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Background: Investigation and analysis of the changes in healthcare resources and burden of schizophrenia in the real world before and after switching from oral antipsychotics (OAPs) to paliperidone palmitate once-monthly (PP1M) could provide evidence to clinicians and patients for choosing treatment modality and data support for health policy optimization Methods: The first dosage of PP1M was set as mirror point, and patients with mirror point between January 2020 and June 2022 were recruited in the study. The differences in treatment patterns, healthcare resource utilization, and costs within one year before and after the mirror point were compared. Results: A total of 72 patients transitioning from OAPs to PP1M (mean age, 35.33 years; 43.06% female) were included in the study. Of the 72 patients, the application of PP1M resulted in a significant reduction in the hospitalization times, emergency room visits, and direct medical costs (P < 0.001), while the pharmacy cost and total cost increased by 222.57% (P < 0.001) and 16.35% (P < 0.001), respectively; PP1M accounted for 88.48% of the pharmacy cost. For patients with ≥1 hospitalization during the OAPs phase (n = 25), the number of hospitalizations, hospitalization days and hospitalization expenses decreased by more than 90% (P < 0.001). Total one-year expenses decreased by 37.67% (P < 0.001), and pharmacy expenses increased by 185.21% (P < 0.001). For patients with no hospitalizations during the OAPs phase (n = 47), emergency and outpatient visits decreased by 70% (P < 0.001) and 30.27% (P < 0.05), respectively, while the total cost increased by 117.56% (P < 0.001), and the pharmacy cost increased by 260.15% (P < 0.001) after initiation of PP1M treatment. Conclusion: After the transition to PP1M, the number of hospitalizations and outpatient and emergency department visits reduced, and healthcare resources were conserved. Switching to PP1M may be more economically beneficial for patients with prior hospitalizations while on OAP regimens. The high price of PP1M might be an obstacle to its widespread use. [ABSTRACT FROM AUTHOR]

Aim Methods Results Conclusions Real‐world data (RWD) for paliperidone palmitate (PP) three‐monthly (PP3M) is lacking based on Japan label requirements. This study evaluated the clinical effectiveness of PP3M versus PP once‐monthly (PP1M) in patients with schizophrenia administered according to Japan label requirements.Retrospective analyses were conducted using RWD from Merative™ MarketScan® Multi‐State Medicaid (MDCD) claims database (June 2015–December 2022). Adult patients with schizophrenia switching from PP1M to PP3M were included. Patients transitioning to PP3M were matched with patients who continued with PP1M using propensity score matching (PSM) at 1:1 ratio. Primary hypothesis aimed to investigate non‐inferiority of PP3M versus PP1M in terms of relapse‐free status at 24 months from index PP injection. Outcome measures were proportions of relapse‐free patients at 24 months, time to relapse, treatment persistence, and adherence.Total 4252 eligible adult schizophrenia patients on PP (PP3M:582; PP1M:3670) were identified. After PSM, each PP cohort comprised 562 matched individuals. Estimated proportion of relapse‐free patients was higher in PP3M (85.7%) versus PP1M (77.9%), per Japan PP label. PP3M demonstrated superiority to PP1M after testing for non‐inferiority in terms of achieving relapse‐free status at 24 months, with an estimated difference of 7.8% (95% CI: 1.7%–13.9%). PP3M cohort had lower risk of relapse (HR: 0.605; CI: 0.427–0.856), longer treatment persistence, and higher treatment adherence versus PP1M cohort.Findings suggests that patients who switched to PP3M might be able to reduce risk of relapse compared to those who continued PP1M after aligning particularly with Japan's label requirements. [ABSTRACT FROM AUTHOR]

Bo-Chieh Chang,1 Meng-Hsuan Kuo,1 Chi-Hui Lee,1 Ya-Lan Chu,1 Kuang-Peng Chen,2 Chun-Liong Tung,2 Ya-Hui Yang,3 Chuan-Sheng Hung,4 Jui-Hsiu Tsai,2,5 Hung-Yi Chuang6 1Department of Pharmacy, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan; 2Department of Psychiatry, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan; 3Department of Long-Term Care and Health Management, Cheng Shiu University, Kaohsiung, Taiwan; 4Department of Computer Science and Engineering, National Sun Yat-Sen University, Kaohsiung, Taiwan; 5School of Medicine, Tzu Chi University, Hualien, Taiwan; 6Department of Environmental and Occupational Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, TaiwanCorrespondence: Jui-Hsiu Tsai, Department of Psychiatry, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, No. 2, Min-Sheng Road, Dalin Town, Chiayi, 622, Taiwan, Email faanvangogh@gmail.comIntroduction: Poor adherence to antipsychotics in patients with schizophrenia is a leading cause of relapse and functional deterioration. Long-acting injectable paliperidone may reduce relapse risks, health-care utilisation, and health-care costs in these patients.Methods: In this 24-month mirror-image study, we compared health-care utilization and costs before and after the initiation of paliperidone palmitate 3-monthly (PP3M) treatment in patients with schizophrenia spectrum disorders. Before the initiation of PP3M, the patients received paliperidone 1-monthly (PP1M) treatment. The primary study outcomes were changes in health-care utilisation and costs over the study period.Results: This study included 34 patients with schizophrenia spectrum disorders. During the 12-months period after the initiation of PP3M treatment, the mean duration of hospitalisation decreased from 57.7 to 28.5 days (p = 0.03). Moreover, significant reductions were noted in emergency room visits (PP1M vs PP3M: 0.3 vs 0.0, respectively; p = 0.05) and health-care costs (PP1M vs PP3M: 107,328.8 vs 57,848.6, respectively; p = 0.03).Conclusion: PP3M may significantly reduce hospitalisation duration, emergency room visits, and health-care costs in patients with schizophrenia.Keywords: schizophrenia, long-acting injectable antipsychotics, paliperidone palmitate, health-care cost, health-care utilisation

