Paliperidone Palmitate Group Research Articles

Cortical thickness, gray-white matter contrast, and intracortical myelin in first-episode schizophrenia patients treated with long-acting paliperidone palmitate versus oral antipsychotics

This longitudinal study evaluated the cortical thickness, gray-to-white matter contrast (GWC), and frontal lobe intracortical myelin (ICM) volume in first-episode schizophrenia (FES) patients treated with oral antipsychotics (OAP) versus a long-acting injectable antipsychotic, paliperidone palmitate (PP). 2D proton density and inversion recovery images, and 3D T1-weighted MPRAGE images were acquired at 3T from 68 FES patients in a randomized clinical trial with PP vs OAP. At baseline, no differences in GWC and ICM were observed between FES patients and HCs, but the thickness of the left precuneus, the right transverse temporal gyrus, and the bilateral superior temporal gyri was found to be thinner in FES patients relative to HCs. Following 9 months of antipsychotics, OAP treatment, compared to PP treatment, resulted in a more widespread cortical thickness reduction including the right lateral occipital and orbitofrontal gyri. No significant ICM and GWC changes were observed in the PP group, whereas OAP treatment led to a significant ICM volume decrease and GWC increase. A negative correlation was found between ICM changes and GWC changes within multiple frontal regions after 9 months of OAP treatment. These preliminary findings suggest that PP treatment might aid preservation of brain morphology.

Effect of treatment with paliperidone palmitate versus oral antipsychotics on frontal lobe intracortical myelin volume in participants with recent-onset schizophrenia: Magnetic resonance imaging results from the DREaM study.

We investigated changes in brain intracortical myelin (ICM) volume in the frontal lobe after 9months of treatment with paliperidone palmitate (PP) compared with 9months of treatment with oral antipsychotics (OAP) in participants with recent-onset schizophrenia or schizophreniform disorder from the Disease Recovery Evaluation and Modification (DREaM) study, a randomized, open-label, delayed-start trial. DREaM included 3 phases: Part I, a 2-month oral run-in; Part II, a 9-month disease progression phase (PP or OAP); and Part III, 9months of additional treatment (participants receiving PP continued PP [PP/PP] and participants receiving OAP were rerandomized to receive either PP [OAP/PP] or OAP [OAP/OAP]). In Part II, magnetic resonance imaging (MRI) and functional and symptomatic assessment was performed at baseline, day 92, and day 260. ICM volume as a fraction of the entire brain volume was quantified by subtraction of a proton density image from an inversion recovery image. Within-treatment-group changes from baseline were assessed by paired t-tests. Analysis of covariance was used to analyze ICM volume changes between treatment groups, adjusting for country. The MRI analysis sample size included 71 DREaM participants (PP, 23; OAP, 48) and 64 healthy controls. At baseline, mean adjusted ICM fraction values did not differ between groups (PP, 0.057; OAP, 0.058, p=0.79). By day 92, the adjusted ICM fraction in the OAP group had decreased significantly (change from baseline, -0.002; p=0.001), whereas the adjusted ICM fraction remained unchanged from baseline in the PP group (0.000; p=0.80). At day 260, the change from baseline in adjusted ICM fraction was -0.004 (p=0.004) in the OAP group and-0.001 (p=0.728) in the PP group. The difference between treatment groups did not reach statistical significance (p=0.147). In participants with recent-onset schizophrenia or schizophreniform disorder, frontal ICM volume was preserved at baseline levels in those treated with PP over 9months. However, a decrease of frontal ICM volume was observed among participants treated with OAPs. clinicaltrials.gov identifier NCT02431702.

Dispersion of cognitive performance test scores on the MATRICS Consensus Cognitive Battery: A different perspective

ObjectivePersons with schizophrenia exhibit greater neurocognitive test score dispersion. Here, we seek to characterize dispersion on the Neurocognitive Composite subtests of the Measurement of Treatment Research to Improve Cognition in Schizophrena Consensus Cognitive Battery (MCCB) and determine the relative effects of different antipsychotic formulations on dispersion and mean performance. MethodIn this post hoc analysis of the DREaM study (NCT02431702), which compared treatment with paliperidone palmitate (PP) long-acting injectable with oral antipsychotic (OAP) treatment over 18 months, dispersion in MCCB neurocognitive subtest performance was calculated for each participant by visit (test occasion). ResultsOver 18 months, mean neurocognitive performance improved in a manner consistent with the expected effects of practice in both groups (p < 0.05); this improvement was observed during the first 9 months (PP: p < 0.05, OAP: p < 0.001), followed by stable performance over the second 9 months (PP: p = 0.821, OAP: p = 0.375). Rates of change did not differ between groups (treatment-by-visit interaction: p = 0.548). In contrast, analyses of dispersion focusing on contrasts between baselines and end points of the first and second 9 months revealed different patterns. Over the first 9 months, dispersion in both groups lessened to a similar extent. However, over the second 9 months, dispersion remained stable in the PP group, whereas neurocognitive performance became significantly more variable in the OAP group (p < 0.01). ConclusionDispersion of neurocognitive test scores provides a different index of cognitive change than that provided by composite scores. Long-term maintenance of therapeutic levels provided by PP over time may limit (relative to oral AP) the extent to which cognitive performance becomes more variable.

