Switching from paliperidone palmitate 3-monthly long-acting injection to oral aripiprazole in a pregnant woman with schizophrenia: a case report and short review.

Treatment with long-acting injection (LAI) antipsychotics, such as paliperidone palmitate, has improved the quality of life in terms of symptoms and prevention of relapses in patients with schizophrenia. Although there are plenty of evidences about the efficacy and safety of paliperidone palmitate 3-monthly injection (PP3M) in adults with schizophrenia, literature appears lacking about the use of LAIs during pregnancy. We hereby describe the clinical case of a pregnant woman affected by schizophrenia (DSM-5-TR), taking pharmacological treatment of PP3M. Considering the inadequate evidence regarding the use of PP3M in pregnancy in agreement with the patient, we switched PP3M to an oral therapy with aripiprazole. The switch to oral aripiprazole allowed the patient to improve her sense of autonomy and strengthen the therapeutic relationship. To our knowledge, this is the first case report monitoring an entire pregnancy of a women affected by schizophrenia in treatment with PP3M injection and oral aripiprazole. No obstetrical or fetal complications were reported. As the research in this field is very demanding, it would be precipitous to derive final conclusions from the current case report, but we hope to build a growing number of data that would allow us to make more appropriate and safe therapeutic choices in such a vulnerable phase as the peripartum.

Evaluating the 6-month formulation of paliperidone palmitate: a twice-yearly injectable treatment for schizophrenia in adults.

INTRODUCTION: 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. AREAS COVERED: 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. EXPERT OPINION: 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.

Relapse Rates With Paliperidone Palmitate in Adult Patients With Schizophrenia: Results for the 6-Month Formulation From an Open-label Extension Study Compared to Real-World Data for the 1-Month and 3-Month Formulations.

BACKGROUND: The 3 paliperidone palmitate (PP) long-acting injectable antipsychotic formulations, PP 1-month (PP1M), PP 3-month (PP3M), and PP 6-month (PP6M), have shown to reduce the risk of relapse in schizophrenia. The current phase-4 study constructed external comparator arms (ECAs) using real-world data for PP3M and PP1M and compared relapse prevention rates with PP6M from an open-label extension (OLE) study in adult patients with schizophrenia. METHODS: PP6M data were derived from a single-arm, 24-month, OLE study (NCT04072575), which included patients with schizophrenia who completed a 12-month randomized, double-blind, noninferiority, phase-3 study (NCT03345342) without relapse. Patients in the PP3M and PP1M ECAs were identified from the IBM® MarketScan® Multistate Medicaid Database based on similar eligibility criteria as the PP6M cohort. RESULTS: A total of 178 patients were included in each cohort following propensity score matching. Most patients were men (>70%; mean age: 39-41 years). Time to relapse (primary analysis based on Kaplan-Meier estimates) was significantly delayed in the PP6M cohort (P < .001, log-rank test). The relapse rate was lower in the PP6M cohort (3.9%) vs PP3M (20.2%) and PP1M (29.8%) cohorts. Risk of relapse decreased significantly (P < .001) by 82% for PP6M vs PP3M (HR = 0.18 [95% CI = 0.08 to 0.40]), 89% for PP6M vs PP1M (HR = 0.11 [0.05 to 0.25]), and 35% for PP3M vs PP1M (HR = 0.65 [0.42 to 0.99]; P = .043). Sensitivity analysis confirmed findings from the primary analysis. Although the ECAs were matched to mimic the characteristics of the PP6M cohort, heterogeneity between the groups could exist due to factors including prior study participation, unmeasured confounders, variations in data capture and quality, and completeness of clinical information. CONCLUSIONS: In a clinical trial setting, PP6M significantly delayed time to relapse and demonstrated lower relapse rates compared with PP3M and PP1M treatments in real-world settings among adult patients with schizophrenia. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04072575; EudraCT number: 2018-004532-30.