Abstract Background To analyze the economic benefits of paliperidone palmitate in the treatment of schizophrenia. Methods We collected 546 patients who met the diagnostic criteria for schizophrenia according to the 《International Statistical Classification of Diseases and Related Health Problems,10th》(ICD-10). We gathered general population data such as gender, age, marital status, and education level, then initiated treatment with paliperidone palmitate. Then Follow-up evaluations were conducted at 1, 3, 6, 9, and 12 months after the start of treatment to assess clinical efficacy, adverse reactions, and injection doses. We also collected information on the economic burden before and after 12 months of treatment, as well as the number of outpatient visits and hospitalizations in the past year to analyze economic benefits. Results The baseline patients totaled 546, with 239 still receiving treatment with paliperidone palmitate 12 months later. After 12 months of treatment, the number of outpatient visits per year increased compared to before (4 (2,10) vs. 12 (4,12), Z=-5.949, P 0.05); the indirect costs of patients after 12 months of treatment (lost productivity costs for patients and families, economic costs due to destructive behavior, costs of seeking non-medical assistance) decreased compared to before (300(150,600) vs. 150(100,200), P

Addictive disorders are a very common comorbidity of schizophrenia, which increases the severity of symptoms, worsens the course of the disease, and is also associated with high nonadherence to therapy. Of the possible therapeutic interventions, according to the available findings, clozapine appears to be the more effective drug. Due to the frequent non-adherence to therapy, the interest of the professional public is also directed towards long-acting injectable forms of antipsychotics, the administration of which is not yet standard for this dual diagnosis. We present a case report of a pharmacoresistant patient with paranoid schizophrenia and co-occurring substance use disorder with predominant marijuana abuse, in whom a positive clinical effect was recorded when the combination of clozapine and the long-acting antipsychotic paliperidone palmitate was administered. We were based on the patient's medication history. The patient's acute psychotic symptoms improved after combination therapy, and paliperidone palmitate also had an effect on the craving for the addictive substance. The patient gradually stopped using marijuana after about 1 year of therapy. The patient's blood count is regularly monitored. In connection with the use of clozapine, post-medication sedation was noted, however, complete withdrawal from clozapine administration was not possible due to the reappearance of acute psychotic symptoms. Antidepressants were used during the therapy in order to affect the negative symptoms appearing as part of the diagnosis. The patient remained long-term stable on the combination therapy, therefore the 1-month dosage form of paliperidone palmitate was replaced by the 3-month dosage form. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Persons 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. METHOD: In 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). RESULTS: Over 18 months, mean neurocognitive performance improved in a manner consistent with the expected effects of practice in both groups (p

Paliperidone Palmitate is the only antipsychotic that has been developed in three different intramuscular long-acting injectable (LAI) dosing regimen: monthly (PP1M), quarterly (PP3M), and from 2020 also twice-yearly (PP6M). The latter was approved for the maintenance treatment of adults with schizophrenia and clinically stabilized with PP1M or PP3M. Data from studies evaluating efficacy in the maintenance treatment of schizophrenia with PP6M are reviewed. Since no post-marketing safety studies are currently available, data from spontaneous reporting system databases, FAERS and Eudravigilance, are analyzed and the reported treatment-emergent adverse events of PP6M are discussed. The efficacy of PP6M is comparable to that of PP3M in terms of relapses prevention in patients with schizophrenia previously stabilized on PP3M or PP1M. Also, the maintenance of clinical efficacy in the long term has been demonstrated. Data from pharmacovigilance analyses, as well as from phase 3 studies, show that PP6M is generally well tolerated, consistently with PP3M safety data. PP6M allows a longer dosing interval than any other LAI antipsychotics, potentially reducing nonadherence and disease relapses. In future, an increase in the prescription rates of PP6M is expected and real-world efficacy and tolerability studies will be conducted. [ABSTRACT FROM AUTHOR]

Hyperammonemia is a well-known adverse effect of valproate that can progress to a potentially fatal condition known as valproate-induced hyperammonemic encephalopathy (VHE). VHE is more common when valproate is used in combination therapy with other antiepileptic medications. A growing number of case reports have pointed to a possible interaction with the antipsychotic risperidone leading to an increased risk of VHE. We present a case of VHE in which a 20-year-old male patient with bipolar affective disorder developed VHE when on concomitant valproate, risperidone, and paliperidone palmitate. On the seventh day of treatment with oral risperidone, oral divalproex sodium was added. Intramuscular paliperidone palmitate was initiated on day 13, and oral risperidone was discontinued after the second loading dose on day 16. The following day, the patient displayed worsening psychomotor retardation, swaying gait, drowsiness, and vomiting. The patient was found to have hyperammonemia and transferred to the emergency department for treatment of suspected VHE.

