Publications by authors named "Adam Savitz"

51 Publications

Efficacy and safety of seltorexant as adjunctive therapy in major depressive disorder: A phase 2b, randomized, placebo-controlled, adaptive dose-finding study.

Int J Neuropsychopharmacol 2021 Jul 29. Epub 2021 Jul 29.

Janssen Research & Development LLC, San Diego, CA.

Background: Seltorexant, a selective antagonist of human orexin-2 receptors, demonstrated antidepressant effects in a previous exploratory study in patients with major depressive disorder (MDD).

Methods: To replicate and extend this observation, a double-blind, adaptive dose-finding study was performed in patients with MDD who had an inadequate response to 1-3 selective serotonin/serotonin-norepinephrine reuptake inhibitors in the current episode. Patients were randomized (2:1:1) to placebo or seltorexant (20 mg or 40 mg) once-daily, administered adjunctively to the antidepressant which the patient had been receiving at screening. After an interim analysis (6 weeks post-randomization of 160 th patient), newly recruited patients randomly received (3:3:1) placebo or seltorexant 10 mg or 20 mg; the 40 mg dose was no longer assigned. Patients were stratified by baseline Insomnia Severity Index scores (ISI ≥15 vs ISI <15). Primary endpoint was change from baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score at week 6.

Results: Mixed-Model for Repeated Measures (MMRM) analysis showed a greater improvement in MADRS total score in the seltorexant 20 mg group vs placebo at weeks 3 and 6; least-square means (LSM) difference (90% CI): -4.5 (-6.96;-2.07), p=0.003 and -3.1 (-6.13; -0.16), p=0.083, respectively. The improvement in MADRS score at week 6 for seltorexant 20 mg was greater in patients with baseline ISI ≥15 vs those with ISI <15; LSM difference (90% CI) vs placebo: -4.9 (-8.98;-0.80) and -0.7 (-5.16;3.76), respectively. The most common (≥5%) adverse events with seltorexant were somnolence, headache, and nausea.

Conclusions: A clinically meaningful reduction of depressive symptoms was observed for seltorexant 20 mg. In the subset of patients with sleep disturbance (ISI ≥15), a larger treatment difference between seltorexant 20 mg and placebo was observed, warranting further investigation. No new safety signal was identified.
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http://dx.doi.org/10.1093/ijnp/pyab050DOI Listing
July 2021

Characteristics of patients with major depressive disorder switching SSRI/SNRI therapy compared with those augmenting with an atypical antipsychotic in a real-world setting.

Curr Med Res Opin 2021 Aug 29;37(8):1377-1384. Epub 2021 Apr 29.

Janssen Research & Development LLC, Titusville, NJ, USA.

Background: Following a partial response of first-line antidepressant therapy for the treatment of major depressive disorder (MDD), there is a choice to augment treatment with another agent or switch to a different antidepressant.

Objective: To report the prevalence and compare the characteristics of patients switching from their initial selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor (SSRI/SNRI) to a new SSRI/SNRI versus those augmenting SSRI/SNRI therapy with a second-generation antipsychotic (SGA).

Methods: MDD patients receiving first-line SSRI/SNRI treatment were identified from a large US-based claims database during 2000-2019. Patients augmenting therapy with an SGA were compared with those who switched to a new SSRI/SNRI. The date of the treatment change was the index date. Previously diagnosed comorbid conditions, medication use and demographics were captured. Treatment patterns following the index date were also captured. Standardized differences (StdDiff) were used to quantify dissimilarities between the two groups.

Results: There were 4572 SGA add-on and 24,409 switching patients identified. SGA augmentation patients had more severe disease (diagnosed severe recurrent major depression: 24.7% vs. 9.5%, StdDiff = 0.41) and more diagnosed psychiatric conditions, including: suicidal thoughts (10.7% vs. 3.2%, StdDiff = 0.29), post-traumatic stress disorder (6.1% vs. 2.6%, StdDiff = 0.17) and alcohol abuse (5.4% vs. 2.7%, StdDiff = 0.14). SGA augmentation patients had higher rates of prior use of anxiolytics (37.4% vs. 28.2%, StdDiff = 0.20) and anticonvulsants (26.0% vs. 13.1%, StdDiff = 0.33).

Conclusions: Patients adding an SGA to their SSRI/SNRI therapy appeared to have more severe depression and comorbid psychiatric profile than those switching their SSRI/SNRI. These differences are important to consider and adequately control for in any future comparative outcome research between these two groups.
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http://dx.doi.org/10.1080/03007995.2021.1911975DOI Listing
August 2021

Abnormal semantic processing of threat words associated with excitement and hostility symptoms in schizophrenia.

Schizophr Res 2021 02 5;228:394-402. Epub 2021 Feb 5.

Brigham & Women's Hospital, Departments of Psychiatry and Radiology, Harvard Medical School, 221 Longwood Avenue, Boston, MA 02115, USA. Electronic address:

Background: Schizophrenia (SZ) is associated with devastating emotional, cognitive and language impairments. Understanding the deficits in each domain and their interactions is important for developing novel, targeted psychotherapies. This study tested whether negative-threat word processing is altered in individuals with SZ compared to healthy controls (HC), in relation to SZ symptom severity across domains.

Methods: Thirty-one SZ and seventeen HC subjects were scanned with functional magnetic resonance imaging while silently reading negative-threat and neutral words. Post-scan, subjects rated the valence of each word. The effects of group (SZ, HC), word type (negative, neutral), task period (early, late), and severity of clinical symptoms (positive, negative, excitement/hostility, cognitive, depression/anxiety), on word valence ratings and brain activation, were analyzed.

