Relapse and Treatment Adherence in Patients with Schizophrenia Switching from Paliperidone Palmitate Once-Monthly to Three-Monthly Formulation: A Retrospective Health Claims Database Analysis.

PURPOSE: Relapse and treatment adherence to paliperidone palmitate once-monthly (PP1M) and three-monthly (PP3M) formulations in patients with schizophrenia were evaluated and compared using health claims data. PATIENTS AND METHODS: Data (June 2015─June 2018) obtained from the MarketScan® Multi-State Medicaid Database were retrospectively analyzed. Patients aged ≥18 years with ≥1 claim for schizophrenia diagnosis prior to and/or at index date (i.e., date of first PP3M prescription record for PP3M patients and same month/year as the matched PP3M patients for PP1M patients) and continuous enrollment in the insurance plan for ≥12 months prior to index date (baseline) were included. PP1M cohort included patients who received ≥4 PP1M doses. PP3M patients were matched with PP1M patients (1:3) using propensity score matching and prevalent new user design. Outcome measures were relapse rate, time to relapse, proportion of days covered (PDC), and level of treatment adherence defined by PDC in five levels. Time to relapse was compared by Kaplan-Meier survival curves and log-rank test with the hazard ratio calculated using Cox proportion hazards model; PDC by t-test, and relapse rate and PDC categories by chi-square test. RESULTS: A total of 1564 patients (428 PP3M and 1136 PP1M) were included. Relapse rate was lower in PP3M cohort (10.5%) compared with PP1M cohort (15.7%). Incidence rate of relapse was 8.98/100 person-years (PY) in PP3M cohort and 13.81/100 PY in PP1M cohort. After a mean (SD) follow-up of 456.1 (240.28) days in PP3M cohort and 465.4 (237.95) days in PP1M cohort, PP3M patients had a significantly lower relapse risk (hazard ratio: 0.65, 95% CI: 0.47, 0.90) than PP1M patients. Treatment adherence was significantly (p<0.0001) higher in PP3M versus PP1M cohort. CONCLUSION: Risk of relapse was significantly lower, and treatment adherence was significantly higher in PP3M cohort compared with PP1M cohort. Higher treatment adherence was associated with lower relapse rate.

Patients' Preference for Long-Acting Injectable versus Oral Antipsychotics in Schizophrenia: Results from the Patient-Reported Medication Preference Questionnaire.

INTRODUCTION: Understanding patients' preferences for long-acting injectable (LAI) or oral antipsychotics (pills) could help reduce potential barriers to LAI use in schizophrenia. METHODS: Post hoc analyses were conducted from a double-blind, randomized, non-inferiority study (NCT01515423) of 3-monthly vs 1-monthly paliperidone palmitate in patients with schizophrenia. Data from the Medication Preference Questionnaire, administered on day 1 (baseline; open-label stabilization phase), were analyzed. The questionnaire includes four sets of items: 1) reasons for general treatment preference based on goals/outcomes and preference for LAI vs pills based on 2) personal experience, 3) injection-site (deltoid vs gluteal), 4) dosing frequency (3-monthly vs 1-monthly). A logistic regression analysis was performed to assess the effect of baseline variables on preference (LAIs or pills). RESULTS: Data from 1402 patients were available for analysis. Patients who preferred LAIs recognized these outcomes as important: "I feel more healthy" (57%), "I can get back to my favorite activities" (56%), "I don't have to think about taking my medicines" (54%). Most common reasons for medication preference (LAI vs pills) were: "LAIs/pills are easier for me" (67% vs 18%), "more in control/don't have to think about taking medicine" (64% vs 14%), "less pain/sudden symptoms" (38% vs 18%) and "less embarrassed" (0% vs 46%). Majority of patients (59%) preferred deltoid over gluteal injections (reasons: faster administration [63%], easier [51%], less embarrassing [44%]). In total, 50% of patients preferred 3-monthly over 1-monthly (38%) or every day (3%) dosing citing reasons: fewer injections [96%], fewer injections are less painful [84%], and fewer doctor visits [80%]. From logistic regression analysis, 77% of patients preferred LAI over pills; culture and race appeared to play a role in this preference. CONCLUSION: Patients who preferred LAI antipsychotics prioritized self-empowerment and quality-of-life-related goals. When given the option, patients preferred less-frequent, quarterly injections over monthly injections and daily oral medications.

Comparison of Relapse Prevention with 3 Different Paliperidone Formulations in Patients with Schizophrenia Continuing versus Discontinuing Active Antipsychotic Treatment: A Post-Hoc Analysis of 3 Similarly Designed Randomized Studies.