A randomized, 13-week study assessing the efficacy and metabolic effects of paliperidone palmitate injection and olanzapine in first-episode schizophrenia patients

BackgroundThis study was conducted to evaluate the efficacy and metabolic effects of paliperidone palmitate (PP) injections against oral olanzapine in first-episode schizophrenia (FES) patients. MethodsEligible patients were randomized to receive PP or olanzapine. Efficacy assessments and weight-related parameters were assessed at baseline, weeks 1, 5, 9, and endpoint or at early withdrawal. Lipid, glucose, insulin and prolactin were evaluated at baseline and endpoint or at early withdrawal. ResultsThe Positive And Negative Syndrome Scale (PANSS) scores declined significantly after treatment in both groups. Significant increases in weight-related parameters from baseline to endpoint were shown in both groups. Although there was no significant difference in PANSS scores and weight-related parameters between the two groups through the whole 13-week study. The increased level of triglyceride and HOMA-IR at endpoint from baseline in the olanzapine group was higher than the PP group. There was a stronger elevation of prolactin level in the PP group. ConclusionsIn summary, PP and olanzapine showed similar improvement in the treatment of FES patients. This study also reinforced the necessity for regular monitoring of metabolic parameters in schizophrenia patients prescribed atypical antipsychotics.Clinical trial registration numbers: ChiCTR-IOR-14005304.Date of registration: 2014-10-11.

Discontinuation, read missions and polytherapy with long-acting antipsychotics: An observational study

Introduction and aimLong-acting antipsychotics (LAIs) provide certain advantages over oral medications. The aim of our study is to determine whether there are differences between the various long-acting injectable antipsychotics available in our environment.MethodsA retrospective observational study with psychotic patients discharged with LAIs was designed. Data on discontinuation, relapses and associated drugs in the discharge and in a year follow-up were collected. Fifty-seven patients were included: 21 risperidone (RLAI), 20 paliperidone palmitate (PP) and 16 first-generation LAIs (FG). Odds ratio was used to compare discontinuation, χ2 test for categorical variables and Kruskal-Wallis test for independent samples.ResultsDiscontinuation was lower with PP: ORRLAI/PP = 2.74 and ORFGLAI/PP = 3.09. There were significant differences in readmissions: rehospitalizations (χ2 = 7.072, P = 0.029) and days of stay (χ2 = 8.251; P = 0.016), both lower in the PP group. We found less use of psychoactive drugs with PP, with significant differences in the discharge (χ2 = 11.518; P = 0.003) and in the follow-up (χ2 = 7.097; P = 0.029). There were also significant differences in the use of oral antipsychotics in the discharge (χ2 = 27.049, P = 0.000); anticholinergic drugs in the discharge (χ2 = 7.001, P = 0.03) and in the follow-up (χ2 = 11.699, P = 0.003) and benzodiazepines in the follow-up (χ2 = 8.493, P = 0.014), always lower in the group of patients treated with PP.ConclusionsTreatment with paliperidone palmitate may be more suitable than other long acting antipsychotics when it starts during the acute episode.Disclosure of interestThe authors have not supplied their declaration of competing interest.

The Comparative Effects of Risperidone Long-Acting Injection and Paliperidone Palmitate on Social Functioning in Schizophrenia: A 6-Month, Open-Label, Randomized Controlled Pilot Trial

Purpose: The aim of this study was to compare the effects of risperidone long-acting injection (RLAI) and paliperidone palmitate (PP) on non-acute-phase social functioning in patients with schizophrenia. Patients and Methods: In this 6-month pilot, open-label, randomized controlled study, 30 patients with schizophrenia who had been treated with RLAI were randomly allocated to the RLAI continuation group or switched to the PP group. Patients were evaluated at baseline and 6 months with the Social Functioning Scale (SFS) as the primary outcome variable and University of California San Diego Performance-Based Skills Assessment Brief (UPSA-B), Social Emotional Cognition Task (SECT), Positive and Negative Syndrome Scale (PANSS), and Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) scores as secondary outcomes. Results: At baseline, the two groups did not significantly differ in demographic or clinical features. The two groups did not differ in total score changes for the UPSA-B, the SECT, the PANSS, and the DIEPSS. However, the total scores and the two subscales of the SFS, i.e. independence-competence and independence-performance, were more improved in the PP group compared to the RLAI group (total scores, p = 0.038; competence, p = 0.001, and performance, p = 0.007, respectively). Conclusion: These results suggest that PP may improve the total social functioning, independent life competence, and performance as compared to the RLAI group. However, these results are preliminary and need independent replication in larger samples before any definitive statement can be made.