Results: SZ and HC subjects rated negative versus neutral words as more negative. The SZ subgroup with severe versus mild excitement/hostility symptoms rated the negative words as more negative. SZ versus HC subjects hyperactivated left language areas (angular gyrus, middle/inferior temporal gyrus (early period)) and the amygdala (early period) to negative words, and the amygdala (late period) to neutral words. In SZ, activation to negative versus neutral words in left dorsal temporal pole and dorsal anterior cingulate was positively correlated with excitement/hostility scores.

Conclusions: A negatively-biased behavioral response to negative-threat words was seen in SZ with severe versus mild excitement/hostility symptoms. The biased behavioral response was mediated by hyperactivation of brain networks associated with semantic processing of emotion concepts. Thus, word-level semantic processing may be a relevant psychotherapeutic target in SZ.
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http://dx.doi.org/10.1016/j.schres.2020.12.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988509PMC
February 2021

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

Neuropsychiatr Dis Treat 2020 19;16:1533-1542. Epub 2020 Jun 19.

Department of Neuroscience, Janssen Research & Development, LLC, Titusville, NJ, USA.

Background: Sudden discontinuation from antipsychotic treatment is a common occurrence in patients with schizophrenia. Lower rates of relapse could be expected for patients discontinuing treatment from longer-acting formulations vs their shorter-acting equivalents.

Objective: To compare relapse rates and time-to-relapse between the active (analogous to adherent patients) and placebo (analogous to non-adherent patients in the real-world) arms of three different formulations of paliperidone (oral paliperidone extended release [paliperidone ER], paliperidone palmitate once monthly [PP1M], and paliperidone palmitate three monthly [PP3M] long-acting injectables).

Methods: Data from three similarly designed, randomized relapse prevention studies in adult patients with schizophrenia were analyzed.

Results: In total, 922 patients were included (active treatment: 473, placebo: 449). Lowest percentage of patients experienced relapse with PP3M PP1M (172 days [134-222 days])> paliperidone ER (58 days [42-114 days]) and was "not-estimable" in the active treatment group due to low relapse rates. Hazard ratios (HR) of the three paliperidone formulations relative to their respective placebos were PP3M ([HR: 3.81; 95% CI: 2.08, 6.99; P< 0.0001]> PP1M [HR: 3.60; 95% CI: 2.45, 5.28; P<0.0001]> paliperidone ER [HR: 2.83; 95% CI: 1.73, 4.63; P<0.001]).

Conclusion: The lower percentage of relapse during active treatment and longer time to relapse after discontinuing active treatment with longer-duration antipsychotic formulations suggests the benefit of longer-acting over shorter-acting formulations, especially in patients susceptible to poor adherence. paliperidone ER (NCT00086320), PP1M (NCT00111189), and PP3M (NCT01529515).
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http://dx.doi.org/10.2147/NDT.S221242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311166PMC
June 2020

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

Schizophr Res Cogn 2020 Jun 2;20:100173. Epub 2020 Mar 2.

Janssen Research & Development LLC, NJ, USA.

Objective: To assess cognitive functioning in adolescents (12-17 years old) with schizophrenia during open-label treatment with paliperidone extended-release (pali ER).

Methods: In this exploratory analysis, adolescents treated with pali ER (oral, flexibly dosed, 1.5-12 mg/day) underwent cognitive assessments at baseline and month 6 using a battery of cognitive tests validated in adolescents. Correlation analysis was used to explore the relationship between cognitive assessments and clinical symptoms (Positive and Negative Syndrome Scales [PANSS] and factors) and functionality (Children Global Assessment Scale [CGAS]) at baseline and at 6 months.

Results: A total of 324 of 393 patients had evaluable neurocognitive data. Changes in cognition function tests from baseline to endpoint were generally small to modest, with improvement noted for most cognitive domains (motor speed, attention/working memory, verbal learning and memory, social cognition, speed of processing, executive functioning). No improvement was noted for visual learning and memory. At baseline, there were modest negative correlations between disorganized thoughts and most cognitive domains; these correlations persisted at 6 months. Other significant negative correlations at 6 months were between speed of processing and PANSS total score, positive symptoms, negative symptoms and uncontrolled hostility (p < 0.05). At 6 months, higher CGAS scores (improved functioning) positively correlated with speed of processing and executive functioning, especially among pali ER responders.

Conclusions: In this large sample of adolescents with schizophrenia, frank cognitive deficits across multiple domains were observed. Treatment with pali ER over 6 months did not worsen neurocognitive functioning and was possibly associated with positive improvement in certain domains.
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http://dx.doi.org/10.1016/j.scog.2020.100173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052566PMC
June 2020

The effects of a staff-training program in behavior management and social-learning principles on staff-patient interactions within a psychiatric rehabilitation inpatient unit.

Am J Orthopsychiatry 2020 5;90(4):419-431. Epub 2020 Mar 5.

Department of Psychiatry.

Despite the existence of effective behavioral interventions for people diagnosed with serious mental illness (SMI), these continue to be underutilized. Barriers to implementation include a low frequency of staff-patient interactions, as well as a lack of knowledge about, and negative attitudes toward, behavioral interventions. Therefore, we examined the effects of a mandatory behavioral staff-training program on staff-patient interactions on a long-term psychiatric inpatient program for individuals with SMI. Staff-training consisted of two-phases: didactic training followed by a written exam, and in vivo training and assessment. From pre- to posttraining, all staff demonstrated increased positive and therapeutic behaviors and decreased negative behaviors when interacting with patients. Additionally, at baseline, nonmedical staff (psychologists, social workers) displayed significantly more therapeutic and fewer negative behaviors compared with medical staff (psychiatrists, nurses, mental health workers), and this pattern persisted at posttraining despite improvements in both groups. Importantly, completion of the staff-training program was associated with improvements in patient behavior. Although both written and in vivo test scores significantly predicted change in negative staff behaviors toward patients, the in vivo test performance increased predictive ability over and above that of written test performance. Staff who disagreed with behavioral management principles displayed less improvement in negative behaviors from pre- to postassessment. These data have implications for clarifying staff training needs in programs for chronically ill people with SMI. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
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http://dx.doi.org/10.1037/ort0000443DOI Listing
March 2021

Pharmacokinetic-Pharmacodynamic Characterization of Relapse Risk for Paliperidone Palmitate 1-Month and 3-Month Formulations.

