Srihari Gopal

We assessed efficacy and tolerability of the injectable atypical antipsychotic paliperidone palmitate in delaying time-to-relapse in adults with schizophrenia.Eligible patients (Positive and Negative Syndrome Scale [PANSS] total score < 120) were transitioned from previous antipsychotics to paliperidone palmitate during a 9-week, open-label phase. Patients received the first 2 intramuscular injections of paliperidone palmitate (50mg eq) one-week apart, then subsequent injections (25, 50, or 100mg eq, flexibly-dosed), once-monthly. Stable patients (PANSS total score < or = 75) continued into the 24-week maintenance phase. At maintenance phase endpoint, stabilized patients were randomized (1:1 ratio) to either continue paliperidone palmitate (at stabilized dose) or begin placebo in the variable-duration, double-blind phase.The preplanned interim analysis (conducted after 68 relapse events) included 312 patients: mean age = 40 years, 55% men, 66% white, and mean transition baseline PANSS total score (SD): placebo, 69.5 (16.89); paliperidone palmitate, 69.3 (17.39). Time-to-relapse (primary endpoint) favored paliperidone palmitate (p<0.0001, log-rank test) at interim and final analysis (n=408). The hazard ratio (placebo/paliperidone palmitate) at the final analysis was 3.60 (95% CI: 2.45, 5.28). Treatment-emergent adverse event rates (final analysis set) were: 67% for transition and maintenance phases, and 45% (placebo) and 44% (paliperidone palmitate) for the double-blind phase. Across phases, the incidence of glucose-related adverse events was low (< or = 4%), while mean weight increased by 1.9 kg for paliperidone palmitate and remained unchanged for placebo patients. Injection site tolerability was comparable between groups.Paliperidone palmitate significantly delayed time-to-relapse compared with placebo and presented no new safety signals.

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

Polygenic scores (PGSs), which assess the genetic risk of individuals for a disease, are calculated as a weighted count of risk alleles identified in genome-wide association studies. PGS methods differ in which DNA variants are included and the weights assigned to them; some require an independent tuning sample to help inform these choices. PGSs are evaluated in independent target cohorts with known disease status. Variability between target cohorts is observed in applications to real data sets, which could reflect a number of factors, e.g., phenotype definition or technical factors.The Psychiatric Genomics Consortium Working Groups for schizophrenia and major depressive disorder bring together many independently collected case-control cohorts. We used these resources (31,328 schizophrenia cases, 41,191 controls; 248,750 major depressive disorder cases, 563,184 controls) in repeated application of leave-one-cohort-out meta-analyses, each used to calculate and evaluate PGS in the left-out (target) cohort. Ten PGS methods (the baseline PC+T method and 9 methods that model genetic architecture more formally: SBLUP, LDpred2-Inf, LDpred-funct, LDpred2, Lassosum, PRS-CS, PRS-CS-auto, SBayesR, MegaPRS) were compared.Compared with PC+T, the other 9 methods gave higher prediction statistics, MegaPRS, LDPred2, and SBayesR significantly so, explaining up to 9.2% variance in liability for schizophrenia across 30 target cohorts, an increase of 44%. For major depressive disorder across 26 target cohorts, these statistics were 3.5% and 59%, respectively.Although the methods that more formally model genetic architecture have similar performance, MegaPRS, LDpred2, and SBayesR rank highest in most comparisons and are recommended in applications to psychiatric disorders.

This study assessed the efficacy and the safety of a dosing regimen that was revised from earlier studies for the investigational injectable atypical antipsychotic paliperidone palmitate (approved in the USA, August 2009) for adult patients with acutely exacerbated schizophrenia. The patients (N = 652) were randomly assigned (1:1:1:1) to paliperidone palmitate at 25, 100, or 150 mg eq. or placebo in this 13-week double-blind study. The patients received an injection of paliperidone palmitate at 150 mg eq. or placebo in the deltoid muscle on day 1 and the assigned fixed dose or placebo in the deltoid or gluteal [corrected] on day 8 and then once monthly (days 36 and 64). No oral supplementation was used. Target plasma levels were achieved by day 8 in all paliperidone palmitate groups. The mean change in Positive and Negative Syndrome Scale total score from baseline to end point improved significantly (P < or = 0.034) in all the paliperidone palmitate dose-groups versus placebo. Paliperidone palmitate treatment with this revised dosing regimen led to the achievement of rapid and consistent therapeutically effective plasma levels that were maintained by once-monthly dosing in either the deltoid or gluteal muscle. Common treatment-emergent adverse events (> or =2% of patients in any of the treatment groups) that occurred more frequently in the total paliperidone palmitate group versus the placebo group (with > or =1% difference) were injection-site pain (7.6% vs 3.7%), dizziness (2.5% vs 1.2%), sedation (2.3% vs 0.6%), pain in the extremity (1.6% vs 0.0%), and myalgia (1.0% vs 0.0%). The paliperidone palmitate treatment was efficacious and generally tolerated across the dose range (25, 100, or 150 mg eq.) in adult patients with acutely exacerbated schizophrenia.

This 13-week double-blind study was designed to assess noninferiority of the recently approved (in the U.S.) injectable atypical antipsychotic paliperidone palmitate (PP) versus risperidone long-acting injectable (RIS-LAI) in adult patients with schizophrenia. Patients (N=1220) were randomized (1:1) to either a) PP: deltoid injections on day 1 (150 mg eq.), day 8 (100 mg eq.), and once-monthly flexible dosing as deltoid or gluteal injections on day 36 (50 mg eq. or 100 mg eq.) and day 64 (50 mg eq. or 100 mg eq. or 150 mg eq.) or b) RIS-LAI: gluteal injections days 8 and 22 (25mg), days 36, 50 (25 or 37.5mg) and days 64, 78 (25, 37.5 or 50mg). RIS-LAI-treated patients received oral supplementation with RIS 1-6 mg/day (days 1 to 28), and PP-treated patients received oral placebo. The safety analysis set (n=1214) included 58% men, 78% white, with mean (SD) baseline PANSS total score: PP, 84.1 (12.09); and RIS-LAI, 83.6 (11.28). Mean (SD) change from baseline to endpoint in PANSS total score decreased similarly in both groups; PP (-18.6 [15.45]) and RIS-LAI (-17.9 [14.24]). PP treatment was noninferior to RIS-LAI (point estimate [95% CI]: 0.4 [-1.62;2.38], per-protocol analysis set [primary analysis]). The tolerability and safety of PP was generally similar to RIS-LAI with no new safety or tolerability findings.

This 13-week, double-blind study evaluated the efficacy and safety of the atypical antipsychotic paliperidone palmitate (recently approved in the United States) versus placebo administered as monthly gluteal injections (after two initial doses given 1 week apart) in acutely symptomatic patients with schizophrenia. Patients (N=388) were randomly assigned (1 : 1 : 1 : 1) to paliperidone palmitate 50, 100, or 150 mg eq. or placebo. As the 150 mg eq. dose was administered to fewer patients (n=30) than planned, meaningful and definitive conclusions cannot be drawn from the results of this group. The change from baseline in Positive and Negative Syndrome Scale total score at endpoint showed improvement in both paliperidone palmitate 50 and 100 mg eq. groups but was significant only in the 100 mg eq. group (P=0.019). The paliperidone palmitate 50 (P=0.004) and 100 mg eq. (P<0.001) groups showed significant improvement in the Personal and Social Performance score from baseline to endpoint versus placebo. Common adverse events (in >or=2% of patients in any group) more frequent with paliperidone palmitate 50 or 100 mg eq. than placebo (>or=5% difference) were headache, vomiting, extremity pain, and injection site pain. Treatment with paliperidone palmitate (100 mg eq.) was efficacious and all doses tested were tolerable.

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

Paliperidone palmitate is a long-acting injectable antipsychotic agent. This 13-week, multicenter, randomized (1 : 1 : 1 : 1), double-blind, parallel-group study evaluated the efficacy, safety, and tolerability of fixed 25, 50, and 100 milligram equivalent (mg equiv.) doses of paliperidone palmitate vs placebo administered as gluteal injections on days 1 and 8, then every 4 weeks (days 36 and 64) in 518 adult patients with schizophrenia. The intent-to-treat analysis set (N=514) was 67% men and 67% White, with a mean age of 41 years. All paliperidone palmitate dose groups showed significant improvement vs placebo in the Positive and Negative Syndrome Scale (PANSS) total score (primary efficacy measure; 25 and 50 mg equiv., p=0.02; 100 mg equiv., p<0.001), as well as Clinical Global Impression Severity scores (p< or =0.006) and PANSS negative and positive symptom Marder factor scores (p< or =0.04). The Personal and Social Performance scale showed no significant difference between treatment groups. The overall incidence of treatment-emergent adverse events was similar between groups. Parkinsonism, the most frequently reported extrapyramidal symptom, was reported at similar rates for placebo (5%) and paliperidone palmitate (5-6% across doses). The mean body mass index and mean weight showed relatively small dose-related increases during paliperidone palmitate treatment. Investigator-evaluated injection-site pain, swelling, redness, and induration were similar across treatment groups; scores for patient-evaluated injection-site pain (visual analog scale) were similar across groups and diminished with time. All doses of once-monthly paliperidone palmitate were efficacious and generally tolerated, both locally and systemically. Paliperidone palmitate offers the potential to improve outcomes in adults with symptomatic schizophrenia.