BACKGROUND: Sudden discontinuation from antipsychotic treatment is a common occurrence in patients with schizophrenia. Lower rates of relapse could be expected for patients discontinuing treatment from longer-acting formulations vs their shorter-acting equivalents. OBJECTIVE: To compare relapse rates and time-to-relapse between the active (analogous to adherent patients) and placebo (analogous to non-adherent patients in the real-world) arms of three different formulations of paliperidone (oral paliperidone extended release [paliperidone ER], paliperidone palmitate once monthly [PP1M], and paliperidone palmitate three monthly [PP3M] long-acting injectables). METHODS: Data from three similarly designed, randomized relapse prevention studies in adult patients with schizophrenia were analyzed. RESULTS: In total, 922 patients were included (active treatment: 473, placebo: 449). Lowest percentage of patients experienced relapse with PP3M PP1M (172 days [134-222 days])> paliperidone ER (58 days [42-114 days]) and was "not-estimable" in the active treatment group due to low relapse rates. Hazard ratios (HR) of the three paliperidone formulations relative to their respective placebos were PP3M ([HR: 3.81; 95% CI: 2.08, 6.99; P< 0.0001]> PP1M [HR: 3.60; 95% CI: 2.45, 5.28; P<0.0001]> paliperidone ER [HR: 2.83; 95% CI: 1.73, 4.63; P<0.001]). CONCLUSION: The lower percentage of relapse during active treatment and longer time to relapse after discontinuing active treatment with longer-duration antipsychotic formulations suggests the benefit of longer-acting over shorter-acting formulations, especially in patients susceptible to poor adherence.Clinical trial registration: paliperidone ER (NCT00086320), PP1M (NCT00111189), and PP3M (NCT01529515).

Cognitive functioning in adolescents with schizophrenia treated with paliperidone extended-release: 6-Month exploratory analysis from an open-label, single-arm safety study.

OBJECTIVE: To assess cognitive functioning in adolescents (12-17 years old) with schizophrenia during open-label treatment with paliperidone extended-release (pali ER). METHODS: In this exploratory analysis, adolescents treated with pali ER (oral, flexibly dosed, 1.5-12 mg/day) underwent cognitive assessments at baseline and month 6 using a battery of cognitive tests validated in adolescents. Correlation analysis was used to explore the relationship between cognitive assessments and clinical symptoms (Positive and Negative Syndrome Scales [PANSS] and factors) and functionality (Children Global Assessment Scale [CGAS]) at baseline and at 6 months. RESULTS: A total of 324 of 393 patients had evaluable neurocognitive data. Changes in cognition function tests from baseline to endpoint were generally small to modest, with improvement noted for most cognitive domains (motor speed, attention/working memory, verbal learning and memory, social cognition, speed of processing, executive functioning). No improvement was noted for visual learning and memory. At baseline, there were modest negative correlations between disorganized thoughts and most cognitive domains; these correlations persisted at 6 months. Other significant negative correlations at 6 months were between speed of processing and PANSS total score, positive symptoms, negative symptoms and uncontrolled hostility (p < 0.05). At 6 months, higher CGAS scores (improved functioning) positively correlated with speed of processing and executive functioning, especially among pali ER responders. CONCLUSIONS: In this large sample of adolescents with schizophrenia, frank cognitive deficits across multiple domains were observed. Treatment with pali ER over 6 months did not worsen neurocognitive functioning and was possibly associated with positive improvement in certain domains.

Efficacy and safety of paliperidone palmitate 3-month formulation in Latin American patients with schizophrenia: A subgroup analysis of data from two large phase 3 randomized, double-blind studies

Objective: To analyze the efficacy and safety of paliperidone palmitate 3-monthly (PP3M) in Latin American patients with schizophrenia vs. rest-of-world (ROW). Methods: We analyzed data from two multinational, double-blind (DB), randomized, controlled phase 3 studies including patients with schizophrenia (DSM-IV-TR) previously stabilized on PP1M/PP3M (open-label [OL] phase). Patients were randomized to PP3M or PP1M (noninferiority study A) and PP3M or placebo (study B) in DB phase. The subgroup analysis included Latin American (Argentina, Brazil, Colombia, Mexico) patients. Primary efficacy endpoints were relapse-free rates (study A) and time-to-relapse (study B). Results: In study A, 63/71 (88.7%) and in study B 38/43 (88.4%) Latin American patients completed the DB phase. In study A, relapse-free percentage was similar in Latin America (PP3M: 97%, PP1M: 100%) and ROW (PP3M: 91%, PP1M: 89%). In study B, median time-to-relapse was not estimable in the Latin American subgroup for either placebo or PP3M groups, nor for the ROW PP3M group; the median time-to-relapse in the ROW placebo group was 395 days. Caregiver burden improved in patients switching from oral antipsychotics (OL baseline) to PP3M/PP1M in DB phase (Involvement Evaluation Questionnaire score mean ± SD change, -9.4±15.16; p < 0.001). Treatment emergent adverse events with PP3M during DB phase were similar in Latin America (study A: 24/34 [70.6%]; study B: 15/21 [71.4%]) and ROW (study A: 318/470 [67.7%]; study B: 84/139 [60.4%]) subgroups. Conclusion: PP3M was efficacious and showed no new safety concerns in patients with schizophrenia from Latin America, corroborating ROW findings. Clinical trial registration: NCT01515423, NCT01529515

Severe odontogenic infections: a 5-year review of a major referral hospital in Ghana.