J Clin Psychopharmacol 2019 Nov/Dec;39(6):567-574

Janssen Research and Development, LLC, Titusville, NJ.

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.
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http://dx.doi.org/10.1097/JCP.0000000000001137DOI Listing
April 2020

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

Neuropsychiatr Dis Treat 2019 21;15:1365-1379. Epub 2019 May 21.

The Zucker Hillside Hospital, Psychiatry Research, Glen Oaks, NY, USA.

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.
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http://dx.doi.org/10.2147/NDT.S197225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535080PMC
May 2019

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

Braz J Psychiatry 2019 Nov-Dec;41(6):499-510

Janssen-Cilag UK, Buckinghamshire, UK.

Objective: To analyze the efficacy and safety of paliperidone palmitate 3-monthly (PP3M) in Latin American patients with schizophrenia vs. rest-of-world (ROW).

Methods: We analyzed data from two multinational, double-blind (DB), randomized, controlled phase 3 studies including patients with schizophrenia (DSM-IV-TR) previously stabilized on PP1M/PP3M (open-label [OL] phase). Patients were randomized to PP3M or PP1M (noninferiority study A) and PP3M or placebo (study B) in DB phase. The subgroup analysis included Latin American (Argentina, Brazil, Colombia, Mexico) patients. Primary efficacy endpoints were relapse-free rates (study A) and time-to-relapse (study B).

Results: In study A, 63/71 (88.7%) and in study B 38/43 (88.4%) Latin American patients completed the DB phase. In study A, relapse-free percentage was similar in Latin America (PP3M: 97%, PP1M: 100%) and ROW (PP3M: 91%, PP1M: 89%). In study B, median time-to-relapse was not estimable in the Latin American subgroup for either placebo or PP3M groups, nor for the ROW PP3M group; the median time-to-relapse in the ROW placebo group was 395 days. Caregiver burden improved in patients switching from oral antipsychotics (OL baseline) to PP3M/PP1M in DB phase (Involvement Evaluation Questionnaire score mean ± SD change, -9.4±15.16; p < 0.001). Treatment emergent adverse events with PP3M during DB phase were similar in Latin America (study A: 24/34 [70.6%]; study B: 15/21 [71.4%]) and ROW (study A: 318/470 [67.7%]; study B: 84/139 [60.4%]) subgroups.

Conclusion: PP3M was efficacious and showed no new safety concerns in patients with schizophrenia from Latin America, corroborating ROW findings.

Clinical Trial Registration: NCT01515423, NCT01529515.
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http://dx.doi.org/10.1590/1516-4446-2018-0153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899357PMC
January 2020

Predictors of achieving remission in schizophrenia patients treated with paliperidone palmitate 3-month formulation.

Neuropsychiatr Dis Treat 2019 22;15:731-737. Epub 2019 Mar 22.

Janssen Scientific Affairs, LLC, Titusville, NJ 08560, USA,

Purpose: Long-acting injectable (LAI) antipsychotic paliperidone palmitate 3-month formulation (PP3M) is indicated in the United States for the treatment of schizophrenia only after adequate treatment with paliperidone palmitate 1-month formulation (PP1M) for ≥4 months. This analysis aimed to identify patient and disease characteristics during PP1M treatment associated with greater likelihood of achieving remission after transition to PP3M.

Methods: A post hoc analysis of a randomized, Phase III, double-blind, noninferiority trial of PP3M vs PP1M (ClinicalTrials.gov identifier: NCT01515423) was conducted in adult patients with schizophrenia. Patients achieving clinical stability after 17 weeks of open-label PP1M were randomized to 48 weeks of double-blind treatment with PP3M or PP1M. The primary objective of this exploratory post hoc analysis was to identify demographic and/or clinical variables associated with persistent remission after treatment with PP3M. Multiple logistic regression analysis identified the following significant predictors of remission: Positive and Negative Syndrome Scale (PANSS) Marder negative symptom factor score, Clinical Global Impression-Severity (CGI-S) total score, and Personal and Social Performance (PSP) total score.

Results: At double-blind baseline, a 1-point reduction in Marder negative symptom factor score was associated with a 20% increase in the odds of achieving remission after PP3M treatment; 1-point reduction in CGI-S was associated with a doubling in remission odds; and 7- and 10-point improvements in PSP scores, respectively, were associated with 42% and 65% increases in remission odds.

Conclusion: Patients with early clinically meaningful improvements in disease symptoms and severity while establishing stable PP1M dosage are more likely to achieve remission after transition to PP3M.
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http://dx.doi.org/10.2147/NDT.S194264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435125PMC
March 2019

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

Neuropsychiatr Dis Treat 2019 21;15:587-602. Epub 2019 Feb 21.

Medical & Scientific Affairs, Janssen Cilag EMEA, Neuss, Germany.

Purpose: This randomized, double-blind (DB), non-inferiority phase 3 study was conducted to assess the efficacy and safety of paliperidone palmitate 3-month (PP3M) vs 1-month formulation (PP1M) in European and non-European patients with schizophrenia.