A comparison of recurrence rates after discontinuation of second-generation antipsychotic long-acting injectable versus corresponding oral antipsychotic in the maintenance treatment of bipolar disorder: A systematic review.

It has been previously reported that among patients with schizophrenia that long-acting injectable (LAI) antipsychotic formulations can delay time to relapse longer when compared to their oral equivalents when patients discontinue therapy. Unanswered is whether this same pattern would be observed for patients with bipolar disorder receiving maintenance treatment. A systematic review was undertaken to identify relevant studies of LAI antipsychotics in maintenance treatment of bipolar disorder, employing a placebo-controlled randomized withdrawal design, and where equivalent studies using the corresponding oral formulation were also available. We found five studies [one aripiprazole monohydrate once monthly (AOM) study, one oral aripiprazole (OARI) study, two 2 weeks risperidone-LAI (RIS-LAI) studies, and one oral paliperidone (OPAL) study]. Numerically lower recurrence rates at 2, 4, 6, 8, 12, 16, 20, and 26 weeks were observed when AOM was discontinued when compared with discontinuation from OARI. Numerically lower recurrence rates at 2, 4, 6, 8, and 16 weeks were observed when RIS-LAI was discontinued when compared with discontinuation from OPAL. These results can be interpreted as a substantial delay in time to recurrence with a LAI antipsychotics formulation compared to the oral equivalent when medication is discontinued in patients with mania who had been stabilized on LAI antipsychotics or corresponding oral antipsychotics.

A multicenter, single-arm, open-label interventional study of adherence to brexpiprazole during switching from previous antipsychotic drugs in patients with schizophrenia or schizoaffective disorder.

The rate of medication persistence was examined in patients with schizophrenia or schizoaffective disorder during switching from previously administered antipsychotics to brexpiprazole, a new dopamine D2 receptor partial agonist. A multicenter, single-arm, open-label 24-week interventional study was conducted, consisting of two 12-week consecutive periods: an initial switch (by plateau cross-titration) with the subsequent period, followed by a second maintenance period. Prior antipsychotics were olanzapine or risperidone/paliperidone. The primary and secondary outcome measures were medication persistence rates after the first 12 weeks and changes from baseline in the Specific Levels of Functioning Scale (SLOF), Subjective Well-being under Neuroleptic drug treatment Short form (SWNS), and Positive and Negative Syndrome Scale (PANSS) scores, respectively. In total, 79 patients were administered brexpiprazole and the medication persistence rate at 12 weeks was 78.5%, which was significantly higher than the predefined threshold of 65%. Regarding the prior medication, the persistence rate at 12 weeks was 84.6% for olanzapine and 72.5% for risperidone/paliperidone. Significant improvements from baseline were observed in the SLOF, SWNS, and PANSS scores. There were no adverse events of concern. Thus, brexpiprazole appeared to be a suitable antipsychotic on switching from olanzapine, risperidone, or paliperidone.

Mortality and Lithium-Protective Effects after First-Episode Mania Diagnosis in Bipolar Disorder: A Nationwide Retrospective Cohort Study in Taiwan.