Abstract Background The utilization of once-monthly paliperidone palmitate (PP1M) in schizophrenia treatment has increased due to its enhanced adherence and convenience. However, there is limited evidence on patient characteristics that may influence treatment outcomes when switching from oral antipsychotics (OAPs) to PP1M therapy. This systematic review aims to identify such patient characteristics and explore potential beneficial factors to aid healthcare professionals in clinical practice. Methods A systematic literature search was conducted in the PubMed, Embase, and Cochrane Library databases up to July 19, 2022. Studies related to patients with schizophrenia who had been previously treated with OAPs and switched to PP1M were identified and included. Outcomes included the Positive and Negative Syndrome Scale (PANSS) total score, the clinical Global Impressions – Severity (CGI-S) score, the Personal and Social Performance (PSP) total score, and hospitalisation rate. Data were independently extracted and analysed. The results were presented through a narrative synthesis. Results Eleven studies with a total of 4150 patients were included, identifying nine potential characteristics. The most commonly reported characteristics was patient’s prior treatment with OAPs, followed by the stage of disease, duration of illness (DI), ethnicity, reason for switching to PP1M, history of hospitalisation, time of start injection of PP1M, the PANSS and PSP total score at baseline. Patients in the acute stage, with a shorter DI, a less than 1-week time interval to PP1M injection, and a lower PANSS total score at baseline may have a trend on providing better improvements on PANSS total score. Acute stage and shorter DI also showed potential trends in reducing CGI-S score. Early initiation of PP1M, switching for reasons other than lack of efficacy, and a higher PSP score at baseline exhibited potential trends towards better PSP total score improvements. Conclusion Our findings may suggest that patients in acute stage, with a shorter duration of illness, with early initiation of PP1M injection, and lower PANSS or PSP scores may trend towards better clinical results when transitioning to PP1M from OAPs. Further research is necessary to validate these potential associations and identify any unexplored characteristics. Such investigations are crucial for providing comprehensive clinical recommendations and informing treatment strategies in this context.

Introduction: Paliperidone palmitate (PP), a second-generation long-acting injectable antipsychotic, requires 2 injections upon initiation. Due to the fast-paced nature of the inpatient setting, the second dose may be administered earlier than recommended by labeled use despite the lack of evidence that evaluates this practice. Methods: This was a retrospective chart review that investigated the outcomes associated with the timing of the second PP initiation dose with the aim of comparing patients who received the second PP dose fewer than 3 days after the first injection with those who received it between 3 and 11 days after the first injection. The primary outcomes included 30-day psychiatric readmission, index hospitalization length of stay, and time until the next psychiatric hospitalization. Secondary outcomes included 6-month readmission and the percentage of patients who experienced an adverse event after the second injection. Results: No statistically significant differences were observed between groups for 30-day readmission. There was a statistically significant shortened index length of hospitalization (median, 2 vs 4 days; P < 0.001) and a non-statistically significant trend for time until the next psychiatric hospitalization (median, 25 vs 47 days) when comparing those who received the nontraditional loading regimen to those who received the traditional labeled loading regimen. No differences were observed in the secondary outcomes or safety/tolerability. Discussion: The results of the study indicate that there are no significant differences in readmission rates and adverse drug reactions in those who received the second PP dose earlier than recommended per labeled use. Larger, controlled studies are needed to further investigate clinical and safety outcomes.

Background: The utilization of once-monthly paliperidone palmitate (PP1M) in schizophrenia treatment has increased due to its enhanced adherence and convenience. However, there is limited evidence on patient characteristics that may influence treatment outcomes when switching from oral antipsychotics (OAPs) to PP1M therapy. This systematic review aims to identify such patient characteristics and explore potential beneficial factors to aid healthcare professionals in clinical practice. Methods: A systematic literature search was conducted in the PubMed, Embase, and Cochrane Library databases up to July 19, 2022. Studies related to patients with schizophrenia who had been previously treated with OAPs and switched to PP1M were identified and included. Outcomes included the Positive and Negative Syndrome Scale (PANSS) total score, the clinical Global Impressions – Severity (CGI-S) score, the Personal and Social Performance (PSP) total score, and hospitalisation rate. Data were independently extracted and analysed. The results were presented through a narrative synthesis. Results: Eleven studies with a total of 4150 patients were included, identifying nine potential characteristics. The most commonly reported characteristics was patient's prior treatment with OAPs, followed by the stage of disease, duration of illness (DI), ethnicity, reason for switching to PP1M, history of hospitalisation, time of start injection of PP1M, the PANSS and PSP total score at baseline. Patients in the acute stage, with a shorter DI, a less than 1-week time interval to PP1M injection, and a lower PANSS total score at baseline may have a trend on providing better improvements on PANSS total score. Acute stage and shorter DI also showed potential trends in reducing CGI-S score. Early initiation of PP1M, switching for reasons other than lack of efficacy, and a higher PSP score at baseline exhibited potential trends towards better PSP total score improvements. Conclusion: Our findings may suggest that patients in acute stage, with a shorter duration of illness, with early initiation of PP1M injection, and lower PANSS or PSP scores may trend towards better clinical results when transitioning to PP1M from OAPs. Further research is necessary to validate these potential associations and identify any unexplored characteristics. Such investigations are crucial for providing comprehensive clinical recommendations and informing treatment strategies in this context. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Long-acting injectable antipsychotics (LAIs), due to a lower frequency of administration, could address the well-established challenge of non-adherence to oral ones. We conducted a Network Meta-Analysis (NMA) to assess the relationship between administration frequency and effectiveness. The recent introduction of a semi-annual paliperidone palmitate formulation, along with the arrival of monthly paliperidone generics, could emphasize LAI’s advantages. Aim of this paper is to present the results derived from an updated version of our previous NMA. These results are used to fuel a budget impact model built to evaluate the economic implications of optimizing dosing intervals. METHODS: We compare the current distribution of patients among available LAI active substances and dosing frequencies with an optimized scenario. In this scenario, 20% of patients are switched to the next permitted regimen with a longer inter-dosing interval. Drug acquisition costs and relapse management costs are taken into account over a one-year simulation period; these last items are estimated by means of the event rates obtained from the updated meta-analysis. The optimized scenario incorporates the reduced cost resulting from the expiration of patents. RESULTS: Throughout the analysis, a total of 11,600 patients were able to switch from shorter to longer dosing intervals, leading to an overall optimization of quality of care. The greater expenditure incurred by the Italian National Health Service (NHS) in the acquisition of newer and longer-lasting drugs is offset by savings associated with the arrival of generics of monthly paliperidone palmitate and the shift toward less-relapsing regimens. The net impact on the NHS budget is a saving of more than 19 million Euros. CONCLUSION: This economic saving has the potential to initiate a virtuous process: it could be reinvested to fund a further shift from oral daily therapies, which are less expensive but marked by poor compliance, to LAIs. According to our simulation, nearly 40 thousand patients could undergo this transition, without additional expenses for the NHS.