Patients And Methods: In this randomized, DB, parallel-group study, adult patients (18-70 years) with schizophrenia (per DSM-IV-TR) having Positive and Negative Syndrome Scale (PANSS) total score between 70 and 120; previously stabilized on PP1M were enrolled. The study had 4 phases: screening (3 weeks), open-label (OL) stabilization (17 weeks), DB (48 weeks) and follow-up (4-12 weeks) phase. Patients were treated with fixed-dose PP3M (175-525 mg eq deltoid/gluteal) or PP1M (50-150 mg eq deltoid/gluteal) for 48 weeks in DB phase.

Results: In total, 487 European (PP3M, n=242; PP1M, n=245) and 508 non-European patients (PP3M, n=241; PP1M, n=267) entered DB phase (modified intent-to-treat (mITT) [DB] analysis set). Among the 508 non-European patients in mITT set, 67.7% were from Asia (n=344) and 32.3% were from rest of world (ROW, n=164). During the DB phase, similar percentage of Europeans (PP3M: 7%; PP1M: 8%) and non-Europeans (PP3M: 9%; PP1M: 10%) experienced relapse (Kaplan-Meier estimate PP3M-PP1M [95% CI] of percentage of relapse-free patients at the end of DB phase [primary endpoint]: European: 1.0% [-4.3%; 6.2%]; non-European: 1.4% [-4.4%; 7.1%]; Asian: 1.6% [-5.7%; 9.0%]; and ROW: 1.4% [-7.0%, 9.8%], per-protocol analysis set). Incidence of treatment-emergent adverse events (TEAEs) was lower in Europeans (PP3M: 56%, PP1M: 59%) than non-Europeans (PP3M: 80%, PP1M: 73%). The most commonly reported TEAE was weight gain.

Conclusion: PP3M showed similar efficacy to PP1M in Europeans and non-Europeans, consistent with non-inferiority of PP3M to PP1M observed in overall population. Rates of AEs were higher in non-Europeans. However, weight gain was greater in non-Europeans, especially the Asian population.
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http://dx.doi.org/10.2147/NDT.S189668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391122PMC
February 2019

Low Incidence of Neuroleptic Malignant Syndrome Associated With Paliperidone Palmitate Long-Acting Injectable: A Database Report and Case Study.

J Clin Psychopharmacol 2019 Mar/Apr;39(2):180-182

The Zucker Hillside Hospital Glen Oaks, NY. and The Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Glen Oaks, NY 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, Germany. Providence Care Hospital Kingston, Ontario, Canada. Janssen Research & Development LLC, Raritan, NJ.

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http://dx.doi.org/10.1097/JCP.0000000000001019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6392211PMC
September 2019

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

Neuropsychiatr Dis Treat 2018 25;14:2807-2816. Epub 2018 Oct 25.

Janssen Research and Development, LLC, Titusville, NJ, USA,

Objective: The aim of this study was to evaluate the safety of 3-monthly paliperidone palmitate (PP3M) vs once-monthly paliperidone palmitate (PP1M) treatment with regard to extrapyramidal symptom (EPS)-related treatment-emergent adverse events (TEAEs) in patients with schizophrenia, previously stabilized on PP1M treatment.

Patients And Methods: Data on overall incidence, time to onset (TTO), and time to resolution (TTR) of EPS-related TEAEs (overall, subclasses such as dyskinesia, dystonia, hyperkinesia, parkinsonism, and tremor) from a randomized double-blind (DB) non-inferiority study were compared between PP3M and PP1M. Subgroup analysis was performed by age (18-25, 26-50, and 50+ years) and final open-label (OL) dose (50/75, 100, and 150 mg eq.).

Results: Overall incidence of spontaneously reported EPS-related TEAEs decreased from 12.6% (PP1M) in OL phase to 8.3% (PP3M) and 7.4% (PP1M) in the DB phase; overall median TTO and TTR values were comparable between both groups. Among patients with reported EPS-related TEAEs, the median TTO for all EPS-related TEAEs was 17 days (PP1M) in OL phase and 115 days (PP3M) and 98.5 days (PP1M) in DB phase; median TTR was 36.5 days (PP1M) in OL phase and 91 days (PP3M) and 85.5 days (PP1M) in DB phase. No clear dose- or age-related differences in TTO and TTR of EPS-related TEAEs were noted.

Conclusion: Despite differences in apparent half-life and pharmacokinetic profiles (peak plasma exposure of PP3M formulation is 70% higher than that of PP1M formulation), both PP3M and PP1M formulations exhibited comparable incidence of EPS-related TEAEs, TTO, and TTR in patients with schizophrenia.
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http://dx.doi.org/10.2147/NDT.S175364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207222PMC
October 2018

The Open Translational Science in Schizophrenia (OPTICS) project: an open-science project bringing together Janssen clinical trial and NIMH data.

NPJ Schizophr 2018 Jun 27;4(1):14. Epub 2018 Jun 27.

Section of General Internal Medicine and the National Clinician Scholars Program, Department of Medicine, Yale University School of Medicine, New Haven, CT, USA.

Clinical trial data are the gold standard for evaluating pharmaceutical safety and efficacy. There is an ethical and scientific imperative for transparency and data sharing to confirm published results and generate new knowledge. The Open Translational Science in Schizophrenia (OPTICS) Project was an open-science initiative aggregating Janssen clinical trial and NIH/NIMH data from real-world studies and trials in schizophrenia. The project aims were to show the value of using shared data to examine: therapeutic safety and efficacy; disease etiologies and course; and methods development. The success of project investigators was due to collaboration from project applications through analyses, with support from the Harvard Catalyst. Project work was independent of Janssen; all intellectual property was dedicated to the public. Efforts such as this are necessary to gain deeper insights into the biology of disease, foster collaboration, and to achieve the goal of developing better treatments, reducing the overall public health burden of devastating brain diseases.
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http://dx.doi.org/10.1038/s41537-018-0055-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6021398PMC
June 2018

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

Clin Drug Investig 2018 Aug;38(8):695-702

Janssen Research & Development, LLC, 1125 Trenton-Harbourton Road, Titusville, NJ, 08560, USA.