INTRODUCTION: Odontogenic infections are fairly common in healthcare settings. However, late presentations such as Ludwig's angina, facial cellulitis, necrotizing cervical fasciitis (NCF), among others could lead to mortality. In view of suggestions that the occurrence of severe, near-fatal odontogenic infections is declining, this study set out to determine the incidence of such severe odontogenic infections over the past 5 years at the Korle-Bu Teaching Hospital, a major referral centre in Ghana. METHODS: A retrospective review was done, involving all patients with severe odontogenic infection, thereby requiring admission, per stated criteria at the Department of Oral and Maxillofacial Surgery (Dental clinic), Korle-Bu Teaching Hospital, in the period between July 2012 and July 2017. The cumulative incidence for the respective years were then computed for the years of review. RESULTS: A total of 243 patients were included in the study. This consisted of 121 males and 122 females, with an average age of 42.9 years (SD = 16.6), ranging from 18 months to 91 years. Incidence proportions for the years of the review were 8.2, 8.9, 17.7, 17.9 and 27.7 people per 1000 cases of tooth-related infections for the respective years. With a fatality rate of 5.8%, the incidence of odontogenic infections among patients attending the outpatient Dental clinic of the hospital is 40.3%, while that of dentoalveolar abscess is 6.2%. Ludwig's angina was the commonest (52%) form of presentation of spreading odontogenic infection. CONCLUSION: This study highlights the importance of persisting severe, near-fatal odontogenic infections in Ghana. Not only is there a need to assess the public, professional and institutional strategies to management, but for more evidence-based studies in our local setting to aid in management.

Clinical relevance of paliperidone palmitate 3-monthly in treating schizophrenia.

Antipsychotics are the mainstay in schizophrenia management, and long-acting injectable (LAI) antipsychotics contribute to the successful maintenance of treatment by improving non-adherence and preventing relapses. Paliperidone palmitate 3-monthly (PP3M) formulation is the only available LAI antipsychotic that offers an extended 3-month window of stable plasma drug concentration, enabling only four injections per year. This paper summarizes clinically relevant endpoints from available evidence for PP3M to bridge translational research gaps and provide measurable outcomes that can be interpreted in clinical practice. Low number-needed-to-treat (NNT) for relapse prevention (NNT [95% CI] 6-month estimate: 4.8 [3.2; 10.0]; 12-month estimate: 3.4 [2.2; 7.0]), and high number-needed-to-harm (NNH [95% CI] akathisia, 27.1 [12.3; -667.1]; tremor, 80.0 [22.5; 67.3]; dyskinesia, -132.6 [44.5; -23.2]; parkinsonism, 160.0 [28.9; -49.8]) quantify the relative benefits and low propensity for adverse events with PP3M. Symptom remission and reductions in positive and negative symptoms indicate treatment stability. Additionally, meaningful functional remission, reduced dosing frequency, and freedom from daily negotiations favorably impact patient preference and attenuate burdensome aspects of caregiving, representing important healthcare determinants that enhance prospects of treatment continuity in schizophrenia. This information can potentially improve clinicians' judgment of treatment choices, clinical response, and patient selection in routine care. Taken together, PP3M is a valuable antipsychotic treatment option, meriting consideration for a broader role in the long-term management of schizophrenia; its utility should not be limited to patients with poor adherence or when oral antipsychotics have failed.

A comparative study of the efficacy of intravenous benzylpenicillin and intravenous augmentin in the empirical management of Ludwig's angina.

Background: Ludwig's angina is a potentially life-threatening condition characterized by bilateral cellulitis of the submandibular, submental, and sublingual spaces. Intravenous (I.V) penicillin G or amoxicillin-clavulanate (Augmentin) has been recommended for use as empirical management before obtaining culture and sensitivity results. Aim: The aim of this study was to compare the therapeutic efficacies and clinical outcomes of I.V benzylpenicillin with I.V Augmentin in the empirical management of Ludwig's angina. Methods: This was a prospective randomized clinical study carried out to measure the rate of swelling reduction (using the lobar rate, Adam's rate, and interincisal distance) and other clinical parameters among the two drug groups (I.V penicillin G and Augmentin). Descriptive summaries of variables were generated, and Student's t-test was used to compare the mean outcomes of the two groups. Results: A total of 26 individuals participated in the study, consisting of 46% (12) males and 54% (14) females. The participants ranged from 13 to 61 years with mean and median of 34.4 (±12.7) and 35 years, respectively. Only 8% of the cases of Ludwig's angina were not attributable to odontogenic factors, compared to 92% resulting from odontogenic causes. There was no significant difference in the efficacy of the two antibiotics used in this study. Conclusion: The efficacies and the clinical outcomes of the two antibiotics were similar. Benzylpenicillin is probably a suitable empirical alternative where Augmentin cannot be afforded, to reduce the mortality associated with the condition.

RésuméContexte: L'angine de Ludwig est une condition potentiellement mortelle caractérisée par la cellulite bilatérale des espaces sousmandibulaires, sousmentaux et souslinguaux. On a recommandé la pénicilline (I.V) intraveineuse G ou l'amoxicilline-clavulanate (Augmentin) pour l'utilisation comme la gestion(direction) empirique avant l'obtention de résultats de sensibilité et la culture. Objectif: Le but de cette étude était de comparer les efficacités thérapeutiques et les résultats cliniques d'I.V benzylpenicillin avec I.V Augmentin dans la gestion(direction) empirique de l'angine de Ludwig. Procédés: C'était une étude clinique randomisée éventuelle a effectué mesurer le taux de réduction se gonflant (utilisant le taux de lobar, le taux d'Adam et la distance interincisal) et d'autres paramètres cliniques parmi les deux groupes de médicament (la pénicilline I.V G et Augmentin). Les résumés descriptifs de variables ont été produits et le t-test de l'Étudiant a été utilisé pour comparer les résultats moyens des deux groupes. Résultats: un total de 26 individus a participé à l'étude, consistant de 46 % (12) mâles et 54 % (14) femelles. Les participants se sont étendus de 13 à 61 ans avec moyen et médian de 34.4 (±12.7) et 35 ans, respectivement. Seulement 8 % des cas(affaires) de l'angine de Ludwig n'étaient pas attribuables aux facteurs odontogenic, comparés à 92 % résultant odontogenic des causes. Il n'y avait aucune différence significative dans l'efficacité des deux antibiotiques utilisés dans cette étude. Conclusion: Il n'y avait aucune différence significative dans les efficacités des deux antibiotiques dans le résultat clinique de traitement. Benzylpenicillin est probablement une alternative empirique appropriée où Augmentin ne peut pas avoir droit, réduire la mortalité associée à la condition.

