Adam Savitz | Weill Cornell Medicine (original) (raw)

Papers by Adam Savitz

60th Annual Meeting, Oct 25, 2013

Molecular and Cellular Biology, Nov 1, 1986

We deduced the complete amino acid sequence of the rat brain Na,K-ATPase ,-subunit from cDNA. The... more We deduced the complete amino acid sequence of the rat brain Na,K-ATPase ,-subunit from cDNA. The rat brain "-subunit exhibits a high degree of primary sequence and secondary structural homology with the human and Torpedo (i-subunit polypeptides. Analysis of rat tissue RNA reveals that the ,B-subunit gene encodes four separate mRNA species which are expressed in a tissue-specific fashion. In ouabain-resistant HeLa C+ cells, ,B-subunit DNA sequences are amplified (-20-fold) and "-subunit mRNAs are overproduced relative to levels in parental HeLa cells. These results suggest that the (-subunit plays an important role in Na,K-ATPase structure-function and in the mechanism underlying cellular resistance to the cardiac glycosides.

Sleep, Apr 1, 2020

B. Clinical Sleep Science and Practice I. Insomnia using the Work and Social Adjustment Scale. Qu... more B. Clinical Sleep Science and Practice I. Insomnia using the Work and Social Adjustment Scale. Quality of life was assessed using the Hotel Dieu-16 Scale. Results: Compared to PMRT, BBTI resulted in a greater reduction in subjective total sleep time variability (F 1,90 =6.61, p<0.01, partial η 2 =0.13) and a greater increase in interdaily stability (F 1,78 =12.41, p<0.01, partial η 2 =0.25). There was a greater decrease in intradaily variability following PMRT (F 1,78 =27.96, p<0.01, partial η 2 =0.42). Across the entire sample, reductions in subjective wake time variability were associated with improved functioning (F 1,88 =4.43, p=0.04, η 2 =0.05) and reductions in subjective total sleep time variability were associated with improved quality of life (F 1,89 =4.91, p=0.03, partial η 2 =0.05). Conclusion: There was significant improvement in the stability of sleep-wake rhythms following BBTI, suggesting that BBTI not only treats insomnia, but also may stabilize circadian rhythms. Interestingly, PMRT resulted in greater intradaily variability reductions than BBTI. One explanation is that due to BBTI stimulus control guidelines, individuals were getting out of bed in the middle of the night more frequently and thus, these awakenings were better captured by actigraphy. Reductions in wake time and total sleep time variability were associated with improved functioning and quality of life, further demonstrating the importance of stable sleep-wake rhythms.

International Journal of Neuropsychopharmacology, 2016

Objective: A post-hoc subgroup analysis was pemathewsMrformed to compare outcomes following admin... more Objective: A post-hoc subgroup analysis was pemathewsMrformed to compare outcomes following administration of paliperidone palmitate 3-monthly (PP3M) versus 1-monthly (PP1M) injectable in patients with schizophrenia previously treated/ not treated with oral risperidone/paliperidone (RIS/PALI) before study entry. Methods: Patients received PP1M (50, 75, 100, or 150 mg eq.) during 17-week open-label (OL) phase, randomized (1:1) to PP3M (175, 263, 350, or 525 mg eq.) or PP1M (50, 75, 100, or 150 mg eq.) during 48-week double-blind (DB) phase. Based on prior RIS/ PALI exposure, outcomes were compared between two subgroups: recent=at least 28 days of RIS/PALI exposure with last dose within 14 days before study entry; no=no RIS/PALI exposure within 60 days before study entry. Results: 452 patients had received recent RIS/PALI (n=323 [71%] randomized to PP3M=166; PP1M=157), and 709 did not receive RIS/PALI (n=506 [71%] randomized to PP3M=254; PP1M=252).

