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Introduction Although delusional jealousy accounts for merely 10% of delusional disorders, it is associated to risk of serious violence and suicide. With this clinical case, we intend to explore the difficulties in the pharmacological approach of delusional jealousy disorder and to summarise the most recent findings in the treatment of this condition. Methods Case report. Case presentation A 76-year-old man involuntarily admitted to a psychiatric ward due to threats of physical aggression to his wife in the context of irreducible ideas of her infidelity. Initially, we observed an improvement of symptomatology with risperidone and its long-acting injectable formulation, but the emergence of hypotensive side effects required the off-label use of paliperidone palmitate 50 mg/ml. Conclusions Few studies, mainly case reports, look at the specific treatment of delusional jealousy. Given the negative consequences for patients and for their spouses, better scientific evidence to treat this condition is needed.

A systematic review and random-effects model network meta-analysis was conducted to compare the efficacy, acceptability, tolerability, and safety of pharmacological interventions for adults with acute bipolar mania. We searched PubMed, the Cochrane Library, and Embase databases for eligible studies published before March 14, 2021. Randomized controlled trials (RCTs) of oral medication monotherapy lasting ≥10 days in adults with mania were included, and studies that allowed the use of antipsychotics as a rescue medication during a trial were excluded. The primary outcomes were response to treatment (efficacy) and all-cause discontinuation (acceptability). The secondary outcomes were the improvement of mania symptoms and discontinuation due to inefficacy. Of the 79 eligible RCTs, 72 double-blind RCTs of 23 drugs and a placebo were included in the meta-analysis (mean study duration = 3.96 ± 2.39 weeks, n = 16442, mean age = 39.55 years, with 50.93% males). Compared with the placebo, aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, lithium, olanzapine, paliperidone, quetiapine, risperidone, tamoxifen, valproate, and ziprasidone outperformed response to treatment (N = 56, n = 14503); aripiprazole, olanzapine, quetiapine, and risperidone had lower all-cause discontinuation; however, topiramate had higher all-cause discontinuation (N = 70, n = 16324). Compared with the placebo, aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, lithium, olanzapine, paliperidone, quetiapine, risperidone, tamoxifen, valproate, and ziprasidone outperformed the improvement of mania symptoms (N = 61, n = 15466), and aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, lithium, olanzapine, paliperidone, quetiapine, risperidone, valproate, and ziprasidone had lower discontinuation due to inefficacy (N = 50, n = 14284). In conclusions, these antipsychotics, carbamazepine, lithium, tamoxifen, and valproate were effective for acute mania. However, only aripiprazole, olanzapine, quetiapine, and risperidone had better acceptability than the placebo.

Purpose Compared to once-monthly paliperidone palmitate (PP1M), once-every-3-months paliperidone palmitate (PP3M) reportedly increases treatment adherence. The objective of this study was to compare treatment patterns, utilization, and costs among Veterans Health Administration (VHA) patients with schizophrenia who transitioned to PP3M versus those remaining on PP1M. Patients and methods Adult VHA patients with ≥2 health care encounters (inpatient or outpatient) that included a schizophrenia diagnosis who initiated PP1M between January 1, 2015, and March 31, 2018 (identification period) were included in this exploratory retrospective cohort study. Propensity scores were used to match cases (PP1M users who transitioned to PP3M during the identification period) with controls (any patient initiating PP1M during the identification period). Data were assessed until death, health plan disenrollment, or study end. Outcomes were compared using chi-square and t-tests. Results A total of 257 eligible PP3M and 2973 eligible PP1M patients were identified among adult VHA patients; mean ages were 53.1 and 53.7 years, respectively. After propensity score matching, the PP3M and PP1M cohorts each held 111 patients. Comorbidities of patients treated with PP3M versus PP1M, respectively, included anxiety (12.5% vs 20%; standardized difference [STD] = 20.6), tobacco use (28.4% vs 43.2%; STD = 31.2), depressive disorder (26.5% vs 36.2%; STD = 21.1), and substance abuse (37.4% vs 44.2%; STD = 13.9). For the PP3M cohort, adherence (proportion of days covered ≥80%) to any antipsychotic agent was higher (78.4% vs 57.7%, P = 0.0009), and all-cause inpatient lengths of stay (LOS) were shorter (3.0 vs 8.3 days, P = 0.0354). Increased all-cause pharmacy costs with PP3M were offset by reduced all-cause medical costs, resulting in overall health care cost-neutrality. Conclusion Relative to those remaining on PP1M, VHA patients with schizophrenia who transitioned to PP3M experienced improved antipsychotic medication adherence and significantly shorter all-cause inpatient LOS; costs remained neutral.

International schizophrenia guidelines endorse seeking the patient's preference for guiding antipsychotic therapy. There exists a small niche of patients who prefer, or are required to use, long-acting injectable antipsychotic medications due to the adherence benefit. However, they may not be able to achieve adequate symptom reduction prior to experiencing treatment-limiting adverse effects from a single agent. Here, we present a patient case prescribed concurrent long-acting injectable antipsychotic therapy with paliperidone palmitate and aripiprazole monohydrate due to patient preference in the setting of a history of nonadherence to oral medications, treatment-limiting adverse effects to long-acting injectable paliperidone, and failure to achieve adequate symptom reduction with long-acting injectable aripiprazole monotherapy.

Background Schizophrenia and bipolar disorder are severe mental illnesses which are highly prevalent worldwide. Risperidone and Paliperidone are treatments for either illnesses, but their efficacy compared to other antipsychotics and growing reports of hormonal imbalances continue to raise concerns. As existing evidence on both antipsychotics are solely based on aggregate data, we aimed to assess the benefits and harms of Risperidone and Paliperidone in the treatment of patients with schizophrenia or bipolar disorder, using individual participant data (IPD), clinical study reports (CSRs) and publicly available sources (journal publications and trial registries). Methods We searched MEDLINE, Central, EMBASE and PsycINFO until December 2020 for randomised placebo-controlled trials of Risperidone, Paliperidone or Paliperidone palmitate in patients with schizophrenia or bipolar disorder. We obtained IPD and CSRs from the Yale University Open Data Access project. The primary outcome Positive and Negative Syndrome Scale (PANSS) score was analysed using one-stage IPD meta-analysis. Random-effect meta-analysis of harm outcomes involved methods for coping with rare events. Effect-sizes were compared across all available data sources using the ratio of means or relative risk. We registered our review on PROSPERO, CRD42019140556. Results Of the 35 studies, IPD meta-analysis involving 22 (63%) studies showed a significant clinical reduction in the PANSS in patients receiving Risperidone (mean difference − 5.83, 95% CI − 10.79 to − 0.87, I2 = 8.5%, n = 4 studies, 1131 participants), Paliperidone (− 6.01, 95% CI − 8.7 to − 3.32, I2 = 4.3%, n = 13, 3821) and Paliperidone palmitate (− 7.89, 95% CI − 12.1 to − 3.69, I2 = 2.9%, n = 5, 2209). CSRs reported nearly two times more adverse events (4434 vs. 2296 publication, relative difference (RD) = 1.93, 95% CI 1.86 to 2.00) and almost 8 times more serious adverse events (650 vs. 82; RD = 7.93, 95% CI 6.32 to 9.95) than the journal publications. Meta-analyses of individual harms from CSRs revealed a significant increased risk among several outcomes including extrapyramidal disorder, tardive dyskinesia and increased weight. But the ratio of relative risk between the different data sources was not significant. Three treatment-related gynecomastia events occurred, and these were considered mild to moderate in severity. Conclusion IPD meta-analysis conclude that Risperidone and Paliperidone antipsychotics had a small beneficial effect on reducing PANSS score over 9 weeks, which is more conservative than estimates from reviews based on journal publications. CSRs also contained significantly more data on harms that were unavailable in journal publications or trial registries. Sharing of IPD and CSRs are necessary when performing meta-analysis on the efficacy and safety of antipsychotics.

Purpose of Review: This is a comprehensive review of the literature regarding the use of paliperidone in the treatment of schizophrenia and schizoaffective disorder. It covers the background and presentation of schizophrenia and schizoaffective disorder, as well as the mechanism of action and drug information for paliperidone. It covers the existing evidence of the use of paliperidone for the treatment of schizophrenia and schizoaffective disorder. Recent Findings: Schizophrenia and schizoaffective disorder lead to significant cognitive impairment. It is thought that dopamine dysregulation is the culprit for the positive symptoms of schizophrenia and schizoaffective disorder. Similar to other second-generation antipsychotics, paliperidone has affinity for dopamine D2 and serotonin 5-HT2A receptors. Paliperidone was granted approval in the United States in 2006 to be used in the treatment of schizophrenia and in 2009 for schizoaffective disorder. Summary: Schizophrenia and schizoaffective disorder have a large impact on cognitive impairment, positive symptoms and negative symptoms. Patients with either of these mental illnesses suffer from impairments in everyday life. Paliperidone has been shown to reduce symptoms of schizophrenia and schizoaffective disorder.