Efficacy and safety of paliperidone palmitate 3-month formulation in Latin American patients with schizophrenia: A subgroup analysis of data from two large phase 3 randomized, double-blind studies.

OBJECTIVE: To analyze the efficacy and safety of paliperidone palmitate 3-monthly (PP3M) in Latin American patients with schizophrenia vs. rest-of-world (ROW). METHODS: We analyzed data from two multinational, double-blind (DB), randomized, controlled phase 3 studies including patients with schizophrenia (DSM-IV-TR) previously stabilized on PP1M/PP3M (open-label [OL] phase). Patients were randomized to PP3M or PP1M (noninferiority study A) and PP3M or placebo (study B) in DB phase. The subgroup analysis included Latin American (Argentina, Brazil, Colombia, Mexico) patients. Primary efficacy endpoints were relapse-free rates (study A) and time-to-relapse (study B). RESULTS: In study A, 63/71 (88.7%) and in study B 38/43 (88.4%) Latin American patients completed the DB phase. In study A, relapse-free percentage was similar in Latin America (PP3M: 97%, PP1M: 100%) and ROW (PP3M: 91%, PP1M: 89%). In study B, median time-to-relapse was not estimable in the Latin American subgroup for either placebo or PP3M groups, nor for the ROW PP3M group; the median time-to-relapse in the ROW placebo group was 395 days. Caregiver burden improved in patients switching from oral antipsychotics (OL baseline) to PP3M/PP1M in DB phase (Involvement Evaluation Questionnaire score mean ± SD change, -9.4±15.16; p < 0.001). Treatment emergent adverse events with PP3M during DB phase were similar in Latin America (study A: 24/34 [70.6%]; study B: 15/21 [71.4%]) and ROW (study A: 318/470 [67.7%]; study B: 84/139 [60.4%]) subgroups. CONCLUSION: PP3M was efficacious and showed no new safety concerns in patients with schizophrenia from Latin America, corroborating ROW findings. CLINICAL TRIAL REGISTRATION: NCT01515423, NCT01529515.

Efficacy and safety of paliperidone palmitate 3-month versus 1-month formulation in patients with schizophrenia: comparison between European and non-European population.

PURPOSE: This randomized, double-blind (DB), non-inferiority phase 3 study was conducted to assess the efficacy and safety of paliperidone palmitate 3-month (PP3M) vs 1-month formulation (PP1M) in European and non-European patients with schizophrenia. PATIENTS AND METHODS: In this randomized, DB, parallel-group study, adult patients (18-70 years) with schizophrenia (per DSM-IV-TR) having Positive and Negative Syndrome Scale (PANSS) total score between 70 and 120; previously stabilized on PP1M were enrolled. The study had 4 phases: screening (3 weeks), open-label (OL) stabilization (17 weeks), DB (48 weeks) and follow-up (4-12 weeks) phase. Patients were treated with fixed-dose PP3M (175-525 mg eq deltoid/gluteal) or PP1M (50-150 mg eq deltoid/gluteal) for 48 weeks in DB phase. RESULTS: In total, 487 European (PP3M, n=242; PP1M, n=245) and 508 non-European patients (PP3M, n=241; PP1M, n=267) entered DB phase (modified intent-to-treat (mITT) [DB] analysis set). Among the 508 non-European patients in mITT set, 67.7% were from Asia (n=344) and 32.3% were from rest of world (ROW, n=164). During the DB phase, similar percentage of Europeans (PP3M: 7%; PP1M: 8%) and non-Europeans (PP3M: 9%; PP1M: 10%) experienced relapse (Kaplan-Meier estimate PP3M-PP1M [95% CI] of percentage of relapse-free patients at the end of DB phase [primary endpoint]: European: 1.0% [-4.3%; 6.2%]; non-European: 1.4% [-4.4%; 7.1%]; Asian: 1.6% [-5.7%; 9.0%]; and ROW: 1.4% [-7.0%, 9.8%], per-protocol analysis set). Incidence of treatment-emergent adverse events (TEAEs) was lower in Europeans (PP3M: 56%, PP1M: 59%) than non-Europeans (PP3M: 80%, PP1M: 73%). The most commonly reported TEAE was weight gain. CONCLUSION: PP3M showed similar efficacy to PP1M in Europeans and non-Europeans, consistent with non-inferiority of PP3M to PP1M observed in overall population. Rates of AEs were higher in non-Europeans. However, weight gain was greater in non-Europeans, especially the Asian population.