INTRODUCTION: This study aimed to estimate all-cause mortality in patients after a first-episode mania (FEM) and examine whether six guideline-recommended medications can reduce mortality. METHODS: The cohort included population-based FEM samples and matched controls from Taiwan, spanning 2007 to 2018. The primary outcomes assessed were all-cause/suicide-related mortality, while the secondary outcome focused on mortality associated with pharmacological treatments. We compared mortality in post-FEM patients and age-/sex-matched controls without any diagnosed bipolar disorders and patients with and without psychopharmacological treatment using Cox regression analysis, respectively. Statistics were presented with time-to-event adjusted hazard ratios (AHRs) and 95% confidence intervals (CIs). RESULTS: The study included 54,092 post-FEM patients and 270,460 controls, totaling 2,467,417 person-years of follow-up. Post-FEM patients had higher risks of all-cause mortality (AHR 2.38, 95% CI: 2.31-2.45) and suicide death (10.80, 5.88-19.84) than controls. Lithium (0.62, 0.55-0.70), divalproex (0.89, 0.83-0.95), and aripiprazole (0.81, 0.66-1.00) were associated with reduced all-cause mortality compared to non-users. There were no significant all-cause mortality differences for quetiapine (0.95, 0.89-1.01), risperidone (0.92, 0.82-1.02), and paliperidone (1.24, 0.88-1.76) users. When accounting for drug action onset times in sensitivity analyses, only lithium significantly reduced all-cause mortality (AHR range 0.65-0.72). There were 35 and 16 suicide deaths in post-FEM patients and controls, respectively. No drug had a significant effect on suicide deaths (lithium: 6; divalproex: 7; aripiprazole: 0; quetiapine: 10; risperidone: 4; paliperidone: 1). CONCLUSION: Post-FEM patients had a higher risk of all-cause/suicide-related mortality, and lithium treatment might reduce all-cause mortality.

Factors Associated with Symptom Stabilization that Allow for Successful Transition from Once-Monthly Paliperidone Palmitate to Three-Monthly Paliperidone Palmitate: A Post Hoc Analysis Examined Clinical Characteristics in Chinese Patients with Schizophrenia.

BACKGROUND AND OBJECTIVES: Identifying key factors for a successful transition from once-monthly paliperidone palmitate (PP1M) to three-monthly paliperidone palmitate (PP3M) is crucial for improving treatment outcomes, enhancing patient adherence, and reducing relapse risk in patients with schizophrenia. Providing region-specific insights for evidence-based clinical decisions can aid clinicians in optimizing transition strategies for Chinese patients with schizophrenia. Therefore, the objective of this post hoc analysis of a double-blind parallel-group multicenter phase 3 study (NCT01515423) was to identify factors related to the disease stabilization that may allow for a successful transition from PP1M to PP3M in the treatment of Chinese patients with schizophrenia. METHODS: Adults (18-70 years) diagnosed with schizophrenia using the Diagnostic and Statistical Manual of Mental Disorders, fourth edition text revision, for over 1 year and with a baseline Positive and Negative Syndrome Scale (PANSS) total score between 70 and 120 were entered into an open-label (OL) phase receiving PP1M for 17 weeks. After the 17-week OL phase, patients who met the criteria necessary for stabilization were randomized (1:1) to PP1M (fixed-dose, 50, 75, 100, or 150 mg eq.) or PP3M (fixed-dose, 175, 263, 350, or 525 mg eq.) in a 48-week double-blind phase. Stabilization was defined as a PANSS total score < 70, PANSS item (P1, P2, P3, P6, P7, G8, G14) scores ≤ 4, and a reduction in Clinical Global Impression Severity (CGI-S) score of ≥ 1 from OL baseline. This post hoc analysis evaluated changes and trends in symptom severity using PANSS, changes in mental states using CGI-S, and changes in personal and social functioning using Personal and Social Performance (PSP) scores from baseline to the endpoint of the OL phase in patients who either met or did not meet the stabilization criteria (stabilized versus non-stabilized group). Comparison of changes and trends in the clinical scores between the stabilized group and non-stabilized group were conducted using linear mixed model and Mann-Kendall trend analysis, respectively. Univariate and multivariate logistic regression analyses were conducted to explore factors associated with stabilization status for transition. RESULTS: Of 296 patients enrolled, 210 achieved disease stabilization (106 patients and 104 patients were randomized to PP1M and PP3M, respectively). Significant downward trends in the PANSS and CGI-S scores were detected in the stabilized patients (n = 210, ZPANSS = -2.21, p = 0.028; ZCGI-S = -2.21, p = 0.028) but not in the non-stabilized patients (n = 86). No significant trends in the PSP scores were observed in either group. The factors significantly associated with disease stabilization were the CGI-S score at baseline [odds ratio (OR) = 0.22, 95% confidence interval (CI): 0.09, 0.5), reduction of the PANSS score at week 13 (OR = 1.11, 95% CI: 1.06, 1.17), and reduction of CGI-S score at week 13 (OR = 2.27, 95% CI: 1.03, 5.02). CONCLUSION: A lower CGI-S total score at baseline and greater reductions in PANSS and CGI-S scores at week 13 were associated with patients achieving disease stabilization, that may allow for a successful transition. Evidence from this study indicates that better disease condition at baseline, early functional improvement and symptomatic relief were the key factors associated with disease stabilization. The findings may guide clinicians to identify suitable patients for transition from PP1M to PP3M and further optimize the use of PP3M in China. CLINICAL TRIALS REGISTRATION: EudraCT number: 2011-004889-15 and ClinicalTrials.gov (identifier: NCT01515423) for the original double-blind randomized study.