Here, we present the case of a patient who initiated risperidone and developed persistent tachycardia, which was exacerbated by subsequent administration of paliperidone palmitate despite treatment with propranolol. This patient’s experience emphasizes the need for psychiatrists to regularly monitor vital signs after risperidone/paliperidone initiation, dosage increase, or overdose to identify and appropriately manage this potentially harmful side effect. Increasing clinician awareness of this rare side effect will help protect patients with serious mental illness who regularly rely upon these medications, particularly in their long-acting injectable formulations.

Aim Several reports have shown that risperidone increases prolactin concentrations, while aripiprazole decreases prolactin concentrations. The frequency of abnormal prolactin concentrations in patients with schizophrenia receiving these drugs is still unknown. Furthermore, although hyperprolactinemia leads to sexual dysfunction, the relationship between hyperprolactinemia and testosterone, which may be directly related to male sexual function, is not well understood. Methods The subjects were 94 male schizophrenia outpatients receiving risperidone or paliperidone (risperidone group) and 83 male schizophrenia outpatients receiving aripiprazole. We measured the serum prolactin and total and free testosterone concentrations. We compared the prolactin and testosterone levels in patients receiving risperidone or paliperidone and patients receiving aripiprazole. Results The average serum prolactin concentration was 27.5 ± 13.1 ng/mL for the risperidone group and 3.9 ± 3.5 ng/mL for the aripiprazole group, and the concentrations were significantly different (P, There were very common hyperprolactinemia and hypoprolactinemia in the risperidone group and aripiprazole group, respectively. Free testosterone concentrations were associated with elevated prolactin levels in patients receiving risperidone or paliperidone.

**Background:** Nonadherence to medication is prevalent in persons diagnosed with schizophrenia, thus increasing the likelihood of relapse, poor health outcomes, hospitalization, high treatment costs, and high rates of both violent and non-violent offenses. **Objective:** To assess the association between long-acting injectable (LAI) antipsychotic use and criminal justice system encounters in patients with schizophrenia or schizoaffective disorder. **Methods:** This retrospective follow-up study was conducted among patients aged ≥18 years treated for schizophrenia or schizoaffective disorder at a community mental health center in Akron, Ohio, between January 1, 2010, and June 15, 2016. The incidence of criminal justice system encounters at 6 months, 1 year, and 2 years pre- versus post-LAI antipsychotic initiation was assessed. A subanalysis was conducted for individuals with a history of prior arrest. **Results:** Overall, the risk ratio (RR) of having an encounter with the criminal justice system was significantly lower for patients treated with LAI antipsychotics 1 year after initiation of treatment compared with a similar time period prior to initiation (RR \[95% confidence interval (CI)\]: 0.74 \[0.59–0.93\]; *P*

OBJECTIVE This study compared relapse prevention and acceptability of long-acting injectable (LAI) antipsychotics in the maintenance treatment of adults with nonaffective psychoses. METHODS The authors searched MEDLINE, Embase, PsycINFO, CINAHL, CENTRAL, and online registers for randomized controlled trials published until June 2020. Relative risks and standardized mean differences were pooled using random-effects pairwise and network meta-analysis. The primary outcomes were relapse rate and all-cause discontinuation ("acceptability"). The quality of included studies was rated with the Cochrane Risk of Bias tool, and the certainty of pooled estimates was measured with GRADE (Grading of Recommendations Assessment, Development, and Evaluation). RESULTS Of 86 eligible trials, 78 (N=11,505) were included in the meta-analysis. Regarding relapse prevention, most of the 12 LAIs included outperformed placebo. The largest point estimates and best rankings of LAIs compared with placebo were found for paliperidone (3-month formulation) and aripiprazole. Moderate to high GRADE certainty for superior relapse prevention compared with placebo was also found for (in descending ranking order) risperidone, pipothiazine, olanzapine, and paliperidone (1-month formulation). In head-to-head comparisons of LAIs, only haloperidol was inferior to aripiprazole, fluphenazine, and paliperidone. For acceptability, most LAIs outperformed placebo, with moderate to high GRADE certainty for (in descending ranking order) zuclopenthixol, aripiprazole, paliperidone (3-month formulation), olanzapine, flupenthixol, fluphenazine, and paliperidone (1-month formulation). In head-to-head comparisons, only LAI aripiprazole had superior acceptability to other LAIs (bromperidol, fluphenazine, paliperidone [1-month formulation], pipothiazine, and risperidone). CONCLUSIONS LAI formulations of paliperidone (3-month formulation), aripiprazole, olanzapine, and paliperidone (1-month formulation) showed the highest effect sizes and certainty of evidence for both relapse prevention and acceptability. Results from this network meta-analysis should inform frontline clinicians and guidelines.

Background Long-acting injectable antipsychotics (LAIs) may be a suitable therapeutic option for those patients in earlier stages of psychosis to avoid relapses and disease progression. Despite that, there is a lack of evidence in the literature regarding the use of LAIs in this profile of patients. Methods This is a retrospective cohort analysis to assess the efficacy, tolerability, and pattern of use of palmitate paliperidone long-acting injectable (PPLAI) formulations (1- and 3-month doses) compared to oral paliperidone/risperidone in patients with a nonaffective first episode of psychosis (FEP) over 12 months of follow-up. Relevant sociodemographic and clinical information were assessed, as well as main clinical scales: Positive and Negative Syndrome Scale, Personal and Social Performance Scale, and Clinical Global Impression Scale Improvement and Severity measures. Results The study included 48 patients, 16 per arm, who were aged 20–50 years and had an FEP. Significant improvements were registered for all treatment groups. Despite that, patients receiving PPLAI 1- and 3-month formulations obtained greater improvements than those in the oral group in the main domains assessed (P < .001). We found no statistically significant differences in hospitalizations between groups. Side effects were presented in 24% of patients. A trend towards reducing antipsychotic doses was observed in 43.8% of patients to achieve the minimum effective dose and avoid the occurrence of side effects. Conclusions To our knowledge, this is the first study assessing the use of palmitate paliperidone long-acting formulations versus oral risperidone or paliperidone in FEP. Treatment with PPLAI formulations seems to be an effective therapeutic choice at earlier stages of the disease.

Background: Persistence and adherence to treatment are considered efficacy outcomes in psychiatric disorders. One of the best ways to improve these values in patients with psychiatric disorders is to prefer Long-Acting Injectable (LAI) drugs to oral AP. Objective: The objective of this study is to evaluate adherence, persistence and switching of antipsychotics and compare in real life long-acting with oral formulations. Materials and methods: This pharmacological, observational, retrospective and non-interventional study involved all patients of the ASL of Pescara treated in the front-line with AP in the period between January 2011 and February 2019. Adherence was measured using the ratio between the received daily dose and prescribed daily dose. Persistence to treatment with antipsychotics was calculated as the daily difference between the beginning and end of treatment. Results: We examined 840 patients treated with aripiprazole, 130 patients treated with paliperidone and 925 patients treated with risperidone. Adherence was significantly better in long-acting formulations with values of 0.89 (aripiprazole) and 0.82 (paliperidone and risperidone) than in oral formulations with values of 0.78, 0.70 and 0.58, respectively (p> 0.999, p= 0.0091, p=< 0.0001). Threeyear persistence curves relating to three study drugs did not show a statistically significant difference (p = 0.3314). Persistence curves based on formulation have not shown a statistically significant difference (p= 0, 4658, p=0, 4794, p=0, 2199 for ariprazolo, paliperidone and risperidone, respectively). 7% of patients were treated with aripiprazole, 12% of patients were treated with risperidone and 28% of patients were treated with paliperidone switched therapy. Conclusions: In all the drugs of present study, adherence values were better in LAI than in OA, whereas no statistically significant difference was found in persistence values.