Genetic correlation is a key population parameter that describes the shared genetic architecture of complex traits and diseases. It can be estimated by current state-of-art methods, i.e., linkage disequilibrium score regression (LDSC) and genomic restricted maximum likelihood (GREML). The massively reduced computing burden of LDSC compared to GREML makes it an attractive tool, although the accuracy (i.e., magnitude of standard errors) of LDSC estimates has not been thoroughly studied. In simulation, we show that the accuracy of GREML is generally higher than that of LDSC. When there is genetic heterogeneity between the actual sample and reference data from which LD scores are estimated, the accuracy of LDSC decreases further. In real data analyses estimating the genetic correlation between schizophrenia (SCZ) and body mass index, we show that GREML estimates based on ∼150,000 individuals give a higher accuracy than LDSC estimates based on ∼400,000 individuals (from combined meta-data). A GREML genomic partitioning analysis reveals that the genetic correlation between SCZ and height is significantly negative for regulatory regions, which whole genome or LDSC approach has less power to detect. We conclude that LDSC estimates should be carefully interpreted as there can be uncertainty about homogeneity among combined meta-datasets. We suggest that any interesting findings from massive LDSC analysis for a large number of complex traits should be followed up, where possible, with more detailed analyses with GREML methods, even if sample sizes are lesser. Genetic correlation is a key population parameter that describes the shared genetic architecture of complex traits and diseases. It can be estimated by current state-of-art methods, i.e., linkage disequilibrium score regression (LDSC) and genomic restricted maximum likelihood (GREML). The massively reduced computing burden of LDSC compared to GREML makes it an attractive tool, although the accuracy (i.e., magnitude of standard errors) of LDSC estimates has not been thoroughly studied. In simulation, we show that the accuracy of GREML is generally higher than that of LDSC. When there is genetic heterogeneity between the actual sample and reference data from which LD scores are estimated, the accuracy of LDSC decreases further. In real data analyses estimating the genetic correlation between schizophrenia (SCZ) and body mass index, we show that GREML estimates based on ∼150,000 individuals give a higher accuracy than LDSC estimates based on ∼400,000 individuals (from combined meta-data). A GREML genomic partitioning analysis reveals that the genetic correlation between SCZ and height is significantly negative for regulatory regions, which whole genome or LDSC approach has less power to detect. We conclude that LDSC estimates should be carefully interpreted as there can be uncertainty about homogeneity among combined meta-datasets. We suggest that any interesting findings from massive LDSC analysis for a large number of complex traits should be followed up, where possible, with more detailed analyses with GREML methods, even if sample sizes are lesser. Genetic correlation is a key population parameter that describes the shared genetic architecture of complex traits and diseases.1Mehta D. Tropf F.C. Gratten J. Bakshi A. Zhu Z. Bacanu S.-A. Hemani G. Magnusson P.K.E. Barban N. Esko T. et al.Schizophrenia Working Group of the Psychiatric Genomics Consortium, LifeLines Cohort Study, and TwinsUKEvidence for genetic overlap between schizophrenia and age at first birth in women.JAMA Psychiatry. 2016; 73: 497-505Crossref PubMed Scopus (30) Google Scholar, 2Lee S.H. Byrne E.M. Hultman C.M. Kähler A. Vinkhuyzen A.A.E. Ripke S. Andreassen O.A. Frisell T. Gusev A. Hu X. et al.Schizophrenia Working Group of the Psychiatric Genomics Consortium and Rheumatoid Arthritis Consortium InternationalSchizophrenia Working Group of the Psychiatric Genomics Consortium AuthorsSchizophrenia Working Group of the Psychiatric Genomics Consortium CollaboratorsRheumatoid Arthritis Consortium International AuthorsRheumatoid Arthritis Consortium International CollaboratorsNew data and an old puzzle: the negative association between schizophrenia and rheumatoid arthritis.Int. J. Epidemiol. 2015; 44: 1706-1721Crossref PubMed Scopus (49) Google Scholar, 3Lee S.H. DeCandia T.R. Ripke S. Yang J. Sullivan P.F. Goddard M.E. Keller M.C. Visscher P.M. Wray N.R. Schizophrenia Psychiatric Genome-Wide Association Study Consortium (PGC-SCZ)International Schizophrenia Consortium (ISC)Molecular Genetics of Schizophrenia Collaboration (MGS)Estimating the proportion of variation in susceptibility to schizophrenia captured by common SNPs.Nat. Genet. 2012; 44: 247-250Crossref PubMed Scopus (439) Google Scholar The genetic correlation is the additive genetic covariance between two traits scaled by the square root of the product of the genetic variance for each trait (i.e., the geometric mean of the trait variances). The sign of the correlation shows the direction of sharing, and the parameter definition is based on genetic variants across the allelic spectrum. Methods to estimate genetic correlation based on genetic covariance structure are well established for both quantitative and disease traits, e.g., (restricted) maximum likelihood for linear mixed models (LMM).4Lee S.H. Yang J. Goddard M.E. Visscher P.M. Wray N.R. Estimation of pleiotropy between complex diseases using single-nucleotide polymorphism-derived genomic relationships and restricted maximum likelihood.Bioinformatics. 2012; 28: 2540-2542Crossref PubMed Scopus (379) Google Scholar, 5Harville D.A. Maximum likelihood approaches to variance component estimation and to related problems.J. Am. Stat. Assoc. 1977; 72: 320-338Crossref Scopus (1543) Google Scholar, 6Patterson H.D. Thompson R. Recovery of inter-block information when block sizes are unequal.Biometrika. 1971; 58: 545-554Crossref Scopus (2718) Google Scholar Genetic covariance structure can be derived from phenotypic records using pedigree information in twin or family-based designs.7Neale M. Cardon L. Methodology for Genetic Studies of Twins and Families. Springer Science & Business Media, 2013Google Scholar Recently, genome-wide single-nucleotide polymorphism (SNP) data have been used to construct a genomic relationship matrix for the genetic covariance structure in LMM that captures the contribution of causal variants that are in linkage disequilibrium (LD) with the genotyped SNPs.4Lee S.H. Yang J. Goddard M.E. Visscher P.M. Wray N.R. Estimation of pleiotropy between complex diseases using single-nucleotide polymorphism-derived genomic relationships and restricted maximum likelihood.Bioinformatics. 2012; 28: 2540-2542Crossref PubMed Scopus (379) Google Scholar, 8VanRaden P.M. Efficient methods to compute genomic predictions.J. Dairy Sci. 2008; 91: 4414-4423Abstract Full Text Full Text PDF PubMed Scopus (3096) Google Scholar, 9Yang J. Lee S.H. Goddard M.E. Visscher P.M. GCTA: a tool for genome-wide complex trait analysis.Am. J. Hum. Genet. 2011; 88: 76-82Abstract Full Text Full Text PDF PubMed Scopus (3814) Google Scholar Such estimates assume that the genetic correlation estimated from common SNPs is representative of the parameter that depends on all genetic variants; this seems like a reasonable assumption. In contrast to the genomic restricted maximum likelihood (GREML) approach, a linkage disequilibrium score regression (LDSC)10Bulik-Sullivan B.K. Loh P.R. Finucane H.K. Ripke S. Yang J. Patterson N. Daly M.J. Price A.L. Neale B.M. Schizophrenia Working Group of the Psychiatric Genomics ConsortiumLD Score regression distinguishes confounding from polygenicity in genome-wide association studies.Nat. Genet. 2015; 47: 291-295Crossref PubMed Scopus (1923) Google Scholar, 11Bulik-Sullivan B. Finucane H.K. Anttila V. Gusev A. Day F.R. Loh P.R. Duncan L. Perry J.R. Patterson N. Robinson E.B. et al.ReproGen ConsortiumPsychiatric Genomics ConsortiumGenetic Consortium for Anorexia Nervosa of the Wellcome Trust Case Control Consortium 3An atlas of genetic correlations across human diseases and traits.Nat. Genet. 2015; 47: 1236-1241Crossref PubMed Scopus (1656) Google Scholar method does not require individual-level genotype data but instead uses GWAS summary statistics, regressing association test statistics of SNPs on their LD scores. The LD score of a SNP is the sum of LD r2 measured with all other SNPs and can be calculated in a reference sample of the same ethnicity when individual genotype data are not available for the GWAS sample, under the assumption that the GWAS sample has been drawn from the same ethnic population as the reference sample used to calculate the LD scores. The method exploits the relationship between association test statistic and LD score expected under polygenicity. Because of this simplicity, and the massively reduced computing burden in terms of memory and time, it is feasible for LDSC to be applied to a large number of multiple traits, e.g., Bulik-Sullivan et al.,11Bulik-Sullivan B. Finucane H.K. Anttila V. Gusev A. Day F.R. Loh P.R. Duncan L. Perry J.R. Patterson N. Robinson E.B. et al.ReproGen ConsortiumPsychiatric Genomics ConsortiumGenetic Consortium for Anorexia Nervosa of the Wellcome Trust Case Control Consortium 3An atlas of genetic correlations across human diseases and traits.Nat. Genet. 2015; 47: 1236-1241Crossref PubMed Scopus (1656) Google Scholar Zheng et al.,12Zheng J. Erzurumluoglu A.M. Elsworth B.L. Kemp J.P. Howe L. Haycock P.C. Hemani G. Tansey K. Laurin C. Pourcain B.S. et al.Early Genetics and Lifecourse Epidemiology (EAGLE) Eczema ConsortiumLD Hub: a centralized database and web interface to perform LD score regression that maximizes the potential of summary level GWAS data for SNP heritability and genetic correlation analysis.Bioinformatics. 2017; 33: 272-279Crossref PubMed Scopus (484) Google Scholar Finucane et al.13Finucane H.K. Bulik-Sullivan B. Gusev A. Trynka G. Reshef Y. Loh P.R. Anttila V. Xu H. Zang C. Farh K. et al.ReproGen ConsortiumSchizophrenia Working Group of the Psychiatric Genomics ConsortiumRACI ConsortiumPartitioning heritability by functional annotation using genome-wide association summary statistics.Nat. Genet. 2015; 47: 1228-1235Crossref PubMed Scopus (980) Google Scholar Given the attractiveness of LDSC for a massive analysis of many sets of GWAS summary statistics, it has been widely used in the community. However, genetic correlations estimated by LDSC are often reported without caution although the approach is known to be less accurate, compared to GREML.11Bulik-Sullivan B. Finucane H.K. Anttila V. Gusev A. Day F.R. Loh P.R. Duncan L. Perry J.R. Patterson N. Robinson E.B. et al.ReproGen ConsortiumPsychiatric Genomics ConsortiumGenetic Consortium for Anorexia Nervosa of the Wellcome Trust Case Control Consortium 3An atlas of genetic correlations across human diseases and traits.Nat. Genet. 2015; 47: 1236-1241Crossref PubMed Scopus (1656) Google Scholar In fact, the accuracies of LDSC estimates have not been thoroughly studied. In this report, we compare both the bias (difference between the simulated true value and estimated value) and accuracy (magnitude of the standard error of an estimate [SE]) between GREML and LDSC for estimation of genetic correlation. We find that both methods show little evidence of bias. However, LDSC is less accurate as reported in Bulik Sullivan et al.,11Bulik-Sullivan B. Finucane H.K. Anttila V. Gusev A. Day F.R. Loh P.R. Duncan L. Perry J.R. Patterson N. Robinson E.B. et al.ReproGen ConsortiumPsychiatric Genomics ConsortiumGenetic Consortium for Anorexia Nervosa of the Wellcome Trust Case Control Consortium 3An atlas of genetic correlations across human diseases and traits.Nat. Genet. 2015; 47: 1236-1241Crossref PubMed Scopus (1656) Google Scholar with SE at least more than 1.5-fold higher than that of GREML regardless of the number of samples in data used to estimate the genetic correlation. When decreasing the number of SNPs, the accuracy of LDSC decreases further. When increasing the degree of genetic heterogeneity between the actual sample and reference data from which LD scores are estimated, the SE of LDSC estimates are up to 3-fold larger than those of the GREML estimates. We also show that GREML is more accurate in genomic partitioning analyses over LDSC or stratified LDSC (sLDSC). In genomic partitioning analyses, the genetic parameters are estimated for genomic subsets defined by user-specified annotations. In analyses of real data, we show that GREML is more accurate and powerful, e.g., GREML estimates based on ∼150,000 individuals give a higher accuracy than LDSC estimates based on 400,000 individuals in estimating genetic correlation between schizophrenia (SCZ) and body mass index (BMI) (−0.136 [SE = 0.017] and p value = 4.54E−15 for GREML versus −0.087 [SE = 0.019] and p value = 4.91E−06 for LDSC). In these analyses, the GREML estimate is based on UK sample only whereas the LDSC estimate is based on combined meta-datasets among which there is uncertainty about homogeneity. Furthermore, a GREML genomic partitioning analysis reveals that the genetic correlation between SCZ and height is significantly negative for regulatory regions, which is less obvious by LDSC when using both whole-genome and partitioned estimates of genetic correlation. In the main methods, we used GREML14Lee S.H. van der Werf J.H. MTG2: an efficient algorithm for multivariate linear mixed model analysis based on genomic information.Bioinformatics. 2016; 32: 1420-1422Crossref PubMed Scopus (90) Google Scholar, 15Maier R. Moser G. Chen G.-B. Ripke S. Coryell W. Potash J.B. Scheftner W.A. Shi J. Weissman M.M. Hultman C.M. et al.Cross-Disorder Working Group of the Psychiatric Genomics ConsortiumJoint analysis of psychiatric disorders increases accuracy of risk prediction for schizophrenia, bipolar disorder, and major depressive disorder.Am. J. Hum. Genet. 2015; 96: 283-294Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar and LDSC10Bulik-Sullivan B.K. Loh P.R. Finucane H.K. Ripke S. Yang J. Patterson N. Daly M.J. Price A.L. Neale B.M. Schizophrenia Working Group of the Psychiatric Genomics ConsortiumLD Score regression distinguishes confounding from polygenicity in genome-wide association studies.Nat. Genet. 2015; 47: 291-295Crossref PubMed Scopus (1923) Google Scholar, 11Bulik-Sullivan B. Finucane H.K. Anttila V. Gusev A. Day F.R. Loh P.R. Duncan L. Perry J.R. Patterson N. Robinson E.B. et al.ReproGen ConsortiumPsychiatric Genomics ConsortiumGenetic Consortium for Anorexia Nervosa of the Wellcome Trust Case Control Consortium 3An atlas of genetic correlations across human diseases and traits.Nat. Genet. 2015; 47: 1236-1241Crossref PubMed Scopus (1656) Google Scholar to compare their estimates of genetic correlation using simulated as well as real data. Simulations were based on UK Biobank imputed genotype data (UKBB16Collins R. What makes UK Biobank special?.Lancet. 2012; 379: 1173-1174Abstract Full Text Full Text PDF PubMed Scopus (449) Google Scholar) after stringent quality control (QC) (see Supplemental Methods). We calculated a ratio of empirical SE and its 95% confidence interval (CI) to assess the accuracy of the methods for each set of simulated data. The 95% CIs of SE were estimated based on the delta method.17Lynch M. Walsh B. Genetics and Analysis of Quantitative Traits. Sinauer Sunderland, MA1998Google Scholar When estimating genetic correlation using simulated phenotypes based on UKBB genotype data, we found that the estimates were unbiased for both GREML and LDSC (Figure S1), but the SE of GREML was at least 1.5 times smaller than that of LDSC (Figure 1). The ratio of the empirical SE from LDSC to GREML was increased up to 3.5-fold when using a smaller number of SNPs (Figure 1). All values of the ratio were significantly different from 1. It is notable that the SE of GREML estimates showed almost no difference across different numbers of SNPs whereas that of LDSC estimates gradually increased with a smaller number of SNPs (Figure S2). The ratio was invariant to sample size (Figure S3). As expected, when using the intercept constrained to zero, LDSC estimates were substantially biased when there were overlapping samples (Figure S4). We also explored alternative genetic architectures (Figure S5), which consistently showed that GREML gives a smaller SE than LDSC in any scenario. To explore the stability of the accuracy for both methods, we used two additional genotype datasets without imputation, Wellcome Trust Case Control Consortium 2 (WTCCC218Sawcer S. Hellenthal G. Pirinen M. Spencer C.C. Patsopoulos N.A. Moutsianas L. Dilthey A. Su Z. Freeman C. Hunt S.E. et al.International Multiple Sclerosis Genetics ConsortiumWellcome Trust Case Control Consortium 2Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.Nature. 2011; 476: 214-219Crossref PubMed Scopus (2024) Google Scholar, 19Mells G.F. Floyd J.A.B. Morley K.I. Cordell H.J. Franklin C.S. Shin S.-Y. Heneghan M.A. Neuberger J.M. Donaldson P.T. Day D.B. et al.UK PBC ConsortiumWellcome Trust Case Control Consortium 3Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis.Nat. Genet. 2011; 43: 329-332Crossref PubMed Scopus (379) Google Scholar, 20Bellenguez C. Bevan S. Gschwendtner A. Spencer C.C. Burgess A.I. Pirinen M. Jackson C.A. Traylor M. Strange A. Su Z. et al.International Stroke Genetics Consortium (ISGC)Wellcome Trust Case Control Consortium 2 (WTCCC2)Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke.Nat. Genet. 2012; 44: 328-333Crossref PubMed Scopus (332) Google Scholar, 21Tsoi L.C. Spain S.L. Knight J. Ellinghaus E. Stuart P.E. Capon F. Ding J. Li Y. Tejasvi T. Gudjonsson J.E. et al.Collaborative Association Study of Psoriasis (CASP)Genetic Analysis of Psoriasis ConsortiumPsoriasis Association Genetics ExtensionWellcome Trust Case Control Consortium 2Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity.Nat. Genet. 2012; 44: 1341-1348Crossref PubMed Scopus (702) Google Scholar) and genetic epidemiology research on adult health and aging cohort (GERA22Banda Y. Kvale M.N. Hoffmann T.J. Hesselson S.E. Ranatunga D. Tang H. Sabatti C. Croen L.A. Dispensa B.P. Henderson M. et al.Characterizing race/ethnicity and genetic ancestry for 100,000 subjects in the genetic epidemiology research on adult health and aging (GERA) cohort.Genetics. 2015; 200: 1285-1295Crossref PubMed Scopus (191) Google Scholar, 23Lee S.H. Weerasinghe W.M.S.P. Wray N.R. Goddard M.E. van der Werf J.H.J. Using information of relatives in genomic prediction to apply effective stratified medicine.Sci. Rep. 2017; 7: 42091Crossref PubMed Scopus (29) Google Scholar), which are publicly available (see Supplemental Methods for detailed data descriptions). We also used UKBB raw (non-imputed) genotype data (UKBBr). We calculated the correlation between the LD scores for the HapMap3 SNPs estimated based on the 1KG CEU reference sample (see Web Resources) and those based on in-sample genotype data, i.e., UKBB, WTCCC2, GERA, and UKBBr dataset (Table 1). We found that the WTCCC2, GERA, and UKBBr (raw) genotypes were less similar to the 1KG reference genotypes, compared to the UKBB (imputed) genotypes (noting that UKBB samples had been imputed to the combined data of 1KG reference and UK10K data). Table 2 shows that the SE ratio of LDSC estimate to GREML estimate was higher for WTCCC2, GERA, and UKBBr than that for UKBB. Figure 2 shows that the accuracy of GREML was consistent across different datasets, whereas that of LDSC was decreased for WTCCC2, GERA, or UKBBr, compared to UKBB dataset. This was probably due to higher (or lower) correlation between LD scores based on the 1KG reference and the in-sample genotype datasets (Table 1) which might positively or (negatively) affect the accuracy of LDSC estimates. For WTCCC2, GERA, and UKBBr data, the SE ratio of LDSC to GREML based on different number of individuals is shown in Figures S6–S8.Table 1Correlation between LD Scores Estimated Based on the HapMap3 SNPs using the 1KG CEU Reference Sample and that from Different Target PopulationsCorrelationNr.SNPsUKBBaUKBB was imputed to the combined data of the 1KG reference and UK10K data.0.946858,991UKBBrbUKBBr was based on the raw genotype data of UK Biobank data.0.720123,615cThe number of SNPs reduced further from the set of the QCed SNPs because of using only SNPs matched with the HapMap3 SNPs used in calculating LD scores.WTCCC20.899421,035cThe number of SNPs reduced further from the set of the QCed SNPs because of using only SNPs matched with the HapMap3 SNPs used in calculating LD scores.GERA0.661238,089cThe number of SNPs reduced further from the set of the QCed SNPs because of using only SNPs matched with the HapMap3 SNPs used in calculating LD scores.a UKBB was imputed to the combined data of the 1KG reference and UK10K data.b UKBBr was based on the raw genotype data of UK Biobank data.c The number of SNPs reduced further from the set of the QCed SNPs because of using only SNPs matched with the HapMap3 SNPs used in calculating LD scores. Open table in a new tab Table 2The Ratio of SE of LDSC Estimate to That of GREML Estimate using Simulated Phenotypes Based on UKBB, WTCCC2, GERA, and UKBBr Genotypes in the Scenarios without Overlapping Individuals800k400k200k100kUKBB1.60 (0.15)1.70 (0.18)1.85 (0.25)2.04 (0.33)WTCCC2NA2.15 (0.31)2.35 (0.43)2.68 (0.61)GERANANA2.87 (0.56)3.31 (1.17)UKBBrNANANA3.74 (0.79) Open table in a new tab Genome partitioning analyses are an emerging tool to estimate the genetic variance and covariance explained by functional categories (e.g., DNase I hypersensitive sites [DHS] and non-DHS24Gusev A. Lee S.H. Trynka G. Finucane H. Vilhjálmsson B.J. Xu H. Zang C. Ripke S. Bulik-Sullivan B. Stahl E. et al.Schizophrenia Working Group of the Psychiatric Genomics ConsortiumSWE-SCZ ConsortiumSchizophrenia Working Group of the Psychiatric Genomics ConsortiumSWE-SCZ ConsortiumPartitioning heritability of regulatory and cell-type-specific variants across 11 common diseases.Am. J. Hum. Genet. 2014; 95: 535-552Abstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar). Currently, genomic partitioning analyses focus on SNP-heritability enrichment analyses, formally testing for enrichment of signal compared to the expectation that the estimates are proportional to the number of SNPs allocated to each annotation. Considering genomic partitioning in cross-disorder analyses is a natural extension to identify regions where genetic correlations between disorders are highest and lowest. Here, we assessed the performance of the methods in the context of genome partitioning analyses using simulated phenotypes based on UKBB genotype data. A better LDSC approach to estimate genetic correlation for each category might be sLDSC, stratifying by genomic annotation; however, this method is currently under development (i.e., there is software [see Web Resources], but there is no published document or paper verifying the method). Nonetheless, since the sLDSC is available to the research community, we applied both LDSC and sLDSC to estimate partitioned genetic correlations for the simulated data (Supplemental Methods). For genome partitioning analyses, we showed that LDSC estimates of genetic correlation were biased whether using LD scores estimated from the 1KG reference or in-sample data (UKBB) while GREML estimates gave unbiased estimates for each functional category (Figure 3). sLDSC estimates were unbiased only when using LD scores from the in-sample data, and their SEs are relatively larger than those of GREML or LDSC (Figure 3). This was probably due to the fact that the different distribution of causal variants and their effects between DHS and non-DHS regions were better captured by an explicit covariance structure fitted in GREML. We also applied the methods to a range of simulation scenarios and found similar results in that GREML performed better than LDSC or sLDSC (Figure S9 and Table S1), which was consistent with the previous results (Figures 1 and 2). It is notable that in a deliberately severe scenario (e.g., causal variants are simulated only within few kb of a boundary), GREML could give biased estimation of genetic correlation.13Finucane H.K. Bulik-Sullivan B. Gusev A. Trynka G. Reshef Y. Loh P.R. Anttila V. Xu H. Zang C. Farh K. et al.ReproGen ConsortiumSchizophrenia Working Group of the Psychiatric Genomics ConsortiumRACI ConsortiumPartitioning heritability by functional annotation using genome-wide association summary statistics.Nat. Genet. 2015; 47: 1228-1235Crossref PubMed Scopus (980) Google Scholar, 24Gusev A. Lee S.H. Trynka G. Finucane H. Vilhjálmsson B.J. Xu H. Zang C. Ripke S. Bulik-Sullivan B. Stahl E. et al.Schizophrenia Working Group of the Psychiatric Genomics ConsortiumSWE-SCZ ConsortiumSchizophrenia Working Group of the Psychiatric Genomics ConsortiumSWE-SCZ ConsortiumPartitioning heritability of regulatory and cell-type-specific variants across 11 common diseases.Am. J. Hum. Genet. 2014; 95: 535-552Abstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar While focusing on the accuracy of genetic correlation estimates, there is an important implication for the bias in SNP-heritability estimates for both GREML and LDSC (Figure S10). When using the WTCCC2, GERA, and UKBBr data, which were less similar to the 1KG reference genotypes, compared to the UKBB data, LDSC estimates were substantially biased whereas GREML estimates were close to the true value in estimation of SNP heritability (Figure S10). However, this result is well known and LDSC was not recommended for SNP heritability by the original authors,10Bulik-Sullivan B.K. Loh P.R. Finucane H.K. Ripke S. Yang J. Patterson N. Daly M.J. Price A.L. Neale B.M. Schizophrenia Working Group of the Psychiatric Genomics ConsortiumLD Score regression distinguishes confounding from polygenicity in genome-wide association studies.Nat. Genet. 2015; 47: 291-295Crossref PubMed Scopus (1923) Google Scholar but rather only for relative enrichment analysis. Despite this, LDSC is widely used for SNP-heritability estimation (because it is quick and simple). Thus, for completeness we include analyses for different scenarios to quantify the properties of the methods. When reducing the number of SNPs, estimated SNP heritabilities from LDSC were consistently unbiased; however, those from GREML were proportionally underestimated (Figure S11). When using non-HapMap3 SNPs, LDSC estimates were consistently biased (Figure S12) and less accurate, compared to GREML estimates (Figures S13 and S14), which probably explains why LDSC is implemented using only HapMap3 SNPs. Although the genetic correlation is robust to such biasedness,4Lee S.H. Yang J. Goddard M.E. Visscher P.M. Wray N.R. Estimation of pleiotropy between complex diseases using single-nucleotide polymorphism-derived genomic relationships and restricted maximum likelihood.Bioinformatics. 2012; 28: 2540-2542Crossref PubMed Scopus (379) Google Scholar, 11Bulik-Sullivan B. Finucane H.K. Anttila V. Gusev A. Day F.R. Loh P.R. Duncan L. Perry J.R. Patterson N. Robinson E.B. et al.ReproGen ConsortiumPsychiatric Genomics ConsortiumGenetic Consortium for Anorexia Nervosa of the Wellcome Trust Case Control Consortium 3An atlas of genetic correlations across human diseases and traits.Nat. Genet. 2015; 47: 1236-1241Crossref PubMed Scopus (1656) Google Scholar SNP heritability itself should be carefully interpreted for both GREML and LDSC. We also noted that LDSC and sLDSC estimates for SNP heritability were biased in the genome partitioning analysis (Figure S15) although the estimated enrichment was close to the true value when using sLDSC and in-sample LD scores (Figure S15). We used real phenotype and individual genotype data from the Psychiatric Genomics Consortium (PGC) and UKBB to estimate genetic variance and covariance between SCZ and BMI using LDSC and GREML (Table 3 and Figure S16). We also used publicly available GWAS summary statistics for LDSC to see how much the SE of estimates could be reduced by increasing the number of samples and number of SNPs. For real data analyses, we obtained theoretical SE to assess the accuracy of the methods. GREML and LDSC estimates for the SNP heritability were 0.192 (SE 0.004) and 0.280 (SE 0.016) for SCZ and 0.184 (SE 0.004) and 0.255 (SE 0.014) for BMI. The notable difference between GREML and LDSC was probably because of a relatively small number of SNPs (500K) that might result in underestimated GREML SNP heritability (see Figure S11). This is one of the caveats of using GREML with real data that usually comprise multiple cohorts genotyped on different platforms, such that, even with imputation, the overlapping set of SNPs imputed with high confidence may be limited. The estimated genetic correlation for GREML and LDSC was −0.136 (SE 0.017) and −0.173 (SE 0.031). This indicated that the GREML estimate was 3.5 and 1.8 times more precise than LDSC estimates for the SNP heritability and genetic correlation, respectively. For LDSC, we also considered using additional GWAS summary statistics from publicly available resources.25Schizophrenia Working Group of the Psychiatric Genomics ConsortiumBiological insights from 108 schizophrenia-associated genetic loci.Nature. 2014; 511: 421-427Crossref PubMed Scopus (5068) Google Scholar, 26Locke A.E. Kahali B. Berndt S.I. Justice A.E. Pers T.H. Day F.R. Powell C. Vedantam S. Buchkovich M.L. Yang J. et al.LifeLines Cohort StudyADIPOGen ConsortiumAGEN-BMI Working GroupCARDIOGRAMplusC

The availability of long-acting injectable (LAI) antipsychotics for the treatment of schizophrenia provides clinicians with options that deliver continuous drug exposure and may improve adherence compared with daily oral antipsychotics. However, all LAI antipsychotics have unique formulations and pharmacokinetic characteristics that have implications for medication selection, administration interval, and injection site. This review outlines key differences in drug formulations and pharmacokinetics among LAI antipsychotics. A systematic search of the PubMed database was conducted to identify physical and formulation properties and pharmacokinetic data of commercially available LAI antipsychotics, including flupentixol decanoate, fluphenazine decanoate, haloperidol decanoate, zuclopenthixol decanoate, aripiprazole monohydrate, aripiprazole lauroxil, olanzapine pamoate, paliperidone palmitate, risperidone microspheres, and risperidone polymeric microspheres. Additional information was obtained from package inserts and product monographs. Relevant data on drug properties, administration details, pharmacokinetic parameters, and oral dose equivalencies of LAI antipsychotics are summarized. Based on our analysis, formulation characteristics (e.g., vehicle medium) and administration characteristics (e.g., injection site) can affect rate of absorption and adverse effects and may factor into whether oral supplementation or an additional injection is needed. Dose adjustments may be necessary based on potential drug-drug interactions, and approximate dose equivalence with oral formulations can help inform titration when switching from oral to LAI formulations. Clinicians administering LAI antipsychotics should consider these formulation and pharmacokinetic factors to maximize clinical impact and to adjust to an individual patient's needs and treatment goals.

Paliperidone palmitate is an investigational, injectable atypical antipsychotic. The safety and tolerability of initiating treatment with paliperidone palmitate via deltoid versus gluteal injections given once monthly, and of switching injection sites, in adults with stable schizophrenia were assessed. In this crossover trial, stable outpatients (N = 252) were randomly assigned 1:1:1 to 3 dose groups (paliperidone palmitate 50, 75, or 100 mg eq.) and 2 treatment sequences (blinded to dose): deltoid muscle (period 1 [13 weeks]) followed by gluteal muscle (period 2 [12 weeks]) or the reverse. The intent-to-treat analysis set had 249 patients: mean age = 43 (SD: 12.8) years; 57% men, 81% white, baseline mean Positive and Negative Syndrome Scale (PANSS) total score = 56 (SD: 11.5). A total of 170 (68%) patients completed the study, with a similar proportion completing each treatment sequence. The incidence of systemic treatment-emergent adverse events (TEAEs) was similar between the 2 injection sites across doses during period 1 (deltoid [D]: 61% to 67%; gluteus [G]: 58% to 65%), and during the last 8 weeks of the 2 study periods (DG: 32% to 45% [period 1], 29% to 42% [period 2]; GD: 31% to 40% [period 1], 30% to 41% [period 2]). During the first treatment week, median plasma paliperidone concentrations were higher with treatment initiation in the deltoid muscle compared with the gluteal muscle. At apparent steady state, there was little difference in plasma paliperidone concentrations between the deltoid and gluteus sites for a given dose. Local tolerability was slightly better with gluteal injections. Patient preference for injection sites differed between geographical regions, e.g. patients from the US preferred deltoid to gluteal sites. The most common (≥ 5% overall) TEAEs were: (period 1) insomnia, anxiety, headache, and agitation; and (period 2) insomnia, psychotic disorder, weight increased, and tachycardia. Paliperidone palmitate treatment was tolerated, irrespective of injection site, and thus could offer the choice of administration into either the deltoid or gluteal muscle to meet patient and physician preference.

The safety and tolerability of paliperidone palmitate, an injectable atypical antipsychotic agent, were assessed in a 1-year open-label extension of a double-blind study in patients with schizophrenia. Patients from the double-blind study who experienced a recurrence, remained recurrence free until study end, or who were in the transition, maintenance or double-blind phases and had received at least one injection of paliperidone palmitate when enrollment was stopped, were eligible for the open-label extension. Patients received gluteal injections of paliperidone palmitate once every 4 weeks: starting dose 50 mg eq. followed by 25, 50, 75, or 100 mg eq. flexible dosing. Of the 388 patients enrolled, 288 completed the open-label extension. During the open-label extension, the median (range) duration of exposure to paliperidone palmitate was 338 days (10; 390), and 74% of patients received all 12 open-label injections of paliperidone palmitate. The most frequent (≥5% in total group) adverse events were insomnia (7%); worsening of schizophrenia; nasopharyngitis; headache; and weight increase (6% each). Potentially prolactin-related adverse events occurred in 13 (3%) patients, mostly women, and none resulted in study discontinuation. Extrapyramidal treatment-emergent adverse events were reported in 25 (6%) patients; tremor was the most frequently reported ( n = 8, 2%). At open-label extension endpoint, investigator-rated redness at the injection site was observed in ≤4% of patients in each group. Injection-site pain was rated by investigators as absent in 82–87% of patients. Schizophrenia symptoms measured by Positive and Negative Syndrome Scale and personal and social performance changes improved during the open-label extension.