Characteristics of patients with schizophrenia switching from oral antipsychotics to once-monthly paliperidone palmitate (PP1M): a systematic review.

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.

An association between PPARα-L162V polymorphism and increased plasma LDL cholesterol levels after risperidone treatment.

Peroxisome proliferator-activated receptor alpha (PPARα) and antipsychotic medications both influence polyunsaturated fatty acids (PUFA) homeostasis, and thus PPARα polymorphism may be linked to antipsychotic treatment response. Here we investigated whether the functional leucine 162 valine (L162V) polymorphism in PPARα influenced antipsychotic treatment in a group of psychosis patients (N = 186), as well as in a patient subgroup with risperidone, paliperidone, or combination treatment (N = 65). Antipsychotic-naïve first-episode patients and nonadherent chronic individuals were genotyped by polymerase chain reaction analysis. At baseline, and after 8 weeks of treatment with various antipsychotic medications, we assessed the patients' Positive and Negative Syndrome Scale (PANSS) scores; PANSS factors; and metabolic syndrome-related parameters, including fasting plasma lipid and glucose levels, and body mass index. In the total patient group, PPARα polymorphism did not affect PANSS psychopathology or metabolic parameters. However, in the subgroup of patients with risperidone, paliperidone, or combination treatment, PPARα polymorphism influenced changes in plasma LDL cholesterol. Specifically, compared to PPARα-L162L homozygous patients, PPARα-L162V heterozygous individuals exhibited significantly higher increases of LDL cholesterol levels after antipsychotic treatment. The PPARα polymorphism had a strong effect size, but a relatively weak contribution to LDL cholesterol level variations (∼12.8 %).

Clozapine augmentation with long-acting antipsychotic injections: A case series and systematic review.

BACKGROUND: Up to 30% of patients with a diagnosis of treatment-resistant psychosis remain symptomatic despite an optimal trial with the gold standard treatment, clozapine. Emerging evidence suggests the clinical utility of long-acting injections (LAI) in such clinical scenarios. In this study, we aimed to describe clozapine augmentation with LAIs in an inner London hospital and explore the literature on the clinical effectiveness of this treatment modality. METHODS: Patients prescribed clozapine, who were commenced on a LAI between 2007 and 2023 by the United Kingdom's largest mental health trust, were identified from electronic patient records. First, routine clinical data were used to describe the use, effectiveness, and safety of this augmentation strategy. Second, we conducted a literature search up to 1st June 2023 to identify published studies describing clinical outcomes after clozapine augmentation with a LAI. Clinical outcomes were collated and presented in a table, including hospitalisation rates and quantitative clinical assessments using validated scales. RESULTS: Of the 1248 patients prescribed clozapine in SLaM, three patients (0.2%) received augmentation with the following LAIs: olanzapine embonate, paliperidone palmitate and pipotiazine palmitate. This treatment strategy was clinically effective and generally well tolerated in all three cases. Twelve published studies between 2010 and 2022 were included in the review. Eight distinct LAIs were reported (4 first and 4 second generation antipsychotics), with risperidone and paliperidone most widely studied. All the identified studies were observational including mirror-image studies, case series and case reports. Duration of follow up varied from 3 months to 3 years. There was evidence that the use of LAIs with clozapine can significantly reduce clinical symptoms, hospitalisation rates and bed days. No serious adverse effects were reported. CONCLUSION: This preliminary evidence suggests clinical utility of LAIs in alleviating residual symptoms and subsequently reducing hospitalisation rates in patients optimised on clozapine treatment. The current study warrants further investigations including a randomised controlled study to establish the clinical efficacy, tolerability, and place in therapy of this treatment modality.