Martin Hýža,1,2 Petr Šilhán,1,2 Eva Češková,1,2 Tomáš Skřont,1 Ivana Kacířová,3,4 Romana Uřinovská,3 Milan Grundmann4 1Department of Psychiatry, University Hospital Ostrava, Ostrava, Czech Republic; 2Department of Clinical Neurosciences, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic; 3Department of Clinical Pharmacology, Institute of Laboratory Diagnostics, University Hospital Ostrava, Ostrava, Czech Republic; 4Department of Clinical Pharmacology, Faculty of Medicine, University of Ostrava, Ostrava, Czech RepublicCorrespondence: Petr ŠilhánDepartment of Psychiatry, University Hospital Ostrava, 17. Listopadu 1790, Ostrava, 708 52, Czech RepublicTel +420 59 737 3145Fax +420 59 737 3314Email petr.silhan@fno.czPurpose: Antipsychotic efficacy in schizophrenia depends on its availability in the body. Although therapeutic outcomes remain still far from satisfactory, therapeutic drug monitoring is not a common part of clinical practice during treatment with long-acting injectable antipsychotics (LAI AP). The real effectiveness of LAI AP is thus uncertain.Patients and Methods: We made a retrospective evaluation of plasma levels of LAI AP. Collection of blood samples was performed just before the drug application and one week later. Forty patients with a stabilized clinical condition and steady-state plasma levels were included.Results: In the observed cohort of patients, flupentixol decanoate (n = 23) was the most often used drug, followed by fluphenazine decanoate (n = 7), haloperidol decanoate (n = 5), paliperidone palmitate (n = 3), and risperidone microspheres (n = 2). Just 5 of 40 patients were treated with a monotherapy. In the period before the application, 60% of the patients did not reach the therapeutic reference range (TRR) and 20% of the patients had an undetectable plasma level. At the time of collection of the second blood samples performed after 7 days, 24% of the patients were under the TRR.Conclusion: We have found a surprisingly high incidence of plasma levels under the TRR in patients treated with LAI AP. Notwithstanding individual variability in pharmacokinetics, it seems that LAI AP may be underdosed in usual clinical practice.Keywords: therapeutic drug monitoring, antipsychotics, psychotic disorders, schizophrenia

Current guidelines for the treatment of patients with schizophrenia advocate that patients receive treatment with a long-acting injectable (LAI) antipsychotic medication if they prefer such treatment or if they have a history of poor or uncertain adherence. Available LAI formulations in the United States include first-generation antipsychotics (fluphenazine decanoate and haloperidol decanoate), risperidone/paliperidone containing products (risperidone microspheres, paliperidone palmitate, and risperidone subcutaneous), aripiprazole containing products (aripiprazole monohydrate and aripiprazole lauroxil), and olanzapine pamoate. LAI antipsychotics can address the guesswork about adherence status and patients may prefer them if they are offered this as a choice, including individuals early in their disease course. Additional approved indications in the United States for LAI antipsychotics include bipolar I disorder maintenance treatment for risperidone microspheres and aripiprazole monohydrate, and schizoaffective disorder for paliperidone palmitate once monthly. Differences and similarities among the different products are discussed, including guidance regarding optimal treatment selection. Tips are provided to enhance effective patient communication to maximize the likelihood of acceptance of this treatment modality.

Introduction Previous evidence demonstrated that patients with schizophrenia consumed substantial healthcare resources in an integrated healthcare system. This study evaluated the impact of initiating once-monthly paliperidone palmitate (PP1M) on healthcare resource utilization (HRU) among patients with schizophrenia treated in a US integrated healthcare system. Methods This retrospective study used electronic medical records from Atrium Health. Adults with at least two diagnoses of schizophrenia who received an initial PP1M dose between September 2009 and April 2019 (the corresponding date defined the index date) and at least one subsequent dose within 90 days were included. Additionally, patients were required to have received active care (at least one healthcare visit every 6 months) during 12-month pre- and post-index periods and at least one oral antipsychotic prescription during the 12-month pre-index period. Inpatient, emergency room (ER), and outpatient visits were compared over 12-month pre- versus post-index periods within the same cohort using McNemar’s and Wilcoxon signed rank tests. Findings were reported for all patients and separately in patients with at least one schizophrenia relapse (schizophrenia-related inpatient or ER visit) during the 12-month pre-index period. Results The study cohort included 210 patients (mean age 34.2 years, 69.5% male, 39.1% had Medicaid). From the 12-month pre- to post-index period, the proportion of patients with visits and mean number of visits reduced for all-cause inpatient (67.6% to 22.4%, 1.2 to 0.4), 30-day readmission (12.4% to 2.4%, 0.2 to 0.1), and ER (68.6% to 45.7%, 2.3 to 1.2) visits, whereas the mean number of outpatient visits increased (8.7 to 11.6) (all P

Patients with schizophrenia often struggle with medication adherence and may benefit from the use of a long-acting injectable antipsychotic, including once-monthly paliperidone palmitate (PP1M), which was previously demonstrated to improve outcomes compared with oral antipsychotics. This study assessed the impact of initiating PP1M therapy on medication adherence, health care resource use (HRU), and costs among Medicaid beneficiaries with schizophrenia and a prior schizophrenia relapse.A 6-state Medicaid database (from quarter 1 of 2009 to quarter 1 of 2018) was used to identify adults with ≥2 schizophrenia diagnoses who started PP1M therapy on or after January 1, 2010. The index date was the first PP1M claim. Patients had ≥12 months of continuous Medicaid enrollment before and after the index date, ≥1 oral antipsychotic claim in the 12 months before the index date, and ≥1 relapse (proxied as a schizophrenia-related inpatient admission or emergency department [ED] visit) during the 12 months before the index date. Generalized estimating equations were used to compare adherence to antipsychotics (proportion of days covered ≥80%), HRU, and costs (reported in 2018 US dollars) in the 12 months after versus before the index date. Sensitivity analyses were conducted (1) accounting for the minimum and cumulative price inflation Medicaid rebates for pharmacy costs of branded psychiatric medications, (2) among patients with ≥2, ≥3, and ≥4 prior schizophrenia-related inpatient admissions or ED visits, (3) among patients not adherent to antipsychotic treatment before the index date, and (4) among patients switching to PP1M directly from oral risperidone or paliperidone.A total of 1725 patients met the study inclusion criteria (mean age, 39.5 years; 43% female). After versus before the index date, patients were 93% more likely to be adherent to antipsychotic treatment (P 0.01). The likelihood of inpatient admissions and ED visits decreased by 89% and 49% (all P 0.01) after initiating PP1M therapy. The number of inpatient days decreased by 31% (P 0.01) and the number of ED visits by 16% (P = 0.03). Pharmacy costs increased by $514 per-patient-per-month (PPPM), whereas medical costs, driven by inpatient costs, decreased by $391 PPPM (all P 0.01). Sensitivity analyses yielded similar trends. Notably, total health care cost savings of $231 PPPM were observed after accounting for the cumulative Medicaid rebate for costs of branded psychiatric medications (P 0.01).In Medicaid beneficiaries with relapsed schizophrenia, transitioning from oral antipsychotics to PP1M was associated with improved adherence to antipsychotics and decreased use of inpatient and ED services. Increased pharmacy costs after the initiation of PP1M were offset by decreased medical costs. After applying the cumulative Medicaid rebate, including the price inflation rebate for costs of branded psychiatric medications, initiation of PP1M therapy resulted in statistically significant health care cost savings.

Paliperidone palmitate is an antipsychotic medication available as long-acting injectable (LAI) formulations. The aim of this study was to investigate the effect of age and gender on paliperidone exposure after administration of LAI formulations. Data on serum concentrations of paliperidone from patients using LAI during were included retrospectively from a therapeutic drug monitoring (TDM) service. Information about dose was obtained from the requisition forms. As a measure of exposure, daily dose-adjusted serum concentration (C/D ratio) was used. Based on initial analysis of C/D ratios versus age, a breaking point close to 50 years was observed, thus deciding the grouping of patients as older (≥50 years) or younger (15–49 years). Linear mixed model analyses, allowing multiple measurements per patients, were used. In total, 1223 patients were included, whereof 1158 patients used paliperidone LAI in once-monthly intervals. In these patients (27.9% older), older patients had significantly higher paliperidone C/D ratio than younger patients (+20%, p 50 years) are likely exposed to high concentration and cautious dosing in this subgroup is required.

To compare adherence, rates of subsequent schizophrenia-related relapses, healthcare resource utilization, and healthcare costs among Medicaid beneficiaries with schizophrenia who initiated once-monthly paliperidone palmitate (PP1M) versus a new oral atypical antipsychotic (OAA) following a recent schizophrenia-related relapse.Six-state Medicaid data (01/2009-03/2018) were used to identify adults with schizophrenia initiated on PP1M or OAA (index date) within 30 days following a schizophrenia-related relapse (defined as a schizophrenia-related inpatient or emergency room visit). Patients were required to have 12 months of continuous eligibility before (baseline) and after (observation) the index date. Differences in baseline characteristics between PP1M and OAA patients were accounted for using 1:3 matching.After matching, characteristics were well-balanced between PP1M (Among patients with a recent schizophrenia-related relapse, PP1M was associated with a lower risk of subsequent relapse while remaining a cost neutral therapeutic option compared to OAAs.