A pragmatic analysis comparing once-monthly paliperidone palmitate versus daily oral antipsychotic treatment in patients with schizophrenia

BackgroundPersons with schizophrenia often come in contact with the criminal justice system (CJS). This analysis of subjects with schizophrenia and a history of contact with the CJS estimated and compared mean cumulative function (MCF) of treatment failure events when treated with paliperidone palmitate (PP) or oral antipsychotics (OAs). All events identified during the full study period of the Paliperidone Palmitate Research in Demonstrating Effectiveness (PRIDE) trial were evaluated. MethodsSubjects were randomly assigned to flexibly dosed, monthly, injectable PP (78–234mg) or daily OA in a 15-month prospective, open-label, multicenter US study (May 5, 2010–December 9, 2013). Subjects could continue participation after a treatment failure event. Multiple treatment failures in individual subjects were analyzed as recurrent events. Analyses estimated MCF of treatment failure events and MCF of institutionalizations (arrests, incarcerations, or psychiatric hospitalizations) during the 15-month study period. ResultsThe ITT population included 226 (PP) and 218 (OA) subjects, of whom 41.2% and 40.4%, respectively, completed 15months of follow-up. The MCF of treatment failures and institutionalizations differed significantly in favor of PP compared with OA (P=0.007 and P=0.005, respectively). Overall, TEAEs were reported by 86.3% of subjects in the PP group and 81.7% in the OA group. ConclusionsThis pragmatic analysis suggests that, compared with OA, PP is not only more effective in delaying median time to treatment failure, but it also reduces the number of treatment failures and institutionalizations per person-year follow-up.Clinical trials registration: Clinicaltrials.gov identifier: NCT01157351

Efficacy and Safety of the 3-Month Formulation of Paliperidone Palmitate vs Placebo for Relapse Prevention of Schizophrenia: A Randomized Clinical Trial.

Treatment nonadherence and relapse are common problems in patients with schizophrenia. The long-acting 3-month formulation of paliperidone palmitate, owing to its extended elimination half-life, may offer a valuable therapeutic option for these patients. To evaluate the efficacy and safety of the 3-month formulation of paliperidone palmitate vs placebo in delaying time to relapse of schizophrenia symptoms. This randomized, multicenter trial conducted from April 26, 2012, through April 9, 2014, in 8 countries consisted of 4 phases: 3-week screening phase, flexible-dose 17-week open-label transition phase, 12-week open-label maintenance phase, and open-ended double-blind (DB) phase. Of the 506 patients enrolled (aged 18-70 years; DSM-IV-TR diagnosis of schizophrenia), 305 were randomized to 3-month paliperidone palmitate (n = 160) or placebo (n = 145) in the DB phase. Patients received once-monthly doses of the 1-month formulation of paliperidone palmitate (50, 75, 100, or 150 mg eq) during the transition phase, followed by a single dose of the 3-month formulation (3.5 times the stabilized dose of once-monthly paliperidone palmitate) during the maintenance phase. Stabilized patients were randomized to receive either a fixed dose of 3-month paliperidone palmitate (175, 263, 350, or 525 mg eq) or placebo once every 3 months during the DB phase. Time from randomization to the first relapse event (time to relapse) in the DB phase. In the interim analysis, time to first relapse was significantly different in favor of the paliperidone palmitate group vs the placebo group (hazard ratio = 3.45; 95% CI, 1.73-6.88; P < .001); median time to relapse was 274 days for placebo but not estimable for 3-month paliperidone palmitate. An independent data monitoring committee recommended early study termination due to efficacy. In the DB phase, 183 of 305 patients (62% with 3-month paliperidone palmitate; 58% with placebo) had at least 1 treatment-emergent adverse event; those noted more frequently in the group receiving paliperidone palmitate than in the placebo group were headache (9% vs 4%), weight increased (9% vs 3%), nasopharyngitis (6% vs 1%), and akathisia (4% vs 1%). Compared with placebo, the 3-month formulation of paliperidone palmitate administered 4 times yearly significantly delayed time to relapse in patients with schizophrenia. The 3-month formulation was generally tolerable and has a safety profile consistent with other marketed paliperidone formulations. clinicaltrials.gov Identifier:NCT01529515.

Cost effectiveness of paliperidone palmitate versus oral antipsychotics in patients with schizophrenia and a history of criminal justice involvement