Time to onset and time to resolution of extrapyramidal symptoms in patients with exacerbated schizophrenia treated with 3-monthly vs once-monthly paliperidone palmitate.

OBJECTIVE: The aim of this study was to evaluate the safety of 3-monthly paliperidone palmitate (PP3M) vs once-monthly paliperidone palmitate (PP1M) treatment with regard to extrapyramidal symptom (EPS)-related treatment-emergent adverse events (TEAEs) in patients with schizophrenia, previously stabilized on PP1M treatment. PATIENTS AND METHODS: Data on overall incidence, time to onset (TTO), and time to resolution (TTR) of EPS-related TEAEs (overall, subclasses such as dyskinesia, dystonia, hyperkinesia, parkinsonism, and tremor) from a randomized double-blind (DB) non-inferiority study were compared between PP3M and PP1M. Subgroup analysis was performed by age (18-25, 26-50, and 50+ years) and final open-label (OL) dose (50/75, 100, and 150 mg eq.). RESULTS: Overall incidence of spontaneously reported EPS-related TEAEs decreased from 12.6% (PP1M) in OL phase to 8.3% (PP3M) and 7.4% (PP1M) in the DB phase; overall median TTO and TTR values were comparable between both groups. Among patients with reported EPS-related TEAEs, the median TTO for all EPS-related TEAEs was 17 days (PP1M) in OL phase and 115 days (PP3M) and 98.5 days (PP1M) in DB phase; median TTR was 36.5 days (PP1M) in OL phase and 91 days (PP3M) and 85.5 days (PP1M) in DB phase. No clear dose- or age-related differences in TTO and TTR of EPS-related TEAEs were noted. CONCLUSION: Despite differences in apparent half-life and pharmacokinetic profiles (peak plasma exposure of PP3M formulation is 70% higher than that of PP1M formulation), both PP3M and PP1M formulations exhibited comparable incidence of EPS-related TEAEs, TTO, and TTR in patients with schizophrenia.

Paliperidone Palmitate 3-Monthly Versus 1-Monthly Injectable in Patients With Schizophrenia With or Without Prior Exposure to Oral Risperidone or Paliperidone: A Post Hoc, Subgroup Analysis.

BACKGROUND AND OBJECTIVE: Paliperidone palmitate 3-monthly (PP3M) injectable formulation offers an advantage of improved medication adherence and lower relapse risk in patients with schizophrenia. This post hoc analysis compared outcomes following PP3M versus paliperidone palmitate 1-monthly (PP1M) treatment in patients with schizophrenia treated/untreated with oral risperidone/paliperidone (RIS/PALI). METHODS: Patients were treated with PP1M (50, 75, 100, or 150 mg equivalent [eq.]) for 17 weeks during an open-label (OL) phase and randomized (1:1) to PP3M (175, 263, 350, or 525 mg eq.) or PP1M (50, 75, 100, or 150 mg eq.) during a 48-week double-blind phase. Efficacy outcomes were compared based on prior oral RIS/PALI exposure: recent (≥ 28 days of oral RIS/PALI exposure with last dose within 14 days before study entry); or no (no oral RIS/PALI exposure within 60 days before study entry). RESULTS: A total of 452 OL patients received recent oral RIS/PALI (n = 323 [71%], randomized to PP3M = 166; PP1M = 157), and 709 OL patients were without recent oral RIS/PALI (n = 506 [71%], randomized to PP3M = 254; PP1M = 252). Improvements in Positive and Negative Syndrome Scale (PANSS) scores (OL baseline-to-endpoint) were similar in recent-RIS/PALI (mean [standard deviation]:18.3 [17.96]) and no-RIS/PALI (- 21.1 [16.40]) subgroups. Relapse-free rates were comparable between recent-RIS/PALI (relapse-free rate [95% confidence interval for difference]: 2.6 [- 4.7 to 10.0]; PP3M: 90%; PP1M: 87%) and no-RIS/PALI subgroups (0.8 [- 4.5 to 6.0]; PP3M: 92%; PP1M: 91%). Weight gain was the most common (> 5% incidence) treatment-emergent adverse event in both subgroups irrespective of the prior treatment. CONCLUSION: Patients with schizophrenia, irrespective of prior treatment with RIS/PALI, had comparable treatment outcomes and tolerability following PP3M or PP1M treatment. REGISTRATION: This study is registered at the EU clinical trial registry (EudraCT Number: 2011-004889-15) and ClinicalTrials.gov (identifier: NCT01515423).

Relapse After Antipsychotic Discontinuation in Schizophrenia as a Withdrawal Phenomenon vs Illness Recurrence: A Post Hoc Analysis of a Randomized Placebo-Controlled Study.