Antipsychotics with reduced dosing frequency may improve adherence and clinical outcomes for patients with schizophrenia. This study compared treatment patterns, healthcare resource utilization (HRU), and costs between Medicaid beneficiaries with schizophrenia treated with once-monthly paliperidone palmitate (PP1M) and those who transitioned to once-every-three-months paliperidone palmitate (PP3M).Adults with schizophrenia were identified in a four-state Medicaid database (18 May 2014 to 31 March 2019). The index date was the first PP3M claim (PP3M cohort), or a random PP1M claim (PP1M cohort), following ≥4 months of continuous PP1M treatment among patients with ≥12 months of continuous Medicaid enrollment pre- and post-index. Adherence (proportion of days covered by the index treatment ≥80%), persistence (no gap90/30 days in the PP3M/PP1M supply), HRU, and costs were compared during the 12-month post-index period between cohorts matched 1:1.Among 2374 patients identified, 374 remained in each cohort after matching (mean age 42 years; 30.5% female). Compared to the PP1M cohort, the PP3M cohort was 2.39 times more likely to be adherent (Medicaid beneficiaries who transitioned to PP3M had higher adherence and persistence, and a reduced likelihood of hospitalization relative to those who continued treatment with PP1M. The results suggest potential clinical value to transitioning eligible patients to PP3M.

Introduction Dosing recommendations for paliperidone long-acting injectable antipsychotic (LAIA) do not include oral antipsychotic (OAP) overlap; however, OAPs are often given concurrently despite limited evidence describing both the risks and benefits of this practice. Methods A retrospective chart review was conducted in patients initiated on paliperidone palmitate (PP) during a psychiatric hospitalization to compare patients who received OAP overlap versus those who did not. The primary outcome is the proportion of patients who receive prescription claims for benztropine, a medication commonly prescribed for extrapyramidal symptoms, at the time of LAIA discontinuation and 6 months postdischarge. Secondary outcomes include prescription claims for beta blockers and diphenhydramine, number of psychiatric emergency visits and hospitalizations, length of stay of the index hospitalization, frequency of LAIA discontinuation and the time to LAIA discontinuation. Results There is a significant difference in the proportion of benztropine prescription claims in the OAP overlap group versus the no-overlap group at the time of LAIA discontinuation (30% vs 0%, P = .046) but not at 6 months postdischarge. There are also significant differences in the number of psychiatric emergency visits (0.7 vs 0.1, P = .02) and psychiatric hospitalizations (0.6 vs 0.1, P = .029) at the time of LAIA discontinuation. No other differences are observed in defined secondary outcomes. Discussion Patients who receive OAP overlap while receiving PP receive more benztropine and have more psychiatric emergency visits and hospitalizations than those treated without OAP. Larger studies with better control for confounding variables are needed to confirm these results.

This article discusses case reports of treatment with paliperidone palmitate in comparison with data from recent publications. Second-generation long-acting injectable antipsychotics have been shown to provide better control of psychiatric manifestations, reduce the severity of negative symptoms, improve social functioning and quality of life of patients and relatives, and reduce the burden of disease for both the healthcare system and the caregivers. The case reports presented in this article demonstrate better quality of remission in schizophrenia patients treated with one- monthly and three-monthly paliperidone palmitate formulations, due to higher effi in preventing relapses, better safety and good tolerability regardless of patient age.

Introduction: At 11:20 on 26 May 2018, a physician from Lianyungang No. 1 People’s Hospital, China, reported that six family members were being treated in the hospital with symptoms from an unknown cause. Methods: A case series for a food poisoning investigation and an environmental survey were conducted. The patients and their relatives were interviewed in person with a questionnaire contained on a digital tablet, and an investigation of the patients’ home was conducted in the presence of police officers. Probable case and confirmed case were defined to serve as a basis for identifying additional cases. Confirmed cases were defined as those probable cases in which blood, stool or vomitus specimens tested positive for paliperidone palmitate and/or its metabolites. A descriptive analysis was performed. Follow-up by telephone was conducted four months later. Results: There were six probable cases. The median age was 35 years (range: 5–76 years). The attack rate was 100% (n = 6/6) of persons who consumed a family dinner, and the hospitalization rate was also 100% (n = 6/6). The median period between exposure and symptom onset was two hours. The main symptoms included vomiting, nausea, drowsiness, dizziness and severe abdominal pain for adults, and vomiting and severe lethargy for children. An 8-year-old girl further showed changes in the ST segment of her electrocardiogram, and a 5-year-old boy showed QT prolongation. The poisoning substance was suspected to be paliperidone palmitate based on the patients’ symptoms and epidemiological findings. Discussion: We investigated the household food poisoning outbreak through epidemiological analysis and an environmental investigation and determined that it was caused by paliperidone palmitate. The source of the paliperidone palmitate was found to be aluminium containers, taken home by the eldest son who worked at a pharmaceutical company. The containers were sent to a drug disposal centre, and the pharmaceutical company was required to enhance the regulation on the pharmaceutical waste materials to prevent drug poisoning events. By the end of September 2018, the six patients recovered and were released from the hospital, and they did not show any clinical sequelae in four follow-up visits.

Als Rhabdomyolyse wird der Zerfall der quergestreiften Muskulatur bezeichnet. Die klinische Symptomatik variiert stark und ist meist mit Myalgien und Anstieg der Creatinkinase verbunden. Als Ursachen kommen neben mechanischen Auslosern, medikamentos-toxischen Ursachen auch diverse pradisponierende Faktoren wie Myopathien in Frage. In dieser Kasuistik wird eine zufallig entdeckte Rhabdomyolyse nach Verabreichung von Paliperidonpalmitat als Depotinjektion nach gut tolerierter oraler Risperidongabe beschrieben. Das routinemasige Screening von klinischen Symptomen und Kontrolle der Serum-CK erscheinen fur die fruhzeitige Entdeckung und Behandlung einer antipsychotikainduzierten Rhabdomyolyse von Wichtigkeit zu sein.

Background Paliperidone palmitate is a once-monthly injectable, atypical antipsychotic. To our knowledge, there has been only one report of paliperidone palmitate-induced angioedema presenting with acute laryngeal edema with subsequent respiratory arrest. Here, we present a case report of paliperidone palmitate-induced angioedema with a relatively mild clinical presentation compared with the previously reported case, and the patient's condition was not complicated by life-threatening anaphylaxis. Case summary A 79-year-old female, who had a major neurocognitive disorder due to Alzheimer's disease with behavioral disturbances. Paliperidone palmitate was off-label used to control her aggression, irritability, and psychosis. After induction doses (150 mg and 100 mg intramuscularly, given 1 wk apart), she developed intermittent swelling of the face, eyelids, and lips on day 17 after the initial dose, and the edema was explicitly seen on day 20. The diagnosis was paliperidone palmitate-induced angioedema. The monthly injection dose was discontinued on day 33 after the initial dose. The angioedema was subsequently alleviated, and it had completely resolved by day 40 after the initial dose. Conclusion Paliperidone palmitate-induced angioedema is a rare condition and can present with a mild, intermittent facial edema, which may be overlooked in clinical practice.

Background Paliperidone palmitate is a long-acting, second-generation antipsychotic (SGA) indicated for the treatment of acute exacerbations and maintenance treatment of adults with schizophrenia. This study addressed the response to paliperidone palmitate in Latin American patients with acute symptoms and recently diagnosed schizophrenia. Objective Explore the efficacy and tolerability of paliperidone palmitate administered once a month for 4 months in patients with acute phase and recent diagnosis (within 1-6 years) of schizophrenia in 3 Latin American countries. Methods This was a non-randomized, open-label, multicenter study with paliperidone palmitate injected intramuscularly in the deltoid muscle at an initial loading dose of 150 mg eq. (234 mg) on day 1 and 100 mg eq. (156 mg) on day 8 (± 4 days). The recommended maintenance dose was 75 mg eq. (117 mg) from day 36 to day 92. Efficacy was evaluated with PANSS and CGI-S. The last observation carried forward (LOCF) was used for efficacy analysis for imputation of missing data; no adjustments were made for multiplicity. Adverse events were evaluated during treatment. Results The patient retention rate was 84.0% (144 patients received study drug; 121 finished the study). The percentage of patients with a reduction of at least 30% in PANSS total score compared to baseline gradually increased during the study, and at the end, 78.4% of patients showed response. The PANSS total score and CGI-S scores decreased significantly from baseline to LOCF endpoint (P