Potential benefits of combining two long-acting injectable antipsychotic: a retrospective study.

OBJECTIVE: The aim of this study was to evaluate the efficacy and tolerability of the combination of two long-acting injectable antipsychotics (LAIA) in psychiatric disorders, especially in schizophrenia. PATIENTS AND METHODS: Eighty-three patients treated with dual LAIA were included in the study by retrospective screening from the hospital registration system. The present study was designed as an observational, retrospective, naturalistic mirror-image study. The number of hospitalizations before and after switching to dual LAIA was compared in patients who received oral antipsychotics and single LAIA during the study period. In addition, it was analyzed which was the preferred dual antipsychotic combination. RESULTS: Of the patients, 44.6% had schizophrenia, 41.0% had schizoaffective disorder, and 14.4% had other psychiatric disorders. The number of patients receiving oral treatment prior to dual LAIA use was 80 (96.4%). Data on dual LAIA regimens showed that 31.3% were receiving paliperidone and aripiprazole, 24.1% were receiving paliperidone and flupenthixol, 18.1% were receiving paliperidone and zuclopenthixol, and 26.5% were receiving the other combinations. After dual LAIA treatment, there was a significant decrease in the number of hospitalizations compared to before (from 5.95 to 0.99, p<0.001). In addition, while the number of patients who did not require hospitalization in the pre-treatment period was 10.8%, it reached 48.1% in the post-treatment period (p<0.001). No significant adverse effect related to the use of dual LAIA was observed in any patient during the treatment period. CONCLUSIONS: The use of dual LAIA instead of oral antipsychotics or single LAIA in chronic psychotic patients with poor social support and irregular medication use is thought to reduce hospitalization and related treatment costs and regularize medication use.

Efficacy and safety of paliperidone palmitate 6-monthly long-acting injectable in reduction of relapses in patients with schizophrenia: An Asian subgroup analysis of phase 3, randomized study.

BACKGROUND: Evaluate efficacy and safety of paliperidone palmitate 6-monthly (PP6M) for patients with schizophrenia in the Asian subgroup of a global, multicenter, noninferiority phase-3 study (NCT03345342). METHODS: Patients received paliperidone palmitate 1-monthly (PP1M, 100/150 mg eq.) or paliperidone palmitate 3-monthly (PP3M, 350/525 mg eq.) during the maintenance phase and entered a 12-month double-blind (DB) phase, wherein they were randomized (2:1) to PP6M (700/1000 mg. eq.) or PP3M (350/525 mg eq.). Subgroup analysis was performed for 90 (12.7%) patients from Asia region (India, Taiwan, Malaysia, Hong Kong, and Korea). Primary endpoint was time-to-relapse during DB phase (Kaplan-Meier estimates). Secondary endpoints were changes from baseline in Positive and Negative Syndrome Scale, Clinical Global Impression-Severity scale, Personal and Social Performance (PSP) scale score. RESULTS: In Asian subgroup, 91.9% (82/90) of patients completed DB phase (PP6M: 54/62 [87%]; PP3M: 28/28 [100%]). Median time-to-relapse was "not-estimable" due to low relapse rates in both groups. Estimated difference (95% confidence interval [CI]) between relapse-free patients in PP6M and PP3M groups of Asian subgroup was -0.1% [-8.5%, 8.4%] (global study population: -2.9% [-6.8%, 1.1%]). Mean change from baseline in secondary efficacy parameters was comparable between both groups, similar to the global study population. The incidence of extrapyramidal symptoms was higher in the Asian subgroup than in the global study population. CONCLUSION: Consistent with the global study population, PP6M was noninferior to PP3M in preventing relapse in patients with schizophrenia from the Asia region. Findings suggest the possibility of switching from PP1M/PP3M to twice-yearly PP6M without loss of efficacy and with no unexpected safety concerns.