BACKGROUND: It has been proposed that relapse rates after antipsychotic discontinuation may be artificially inflated and that some of these symptom recurrences may be due to rebound or withdrawal phenomena rather than due to illness recurrence. METHODS: Post hoc analysis of data from a relapse-prevention study (conducted from March 2005 to February 2007) of paliperidone palmitate once-monthly (PP1M) versus placebo was conducted to compare the nature of operationally defined relapse events in schizophrenia patients (diagnosed by DSM-IV criteria) experiencing relapses after randomization to placebo (n = 97) with those in patients receiving maintenance PP1M treatment (n = 36). These 2 groups were compared for onset and severity of recurrence symptoms, symptom profiles at relapse, and postrelapse treatment response. Psychological and physiological signs of discontinuation and signs of antipsychotic tolerance, dyskinesia, and prolactin elevation that might indicate dopamine receptor supersensitivity were compared. RESULTS: Both groups were similar in terms of relapse symptom profiles, onset and severity of relapse symptoms, and postrelapse treatment response. The Positive and Negative Syndrome Scale total score (mean ± SD) for placebo versus maintenance treatment group at baseline was 54.5 ± 11.74 vs 54.1 ± 11.64 and at relapse was 75.6 ± 16.79 vs 75.2 ± 17.23 (P = .9). No elevated blood pressure or heart rate, dyskinesia, antipsychotic tolerance, or elevated prolactin in the patients relapsing after antipsychotic discontinuation was noted. CONCLUSIONS: Findings suggest that relapses after treatment discontinuation reflect recurrence of the underlying illness and may be consistent with a hypothesis of direct relationship between dopamine and psychosis. No evidence was obtained for withdrawal-related phenomena contributing to the high relapse rates after treatment discontinuation. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00111189.

An assessment of injection site reaction and injection site pain of 1-month and 3-month long-acting injectable formulations of paliperidone palmitate.

PURPOSE: To evaluate injection site reactions and pain following paliperidone palmitate 1-month (PP1M) and 3-month (PP3M) administration using safety data of double-blind (DB), noninferiority study. METHODS: Patients (n = 1,429) with schizophrenia, treated with PP1M (50-150 mg-eq, 17-week open-label [OL] phase) were randomized to PP1M or PP3M in 48-week DB phase. FINDINGS: PP1M and PP3M injections were well tolerated. Incidence of induration, redness, and swelling were low in both phases (OL: 9-12%; DB: 7-13%), and were mostly mild in both groups. Mean (SD) visual analog scale scores decreased from OL-baseline (22.0 [21.6]) to DB-baseline (19.5 [20.6] vs. 18.4 [20.4]) and DB-endpoint (15.6 [17.9] vs. 15.5 [18.3]). PRACTICE IMPLICATIONS: Injection site reactions and pain were low and similar between both treatments, regardless of administration site and dose.

Efficacy and safety of paliperidone palmitate three-monthly formulation in East Asian patients with schizophrenia: subgroup analysis of a global, randomized, double-blind, Phase III, noninferiority study.

OBJECTIVE: To demonstrate the efficacy and safety of paliperidone palmitate three-monthly (PP3M) formulation in an East Asian population with schizophrenia by subgroup analysis of a double-blind (DB), multicenter, noninferiority study. PATIENTS AND METHODS: Of 1,429 patients who entered the open-label (OL) phase, 510 were East Asian (China: 296 [58%], Japan: 175 [34%], South Korea: 19 [4%] and Taiwan: 20 [4%]). In the 17-week OL phase, patients received paliperidone palmitate once-monthly (PP1M) formulation on day 1 (150 mg eq.), day 8 (100 mg eq.) and once-monthly thereafter (50-150 mg eq., flexible). Following the OL phase, patients (n=344 East Asian) entered DB phase and were randomized (1:1) to PP1M (n=174) or PP3M (n=170). Primary efficacy endpoint was the percentage of patients who remained relapse free at the end of the 48-week DB phase, using Kaplan-Meier cumulative survival estimate. Secondary efficacy endpoints included change from DB baseline to endpoint in Positive and Negative Syndrome Scale, Clinical Global Impression Severity, Personal and Social Performance scores and symptomatic remission. Additional assessments included caregiver burden and safety. RESULTS: A total of 285/344 (83%) randomized East Asian patients completed the DB phase. The percentage of patients who had a relapse event was similar on comparing PP3M (17 [10.2%]) to PP1M (20 [11.8%]), and also for Japan (PP3M: 9 [17.6%], PP1M: 13 [23.2%]) and China (PP3M: 6 [5.9%], PP1M: 7 [6.9%]). Mean change from baseline in secondary efficacy parameters was similar to the global population, regardless of treatment. Symptomatic remission was attained by 50% of the treated patients. Caregiver burden was significantly reduced (P<0.001) following treatment with PP3M/PP1M. Frequency of treatment-emergent adverse events in PP3M group during DB phase was greater in the East Asian subgroup (81%) than the global population (68%) and was higher in Japan (92%) than China (75%). CONCLUSION: Results suggest that PP3M is efficacious in the East Asian subgroup. Although treatment-emergent adverse events were slightly higher in the East Asian subgroup versus the global population, no new safety signals were identified.

Paliperidone palmitate 3-month treatment results in symptomatic remission in patients with schizophrenia: a randomized, multicenter, double-blind, and noninferiority study.