Paliperidone palmitate (PP) is a recently (USA) approved injectable new-generation antipsychotic. This 53-wk, Phase-III double-blind study was designed to assess the non-inferiority of PP to risperidone long-acting injectable (RIS-LAI) in schizophrenia treatment. Acutely symptomatic patients (n=749), with a Positive and Negative Syndrome Scale (PANSS) total score between 60 and 120 were randomly allocated to gluteal injections of either (a) PP: 50 mg eq. on days 1 and 8, and flexible dosing [25-100 mg eq. (i.e. 39-156 mg USA dosing)] once-monthly; or (b) RIS-LAI: bi-weekly injections of 25 mg on days 8 and 22, and flexible dosing (25-50 mg) starting from day 36, with allowed oral supplementation. Patients (n=747) were 59% men, 92% white, mean (s.d.) age of 41 (11.95) yr and 45% (n=339) completed the study. Mean (s.d.) change from baseline to endpoint in PANSS total score was: -11.6 (21.22) PP; and -14.4 (19.76) RIS-LAI (per-protocol analysis set, primary measure); least-squares means difference was -2.6 (95% CI -5.84 to 0.61), with a prespecified 5-point non-inferiority margin. PP's suboptimal dosing regimen (<150 mg eq. initial dose) resulted in lower median plasma levels of the active moiety in PP-treated vs. RIS-LAI-treated patients. Insomnia was the most common treatment-emergent adverse event, with a similar incidence in both groups (15%). PP did not demonstrate comparable efficacy to RIS-LAI, which may be attributable to the initiation dosing strategy employed. Tolerability of both treatments was comparable to previous studies, with no new safety signals detected.

While placebo-controlled studies continue to be required by regulatory authorities for the licensing of new drugs for schizophrenia to demonstrate maintenance of effect, the long-term risks to participants are largely unknown. We compared the response to treatment with paliperidone palmitate before and after relapse in such a study. This was a post-hoc analysis of 97 patients with schizophrenia who relapsed while receiving placebo in a multinational relapse prevention clinical trial. Patients underwent an initial open-label treatment phase of 33 weeks (comprising a 9-week transition phase to switch patients to paliperidone palmitate, a 12-week flexible-dose phase and a 12-week fixed-dose phase); a double-blind phase of variable duration during which stabilized patients were randomized 1:1 to either continue paliperidone palmitate or receive placebo; and an optional 52-week open-label flexible-dose extension phase. There was a small but significant increase in PANSS total scores after eight months of treatment following relapse (56.7[12.68]) compared with prerelapse endpoint (54.5[11.74]) (p=0.026). Fourteen of 97 (14.4%) patients who had initially responded favorably to treatment met predefined nonresponse criteria in the postrelapse treatment phase, suggesting that treatment refractoriness may evolve in a subset of patients after relapse. However, relapses occurred in 18% of patients randomized to ongoing treatment in the double-blind phase, raising the possibility that treatment failure may also evolve in patients receiving continuous treatment. These findings may help inform decisions regarding the future of placebo-controlled trials in schizophrenia.

This multicenter, randomized, open-label, parallel-group, phase-1 study assessed the pharmacokinetics (PK), safety, and tolerability of the investigational intramuscular paliperidone palmitate 3-month (PP3M) formulation in patients with schizophrenia or schizoaffective disorder. A total of 328 patients (men or women, aged 18-65 years) were enrolled in 1 of 4 separately conducted panels (A to D). Each panel had 2 single-dose treatment periods (period 1, 1 mg intramuscular paliperidone immediate release [IR]; period 2, intramuscular PP3M 75-525 mg eq) separated by a washout of 7-21 days. Overall, 245 of 308 (79.5%) PP3M-dosed patients completed the study. Because the PK studies of panels A and C were compromised by incomplete injection in some patients, PK data from only panels B and D are presented. Safety data from all panels are presented. Peak paliperidone plasma concentration was achieved between 23 and 34 days, and apparent half-life was ∼2-4 months. Mean plasma AUC∞ and Cmax of paliperidone appeared to be dose-proportional. Relative bioavailability in comparison with paliperidone was ∼100% independent of the dose and injection site. Headache and nasopharyngitis were the most common (>7%) treatment-emergent adverse events. Overall, safety and tolerability were similar to those of the 1-month formulation. Results support a once-every-3-months dosing interval in patients with schizophrenia or schizoaffective disorder.

To evaluate the effect of 1 oral and 2 distinct long-acting injectable (LAI) formulations of the same antipsychotic on times to relapse following medication discontinuation.Data were drawn from 3 similarly designed, multicenter, double-blind, placebo-controlled, randomized-withdrawal studies of paliperidone in adults with a schizophrenia diagnosis (according to DSM-IV criteria for ≥ 1 year before screening): once-daily extended-release oral paliperidone (ORAL paliperidone), once-monthly paliperidone palmitate (PP1M), and once-every-3-months paliperidone palmitate (PP3M). In a post hoc analysis, we compared median time to relapse across the treatment-withdrawal arms of the 3 studies using final analysis datasets. Time to relapse in the withdrawal arm of each study was examined using log-rank tests and Cox proportional hazards models.Four hundred forty-nine patients were withdrawn from 3 paliperidone formulations: 101 from ORAL paliperidone, 203 from PP1M, and 145 from PP3M. Postwithdrawal median (95% confidence interval [CI]) days to relapse were 58 days (42-114 days) for ORAL paliperidone, 172 days (134-222 days) for PP1M, and 395 days (274 days-not reached) for PP3M (P < .0001, pairwise comparisons). Relapse risk was significantly lower (P < .001) for patients who withdrew from either PP formulation relative to ORAL paliperidone and additionally for patients who withdrew from PP3M relative to PP1M.Results demonstrate that 50% of patients who withdrew treatment from ORAL paliperidone, PP1M, or PP3M remained relapse free for approximately 2 months, 6 months, and 13 months, respectively. This may be relevant for risk mitigation strategies in schizophrenia, a condition in which interruptions in maintenance antipsychotic treatment are commonplace and unpredictable. LAI antipsychotic formulations may provide substantial delays over oral equivalents in times to relapse when patients discontinue therapy.ClinicalTrials.gov identifiers: NCT00086320, NCT00111189, and NCT01529515.

This double-blind (DB), randomized, parallel-group study was designed to evaluate efficacy and safety of paliperidone palmitate 6-month (PP6M) formulation relative to paliperidone palmitate 3-month (PP3M) formulation in patients with schizophrenia.Following screening, patients entered an open-label (OL) maintenance phase and received 1 injection cycle of paliperidone palmitate 1-month (PP1M; 100 or 150 mg eq.) or PP3M (350 or 525 mg eq.). Clinically stable patients were randomized (2:1) to receive PP6M (700 or 1000 mg eq., gluteal injections) or PP3M (350 or 525 mg eq.) in a 12-month DB phase; 2 doses of PP6M (corresponding to doses of PP1M and PP3M) were chosen.Overall, 1036 patients were screened, 838 entered the OL phase, and 702 (mean age: 40.8 years) were randomized (PP6M: 478; PP3M: 224); 618 (88.0%) patients completed the DB phase (PP6M: 416 [87.0%]; PP3M: 202 [90.2%]). Relapse rates were PP6M, 7.5% (n = 36) and PP3M, 4.9% (n = 11). The Kaplan-Meier estimate of the difference (95% CI) between treatment groups (PP6M - PP3M) in the percentages of patients who remained relapse free was -2.9% (-6.8%, 1.1%), thus meeting noninferiority criteria (95% CI lower bound is larger than the pre-specified noninferiority margin of -10%). Secondary efficacy endpoints corroborated the primary analysis. Incidences of treatment-emergent adverse events were similar between PP6M (62.1%) and PP3M (58.5%). No new safety concerns emerged.The efficacy of a twice-yearly dosing regimen of PP6M was noninferior to that of PP3M in preventing relapse in patients with schizophrenia adequately treated with PP1M or PP3M.Clinical Trials.gov identifier: NCT03345342.

Abstract Suicide is a worldwide health crisis. We aimed to identify genetic risk variants associated with suicide death and suicidal behavior. Meta-analysis for suicide death was performed using 3765 cases from Utah and matching 6572 controls of European ancestry. Meta-analysis for suicidal behavior using data across five cohorts ( n = 8315 cases and 256,478 psychiatric or populational controls of European ancestry) was also performed. One locus in neuroligin 1 ( NLGN1 ) passing the genome-wide significance threshold for suicide death was identified (top SNP rs73182688, with p = 5.48 × 10 −8 before and p = 4.55 × 10 −8 after mtCOJO analysis conditioning on MDD to remove genetic effects on suicide mediated by MDD). Conditioning on suicidal attempts did not significantly change the association strength ( p = 6.02 × 10 −8 ), suggesting suicide death specificity. NLGN1 encodes a member of a family of neuronal cell surface proteins. Members of this family act as splice site-specific ligands for beta-neurexins and may be involved in synaptogenesis. The NRXN-NLGN pathway was previously implicated in suicide, autism, and schizophrenia. We additionally identified ROBO2 and ZNF28 associations with suicidal behavior in the meta-analysis across five cohorts in gene-based association analysis using MAGMA. Lastly, we replicated two loci including variants near SOX5 and LOC101928519 associated with suicidal attempts identified in the ISGC and MVP meta-analysis using the independent FinnGen samples. Suicide death and suicidal behavior showed positive genetic correlations with depression, schizophrenia, pain, and suicidal attempt, and negative genetic correlation with educational attainment. These correlations remained significant after conditioning on depression, suggesting pleiotropic effects among these traits. Bidirectional generalized summary-data-based Mendelian randomization analysis suggests that genetic risk for the suicidal attempt and suicide death are both bi-directionally causal for MDD.

Medication nonadherence in schizophrenia can have serious implications including relapses and hospitalization. Long-acting injectable (LAI) antipsychotics require fewer administrations, while ensuring sustained medication coverage. In this review, we summarize the expected real-world benefits of longer dosing intervals in the management of schizophrenia. LAIs are associated with improved clinical outcomes of less frequent relapses and reduced functional impairment, encouraging patients to regain control of their lives. Aripiprazole lauroxil and paliperidone palmitate three-monthly (PP3M) LAIs have longer dosing intervals of 2-3 months and provide improved outcomes in patients with schizophrenia. Paliperidone palmitate six-monthly (PP6M) LAI provides the longest dosing interval, twice-yearly dosing, among existing LAIs. Decreasing the frequency of LAI administrations has the potential to reduce occurrence of serious outcomes associated with poor medication adherence. By eliminating the need for daily oral antipsychotic dosing, LAIs could increase the likelihood of patient acceptance, decrease stigma, and promote self-esteem. Longer intervals of medication coverage may be desirable for patients with higher risk of relapse including adults with recent-onset schizophrenia, those living in circumstances that may deprive them of regular access (eg, homeless), those that are in transitions between care settings or to reduce interpersonal contact during public health emergencies (eg, COVID-19 pandemic).

Objective:This article overviews the recommended dosing strategies for the treatment of schizophrenia patients using the recently FDA-approved once-monthly long-acting injectable atypical antipsychotic, paliperidone palmitate.Methods:Using pharmacokinetic (PK), efficacy and safety data from clinical trials and a comprehensive population PK simulation model, dosing recommendations for paliperidone palmitate have been generated.Results:The recommended initiation regimen is 150 mg eq. paliperidone palmitate (234 mg) on Day 1 followed by 100 mg eq. paliperidone palmitate (156 mg) on Day 8, each administered into the deltoid muscle, using a 1-inch 23 gauge (G) needle in those <90 kg and a 1.5-inch 22 G needle in those ≥90 kg. No oral supplementation is required. Monthly maintenance doses of paliperidone palmitate range from 25–150 mg eq. (39–234 mg; recommended dose of 75 mg eq. [117 mg]) injected into the deltoid (using weight-adjusted needle) or gluteal (using 1.5 inch 22 G needle) muscle. The Day 8 dose may be administered ±2 days and monthly doses ±7 days, without a clinically significant impact on plasma concentrations. In patients with mild renal impairment (creatinine clearance [CrCL]: 50–80 mL/min), dosage should be adjusted. No dose adjustment is required in patients with mild or moderate hepatic impairment; no data currently exist regarding severe hepatic impairment. Elderly patients with normal renal function should receive the same dosage as younger adult patients with normal renal function. In the event of an age-related decline in CrCL, dosage should be adjusted accordingly. Paliperidone palmitate treatment can be initiated the day after discontinuing previous oral antipsychotic treatment. Paliperidone palmitate should be initiated at the next scheduled injection, and monthly thereafter, in patients switching from other long-acting injectable antipsychotics, including long-acting risperidone.Conclusions:These data provide practical guidance to clinicians on how to use paliperidone palmitate in adult patients with schizophrenia.

There are no previous reports of paliperidone palmitate's (PP) long term tolerability or pharmacokinetics of the highest dose in patients with schizophrenia. This study evaluates safety and tolerability, as well as pharmacokinetics, of the highest marketed dose of PP (150 mg eq. [234 mg]) in stable patients with schizophrenia over a 1-year period.In this 1-year prospective study, eligible patients (aged 18-65 years; Positive and Negative Syndrome Scale's total score ≤ 70) received an initial deltoid injection of PP 150 mg eq. The second injection one week later and subsequent once-monthly injections were deltoid or gluteal. All injections were to be PP 150 mg eq. Patients willing to participate in intensive pharmacokinetic sampling were classified as Treatment A. Patients unwilling to undergo intensive pharmacokinetic sampling or unable to tolerate the 150 mg eq. dose (consequently receiving flexible doses of 50, 100 or 150 mg eq.) were classified as Treatment B.Of the 212 patients (safety analysis set), 73% were men; 45% white; 20% black; 34% Asians; mean (SD) age 41 (10.2) years, and mean (SD) baseline Positive and Negative Syndrome Scale total score 54.9 (9.03). A total of 53% (n = 113) patients completed the study and 104 received PP 150 mg eq. throughout. Mean (SD) mode dose of PP was 144.8 (19.58) mg eq. The dosing initiation regimen resulted in rapidly achieved and maintained therapeutic paliperidone levels over the study (average concentrations during the dosing interval were 34.7, 40.0, and 47.8 ng/mL after the 2nd, 8th, and 14th injection respectively). Most frequent (≥ 10%) treatment-emergent adverse events were nasopharyngitis (n = 37), insomnia (n = 32), injection-site pain (n = 32), headache (n = 28), and tachycardia (n = 27). Akathisia (n = 19) and tremor (n = 11) were the most common extrapyramidal adverse events. 33 patients had an SAE and 27 discontinued due to treatment-emergent adverse events. No deaths were reported. Mean (SD) weight change from baseline was 2.5 (5.41) kg at endpoint. Patients' psychoses remained stable.Safety results after one-year therapy with the highest available dose of once-monthly paliperidone palmitate were consistent with results from previous studies, with no new concerns noted. Plasma concentrations were within the expected range.ClinicalTrials.gov: NCT01150448.

We carried out a GWAS meta-analysis of combined mixed-ancestry schizophrenia, schizoaffective, and bipolar cohorts that resulted in the identification of six genome-wide significant loci, including one novel locus at chr8q24.3, encompassing TSNARE1 (P = 1.28 × 10−9). The analysis included a total of 13,394 cases and 34,676 controls. While the function of TSNARE1 remains unknown, bioinformatic predictions based on phylogenetic ancestry indicate it may have a vertebrate-specific function in intracellular protein transport and synaptic vesicle exocytosis.

Clinical response to the atypical antipsychotic paliperidone is known to vary among schizophrenic patients. We carried out a genome-wide association study to identify common genetic variants predictive of paliperidone efficacy.We leveraged a collection of 1390 samples from individuals of European ancestry enrolled in 12 clinical studies investigating the efficacy of the extended-release tablet paliperidone ER (n1=490) and the once-monthly injection paliperidone palmitate (n2=550 and n3=350). We carried out a genome-wide association study using a general linear model (GLM) analysis on three separate cohorts, followed by meta-analysis and using a mixed linear model analysis on all samples. The variations in response explained by each single nucleotide polymorphism (hSNP) were estimated.No SNP passed genome-wide significance in the GLM-based analyses with suggestive signals from rs56240334 [P=7.97×10 for change in the Clinical Global Impression Scale-Severity (CGI-S); P=8.72×10 for change in the total Positive and Negative Syndrome Scale (PANSS)] in the intron of ADCK1. The mixed linear model-based association P-values for rs56240334 were consistent with the results from GLM-based analyses and the association with change in CGI-S (P=4.26×10) reached genome-wide significance (i.e. P<5×10). We also found suggestive evidence for a polygenic contribution toward paliperidone treatment response with estimates of heritability, hSNP, ranging from 0.31 to 0.43 for change in the total PANSS score, the PANSS positive Marder factor score, and CGI-S.Genetic variations in the ADCK1 gene may differentially predict paliperidone efficacy in schizophrenic patients. However, this finding should be replicated in additional samples.

Many patients with schizophrenia will relapse despite uninterrupted antipsychotic (AP) long-acting therapy (LAT). This exploratory analysis examined variables associated with relapse despite ensured adherence to LAT. This was a post-hoc exploratory analysis of a 1-year study of risperidone long-acting injection in patients with stable schizophrenia or schizoaffective disorder (NCT00297388; N=323). Patients were discontinued from previous oral APs and randomly assigned to biweekly intramuscular injections of risperidone long-acting injectable 50 (n=163) or 25 mg (n=161) for 52 weeks. Cox proportional hazards regression models examined variables putatively associated with relapse. A total of 59/323 (18.3%) patients relapsed over 12 months despite continuous AP LAT. Variables associated with the risk of relapse included illness duration (6.0% increase each year; P=0.0003) and country (Canada vs. USA, 4.7-fold risk increase; P=0.0008). When illness duration was further categorized as ≤5, 6–10, and >10 years, patients with an illness duration of >10 versus ≤5 years were at greatest risk of relapse (>10 vs. ≤5 years associated with a 4.4-fold increase in the risk of relapse; P=0.0181). Findings suggest that patients with more chronic illness have a greater risk of relapse despite ensured treatment adherence, supporting the need for early intervention to prevent the deleterious effects of chronicity.

Understanding patients' preferences for long-acting injectable (LAI) or oral antipsychotics (pills) could help reduce potential barriers to LAI use in schizophrenia.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).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.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.

To evaluate the efficacy, safety, and tolerability of paliperidone extended release (ER) relative to aripiprazole in adolescent schizophrenia.In this multicenter, double-blind, phase 3 study (screening [≤3 weeks], with an acute treatment period [8 weeks] and a maintenance period [18 weeks]), adolescents (12-17 years old) with schizophrenia (DSM-IV diagnosis; Positive and Negative Symptom Score [PANSS] total score 60-120) were randomized (1:1) to once-daily paliperidone ER (6 mg per day [days 1-7], flexibly dosed 3, 6, or 9 mg per day from week 2 to end of study [EOS]), or to aripiprazole (2 mg per day [days 1 and 2], 5 mg per day [days 3 and 4], 10 mg per day [days 5-7], flexibly dosed 5, 10, or 15 mg per day [week 2 to EOS]).Overall, 76% of enrolled patients (174/228) completed the study (paliperidone ER, 75% [85/113]; aripiprazole, 77% [89/115]). There was no significant difference in change in PANSS total scores from baseline to day 56 (primary endpoint) (paliperidone ER versus aripiprazole, -19.3 [13.80] versus -19.8 [14.56], p = .935); responders, 67.9% versus 76.3%, p = .119) and day 182 (-25.6 [16.88] versus -26.8 [18.82], p = .877; responders, 76.8% versus 81.6%, p = .444). All secondary endpoints (maintenance of clinical stability, change in PANSS-negative symptoms, Clinical Global Impression-Severity, and Personal and Social Performance scores) were similar in both treatment groups. The most common (>10% patients) treatment-emergent adverse events for paliperidone ER were akathisia, headache, somnolence, tremor, and weight gain, and for aripiprazole were worsening of schizophrenia and somnolence. Extrapyramidal symptoms including dystonia and hyperkinesia occurred in >2% in paliperidone ER-treated versus aripiprazole-treated patients.Paliperidone ER did not demonstrate superior efficacy to aripiprazole in treating adolescent schizophrenia. Both drugs showed clinically meaningful improvements in symptom and functional measurements and were generally tolerable. Clinical Trial Registration Information-An Efficacy and Safety Study of Extended-Release (ER) Paliperidone in Adolescent Participants With Schizophrenia; http://clinicaltrials.gov; NCT01009047.