Barriers to the use of three-month Paliperidone Palmitate formulation: a study from an Italian real-world setting.

BACKGROUND: Long-acting injectable paliperidone can improve adherence in psychotic patients and reduce relapses and healthcare resource utilization (HRU). This study compares the effectiveness of the three-monthly paliperidone palmitate (PP3M) with the one-monthly formulation (PP1M) and investigates reasons that hinder the use of PP3M in real-world settings. METHODS: The authors conducted a three-phase observational study. For subjects recruited from six psychiatric services in Milan, HRU outcomes of PP3M prescription were evaluated through a 12-month mirror-image design (phase 1) and a comparison of HRU of PP1M-only subjects and PP3M subjects during the year prior to PP3M initiation (phase 2). Lastly, they conducted a survey among physicians concerning reasons for not switching to PP3M (phase 3). RESULTS: A total of 119 subjects (61 on PP3M and 58 on PP1M) were included. One year after PP3M initiation, outpatients' visits decreased significantly. Comparing PP3M with PP1M subjects, no significant difference was found in HRU. Perception of patient's unstable clinical condition was the main reason for maintaining PP1M (32.8%), followed by the need for monthly monitoring (19.7%). CONCLUSION: PP3M initiation was associated with an overall HRU reduction. Subjects switched to PP3M had similar HRU when compared to those who did not, suggesting similar clinical conditions in both groups.

Continuity of care among patients newly initiated on second-generation oral or long-acting injectable antipsychotics during a schizophrenia-related inpatient stay.

BACKGROUND: Maintaining continuity of care after schizophrenia-related hospitalization is challenging for patients and healthcare providers and systems. Prior evidence suggests that second-generation long-acting injectable antipsychotics (SGLAIs) may reduce the risk of treatment nonadherence and readmission versus oral atypical antipsychotics (OAAs). Therefore, quality measures were compared between patients initiated on SGLAIs and OAAs in the United States. METHODS: Adults newly initiated on an SGLAI or OAA during a schizophrenia-related inpatient stay were identified in HealthVerity databases (01/2015-12/2020); the index date was the hospital discharge date. Patients had continuous health insurance coverage for pharmacy and medical services for 6 months pre-admission and post-discharge from the inpatient stay and ≥1 pharmacy or medical claim (i.e. treatment as indicated by the observed insurance claims) for an antipsychotic other than the index SGLAI or OAA in the 6 months pre-admission. Antipsychotic use and adherence, and schizophrenia-related readmissions and outpatient visits were compared during the 6-month period post-discharge. Characteristics between cohorts were balanced using inverse probability weights. RESULTS: Post-discharge, only 36.9% and 40.7% of weighted SGLAI (N = 466) and OAA (N = 517) patients had ≥1 pharmacy or medical claim for the antipsychotic initiated during the inpatient stay, among whom SGLAI patients were 4.4 times more likely to be adherent to that antipsychotic compared to OAA patients (p < .001). Additionally, SGLAI patients were 2.3 and 3.0 times more likely to have a pharmacy or medical claim for and be adherent to any antipsychotic relative to OAA patients (including index antipsychotic; all p < .001). Within 7 and 30 days post-discharge, 1.7% and 13.0% of SGLAI patients and 4.1% and 12.6% of OAA patients had a readmission. Further, SGLAI patients were 51% more likely to have an outpatient visit compared to OAA patients (p = .044). CONCLUSIONS: Less than half of patients initiated on antipsychotics during a schizophrenia-related inpatient stay continued the same treatment post-discharge. However, SGLAI patients were more likely to be adherent to the initiated antipsychotic and to have an outpatient visit, which may suggest improved continuity of care post-discharge relative to OAA patients.