Antipsychotic drugs (AP) are widely prescribed for the treatment of schizophrenia and psychosis. The pharmacological treatment of schizophrenia is often performed with the simultaneous use of two or more antipsychotic agents to achieve the desired control of psychotic symptoms Available AP include both conventional (typical) and new (atypical) antipsychotic medications. Atypical AP, such as quetiapine, now account for the vast majority of AP prescriptions. In forensic toxicology, AP are of considerable interest because of their potential abuse and their involvement in intoxications and suicides. The authors retrospectively examined AP positive cases detected in samples collected during autopsies performed in the Forensic Clinical and Pathology Service of National Institute of Legal Medicine and Forensic Sciences Centre Branch or in other autopsies carried out in the central region of Portugal, between January 2016 and December 2018. A quantitative liquid chromatography–tandem mass spectrometry assay was developed for the simultaneous determination of 16 AP (amisulpride, aripiprazole, chlorpromazine, clozapine, cyamemazine, fluphenazine, haloperidol, levomepromazine, melperone, olanzapine, paliperidone, promethazine, quetiapine, risperidone, sulpiride and ziprasidone) in blood samples of postmortem cases. The Laboratory of Forensic Chemistry and Toxicology received 3,588 requests for toxicological analysis: 1,413 cases were positive for drugs from which 351 (24.8%) cases were positive for AP, 60.1% from male individuals and 39.9% from female. Quetiapine was the most prevalent AP (36.5%) followed by olanzapine (20.8%). During this period, there were 25 postmortem cases with AP blood concentrations above therapeutic range, in which 36% of those are in agreement with the information received (psychological history or acute intoxication suspicion) and the manner of death was suicide. Our results point that antipsychotics are an increasingly prevalent class of drugs. AP must be measured not only in toxic concentrations but also in therapeutic levels in postmortem cases; therefore, it is important to come up with a sensitive method to cover the low therapeutic range in which AP are usually present.

Purpose A case of hepatotoxicity likely due to use of risperidone and paliperidone is reported. Summary A 23-year-old man with schizophrenia was admitted to an inpatient psychiatric unit after an exacerbation of mental illness secondary to medication nonadherence. During 13 days of treatment with risperidone, the patient’s liver enzyme levels rose sharply, so antipsychotic therapy was switched to oral paliperidone. After a 5-day downward trend in liver enzyme levels, a dose of intramuscular paliperidone was administered to augment oral paliperidone therapy. After 10 days of paliperidone use, abnormally high liver enzyme levels were again noted; both oral and intramuscular paliperidone therapy were discontinued and haloperidol was initiated, with complete resolution of liver enzyme abnormalities within approximately 4 weeks. Scoring of this case using the algorithm of Naranjo et al indicated probable associations between risperidone use and hepatotoxicity (a score of 7) and paliperidone use and hepatotoxicity (a score of 8). To our knowledge, this is the first case report describing a patient who developed hepatotoxicity during risperidone use that did not remit with a switch to paliperidone therapy. Conclusion Findings of this case suggest that patients who develop hepatotoxicity with use of risperidone may also do so with paliperidone use; this, in turn, suggests that both risperidone and its metabolite are capable of causing hepatotoxicity. Patients who develop hepatotoxicity in response to risperidone or paliperidone therapy may benefit from treatment with an alternative antipsychotic with a different chemical structure.

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.

Summary Paliperidone (9-hydroxyrisperidone), the primary active metabolite of risperidone, is a benzisoxazole derivative of the second-generation antipsychotics. Paliperidone palmitate or PP (the palmitate ester of paliperidone) is available as a once-daily oral tablet, a once-monthly injection or PP1M, and a 3-monthly injection or PP3M (marketed under the name of Trevicta® in the European Union). Despite the recent availability of PP3M, several cases of intoxication have been reported worldwide, including lethal cases. However, in Europe, no case of fatal poising has been reported to date. A 33-year-old man was found dead in his room at his parents’ home. His only medical background was a history of schizophrenia. The external examination was without any particularity except a runny nose of brownish liquid with an alcoholic smell. Given the context and the lack of evidence of a third party intervention, an autopsy was not considered necessary. Toxicological analysis of right femoral blood highlighted the presence of paliperidone (240 μg/L) only. The risk associated with the use of PP3M formulation is still imperfectly evaluated and several cases of intoxication have been reported worldwide, including fatal cases. In this case, paliperidone poisoning appears to be the highly likely cause of death. In fact, the blood concentration of paliperidone is high, twice the toxicity threshold used in therapeutic monitoring, and no other substances have been identified. This case highlights: the necessity to always evaluate the benefit-risk balance when prescribing this sustained-release form of paliperidone and the difficulties in interpreting paliperidone concentration in forensic cases.

Maju Mathews,1 Srihari Gopal,2 Arun Singh,3 Isaac Nuamah,4 Katalin Pungor,5 Wilson Tan,6 Bernardo Soares,7 Edward Kim,8 Adam J Savitz2 1Global Medical Affairs, Janssen Research & Development, LLC, Titusville, NJ, USA; 2Department of Neuroscience, Janssen Research & Development, LLC, Titusville, NJ, USA; 3Department of Neuroscience, Janssen Research & Development, LLC, Pennington, PA, USA; 4Clinical Biostatistics, Janssen Research & Development, LLC, Titusville, NJ, USA; 5Medical Affairs, Janssen-Cilag GmbH, Neuss, North Rhine-Westphalia, Germany; 6Regional Medical Affairs, Janssen Pharmaceutical Companies of Johnson and Johnson, Singapore; 7Medical Affairs, Jan-Cil, High Wycombe, Buckinghamshire, UK; 8Janssen Scientific Affairs, Janssen Scientific Affairs, LLC, Titusville, NJ, USACorrespondence: Maju MathewsGlobal Medical Affairs, Janssen Research & Development, LLC, 1125 Trenton-Harbourton Road, Titusville, NJ, USATel +1 609 433-9257Email mmathe20@its.jnj.comBackground: 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).Keywords: relapse prevention, schizophrenia, oral paliperidone extended release, paliperidone palmitate once monthly, paliperidone palmitate three monthly

Objective Long-acting injectable (LAI) antipsychotics, such as paliperidone palmitate (PP), are known to improve treatment adherence in patients with schizophrenia, which can lead to reductions in relapse and hospitalization rates. However, relatively few studies have demonstrated the economic impact of LAIs, especially in Asian populations. Methods We conducted a claim-based mirror-image study to explore changes in healthcare utilization and associated costs, among 1,272 South Korean patients with schizophrenia (ICD-10-CM code F20), between the 1-year periods before and after the initiation of PP treatment. Results Patients accessed outpatient services more frequently after versus before starting PP treatment, with the number of prescription days increasing by 133.45 (p ＜ 0.0001) and the associated costs increasing by USD 1,497.15 (p ＜ 0.0001). The number of admission days was reduced by 11.33 after starting PP treatment (p ＜ 0.0001) and the associated costs were reduced by USD 1,220.75 (p ＜ 0.0001). However, admission cost savings were different according to patients' oral drug compliance. The daily dosages for benztropine, procyclidine, and propranolol decreased, showing that there were fewer side-effects after PP-treatment (p ＜ 0.0001). Conclusion Although the high acquisition cost of PP has been regarded as an obstacle to its clinical use, our results imply that the high prescription costs for PP may be counterbalanced by the reduced admission costs associated with its use. Economic outcomes for patients treated with LAIs should be investigated further to help healthcare decision-makers and providers to determine the value of LAIs relative to other treatment medications.

Purpose To illuminate user experiences of schizophrenia, reasons for receiving antipsychotic medication, and encounters with mental health services. Design and methods 24 semistructured qualitative research interviews with schizophrenia patients treated with 3-monthly paliperidone palmitate across Scandinavia were synthesized in qualitative content analysis. Findings Participants describe considerable challenges in everyday functioning. Simultaneously, they rate their current mental and physical well-being high and seem satisfied with their lives. These pathways indicate personal recovery. Practice implications The participants emphasize the importance of trustful relations with healthcare professionals, therapeutic conversations, antipsychotic medication in a 3-monthly formulation, and support from relatives.

