versa) impacted the conclusion of the treatment dis- PP versus RLAI. An American retrospective longitudinal cohort continuation analysis as a total of 30 patients switched from RLAI to study demonstrated that the use of PP was associated with better ad- PP and 2 patients switched from PP to RLAI. Results for the analysis herence, lower discontinuation rates, and longer treatment durations of treatment discontinuations were significantly in favor of PP compared to RLAI. Paliperidone palmitate was also associated with 24 www.psychopharmacology.com © 2017 Wolters Kluwer Health, Inc. All rights reserved. Journal of Clinical Psychopharmacology Volume 38, Number 1, February 2018 Cohort Study in Schizophrenia a lower risk of hospitalization and shorter hospitalization lengths. result is compromised by patients who switched between RLAI A double-blind randomized trial also showed that PP was non- and PP and would need to be confirmed by a dedicated study. inferior to RLAI based on the change in the PANSS total score from baseline and a French retrospective study based on pharmacy AUTHOR DISCLOSURE INFORMATION treatment issuance reported significantly longer treatment duration F Limosin received honorarium from Janssen for his partici- for PP compared with RLAI. pation in the LAOS study design, writing the protocol, data interpre- Our study also has some limitations. For instance, length of tation, and approving the final manuscript. F Limosin received also hospital stay is driven by the diversity of health care institutions honorarium as consultant or board participation from AstraZeneca, in France. In 2011, an IRDES study reported a mean length of stay Euthérapie-Servier, Janssen, Lundbeck, Otsuka Pharmaceuticals of 83 days over 1 year, varying from 75 to 78 days in multidisciplin- France, and Roche. D Belhadi and M Pacou work for Amaris Com- ary public institutions to 85 to 97 in specialized public structures. pany and report no conflict of interest. D Comet works for Axonal- The variety of type of institutions participating in the LAOS study Biostatem Company and reports no conflict of interest. P Guillon, could thus have introduced some heterogeneity in length and fre- S Bouju, and K Van Impe are employees of Janssen-Cilag. quency of hospital stays. Moreover, the study design was also associated with some limitations. 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Journal of Clinical Psychopharmacology – Pubmed Central

Published: Dec 11, 2017

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