Objective:Conduct a cost effectiveness analysis for the Paliperidone palmitate Research In Demonstrating Effectiveness (PRIDE) trial.Research design and methods:PRIDE was a 15 month, prospective, randomized, open-label study in which once monthly paliperidone palmitate significantly delayed the time to first treatment failure (healthcare or criminal justice system [HC/CJS] events) versus oral antipsychotics in recently incarcerated adults with schizophrenia. The present analysis used a state government perspective and HC/CJS event data that were collected on a resource use questionnaire (RUQ) every 3 months.Main outcome measures:Since cost information was not collected in the trial, cost estimates from published literature and an analysis of multistate Medicaid data for CJS and HC events, respectively, were applied to RUQ event data. Effectiveness and costs were adjusted to 456 days (trial duration). Incremental cost effectiveness was calculated as the adjusted cost difference divided by the adjusted effectiveness difference.Results:Adjusted costs (in US dollars) in the paliperidone palmitate group (n = 198) and the oral antipsychotic group (n = 193), respectively, were: non-drug costs $22,331 and $25,027; drug costs $18,592 and $7833; and total costs $40,923 and $32,860. Adjusted effectiveness differences and corresponding incremental cost effectiveness per event avoided (in parentheses) for paliperidone palmitate versus oral antipsychotics were as follows: 0.33 fewer CJS events ($24,409), 0.13 fewer psychiatric hospitalizations ($60,484), 0.46 fewer psychiatric hospitalizations or CJS events combined ($17,391), and 0.30 fewer incarcerations ($26,754).Conclusions:Costs for HC/CJS events avoided offset 25% of the greater drug cost for the paliperidone palmitate versus oral antipsychotic treatment group in this vulnerable population. Use of a recall-dependent RUQ for event rates and cost estimates instead of actual costs are potential limitations and may make the results conservative from a state government perspective. Indirect costs are likely to be substantial for this population, but were not considered in the analysis.

Effectiveness of paliperidone palmitate vs haloperidol decanoate for maintenance treatment of schizophrenia: a randomized clinical trial.

Long-acting injectable antipsychotics are used to reduce medication nonadherence and relapse in schizophrenia-spectrum disorders. The relative effectiveness of long-acting injectable versions of second-generation and older antipsychotics has not been assessed. To compare the effectiveness of the second-generation long-acting injectable antipsychotic paliperidone palmitate with the older long-acting injectable antipsychotic haloperidol decanoate. Multisite, double-blind, randomized clinical trial conducted from March 2011 to July 2013 at 22 US clinical research sites. Randomized patients (n = 311) were adults diagnosed with schizophrenia or schizoaffective disorder who were clinically assessed to be at risk of relapse and likely to benefit from a long-acting injectable antipsychotic. Intramuscular injections of haloperidol decanoate 25 to 200 mg or paliperidone palmitate 39 to 234 mg every month for as long as 24 months. Efficacy failure, defined as a psychiatric hospitalization, a need for crisis stabilization, a substantial increase in frequency of outpatient visits, a clinician's decision that oral antipsychotic could not be discontinued within 8 weeks after starting the long-acting injectable antipsychotics, or a clinician's decision to discontinue the assigned long-acting injectable due to inadequate therapeutic benefit. Key secondary outcomes were common adverse effects of antipsychotic medications. There was no statistically significant difference in the rate of efficacy failure for paliperidone palmitate compared with haloperidol decanoate (adjusted hazard ratio, 0.98; 95% CI, 0.65-1.47). The number of participants who experienced efficacy failure was 49 (33.8%) in the paliperidone palmitate group and 47 (32.4%) in the haloperidol decanoate group. On average, participants in the paliperidone palmitate group gained weight and those in the haloperidol decanoate group lost weight; after 6 months, the least-squares mean weight change for those taking paliperidone palmitate was increased by 2.17 kg (95% CI, 1.25-3.09) and was decreased for those taking haloperidol decanoate (-0.96 kg; 95% CI, -1.88 to -0.04). Patients taking paliperidone palmitate had significantly higher maximum mean levels of serum prolactin (men, 34.56 µg/L [95% CI, 29.75-39.37] vs 15.41 µg/L [95% CI, 10.73-20.08]; P <.001, and for women, 75.19 [95% CI, 63.03-87.36] vs 26.84 [95% CI, 13.29-40.40]; P<.001). Patients taking haloperidol decanoate had significantly larger increases in global ratings of akathisia (0.73 [95% CI, 0.59-0.87] vs 0.45 [95% CI, 0.31-0.59]; P=.006). In adults with schizophrenia or schizoaffective disorder, use of paliperidone palmitate vs haloperidol decanoate did not result in a statistically significant difference in efficacy failure, but was associated with more weight gain and greater increases in serum prolactin, whereas haloperidol decanoate was associated with more akathisia. However, the CIs do not rule out the possibility of a clinically meaningful advantage with paliperidone palmitate. clinicaltrials.gov Identifier: NCT01136772.

EPA-1627 – Brief assesment of funcionality in psycotic patients treated with long-acting injectable antipsycotic

Introduction An early symptomatic response has been related with an early improvement in functionality, quality of life and subjective well-being. The short version of the Social Functioning Scale (SFS) has been validated to get round the difficulty of lack of time in our clinical practice. Objectives Evaluate functionality with SFS in a sample of schizophrenic outpatients treated with long-acting injectable antipsychotics. Methods 20 outpatients with schizophrenia according to ICD-10 criteria. These patients were in treatment with long-term antipsychotic monotherapy during the past three months. Two treatment groups were established: paliperidone palmitate treatment group and another with the other long-acting injectable antipsychotics marketed in our country (constant release risperidone, olanzapine pamoate, zuclopenthixol, fluphenazine decanoate). The severity of the disease was assesed by the CGI-S and function was assessed using the SFS. Antipsychotic medication was computed in equivalent mg of chlorpromazine (CPZe). Socio-demographic data were also collected. Results Mean scores of SFS were: 25.91(SD 5.66) in paliperidone palmitate group and 27 (SD 6.78) in the other antipsycotics group. Mean score of CGIS were: 3.91 (SD 0.94) in paliperidone palmitate group and 3.33 (SD 1.41) in the other antipsycotics group. Mean score of CPZe was: 427.1 (SD 102,54) in paliperidone palmitate group and 580,59 (SD 332,54) in the other antipsycotics group. Conclusions We don’t find significant differences between the two groups. It should be noted observational design prevent us from make relevant inferences. It is likely that with a larger sample size these data can be modified.