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

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

Real-world effectiveness of long-acting injectable antipsychotic treatments in a nationwide cohort of 12,373 patients with schizophrenia-spectrum disorders.

This mirror-image study aimed to evaluate the real-life effectiveness of long-acting injectable antipsychotics (LAI) in schizophrenia. Patients with schizophrenia initiating LAIs January 2015-December 2016 were enrolled from the French National Health Data System (SNDS). Standardized mean differences (SMD > 0.1 deemed clinically significant) were calculated for psychiatric healthcare resource utilization measures assessed one year before (during oral AP treatment) and one year after LAI initiation. LAI effectiveness was analyzed overall and by age group, gender and compliance to oral AP, defined as exposure to an AP for at least 80% of the year before LAI initiation. 12,373 patients were included. LAIs were more frequently initiated in men (58.1%), young (18-34 years, 42.0%) and non-compliant (63.7%) patients. LAI initiation was effective in reducing the number and duration of psychiatric hospitalizations and psychiatric emergency department (ED) admissions in non-compliant patients (SMD = -0.19, -0.26 and -0.12, respectively), but not in compliant patients. First-generation LAIs, paliperidone and aripiprazole LAIs reduced psychiatric hospitalizations (SMD = -0.20, -0.24, -0.21, respectively) and ED admissions (SMD = -0.15, -0.13, -0.15, respectively). No differences in effectiveness were found for age or gender. In compliant patients, only aripiprazole LAI reduced the number of psychiatric hospitalizations (SMD = -0.13). Risperidone and paliperidone LAIs increased hospitalization duration (SMD = 0.15 and 0.18, respectively). The prescription of LAIs (except risperidone) should be recommended in all non-compliant patients, even in women and patients aged 35 or older. The lower frequency of administration of LAIs than of oral APs may improve compliance and hence reduce the risk of relapse. Aripiprazole LAI may represent a treatment of choice for compliant patients that should be further investigated.

Initial severity of the Positive and Negative Syndrome Scale (PANSS)-30, its main subscales plus the PANSS-6, and the relationship to subsequent improvement and trial dropout: a pooled participant-level analysis of 18 placebo-controlled risperidone and paliperidone trials.

Greater initial severity on the 30-item Positive and Negative Syndrome Scale (PANSS-30) correlates positively with antipsychotic-placebo separation and trial dropout, but it is unknown whether these associations are present also on PANSS-derived subscales. We assessed the relationship between initial severity and antipsychotic-placebo separation as measured by PANSS-30 and four PANSS symptom subscales: the positive (PANSS-POS), negative (PANSS-NEG), general (PANSS-GEN) and 6-item (PANSS-6) subscales, using patient-level data from 18 placebo-controlled risperidone and paliperidone trials. Analysis of covariance in the intention-to-treat population (last-observation-carried-forward) was used to assess antipsychotic-placebo separation and trial dropout. Across 6685 participants (90% schizophrenia, 10% schizoaffective disorder), the initial severity-by-treatment interaction was statistically significant for PANSS-30 (beta: -0.155; p < 0.001) and all PANSS subscales (beta range: -0.097 to -0.135; p-value range: < 0.001 to 0.002). In all cases, antipsychotic-placebo differences increased with initial severity. Judging by the distribution of relative outcomes (percent remaining symptoms), the interaction was partly explained by an increased chance of responding, but also by larger numerical responses in those who did respond, as initial severity increased. Except for PANSS-NEG, high initial severity on all PANSS scales predicted increased trial dropout, although not statistically significantly so for PANSS-6. In summary, we thus replicate previous findings showing greater initial severity to predict larger antipsychotic-placebo separation and extend these results to four PANSS subscales. For PANSS-POS and PANSS-GEN, but not for PANSS-NEG and PANSS-6, we also replicate the association between initial severity and trial dropout. Patients with low initial negative symptom severity were identified as a group of particular interest for further study since their results diverged most from the average both with regard to antipsychotic-placebo separation (low separation measured by PANSS-NEG) and trial dropout (high level).