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

Schizophrenia affects ∼1.1% of the United States population, resulting in substantial direct, indirect and societal costs.To evaluate hospitalization rates associated with use of paliperidone palmitate (PP).Data were from a variable-duration double-blind (DB), randomized, relapse-prevention comparison (NCT00111189) of PP vs. placebo (Pbo), followed by a 1-year open-label extension (OLE). Between-phase change in schizophrenia-related hospitalizations was evaluated using data from an investigator-completed questionnaire. Change in hospitalizations using patients before enrollment who participated in the OLE phase was also analyzed. Poisson regression was used to evaluate changes in incidence density within exposure category and by schizophrenia duration.A total of 160 patients in the PP-PP group and 153 in the Pbo-PP group from the DB to the OLE phase were included. Mean age (standard deviation [SD]), gender, and duration of schizophrenia were similar at the start of the DB phase (Pbo: 38.5 years [10.6], 51.0% male, 68.0% ≥5 years' duration; PP: 37.3 years [11.4] (p = 0.342); 51.9% male (p = 0.874); 70.0% ≥5 years' duration (p = 0.698), respectively. From the DB to the end of the OLE phase, the number of hospitalizations per person-year for patients treated during the DB phase with Pbo significantly declined from 0.27 to 0.06 (78% reduction; p = 0.005). A statistically nonsignificant difference was observed for PP patients treated during the DB phase with PP (0.11-0.04; 63.6% reduction; p = 0.076), compared with the OLE phase. Change from before enrollment to the end of the OLE phase (n = 381) produced similar results (0.35-0.04; 88.6% reduction; p < 0.001). Patients who enroll in a clinical trial may be different from the general population and this may affect the generalizability of results.From the double-blind to the open-label phase and from prior to the trial until the end of the open-label phase, hospitalizations significantly decreased for patients with schizophrenia treated with PP.

Abstract Paliperidone palmitate (PP) is a long‐acting injectable (LAI) antipsychotic, developed for monthly intramuscular (i.m.) administration into deltoid/gluteal muscle, approved for the treatment of schizophrenia in many countries. To assess the options for i.m. injection sites, dose‐proportionality of PP was investigated after injection of a single dose (25–150 mg eq.) of PP in either gluteal (n = 106) or deltoid (n = 95) muscle of schizophrenic patients. Overall, mean (geometric) area under plasma concentration–time curve from time zero to infinity (AUC ∞ ) of paliperidone increased proportionally with increasing PP doses, regardless of injection site. Mean maximum plasma concentration (C max ) was slightly less than dose‐proportional for both injection sites at PP doses &gt;50 mg eq. Mean C max was higher after injection in the deltoid compared with the gluteal muscle, except for the 100 mg eq. dose, while AUC ∞ for both injection sites was comparable at all doses. Median time to reach C max (t max ) ranged from 13–14 days after deltoid and 13–17 days after gluteal injection across all doses. Single PP injections in deltoid and gluteal muscles in the dose range of 25–150 mg eq. were generally tolerable both locally and systemically.

This commentary summarizes recommended dosing strategies for a recently developed 3 monthly long-acting injectable 1 (LAI) formulation of paliperidone palmitate (PP3M) for the treatment of schizophrenia in adults.Recommendations for different dosing scenarios are based on the pharmacokinetic, efficacy and safety outcomes from phase 1 and phase 3 studies, population pharmacokinetic models, and model based simulations.Switching to PP3M treatment is recommended only in patients previously treated with once monthly paliperidone palmitate LAI (PP1M) for at least 4 months. The first injection of PP3M (175 to 525 mg equivalent [eq.]) should be given at the time of next scheduled injection of PP1M as a 3.5-fold multiple of the last PP1M dose (50-150 mg eq.), with a dosing window of ± 1 week. Following that first injection of PP3M, once-every-three-months maintenance injections with PP3M are recommended, with a dosing window of ± 2 weeks. The doses of PP3M can be administered in either deltoid (≥ 90 kg: 1.5 inch 22 G needle; <90 kg: 1.0 inch 22 G needle) or gluteal muscles (1.5 inch 22 G needle regardless of weight). In patients with mild renal impairment (creatinine clearance: 50-80 mL/min), a 25% dose reduction in PP1M and subsequent switching to a corresponding 3.5-dose multiple of PP3M (but not exceeding 350 mg eq.) is recommended. Appropriate dosing is recommended in elderly patients with diminished renal function not exceeding mild renal impairment. Similarly to PP1M, PP3M is not recommended in patients with moderate/severe renal impairment. Like PP1M, no dosage adjustment is required in patients with mild or moderate hepatic impairment or elderly patients with normal renal function.These data provide clinical guidelines for the optimum use of PP3M in patients with schizophrenia previously treated with PP1M for at least 4 months.ClinicalTrials.gov identifier: NCT01559272 and NCT01529515.

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

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

Article AbstractBackground: The purpose of this analysis was to assess rates of symptomatic remission in patients with bipolar mania receiving risperidone in a double-blind, parallel-group, multicenter, placebo-controlled trial conducted in India. Method: Two hundred ninety-one adult patients who met DSM-IV criteria for bipolar I disorder manic or mixed episode were randomly assigned to flexible doses of risperidone (1-6 mg/day, N = 146) or placebo (N = 145) for up to 3 weeks. An entry Young Mania Rating Scale (YMRS) score of >= 20 was required at trial screening and baseline. Remission was defined as achieving and maintaining a YMRS score <= 8 for the remainder of the trial or until censor. Time to first onset of remission was assessed using Cox proportional hazards model. Presence or absence of remission was analyzed using logistic regression. Data were collected from March 2001 to December 2001. Results: Of the 291 patients randomly assigned to treatment, 290 received at least 1 postbaseline assessment and were included in the analysis. The patients†mean YMRS score at baseline was 37.2 ± 7.9. Remission was achieved by 42% of patients in the risperidone group and 13% of patients in the placebo group. After adjusting for psychosis, baseline YMRS score, sex, number of mood cycles in the previous year, and treatment, the odds of remission for patients receiving risperidone was 5.6 (95% CI = 3.0 to 10.4; c2 = 29.9, p < .0001). Similarly, the adjusted hazard of remission for the risperidone patients was 4.0 (95% CI = 2.3 to 6.8; c2 = 25.9, p < .0001). Conclusion: A significant proportion of acutely manic patients receiving risperidone monotherapy achieved symptomatic remission within 3 weeks.

A post hoc analysis of the risperidone (RIS)/paliperidone (Pali) clinical trials database comprising 64 studies was conducted. Risk of sudden death, cardiovascular (CV), and cerebrovascular events during RIS or Pali treatment was estimated. Treatment emergent CV adverse events were identified using 7 prespecified Standardised MedDRA Queries as follows: embolic/thrombotic events, cerebrovascular disorders, ischemic heart disease, cardiac arrhythmias, cardiac failure, torsades/QT prolongation, and convulsions. Risk in the RIS/Pali pooled group was significantly increased compared to placebo for the following adverse events: syncope, tachycardia, palpitations, edema peripheral, dysarthria, and transient ischemic attack. Incidence of death related to CV events was low and similar across groups. Consistent with the known pharmacologic profile and product information, this analysis of treatment emergent adverse event data from a large, randomized, controlled clinical trials database described increased risk versus placebo for several specific CV events. Apart from events described in existing product labeling, no new safety findings emerged.

Increasing availability and use of long-acting injectable antipsychotics have generated a need to compare these formulations with their oral equivalents; however, a paucity of relevant data is available.This post hoc comparison of the long-term efficacy, safety and tolerability of maintenance treatment with paliperidone palmitate (PP) versus oral paliperidone extended release (ER) used data from two similarly designed, randomised, double-blind (DB), placebo-controlled schizophrenia relapse prevention trials. Assessments included measures of time to relapse, symptom changes/functioning and treatment-emergent adverse events (TEAEs). Time to relapse between treatment groups was evaluated using a Cox proportional hazards model. Between-group differences for continuous variables for change scores during the DB phase were assessed using analysis of co-variance models. Categorical variables were evaluated using Chi-square and Fisher's exact tests. No adjustment was made for multiplicity.Approximately 45% of enrolled subjects in both trials were stabilised and randomised to the DB relapse prevention phase. Risk of relapse was higher in subjects treated with paliperidone ER than in those treated with PP [paliperidone ER/PP hazard ratio (HR), 2.52; 95% confidence interval (CI), 1.46-4.35; p < 0.001]. Similarly, risk of relapse after withdrawal of paliperidone ER treatment (placebo group of the paliperidone ER study) was higher than after withdrawal of PP (paliperidone ER placebo/PP placebo HR, 2.25; 95% CI, 1.59-3.18; p < 0.001). Stabilised schizophrenic subjects treated with PP maintained functioning demonstrated by the same proportions of subjects with mild to no difficulties in functioning at DB baseline and end point [Personal and Social Performance (PSP) scale total score >70, both approximately 58.5%; p = 1.000] compared with a 10.9% decrease for paliperidone ER (58.5% vs 47.6%, respectively; p = 0.048). The least squares mean change for Positive and Negative Syndrome Scale (PANSS) total score at DB end point in these previously stabilised subjects was 3.5 points in favour of PP (6.0 vs 2.5; p = 0.025). The rates of TEAEs and AEs of interest appeared similar.This analysis supports maintenance of effect with the injectable compared with the oral formulation of paliperidone in patients with schizophrenia. The safety profile of PP was similar to that of paliperidone ER. Future studies are needed to confirm these findings.

Effective early detection of impending relapse may offer opportunities for early interventions to prevent full relapse in schizophrenia patients. Previously reported early warning signs were not consistently validated by prospective studies. It remains unclear which symptoms are most predictive of relapse. To prioritize the symptoms to be captured by periodic self-report in technology-enabled remote assessment solutions for monitoring symptoms and detecting relapse early, we analyzed data from three relapse-prevention studies to identify individual items of the Positive and Negative Syndrome Scale (PANSS) that changed the most prior to relapse and to understand exactly when these symptoms manifested. Relapse was defined by a composite endpoint: hospitalization, suicidal/homicidal ideation, violent behavior, a 25% increase in the PANSS total score, or a significant increase in at least one of several pre-specified PANSS items. Longitudinal mixed effect models were applied to model the trajectories of individual PANSS items before relapse. Among 267 relapsed patients, the PANSS items that increased the most at relapse from randomization did not differ much by different relapse reasons or medications. A subset of seven PANSS items, including delusions, suspiciousness, hallucinations, anxiety, excitement, tension, and conceptual disorganization, had on average > 1-point of increase at relapse. The trajectories of these items suggested these items started to increase 7-10 days before relapse and reached on average 1-point of increase 0.3 ~ 1.2 days before relapse. Our results indicated that a subset of PANSS items could be leveraged to develop remote assessment solutions for monitoring symptoms and detecting relapse early in schizophrenia patients.

To quantify clinical trial participants' and investigators' judgments with respect to the relative importance of efficacy and safety attributes of antipsychotic treatments for schizophrenia, and to assess the impact of formulation and adherence.Discrete-choice experiment surveys were completed by patients with schizophrenia and physician investigators participating in two phase-3 clinical trials of paliperidone palmitate 3-month long-acting injectable (LAI) antipsychotic. Respondents were asked to choose between hypothetical antipsychotic profiles defined by efficacy, safety, and mode of administration. Data were analyzed using random-parameters logit and probit models.Patients (N=214) and physicians (N=438) preferred complete improvement in positive symptoms (severe to none) as the most important attribute, compared with improvement in any other attribute studied. Both respondents preferred 3-month and 1-month injectables to oral formulation (P<0.05), irrespective of prior adherence to oral antipsychotic treatment, with physicians showing greater preference for a 3-month over a 1-month LAI for nonadherent patients. Physicians were willing to accept treatments with reduced efficacy for patients with prior poor adherence. The maximum decrease in efficacy (95% confidence interval [CI]) that physicians would accept for switching a patient from daily oral to 3-month injectable was as follows: adherent: 9.8% (95% CI: 7.2-12.4), 20% nonadherent: 25.4% (95% CI: 21.0-29.9), and 50% nonadherent: >30%. For patients, adherent: 10.1% (95% CI: 6.1-14.1), nonadherent: the change in efficacy studied was regarded as unimportant.Improvement in positive symptoms was the most important attribute. Patients and physicians preferred LAIs over oral antipsychotics, with physicians showing a greater preference for 3-month over 1-month LAI. Physicians and patients were willing to accept reduced efficacy in exchange for switching a patient from an oral formulation to a LAI.

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

We analyzed data retrieved through a PubMed search of randomized, placebo-controlled trials of first-generation antipsychotic long-acting injectables (haloperidol decanoate, bromperidol decanoate, and fluphenazine decanoate), and a company database of paliperidone palmitate, to compare the benefit-risk ratio in patients with schizophrenia.From the eight studies that met our selection criteria, two efficacy and six safety parameters were selected for calculation of number needed to treat (NNT), number needed to harm (NNH), and the likelihood of being helped or harmed (LHH) using comparisons of active drug relative to placebo. NNTs for prevention of relapse ranged from 2 to 5 for paliperidone palmitate, haloperidol decanoate, and fluphenazine decanoate, indicating a moderate to large effect size.Among the selected maintenance studies, NNH varied considerably, but indicated a lower likelihood of encountering extrapyramidal side effects, such as akathisia, tremor, and tardive dyskinesia, with paliperidone palmitate versus placebo than with first-generation antipsychotic depot agents versus placebo. This was further supported by an overall higher NNH for paliperidone palmitate versus placebo with respect to anticholinergic use and Abnormal Involuntary Movement Scale positive score. LHH for preventing relapse versus use of anticholinergics was 15 for paliperidone palmitate and 3 for fluphenazine decanoate, favoring paliperidone palmitate.Overall, paliperidone palmitate had a similar NNT and a more favorable NNH compared with the first-generation long-acting injectables assessed.

The objective of this study was to evaluate the long-term efficacy, safety, and tolerability of paliperidone extended-release (pali ER), in Chinese patients with schizophrenia.In this parallel-group, relapse prevention, phase-3 study (screening [14-day], pali ER open-label run-in [8-week] and stabilization [6-week] phases, and double-blind (DB) treatment [variable duration], and open-label extension phases [24-week]), 136/201 patients with schizophrenia were randomized (1:1) to pali ER (3-12 mg) or placebo during the DB phase.Final analysis showed that, out of 135 patients in ITT (DB) population, 71 (52.6%) had a relapse event, 45 (33.3%) were ongoing at the time the study was stopped, and 19 (14.1%) discontinued from the DB phase. Time to relapse (primary endpoint) favored pali ER (hazard ratio=5.23 [95% CI: 2.96, 9.25], p <0.0001). Rate of relapses (55/71 [77.5%] placebo; 16/64 [25%] pali ER) and secondary endpoints (change from baseline in Positive And Negative Syndrome Scale [PANSS] and Clinical Global Impression - Severity Scores) were significantly lower (p<0.001) in pali ER group vs placebo, in favor of pali ER. More psychiatric-related treatment-emergent adverse events (TEAEs) occurred in placebo- (21.1%) than pali ER group (10.9%). Most common (>3%) TEAEs in placebo group were insomnia and schizophrenia (8.5% each), while in pali ER group were aggression and akathisia (4.7% each), and schizophrenia, tremor, nausea, amenorrhea, and salivary hypersecretion (3.1% each). All serious TEAEs were psychiatric-related (schizophrenia, aggression, completed suicide, auditory hallucination, suicide attempt) and more frequent in placebo- (11.3%) versus pali ER group (3.1%). Death and tardive dyskinesia-related discontinuation (n=1 each) occurred in placebo group. Body weight increase from run-in baseline was greater in pali ER group (mean increase: 3.90 kg) versus placebo (mean increase: 2.05 kg).This study confirms the findings from earlier pali ER global relapse-prevention studies and demonstrates that pali ER treatment (3-12 mg) is efficacious over the long-term and significantly delays relapse in Chinese patients with schizophrenia. No new safety signals were detected in this population.

Background:Relapse prevention and maintenance of social functioning are important treatment objectives in the long-term management of schizophrenia. However, relatively little is known about measuring maintenance of social functioning to assess treatment benefit in relapse prevention clinical trials or as a tool to predict relapse in clinical practice. This study aims (1) to define a clinically meaningful decrease in the Personal and Social Performance scale (PSP) to assess antipsychotic treatment benefit in terms of maintenance of functioning and (2) to explore the threshold value of PSP decline as a useful tool to predict relapse in clinical practice.Methods:This post hoc analysis of two similar placebo-controlled relapse prevention clinical trials consisted of an exploration of change in PSP that would represent a clinically important decrement to measure treatment benefit in terms of time to PSP decrement (ITT analysis set; Study 1: n = 205) and an assessment of predictive value of PSP decrement and relapse status (ITT analysis set; Study 2: n = 408).Results:A 10-point decrement in PSP score was the threshold value for a clinically meaningful decline in personal and social functioning in a relapse prevention trial (Study 1). A strong association was found with relapse status: 61% of subjects with at least a 10-point decrease in PSP experienced the decrement prior to (between start of double-blind phase and before day of relapse) or on the day of relapse (Study 2). Kaplan–Meier survival analysis of time to at least a 10-point decrement in PSP showed that the proportion of subjects who did not experience at least a 10-point PSP decrease was statistically significantly greater in the paliperidone palmitate group than in the placebo group (p = 0.0014) (Study 2).Conclusions:Findings suggest a 10-point PSP decrement is a clinically relevant measure of maintenance of functioning in patients stabilized with antipsychotic therapy. Paliperidone palmitate demonstrated a statistically significant treatment benefit in terms of maintenance of functioning versus placebo. Furthermore, measuring a clinically relevant PSP decrement may be useful as an early functional indicator of relapse in clinical practice.Limitations:The exploration and validation of the threshold value of change in the PSP was designed and conducted post hoc. Predictive value is limited by the frequency in which PSP assessments were carried out in these trials, underscoring the importance of regular assessment.

Long-acting injectable (LAI) formulations of antipsychotics are valuable treatment alternatives for patients with psychotic disorders, and understanding their safe use is critical.Post-injection delirium/sedation syndrome (PDSS) has been reported following treatment with one atypical antipsychotic LAI.Clinical databases of risperidone LAI and paliperidone palmitate were explored to identify if cases of PDSS had been observed.No cases of PDSS were identified in 15 completed trials of 3,164 subjects (approximately 115,000 injections) or the postmarketing safety database of risperidone LAI.Only one case of PDSS was identified among 10 completed trials (3,817 subjects, 33,906 injections) of paliperidone palmitate-that case having been reported in a patient randomized to treatment with placebo.Examination of these prospective databases finds no evidence that risperidone LAI and paliperidone palmitate are associated with PDSS and suggest that findings seen with another antipsychotic LAI are not generalizable.

The purpose of this study was to compare incidence rates and time course of extrapyramidal symptom (EPS)-related treatment-emergent adverse events (TEAEs) between oral and long-acting injectable (LAI) paliperidone.The analysis included pooled data (safety analysis set, 2,256 antipsychotic-treated and 865 placebo-treated patients with schizophrenia) from seven randomized, double-blind, placebo-controlled paliperidone studies (three oral [6 weeks each] and four LAI [9-13 weeks]) and assessed comparable doses (oral, 3-15 mg; LAI, 25-150 mg eq. [US doses 39-234 mg]). We summarized incidence rates and time of onset for EPS-related TEAE, categorized by EPS group terms, ie, tremor, dystonia, hyperkinesia, parkinsonism, and dyskinesia, and use of anti-EPS medication. Mean scores over time for the Abnormal Involuntary Movement Scale (AIMS, for dyskinesia), Barnes Akathisia Rating Scale (BARS, for akathisia), and Simpson Angus Rating Scale (SAS, for parkinsonism) were graphed.Incidence rates for all categories of spontaneously reported EPS-related TEAEs except for hyperkinesia, were numerically lower in pooled LAI studies than in pooled oral studies. Highest rates were observed in the first week of paliperidone-LAI (for all EPS symptoms except dyskinesia) and oral paliperidone treatment (except parkinsonism and tremor). Anti-EPS medication use was significantly lower in LAI (12%) versus oral studies (17%, P = 0.0035). Mean values for EPS scale scores were similar between LAI and oral treatment at endpoint, and no dose response was evident. Mean reductions (standard deviation) from baseline to endpoint in EPS scale scores were larger for LAI (AIMS, -0.10 [1.27]; BARS, -0.09 [1.06]; SAS, -0.04 [0.20]) versus oral studies (AIMS, -0.08 [1.32]; BARS, -0.03 [1.24]; SAS, 0.0 [0.23]). These changes favored LAI for BARS (P = 0.023) and SAS (P < 0.0001), but not for AIMS (P = 0.49), at endpoint for the studies.In this posthoc descriptive analysis, incidence rates of spontaneously reported EPS-related TEAEs were numerically lower following approximately 90 days of exposure with LAI and approximately 40 days with oral paliperidone at comparable doses.

To assess the tardive dyskinesia (TD) rate in studies of once-monthly long-acting injectable (LAI) paliperidone palmitate (PP) and once-daily oral paliperidone extended release (Pali ER).Completed schizophrenia and bipolar studies for PP and Pali ER (≥ 6 month duration with retrievable patient-level data) were included in this post hoc analysis. Schooler-Kane research criteria were applied using Abnormal Involuntary Movement Scale (AIMS) scores to categorise probable (qualifying AIMS scores persisting for ≥ 3 months) and persistent TD (score persisting ≥ 6 months). Spontaneously reported TD adverse events (AEs) were also summarised. Impact of exposure duration on dyskinesia (defined as AIMS total score ≥ 3) was assessed by summarising the monthly dyskinesia rate.In the schizophrenia studies, TD rates for PP (four studies, N = 1689) vs. Pali ER (five studies, N = 2054), were: spontaneously reported AE, 0.18% (PP) vs. 0.10% (Pali ER); probable TD, 0.12% (PP) vs. 0.19% (Pali ER) and persistent TD, 0.12% (PP) vs. 0.05% (Pali ER). In the only bipolar study identified [Pali ER (N = 614)], TD rate was zero (spontaneously reported AE reporting, probable and persistent TD assessments). Dyskinesia rate was higher within the first month of treatment with both PP (13.1%) and Pali ER (11.7%) and steadily decreased over time (months 6-7: PP: 5.4%; Pali ER: 6.4%). Mean exposure: PP, 279.6 days; Pali ER, 187.2 days.Risk of TD with paliperidone was low (< 0.2%), regardless of the formulation (oral or LAI), in this clinical trial dataset. Longer cumulative exposure does not appear to increase the risk of dyskinesias.