The dose-response relationships of antipsychotic drugs for schizophrenia are not well defined, but such information would be important for decision making by clinicians. The authors sought to fill this gap by conducting dose-response meta-analyses.A search of multiple electronic databases (through November 2018) was conducted for all placebo-controlled dose-finding studies for 20 second-generation antipsychotic drugs and haloperidol (oral and long-acting injectable, LAI) in people with acute schizophrenia symptoms. Dose-response curves were constructed with random-effects dose-response meta-analyses and a spline model. The outcome measure was total score reduction from baseline on the Positive and Negative Syndrome Scale or the Brief Psychiatric Rating Scale. The authors identified 95% effective doses, explored whether higher or lower doses than the currently licensed ones might be more appropriate, and derived dose equivalencies from the 95% effective doses.Sixty-eight studies met the inclusion criteria. The 95% effective doses and the doses equivalent to 1 mg of oral risperidone, respectively, were as follows: amisulpride for patients with positive symptoms, 537 mg/day and 85.8 mg; aripiprazole, 11.5 mg/day and 1.8 mg; aripiprazole LAI (lauroxil), 463 mg every 4 weeks and 264 mg; asenapine, 15.0 mg/day and 2.4 mg; brexpiprazole, 3.36 mg/day and 0.54 mg; haloperidol, 6.3 mg/day and 1.01 mg; iloperidone, 20.13 mg/day and 3.2 mg; lurasidone, 147 mg/day and 23.5 mg; olanzapine, 15.2 mg/day and 2.4 mg; olanzapine LAI, 277 mg every 2 weeks and 3.2 mg; paliperidone, 13.4 mg/day and 2.1 mg; paliperidone LAI, 120 mg every 4 weeks and 1.53 mg; quetiapine, 482 mg/day and 77 mg; risperidone, 6.3 mg/day and 1 mg; risperidone LAI, 36.6 mg every 2 weeks and 0.42 mg; sertindole, 22.5 mg/day and 3.6 mg; and ziprasidone, 186 mg/day and 30 mg. For amisulpride and olanzapine, specific data for patients with predominant negative symptoms were available. The authors have made available on their web site a spreadsheet with this method and other updated methods that can be used to estimate dose equivalencies in practice.In chronic schizophrenia patients with acute exacerbations, doses higher than the identified 95% effective doses may on average not provide more efficacy. For some drugs, higher than currently licensed doses might be tested in further trials, because their dose-response curves did not plateau.

Introduction The objective of this study was the evaluation of utility of plasma level monitoring in the clinical stabilizing efficacy and tolerability of paliperidone palmitate (PP) vs. aripiprazole monohydrate (AM) in bipolar disorder I (BD I) with manic predominance. Methods Fifty-six outpatients of both sexes, age ranging from 18 to 65 years, affected by BD I with manic predominance, orally treated and stabilized after acute episode for at least 2 weeks with paliperidone or aripiprazole (n=31, paliperidone; n=25, aripiprazole) underwent a prospective observational study of switching to the corresponding long-acting injection (LAI) on the basis of clinical evaluation. The efficacy and tolerability of the 2 treatments were assessed by BPRS, PANSS, HAMD21, and MRS rating scales and a check list every month for 12 months. Drug plasma levels determinations (PLs) were performed at the same times. Results A good clinical stability and tolerability of both drugs were reported. Lower mean PLs of PP showed a positive effect on depressive symptoms. AM PLs variability was associated with greater instability of manic symptoms whereas intermediate PLs seem to have more influence on depressive symptomatology. Discussion PLs drug monitoring has been proven to be useful, and further investigations to identify optimal therapeutic ranges for LAI formulations are needed.

Srihari Gopal,1 Jagadish Gogate,1 Katalin Pungor,2 Edward Kim,3 Arun Singh,1 Maju Mathews1 1Janssen Research and Development, LLC, Titusville, NJ, USA; 2Medical Affairs, EMEA, Janssen-Cilag, Neuss, Germany; 3Janssen Scientific Affairs, Janssen Pharmaceuticals, Titusville, NJ, USACorrespondence: Srihari GopalJanssen Research and Development, LLC, 1125 Trenton Harbourton Road, Titusville, NJ 08560, USAEmail sgopal2@its.jnj.comBackground: Negative symptoms in schizophrenia are associated with impairments in social and cognitive functioning leading to substantial long-term disability. Available antipsychotic treatments have demonstrated only modest benefit in the improvement of negative symptoms.Objective: To compare improvements in negative symptoms among patients treated with paliperidone palmitate 3-month (PP3M) or paliperidone palmitate 1-month (PP1M) long-acting injectable (LAI) formulations.Methods: Data from a randomized double-blind (DB), phase-3, non-inferiority study in patients with schizophrenia were analyzed. Following screening, patients entered a 17-week open-label (OL) phase to receive flexibly dosed PP1M followed by a 48-week DB phase where patients were randomized (1:1) to receive either PP1M or PP3M. Positive and Negative Syndrome Scale (PANSS) total scores with emphasis on 7-item negative subscale scores for PP1M vs PP3M were assessed.Results: Of 1429 patients enrolled, 1016 were randomized to receive PP3M (n=504) or PP1M (n=512). At baseline, mean (SD) PANSS negative subscale was 23.2 (4.60) and negative symptom factor score was 22.3 (4.87), indicating moderate-to-severe negative symptoms. Negative subscale and symptoms factor scores showed continuous improvements throughout OL (15.9 [4.99]) and DB (14.9 [4.81]) phases. Mean (SD) changes from DB baseline in the PANSS negative subscale score were comparable between PP1M (– 1.4 [3.67]) and PP3M (– 1.4 [3.63]) treatment groups.Conclusion: Treatment with PP3M or PP1M demonstrated comparable improvement in negative symptoms in patients with moderate-to-severe negative symptoms and in patients with prominent negative symptoms. Long-term treatment with PP3M demonstrated benefit, suggesting that continuous antipsychotic medication treatment for > 1 year is needed to achieve greater benefit for negative symptoms.Trial Registration: ClinicalTrials.gov Identifier: NCT01515423.Keywords: negative symptoms, paliperidone palmitate 3-month formulation, paliperidone palmitate 1-month formulation

Obsessive-compulsive disorder is often associated with schizophrenia and may represent a significant challenge in the treatment as this comorbidity may not respond properly to antipsychotic medication and usually require a pharmacological and psychotherapeutic add-on. In the present case report, we present the case of a 26-year-old male blue-collar subject who developed obsessive-compulsive disorder after a year of complete remission of schizophrenia symptoms under paliperidone long-acting injection that rapidly resolved after low-dosage cariprazine add-on. No adverse effects were reported due to cariprazine- paliperidone long-acting injection combination.

The objective of this study was to investigate associations between pharmacokinetic correlates and once-monthly paliperidone palmitate (PP1M)-related adverse drug reactions (ADRs). Plasma concentrations and dose-adjusted plasma concentrations (‘concentration-by-dose’ [C/D]) of paliperidone from a naturalistic therapeutic drug monitoring database of PP1M-treated patients were compared between patients with ADRs, classified according to the Udvalg for Kliniske Undersogelser side-effect rating scales categories, and patients without ADRs. Analyses included non-parametric tests and a logistic regression model with a significance level set at 0.05. In 172 patients, we found no differences in sex, age, smoking, body mass index, PP1M dose, paliperidone plasma concentrations, and C/D values (p > 0.05) between 44 patients with and 128 patients without PP1M-related ADRs. We did not detect differences when specifying for different types of ADRs (p > 0.05). Injection intervals were shorter in patients with vs patients without ADRs (p = 0.03). The logistic regression did not report effects for sex, plasma concentrations, or C/D values (p > 0.05). Post hoc analyses in male patients receiving PP1M every 28 weeks reported higher paliperidone concentrations and C/D values in patients with vs without ADRs (p = 0.049 and p = 0.022). Within the group of male patients, we found an odds ratio of 3.07 for PP1M-associated ADRs in patients with C/D values above 7.7 (ng/mL)/(mg/day). Our findings did not reveal distinct patterns of paliperidone concentrations in patients with PP1M-related ADRs. However, male patients receiving PP1M every 28 days with C/D values higher than 7.7 (ng/mL)/(mg/day) showed a higher risk for ADRs, implying that therapeutic drug monitoring may be useful in assessing the risk of PP1M-related ADRs.

BackgroundPaliperidone 3-monthly (PP3M) long-acting injection has proven efficacy and effectiveness in schizophrenia. Little is known of its effectiveness in other diagnoses.MethodsAll patients starting PP3M were followed up for 2 years. Main outcome measures were relapse and discontinuation from PP3M.Post hocwe examined outcomes in those switched back to one monthly paliperidone (PP1M) long-acting injection.ResultsOverall, 186 patients were followed-up. At the 2-year end point, 110 patients (59%) were still receiving PP3M, and 129 (70%) were receiving some form of paliperidone long-acting injection. Discontinuation from paliperidone long-acting injections (PPLAIs) was more likely with a nonschizophrenia diagnosis (hazard ratio [HR] for continuation 0.429 [95% confidence intervals (CI) – 0.21, 0.87p = 0.018)), and prior clozapine use [in PP3M patients; HR for discontinuation 1.87 [95% CI – 1.05, 3.30p = 0.032]). Relapse occurred in 20 (11%) of those receiving PP3M. Relapse on PP3M and PPLAIs was more likely in nonschizophrenia diagnosis (HR 0.17 for remaining relapse-free [95% CI – 0.06, 0.50;p = 0.001]; HR 0.21 [95% CI – 0.08, 0.58p = 0.002], respectively), polypharmacy in PP3M patients (HR for relapse 7.91 [95% CI – 3.73, 22.9;p p p = 0.003]) and PPLAI patients (HR for relapse 4.52 (95% CI – 1.51, 13.5;p = 0.007).ConclusionsOutcomes with PP3M are excellent in practice, even when used outside its formal license. PP3M was relatively more effective in those with an F20 schizophrenia diagnosis and in those never before considered for or prescribed clozapine.