The International Journal of Neuropsychopharmacology, May 27, 2016

perception bias was associated with trait anxiety [beta=0.49, t=4.3, p<0.001, R-square=0.23, F(1,... more perception bias was associated with trait anxiety [beta=0.49, t=4.3, p<0.001, R-square=0.23, F(1,58)=18.7, p<0.001] and blame bias [F(2,56)=14.4, p<0.001] was associated with trait anxiety (beta=0.27, t=2.0, p=0.047) and low self-esteem (beta=-0.38, t=-2.9, p=0.006) in UHR individuals. Conclusion: These findings suggest that attribution bias may have been ahead of the onset of overt psychosis. In addition, psychosocial intervention for attribution bias in UHR individuals should be focusing the emotional dysregulation factors rather than neurocognitive function.

The International Journal of Neuropsychopharmacology, May 27, 2016

perception bias was associated with trait anxiety [beta=0.49, t=4.3, p<0.001, R-square=0.23, F(1,... more perception bias was associated with trait anxiety [beta=0.49, t=4.3, p<0.001, R-square=0.23, F(1,58)=18.7, p<0.001] and blame bias [F(2,56)=14.4, p<0.001] was associated with trait anxiety (beta=0.27, t=2.0, p=0.047) and low self-esteem (beta=-0.38, t=-2.9, p=0.006) in UHR individuals. Conclusion: These findings suggest that attribution bias may have been ahead of the onset of overt psychosis. In addition, psychosocial intervention for attribution bias in UHR individuals should be focusing the emotional dysregulation factors rather than neurocognitive function.

The International Journal of Neuropsychopharmacology, May 27, 2016

Conclusion: Clinically relevant improvements in psychopathology were observed in patients with ac... more Conclusion: Clinically relevant improvements in psychopathology were observed in patients with acute schizophrenia treated with brexpiprazole or aripiprazole. Brexpiprazole was well tolerated with a lower incidence of EPS-related adverse events than aripiprazole.

The International Journal of Neuropsychopharmacology, May 27, 2016

Background: This post-hoc analysis was performed to compare the overall incidence, time-to-onset ... more Background: This post-hoc analysis was performed to compare the overall incidence, time-to-onset (TTO) and time-to-resolution (TTR) of extrapyramidal symptoms (EPS)-related adverse events (AEs) after treatment with paliperidone palmitate (PP) 3-monthly (PP3M) vs. 1-monthly (PP1M) long-acting injectable in patients with schizophrenia. Methods: EPS-related AEs were summarized by grouped terms (Overall and further classified into Dystonia, Dyskinesia, Hyperkinesia, Parkinsonism and Tremor), study phases (openlabel [OL]: PP1M, double-blind [DB]: PP1M or PP3M), TTO and TTR, and descriptively compared. TTO and TTR were further analyzed by final OL dose (50/75 mg eq., 100 mg eq. and 150 mg eq.) and age (18-25, 26-50 and 50+ years) subgroups. Results: Overall incidence of EPS-related AEs was 12.6% (PP1M) during OL phase, reducing to 8.3% (PP3M) and 7.4% (PP1M) during DB phase. Median TTO for all EPS-related AEs was 17 days (range: 1-120) after PP1M OL treatment; 115 days (range: 1-323) and 98.5 days (range: 1-322) after treatment with PP3M and PP1M, respectively (DB phase). Median TTR was 36.5 days (range: 1-127) in PP1M group (OL), and was generally similar for PP3M (91 days [range: 1-336]) vs. PP1M (85.5 days [range: 1-337]) during DB phase. Overall median TTO and TTR values were comparable between PP3M and PP1M formulations. Subgroup analysis revealed no clear dose-response or age-related differences in TTO and TTR of EPS-events for the two formulations. Discussion: The overall incidence of EPS-related AEs, TTO and TTR of EPS-events were found to be comparable in patients with schizophrenia receiving either PP3M or PP1M long-acting injectable.

Neuropsychiatric Disease and Treatment, Oct 1, 2018

The aim of this study was to evaluate the safety of 3-monthly paliperidone palmitate (PP3M) vs on... more 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.