Previous studies have shown an increased risk for mental health problems in children born to both younger and older parents compared to children of average-aged parents. We previously used a novel design to reveal a latent mechanism of genetic association between schizophrenia and age at first birth in women (AFB). Here, we use independent data from the UK Biobank (N = 38,892) to replicate the finding of an association between predicted genetic risk of schizophrenia and AFB in women, and to estimate the genetic correlation between schizophrenia and AFB in women stratified into younger and older groups. We find evidence for an association between predicted genetic risk of schizophrenia and AFB in women (P-value = 1.12E-05), and we show genetic heterogeneity between younger and older AFB groups (P-value = 3.45E-03). The genetic correlation between schizophrenia and AFB in the younger AFB group is -0.16 (SE = 0.04) while that between schizophrenia and AFB in the older AFB group is 0.14 (SE = 0.08). Our results suggest that early, and perhaps also late, age at first birth in women is associated with increased genetic risk for schizophrenia in the UK Biobank sample. These findings contribute new insights into factors contributing to the complex bio-social risk architecture underpinning the association between parental age and offspring mental health.

The purpose of this study was to evaluate the long-term safety and tolerability of paliperidone extended-release (ER) in adolescents with schizophrenia.This was a 2 year open-label, multicenter study in adolescents (12-17 years of age, inclusive) with schizophrenia. Eligible patients were initially treated with 6 mg/day paliperidone ER, and the dose could be adjusted between 1.5 and 12 mg/day based on clinical need. Safety parameters were treatment-emergent adverse events (TEAEs), weight, Tanner staging, blood chemistry (including prolactin, glucose, insulin, and lipid levels), and extrapyramidal symptom (EPS) scales. The main efficacy end-point was change from baseline to endpoint in Positive and Negative Syndrome Scale for Schizophrenia (PANSS) total score.Of 400 enrolled patients (mean age, 15.4 years; boys, 61%), 220 were completers. Median (range) exposure was 604.5 (2-765) days. TEAEs were reported in 85.3% of patients; most frequently reported TEAEs included somnolence, increased weight, headache, insomnia, nasopharyngitis, akathisia, schizophrenia exacerbation, and tremor. No deaths were reported. There were no clinically significant mean changes in growth-adjusted z score for change in weight, height, or body mass index (BMI). Tanner ratings showed normal maturation. Most frequently occurring EPS-related events were related to Parkinsonism (15.5%) and hyperkinesia (13.8%). No cases of tardive dyskinesia were reported. Hyperprolactinemia (based on laboratory values) was noted in 56% of patients and 9.3% of patients had prolactin-related TEAEs. A low percentage of patients (4.3%, n=14) had a shift from normal or impaired fasting glucose to high levels. Mean (SD) decrease (improvement) in PANSS total score from baseline to end-point was -19.1 (21.89). The majority of patients had a ≥20% improvement in PANSS total score (responders) from initial treatment with paliperidone ER. Overall, 41.7% of patients achieved remission during the study.Paliperidone ER was generally tolerable, and exhibited efficacy in the maintenance treatment of schizophrenia in adolescents in this large 2 year study.

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.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).Data from three similarly designed, randomized relapse prevention studies in adult patients with schizophrenia were analyzed.In total, 922 patients were included (active treatment: 473, placebo: 449). Lowest percentage of patients experienced relapse with PP3M <PP1M <paliperidone and ER, in both the active treatment (PP3M, 9% <PP1M, 18% <paliperidone ER, 22%) and placebo (PP3M, 29% <PP1M, 48% <paliperidone ER, 52%) groups. The post-discontinuation median-time-to-relapse was significantly longer with PP3M (395 days [274 days to "not-reached"])> 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]).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).

To examine efficacy and safety of paliperidone palmitate (PP) 6-month (PP6M) vs PP3-month (PP3M) long acting injectable (LAI) in patients with schizophrenia from European sites previously stabilized on PP3M or PP1-month (PP1M).This post-hoc subgroup analysis used data from a global phase-3 double-blind (DB) randomized non-inferiority study (NCT03345342). Patients were randomized (2:1, respectively) to receive dorsogluteal injections of PP6M (700 mg eq. or 1000 mg eq.) or PP3M (350 mg eq. or 525 mg eq.) in the 12-month DB phase. Primary endpoint was time-to-relapse during the DB phase, using a Kaplan-Meier cumulative survival estimate (non-inferiority margin 95% CI lower bound larger than prespecified as -10%). Treatment emergent adverse events (TEAEs), physical examinations, and laboratory tests were also evaluated.A total of 384 patients who entered the DB phase were included in European sites (PP6M, n = 260; PP3M, n = 124) with a mean age similar in both groups (mean age [SD] years: PP6M, 40.0 [11.39]; PP3M, 38.8 [10.41]). Baseline characteristics were similar across both groups. The number of patients who experienced a relapse during DB phase were PP6M: 18 (6.9%) vs PP3M: 3 (2.4%) with percentage relapse-free difference of -4.9% (95% CI: -9.2%, -0.5%), thus achieving non-inferiority criteria. Secondary efficacy endpoints indicated comparable improvements. Incidence of TEAEs was similar between PP6M (58.8%) and PP3M (54.8%) groups. Nasopharyngitis, headache, increased weight, and injection-site pain were the most common TEAEs.The efficacy of PP6M was non-inferior to that of PP3M in preventing relapse in the European subgroup previously treated with PP1M or PP3M, which was consistent with the global study. No new safety signals were identified.

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

Objective Clinical response to antipsychotic medications can vary markedly in patients with schizophrenia. Identifying genetic variants associated with treatment response could help optimize patient care and outcome. To this end, we carried out a large-scale candidate gene study to identify genetic risk factors predictive of paliperidone efficacy. Patients and methods A central nervous system custom chip containing single nucleotide polymorphisms from 1204 candidate genes was utilized to genotype a discovery cohort of 684 schizophrenia patients from four clinical studies of paliperidone extended-release and paliperidone palmitate. Variants predictive of paliperidone efficacy were identified and further tested in four independent replication cohorts of schizophrenic patients (N=2856). Results We identified an SNP in ERBB4 that may contribute toward differential treatment response to paliperidone. The association trended in the same direction as the discovery cohort in two of the four replication cohorts, but ultimately did not survive multiple testing corrections. The association was not replicated in the other two independent cohorts. We also report several SNPs in well-known schizophrenia candidate genes that show suggestive associations with paliperidone efficacy. Conclusion These preliminary findings suggest that genetic variation in the ERBB4 gene may differentially affect treatment response to paliperidone in individuals with schizophrenia. They implicate the neuregulin 1 (NRG1)–ErbB4 pathway for modulating antipsychotic response. However, these findings were not robustly reproduced in replication cohorts.

Background: Paliperidone palmitate has been associated with serum prolactin elevations in some patients. However, few individuals with elevated prolactin levels (hyperprolactinomia) have symptomatic potentially prolactin-related adverse events (PPR-AEs). Objective: To quantify rates of hyperprolactinemia in subjects treated with the newly marketed paliperidone palmitate long-acting injection (PP-LAI) in randomized clinical trials, summarize rates of PPR-AEs in those trials by sex and dose, and determine how many PPR-AEs required treatment. Methods: Numbers and rates of investigator-reported hyperprolactinemia and PPR-AEs wore obtained from the sponsor's clinical trial database and have been included in regulatory filings. Results were tabulated for males, females, and overall, and by dose administered, using descriptive statistics. Those requiring treatment were described as well. Results: There were 3173 subjects (61.4% males) exposed to PP-LAI in 10 clinical trials; 2831 (89.2%) patients had recorded prolactin levels, including 1759 males (90, 3% of exposed males) and 1072 females (87.5% of exposed females). Overall, at any time, prolactin levels were elevated for 38.8% of the subjects (39.5% for males and 37.7% for females; p = 0.354 between sexes). However, them was no significant correlation between monthly dose and proportion of subjects with elevated prolactin levels (p = 0.109). There were 115 PPR-AEs in 107 patients (3.4%); 51 (44.3% of PPR-AEs) cases represented asymptomatic hyperprolactinemia. The remaining 64 symptomatic PPR-AEs affected 2.0% of the total number of subjects. Fifteen events in 13 participants (0.41% of patients or 4.7 events/1000 patients) required treatment. Conclusions: Clinicians should periodically assess patients on paliperidone palmitate for any PPR-AEs and carefully assess the benefits and risks when managing these effects.

Paliperidone palmitate once-monthly injectable (PP1M) is approved in Japan and other countries for the treatment of schizophrenia. During the 6 month Japanese early postmarketing phase vigilance (EPPV) period, 32 deaths were reported. This report reviews potential contributing factors to the fatal outcomes in the PP1M-treated population.All spontaneously reported adverse events following PP1M use received during EPPV from 19 November 2013 to 18 May 2014 were entered into the global safety database and these events were analyzed.During the EPPV period, 10,962 patients were estimated to have been treated with PP1M in Japan. The mortality reporting rate during this EPPV period was higher than that observed in the US or globally after PP1M launch (5.84, 0.43, and 0.38 per 1000 patient-years, respectively), but was consistent with the mortality incidence rates (10.2 per 1000 person-years) observed during interventional clinical studies in Japan and in observational patient cohorts. Of the 32 deaths reported during the Japanese PP1M EPPV period, 19/32 (59.4%) were in patients over 50 years of age, 23/32 (71.9%) reported cardiovascular risk factors and 25/32 (78.1%) received antipsychotic polypharmacy.Based on this review of the 32 fatal cases in the PP1M EPPV period, the observed death rate does not necessarily result from a risk with PP1M treatment in Japanese patients. The higher mortality reporting rates in Japan may be attributed to a variety of factors: the effectiveness of mortality reporting in the unique Japanese EPPV program, the advanced age of the fatal cases, high cardiovascular risk factors, multiple underlying diseases and high antipsychotic polypharmacy among the cases with fatal outcomes.

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

International Journal of Clinical PracticeVolume 72, Issue 6 e13089 ORIGINAL PAPEROpen Access Maintenance dose conversion between oral risperidone and paliperidone palmitate 1 month: Practical guidance based on pharmacokinetic simulations Alberto Russu, Corresponding Author Alberto Russu arussu@its.jnj.com orcid.org/0000-0003-2095-4365 Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium Correspondence Alberto Russu, PhD, Global Clinical Pharmacology, Quantitative Sciences, Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium. Email: arussu@its.jnj.comSearch for more papers by this authorJennifer Kern Sliwa, Jennifer Kern Sliwa Janssen Scientific Affairs, LLC, Titusville, NJ, USASearch for more papers by this authorPaulien Ravenstijn, Paulien Ravenstijn Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Beerse, BelgiumSearch for more papers by this authorArun Singh, Arun Singh Janssen Research & Development, Titusville, NJ, USASearch for more papers by this authorMaju Mathews, Maju Mathews Janssen Research & Development, Titusville, NJ, USASearch for more papers by this authorEdward Kim, Edward Kim Janssen Scientific Affairs, LLC, Titusville, NJ, USASearch for more papers by this authorSrihari Gopal, Srihari Gopal Janssen Research & Development, Titusville, NJ, USASearch for more papers by this author Alberto Russu, Corresponding Author Alberto Russu arussu@its.jnj.com orcid.org/0000-0003-2095-4365 Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium Correspondence Alberto Russu, PhD, Global Clinical Pharmacology, Quantitative Sciences, Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium. Email: arussu@its.jnj.comSearch for more papers by this authorJennifer Kern Sliwa, Jennifer Kern Sliwa Janssen Scientific Affairs, LLC, Titusville, NJ, USASearch for more papers by this authorPaulien Ravenstijn, Paulien Ravenstijn Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Beerse, BelgiumSearch for more papers by this authorArun Singh, Arun Singh Janssen Research & Development, Titusville, NJ, USASearch for more papers by this authorMaju Mathews, Maju Mathews Janssen Research & Development, Titusville, NJ, USASearch for more papers by this authorEdward Kim, Edward Kim Janssen Scientific Affairs, LLC, Titusville, NJ, USASearch for more papers by this authorSrihari Gopal, Srihari Gopal Janssen Research & Development, Titusville, NJ, USASearch for more papers by this author First published: 30 April 2018 https://doi.org/10.1111/ijcp.13089Citations: 9 Funding information This study was funded by Janssen Research & Development, LLC, USA. AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Summary Aim We assessed the dosage strengths of paliperidone palmitate 1-month (PP1M) long-acting injectable resulting in similar steady-state (SS) exposures to the dosage strengths of oral risperidone using pharmacokinetic (PK) simulations. Methods Population PK simulations of SS PK were performed using the PK models of oral risperidone and PP1M. The concentrations of active moiety (risperidone + paliperidone) from risperidone were compared to paliperidone concentrations resulting from PP1M administration. Similarity was assessed via graphical evaluation of median and 90% prediction intervals of SS PK profiles over 28 days. Results Oral risperidone doses of 1, 2, 3, 4, and 6 mg/d are expected to result in similar SS PK as PP1M doses of 25, 50, 75, 100, and 150 mg eq. (which correspond to 39, 78, 117, 156, and 234 mg of paliperidone palmitate) respectively (ie 25-fold dose conversion factor from oral risperidone to PP1M). Conclusions This study provides clinicians with a practical guidance to establish suitable maintenance dose levels of PP1M and oral risperidone when transitioning patients from one formulation to another. What's known Paliperidone palmitate 3-month formulation can be administered after patients are adequately treated and stabilised for at least 4 months on the 1-month formulation. The corresponding oral paliperidone to paliperidone palmitate 1-month (PP1M) maintenance dose conversion has previously been described (PP1M product information). What's new This study provides clinicians with a practical guidance to establish suitable maintenance dose levels of PP1M and oral risperidone when transitioning patients from one formulation to another. 1 INTRODUCTION Schizophrenia is a chronic debilitating illness, often with high relapse rates and a chronic course.1 Most patients require long-term treatment with antipsychotic medications.1 Frequent switching of antipsychotic medications due to lack of efficacy, tolerability and non-adherence issues are common in schizophrenia treatment.2 Long-acting injectable (LAI) formulations provide an advantage over oral antipsychotics with improved treatment outcomes including improved medication adherence and persistence, lower rates of hospitalisations, and a pharmacokinetic (PK) profile characterised by a prolonged terminal phase that helps delay relapse compared to oral formulations.3 Paliperidone (9-hydroxyrisperidone) is the major metabolite of risperidone, with a similar serotonin (5HT2A) and dopamine (D2) antagonism and receptor binding profile.4 Patients taking risperidone are therefore exposed as well to paliperidone following in vivo conversion and the clinical effects of oral risperidone result from the combined concentrations of risperidone and paliperidone (ie active-moiety).5 Paliperidone palmitate is a long-acting injectable formulation of paliperidone that is available in 1-month and 3-month formulations. The paliperidone palmitate 3-month formulation (PP3M) can be administered after patients are adequately treated and symptomatically stabilised for at least 4 months on the paliperidone palmitate 1-month formulation (PP1M). The corresponding PP3M dose is 3.5 times the maintenance PP1M dose. The corresponding oral paliperidone to PP1M maintenance dose has already been established (PP1M prescribing information).6 However, data are not available describing corresponding maintenance dose levels of PP1M for patients previously stabilised on oral risperidone. Moreover, to our knowledge, no clinical studies have been performed that provide a direct comparison of steady-state (SS) risperidone and paliperidone exposures following oral risperidone or PP1M administration. This study aims to assess the dose strengths of PP1M that result in similar SS exposures to the dose strengths of oral risperidone, using PK simulations based on population PK models developed for the two formulations. Population PK techniques provide a unified framework to characterise the PK of a compound by condensing observations from multiple studies while accounting for differences in patient factors and study design. Both short-term and long-term studies utilising sparse and/or rich PK sampling contribute to the understanding of the PK properties. The use of population PK approaches is well accepted and has been advocated by many regulatory agencies including FDA and CHMP.7, 8 A similar methodology to that described in this work has been applied to derive the dose conversion factor between PP1M and PP3M,9, 10 between oral paliperidone extended-release (ER) or risperidone LAI and PP1M,11 and between paliperidone ER and PP1M.6 In this work, we leverage population PK simulations to provide prescribers with practical guidance on PP1M maintenance dosing after transition from oral risperidone. 2 METHODS To estimate the maintenance dose conversion between formulations, model-based PK simulations were performed using the population PK models of oral risperidone and PP1M, which were developed and validated based on extensive clinical study data, ie 780 patients from 9 studies for risperidone12 and 1795 patients from 11 trials for PP1M.13 For oral risperidone, the PK of the active antipsychotic fraction (ie active moiety, risperidone plus paliperidone) was characterised by a first-order absorption process with delay, describing absorption from gut to the central (plasma) compartment, and by a two-compartment disposition model with linear elimination. Variability in PK was described via covariate effects of body weight on volume of distribution (ie larger volume for heavier patients) and of body weight, age, and renal function on oral clearance (ie reduced clearance for older patients and for patients with reduced renal function, as measured by creatinine clearance, and greater clearance for heavier patients), as well as via random inter-individual variability terms accounting for unexplained variability sources on absorption and disposition. While risperidone metabolism is known to be influenced by CYP2D6 genotype, the PK of the active moiety has been shown to be on average similar across different metabolic phenotypes, ie poor, intermediate, and extensive metabolisers.14 Therefore, no inter-patient variability in CYP2D6 metabolic status needed to be accounted for in the active moiety PK model of oral risperidone. For PP1M, a dual-input absorption process from the depot compartment was used to describe the poly-phasic release profile of paliperidone in the central compartment. Briefly, a zero-order absorption process directly in the central compartment (accounting for about 17% of the total dose) described the rapid appearance of paliperidone in the systemic circulation immediately following intramuscular injection. The remaining fraction of dose was assumed to be absorbed via a linear process following a given lag time (equal to the duration of the zero-order process, about 13 days). Disposition was described via a one-compartment model with linear elimination. As established in a previous study,13 the patient characteristics influencing inter-patient variability in PP1M PK were consistent with those identified for oral risperidone, eg covariate effects of body mass index (BMI) on volume of distribution (ie larger volume for larger BMI) and of renal function on apparent clearance (ie reduced clearance for patients with reduced renal function). Injection site (deltoid vs gluteal) was found to influence the absorption process of PP1M (ie slower first-order absorption process for gluteal vs deltoid site; higher fraction of dose absorbed via the "fast" zero-order process for deltoid vs gluteal site), which is likely due to different distribution of muscle and adipose tissues in the 2 injection sites. Additional covariate effects have been described elsewhere.13 Paliperidone is not significantly metabolised by the CYP2D6 enzyme and hence is also not impacted by this genotype. The population PK models described above were used to simulate SS PK profiles according to the following dosing regimens: Oral risperidone once-daily at doses of 1, 2, 3, 4, and 6 mg; PP1M every 4 weeks (deltoid or gluteal injections) at doses of 25, 50, 75, 100, and 150 mg equivalents (mg eq.) of paliperidone (the corresponding doses of paliperidone palmitate substance are 39, 78, 117, 156, and 234 mg, respectively; the conversion factor from mg eq. to mg is 1.56). Initiation with deltoid injections of 150 mg eq. (234 mg) on day 1 and 100 mg eq. (156 mg) on day 8 was simulated. Similarity between given doses of oral risperidone and PP1M was assessed via graphical evaluation of central tendency and variability in the population as median and 90% prediction interval of 1000 simulated individual PK profiles for each formulation. Since the primary purpose of this analysis was to establish dose conversion factors between the two drugs for maintenance treatment (when PK SS can be assumed), the simulated PK profiles were depicted over a hypothetical time frame of 28 days at SS. Paliperidone concentrations following PP1M administration were overlaid on active-moiety concentrations following oral risperidone administration to enable graphical comparison of the whole SS PK profile. 3 RESULTS The PP1M maintenance doses of 25, 50, 75, 100 and 150 mg eq. (injected either in the deltoid or gluteus) are expected to result in similar SS exposure range (based on median and 90% prediction interval) to oral risperidone doses of 1, 2, 3, 4, and 6 mg once-daily, respectively, which results in a 25-fold dose conversion factor from oral risperidone to PP1M. Table 1 summarises the PP1M dose levels that are projected to attain similar SS exposures to corresponding oral risperidone doses for maintenance treatment. Figures 1 and 2 show the comparison of PK profiles between oral risperidone 3 mg and PP1M 75 mg eq., and between oral risperidone 6 mg and PP1M 150 mg eq. respectively. Graphical comparisons between the other 3 oral risperidone dose levels and the respective 25-fold PP1M dose levels are provided in Figures S1, S2, and S3. Figure 1Open in figure viewerPowerPoint Comparison between oral risperidone 3 mg once-daily and PP1M 75 mg eq. (deltoid or gluteal injections) every 4 weeks. Top panel shows PP1M deltoid injections, while bottom panel shows PP1M gluteal injections. Simulations are shown as median and 90% prediction interval of 1000 individual simulated concentration-time profiles (oral risperidone: active moiety; PP1M: paliperidone palmitate once-monthly) over a hypothetical 28-day time frame at steady-state for both drugs. For PP1M, (dose in mg) = 1.56 × (dose in mg eq.) Table 1. Doses of oral risperidone and PP1M expected to result in similar active moiety at steady-state based on pharmacokinetic simulations Paliperidone palmitate 1-mo (PP1M)a Oral risperidone (mg) (mg eq.) (mg) 1 25 39 2 50 78 3 75 117 4 100 156 6 150 234 a For PP1M the conversion factor from mg eq. to mg is 1.56. Figure 2Open in figure viewerPowerPoint Comparison between oral risperidone 6 mg once-daily and PP1M 150 mg eq. (deltoid or gluteal injections) every 4 weeks. Top panel shows PP1M deltoid injections, while bottom panel shows PP1M gluteal injections. Simulations are shown as median and 90% prediction interval of 1000 individual simulated concentration-time profiles (oral risperidone: active moiety; PP1M: paliperidone palmitate once-monthly) over a hypothetical 28-day time frame at steady-state for both drugs. For PP1M, (dose in mg) = 1.56 × (dose in mg eq.) Because the PK of the active moiety following oral risperidone treatment is linear,12 administering the same total daily dose in a twice-daily regimen (eg 6 mg/d administered as 3 mg twice-daily) is only expected to result in a reduced peak-trough ratio, compared to a once-daily regimen. The average plasma concentration over the dosing interval is not affected. Therefore, the above dose conversion results can be assumed to hold also for oral risperidone administered twice-daily for the same total daily dose. 4 DISCUSSION This work describes the exposure-matching between oral risperidone and paliperidone palmitate dose levels based on PK similarity at SS, using population PK simulations. Population PK approaches provide a comprehensive framework to characterise the PK of a compound from multiple studies while accounting for inter-subject variability. Dose conversion factors derived from population PK simulations have been accepted by the Health Authorities and are currently featured in label language of PP1M and PP3M worldwide.6, 15-17 Based on the population PK simulations presented here, a 25-fold dose multiple between oral risperidone and PP1M may be considered to attain similar SS exposures for the two formulations. These results are based on comparing the whole PK profile at steady-state between the two formulations, and not only a single PK parameter (such as eg trough concentration, or area under the concentration-time curve [AUC]). In addition, the model-based PK simulations presented here allowed characterising the variability of PK in the population, thereby providing stronger support to the dose conversion results compared to using only mean patient data. The transition from oral risperidone to PP1M must include the recommended initiation regimen of 150 mg eq. (234 mg) and 100 mg eq. (156 mg) on Day 1 and Day 8, respectively, in the deltoid, in accordance with the approved prescribing information for PP1M to ensure attainment of adequate SS exposures, without oral antipsychotic supplementation.6 Once treatment with PP1M has been initiated (ie on day 1), oral antipsychotics can be discontinued.6, 11, 18 Clinical factors related to adherence, efficacy and tolerability are critically important when establishing a suitable maintenance dose level in a given patient. The conversion does not take into account the potential effects of CYP2D6 inhibitors (ie paroxetine, sertraline or fluoxetine) or CYP3A and PgP inducers (ie carbamazepine) on active-moiety concentrations.5 Our results provide supplementary guidance to clinicians when considering the appropriate maintenance dose for patients transitioning from stable doses of oral risperidone to long-acting injectable PP1M. 5 CONCLUSION This analysis provides the clinician with a practical guidance to establish suitable maintenance dose levels of PP1M and oral risperidone when transitioning patients from one formulation to another, such that SS active-moiety exposures are similar between the two drugs. In addition to PK considerations, clinical symptoms should always be considered when switching medications. Patients undergoing a switch should be monitored closely before and after switching the medications. ACKNOWLEDGEMENTS This study was funded by Janssen Research & Development, LLC, USA. Authors thank Dr Himabindu Gutha (SIRO Clinpharm Pvt. Ltd.) for providing writing assistance and Dr Ellen Baum (Janssen Research & Development, LLC) for providing editorial support for this manuscript. Authors also thank the study participants, without whom this study would never have been accomplished and all the investigators for their participation in this study. DISCLOSURES The studies presented in this report were sponsored by Janssen Research & Development, LLC, USA. All authors are employees of Janssen Research & Development or Janssen Scientific Affairs, LLC and are shareholders in the parent company (Johnson & Johnson). The sponsor of the study had roles in the study design and conduct; collection, analysis and interpretation of the data. AUTHOR CONTRIBUTIONS Drs. Alberto Russu, Arun Singh, Maju Mathews, and Srihari Gopal were involved in study design, conduct, analysis and interpretation of data. Paulien Ravenstijn was the clinical pharmacokinetic leader, contributing to data analysis and interpretation. Alberto Russu was the pharmacometric leader for the study and had the primary role in pharmacokinetic analyses and data interpretation. Jennifer Kern Sliwa and Edward Kim identified the customer need for this pharmacokinetic analysis and contributed to the development and review of this manuscript. All authors contributed to data interpretation, development and review of this manuscript and confirm that they have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. All authors meet ICMJE criteria and all those who fulfilled those criteria are listed as authors. All authors had access to the study data, provided direction and comments on the manuscript, made the final decision about where to publish these data and approved submission to this journal. Supporting Information Filename Description ijcp13089-sup-0001-FigS1.tiffTIFF image, 14.6 MB ijcp13089-sup-0002-FigS2.tiffTIFF image, 14.6 MB ijcp13089-sup-0003-FigS3.tiffTIFF image, 14.6 MB Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. REFERENCES 1Zhao YJ, Lin L, Teng M, et al. Long-term antipsychotic treatment in schizophrenia: systematic review and network meta-analysis of randomised controlled trials. BJPsych Open. 2016; 2: 59- 66. 2Peuskens J, Rubio G, Schreiner A. Dosing and switching of paliperidone ER in patients with schizophrenia: recommendations for clinical practice. Ann Gen Psychiatry. 2014; 13: 10. 3Zhornitsky S, Stip E. Oral versus long-acting injectable antipsychotics in the treatment of schizophrenia and special populations at risk for treatment nonadherence: a systematic review. Schizophr Res Treatment. 2012; 2012: 407171. 4Mauri MC, Paletta S, Maffini M, et al. Clinical pharmacology of atypical antipsychotics: an update. EXCLI Journal. 2014; 13: 1163- 1191. 5 Risperdal® (risperidone) tablets/oral solution: US prescribing information. Janssen Pharmaceuticals, Inc. Titusville, NJ. 2016 [Available online https://www.janssenmd.com/pdf/risperdal/risperdal_pi.pdf] Accessed Feb 14, 2018 6 INVEGA SUSTENNA® (paliperidone palmitate): US prescribing information. Janssen Pharmaceuticals, Inc. Titusville, NJ. cited 2017 [Available online at https://www.invegasustenna.com/important-product-information.] Accessed Feb 14, 2018 7 Food and Drug Administration (FDA). Guidance for Industry, Population Pharmacokinetics. cited 1999 [Available online at https://www.fda.gov/downloads/drugs/guidances/UCM072137.pdf]. Accessed Feb 14, 2018 8 Committee for Medicinal Products for Human Use (CHMP). Guideline on Reporting the Results of Population Pharmacokinetic Analyses (effective 1 January 2008). Doc. Ref. CHMP/EWP/185990/06. [Available online at http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003067.pdf]. Accessed Feb 14, 2018 9Gopal S, Vermeulen A, Nandy P, et al. Practical guidance for dosing and switching from paliperidone palmitate 1 monthly to 3 monthly formulation in schizophrenia. Curr Med Res Opin. 2015; 31: 2043- 2054. 10Magnusson MO, Samtani MN, Plan EL, et al. Dosing and Switching Strategies for Paliperidone Palmitate 3-Month Formulation in Patients with Schizophrenia Based on Population Pharmacokinetic Modeling and Simulation, and Clinical Trial Data. CNS Drugs. 2017; 31: 273- 288. 11Samtani MN, Gopal S, Gassmann-Mayer C, Alphs L, Palumbo JM. Dosing and switching strategies for paliperidone palmitate: based on population pharmacokinetic modelling and clinical trial data. CNS Drugs. 2011; 25: 829- 845. 12Thyssen A, Vermeulen A, Fuseau E, Fabre MA, Mannaert E. Population pharmacokinetics of oral risperidone in children, adolescents and adults with psychiatric disorders. Clin Pharmacokinet. 2010; 49: 465- 478. 13Samtani MN, Vermeulen A, Stuyckens K. Population pharmacokinetics of intramuscular paliperidone palmitate in patients with schizophrenia: a novel once-monthly, long-acting formulation of an atypical antipsychotic. Clin Pharmacokinet. 2009; 48: 585- 600. 14Vermeulen A, Piotrovsky V, Ludwig EA. Population pharmacokinetics of risperidone and 9-hydroxyrisperidone in patients with acute episodes associated with bipolar I disorder. J Pharmacokinet Pharmacodyn. 2007; 34: 183- 206. 15 Xeplion, INN-paliperidone palmitate: Summary of Product Characteristics (SmPC). Janssen-Cilag. cited 2017 [Available online at http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002105/WC500103317.pdf.] Accessed Feb 14, 2018 16 INVEGA TRINZA®: US prescribing information. Janssen Pharmaceuticals, Inc. Titusville, NJ. cited 2017 [Available online at https://www.janssenmd.com/pdf/invega-trinza/invega-trinza_pi.pdf] Accessed Feb 14, 2018 17 Trevicta, INN-paliperidone palmitate: Summary of Product Characteristics (SmPC). Janssen-Cilag. cited 2017 [Available online at http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/004066/WC500180640.pdf]. Accessed Feb 14, 2018 18Gopal S, Gassmann-Mayer C, Palumbo J, Samtani MN, Shiwach R, Alphs L. Practical guidance for dosing and switching paliperidone palmitate treatment in patients with schizophrenia. Curr Med Res Opin. 2010; 26: 377- 387. Citing Literature Volume72, Issue6June 2018e13089 FiguresReferencesRelatedInformation