Background And Objective: Paliperidone palmitate 3-monthly (PP3M) injectable formulation offers an advantage of improved medication adherence and lower relapse risk in patients with schizophrenia. This post hoc analysis compared outcomes following PP3M versus paliperidone palmitate 1-monthly (PP1M) treatment in patients with schizophrenia treated/untreated with oral risperidone/paliperidone (RIS/PALI).

Methods: Patients were treated with PP1M (50, 75, 100, or 150 mg equivalent [eq.]) for 17 weeks during an open-label (OL) phase and randomized (1:1) to PP3M (175, 263, 350, or 525 mg eq.) or PP1M (50, 75, 100, or 150 mg eq.) during a 48-week double-blind phase. Efficacy outcomes were compared based on prior oral RIS/PALI exposure: recent (≥ 28 days of oral RIS/PALI exposure with last dose within 14 days before study entry); or no (no oral RIS/PALI exposure within 60 days before study entry).

Results: A total of 452 OL patients received recent oral RIS/PALI (n = 323 [71%], randomized to PP3M = 166; PP1M = 157), and 709 OL patients were without recent oral RIS/PALI (n = 506 [71%], randomized to PP3M = 254; PP1M = 252). Improvements in Positive and Negative Syndrome Scale (PANSS) scores (OL baseline-to-endpoint) were similar in recent-RIS/PALI (mean [standard deviation]:18.3 [17.96]) and no-RIS/PALI (- 21.1 [16.40]) subgroups. Relapse-free rates were comparable between recent-RIS/PALI (relapse-free rate [95% confidence interval for difference]: 2.6 [- 4.7 to 10.0]; PP3M: 90%; PP1M: 87%) and no-RIS/PALI subgroups (0.8 [- 4.5 to 6.0]; PP3M: 92%; PP1M: 91%). Weight gain was the most common (> 5% incidence) treatment-emergent adverse event in both subgroups irrespective of the prior treatment.

Conclusion: Patients with schizophrenia, irrespective of prior treatment with RIS/PALI, had comparable treatment outcomes and tolerability following PP3M or PP1M treatment.

Registration: This study is registered at the EU clinical trial registry (EudraCT Number: 2011-004889-15) and ClinicalTrials.gov (identifier: NCT01515423).
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http://dx.doi.org/10.1007/s40261-018-0647-zDOI Listing
August 2018

Use of antipsychotic blood levels in clinician decision making: A cross-over study using clinical vignettes of patients with schizophrenia.

Psychiatry Res 2018 09 19;267:25-29. Epub 2018 May 19.

Clinical Research, Neurosciences, Janssen Research & Development, LLC, 1125 Trenton-Harbourton Road, Titusville, NJ 08560, United States.

The cause of treatment failure of antipsychotic medications is often difficult to determine in patients with schizophrenia. Evaluation of antipsychotic blood levels (ABLs) may aid clinicians in determining the cause of antipsychotic failure. The Clinical Assessment of the Schizophrenia Patient (CASP) was developed to evaluate clinical decision making during outpatient visits. The CASP assesses changes in medications, psychosocial treatments, and acute interventions along with factors influencing clinical decision making. Nine vignettes representative of clinical situations in patients with schizophrenia were created in two versions (one with ABLs, one without ABLs). The CASP was used to evaluate clinical decisions using the vignettes. Thirty-four clinicians participated in the study. In 8 out of 9 vignettes, most clinicians (at least 89.7%) made a different clinical decision with ABLs compared to without ABLs. In assessing the usefulness of ABLs, a majority (60.7%-85.7%, depending on the vignette) of clinicians responded that ABLs changed their clinical decision for 8 vignettes. Most clinicians (79%-93%) responded that they were more confident in their decisions with ABL information. This study demonstrated that ABLs have the potential to influence clinical decision making in the treatment of patients with schizophrenia.
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http://dx.doi.org/10.1016/j.psychres.2018.05.014DOI Listing
September 2018

Relationship between antipsychotic blood levels and treatment failure during the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study.

Schizophr Res 2018 11 24;201:324-328. Epub 2018 May 24.

Neurosciences, Janssen Research & Development, 1800 American Boulevard, Pennington, NJ, 08534, United States.

Objective: Antipsychotic blood levels (ABLs) may help identify patients at risk for treatment failure. Reference ranges (RR) for plasma concentrations of ABLs that account for between-patient variability were developed for risperidone and olanzapine based on population pharmacokinetic models. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) collected clinical outcomes and ABLs, allowing testing of the relationship of ABLs with outcomes.

Methods: ABLs from 694 patients who were randomized to olanzapine or risperidone were compared to the 80% RRs and were assessed as below or within/above the RR. Treatment failure was defined per any of these criteria: (1) emergency room visit for psychiatric reasons, (2) hospitalization for psychiatric reasons, (3) adverse event of completed suicide, suicidal ideation, or suicide attempt, (4) assaultive behavior, (5) arrested or jailed, (6) 2-point increase from baseline in Clinical Global Impression-Severity score, (7) 25% increase in Positive and Negative Syndrome Scale total score. Patients assessed with treatment failure within 100 days of drug concentration measurement were analyzed.

Results: Treatment failure occurred in 126 of 323 patients. The proportion of patients with ABLs below RR was 18.3% (59/323) compared to 10% expected in a fully adherent population. Among the 59 with ABLs below RR, 50.8% had treatment failure (compared to 36.4% for the 264 with ABLs within/above RR). The difference between groups was significant (odds ratio = 1.810; 95% CI = 1.025, 3.197; p = 0.0408).