Neuropsychiatric Disease and Treatment, Feb 1, 2019

Purpose: This randomized, double-blind (DB), non-inferiority phase 3 study was conducted to asses... more 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.

CPT: pharmacometrics & systems pharmacology, Jul 13, 2017

The Journal of Clinical Pharmacology, Oct 5, 2015

This multicenter, randomized, open-label, parallel-group, phase-1 study assessed the pharmacokine... more 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 1 and C max 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.

The International Journal of Neuropsychopharmacology, Feb 22, 2016

Background: This double-blind, parallel-group, multicenter, phase-3 study was designed to test th... more Background: 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. Methods: After screening (≤3 weeks) 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) for a 48-week double-blind phase. Results: 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. Conclusion: Taken together, PP3M with its 3-month dosing interval is a unique option for relapse prevention in schizophrenia.

European Psychiatry, Apr 1, 2017

Neuropsychiatric Disease and Treatment, Aug 1, 2017

Objective: To demonstrate the efficacy and safety of paliperidone palmitate three-monthly (PP3M) ... more 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.

Neuropsychiatric Disease and Treatment, Jun 1, 2020

Background: Sudden discontinuation from antipsychotic treatment is a common occurrence in patient... more 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 <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]). Conclusion: The lower percentage of relapse during active treatment and longer time to relapse after discontinuing active treatment with longer-duration antipsychotic formulations suggests the benefit of longer-acting over shorter-acting formulations, especially in patients susceptible to poor adherence. Clinical trial registration: paliperidone ER (NCT00086320), PP1M (NCT00111189), and PP3M (NCT01529515).

European Neuropsychopharmacology, 2016

Purpose: People with first-episode schizophrenia exhibit increased treatment responsiveness and a... more Purpose: People with first-episode schizophrenia exhibit increased treatment responsiveness and an increased sensitivity to adverse effects compared with people with multi-episode schizophrenia [1]. Early treatment choice is critical and highly predictive of long-term disease consequences [2]. The present study aimed to examine changes in the prescribing patterns of antipsychotics and other psychotropic drugs in first-episode schizophrenia between 2005, when the major second generation antipsychotics (SGAs) had become commercialized in Bulgaria (although their prescribing was influenced by prior-authorization policies) and 2015, when generic versions of the major SGAs were already available reflecting on the prescribing restrictions. Methods: Data were collected retrospectively from medical records of all patients with a diagnosis of first-episode schizophrenia (using ICD-10 criteria), discharged from a university psychiatric clinic in Varna, Bulgaria, between January 1, and December 31, 2005 and 2015 respectively. The prescription status of all psychotropic drugs at the time of discharge was analyzed. We defined patients as receiving a high antipsychotic dose if their ratio of prescribed daily dose (PDD) to defined daily dose (DDD) was greater than 1.5 [3]. Analysis was carried out using SPSS, version 20.0. Results: Treated with first-episode schizophrenia were 30 and 36 patients respectively in 2005 and 2015. None of them was discharged on antipsychotic polypharmacy. The most common first-prescribed antipsychotics were (in descending order of prescription frequency): haloperidol 10 (33.3%), risperidone 6 (20%), olanzapine 5 (16.7%), quetiapine 4 (10%) in 2005 and olanzapine 17 (47.2%), risperidone 14 (38.9%), aripiprazole 3 (8.3%) and amisulpride 2 (5.6%) in 2015. High dose antipsychotics received 6 (20%) in 2005 and 20 (55.6%) of the patients in 2015 and it was mainly associated with olanzapine prescriptions, mean dose for olanzapine: 16±1.8 mg/day in 2005 and 18.5±1.3 mg/day in 2015. The mean number of prescribed psychotropic drugs was 2.1 (SD 0.85) in 2005 and 1.8 (SD 0.81) in 2015 with 7 (23.3%) of the patients in 2005 and 14 (38.9%) in 2015 receiving only one drug. Two drugs were prescribed to 15 (50%) in 2005 and 15 (41.7%) of the patients in 2015 respectively. The most common