Aims To prospectively select the dose of the paliperidone palmitate 3‐month (PP3M) formulation, using a pharmacometric bridging strategy based on the paliperidone palmitate 1‐month (PP1M) formulation previously approved for schizophrenia treatment. Methods Pharmacokinetic (PK) data from a 6‐month interim analysis of a single dose PP3M Phase I clinical trial was integrated with a previously developed PP1M population‐PK model. The model was updated to incorporate formulation as a covariate on absorption parameters and to explore the most critical design element of the Phase III study: the PP1M‐to‐PP3M dose multiplier for patients switching formulations. Plasma paliperidone concentrations were measured at predetermined intervals during Phase III, enabling comparison of the multiple‐dose PK between PP1M and PP3M. Exposure matching was assessed graphically to determine whether paliperidone plasma concentrations from the two formulations overlapped. Results Prospective steady‐state PK simulations revealed that a 3.5 multiple of the PP1M dose would yield a corresponding PP3M dose with comparable exposure. The prospective pharmacometric simulation and observed Phase III PK data agreed closely. Phase III results confirmed the hypothesis that efficacy of PP3M was noninferior to that of PP1M. The similarity in exposures between the two formulations was likely a key determinant of the equivalent efficacy between the two products observed in the Phase III study. Conclusions Successful prospective PP3M Phase III clinical trial dose selection was achieved through the use of pharmacometric bridging, without conducting a Phase II study and using only limited Phase I data for PP3M. We estimate that this strategy reduced development time by 3–5 years and may be applicable to other drug development projects.

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

To the Editors Neuroleptic malignant syndrome (NMS) is a rare, potentially fatal, and idiosyncratic adverse reaction that occurs in approximately 0% to 3% of individuals taking conventional antipsychotic medication.1–4 This syndrome usually presents with rigidity, abrupt onset of fever, autonomic dysregulation, and altered mental status.1 Other symptoms associated with NMS include tremor, extrapyramidal symptoms, altered electrocardiogram, and laboratory abnormalities, such as elevated serum creatine kinase (CK), impaired liver function tests, leukocytosis, electrolyte abnormalities, renal impairment, and altered coagulation (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria for NMS). The primary cause of NMS is thought to be dopamine receptor blockade, particularly with the use of antipsychotic medications.5 Available evidence of NMS associated with oral antipsychotics suggests that second-generation oral antipsychotics have a lower incidence of NMS, with less severity and infrequent fatal outcomes, compared with first-generation oral antipsychotics.6–9 In contrast, little is known about the frequency and management of NMS associated with long-acting injectables (LAIs) prescribed for treatment of schizophrenia, including LAIs of paliperidone (9-OH metabolite of risperidone) such as paliperidone palmitate 1-monthly (PP1M) and 3-monthly (PP3M). The concern about NMS development due to LAI antipsychotics and the associated hospitalization, morbidity, and mortality limits LAI usage in clinical practice in the United States. Also, LAIs may be underutilized because of the perception that an LAI antipsychotic is not quickly cleared from the patient's system and may hinder NMS management. This letter discusses the incidence and nature of NMS associated with paliperidone palmitate LAI formulations identified from Janssen clinical trial databases of PP1M and PP3M and the treatment implications for NMS associated with second-generation antipsychotic LAI formulations. All cases of NMS in the Janssen PP1M and PP3M phases 1 to 3 clinical trial databases were searched cumulatively through April 30, 2018. Specific Medical Dictionary for Regulatory Activities (MedDRA, version 16.0) preferred terms used in the search for NMS are listed in Table 1. Individual case review was performed for each patient who experienced at least one of the terms listed. In each identified case, reports of treatment-emergent adverse events, vital signs, physical examination, laboratory findings, and clinical management of the event were reviewed. The incidence rate of NMS was calculated based on the number of identified cases divided by the total person-time at risk.TABLE 1: List of Preferred Terms Used in the Search for NMS in the Janssen Clinical Trial DatabaseThe Janssen clinical trial database search identified 1 credible case of NMS from 5008 patients who received 1 or more injection of PP1M or PP3M and were followed for 2271.6 patient-years. A second case of NMS was identified but was not included in this study because the patient (from a single-dose pharmacokinetics study in Japan; NCT01606254) was diagnosed with NMS more than 3 months (approximately 3 half-lives) after the last injection of PP1M. Furthermore, the patient was receiving other antipsychotics at the time of diagnosis of NMS. The resulting raw incidence of NMS was 0.020% (95% confidence interval, 0.0028%–0.14%), and the incidence rate was 0.044% (95% confidence interval, 0.042%–0.13%) per year. CASE REPORT The patient identified with NMS was a 55-year-old, white man with a diagnosis of schizophrenia, paranoid type, since 17 years of age who was enrolled in a randomized, double-blind, parallel-group study of flexibly dosed PP1M versus Risperdal CONSTA (Risperidone LAI).10 The patient had 4 prior hospitalizations for psychosis and a history of smoking, had no alcohol or drug abuse, and had no other significant medical history reported. The physical examination at screening was unremarkable, except for reduced hearing in the left ear, cerumen in both ear canals, gum disease, cavities, and a body mass index of 25.7 kg/m2 (overweight). The patient was previously treated with flupenthixol decanoate 15 mg intramuscularly every 2 weeks for 6 years, which was discontinued 22 days prior to randomization. From day −6 to day −3 of the screening period, the patient was given paliperidone extended release 3 mg for oral tolerability testing. On days 1 and 8 of the double-blind period, the patient received an injection of 50 mg eq PP1M in the gluteal muscle. A predose pharmacokinetic plasma sample was collected on day 1, and paliperidone levels were below the limit of quantification. On day 15, the patient was hospitalized for confused mental state and had experienced a fever (38.8°C) and little rigidity and had “trouble relaxing” his muscles. The diagnosis of mild NMS was made, and laboratory results showed elevated levels of CK (5824 U/L [reference range, 55–197 U/L]) and hepatic enzymes, including aspartate transaminase (128 U/L [reference range, 12–45 U/L]) and alanine transaminase (91 U/L [reference range, 7–40 U/L]). Blood pressure and pulse rate were normal. On day 16, lorazepam 0.5 to 1 mg/d as a rescue medication was initiated and continued as needed for 2 days, and ciprofloxacin 500 mg twice daily for 6 days was given for suspected infection that was later ruled out. Treatment with PP1M was discontinued on day 19 (last dose was on day 8), and the patient was withdrawn from the study because of the serious treatment-emergent adverse event of NMS. On day 20, the CK level was 860 U/L, alanine transaminase was 52 U/L, and aspartate transaminase was 49 U/L. Benztropine 1 to 2 mg/d was given from days 19 to 26, then the dose was tapered and discontinued over 2 days. Flupenthixol decanoate 15 mg intramuscularly every 2 weeks was resumed on day 23. The pyrexia was treated with acetaminophen as needed. No additional treatment was given for dizziness, psychotic disorder, elevated liver enzymes, or elevated CK levels. On day 28, the patient went on a “leave of absence” from the hospital as he was reported to have done reasonably well but returned to the hospital on day 34 after feeling unwell, with disorientation. The patient had fever of 38.5°C on day 34, but his temperature soon returned to normal (patient's home was not air conditioned, and the city of residence was warm at that time). After all investigations were normal, the patient went on a second leave of absence from days 36 to 46. The patient was discharged from the hospital on day 46 following complete recovery. DISCUSSION From data of 5008 patients analyzed in the Janssen clinical trial database for NMS with PP1M and PP3M, a single case of NMS associated with PP1M LAI was identified. The most common manifestations of NMS, including altered mental state, muscle rigidity, fever, and elevated CK (>1000 U/L), were reported in this case. The severity of NMS appeared to be mild, and the patient recovered completely. This database review illustrates the low propensity for NMS events during PP1M or PP3M treatment and successful management of this complication in the single case identified with symptomatic treatment. Given that NMS is a known and rare adverse event associated with use of antipsychotics, the investigator judged that the etiology of NMS was possibly related to PP1M. However, the patient was also receiving flupenthixol decanoate 15 mg intramuscularly every 2 weeks (variable half-life between 3 weeks and 3 months) for 6 years prior to randomization, which was discontinued 22 days before PP1M administration. Thus, it is possible that initiation of NMS on day 15 cannot be attributed solely to PP1M, but rather could be related to a combined effect of both LAI antipsychotic agents (flupenthixol decanoate and PP1M). Also, worsening of symptoms on day 34 could likely be related to the flupenthixol depot given on day 23, further supporting the additive effect of the 2 drugs. Findings from a retrospective study also showed that the use of depot flupenthixol was significantly associated with increased risk of NMS.11 In the present case, oral tolerability medication (paliperidone extended release), although below limit of quantification at baseline, may also be a contributory factor. Potential limitations of this study include possible underreporting of adverse drug reaction, inadequate sensitivity of the search method, and relatively short follow-up time of patients (on average, ~5.4 months). In summary, based on the search conducted in the Janssen clinical trial database, the occurrence of NMS events associated with PP1M or PP3M was very low (4/10,000 patient-years); clinicians must, however, be cautious to identify potential NMS symptoms after administration of LAI antipsychotics, especially when patients have been recently taking long-acting first-generation antipsychotics. The presented case indicates that NMS can be managed symptomatically even when the patient is on an LAI antipsychotic, and it underscores the importance of early detection and pharmacological intervention in preventing the progression of this potentially life-threatening complication of antipsychotic use. John M. Kane, MD The Zucker Hillside Hospital Glen Oaks, NY and The Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Glen Oaks, NY [email protected]Christoph U. Correll, MD The Zucker Hillside Hospital Glen Oaks, NY The Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Glen Oaks, NY and Department of Child and Adolescent Psychiatry Charité Universitätsmedizin Berlin, GermanyNicholas Delva, MD Providence Care HospitalKingston, Ontario, CanadaSrihari Gopal, MD, MHSAdam Savitz, MD, PhDMaju Mathews, MD Janssen Research & Development LLC, Raritan, NJ

Advanced paternal age (APA) is associated with increased risk for schizophrenia, but its effect on treatment response has not been longitudinally studied. Association of parental ages at the time of the child's birth with age of onset, initial symptom severity and treatment response (to placebo and three different weight-based doses of paliperidone ER) in adolescents with schizophrenia was assessed in a post-hoc analysis using data from a 6-week double-blind study, the primary results of which are published (NCT00518323). The mean (SD) paternal age was 29.2 (6.2) years, range (16–50) and maternal age was 26.8 (5.7) years, range (17–42) at childbirth for the 201 adolescents (ages 12–17 years) included in the analysis. While parental ages were uncorrelated with age of onset or initial symptom severity, both maternal and paternal ages showed significant effects on treatment response (p < 0.03) of all paliperidone ER arms versus placebo. Paternal age was significantly correlated to improvement in positive symptoms and maternal age significantly related to negative symptoms, although only paternal age remained significantly associated with the treatment response in analyses that included both parents' ages. APA was associated with greater treatment response to both paliperidone ER and placebo, but not to age of onset or initial symptom severity in adolescents with schizophrenia. The results support the contention that APA-related schizophrenia has distinct underpinnings from other cases. Further studies are required to explore the role of genetic and environmental factors, and their interactions, in treatment response in this complex disorder.