Conclusions: Analysis of CATIE data showed that ABLs within the context of RRs may identify patients with higher risk of relapse.
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http://dx.doi.org/10.1016/j.schres.2018.05.028DOI Listing
November 2018

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

Perspect Psychiatr Care 2018 Oct 14;54(4):530-538. Epub 2018 Feb 14.

Janssen Scientific Affairs, LLC, Titusville, New Jersey, USA.

Purpose: To evaluate injection site reactions and pain following paliperidone palmitate 1-month (PP1M) and 3-month (PP3M) administration using safety data of double-blind (DB), noninferiority study.

Methods: Patients (n = 1,429) with schizophrenia, treated with PP1M (50-150 mg-eq, 17-week open-label [OL] phase) were randomized to PP1M or PP3M in 48-week DB phase.

Findings: PP1M and PP3M injections were well tolerated. Incidence of induration, redness, and swelling were low in both phases (OL: 9-12%; DB: 7-13%), and were mostly mild in both groups. Mean (SD) visual analog scale scores decreased from OL-baseline (22.0 [21.6]) to DB-baseline (19.5 [20.6] vs. 18.4 [20.4]) and DB-endpoint (15.6 [17.9] vs. 15.5 [18.3]).

Practice Implications: Injection site reactions and pain were low and similar between both treatments, regardless of administration site and dose.
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http://dx.doi.org/10.1111/ppc.12267DOI Listing
October 2018

Bifactor Modeling of the Positive and Negative Syndrome Scale: Generalized Psychosis Spans Schizoaffective, Bipolar, and Schizophrenia Diagnoses.

Schizophr Bull 2018 10;44(6):1204-1216

Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA.

Objective: Common genetic variation spans schizophrenia, schizoaffective and bipolar disorders, but historically, these syndromes have been distinguished categorically. A symptom dimension shared across these syndromes, if such a general factor exists, might provide a clearer target for understanding and treating mental illnesses that share core biological bases.

Method: We tested the hypothesis that a bifactor model of the Positive and Negative Syndrome Scale (PANSS), containing 1 general factor and 5 specific factors (positive, negative, disorganized, excited, anxiety), explains the cross-diagnostic structure of symptoms better than the traditional 5-factor model, and examined the extent to which a general factor reflects the overall severity of symptoms spanning diagnoses in 5094 total patients with a diagnosis of schizophrenia, schizoaffective, and bipolar disorder.

Results: The bifactor model provided superior fit across diagnoses, and was closer to the "true" model, compared to the traditional 5-factor model (Vuong test; P < .001). The general factor included high loadings on 28 of the 30 PANSS items, omitting symptoms associated with the excitement and anxiety/depression domains. The general factor had highest total loadings on symptoms that are often associated with the positive and disorganization syndromes, but there were also substantial loadings on the negative syndrome thus leading to the interpretation of this factor as reflecting generalized psychosis.

Conclusions: A bifactor model derived from the PANSS can provide a stronger framework for measuring cross-diagnostic psychopathology than a 5-factor model, and includes a generalized psychosis dimension shared at least across schizophrenia, schizoaffective, and bipolar disorder.
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http://dx.doi.org/10.1093/schbul/sbx163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192503PMC
October 2018

Measuring pathology using the PANSS across diagnoses: Inconsistency of the positive symptom domain across schizophrenia, schizoaffective, and bipolar disorder.

Psychiatry Res 2017 12 16;258:207-216. Epub 2017 Aug 16.

University of California, Los Angeles, Department of Psychiatry and Biobehavioral Sciences, Los Angeles, CA, USA; University of California, Los Angeles, Department of Psychology, Los Angeles, CA, USA.

Although the Positive and Negative Syndrome Scale (PANSS) was developed for use in schizophrenia (SZ), antipsychotic drug trials use the PANSS to measure symptom change also for bipolar (BP) and schizoaffective (SA) disorder, extending beyond its original indications. If the dimensions measured by the PANSS are different across diagnoses, then the same score change for the same drug condition may have different meanings depending on which group is being studied. Here, we evaluated whether the factor structure in the PANSS was consistent across schizophrenia (n = 3647), bipolar disorder (n = 858), and schizoaffective disorder (n = 592). Along with congruency coefficients, Hancock's H, and Jaccard indices, we used target rotations and statistical tests of invariance based on confirmatory factor models. We found the five symptom dimensions measured by the 30-item PANSS did not generalize well to schizoaffective and bipolar disorders. A model based on an 18-item version of the PANSS generalized better across SZ and BP groups, but significant problems remained in generalizing some of the factors to the SA sample. Schizophrenia and bipolar disorder showed greater similarity in factor structure than did schizophrenia and schizoaffective disorder. The Anxiety/Depression factor was the most consistent across disorders, while the Positive factor was the least consistent.
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http://dx.doi.org/10.1016/j.psychres.2017.08.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5681392PMC
December 2017

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

Neuropsychiatr Dis Treat 2017 17;13:2193-2207. Epub 2017 Aug 17.

Department of Geriatric Psychiatry, Taoyuan Mental Hospital, Taoyuan, Taiwan.

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 (<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.
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http://dx.doi.org/10.2147/NDT.S134287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5566420PMC
August 2017

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

Int Clin Psychopharmacol 2017 11;32(6):329-336

aJanssen Research and Development bJanssen Scientific Affairs, LLC, Titusville, New Jersey, USA.

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.
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http://dx.doi.org/10.1097/YIC.0000000000000190DOI Listing
November 2017

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

NPJ Schizophr 2017 Jul 27;3(1):23. Epub 2017 Jul 27.