60th Annual Meeting, Oct 25, 2013

Molecular and Cellular Biology, Nov 1, 1986

We deduced the complete amino acid sequence of the rat brain Na,K-ATPase ,-subunit from cDNA. The... more We deduced the complete amino acid sequence of the rat brain Na,K-ATPase ,-subunit from cDNA. The rat brain "-subunit exhibits a high degree of primary sequence and secondary structural homology with the human and Torpedo (i-subunit polypeptides. Analysis of rat tissue RNA reveals that the ,B-subunit gene encodes four separate mRNA species which are expressed in a tissue-specific fashion. In ouabain-resistant HeLa C+ cells, ,B-subunit DNA sequences are amplified (-20-fold) and "-subunit mRNAs are overproduced relative to levels in parental HeLa cells. These results suggest that the (-subunit plays an important role in Na,K-ATPase structure-function and in the mechanism underlying cellular resistance to the cardiac glycosides.

Sleep, Apr 1, 2020

B. Clinical Sleep Science and Practice I. Insomnia using the Work and Social Adjustment Scale. Qu... more B. Clinical Sleep Science and Practice I. Insomnia using the Work and Social Adjustment Scale. Quality of life was assessed using the Hotel Dieu-16 Scale. Results: Compared to PMRT, BBTI resulted in a greater reduction in subjective total sleep time variability (F 1,90 =6.61, p<0.01, partial η 2 =0.13) and a greater increase in interdaily stability (F 1,78 =12.41, p<0.01, partial η 2 =0.25). There was a greater decrease in intradaily variability following PMRT (F 1,78 =27.96, p<0.01, partial η 2 =0.42). Across the entire sample, reductions in subjective wake time variability were associated with improved functioning (F 1,88 =4.43, p=0.04, η 2 =0.05) and reductions in subjective total sleep time variability were associated with improved quality of life (F 1,89 =4.91, p=0.03, partial η 2 =0.05). Conclusion: There was significant improvement in the stability of sleep-wake rhythms following BBTI, suggesting that BBTI not only treats insomnia, but also may stabilize circadian rhythms. Interestingly, PMRT resulted in greater intradaily variability reductions than BBTI. One explanation is that due to BBTI stimulus control guidelines, individuals were getting out of bed in the middle of the night more frequently and thus, these awakenings were better captured by actigraphy. Reductions in wake time and total sleep time variability were associated with improved functioning and quality of life, further demonstrating the importance of stable sleep-wake rhythms.

International Journal of Neuropsychopharmacology, 2016

Objective: A post-hoc subgroup analysis was pemathewsMrformed to compare outcomes following admin... more Objective: A post-hoc subgroup analysis was pemathewsMrformed to compare outcomes following administration of paliperidone palmitate 3-monthly (PP3M) versus 1-monthly (PP1M) injectable in patients with schizophrenia previously treated/ not treated with oral risperidone/paliperidone (RIS/PALI) before study entry. Methods: Patients received PP1M (50, 75, 100, or 150 mg eq.) during 17-week open-label (OL) phase, randomized (1:1) to PP3M (175, 263, 350, or 525 mg eq.) or PP1M (50, 75, 100, or 150 mg eq.) during 48-week double-blind (DB) phase. Based on prior RIS/ PALI exposure, outcomes were compared between two subgroups: recent=at least 28 days of RIS/PALI exposure with last dose within 14 days before study entry; no=no RIS/PALI exposure within 60 days before study entry. Results: 452 patients had received recent RIS/PALI (n=323 [71%] randomized to PP3M=166; PP1M=157), and 709 did not receive RIS/PALI (n=506 [71%] randomized to PP3M=254; PP1M=252).