Abstract Backgrounds Meta-analyses can be a powerful tool but need to calibrate potential unrepresentativeness of the included trials to a target population. Estimating target population average treatment effects (TATE) in meta-analyses is important to understand how treatments perform in well-defined target populations. This study estimated TATE of paliperidone palmitate in patients with schizophrenia using meta-analysis with individual patient trial data and target population data. Methods We conducted a meta-analysis with data from four randomized clinical trials and target population data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study. Efficacy was measured using the Positive and Negative Syndrome Scale (PANSS). Weights to equate the trial participants and target population were calculated by comparing baseline characteristics between the trials and CATIE. A calibrated weighted meta-analysis with random effects was performed to estimate the TATE of paliperidone compared to placebo. Results A total of 1,738 patients were included in the meta-analysis along with 1,458 patients in CATIE. After weighting, the covariate distributions of the trial participants and target population were similar. Compared to placebo, paliperidone palmitate was associated with a significant reduction of the PANSS total score under both unweighted (mean difference 9.07 [4.43, 13.71]) and calibrated weighted (mean difference 6.15 [2.22, 10.08]) meta-analysis. Conclusions The effect of paliperidone palmitate compared with placebo is slightly smaller in the target population than that estimated directly from the unweighted meta-analysis. Representativeness of samples of trials included in a meta-analysis to a target population should be assessed and incorporated properly to obtain the most reliable evidence of treatment effects in target populations.

Schizophrenia (SZ) is among the twenty most disabling diseases worldwide. Subjective quality of life, well-being, and satisfaction are core elements to achieving personal recovery from the disorder. Long-acting injectable second-generation antipsychotics (SGA-LAIs) represent a valid therapeutic option for the treatment of SZ as they guarantee good efficacy and adherence to treatment. The aim of this rapid review is to summarize the evidence on the efficacy of SGA-LAIs in improving subjective quality of life, well-being, and satisfaction. The PubMed database was searched for original studies using SGA, LAI, risperidone, paliperidone, aripiprazole, olanzapine, SZ, and psychosis as keywords. Twenty-one studies were included: 13 clinical trials, 7 observational studies, and 1 post hoc analysis. It has been shown that SGA-LAIs bring an improvement to specific domains of subjective and self-rated quality of life, well-being, or satisfaction in prospective observational studies without a control arm and in randomized controlled trials versus placebo. The superiority of SGA-LAIs as compared with oral equivalents and haloperidol-LAI has been reported by some randomized controlled and observational studies. Although promising, the evidence is still limited because of the lack of studies and several methodological issues concerning the choice of the sample, the evaluation of the outcome variables, and the study design. New methodologically sound studies are needed. [ABSTRACT FROM AUTHOR]

Mingjun Zhao,1,&ast; Bin Qin,2,&ast; Yage Mao,3 Yang Zhang,4 Ruisheng Zhao,5 Aiqin Wang,1 Hailing Wang,1 Jianting Zhao,6 Changhong Wang7 1Department of Pharmacy, The Second Affiliated Hospital of Xinxiang Medical University (Henan Mental Hospital), Xinxiang, People’s Republic of China; 2Department of Neurology, Liuzhou General Hospital, Liuzhou, People’s Republic of China; 3Department of Pharmacy, Maternal and Child Health Care hospital of Xinxiang City, Xinxiang, People’s Republic of China; 4Department of Respiratory, The People’s Hospital of Jiaozuo City, Jiaozuo, People’s Republic of China; 5Department of Pharmacy, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, People’s Republic of China; 6Department of Neurology, Central Hospital of Xinxiang City, Xinxiang, People’s Republic of China; 7Department of Psychiatry, The Second Affiliated Hospital of Xinxiang Medical University (Henan Mental Hospital), Xinxiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Changhong Wang, Department of Psychiatry, The Second Affiliated Hospital of Xinxiang Medical University (Henan Mental Hospital), 207&num; QianJin Road, Xinxiang, Henan, 453000, People’s Republic of China, Tel +86-373-3388798, Fax +86-373-3374082, Email wangchdr@163.comPurpose: The aim of this study was to assess the efficacy and safety of paliperidone palmitate (PP) treatment compared with risperidone long-acting injectable (LAI) treatments for patients with schizophrenia.Patients and Methods: Data mining was conducted in April 2022 across PubMed, Web of Science, Embase, the Cochrane Library, ClinicalTrials.gov, and PsycINFO. All published randomized controlled trials (RCTs) that assessed the effect of PP treatment for patients with schizophrenia when compared with the risperidone-LAIAs group were included. Relevant data were extracted and synthesized narratively. Results were expressed as standardized mean differences (SMDs) or risk ratios (RRs), with 95% confidence intervals (CIs).Results: Four RCTs with 2451 patients met all the inclusion and exclusion criteria. Efficacy analyses showed no significant statistical differences in Positive and Negative Syndrome Scale (PANSS) total score changes at the endpoint (SMD = 0.10, P = 0.19), or in response rates (RR = 0.93; P = 0.40). Regarding the safety outcomes, PP treatment showed significantly increased risks of discontinuation rates for any reason (35.7% vs 30.4%; RR = 1.19; 95% CI, 1.03 to 1.39; P = 0.02) and nonsignificantly increased risks of total treatment emergent adverse events (TEAEs) (66.6% vs.64.8%; RR = 1.01; 95% CI, 0.94 to 1.09; P = 0.78) compared with the risperidone-LAIAs-treated group. Furthermore, PP may significantly increase total discontinuation rates compared with risperidone-LAIAs.Conclusion: Our meta-analysis did not find a more beneficial effect of PP compared to risperidone-LAIAs treatments for schizophrenia. Clinicians should interpret and translate our data with caution, as the meta-analysis was based on a limited number of randomized controlled trials and patients.Keywords: paliperidone palmitate, risperidone, long-acting injectable, schizophrenia, meta-analysis