EPA-1631 – Subjective well-being and long-acting injectable anti psychotics in schizophrenia

Introduction Subjective well-being (SW) has a strong direct relationship with quality of life. It has also been strongly associated with adherence, and with a lasting symptomatic remission. Several studies point to the SW one of the main predictors of a comprehensive response to treatment Objectives Evaluate the subjective response to neuroleptics (both SW and attitudes towards medication) in patients with schizophrenia treated with longacting injectable antipsychotics. Methods 20 outpatients with schizophrenia according to ICD-10 criteria. These patients were in treatment with long-term antipsychotic monotherapy during the past three months. Two treatment groups were established: paliperidone palmitate treatment group and another group with other long-acting injectable antipsychotics (constant release risperidone, olanzapine pamoate, zuclopentixol and fluphenazine decanoate). SW was assesed by the Subjective Well-being under Neuroleptic Treatment Scale (SWN-K) The attitude towards medication was assessed by the Drug attitude inventory (DAI). Results Mean scores of SWK-N were: 87.64 (16.22) in paliperidone palmitate group and 89.67 (17.19) in the other antipsychotics group. Mean score of DAI was 17.09 (SD 3.08) in paliperidone palmitate group and 18.78 (SD 1.09) in the other antipsycotics group. Conclusions We did not find significant differences between the two groups. It should be noted observational design prevent us from make relevant inferences. It is likely that with a larger sample size these data can be modified.

EPA-1601 - Long-acting injectable antipsychotics in patients with schizophrenia: a 18 months study

The expectative in regards achieving better therapeutic adherence related to medication compliance in schizophrenia has been shown to be greater in patients treated with long-acting injectable antipsychotics. The purpose of the present study was to investigate whether or not the schizophrenia treatment under evidence-based clinical practice conditions with Palmitate Paliperidone in comparison with conventional depots antipsychotics, will improve the patient evolution and prognosis in schizophrenia. This 18 months study, the patient population consisted of 30 outpatients, all diagnosed with schizophrenia, who received treatment with Paliperidone Palmitate (n=15). A comparison was conducted with the same number of patients who received treatment with depot conventional antipsychotic. All patients were evaluated every three months and the following scales were used for assessment and measurement: Positive and Negative Syndrome Scale (PANSS) Global illness Severity (Global Clinical Impression CGI), Treatment Satisfaction Scale, Remission Criteria (Andreassen criteria,) Personal and Social Performance (PSP) and the Subjective Well-being under Neuroleptic Scale (SWN-K) At endpoint, we found statistical differences among both study groups: The Paliperidone Palmitate group showed significantly higher remission rates (p < 0.05) and treatment satisfaction scores (p < 0.05). Also an improvement in global clinical impression (p < 0.05), PSP (p < 0.05) and SWN-K (p < 0.05) Paliperidone Palmitate group showed lower sexual dysfunction (p < 0.05) compared to conventional depot. The presented data demonstrated that Paliperidone Palmitate was an efficacy and safety treatment and could improve the outcomes prognosis and the clinical course of the illness in schizophrenic patients when compared with conventional depot

Randomized, placebo-controlled, double-blind study assessing the efficacy and safety of paliperidone palmitate in Asian patients with schizophrenia

BackgroundThis 13-week, double-blind study was conducted to confirm the efficacy and safety of paliperidone palmitate (PP), at dosing regimens approved in other countries, in Asian patients with schizophrenia.MethodsAsian patients (aged ≥20 years) diagnosed with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Text Revision criteria), and having a Positive and Negative Syndrome Scale (PANSS) total score of 60 to 120 were enrolled and randomized (1:1) to a PP or placebo group. Patients received PP intramuscularly at recommended doses: initiation dose 150 mg equivalent (eq) PP on day 1 and 100 mg eq PP on day 8 (deltoid); and a monthly maintenance dose of 75 mg eq PP on days 36 and 64 (deltoid or gluteal). The change from baseline to week 13 in PANSS total scores (primary endpoint), Clinical Global Impression-Severity (CGI-S) scores, and PANSS Marder factor scores and subscales, and responder rate at week 13 were evaluated. Safety was also assessed.ResultsThe PANSS total score (P<0.0001, least-squares mean change from baseline to week 13: PP, −3.5; placebo, +6.2), CGI-S score (P<0.0001), and PANSS Marder factor scores (P≤0.0025) were significantly improved at week 13 in the PP group versus placebo. More treatment responders (≥30% decrease in PANSS total score) were in the PP group (22.8%) versus placebo (8.5%). Insomnia (PP 17.0% versus placebo 15.2%), injection site pain (13.2% versus 6.7%), nasopharyngitis (12.6% versus 6.1%), psychiatric symptoms (11.3% versus 26.2%), and extrapyramidal symptoms (10.1% versus 4.9%) were the most frequently occurring treatment-emergent adverse events.ConclusionPP is efficacious for Asian patients with schizophrenia at the dosing regimen approved in other countries, with a similar safety and tolerability profile.