Janssen Scientific Affairs, LLC, Raritan, NJ, USA.

The pooled analysis of two double-blind, randomized, multicenter, phase-3 studies evaluated predictors of improvement or worsening of schizophrenia-related caregiver burden following paliperidone palmitate long-acting injectables (1-monthly [PP1M] and 3-monthly [PP3M]) treatment. Caregivers were offered to complete the involvement evaluation questionnaire (involvement evaluation questionnaire; 31-item scale). Total, 1498 caregivers (intent-to-treat open-label analysis set, n = 1497; mean [SD] age: 51.5 [13.02] years, 27 countries) were included: 49% were parents and >50% caregivers spent >32 hours/week in caregiving. Majority of caregivers with considerable burden (n = 1405; mean [SD] baseline involvement evaluation questionnaire scores: 28.4 [15.07]) improved significantly from baseline to end-of-study (n = 756; mean [SD] change from open-label baseline to double-blind endpoint in long-acting injectable scores:-8.9 [14.73]); most improvements were seen in urging followed by worrying, tension, and supervision domains (mean [SD] change from open-label baseline to double-blind endpoint in involvement evaluation questionnaire scores, urging: -3.7 [6.45]; worrying:-2.6 [5.11]; tension:-2.3 [4.84]; supervision: -1.3 [3.69]). Improvements significantly correlated with relapse status, patient age, and age of diagnosis (p < 0.001) while long-acting injectable use at baseline, number, and duration of prior psychiatric hospitalizations (<24 months) had no significant correlation. Caregiver burden was significantly improved for patients on prior oral antipsychotics post-switching to long-acting injectable, with less impact on leisure days and hours spent in caregiving (p < 0.001). Family members of patients with schizophrenia experience considerable caregiver burden. Switching from oral antipsychotic to long-acting injectable can provide meaningful and significant improvement in caregiver burden.

Drug Formulation: EASING THE TOLL OF CAREGIVING: Switching from oral to long-acting injectable antipsychotic medication improves overall caregiver burden. The physical, emotional and financial toll of providing care for patients with schizophrenia is often underestimated. Poor adherence to conventional oral antipsychotics is a major cause of symptomatic relapse in patients and of stress for carers. Srihari Gopal and colleagues at Janssen Pharmaceuticals have pooled data from two large studies involving 1498 caregivers across 27 countries. They found that administration of either 1- or 3-monthly long-acting injectable antipsychotics not only eased the burden of daily dosing and patient compliance, but also had a positive impact on the stress conditions of caregivers. Using the Involvement Evaluation Questionnaire to measure caregiver burden, the authors showed that the switch in drug formulation decreased the need to urge patients to self-care and the hours spent caregiving.
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http://dx.doi.org/10.1038/s41537-017-0025-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5532271PMC
July 2017

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

CNS Drugs 2017 Sep;31(9):797-808

Neurosciences, Janssen Research & Development, LLC, 1125 Trenton-Harbourton Road, Titusville, NJ, 08560, USA.

Background: Elevated prolactin levels (hyperprolactinemia) are a frequent adverse effect of antipsychotic medications, especially in young populations. Prolonged hyperprolactinemia may affect sexual functioning and the onset and progression of puberty.

Objective: This study assessed potentially prolactin-related treatment-emergent adverse events (PPRL-TEAEs) and sexual maturation during long-term treatment of adolescents with paliperidone extended-release (ER).

Methods: This post hoc analysis of a 2-year open-label multicenter study (NCT00488319) included patients of either sex aged 12-17 years at study enrollment, diagnosed with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, 4th edition [DSM-IV]) for ≥1 year, who had received one or more adequate antipsychotic treatment prior to enrollment but had not responded sufficiently. Patients were initially treated with 6 mg/day paliperidone ER and further titrated between 1.5 and 12 mg/day based on clinical response and tolerability. The primary objective was to determine the relationship between characteristics (including sex, age at study entry, ethnicity, geographic region, age at diagnosis, duration of illness, number of prior hospitalizations, serum prolactin, and baseline Tanner stages) and onset or risk of PPRL-TEAEs. The secondary objective was to assess sexual maturation during long-term treatment with paliperidone ER.

Results: In total, 400 patients were enrolled in the study and 184 patients completed the 2-year study; the majority were boys (61%), White (66%), and aged >14 years at study enrolment (73%) with mean (standard deviation [SD]) body mass index (BMI) of 21.96 (4.375) kg/m at baseline. Girls (18.5%) had a higher incidence of PPRL-TEAEs than did boys (3.3%). Most of these events were mild to moderate in severity, and none were serious; four patients discontinued the study due to PPRL-TEAEs. Mean prolactin levels in the total population of boys and girls increased early during treatment then stabilized with time. Mean ± SD maximum changes in prolactin levels from baseline were higher in girls and boys with PPRL-TEAEs than in those without (Girls: 74.7 ± 32.3 ng/ml [n = 28] vs. 50.5 ± 44.9 ng/ml [n = 114]; p = 0.008. Boys: 33.6 ± 23.7 ng/ml [n = 8] vs. 31.0 ± 24.5 ng/ml [n = 205]; p = 0.77). No clinically significant mean changes from baseline in growth-adjusted z-score for weight, height, or BMI were observed. Overall, ~90% of the patients who completed the 2-year study achieved Tanner stages 4-5 by study endpoint. Female sex, age at diagnosis (13-14 years), girls of Hispanic ethnicity, and region (EU and North America) were associated with a greater risk for PPRL-TEAEs; higher baseline Tanner stages for pubic hair (boys and girls) and breast development (stage 3 vs. 4 or 5) also seemed to be associated with a higher incidence of PPRL-TEAEs.