Ruth Milz,1 Carmela Benson,1 Karl Knight,1 Jose Antunes,2 Dean Najarian,3 Paola-Maria Lopez Rengel,4 Steven Wang,1 Ute Richarz,5 Srihari Gopal,1 John M Kane6,7 1Janssen Research & Development LLC, Titusville, NJ, USA; 2Janssen-Cilag, Porto Salvo, Portugal; 3Janssen Scientific Affairs, LLC, Raritan, NJ, USA; 4Janssen Cilag, Madrid, Spain; 5Janssen Global Medical Affairs, Cilag, Zug, Switzerland; 6Department of Psychiatry, The Zucker Hillside Hospital, Northwell Health, Queens, NY, USA; 7Institute of Behavioral Science, Feinstein Institutes for Medical Research, Manhasset, NY, USACorrespondence: Ruth Milz, Janssen Research & Development, LLC, 1125 Trenton-Harbourton Road, Titusville, NJ, 08560, USA, Email rmilz@ITS.JNJ.comAbstract: Medication nonadherence in schizophrenia can have serious implications including relapses and hospitalization. Long-acting injectable (LAI) antipsychotics require fewer administrations, while ensuring sustained medication coverage. In this review, we summarize the expected real-world benefits of longer dosing intervals in the management of schizophrenia. LAIs are associated with improved clinical outcomes of less frequent relapses and reduced functional impairment, encouraging patients to regain control of their lives. Aripiprazole lauroxil and paliperidone palmitate three-monthly (PP3M) LAIs have longer dosing intervals of 2– 3 months and provide improved outcomes in patients with schizophrenia. Paliperidone palmitate six-monthly (PP6M) LAI provides the longest dosing interval, twice-yearly dosing, among existing LAIs. Decreasing the frequency of LAI administrations has the potential to reduce occurrence of serious outcomes associated with poor medication adherence. By eliminating the need for daily oral antipsychotic dosing, LAIs could increase the likelihood of patient acceptance, decrease stigma, and promote self-esteem. Longer intervals of medication coverage may be desirable for patients with higher risk of relapse including adults with recent-onset schizophrenia, those living in circumstances that may deprive them of regular access (eg, homeless), those that are in transitions between care settings or to reduce interpersonal contact during public health emergencies (eg, COVID-19 pandemic).Keywords: adherence, long-acting injectable, paliperidone palmitate, schizophrenia

Objective: Long-acting injections (LAIs) of paliperidone palmitate have been shown to improve medication adherence and relieve psychotic symptoms. However, the specific cost-utility analysis of these LAIs in schizophrenia in China remains unclear. Methods: A multi-state Markov model was constructed to simulate the economic outcomes of patients with schizophrenia in China who received paliperidone palmitate 1-month formulation (PP1M), paliperidone palmitate 3-month formulation (PP3M), and paliperidone extended-release (ER). A cost-utility analysis was conducted, mostly derived from published literature and clinical databases. All costs and utilities were discounted at a rate of 5% per annum. The primary outcome measure was the incremental cost-effectiveness ratios (ICERs). A series of sensitivity analyses were also applied. Results: After 20 years, compared to ER, using PP1M resulted in an increased discounted cost from $36,252.59 to $43,207.28. This increased cost was associated with a gain in quality-adjusted life years (QALYs) from 8.60 to 9.45. As a result, the ICER for PP1M was estimated to be $8,247.46/QALY, which was lower than the willingness-to-pay (WTP) threshold of $12,756.55/QALY. When using PP3M instead of ER, the incremental cost was $768.81 and the incremental utility was 0.88 QALYs, projecting an ICER of $873.13/QALY, which was also lower than the WTP threshold of $12,756.55/QALY. The univariate sensitivity analysis showed that the costs of PP1M, PP3M, and ER had the greatest impact on ICERs. The probability sensitivity analysis (PSA) revealed that when the WTP thresholds were $12,756.55/QALY, the probability of PP1M and PP3M being cost-effective was 59.2% and 66.0%, respectively. Conclusion: From the Chinese healthcare system perspective, PP3M and PP1M are both more cost-effective compared to ER, and PP3M has notable cost-utility advantages over PP1M. [ABSTRACT FROM AUTHOR]