Long-Acting Injectable Antipsychotics and the Development of Postinjection Delirium/Sedation Syndrome (PDSS)

Five long-acting injectable (LAI) antipsychotics are currently available in the United States for the treatment of schizophrenia: fluphenazine decanoate, haloperidol decanoate, risperidone microspheres, paliperidone palmitate, and olanzapine pamoate. Additionally, aripiprazole LAI is currently under FDA review. However, research into the safety and tolerability of these LAIs, with particular regard to the development of postinjection delirium/sedation syndrome (PDSS), is limited and has been focused mainly on olanzapine pamoate. This proposal seeks to review data regarding all currently available LAI antipsychotics to determine if a significant association exists between these depot formulations and the development of PDSS. A review of all published literature from 2005 to the present was obtained via a PubMed search for current data regarding the topic of LAIs and the development of PDSS. Keywords used for the search were "long-acting injectable antipsychotics" in association with one of the following: "post-injection delirium/sedation syndrome," "PDSS, " "side effects, " and "tolerability." References to key articles were further explored for relevancy to this proposal. A case analysis based on all 8 olanzapine LAI clinical trials conducted between August 2000 and October 2008 showed an occurrence of PDSS in approximately 0.07% of injections or 1.4% of patients (30 cases in 29 patients). A second case analysis reviewing the clinical trial databases for 15 completed studies and the postmarketing safety database for risperidone LAI versus 10 completed clinical trials of paliperidone palmitate failed to demonstrate an occurrence of PDSS events in patients receiving either LAI treatment. However, one case of PDSS was identified in a placebo group. In 4 randomized, double-blind, placebo-controlled trials, treatment-emergent adverse events leading to treatment discontinuation were similar for paliperidone palmitate and placebo; however, among the most frequently occurring treatment-emergent adverse events was somnolence/sedation (5%-7% paliperidone palmitate group vs 3% placebo). Postinjection delirium/sedation syndrome is a potentially serious adverse event that has been shown to be associated with one currently available LAI antipsychotic, olanzapine pamoate. However, further data are still needed to both support this conclusion and determine if an association exists among other currently available LAIs and PDSS. With the bulk of current evidence coming from registration studies, head-to-head comparison studies between 2 LAIs would help to determine whether the risk of postinjection complications differs among different agents. Further observational studies are also needed to address the incidence, severity, and optimal clinical management of this syndrome.

Paliperidone palmitate and risperidone long-acting injectable in subjects with schizophrenia recently treated with oral risperidone or other oral antipsychotics.

This post hoc subgroup analysis of a randomized, double-blind trial evaluated the response to treatment with two long-acting injectable atypical antipsychotics, ie, paliperidone palmitate and risperidone long-acting injectable (RLAI), in subjects with schizophrenia experiencing clinically significant symptoms despite recent treatment with oral risperidone only or other oral antipsychotics. Adult subjects were eligible for the 13-week, double-blind, double-dummy trial (NCT00589914) if they had an established diagnosis of schizophrenia for at least one year and a Positive and Negative Syndrome Scale (PANSS) total score of 60-120 inclusive at screening. Subjects received either paliperidone palmitate (234 mg, day 1; 156 mg, day 8; then once-monthly flexible dosing) or RLAI (25-50 mg biweekly, with oral risperidone supplementation on days 1-28), plus matched placebo injections/tablets. This post hoc analysis reports data on 747 subjects who, within 2 weeks of starting double-blind study medication, had reportedly received oral risperidone only (paliperidone palmitate group, n = 126; RLAI group, n = 107), other oral antipsychotics (paliperidone palmitate group, n = 199; RLAI group, n = 203), or no antipsychotic (paliperidone palmitate group, n = 56; RLAI group, n = 56). Mean PANSS total scores improved significantly at end point across all subgroups (mean change from baseline ranged from -17.5 to -19.5, all P < 0.0001). Clinical Global Impression-Severity and Personal and Social Performance scale measures also significantly improved from baseline (all P < 0.0001). Treatment with paliperidone palmitate or RLAI resulted in a significant reduction in the symptoms of schizophrenia irrespective of previous recent treatment with oral risperidone only or other oral antipsychotics. For subjects who had previously received oral risperidone only, the difference in formulation was the main change in the intervention because the molecule delivered remained the same or similar. These data support the contribution of a long-acting formulation to improving the treatment response and suggest that nonadherence may be a significant contributor to inadequate efficacy of oral formulations in subjects with schizophrenia.