Background Schizophrenia is a severe psychiatric disorder. Poor medical adherence increases relapse rate. Long-acting injection of antipsychotic agent is developed for improving medical adherence. In this study, we examined the effect of paliperidone long-acting injection (PLAI) treatment in patients with schizophrenia in a real-world setting. Methods In this retrospective cohort study, 467 patients with schizophrenia were enrolled, treated with risperidone PLAI or oral antipsychotics, and followed for 1 year. Concomitant medication, namely anticonvulsants, antidepressants, anxiolytics, sedatives or hypnotics, anticholinergics, and beta-blockers, were administered. Patients were classified into 2 groups: the LAI group (patients received LAI for treatment) and the NLAI group (patients taking only oral antipsychotics). The incidence of hospitalization, the length of hospitalization, and the incidence of emergency room visits were assessed. Results The LAI group had a higher incidence of psychiatric acute ward admission (NLAI group = 4.8%; LAI = 30.3%) and emergency room visits (NLAI group = 7.3%; LAI group = 36.0%) before enrolment. During the one-year follow-up, the incidence of acute ward admission and emergency room visit did not differ in the NLAI group (P = .586 and .241) compared with before enrolment, whereas both incidences were significantly decreased in the LAI group (P Conclusions PLAI reduces the incidence of admission and emergency room visits.

Gang Li,1 Alexander Keenan,2 Mehmet Daskiran,1 Maju Mathews,3 Isaac Nuamah,3 Camille Orman,3 Kruti Joshi,4 Arun Singh,3 Annabelle Godet,5 Katalin Pungor,6 Srihari Gopal3 1Janssen Research & Development, LLC, Raritan, NJ, USA; 2Janssen Research & Development, LLC, Pennington, NJ, USA; 3Janssen Research & Development, LLC, Titusville, NJ, USA; 4Janssen Pharmaceuticals, Titusville, NJ, USA; 5Janssen-Cilag France, Issy-les-Moulineaux, Ile-de-France, France; 6Janssen-Cilag Germany, Neuss, North Rhine-Westphalia, GermanyCorrespondence: Gang LiEisai Inc., 4 Heitz Lane, Hillsborough, NJ, 08844, USATel +1 908 566-2730Email ligang8844@gmail.comPurpose: 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&boxh;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.Keywords: health claims, paliperidone palmitate, relapse rate, schizophrenia, three-monthly, treatment adherence

Background A randomized, controlled, phase 3b study (ALPINE) evaluated efficacy and safety of a 2-month formulation of aripiprazole lauroxil (AL) using a 1-day initiation regimen in patients hospitalized for an acute exacerbation of schizophrenia. Paliperidone palmitate (PP) was used as an active control. Exploratory endpoint assessments included severity of illness, positive and negative symptoms, quality of life, caregiver burden, and satisfaction with medication. Methods Adults were randomly assigned to AL 1064 mg q8wk or PP 156 mg q4wk as inpatients, discharged after 2 weeks, and followed through week 25. Exploratory efficacy measures included the 3 original PANSS subscales, Clinical Global Impression−Severity (CGI-S) subscale, and caregiver Burden Assessment Scale. Exploratory patient-reported outcomes (PROs) included the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) and the Medication Satisfaction Questionnaire. Within-group changes from baseline through week 25 were analyzed for AL and PP separately. PROs were summarized based on observed data. Results Of 200 patients randomized (AL, n = 99; PP, n = 101), 99 completed the study (AL, n = 56; PP, n = 43). For AL, PANSS subscale and CGI-S scores improved from baseline through week 25 (mean [SE] change from baseline at week 25: Positive, −7.5 [0.70]; Negative, −3.9 [0.46]; General, −11.8 [0.83]; CGI-S, −1.3 [0.12]). Caregiver burden also improved (mean [SD] changes from baseline at week 9: −8.4 [10.15]; week 25: −8.9 [12.36]). Most AL patients were somewhat/very satisfied with treatment at each timepoint (70.8%–74.7%); mean Q-LES-Q-SF total scores were stable in the outpatient period. For PP, results were similar: PANSS Positive, −7.3 (0.67); Negative, −3.6 (0.69); General, −10.9 (1.22); CGI-S, −1.4 (0.16); caregiver burden, week 9: −8.8 (11.89) and week 25: −9.2 (14.55); satisfaction with treatment, 64.7%–69.3%; and stable Q-LES-Q-SF scores. Conclusions ALPINE patients initiating the 2-month AL formulation using the 1-day initiation regimen as inpatients and continuing outpatient care experienced schizophrenia symptom improvement, sustained patient satisfaction with medication, stable quality of life, and reduced caregiver burden. A similar benefit pattern was observed for PP. These results support the feasibility of starting either long-acting injectable in the hospital and transitioning to outpatient treatment. Trial registration ClinicalTrials.gov identifier: NCT03345979 [trial registration date: 15/11/2017].

Antipsychotic pharmacotherapy is considered a first-line treatment in schizophrenia-related disorders and is associated with favorable prognosis and lower mortality rates. However, low adherence rates present a major clinical challenge. In this paper, we will review contemporary approaches to improve adherence to antipsychotic treatment, considering their mechanism of action, safety, tolerability and acceptability.Novel pharmacological delivery methods included different routes of administration of registered medications (such as intramuscular clozapine preparation and transdermal asenapine), modifications of existing compounds (such as 3-monthly injectable formulation of paliperidone palmitate), and increased interest in oral long-acting medication formulations (such as with penfluridol). In addition, we reviewed innovative technology to monitor adherence, based on the use of electronic digital medicine systems and ingestible sensors.All of these diverse approaches were clinically relevant in enhancing treatment adherence and found to be safe and tolerable. The place of each approach is predicated on a personalized approach in each patient, and future research could usefully use large comparative studies to establish robust treatment guidelines. The implementation of new and varied approaches to antipsychotic treatment adherence is welcomed and have the potential to make a significant impact on morbidity in this often difficult-to-treat population.

Long-acting injectable (LAI) antipsychotics were developed to improve adherence to schizophrenia treatment. Paliperidone palmitate (PP) has two LAI forms: Monthly (PP1M) and three-monthly (PP3M). PP3M shows less difference in Peak-to-Trough drug concentration levels. This could be related to a lower incidence of hyperprolactinemia, which may negatively affect adherence. We aimed to compare prolactin levels and investigate relationships between prolactin levels, symptomatology and sexual function in patients with schizophrenia after switching from PP1M to PP3M.Twenty-five patients were enrolled. The sociodemographic data form, the Positive and Negative Syndromes Scale (PANSS) and the Arizona Sexual Experience Scale (ASEX) were used. Morning blood samples were drawn to determine prolactin levels.Prolactin level (p 0.001), the total score and arousal sub-score of ASEX (respectively; p = 0.015, p = 0.020) and the total score and positive scale of PANSS (respectively; p = 0.017, p = 0.021) were decreased on the 90th day (±15 days).After switching to PP3M, the decreases in prolactin levels and potentially related sexual side effects was statistically significant. There may be a difference between two formulations of the same drug in terms of side effects, and there is a need for prospective follow-up studies with larger samples.