The current analysis assessed symptomatic and functional remission achieved following paliperidone palmitate 3-month (PP3M) versus 1-month (PP1M) treatment in patients (age: 18-70 years) with schizophrenia, previously stabilized on PP1M. Following a less than or equal to 3-week screening, and a 17-week, flexible-dosed, open-label phase [PP1M: day 1 (150 mg eq. deltoid), day 8 (100 mg eq. deltoid), weeks 5, 9, and 13 (50, 75, 100, or 150 mg eq., deltoid/gluteal)], clinically-stable patients were randomized (1 : 1) to PP3M (fixed-dose, 175, 263, 350, or 525 mg eq. deltoid/gluteal) or PP1M (fixed-dose, 50, 75, 100, or 150 mg eq. deltoid/gluteal) in 48-week double-blind (DB) phase. Symptomatic remission was assessed using Andreasen's criteria. Functional remission was assessed using Personal and Social Performance scale (PSP). More than 50% patients in both groups achieved symptomatic remission (PP3M: 50.3%; PP1M: 50.8%) during last 6 months of DB phase. Similar percentage of patients of both groups achieved functional remission (defined as PSP score>70, PP3M: 42.5%; PP1M: 43.9%) and combined remission (symptomatic and functional remission, PP3M: 25.1%; PP1M: 26.6%) during last 6 months of DB phase. Most patients who achieved remission at DB baseline maintained their remission status throughout the DB phase. PP3M and PP1M achieved comparable symptomatic and functional remissions during the DB phase.

Caregiver burden in schizophrenia following paliperidone palmitate long acting injectables treatment: pooled analysis of two double-blind randomized phase three studies.

The pooled analysis of two double-blind, randomized, multicenter, phase-3 studies evaluated predictors of improvement or worsening of schizophrenia-related caregiver burden following paliperidone palmitate long-acting injectables (1-monthly [PP1M] and 3-monthly [PP3M]) treatment. Caregivers were offered to complete the involvement evaluation questionnaire (involvement evaluation questionnaire; 31-item scale). Total, 1498 caregivers (intent-to-treat open-label analysis set, n = 1497; mean [SD] age: 51.5 [13.02] years, 27 countries) were included: 49% were parents and >50% caregivers spent >32 hours/week in caregiving. Majority of caregivers with considerable burden (n = 1405; mean [SD] baseline involvement evaluation questionnaire scores: 28.4 [15.07]) improved significantly from baseline to end-of-study (n = 756; mean [SD] change from open-label baseline to double-blind endpoint in long-acting injectable scores:-8.9 [14.73]); most improvements were seen in urging followed by worrying, tension, and supervision domains (mean [SD] change from open-label baseline to double-blind endpoint in involvement evaluation questionnaire scores, urging: -3.7 [6.45]; worrying:-2.6 [5.11]; tension:-2.3 [4.84]; supervision: -1.3 [3.69]). Improvements significantly correlated with relapse status, patient age, and age of diagnosis (p < 0.001) while long-acting injectable use at baseline, number, and duration of prior psychiatric hospitalizations (<24 months) had no significant correlation. Caregiver burden was significantly improved for patients on prior oral antipsychotics post-switching to long-acting injectable, with less impact on leisure days and hours spent in caregiving (p < 0.001). Family members of patients with schizophrenia experience considerable caregiver burden. Switching from oral antipsychotic to long-acting injectable can provide meaningful and significant improvement in caregiver burden. DRUG FORMULATION: EASING THE TOLL OF CAREGIVING: Switching from oral to long-acting injectable antipsychotic medication improves overall caregiver burden. The physical, emotional and financial toll of providing care for patients with schizophrenia is often underestimated. Poor adherence to conventional oral antipsychotics is a major cause of symptomatic relapse in patients and of stress for carers. Srihari Gopal and colleagues at Janssen Pharmaceuticals have pooled data from two large studies involving 1498 caregivers across 27 countries. They found that administration of either 1- or 3-monthly long-acting injectable antipsychotics not only eased the burden of daily dosing and patient compliance, but also had a positive impact on the stress conditions of caregivers. Using the Involvement Evaluation Questionnaire to measure caregiver burden, the authors showed that the switch in drug formulation decreased the need to urge patients to self-care and the hours spent caregiving.

Evaluation of Potentially Prolactin-Related Adverse Events and Sexual Maturation in Adolescents with Schizophrenia Treated with Paliperidone Extended-Release (ER) for 2 Years: A Post Hoc Analysis of an Open-Label Multicenter Study.