Effects of acute paliperidone palmitate treatment in subjects with schizophrenia recently treated with oral risperidone

ObjectiveTo examine efficacy and safety of acute treatment with paliperidone palmitate in subjects with schizophrenia whose disease remained symptomatic despite recent treatment with oral risperidone. MethodsPost hoc analysis of a 13-week, double-blind, placebo-controlled study of subjects with symptomatic schizophrenia randomized to paliperidone palmitate 39, 156, or 234mg (25, 100, or 150mg equivalents of paliperidone) or placebo. Paliperidone palmitate subjects received a 234-mgday 1 dose, followed by their assigned dose on day 8 and monthly thereafter. Subjects treated with oral risperidone within 2weeks before randomization regardless of duration were included. Assessments: PANSS, CGI-S, PSP scores; AEs. ANCOVA models with LOCF methodology evaluated treatment group differences. Results216 subjects received prior oral risperidone (paliperidone palmitate 39mg, n=53; 156mg, n=58; 234mg, n=48; placebo, n=57). Median prior risperidone use was 22days. Significant improvement was observed with paliperidone palmitate 156-mg or 234-mg versus placebo in least-squares mean (SE) score change at end point in PANSS total (156mg, −15.8 [3.0], p=0.0001; 234mg, −17.6 [3.2], p=0.0001), CGI-S (156mg, −0.9 [0.2], p=0.0068; 234mg, −1.1 [0.2], p=0.0003), and PSP (156mg, 10.7 [2.3], p=0.0061; 234mg, 12.9 [2.4], p=0.0009). Most common AEs (≥10%) in any paliperidone palmitate group were insomnia, anxiety, and headache. ConclusionsIn subjects with schizophrenia who recently received oral risperidone but who remained symptomatic, acute treatment with monthly doses of 156-mg and 234-mg paliperidone palmitate significantly improved clinical symptoms, global illness ratings, and functioning compared with placebo, with no unexpected safety findings.

Onset of efficacy and tolerability following the initiation dosing of long-acting paliperidone palmitate: post-hoc analyses of a randomized, double-blind clinical trial

BackgroundPaliperidone palmitate is a long-acting injectable atypical antipsychotic for the acute and maintenance treatment of adults with schizophrenia. The recommended initiation dosing regimen is 234 mg on Day 1 and 156 mg on Day 8 via intramuscular (deltoid) injection; followed by 39 to 234 mg once-monthly thereafter (deltoid or gluteal). These post-hoc analyses addressed two commonly encountered clinical issues regarding the initiation dosing: the time to onset of efficacy and the associated tolerability.MethodsIn a 13-week double-blind trial, 652 subjects with schizophrenia were randomized to paliperidone palmitate 39, 156, or 234 mg (corresponding to 25, 100, or 150 mg equivalents of paliperidone, respectively) or placebo (NCT#00590577). Subjects randomized to paliperidone palmitate received 234 mg on Day 1, followed by their randomized fixed dose on Day 8, and monthly thereafter, with no oral antipsychotic supplementation. The onset of efficacy was defined as the first timepoint where the paliperidone palmitate group showed significant improvement in the Positive and Negative Syndrome Scale (PANSS) score compared to placebo (Analysis of Covariance [ANCOVA] models and Last Observation Carried Forward [LOCF] methodology without adjusting for multiplicity) using data from the Days 4, 8, 22, and 36 assessments. Adverse event (AE) rates and relative risks (RR) with 95% confidence intervals (CI) versus placebo were determined.ResultsPaliperidone palmitate 234 mg on Day 1 was associated with greater improvement than placebo on Least Squares (LS) mean PANSS total score at Day 8 (p = 0.037). After the Day 8 injection of 156 mg, there was continued PANSS improvement at Day 22 (p ≤ 0.007 vs. placebo) and Day 36 (p < 0.001). Taken together with results in the 39 mg and 234 mg Day 8 arms, these findings suggest a trend towards a dose-dependent response. During Days 1 to 7, AEs reported in ≥2% of paliperidone palmitate subjects (234 mg) and a greater proportion of paliperidone palmitate than placebo subjects were: agitation (3.2% vs. 1.3%; RR 2.52 [95% CI 0.583, 10.904]), headache (4.0% vs. 3.8%; RR 1.06 [95% CI 0.433, 2.619]), and injection site pain (6.7% vs. 3.8%; RR 1.79 [95% CI 0.764, 4.208]). Days 8 to 36 AEs meeting the same criteria in the 156 mg Day 8 arm were: anxiety (3.1% vs. 2.5%; RR 1.24 [95% CI 0.340, 4.542]), psychotic disorder (2.5% vs. 1.3%; RR 1.99 [95% CI 0.369, 10.699]), dizziness (2.5% vs. 1.3%; RR 1.99 [95% CI 0.369, 10.699]), and injection site pain (2.5% vs. 1.3%; RR 1.99 [95% CI 0.369, 10.699]). Corresponding Days 8 to 36 AEs in the 39 mg Day 8 group were: agitation (4.5% vs. 4.4%; RR 1.03 [95% CI 0.371, 2.874]), anxiety (3.9% vs. 2.5%; RR 1.55 [95% CI 0.446, 5.381]), and psychotic disorder (2.6% vs. 1.3%; RR 2.07 [95% CI 0.384, 11.110]) while in the 234 mg Day 8 group it was anxiety (3.1% vs. 2.5%, RR 1.25 [95% CI 0.342, 4.570]).ConclusionsSignificantly greater symptom improvement was observed by Day 8 with paliperidone palmitate (234 mg on Day 1) compared to placebo; this effect was maintained after the 156 mg Day 8 injection, with a trend towards a dose-dependent response. No unexpected tolerability findings were noted in the first week or month after the initiation dosing.Trial registrationClinicalTrials.gov: NCT#00590577