The International Journal of Neuropsychopharmacology, May 27, 2016

perception bias was associated with trait anxiety [beta=0.49, t=4.3, p<0.001, R-square=0.23, F(1,... more perception bias was associated with trait anxiety [beta=0.49, t=4.3, p<0.001, R-square=0.23, F(1,58)=18.7, p<0.001] and blame bias [F(2,56)=14.4, p<0.001] was associated with trait anxiety (beta=0.27, t=2.0, p=0.047) and low self-esteem (beta=-0.38, t=-2.9, p=0.006) in UHR individuals. Conclusion: These findings suggest that attribution bias may have been ahead of the onset of overt psychosis. In addition, psychosocial intervention for attribution bias in UHR individuals should be focusing the emotional dysregulation factors rather than neurocognitive function.

The International Journal of Neuropsychopharmacology, May 27, 2016

perception bias was associated with trait anxiety [beta=0.49, t=4.3, p<0.001, R-square=0.23, F(1,... more perception bias was associated with trait anxiety [beta=0.49, t=4.3, p<0.001, R-square=0.23, F(1,58)=18.7, p<0.001] and blame bias [F(2,56)=14.4, p<0.001] was associated with trait anxiety (beta=0.27, t=2.0, p=0.047) and low self-esteem (beta=-0.38, t=-2.9, p=0.006) in UHR individuals. Conclusion: These findings suggest that attribution bias may have been ahead of the onset of overt psychosis. In addition, psychosocial intervention for attribution bias in UHR individuals should be focusing the emotional dysregulation factors rather than neurocognitive function.

The International Journal of Neuropsychopharmacology, May 27, 2016

Conclusion: Clinically relevant improvements in psychopathology were observed in patients with ac... more Conclusion: Clinically relevant improvements in psychopathology were observed in patients with acute schizophrenia treated with brexpiprazole or aripiprazole. Brexpiprazole was well tolerated with a lower incidence of EPS-related adverse events than aripiprazole.

The International Journal of Neuropsychopharmacology, May 27, 2016

Background: This post-hoc analysis was performed to compare the overall incidence, time-to-onset ... more Background: This post-hoc analysis was performed to compare the overall incidence, time-to-onset (TTO) and time-to-resolution (TTR) of extrapyramidal symptoms (EPS)-related adverse events (AEs) after treatment with paliperidone palmitate (PP) 3-monthly (PP3M) vs. 1-monthly (PP1M) long-acting injectable in patients with schizophrenia. Methods: EPS-related AEs were summarized by grouped terms (Overall and further classified into Dystonia, Dyskinesia, Hyperkinesia, Parkinsonism and Tremor), study phases (openlabel [OL]: PP1M, double-blind [DB]: PP1M or PP3M), TTO and TTR, and descriptively compared. TTO and TTR were further analyzed by final OL dose (50/75 mg eq., 100 mg eq. and 150 mg eq.) and age (18-25, 26-50 and 50+ years) subgroups. Results: Overall incidence of EPS-related AEs was 12.6% (PP1M) during OL phase, reducing to 8.3% (PP3M) and 7.4% (PP1M) during DB phase. Median TTO for all EPS-related AEs was 17 days (range: 1-120) after PP1M OL treatment; 115 days (range: 1-323) and 98.5 days (range: 1-322) after treatment with PP3M and PP1M, respectively (DB phase). Median TTR was 36.5 days (range: 1-127) in PP1M group (OL), and was generally similar for PP3M (91 days [range: 1-336]) vs. PP1M (85.5 days [range: 1-337]) during DB phase. Overall median TTO and TTR values were comparable between PP3M and PP1M formulations. Subgroup analysis revealed no clear dose-response or age-related differences in TTO and TTR of EPS-events for the two formulations. Discussion: The overall incidence of EPS-related AEs, TTO and TTR of EPS-events were found to be comparable in patients with schizophrenia receiving either PP3M or PP1M long-acting injectable.

Neuropsychiatric Disease and Treatment, Oct 1, 2018

The aim of this study was to evaluate the safety of 3-monthly paliperidone palmitate (PP3M) vs on... more 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.