AIM Globally, evidence from short-term studies is insufficient for the guidelines to uniformly recommend a particular antipsychotic(s) for the maintenance treatment of schizophrenia. Therefore, long-term comprehensive evaluation of antipsychotics is required from a social rehabilitation perspective, especially for drugs that have not yet been studied. The Japan Useful Medication Program for Schizophrenia (JUMPs) is a large-scale, long-term naturalistic study to present pivotal 52-week data on the continuity of second-generation antipsychotics (SGA: aripiprazole, blonanserin, and paliperidone). METHODS JUMPs was an open-label, three-arm, randomized, parallel-group, 52-week study. Enrolled patients had schizophrenia, were ≥20 years old, and required antipsychotic treatment or switched from previous therapy. The primary endpoint was treatment discontinuation rate over 52 weeks. Secondary outcomes included remission rate, social functioning, and quality-of-life scores [Personal and Social Performance Scale (PSP) and EuroQol-5 dimensions], and safety. RESULTS In total, 251 patients received aripiprazole (n = 82), blonanserin (n = 85), or paliperidone (n = 84). The discontinuation rate (P = 0.9771) and remission rates (P > 0.05) over 52 weeks did not differ significantly between the three treatment groups. The discontinuation rates were 68.3%, 68.2%, and 65.5% in the aripiprazole, blonanserin, and paliperidone groups, respectively. Significant improvements (all P

Given the typical age onset of schizophrenia, there are tremendous economic and social impacts that extend beyond the person and their families. One critical determinant of the diseases' impact is the patient's adherence to antipsychotic drug treatment. Approved in 2015 for the treatment of schizophrenia, paliperidone palmitate (Invega Trinza, a 3-month injection, noted as PP3M) is a second-generation long-acting injectable antipsychotic medication. Among the different formulations offered for palmitate paliperidone, including the 1 and 3-month formulations, the longer duration 3-month formulation was better at preventing relapse in schizophrenic patients. To date, different formulations of palmitate paliperidone that have been studied on relapse episodes of schizophrenia include once-daily extended-release oral paliperidone (ORAL paliperidone), once-monthly paliperidone palmitate (PP1M), and once-every-3-months paliperidone palmitate (PP3M). Post-hoc analyses show that patients who were withdrawn from PP1M paliperidone had the least risk of relapse, followed by patients withdrawn from PP3M and patients withdrawn from ORAL paliperidone. PP3M was better at preventing relapse compared to ORAL paliperidone. The results demonstrated that 50% of patients who were withdrawn from ORAL paliperidone, PP1M, or PP3M remained relapse-free for ~2, 6, and 13 months, respectively. Compared to PP1M, PP3M is just as safe and effective and has the added advantage of increased adherence related to a longer dose interval, decreasing the risk of relapse.

This clinical case reports the use of paliperidone palmitate 3‐monthly long‐acting injection during pregnancy without known adverse effects on the baby's development.

Tianeptine is an atypical mu-opioid receptor agonist. It is available as an antidepressant outside the United States, but it is also classified as a controlled substance in many other countries. It is not approved by the United States Food and Drug Administration for the treatment of depression but it can be obtained online without a prescription. The case described in this article involved a patient who developed symptoms of psychosis on supratherapeutic doses of tianeptine, highlighting the importance of inquiring into all supplements taken by patients when conducting an initial psychiatric evaluation.

Recent evidence has demonstrated that, over 12 months, pharmacy costs associated with switching nonadherent recently relapsed patients from oral atypical antipsychotics (OAAs) to once-monthly paliperidone palmitate (PP1M) were offset by reduced relapse rates and schizophrenia-related health care costs. In addition, earlier use of PP1M may generate greater cost savings.To project the long-term economic impact when a proportion of nonadherent patients with a recent relapse switch from OAAs to PP1M.A 36-month decision-tree model with twelve 3-month cycles was developed from a Medicaid payer's perspective. The target population was nonadherent, recently relapsed OAA patients. At equal adherence, probability of relapse was equal between PP1M and OAAs, and OAA patients were nonadherent until treatment switch. Event rates (adherence, relapse, and switch) and cost inputs (pharmacy and relapse) were based on the literature, and rates remained constant. Outcomes included number of relapses, pharmacy costs, and relapse costs (2017 U.S. dollars) at years 1, 2, and 3. One-way sensitivity (OSA) and probabilistic sensitivity analyses (PSA) evaluated the effect of varying model inputs on health plan and per-patient level costs.Based on a hypothetical health plan of 1 million members, 3,037 OAA patients were recently relapsed and nonadherent. Compared with continuing OAAs, switching 5% of patients (n = 152) to PP1M resulted in net cost savings of $674,975, $723,298, and $562,310 at the plan level; $4,445, $4,764, and $3,703 per patient switched per year; and $0.0562, $0.0603, and $0.0469 per member per month in years 1, 2, and 3, respectively, resulting in total plan-level savings of$1.9 million over 3 years. A total of 221 relapses were avoided (year 1: 92; year 2: 72; and year 3: 57). In years 1, 2, and 3, respectively, total annual plan-level schizophrenia-related costs were $114.1 million, $107.2 million, and $105.8 million when all patients switched to PP1M before any subsequent relapse (n = 3,037); $123.4 million, $109.6 million, and $106.7 million when patients switched to PP1M after a first subsequent relapse (n = 2,631); and $127.6 million, $121.6 million, and $117.0 million when all patients remained on OAAs. The cost per patient switched to PP1M was lower when all patients received PP1M before a subsequent relapse versus after their first subsequent relapse at all years (year 1: $37,559 vs. $45,089; year 2: $35,288 vs. $36,321; and year 3: $34,826 vs. $35,155). OSA demonstrated consistent net cost savings per patient switched, ranging from $640 to $10,484 (year 1); $1,774 to $9,245 (year 2); and $1,354 to $7,026 (year 3). PSA demonstrated 96.3%, 99.7%, and 99.7% of iterations were cost saving in years 1, 2 and 3, respectively.Pharmacy costs associated with switching nonadherent OAA patients with a recent relapse to PP1M were offset by reduced relapse rates and health care costs at years 1, 2, and 3, with earlier use of PP1M resulting in increased cost savings at all years.This research was funded by Janssen Scientific Affairs. Pilon, Morrison, Lefebvre, and Shak are employees of Analysis Group, a consulting company that received research grants from Janssen Scientific Affairs to conduct this study. El Khoury and Kim are employees of Janssen Scientific Affairs. At the time this study was conducted, Llaneza was an employee of HireGenics, which provided services to Janssen Scientific Affairs for the study. Part of the material in this manuscript was presented at the Academy of Managed Care Pharmacy 2019 Annual Meeting; March 25-29, 2019; San Diego, CA.

Purpose Brexpiprazole is an oral atypical antipsychotic (OAA) for the treatment of schizophrenia (SCZ). This study compared all-cause and psychiatric inpatient hospitalization and medical costs in adult patients with SCZ newly treated with brexpiprazole versus other US Food and Drug Administration–approved OAAs in a real-world setting. Methods This retrospective cohort study analyzed data from: (1) the IBM MarketScan Commercial and Medicare Supplemental databases, and the MarketScan Multi-State Medicaid database; and (2) the de-identified Optum Clinformatics Datamart. Adult patients were identified if they had SCZ and initiated either brexpiprazole or another OAA during the study identification period (July 1, 2015, to September 30, 2016, for MarketScan Commercial and Medicare Supplemental and for Optum; July 1, 2015, to June 30, 2016, for MarketScan Multi-State Medicaid) and had ≥12 months of continuous enrollment before (baseline) and after (follow-up) the first treatment date. Linear regression analyses were performed to test associations between treatment groups (brexpiprazole vs another OAA) and costs (total and medical); negative binomial regression models were used to estimate number of hospitalizations per year, adjusting for baseline characteristics and medication adherence to index treatment during the 12-month follow-up. Findings The final study sample consisted of 6254 patients with SCZ: 176 initiated brexpiprazole; 391, ziprasidone; 453, paliperidone; 523, lurasidone; 786, aripiprazole; 1234, quetiapine; 1264, olanzapine; and 1427, risperidone. Controlling for baseline characteristics and medication adherence, the adjusted number of hospitalizations (both all-cause and psychiatric), all-cause total costs, and all-cause medical costs did not differ across groups. Brexpiprazole users had the lowest mean psychiatric costs among all OAA users ($12,013; 95% bootstrap CI, 7488–16,538). Compared with brexpiprazole users, paliperidone (incidence rate ratio [95% CI], 1.52 [1.05–2.19]; P = 0.027) and quetiapine (incidence rate ratio [95% CI], 1.47 [1.04–2.07]; P = 0.029) users had more psychiatric hospitalizations per year. Paliperidone had higher psychiatric costs than brexpiprazole (total, $32,066 [95% bootstrap CI, 28,779–35,353] vs $23,851 [18,907–28,795]; medical, $19,343 [16,294–22,392] vs $12,013 [7488–16,538]). Psychiatric medical costs were also $6744 higher in olanzapine users (95% bootstrap CI, 1694–11,795; P = 0.009) than in brexpiprazole users. Implications Patients with SCZ treated with brexpiprazole had fewer psychiatric hospitalizations and lower psychiatric costs than those treated with paliperidone. Differences in the number of all-cause hospitalizations and medical costs among treatments were not statistically significant. Although treatment decisions are driven by a number of factors (eg, clinical circumstances and drug costs), choice of OAA may affect health care costs.