A comparative study of paliperidone palmitate and risperidone long-acting injectable therapy in schizophrenia

This open-label, rater-blinded, parallel-group study was designed to evaluate noninferiority of paliperidone palmitate (PP), a once-monthly injectable atypical antipsychotic, to once-biweekly risperidone long-acting injectable (RIS-LAI) in adult Chinese patients with acute schizophrenia. Eligible Chinese adults (N=452) with schizophrenia were randomized (1:1) to either PP (N=229; deltoid injections on day 1 [150 mg eq.] and day 8 [100 mg eq.]; then once-monthly deltoid or gluteal injections, flexibly dosed [50, 100, or 150 mg eq.]), or RIS-LAI (N=223; once-biweekly gluteal injections, flexibly dosed [25, 37.5 or 50 mg]). RIS-LAI-treated patients received oral risperidone supplementation (1-6 mg/day) at initiation and with RIS-LAI dose increases. Mean (SD) Positive and Negative Syndrome Scale (PANSS) total score at baseline was 83.2 (12.44). Mean (SD) change from baseline to endpoint in PANSS total scores (primary efficacy measure) was: -23.6 (16.28) for PP group and -26.9 (15.43) for RIS-LAI group. PP was noninferior to RIS-LAI (least squares mean difference [95% CI]: -2.3 [-5.20; 0.63]; predetermined non-inferiority margin: -5.5). Mean (SD) change from baseline to endpoint in Clinical Global Impression-Severity scale score was: -1.5 (1.24; PP group), -1.7 (1.16; RIS-LAI group) and in Personal and Social Performance Scale scores was: 16.8 (14.76; PP group), 18.6 (13.92; RIS-LAI group). The incidence of treatment-emergent adverse events (TEAEs) was similar between the two groups (73% [PP]; 75% [RIS-LAI]). The most common TEAEs were akathisia, tremor, and insomnia. The study demonstrated the noninferiority of PP (50-150 mg eq., flexibly dosed, without oral paliperidone supplementation) to risperidone-LAI (25-50 mg, flexibly dosed, with oral risperidone supplementation) for the treatment of acute schizophrenia in adult Chinese patients. PP injections were generally tolerable, and no new safety signals were detected in this population.

P.3.c.063 QoL, global functioning and social adaptation of schizophrenic subjects treated with long-acting risperidone

To examine efficacy and safety of acute treatment with paliperidone palmitate in subjects with schizophrenia whose disease remained symptomatic despite recent treatment with oral risperidone.Post hoc analysis of a 13-week, double-blind, placebo-controlled study of subjects with symptomatic schizophrenia randomized to paliperidone palmitate 39, 156, or 234 mg (25, 100, or 150 mg equivalents of paliperidone) or placebo. Paliperidone palmitate subjects received a 234-mg day 1 dose, followed by their assigned dose on day 8 and monthly thereafter. Subjects treated with oral risperidone within 2 weeks before randomization regardless of duration were included. Assessments: PANSS, CGI-S, PSP scores; AEs. ANCOVA models with LOCF methodology evaluated treatment group differences.216 subjects received prior oral risperidone (paliperidone palmitate 39 mg, n = 53; 156 mg, n = 58; 234 mg, n = 48; placebo, n = 57). Median prior risperidone use was 22 days. Significant improvement was observed with paliperidone palmitate 156-mg or 234-mg versus placebo in least-squares mean (SE) score change at end point in PANSS total (156 mg, −15.8 [3.0], p = 0.0001; 234 mg, −17.6 [3.2], p = 0.0001), CGI-S (156 mg, −0.9 [0.2], p = 0.0068; 234 mg, −1.1 [0.2], p = 0.0003), and PSP (156 mg, 10.7 [2.3], p = 0.0061; 234 mg, 12.9 [2.4], p = 0.0009). Most common AEs (≥ 10%) in any paliperidone palmitate group were insomnia, anxiety, and headache.In subjects with schizophrenia who recently received oral risperidone but who remained symptomatic, acute treatment with monthly doses of 156-mg and 234-mg paliperidone palmitate significantly improved clinical symptoms, global illness ratings, and functioning compared with placebo, with no unexpected safety findings.