Calibrated meta-analysis to estimate the efficacy of mental health treatments in target populations: an application to paliperidone trials for treatment of schizophrenia.

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.

Effects of risperidone/paliperidone versus placebo on cognitive functioning over the first 6 months of treatment for psychotic disorder: secondary analysis of a triple-blind randomised clinical trial.

The drivers of cognitive change following first-episode psychosis remain poorly understood. Evidence regarding the role of antipsychotic medication is primarily based on naturalistic studies or clinical trials without a placebo arm, making it difficult to disentangle illness from medication effects. A secondary analysis of a randomised, triple-blind, placebo-controlled trial, where antipsychotic-naive patients with first-episode psychotic disorder were allocated to receive risperidone/paliperidone or matched placebo plus intensive psychosocial therapy for 6 months was conducted. A healthy control group was also recruited. A cognitive battery was administered at baseline and 6 months. Intention-to-treat analysis involved 76 patients (antipsychotic medication group: 37; 18.6Mage [2.9] years; 21 women; placebo group: 39; 18.3Mage [2.7]; 22 women); and 42 healthy controls (19.2Mage [3.0] years; 28 women). Cognitive performance predominantly remained stable (working memory, verbal fluency) or improved (attention, processing speed, cognitive control), with no group-by-time interaction evident. However, a significant group-by-time interaction was observed for immediate recall (p = 0.023), verbal learning (p = 0.024) and delayed recall (p = 0.005). The medication group declined whereas the placebo group improved on each measure (immediate recall: p = 0.024; ηp2 = 0.062; verbal learning: p = 0.015; ηp2 = 0.072 both medium effects; delayed recall: p = 0.001; ηp2 = 0.123 large effect). The rate of change for the placebo and healthy control groups was similar. Per protocol analysis (placebo n = 16, medication n = 11) produced similar findings. Risperidone/paliperidone may worsen verbal learning and memory in the early months of psychosis treatment. Replication of this finding and examination of various antipsychotic agents are needed in confirmatory trials. Antipsychotic effects should be considered in longitudinal studies of cognition in psychosis.Trial registration: Australian New Zealand Clinical Trials Registry ( http://www.anzctr.org.au/ ; ACTRN12607000608460).

Structure-based discovery of an antipsychotic drug, paliperidone, as a modulator of human superoxide dismutase 1: a potential therapeutic target in amyotrophic lateral sclerosis.

Aggregates of the antioxidant superoxide dismutase 1 (SOD1) are one of the major contributors to the pathogenesis of amyotrophic lateral sclerosis (ALS). Mutations in SOD1 lead to an unstable structure and aggregation that perturbs the balance of reactive oxygen species in cells. Oxidation damage to the solvent-exposed Trp32 also causes aggregation of SOD1. Here, the FDA-approved antipsychotic drug paliperidone is identified to interact with Trp32 of SOD1 by structure-based pharmacophore mapping and crystallographic studies. Paliperidone is used for the treatment of schizophrenia. The crystal structure of the complex with SOD1, refined to 2.1 Šresolution, revealed that the ligand binds to the SOD1 ß-barrel in the ß-strand 2 and 3 regions, which are known to scaffold SOD1 fibrillation. The drug also makes substantial π-π interaction with Trp32. Microscale thermophoresis studies confirm significant binding affinity of the compound, suggesting that the ligand can inhibit or prevent tryptophan oxidation. Thus, the antipsychotic drug paliperidone or a derivative may avert SOD1 aggregation and can be used as a lead for ALS drug development.