BACKGROUND: Elevated prolactin levels (hyperprolactinemia) are a frequent adverse effect of antipsychotic medications, especially in young populations. Prolonged hyperprolactinemia may affect sexual functioning and the onset and progression of puberty. OBJECTIVE: This study assessed potentially prolactin-related treatment-emergent adverse events (PPRL-TEAEs) and sexual maturation during long-term treatment of adolescents with paliperidone extended-release (ER). METHODS: This post hoc analysis of a 2-year open-label multicenter study (NCT00488319) included patients of either sex aged 12-17 years at study enrollment, diagnosed with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, 4th edition [DSM-IV]) for ≥1 year, who had received one or more adequate antipsychotic treatment prior to enrollment but had not responded sufficiently. Patients were initially treated with 6 mg/day paliperidone ER and further titrated between 1.5 and 12 mg/day based on clinical response and tolerability. The primary objective was to determine the relationship between characteristics (including sex, age at study entry, ethnicity, geographic region, age at diagnosis, duration of illness, number of prior hospitalizations, serum prolactin, and baseline Tanner stages) and onset or risk of PPRL-TEAEs. The secondary objective was to assess sexual maturation during long-term treatment with paliperidone ER. RESULTS: In total, 400 patients were enrolled in the study and 184 patients completed the 2-year study; the majority were boys (61%), White (66%), and aged >14 years at study enrolment (73%) with mean (standard deviation [SD]) body mass index (BMI) of 21.96 (4.375) kg/m2 at baseline. Girls (18.5%) had a higher incidence of PPRL-TEAEs than did boys (3.3%). Most of these events were mild to moderate in severity, and none were serious; four patients discontinued the study due to PPRL-TEAEs. Mean prolactin levels in the total population of boys and girls increased early during treatment then stabilized with time. Mean ± SD maximum changes in prolactin levels from baseline were higher in girls and boys with PPRL-TEAEs than in those without (Girls: 74.7 ± 32.3 ng/ml [n = 28] vs. 50.5 ± 44.9 ng/ml [n = 114]; p = 0.008. Boys: 33.6 ± 23.7 ng/ml [n = 8] vs. 31.0 ± 24.5 ng/ml [n = 205]; p = 0.77). No clinically significant mean changes from baseline in growth-adjusted z-score for weight, height, or BMI were observed. Overall, ~90% of the patients who completed the 2-year study achieved Tanner stages 4-5 by study endpoint. Female sex, age at diagnosis (13-14 years), girls of Hispanic ethnicity, and region (EU and North America) were associated with a greater risk for PPRL-TEAEs; higher baseline Tanner stages for pubic hair (boys and girls) and breast development (stage 3 vs. 4 or 5) also seemed to be associated with a higher incidence of PPRL-TEAEs. CONCLUSIONS: Female sex appeared to be associated with an increased risk for PPRL-TEAEs. Other potential predictors, such as ethnicity, region, age at diagnosis, and Tanner stage 4 or 5, all seemed to be related to sex. Evidence from this study was insufficient to definitively conclude that prolactin values at baseline and change during treatment were predictive of PPRL-TEAEs, although there is a signal that this may be the case in girls. These results are exploratory in nature, and confirmatory studies are needed to confirm these observations. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00488319.

Health care resource use analysis of paliperidone palmitate 3 month injection from two phase 3 clinical trials.

OBJECTIVE: The objective of this study was to compare occupational status and health care resource use between treatment groups in clinical trials 3012 (PP3M versus placebo) and 3011 (PP3M versus PP1M). METHODS: Occupational status was assessed at each study visit. Logistic regressions modeled the probability of hospitalization during the double-blind phase. RESULTS: At the start of each study, a low percentage of patients were full-time employed or gainfully self-employed (approximately 10% in trial 3012 and 11%-13% in trial 3011). Improvement from baseline in occupational status was slightly higher in the PP3M group than in placebo or PP1M groups. The odds of a hospitalization for psychiatric and social reasons during 1 year was 7.74 (95% CI, 2.39-25.05; p < .001) for a patient on placebo compared with the odds of hospitalization during 1 year for a patient on PP3M. No statistically significant difference was observed between PP3M and PP1M (odds ratio, 1.16; 95% CI, 0.70-1.93). Very similar results were observed for hospitalizations due to psychiatric reasons only, within each trial. CONCLUSIONS: In both trials, most patients were unemployed and not seeking work or were retired at open-label baseline, and only a small number of patients changed their occupational status during the trials. In trial 3012, subjects who received placebo had significantly higher odds of hospitalization for either psychiatric and social reasons or for psychiatric reasons alone compared with subjects who received PP3M. In contrast, in trial 3011, the odds of hospitalizations were not significantly different between PP3M and PP1M.

Efficacy and Safety of Paliperidone Palmitate 3-Month Formulation for Patients with Schizophrenia: A Randomized, Multicenter, Double-Blind, Noninferiority Study.

BACKGROUND: This double-blind, parallel-group, multicenter, phase-3 study was designed to test the noninferiority of paliperidone palmitate 3-month formulation (PP3M) to the currently marketed 1-month formulation (PP1M) in patients (age 18-70 years) with schizophrenia, previously stabilized on PP1M. METHODS: After screening (≤3 weeks) and a 17-week, flexible-dosed, open-label phase (PP1M: day 1 [150mg eq. deltoid], day 8 [100mg eq. deltoid.], weeks 5, 9, and 13 [50, 75, 100, or 150mg eq., deltoid/gluteal]), clinically stable patients were randomized (1:1) to PP3M (fixed-dose, 175, 263, 350, or 525mg eq. deltoid/gluteal) or PP1M (fixed-dose, 50, 75, 100, or 150mg eq. deltoid/gluteal) for a 48-week double-blind phase. RESULTS: Overall, 1016/1429 open-label patients entered the double-blind phase (PP3M: n=504; PP1M: n=512) and 842 completed it (including patients with relapse). PP3M was noninferior to PP1M: relapse rates were similar in both groups (PP3M: n=37, 8%; PP1M: n=45, 9%; difference in relapse-free rate: 1.2% [95% CI:-2.7%; 5.1%]) based on Kaplan-Meier estimates (primary efficacy). Secondary endpoint results (changes from double-blind baseline in positive and negative symptom score total and subscale scores, Clinical Global Impression-Severity, and Personal and Social Performance scores) were consistent with primary endpoint results. No clinically relevant differences were observed in pharmacokinetic exposures between PP3M and PP1M. Both groups had similar tolerability profiles; increased weight was the most common treatment-emergent adverse event (double-blind phase; 21% each). No new safety signals were detected. CONCLUSION: Taken together, PP3M with its 3-month dosing interval is a unique option for relapse prevention in schizophrenia.