Neuropsychiatric Disease and Treatment, Feb 1, 2019

Purpose: This randomized, double-blind (DB), non-inferiority phase 3 study was conducted to asses... more 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.

CPT: pharmacometrics & systems pharmacology, Jul 13, 2017

The Journal of Clinical Pharmacology, Oct 5, 2015

This multicenter, randomized, open-label, parallel-group, phase-1 study assessed the pharmacokine... more 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 1 and C max 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.

The International Journal of Neuropsychopharmacology, Feb 22, 2016

Background: This double-blind, parallel-group, multicenter, phase-3 study was designed to test th... more Background: 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. Methods: After screening (≤3 weeks) 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) for a 48-week double-blind phase. Results: 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. Conclusion: Taken together, PP3M with its 3-month dosing interval is a unique option for relapse prevention in schizophrenia.

European Psychiatry, Apr 1, 2017

Neuropsychiatric Disease and Treatment, Aug 1, 2017

Objective: To demonstrate the efficacy and safety of paliperidone palmitate three-monthly (PP3M) ... more 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.

Neuropsychiatric Disease and Treatment, Jun 1, 2020

Background: Sudden discontinuation from antipsychotic treatment is a common occurrence in patient... more 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 <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]). Conclusion: The lower percentage of relapse during active treatment and longer time to relapse after discontinuing active treatment with longer-duration antipsychotic formulations suggests the benefit of longer-acting over shorter-acting formulations, especially in patients susceptible to poor adherence. Clinical trial registration: paliperidone ER (NCT00086320), PP1M (NCT00111189), and PP3M (NCT01529515).

European Neuropsychopharmacology, 2016

Purpose: People with first-episode schizophrenia exhibit increased treatment responsiveness and a... more Purpose: People with first-episode schizophrenia exhibit increased treatment responsiveness and an increased sensitivity to adverse effects compared with people with multi-episode schizophrenia [1]. Early treatment choice is critical and highly predictive of long-term disease consequences [2]. The present study aimed to examine changes in the prescribing patterns of antipsychotics and other psychotropic drugs in first-episode schizophrenia between 2005, when the major second generation antipsychotics (SGAs) had become commercialized in Bulgaria (although their prescribing was influenced by prior-authorization policies) and 2015, when generic versions of the major SGAs were already available reflecting on the prescribing restrictions. Methods: Data were collected retrospectively from medical records of all patients with a diagnosis of first-episode schizophrenia (using ICD-10 criteria), discharged from a university psychiatric clinic in Varna, Bulgaria, between January 1, and December 31, 2005 and 2015 respectively. The prescription status of all psychotropic drugs at the time of discharge was analyzed. We defined patients as receiving a high antipsychotic dose if their ratio of prescribed daily dose (PDD) to defined daily dose (DDD) was greater than 1.5 [3]. Analysis was carried out using SPSS, version 20.0. Results: Treated with first-episode schizophrenia were 30 and 36 patients respectively in 2005 and 2015. None of them was discharged on antipsychotic polypharmacy. The most common first-prescribed antipsychotics were (in descending order of prescription frequency): haloperidol 10 (33.3%), risperidone 6 (20%), olanzapine 5 (16.7%), quetiapine 4 (10%) in 2005 and olanzapine 17 (47.2%), risperidone 14 (38.9%), aripiprazole 3 (8.3%) and amisulpride 2 (5.6%) in 2015. High dose antipsychotics received 6 (20%) in 2005 and 20 (55.6%) of the patients in 2015 and it was mainly associated with olanzapine prescriptions, mean dose for olanzapine: 16±1.8 mg/day in 2005 and 18.5±1.3 mg/day in 2015. The mean number of prescribed psychotropic drugs was 2.1 (SD 0.85) in 2005 and 1.8 (SD 0.81) in 2015 with 7 (23.3%) of the patients in 2005 and 14 (38.9%) in 2015 receiving only one drug. Two drugs were prescribed to 15 (50%) in 2005 and 15 (41.7%) of the patients in 2015 respectively. The most common