Paliperidone extended-release (paliperidone ER) is an approved oral antipsychotic medication (dosing range 3-12 mg/day) for treatment of schizophrenia and schizoaffective disorder in adults.In this 3-arm, double-blind, placebo- and active-controlled, parallel-group study, paliperidone ER 1.5 mg was assessed to determine the lowest efficacious dose in patients (N = 201) with acute schizophrenia. Paliperidone ER 6 mg was included for assay sensitivity.Patients (intent-to-treat analysis set) had a mean age of 39.4 years; 74% were men, 43% Asian, and 40% black. The baseline mean (SD) Positive and Negative Syndrome Scale (PANSS) total score was 92.6 (13.02) and the mean (SD) change from baseline to endpoint was: placebo group, -11.4 (20.81); paliperidone ER 1.5 mg group, -8.9 (23.31); and paliperidone ER 6 mg group, -15.7 (26.25). Differences between paliperidone groups versus placebo were not significant (paliperidone ER 1.5 mg [p = 0.582], paliperidone ER 6 mg, [p = 0.308]). Safety results of paliperidone ER 1.5 mg and placebo were comparable. The most frequently reported treatment emergent adverse events (≥10%) were: placebo group-headache (15.6%) and psychotic disorder (14.1%); paliperidone ER 1.5 mg group-insomnia (13.6%); and paliperidone ER 6 mg group-headache (11.4%), insomnia (10%), and tremor (10%).In this study, paliperidone ER 1.5 mg did not demonstrate efficacy in patients with acute schizophrenia. A markedly high placebo response was noted. Assay sensitivity with the 6 mg dose was not established. Paliperidone ER 1.5 mg was generally tolerable with a safety profile comparable to placebo.

Objectives:The long-term safety, tolerability, and efficacy of paliperidone extended-release (ER) were evaluated in Chinese patients with schizophrenia.Methods: Patients (aged 18 years) with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, 4th edition criteria) who had completed run-in (8-week), stabilization (6-week), and double-blind (DB) phases (variable) of a phase-3, placebo-controlled study entered this 24-week, open-label extension (OLE) study.These patients, who had either experienced a relapse or remained relapse-free through DB phase of the study, were treated with flexible-dose paliperidone-ER (3-12 mg/day) during the OLE phase.Major safety evaluations included treatment-emergent adverse events (TEAEs) and extrapyramidal symptoms.Efficacy endpoints included changes in Positive and Negative Syndrome Scale total score, Clinical Global Impression-Severity scale, and Personal and Social Performance scale from OLE baseline to OLE endpoint.Results: Out of 106 patients who entered the OLE phase (placebo: 59, paliperidone-ER: 47), a total of 85 (80%) completed it.Thirty-five (33%) patients experienced at least one TEAE; most common were akathisia, somnolence, nasopharyngitis, and constipation (3.8% each).Serious TEAEs were noted in two patients (completed suicide; schizophrenia worsening).No TEAEs with an onset during the OLE phase led to discontinuation.Extrapyramidal symptoms related-TEAEs were reported in eight (7.5%) patients.Mean (standard deviation) changes in Positive and Negative Syndrome Scale total scores (-10.4 [13.2]),Clinical Global Impression-Severity scores (-0.6 [0.96]) and Personal and Social Performance scores (7.4 [13.2]) from OLE baseline to OLE endpoint showed patients who had been treated with placebo during the DB phase experienced more pronounced improvements. Conclusion:In this OLE study, flexibly dosed paliperidone-ER (3-12 mg/day) was tolerable and efficacious in Chinese patients with schizophrenia.

First-month data of a 13-week acute schizophrenia study were used to compare paliperidone palmitate to oral risperidone during initiation of long-acting injectable risperidone.Double-blind, randomized study.Outpatient or inpatient.Adults with established (≥1 year) schizophrenia. Those assigned to risperidone long-acting injectable (n=460) received 25mg on Days 8 and 22 with oral risperidone (l-6mg) supplementation for the first 28 days. The paliperidone palmitate group (n=453) received 150mg eq. on Day 1, l00mg eq. on Day 8, and oral placebo supplementation for the first 28 days.Positive and Negative Syndrome Scale, Personal and Social Performance Scale, Clinical Global Impression-Severity score, and responder rate (percentage of patients with ≥30% reduction in PANSS total score). An analysis of covariance model estimated least-square mean differences between treatment groups. A post-hoc analysis of efficacy data for the period of interest, i.e., at the time points before and after the first 28 days, was conducted.Positive and Negative Syndrome Scale, Personal and Social Performance Scale, Clinical global Impression-Severity scores showed similar efficacy between the treatment groups during the first weeks of treatment, corresponding to the risperidone long-acting injection initiation period. Mean Positive and Negative Syndrome Scale total score at baseline was 84.7 for paliperidone palmitate and 84.4 for oral risperidone, on Day 22 was 73.6 and 74.1, respectively, and on Day 36 was 71.8 and 72.8, respectively. Overall incidence of adverse events in the first 28 days was generally similar (45% for paliperidone palmitate vs. 35% for oral risperidone), except for injection site pain (4.6% vs. 0.7%). Similar active moiety plasma concentrations were obtained during this period.During the first month, paliperidone palmitate without oral supplementation has similar efficacy and safety to oral risperidone (during initiation of risperidone long-acting injectable) in acutely exacerbated schizophrenia.

Based on previous pharmacogenetic findings, we investigated the possible association between SULT4A1-1 haplotype and antipsychotic treatment response.Using Mixed Model Repeated Measures, we tested the relationship between SULT4A1-1 status (+carrier, -noncarrier) and clinical improvement (in Positive and Negative Syndrome Scale total score) among European ancestry patients treated with paliperidone extended release (n=937), paliperidone palmitate (n=990), risperidone (n=507) and olanzapine (n=381) in 12 schizophrenia, two schizoaffective disorder and three bipolar I disorder trials. SULT4A1-1 haplotype was determined using tagging SNP rs763120.There was no significant difference between SULT4A1-1(+) and SULT4A1-1(-) patients for treatment response to paliperidone or olanzapine. SULT4A1-1(-) patients had better treatment response to risperidone in one schizophrenia trial, but not in another schizophrenia trial or bipolar mania trial.Across three psychiatric disorders (n=2815 patients), we observed no consistent association between SULT4A1-1 status and atypical antipsychotic effect.

Abstract Background Pharmacokinetic-pharmacodynamic (PK/PD) models were developed to describe the relationship between the time course of paliperidone plasma concentrations and the risk of relapse of schizophrenia symptoms following administration of paliperidone palmitate 1-month (PP1M) and 3-month (PP3M) long-acting injectables, and to identify relevant covariates for relapse and dropout events. Methods Patient data from two global phase 3, relapse prevention studies comparing PP3M to placebo (study A) and PP3M to PP1M (study B) were analyzed. Dropout and relapse data were assessed using survival analysis as two separate single time-to-event models. Baseline covariates included age, sex, race/country, duration of illness, previous hospitalizations, prior use of long-acting injectables and use of multiple (≥2) antipsychotics at screening. Results The PK/PD analysis data set included 305 patients who were randomized to receive PP3M or placebo in the double-blind phase of study A and 1002 patients randomized to receive PP3M or PP1M in the double-blind phase of study B. Risk of relapse decreased with increasing paliperidone concentrations for both PP1M and PP3M, while it appeared to increase in patients with higher number of previous hospitalizations and/or with higher prerandomization (trough) paliperidone concentration (study A), and in patients on concomitant benzodiazepine medication and/or at Japan centers (study B). These findings are reflective of different illness severity in the population and of differences in medical practice for Japanese patients. In model-based simulations, PP3M and PP1M displayed similar relapse rates over time. Conclusions This PK/PD analysis confirmed that PP1M and PP3M provide comparable efficacy in terms of relapse prevention, and that PP3M is superior to placebo. The PK/PD models presented here may as well be applied to studies with similar designs as either study A or B.

This pragmatic clinical study aimed to assess goal attainment among patients with schizophrenia treated with paliperidone palmitate 3-monthly (PP3M) and its relation to their level of disability, and whether patients achieved symptomatic remission at the study endpoint.Goal attainment was assessed as a secondary endpoint using Goal Attainment Scaling (GAS) within a 52-week, prospective, single-arm, non-randomized, open-label, international, multicenter study evaluating the impact of transitioning stable patients with schizophrenia from paliperidone palmitate 1-monthly (PP1M) to PP3M. Additional exploratory analyses were performed to investigate the relationship between disability and functioning as measured by the World Health Organization Disability Assessment Schedule (WHODAS), Version 2.0, symptomatic remission, and goal attainment.Overall, 305 patients were enrolled, of whom 281 (92.1%) provided GAS data at baseline. Of these, 160 achieved symptomatic remission at the last observation carried forward (LOCF) endpoint. The most common category of goals was "self" related, of which work-related was most frequent. Two-thirds of patients (67.7%) achieved at least one goal at the LOCF endpoint. Goal achievement was positively associated with lower baseline symptoms and symptomatic remission at LOCF endpoint, and with lower WHODAS scores at baseline and LOCF endpoint and greater WHODAS score improvements from baseline. Age, duration of disease, and duration of PP1M treatment before the switch did not impact goal setting and goal attainment. The proportion of patients with remunerated work status increased by 11.3% at LOCF endpoint.The results of this secondary endpoint analysis indicate that continued treatment of patients with schizophrenia with PP3M following stabilization with PP1M may facilitate attainment of patients' personal goals and reduce disability, especially, but not exclusively, in patients with symptomatic remission achieved at LOCF.

Reducing the frequency of long-acting injectable antipsychotic medication may reduce carer burden.To evaluate the impact of reduced frequency of long-acting injectable antipsychotic medication on carer burden in stable patients with schizophrenia.Carer burden was assessed using the Involvement Evaluation Questionnaire (IEQ) within a 52-week, prospective, single-arm, non-randomised, open-label, international, multicentre study evaluating the impact of transitioning stable patients with schizophrenia to paliperidone palmitate 3-monthly (PP3M) from paliperidone palmitate 1-monthly (PP1M).159 carers completed the IEQ (mean [standard deviation, SD] age: 54.8 [12.8] years); 52.2% were the patients' parent and > 50% had >32 h/week of patient contact. At baseline, mean [SD] IEQ total score was in the lower range (23.8 [12.6]), reflecting patient stabilisation. At last observation carried forward (LOCF) endpoint, the IEQ total score decreased by a mean (95% CI) of -4.0 (-5.9, -2.1), indicating a significant overall reduction in carer burden (P < 0.0001). The six IEQ items with the highest carer burden at baseline were within the urging and worrying domains, in which burden was significantly improved at LOCF endpoint (P < 0.0001). Exploratory analyses found that higher carer burden was associated with lower functional remission (Personal and Social Performance score >70) at baseline and LOCF endpoint, and with the patient being part of the carer's household. Shorter disease duration correlated with better general health of carers at LOCF endpoint.Reducing the frequency of antipsychotic medication administration in stable patients with schizophrenia by switching from PP1M to PP3M may reduce carer burden.

The purpose of this study was to conduct a post-hoc benefit–risk assessment of paliperidone palmitate once-monthly (PP1M) injectable versus oral paliperidone extended-release (ER) in schizophrenia maintenance treatment. The Benefit–Risk Action Team framework was used to structure the analysis based on patient-level data from two similar, double-blind, placebo-controlled relapse studies. Efficacy outcomes were relapse, psychiatric hospitalization, Clinical Global Impression–Severity scale, Personal and Social Performance (PSP) scale, and Positive and Negative Syndrome Scale (PANSS). Safety outcomes were extrapyramidal symptom–related adverse events, weight gain, prolactin-related adverse events, somnolence, orthostatic hypotension, anticholinergic use, fasting plasma glucose, and total cholesterol/high–density lipoprotein. For the first 8 weeks of maintenance treatment, most efficacy outcomes significantly favored PP1M compared with paliperidone ER. Per 1000 patients, there would be 165, 115, 85, and 53 fewer cases of PSP worsening, relapse, PANSS worsening, and hospitalizations, respectively. For the first 40 weeks, PSP worsening significantly favored PP1M (140 fewer cases). Relapse, PANSS, hospitalizations, and Clinical Global Impression–Severity scale showed a consistent pattern favoring PP1M but were not significant. Safety outcomes for both 8-week and 40-week periods demonstrated no statistically significant differences between groups. These analyses suggest a benefit–risk profile favoring PP1M over oral paliperidone ER throughout 40 weeks of treatment, particularly in early treatment.

To the Editors In the report by Yin et al,1 the statement that “many clinicians may misinterpret these directions (in paliperidone palmitate product monograph) to mean that these intramuscular sites (deltoid or gluteal) are interchangeable, and thus therapeutically equivalent” is, in our opinion, not correct. We are writing to clarify some statements from the Yin et al article concerning the deltoid versus gluteal intramuscular injection of paliperidone palmitate. The recommended initiation as stated in the product label of paliperidone palmitate 1-month injection is with a dose of 150 mg eq on treatment day 1 and 100 mg eq 1 week later, both administered in the deltoid muscle. Here, the deltoid and gluteal injection sites are not interchangeable, and from a clinical point of view, it is important to reach therapeutic concentrations quickly when starting a new antipsychotic. However, after the second initiation dose, monthly maintenance doses can be administered in either the deltoid or gluteal muscle. The injection sites of the maintenance doses can be used interchangeably, but for deltoid injections, the appropriate needle length is based on the patient's weight (1-in 23G needle for patients weighing <90 kg and 1.5-in 22G needle for patients weighing ≥90 kg). For gluteal injection, regardless of patient weight, the use of a 1.5-in 22G needle is recommended. The use of differently sized needles depending on the weight of the patient for injection into the deltoid muscle is recommended to limit the risk of drug administration into the subcutaneous tissues, which would result in a decreased rate of absorption from the intramuscular site of injection. Different distributions of muscle and adipose tissue, as well as difference in blood flow between the deltoid and gluteal sites,2–4 may affect the uptake rate of paliperidone into the circulation from the site of injection. At the deltoid site, the likelihood of an injection that is purely intramuscular is higher compared with that at the gluteal injection site. The hypovascularity of subcutaneous adipose tissue compared with muscle tissue may result in a slower uptake of paliperidone from the gluteal compared with the deltoid injection site. We agree that there is a different rate of absorption between the deltoid and gluteal injection sites, as presented in the articles cited by Yin et al,4–6 as well as in a more recent publication,7 but we do not consider these differences therapeutically relevant after multiple doses as discussed hereinafter. The statement made by Yin et al,1 “This is concerning as the observed Cmax for the 150 mg dose is considerably higher (i.e., 65%) than the average value reported in the product monograph,” is based on a single dose pharmacokinetic study by Cleton et al.6 In the study described by Rossenu et al,7 a Cmax difference was also observed after the first and fourth injections (30% higher Cmax after deltoid injection compared with gluteal injection). However, Rossenu et al7 showed that steady state was not reached entirely after the 4 gluteal injections, and so this difference in Cmax cannot be extrapolated to Cmax at steady state. In addition, Samtani et al8 have shown that the median peak paliperidone concentrations at steady state for repeated gluteal and deltoid injections were 46 versus 50 ng/mL, respectively, for a dose strength of 150 mg eq, which is only a 9% difference. Thus, the statistics obtained from only a single dose or even a few doses at initiation cannot be extrapolated to the steady state condition during maintenance therapy. The following statement made by Yin et al1 is taken out of context: “the observed Cmax and AUC were 20% to 50% higher after injection in the deltoid muscle compared with the gluteal muscle.” The 50% higher area under the curve (AUC) is not total exposure but a partial AUC (AUC0-36 days) from Study USA-03, which studied deltoid dosing with a longer 1.5-in needle length. Yin et al fail to mention that the AUC∞ in the same study was similar between deltoid and gluteal dosing (4% higher AUC∞ after deltoid injection of 150 mg eq, which is a commonly used PP1M dose).9 This similarity in AUC∞ for deltoid versus gluteal dosing was also observed in the study by Cleton et al6 where the AUC∞ was only 3% to 18% higher across the 4 dose strengths after a single deltoid dose compared with a single gluteal dose. The population pharmacokinetic model (built on 1795 subjects from 6 phase 1 trials and 5 phase 2 and 3 trials, with a total of 18 530 pharmacokinetic samples from many different countries and ethnicities) confirmed not only the observed differences in pharmacokinetics upon the initiation of paliperidone palmitate treatment but also that differences between the gluteal and deltoid injection sites become less apparent after multiple injections.10 The final covariate model indicated that, among other variables, injection site had a significant influence also on the first-order absorption rate constant (ka), indicating a slower absorption rate after gluteal injection. However, paliperidone palmitate offered complete bioavailability of paliperidone at all dose strengths and from both injection sites.10 Taken together, these data confirm that the total exposure at steady state is similar between the deltoid and gluteal injection sites. We acknowledge that, in principle, the time to reach steady state is longer for the gluteal injection site. This is why the 2 initiation doses of once-monthly paliperidone palmitate are required to be administered in the deltoid muscle, in addition to the requirement for weight-based selection of the appropriate needle size for administration, to rapidly attain therapeutic concentrations. Therefore, Yin et al did not provide the appropriate background and context when they state that “The US Food and Drug Administration (FDA) also reviewed this data and commented that ‘compared with deltoid injections, repeated administration in the gluteal muscle resulted in a delayed time to achieve steady state (approximately 4 weeks longer)’.1” In summary, the results of multiple studies of paliperidone palmitate indicate that, at the initiation of treatment, injection in the deltoid muscle results in higher initial exposures compared with injection in the gluteal muscle. After multiple injections and at steady state, the difference in exposure between gluteal and deltoid muscles is less apparent. In view of the totality of the evidence as described in this letter, we do not agree with the statement by Yin et al1 that the deltoid and gluteal injection sites are not interchangeable or therapeutically not equivalent. Paulien Ravenstijn, PhD Janssen Research & Development LLC, a Division of Janssen Pharmaceutica NV Beerse, Belgium [email protected]Mahesh Samtani, PhD Janssen Research & Development LLC, Raritan, NJAlberto Russu, PhD Janssen Research & Development LLC, a Division of Janssen Pharmaceutica NV Beerse, BelgiumDavid Hough, MDSrihari Gopal, MD Janssen Research & Development LLC, Titusville, NJ

Dear Dr Jackson, In the recent review article by Dr Citrome (Olanzapine Pamoate: a stick in time? A review of the efficacy and safety profile of a new depot formulation of a second-generation antipsychotic), indirect comparisons between risperidone long-acting injectable (RLAI) and olanzapine long-acting injectable (OLAI) were described. These comparisons were based on an abstract published in the International Journal of Neuropsychopharmacology. We believe that the section of the article that describes these comparisons fails to reach a reasonable standard of scientific correctness, as the original data referenced in the abstract is inaccurate. This may lead to faulty interpretations, which may misinform treating physicians. We are specifically concerned about the following points: First, a reference group common to both studies must exist when indirect comparisons of agents are asserted. In the analysis presented in the original abstract, this is clearly not the case. This makes the conclusion from the indirect comparison claim invalid. Presentation of completion rates across different study designs without accounting for between-study variability is potentially misleading. The proper approach would have been to use meta-analytic techniques to construct a standardised mean difference in completion rates across the different studies. Secondly, the designs of the studies cited by Citrome for comparison were remarkably disparate in plan, hypothesis and intent, and are, therefore, further incompatible with the conduct of any indirect comparison. These incompatibilities include: The OLAI HGKB study (long-term open label study; ClinicalTrials.gov ID: 00088465) is a ‘rolling study’, which allowed the enrolment of patients who completed previous OPD trials. The data presented from the OLAI HGKB study is a subgroup analysis of patients who completed the feeder study HGKA. One OLAI study (HGKA) also included pretreatment with olanzapine oral, during which time patients were clinically stabilised with the oral agent prior to OLAI administration. The RLAI studies were differently designed. One study (Simpson et al.) was a randomised, double-blind study with a primary endpoint of time to relapse. This specific time to relapse design removes all patients from further analysis once the predefined event of relapse occurs. There can be no relevant comparison, by default, to completion rates for OLAI, as the design in the latter instance measures time on drug, independent of a binary measure of efficacy (time to relapse). A second study of RLAI was designed to answer a very different question. This small (n = 40), single centre study in Korea was intended to investigate symptoms and quality of life among patients who switch from oral antipsychotics to RLAI. It was not designed or statistically powered to assess either the safety or effectiveness of RLAI. Furthermore, the RLAI completion rates reported in these studies were based on the intent-to-treat population, whereas the OLAI completion rate was based on the cohort of patients followed for 12 months. Thirdly, the populations included in the RLAI and OLAI studies were either specifically different, or in the case of OLAI could not be determined from the available information. Based on the data included in the OLAI poster from the congress, baseline characteristics of key clinical parameters such as Positive and Negative Syndrome Scale (PANSS), Clinical Global Impressions (CGI), mean age and age at onset of the disease were either dissimilar between the studies, or listed in the poster as ‘not reported’. Furthermore, the definition of ‘completer’ and ‘relapse’ may differ between studies. The authors of the original abstract suggest that this is ‘a systematic review’ of all evidence available on both agents in question. However, as reported in the poster, the references for OLAI studies are reported as ‘data on file’. Unpublished internal company reports are not subject to the scrutiny typical of the peer review process. Each of the manuscripts referenced for RLAI in the review was published after peer review. More concerning is the fact that data from a long-term, open-label study of RLAI, presented in an abstract in 2007 at the International Society of Pharmacoeconomics and Outcomes Research and more recently published in the February 2009 issue of European Psychiatry, were absent from the review (1). This particular study, the RLAI study that is the closest in design to the HGKB study, from which the 12-month OLAI completion rates were used, found that the 12- and 24-month treatment completion rates for RLAI were 86.1% and 81.8%, respectively, numerically higher than the treatment completion rate for OLAI. A similar 12-month treatment completion rate (89.7%) with RLAI was reported by other observers (2). More recently, a post hoc analysis of two open-label studies of RLAI vs. oral treatment in patients with early psychosis reported 12- and 24-month completion rates for RLAI to be consistent with the above findings (80% and 74% respectively) (3). Lastly, while we agree with the statement that focusing on ‘treatment completion rate as a proxy measure of treatment effectiveness’ is important, we also believe that other effectiveness measures, such as relapses and re-hospitalisations, are very important. RLAI has been documented to reduce relapses and re-hospitalisations over the long-term, which are key drivers from an economic standpoint (4,5). Therefore, we believe that the comparison section in this review article will be liable to mislead prescribing physicians, as it did not thoroughly evaluate the published and publicly available evidence relevant to RLAI. Conversely, conclusions regarding OLAI were referenced upon unpublished data. Interestingly enough, the same authors presented the poster at the Schizophrenia International Research Society Conference held on 21–25 June 2008 in Venice, Italy. At that time, the authors were clear to acknowledge that comparisons were ‘subject to major non-quantifiable biases. As such, any differences seen could be due to the differences in study procedures or study populations’. Acknowledging this major limitation should avoid any comparative conclusions, such as the 12-month treatment completion rate being significantly higher for OLAI than for RLAI therapy. We hope that the points we made above will clarify to the reader the danger of making inaccurate comparisons, as the interpretations of the findings have implications from a clinical as well as patient outcomes perspective. Without direct comparisons of completion rates in the context of a blinded randomised controlled trial, comparisons regarding efficacy differences between OLAI and RLAI are difficult. Sincerely, All authors are employees of Johnson & Johnson.