Background/Aim. There is no available published data about the use of long-acting injectable paliperidone palmitate (PP) in schizophrenia patients in the Republic of Serbia. The aim of this study was to assess hospitalization rates before and after the switch to once-monthly long-acting injectable PP in schizophrenia patients, as well as their compliance with this drug. Methods. We conducted a retrospective cross-sectional study in which hospitalization rates were evaluated 12 months before and 12 months after the switch to once-monthly long-acting injectable PP in 113 schizophrenia patients. The age of the enrolled patients was between 18 and 66 years. Results. The average age of the enrolled patients was 38.36 ± 11.62 years. Among them, 77 (68.1%) were male, and 36 (31.9%) were female. Out of the total number of 113 patients treated with once-monthly injectable PP, 78 (69.03%) were on monotherapy, while 35 (30.97%) had one additional oral antipsychotic (risperidone, olanzapine, aripiprazole, or clozapine). Out of the total number of 113 patients, 68 (60.18%) were not hospitalized in the 12-month period before the switch to once-monthly long-acting injectable PP, while 45 (39.82%) were hospitalized in the same period. Given that 8 patients out of the total number of 113 were excluded from therapy due to an adverse event or their own decision in the period after the switch to PP, the analysis of the hospitalization rate after the switch to PP was performed for the remaining 105 patients, of which 9 (8.57%) were hospitalized in the period after the switch to PP, and 96 (91.43%) were not. Conclusion. Our results show high compliance in the treatment with once-monthly injectable PP and a positive impact of treatment with this drug on low hospitalization rate in a 12-month period in patients with schizophrenia. Considering the availability of this drug in the Republic of Serbia, these results encourage the use of once-monthly injectable PP as an important therapeutic option in schizophrenia patients. [ABSTRACT FROM AUTHOR]

[Display omitted] Long-acting injectable formulations represent a rapidly emerging category of drug delivery systems that offer several advantages compared to orally administered medicines. Rather than having to frequently swallow tablets, the medication is administered to the patient by intramuscular or subcutaneous injection of a nanoparticle suspension that forms a local depot from which the drug is steadily released over a period of several weeks or months. The benefits of this approach include improved medication compliance, reduced fluctuations of drug plasma level, or the suppression of gastrointestinal tract irritation. The mechanism of drug release from injectable depot systems is complex, and there is a lack of models that would enable quantitative parametrisation of the process. In this work, an experimental and computational study of drug release from a long-acting injectable depot system is reported. A population balance model of prodrug dissolution from a suspension with specific particle size distribution has been coupled with the kinetics of prodrug hydrolysis to its parent drug and validated using in vitro experimental data obtained from an accelerated reactive dissolution test. Using the developed model, it is possible to predict the sensitivity of drug release profiles to the initial concentration and particle size distribution of the prodrug suspension, and subsequently simulate various drug dosing scenarios. Parametric analysis of the system has identified the boundaries of reaction- and dissolution-limited drug release regimes, and the conditions for the existence of a quasi-steady state. This knowledge is crucial for the rational design of drug formulations in terms of particle size distribution, concentration and intended duration of drug release. [ABSTRACT FROM AUTHOR]

Objective: Limited evidence exists regarding real-world 3-monthly paliperidone palmitate (PP3M) treatment retention and associated factors. Methods: We conducted a retrospective, nationwide cohort study using the Taiwan National Health Insurance Research Database between October 2017 and December 2019. Adult patients with schizophrenia initiated on PP3M were enrolled. The primary outcomes were time to PP3M discontinuation, time to psychiatric hospitalization, and the proportions of patients receiving the next PP3M dose within 120 days among first-, second-, and third-dose completers. Key covariates included prior PP1M duration and adequate PP3M initiation. Results: The PP3M treatment retention rates were 79.7%, 66.3%, and 52.5% after 6, 12, and 24 months, respectively, with 86.4%, 90.6%, and 90.0% of respective first-, second-, and third-dose completers receiving the next PP3M dose. Adequate PP3M initiation and prior PP1M treatment duration ＞ 180 days were associated with favorable PP3M treatment retention. In multivariate analyses, PP1M durations of 180−360 days (adjusted relative risk [aRR], 1.76) or ＜ 180 days (aRR, 2.79) were associated with PP3M discontinuation at the second dose. Inadequate PP3M initiation was associated with discontinuation at the third dose (aRR, 2.18). Patients fully adherent to PP3M treatment in the first year had a higher probability of being free from psychiatric hospitalization (86.7% at 2 years), compared with those partially adherent or non-adherent to PP3M in the first year. Conclusion: Prior PP1M duration and adequate PP3M initiation are major factors affecting PP3M treatment retention. Higher PP3M treatment retention is associated with a lower risk of psychiatric hospitalization. [ABSTRACT FROM AUTHOR]

Backgrounds: Meta-analyses can be a powerful tool but need to calibrate potential unrepresentativeness of the included trials to a target population. Estimating target population average treatment effects (TATE) in meta-analyses is important to understand how treatments perform in well-defined target populations. This study estimated TATE of paliperidone palmitate in patients with schizophrenia using meta-analysis with individual patient trial data and target population data. Methods: We conducted a meta-analysis with data from four randomized clinical trials and target population data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study. Efficacy was measured using the Positive and Negative Syndrome Scale (PANSS). Weights to equate the trial participants and target population were calculated by comparing baseline characteristics between the trials and CATIE. A calibrated weighted meta-analysis with random effects was performed to estimate the TATE of paliperidone compared to placebo. Results: A total of 1,738 patients were included in the meta-analysis along with 1,458 patients in CATIE. After weighting, the covariate distributions of the trial participants and target population were similar. Compared to placebo, paliperidone palmitate was associated with a significant reduction of the PANSS total score under both unweighted (mean difference 9.07 [4.43, 13.71]) and calibrated weighted (mean difference 6.15 [2.22, 10.08]) meta-analysis. Conclusions: The effect of paliperidone palmitate compared with placebo is slightly smaller in the target population than that estimated directly from the unweighted meta-analysis. Representativeness of samples of trials included in a meta-analysis to a target population should be assessed and incorporated properly to obtain the most reliable evidence of treatment effects in target populations. [ABSTRACT FROM AUTHOR]