Conclusions: Female sex appeared to be associated with an increased risk for PPRL-TEAEs. Other potential predictors, such as ethnicity, region, age at diagnosis, and Tanner stage 4 or 5, all seemed to be related to sex. Evidence from this study was insufficient to definitively conclude that prolactin values at baseline and change during treatment were predictive of PPRL-TEAEs, although there is a signal that this may be the case in girls. These results are exploratory in nature, and confirmatory studies are needed to confirm these observations.

Trial Registration: ClinicalTrials.gov identifier: NCT00488319.
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http://dx.doi.org/10.1007/s40263-017-0437-9DOI Listing
September 2017

Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects.

Nat Genet 2017 01 21;49(1):27-35. Epub 2016 Nov 21.

Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 × 10), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 × 10). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 × 10) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 × 10). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination.
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http://dx.doi.org/10.1038/ng.3725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5737772PMC
January 2017

Genome-wide association study of paliperidone efficacy.

Pharmacogenet Genomics 2017 01;27(1):7-18

aNeuroscience, Janssen Research & Development, LLC bJanssen Scientific Affairs, LLC, Titusville cJanssen Research & Development, LLC, Raritan dBlue Note Biosciences, LLC, Princeton, New Jersey eBiostatistics and Bioinformatics, The Scripps Translational Science Institute fDepartment of Molecular and Experimental Medicine, The Scripps Research Institute gScripps Health hHuman Biology, J. Craig Venter Institute, La Jolla iMD Revolution, San Diego, California, USA.

Objective: 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.

Methods: 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.

Results: 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.

Conclusion: Genetic variations in the ADCK1 gene may differentially predict paliperidone efficacy in schizophrenic patients. However, this finding should be replicated in additional samples.
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http://dx.doi.org/10.1097/FPC.0000000000000250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5152628PMC
January 2017

Comparison of Capillary and Venous Drug Concentrations After Administration of a Single Dose of Risperidone, Paliperidone, Quetiapine, Olanzapine, or Aripiprazole.

Clin Pharmacol Drug Dev 2016 Nov 28;5(6):528-537. Epub 2016 Sep 28.

Janssen Research & Development, LLC, Raritan, NJ, USA.

Risperidone, paliperidone, quetiapine, olanzapine, and aripiprazole are antipsychotic drugs approved for treating various psychiatric disorders, including schizophrenia. The objective of this randomized, parallel-group, open-label study was to compare finger-stick-based capillary with corresponding venous whole-blood and plasma concentrations for these drugs after administration of a single dose to healthy volunteers. All whole-blood and plasma drug concentrations were measured with validated liquid chromatography-tandem mass spectrometry methods. Capillary and venous concentrations (both in plasma and whole blood) were in close agreement, although a time-dependent difference was observed, most obviously for olanzapine and paliperidone, with slightly higher capillary versus venous drug concentrations during the first hours after administering a single dose. The observed difference between capillary and venous plasma drug concentrations is expected not to be relevant in clinical practice, considering the wide window of therapeutic concentrations and the wide range of drug concentrations in the patient population for a given dose. Based on these results, finger-stick-based capillary drug concentrations have been shown to approximate venous drug concentrations.
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http://dx.doi.org/10.1002/cpdd.290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5132056PMC
November 2016

Comparison of Capillary and Venous Plasma Drug Concentrations After Repeated Administration of Risperidone, Paliperidone, Quetiapine, Olanzapine, or Aripiprazole.

Clin Pharmacol Drug Dev 2016 Nov 17;5(6):538-547. Epub 2016 Aug 17.

Janssen Research & Development, LLC, Raritan, NJ, USA.

Quantification of blood levels of antipsychotic drugs may be useful for managing medication therapy. This open-label, parallel-group study was performed to compare finger-stick-based capillary with corresponding venous plasma concentrations for risperidone, paliperidone, quetiapine, olanzapine, and aripiprazole and their major metabolites after repeated dosing in patients with schizophrenia or related illnesses. Finger-stick-based capillary and venous blood samples were collected at various times within a dosing interval. All drug concentration measurements in the derived plasma samples were performed with validated liquid chromatography-tandem mass spectrometry methods. Finger-stick-based capillary and venous plasma drug concentrations after repeated dosing were generally similar. Olanzapine capillary plasma concentrations, however, were on average approximately 20% higher than venous concentrations, with a trend for a relatively greater difference occurring shortly after dosing. In addition, smaller capillary-venous differences were observed for extended-release and long-acting intramuscular formulations and for aripiprazole, a drug with a long half-life, compared with drugs administered as an immediate-release formulation (risperidone, olanzapine). After repeated dosing, plasma derived from finger-stick-based blood was observed to be predictive of the venous concentrations. Capillary sampling may be an appropriate alternative to venous sampling to readily evaluate systemic drug concentrations.
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http://dx.doi.org/10.1002/cpdd.291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5132144PMC
November 2016

Prospective dose selection and acceleration of paliperidone palmitate 3-month formulation development using a pharmacometric bridging strategy.

Br J Clin Pharmacol 2016 11 24;82(5):1364-1370. Epub 2016 Jul 24.

Janssen Research & Development LLC, New Jersey, USA.

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.
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http://dx.doi.org/10.1111/bcp.13050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5061800PMC
November 2016

Paliperidone palmitate: Japanese postmarketing mortality results in patients with schizophrenia.

Curr Med Res Opin 2016 Oct 28;32(10):1671-1679. Epub 2016 Jun 28.

a Janssen Pharmaceutical Research and Development , USA.

Objective: 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.

Research Design And Methods: 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.

Results: 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.

Conclusions: 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.
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http://dx.doi.org/10.1080/03007995.2016.1198755DOI Listing
October 2016
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