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

Abstract The paliperidone pharmacokinetics after intramuscular administration of once‐monthly paliperidone palmitate in Japanese patients were studied in 3 phase 1 studies and in 2 phase 3 studies performed in Japan, Korea, and Taiwan. These data (Japanese, n = 509; Korean, n = 31; Taiwanese, n = 47) were used to describe the paliperidone palmitate pharmacokinetics in Japanese, to compare with non‐Japanese, and to validate the historical population pharmacokinetic (Pop‐PK) model for paliperidone palmitate, developed using data from studies in patients with schizophrenia outside Japan. The final historical Pop‐PK model, including all significant patient covariates of Japanese studies, was used to simulate paliperidone plasma concentration–time data using nonlinear mixed effects, followed by comparison with actual data. Visual predictive checks displayed considerable overlap between predicted and actual plasma concentrations; the majority of observations were within the 90% prediction interval. Japanese, Korean, and Taiwanese patients had comparable plasma concentrations. Covariate distributions demonstrated comparatively lower median body mass index in Japanese, Korean, and Taiwanese patients versus rest‐of‐world population. Prediction errors for the data set used for external validation were within cutoff values, confirming accuracy/precision of the model. Paliperidone pharmacokinetics were adequately predicted for Japanese studies using the historical Pop‐PK model, confirming its robustness. Pharmacokinetics in Japanese, Korean, and Taiwanese patients with schizophrenia were comparable with rest‐of‐world population.

a Methods and results are detailed in a clinical pharmacology and biopharmaceutics review by the United States Center for Drug Evaluation and Research.5 Funding/financial disclosures.: This work was supported by Janssen Scientific Affairs, LLC. Gopal and Nuamah are employees of Janssen Research & Development, LLC, and are Johnson & Johnson stockholders; Palermo is an independent practitioner; and Sliwa, Fu, and Alphs are employees of Janssen Scientific Affairs, LLC, and are Johnson & Johnson stockholders.

Paliperidone palmitate (PP) is a long-acting injectable formulation of an atypical antipsychotic, paliperidone. Its dose can be expressed in milligram or milligram equivalents (mg eq) of active paliperidone (39, 78, 117, 156, and 234 mg of PP correspond to 25, 50, 75, 100, and 150 mg eq of paliperidone). The recommended initiation dosing regimen for PP is 150 [day 1]/100[day 8] mg eq. Labeling guidance allowed a ± 2 day window for the day 8 injection that provides more flexibility with patient scheduling and avoids missing the day 8 initiation dose. Recently, expansion of the day 8 dosing window from ±2 to ±4 days has been approved in the United States based on results obtained from the model-based simulations and review of safety data presented here.The predicted exposure for the recommended initiation regimen of PP was compared with day 1/day 4, and day 1/day 12 dosing scenarios; each scenario was compared with the highest clinically evaluated initiation regimen (150[day 1]/150[day 8] mg eq) and to the recommended 6 mg/day oral dose of extended-release paliperidone.Simulated exposures with PP 150 mg eq on day 1 and 100 mg eq on days 4, 8, or 12 overlap considerably, with ±3 ng/mL variation in median maximum plasma concentrations. Based upon pharmacokinetic bridging/bracketing, the peak concentration with PP 150/100 mg eq [days 1/4] was lower than that with the highest initiation regimen. Exposures for PP 150 mg eq on day 1 and 100 mg eq on days 4, 8, or 12 were maintained close to those of 6 mg of paliperidone extended-release.These simulations indicate that using the expanded dosing window of ±4 days has little effect on paliperidone exposure. A review of the overall pattern of treatment-emergent adverse events did not identify any new safety risks associated with the expanded dosing window.

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

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

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.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.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.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.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.ClinicalTrials.gov Identifier: NCT01515423.

This double-blind (DB), relapse prevention, phase-3 study was designed to evaluate the efficacy and safety of paliperidone palmitate long-acting 3-monthly formulation (PP3M) versus placebo in delaying time-to-relapse of schizophrenia symptoms. Adults (18-70 years old) with schizophrenia (DSM-IV-TR) were treated with PP (17-week, open-label [OL] transition phase: 50, 75, 100, or 150 mg eq, once-monthly, [PP1M]; 12-week OL maintenance phase: 3.5-fold PP1M stabilized dose, single injection), and then randomized (1:1) to PP3M fixed doses (175, 263, 350 or 525 mg eq.) or placebo. 305/506 patients enrolled were randomized (PP3M: n=160; placebo: n=145); majority were men (75%), white (59%), mean age 38.4 years. Interim analysis results favored PP3M vs. placebo (p = 0.0002, two-sided log-rank test; HR: 3.45, 95% CI: 1.73; 6.88); median time-to-relapse was 274 days in placebo and not estimable in PP3M group. Final results were consistent with interim analysis. Both PANSS total score and CGI-S score showed a significant effect over time in PP3M- vs. placebo-treated patients (p>0.001). 330/506 (65.2%) patients in OL phase and 183/305 (60.0%) in DB phase (PP3M: 61.9% vs. placebo: 57.9%) had ≥1 treatment-emergent adverse event (TEAE). The TEAEs noted more frequently in PP3M-vs. placebo (DB phase) were nasopharyngitis (5.6% vs. 1.4%), weight gain (8.8% vs. 3.4%), headache (8.8% vs.4.1%) and akathisia (4.4% vs. 0.7%). Compared with placebo, PP3M significantly delayed time to first relapse in patients with schizophrenia, previously treated for 4 months with PP1M. PP3M was tolerable with a safety profile generally consistent with other marketed formulations of paliperidone.

This retrospective cohort study evaluated real-world data on relapses in adult patients with schizophrenia who transitioned to long-acting injectable paliperidone palmitate once-every-3-months (PP3M) following treatment with once-monthly paliperidone palmitate (PP1M).Data derived from the IBM® MarketScan® Multi-State Medicaid Database were analyzed. Adults aged ≥18 years with ≥1 schizophrenia diagnosis claim and ≥12 months of continuous medical and prescription enrollment before and/or at index date of PP3M were eligible for inclusion. Patients were matched on propensity score to 2 PP3M cohorts: (1) adequately treated (AT), defined as patients treated with PP1M for ≥4 months, with the last 2 doses the same and a PP3M initiation dose meeting the corresponding PP1M-to-PP3M dose conversion, or (2) not adequately treated (NAT), defined as patients who received ≤2 or no PP1M doses. Relapse rates and time to relapse distributions based on the first occurrence of a qualifying event during the 2-year follow-up period were compared between PP3M cohorts using Kaplan-Meier survival curves and log rank test statistics. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards models. Two sensitivity analyses using different matched populations were performed to assess the robustness of the primary findings.Propensity score matching yielded a sample of 1314 patients (657 per group). Most patients were male (68.9%) and aged 25-64 years (90.1%). The relapse rate was significantly lower in the AT (18.4%) versus NAT cohort (26.8%), P = 0.0002. Risk of relapse decreased by 35% for AT versus NAT (HR: 0.65 [95% CI: 0.51-0.81]). Relapse reductions favored the AT cohort in both sensitivity analyses (HR: 0.67 [95% CI: 0.54-0.83] and HR: 0.74 [95% CI: 0.56-0.97]).In this analysis of Medicaid claims data, patients adequately treated with PP1M before transitioning to PP3M demonstrated significantly lower relapse rates and delayed time to relapse.

Background: Paliperidone palmitate 3-monthly (PP3M) is a second-generation, long-acting injectable antipsychotic formulation indicated for the maintenance treatment of adults with schizophrenia first stabilized with paliperidone palmitate 1-monthly (PP1M). This exploratory post hoc subgroup analysis of the 52-week, phase 3b REMISSIO study analysed outcomes according to patient age and disease duration in a naturalistic clinical setting. Methods: Outcomes of patients with schizophrenia were analysed according to age [&lt;35 years ( n = 123) versus ⩾35 years ( n = 182)] and disease duration [⩽3 years ( n = 72) versus &gt;3 years ( n = 233)]. The primary efficacy outcome was the proportion of patients achieving symptomatic remission according to the Andreasen criteria. Adverse events were monitored throughout the study. Results: At endpoint (last observation carried forward), 60.7% (95% CI: 51.4%, 69.4%) of younger patients and 54.1% of older patients (95% CI: 46.6%, 61.6%) achieved symptomatic remission. The proportions for patients with disease duration ⩽3 years and &gt;3 years were similar: 57.8% (45.4%, 69.4%) versus 56.5% (49.8%, 62.9%). Functional remission was reached by 45.4% (36.2%, 54.8%) of patients aged &lt;35 years and 36% (28.9%, 43.6%) of patients aged ⩾35 years with a similar pattern when analysed by disease duration. PP3M had a favourable safety profile and was generally well tolerated in both age groups. Conclusion: Patients with schizophrenia, previously stabilized on PP1M, may benefit from PP3M treatment with some additional potential improvements if started early in the disease course. Clinical trials.gov: NCT02713282

Paliperidone palmitate once every 3 months (PP3M) is indicated in adults with schizophrenia adequately treated with once-monthly paliperidone palmitate (PP1M) for at least 4 months, in whom the last two consecutive doses are the same. The decision of when to transition to PP3M is based on the patient's symptom status while receiving PP1M.In a double-blind relapse-prevention study (NCT01529515), patients who met Positive and Negative Syndrome Scale (PANSS) score stabilization criteria after 4 months of PP1M were eligible for transition to PP3M; those who continued to meet stabilization criteria after 12 weeks following an open-label PP3M dose were randomized to receive PP3M or placebo. We compared (post hoc) PANSS, Clinical Global Impression-Severity (CGI-S), and Personal and Social Performance (PSP) scores during the pre-randomization, open-label phase in patients in randomized versus non-randomized groups using analysis of variance or chi-square tests.Of 506 patients enrolled, 305 were randomized. After 4 months' PP1M treatment, PANSS and CGI-S scores were significantly lower and PSP scores significantly higher in randomized patients versus non-randomized patients (least squares means [95% CI]: 57.1 [55.7, 58.6] vs 62.2 [60.0, 64.3], 2.9 [2.8, 3.1] vs 3.3 [3.1, 3.4], and 67.0 [65.7, 68.3] vs 64.5 [62.6, 66.4], respectively); changes from baseline between groups differed significantly (all P ≤0.009).Confirming adequate stabilization with PP1M prior to transitioning to PP3M is critical in maximizing treatment response; clinicians should consider transitioning patients to PP3M only if patients respond well to PP1M for at least 4 months and their last two consecutive doses are the same.

Introduction: Cognitive decline includes a wide spectrum of changes in cognitive function due to age-related and pathological decline. Many unhealthy behaviors like substance use accelerate cognitive decline. Long term alcohol is associated with cognitive impairment but effect of comorbid nicotine dependence has not yet been studied over in our region. The Objectives: study was planned to examine the concurrent effect of use of nicotine on cognitive impairment in patients of alcohol dependence syndrome. Methods: 30 patients each of Alcohol dependence without concurrent Nicotine Dependence (group A) and Alcohol dependence with concurrent Nicotine Dependence (group B) were enrolled in this study. Montreal Cognitive Assessment (MoCA) Test was used for assessment of cognitive functions. Among the various domain of MoCA, attention and orientation was found to be bet Results: ter in Group B patients, i.e patients with concurrent alcohol and nicotine dependence syndrome. All other domains were more impaired in Group B as compared to Group A patients. Overall, patients with alcohol dependence with nicotine dependence had a lower MoCA score i.e. 23.4±2.2 and 22.4±1.8 in group A and B respectively (p-value-0.82) suggesting greater cognitive decline in patients of Group B. T Conclusion: he present study suggests that the decline in cognitive performance is more in patients with concurrent use of alcohol and nicotine as compared to patients of alcohol dependence alone. However, attention and orientation were found to be better in patients with concurrent use of alcohol and nicotine.

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).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.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.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.

In a randomized clinical study, paliperidone palmitate 3-month formulation (PP3M) significantly delayed time to relapse in patients with schizophrenia. The hazard ratio comparing PP3M with placebo was 3.45 (95% CI: 1.73, 6.88), demonstrating superiority of PP3M in preventing relapse. Number needed to treat (NNT) and number needed to harm (NNH) analyses provide an alternative approach to assess the magnitude of treatment effect and can provide valuable additional information on therapeutic gain.

Hough, David W. MD*; Gopal, Srihari MD, MHS*; Coppola, Danielle MD*; Remmerie, Bart M. Chem Eng†; Berwaerts, Joris MD*; Nuamah, Isaac F. PhD*; Sterkens, Patrick C. M. MSc†; Xu, Yimei MD* Author Information

The need to predict relapse in schizophrenic patients for early intervention is critical. Here we explored biomarkers in patients who relapsed (paliperidone palmitate 3-monthly [PP3M] or placebo) compared to biomarkers in patients who remained stable during a randomized, double-blind (DB), multicenter, phase-3 study.

This study aims to evaluate the serum S100B levels to predict neuronal damage and poor clinical outcomes associated with the use of synthetic cannabinoids.Thirty patients identified as synthetic cannabinoid users and 30 healthy controls were included in the study. S100B levels were compared between healthy controls and synthetic cannabinoid users. The following were considered to be composite outcomes: the need for endotracheal intubation, incidence of seizures, the need for intensive care unit admission, and in-hospital mortality. Clinical and laboratory findings associated with composite clinical outcomes were examined.The mean S100B level was 19.3 (95% CI: 17.7 to 21.4) pg/mL in patients who use synthetic cannabinoid, and 15.9 (95% CI: 15 to 16.9) pg/mL in the controls; mean df: –3.6 (95% CI: –5.6 to − 1.6). In patients with and without composite clinical outcomes, the mean S100B level measured 24.5 (95% CI: 21.2 to 27.9) pg/mL and 17.4 (95% CI: 15.8 to 18.4) pg/mL, respectively; mean df: –7.4 (95% CI: –10.2 to − 4.6). With the cut-off value for S100B set at 20 pg/mL based on the highest sensitivity, the sensitivity, specificity, PPV, and NPV for S100B were 89.9%, 52.0%, 44.4%, and 91.9%, respectively; odds ratio: 13.2, 95% CI (2.1 to 28.1).Our data suggest that serum S100B levels are elevated in patients using synthetic cannabinoids. These results show that S100B can help clinicians stratify risk or may have a role in excluding those with neuronal damage.

Negative symptoms of schizophrenia are key predictors of long-term disability. It is important to understand whether treatment with long-acting injectable antipsychotics can improve negative symptom psychopathology. Paliperidone palmitate 3-month formulation (PP3M) provides a sustained release of paliperidone, permitting a significantly extended dosing interval of only 4 doses per year in patients with schizophrenia. The efficacy of PP3M as assessed by relapse rate is comparable to the paliperidone palmitate 1-month formulation (PP1M). The purpose of this post-hoc analysis was to compare the improvement in negative symptoms in patients treated with PP1M and PP3M. Data from a randomized, double-blind (DB), parallel-group, multicenter, phase 3 study in patients with schizophrenia were analyzed. Patients aged 18 to 70 years with schizophrenia (DSM-IV-TR) and a total Positive and Negative Syndrome Scale (PANSS) score of 70–120 at screening were enrolled. After screening (3 weeks), patients entered a 17-week open-label (OL) phase, to receive PP1M (day 1 [150 mg eq. deltoid], day 8 [100 mg eq. deltoid], weeks 5, 9 and 13 [50, 75, 100, or 150 mg eq., deltoid/gluteal]) and entered a 48-week DB phase and were randomized (1:1) to receive fixed doses of either PP1M (50, 75, 100, or 150 mg eq., stabilized in OL) or PP3M (175, 263, 350, or 525 mg eq.) in deltoid or gluteal muscle until they relapsed or withdrew from study. The PANSS total scores with emphasis on 7-item negative subscale scores for PP1M vs PP3M were assessed. Of 1429 patients enrolled, 1016 were randomized to receive PP3M (n=504) or PP1M (n=512) in DB phase. Majority of patients were men and white (both 55%), with a mean (SD) age of 38.4 (11.86) years. At baseline, the mean (SE) negative subscale total was 23.2 (0.12), indicating a moderate to severe level of negative symptoms. Negative subscale and negative symptoms factor scores showed continuous improvements throughout the OL and double-blind phases of the study - mean (SD) at OL baseline and DB endpoint for total negative subscale score and symptom factor score were 23.2 (4.60) and 22.3 (4.87), and 15.9 (4.99) and 14.9 (4.81), both R2:0.16, respectively. The mean (SD) PANSS negative subscale score changes from DB baseline for PP1M vs PP3M were similar over time (mean change from baseline to DB endpoint was -1.4 (3.67), R2:0.06 vs -1.4 (3.63), R2:0.05). Development of an LAI antipsychotic with less frequent dosing than those currently available would be of potential advantage to patients, caregivers, and prescribers. PP3M and PP1M demonstrated consistent and similar efficacy in patients with moderate to severe negative symptoms of schizophrenia over the observed timepoints, including impact on patients with predominantly negative symptoms. Longer continuous treatment with PP3M showed greater benefit. This indicates that long-acting therapies are associated with continued improvement in negative symptoms over time. Treatment with LAIs for longer than a year was associated with the greatest improvements in negative symptoms.

Background and objectives. Due to the large migrations over the past three decades, large numbers of individuals with schizophrenia are learning a second language and being seen in clinics in that second language. We conducted within-subject comparisons to clarify the contribution of clinical, linguistic and bilingual features in the first and second languages of bilinguals with schizophrenia.Methods. Ten bilingual Russian(L1) and Hebrew(L2) proficient patients, who developed clinical schizophrenia after achieving proficiency in both languages, were selected from 60 candidates referred for the study; they were resident in Israel 7–32 years with 3–10 years from immigration to diagnosis. Clinical, linguistic and fluency markers were coded in transcripts of clinical interviews.Results. There was a trend toward more verbal productivity in the first language (L1) than the second language (L2). Clinical speech markers associated with thought disorder and cognitive impairment (blocking and topic shift) were similar in both languages. Among linguistic markers of schizophrenia, Incomplete syntax and Speech role reference were significantly more frequent in L2 than L1; Lexical repetition and Unclear reference demonstrated a trend in the same direction. For fluency phenomena, Discourse markers were more prevalent in L1 than L2, and Codeswitching was similar across languages, showing that the patients were attuned to the socio-pragmatics of language use.Conclusions. More frequent linguistic markers of schizophrenia in L2 show more impairment in the syntactic/semantic components of language, reflecting greater thought and cognitive dysfunction. Patients are well able to acquire a second language. Nevertheless, schizophrenia finds expression in that language. Finally, more frequent fluency markers in L1 suggests motivation to maintain fluency, evidenced in particular by codeswitched L2 lexical items, a compensatory resource.

Schizophrenia-related caregiver burden is often under-recognized and associated with significant psychological and physical stress and increased indirect costs on the caregiver. The pooled analysis of 2 double-blind, randomized, multicenter, phase 3 studies (NCT01529515 and NCT01515423) evaluated the predictors of improvement or worsening of schizophrenia-related caregiver burden following paliperidone palmitate (including 1-month and 3-month formulations) treatment. Caregivers (family members/friends who had ≥1 hour of contact per week with the patients treated with PP 1-month) were offered to complete the involvement evaluation questionnaire (IEQ; 46 items; each item score: 0-4; total score: sum of all items in module 2 [0-124]). Total, 1497 caregivers (mean [SD] age: 51.5 [13.02] years) were included: 49.3% were parents and >50% of caregivers spent >32 hours/week in caregiving. Caregivers had significant improvement in IEQ sum scores from baseline to end-of-study (n=756; mean [SD] baseline score: 28.3 [15.34] points; mean [SD] improvement: 8.9 [14.73] points); most improvements seen in worrying (2.6 points) and urging (3.7 points) domains. There was significant relationship between improvement in IEQ sum scores and relapse status (p<0.001), and patient age (p<0.05); age of diagnosis, long-acting injectable (LAI) use at baseline, number and duration of prior psychiatric hospitalizations (<24 months) had no significant effect on improvement. Caregiver burden improvement was significant in patients on prior oral antipsychotics post switching to LAI with less leisure days being impacted and less hours spent in caregiving (p<0.001). Caregiver burden in family members of patients treated for schizophrenia is considerable. Switching from an oral antipsychotic to an LAI can provide a meaningful and significant improvement in caregiver burden.