Background/Aim. There is no available published data about the use of long-acting injectable paliperidone palmitate (PP) in schizophrenia patients in the Republic of Serbia. The aim of this study was to assess hospitalization rates be-fore and after the switch to once-monthly long-acting injectable PP in schizophrenia patients, as well as their compliance with this drug. Methods. We conducted a retrospective cross-sectional study in which hospitalization rates were evaluated 12 months before and 12 months after the switch to once-monthly long-acting injectable PP in 113 schizophrenia patients. The age of the enrolled patients was between 18 and 66 years. Results. The average age of the enrolled patients was 38.36 ± 11.62 years. Among them, 77 (68.1%) were male, and 36 (31.9%) were female. Out of the total number of 113 patients treated with once-monthly injectable PP, 78 (69.03%) were on monotherapy, while 35 (30.97%) had one additional oral antipsychotic (risperidone, olanzapine, aripiprazole, or clozapine). Out of the total number of 113 patients, 68 (60.18%) were not hospitalized in the 12-month period before the switch to once-monthly long-acting injectable PP, while 45 (39.82%) were hospitalized in the same period. Given that 8 patients out of the total number of 113 were excluded from therapy due to an adverse event or their own decision in the period after the switch to PP, the analysis of the hospitalization rate after the switch to PP was performed for the remaining 105 patients, of which 9 (8.57%) were hospitalized in the period after the switch to PP, and 96 (91.43%) were not. Conclusion. Our results show high compliance in the treatment with once-monthly injectable PP and a positive impact of treatment with this drug on low hospitalization rate in a 12-month period in patients with schizophrenia. Considering the availability of this drug in the Republic of Serbia, these results encourage the use of once-monthly injectable PP as an important therapeutic option in schizophrenia patients.

Widespread anatomical alterations and abnormal functional connectivity have shown strong association with symptom severity in first-episode schizophrenia (FES) patients. Second-generation antipsychotic treatment might slow disease progression and possibly modify the cerebral plasticity in FES patients. However, whether a long-acting injectable antipsychotic (paliperidone palmitate [PP]), available in monthly and every-3-months formulations, is more effective than oral antipsychotics (OAP) in improving cerebral organization has been unclear. Therefore, in the current longitudinal study, we evaluated the differences in functional and microstructural changes of 68 FES patients in a randomized clinical trial of PP vs OAP. When compared to OAP treatment, PP treatment was more effective in decreasing abnormally high fronto-temporal and thalamo-temporal connectivity, as well as increasing fronto-sensorimotor and thalamo-insular connectivity. Consistent with previous studies, multiple white matter pathways showed larger changes in fractional anisotropy (FA) and mean diffusivity (MD) in response to PP compared with OAP treatment. These findings suggest that PP treatment might reduce regional abnormalities and improve cerebral connectivity networks compared with OAP treatment, and identified changes that may serve as reliable imaging biomarkers associated with medication treatment efficacy. [ABSTRACT FROM AUTHOR]

We investigated changes in brain intracortical myelin (ICM) volume in the frontal lobe after 9 months of treatment with paliperidone palmitate (PP) compared with 9 months 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, 9 months 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 9 months. However, a decrease of frontal ICM volume was observed among participants treated with OAPs. clinicaltrials.gov identifier NCT02431702. [ABSTRACT FROM AUTHOR]

Introduction: Long-acting injectable antipsychotics (LAIs) have proven to be effective in the maintenance treatment of patients suffering from schizophrenia, and their safety and tolerability profiles represent a key factor in their long-term use and choice in clinical practice. Paliperidone palmitate (PP) is the only secondgeneration LAI (SGA-LAI), available in both one- (PP1M) and 3-month (PP3M) formulations. However, real-world prospective studies on PP1M and PP3M are still few and mostly conducted on small samples. In this context, we aimed to better define the safety and tolerability profile of PP using real world pharmacovigilance data. Methods: We retrospectively analyzed the publicly available data regarding Individual Case Safety Reports (ICSRs), presenting PP1M and/or PP3M as suspected drugs, reported on EUDRAVigilance between 2011 and June 30th, 2022. ICSRs relative to at least one SGA-LAI other than PP, reported between 2003 and June 30th, 2022, were also examined as reference group. Data were evaluated with a descriptive analysis, and then, as disproportionality measures, crude reporting odds ratio (ROR) and 95% confidence interval (CI) were calculated. Results: A total of 8,152 ICSRs met the inclusion criteria, of those 77.7% (n = 6,332) presented as suspected drug PP1M, 21.2% (n = 1,731) PP3M, while 89 cases indicated both PP1M and PP3M. Significantly higher probabilities of reporting in PP-related reports were observed for the primary Standardized MedDRA Queries “Sexual Dysfunctions” (ROR = 1.45; 95% CI 1.23-1.70), “Haemodynamic oedema, effusions and fluid overload” (ROR = 1.42; 1.18-1.70), as well as “Fertility disorders” (ROR = 2.69; 1.51-4.80). Discussion: Our analysis indicates that the tolerability and safety profiles of PP are in line with what is known for the other SGA-LAIs. However, differences regarding endocrine system ADRs have been noticed. The results presented in this work do not discourage the prescription of SGA-LAI formulations but aim to enhance their safety. [ABSTRACT FROM AUTHOR]

We hypothesized that shifting from oral second-generation antipsychotics (SGA) to their long-acting injectable (LAI) counterpart would be beneficial for the psychopathological, cognitive, social, and general health domains in outpatients suffering from schizophrenia. We aimed to evaluate the prospective usefulness of SGA-LAI treatment by carrying out a head-to-head comparison of two different medications (i.e., aripiprazole monohydrate (Ari-LAI) and paliperidone palmitate 1 and 3 month (PP1M, PP3M)) in a real-world setting, assessing the effectiveness and tolerability of Ari-LAI and PP1M/PP3M over a 15 month follow-up. A total of 69 consecutive individuals affected by schizophrenia were screened for eligibility. Finally, 46 outpatients (29 treated with Ari-LAI, 13 with PP1M, and four with PP3M) were evaluated through clinical, functional, and neuropsychological assessment administrated at baseline and after 3-, 12-, and 15-month follow-up periods. Moreover, periodic general medical evaluations were carried out. We estimated an overall improvement over time on the explored outcomes, without differences with respect to the type of LAI investigated, and with a global 16.4% dropout rate. Our findings suggest that switching from oral SGA to SGA-LAIs represents a valid and effective treatment strategy, with significant improvements on psychopathological, cognitive, social, and clinical variables for patients suffering from schizophrenia, regardless of the type of molecule chosen. [ABSTRACT FROM AUTHOR]

Modeling dose-response relationships of drugs is essential to understanding their safety effects on patients under realistic circumstances. While intention-to-treat analyses of clinical trials provide the effect of assignment to a particular drug and dose, they do not capture observed exposure after factoring in nonadherence and dropout. We develop a Bayesian method to flexibly model the dose-response relationships of binary outcomes with continuous treatment, permitting multiple evidence sources, treatment effect heterogeneity, and nonlinear dose-response curves. In an application, we examine the risk of excessive weight gain for patients with schizophrenia treated with the second-generation antipsychotics paliperidone, risperidone, or olanzapine in 14 clinical trials. We define exposure as total cumulative dose (daily dose × duration) and convert to units equivalent to 100 mg of olanzapine (OLZ doses). Averaging over the sample population of 5891 subjects, the median dose ranged from 0 (placebo randomized participants) to 6.4 OLZ doses (paliperidone randomized participants). We found paliperidone to be least likely to cause excessive weight gain across a range of doses. Compared with 0 OLZ doses, at 5.0 OLZ doses, olanzapine subjects had a 15.6% (95% credible interval: 6.7, 27.1) excess risk of weight gain; corresponding estimates for paliperidone and risperidone were 3.2% (1.5, 5.2) and 14.9% (0.0, 38.7), respectively. Moreover, compared with nonblack participants, black participants had a 6.8% (1.0, 12.4) greater risk of excessive weight gain at 10.0 OLZ doses of paliperidone. Nevertheless, our findings suggest that paliperidone is safer in terms of weight gain risk than risperidone or olanzapine for all participants at low to moderate cumulative OLZ doses.

Ibrahim Turkoz,1 Mehmet Daskiran,1 H Lynn Starr,2 Dean Najarian,2 Oliver Lopena,2 Camilo Obando,2 Alexander Keenan,3 Carmela Benson,3 Srihari Gopal4 1Statistics & Decision Sciences, Janssen Research and Development, LLC, Titusville, NJ, USA; 2Neuroscience, Janssen Scientific Affairs, LLC, Titusville, NJ, USA; 3Real World Value & Evidence, Neuroscience, Janssen Scientific Affairs, LLC, Titusville, NJ, USA; 4Schizophrenia/Neuroscience Therapeutic Area, Janssen Research and Development, LLC, Titusville, NJ, USACorrespondence: Ibrahim Turkoz, Statistics & Decision Sciences, Janssen Research & Development, 1125 Trenton-Harbourton Road, Titusville, NJ, 08560, USA, Tel +1 609-730-7719, Fax +1 609-730-3232, Email ITukoz@its.jnj.comPurpose: This retrospective cohort study evaluated real-world data on relapses in adult patients with schizophrenia who transitioned to long-acting injectable paliperidone palmitate once-every-3-months (PP3M) following treatment with once-monthly paliperidone palmitate (PP1M).Patients and Methods: Data derived from the IBM® MarketScan® Multi-State Medicaid Database were analyzed. Adults aged ≥ 18 years with ≥ 1 schizophrenia diagnosis claim and ≥ 12 months of continuous medical and prescription enrollment before and/or at index date of PP3M were eligible for inclusion. Patients were matched on propensity score to 2 PP3M cohorts: (1) adequately treated (AT), defined as patients treated with PP1M for ≥ 4 months, with the last 2 doses the same and a PP3M initiation dose meeting the corresponding PP1M-to-PP3M dose conversion, or (2) not adequately treated (NAT), defined as patients who received ≤ 2 or no PP1M doses. Relapse rates and time to relapse distributions based on the first occurrence of a qualifying event during the 2-year follow-up period were compared between PP3M cohorts using Kaplan–Meier survival curves and log rank test statistics. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards models. Two sensitivity analyses using different matched populations were performed to assess the robustness of the primary findings.Results: Propensity score matching yielded a sample of 1314 patients (657 per group). Most patients were male (68.9%) and aged 25– 64 years (90.1%). The relapse rate was significantly lower in the AT (18.4%) versus NAT cohort (26.8%), P = 0.0002. Risk of relapse decreased by 35% for AT versus NAT (HR: 0.65 [95% CI: 0.51– 0.81]). Relapse reductions favored the AT cohort in both sensitivity analyses (HR: 0.67 [95% CI: 0.54– 0.83] and HR: 0.74 [95% CI: 0.56– 0.97]).Conclusion: In this analysis of Medicaid claims data, patients adequately treated with PP1M before transitioning to PP3M demonstrated significantly lower relapse rates and delayed time to relapse.Keywords: paliperidone palmitate, schizophrenia, real-world, relapse, long-acting injectable antipsychotic