Esketamine versus placebo on time to remission in major depressive disorder with acute suicidality.

BACKGROUND: Esketamine (ESK) nasal spray, taken with oral antidepressant therapy, is approved for the treatment of depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior. In pooled analyses of two pivotal phase 3 studies, ASPIRE I and II, remission rates were consistently higher among patients with MDD with active suicidality who were treated with ESK + standard of care (SOC) versus placebo (PBO) + SOC at all time points in the double-blind and most time points in the follow-up phases. The current analysis of the ASPIRE data sets assessed the effect of ESK + SOC versus PBO + SOC on additional remission-related endpoints: time to achieving remission and consistent remission, proportion of patients in remission and consistent remission, and days in remission. METHODS: Post hoc analysis of pooled data from ASPIRE I and II (N = 451). Remission and consistent remission were defined as Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≤ 12 at any given visit or two consecutive visits, respectively. Combined endpoints utilizing Clinical Global Impression-Severity of Suicidality-revised version [CGI-SS-r] ≤ 1 (i.e., not suicidal/questionably suicidal) along with the remission and consistent remission definitions (i.e., MADRS total score ≤ 12) were also examined. RESULTS: The median times to remission and consistent remission of MDD were significantly shorter in ESK + SOC versus PBO + SOC (15 versus 23 [p = 0.005] and 23 versus 50 days [p = 0.007], respectively) and a greater proportion of patients in ESK + SOC achieved remission and consistent remission by Day 25 (65.2% versus 55.5% and 54.2% versus 39.8%, respectively). Similar results were obtained using the combined endpoint for both remission definitions. The median percent of days in remission during the double-blind treatment phase was significantly greater in ESK + SOC (27.1% or 5 days) versus PBO + SOC (8.3% or 2 days; p = 0.006), and the significant difference was maintained during follow-up. CONCLUSION: Treatment with ESK + SOC versus PBO + SOC resulted in significantly shorter time to remission, greater proportion of patients in remission, and greater percent of days in remission using increasingly rigorous definitions of remission. These findings underscore the clinical benefits of ESK for adults with MDD with suicidality. TRIAL REGISTRATION: ClinicalTrials.gov registry NCT03039192 (registered February 1, 2017) and NCT03097133 (registered March 31, 2017).

Impact on carer burden when stable patients with schizophrenia transitioned from 1-monthly to 3-monthly paliperidone palmitate.

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

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

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.

Maintenance dose conversion between oral risperidone and paliperidone palmitate 1 month: Practical guidance based on pharmacokinetic simulations.

AIM: We assessed the dosage strengths of paliperidone palmitate 1-month (PP1M) long-acting injectable resulting in similar steady-state (SS) exposures to the dosage strengths of oral risperidone using pharmacokinetic (PK) simulations. METHODS: Population PK simulations of SS PK were performed using the PK models of oral risperidone and PP1M. The concentrations of active moiety (risperidone + paliperidone) from risperidone were compared to paliperidone concentrations resulting from PP1M administration. Similarity was assessed via graphical evaluation of median and 90% prediction intervals of SS PK profiles over 28 days. RESULTS: Oral risperidone doses of 1, 2, 3, 4, and 6 mg/d are expected to result in similar SS PK as PP1M doses of 25, 50, 75, 100, and 150 mg eq. (which correspond to 39, 78, 117, 156, and 234 mg of paliperidone palmitate) respectively (ie 25-fold dose conversion factor from oral risperidone to PP1M). CONCLUSIONS: This study provides clinicians with a practical guidance to establish suitable maintenance dose levels of PP1M and oral risperidone when transitioning patients from one formulation to another.

Asenapine for the treatment of adults with an acute exacerbation of schizophrenia: results from a randomized, double-blind, fixed-dose, placebo-controlled trial with olanzapine as an active control.

OBJECTIVE: Evaluate the efficacy and safety of asenapine 2.5 mg twice daily (bid; n=97) or 5 mg bid (n=113) versus placebo (n=101) in adults with acute exacerbation of schizophrenia. METHODS: Adults with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) schizophrenia diagnosis were randomized to asenapine 2.5 mg bid, 5 mg bid, placebo, or olanzapine 15 mg once daily. The primary objective was to test superiority of asenapine versus placebo as measured by the change from baseline to day 42 in the Positive and Negative Syndrome Scale (PANSS) total score. The key safety objective was to evaluate weight change in asenapine versus olanzapine at day 42. RESULTS: The primary efficacy endpoint was met; the difference in least squares mean change from baseline to day 42 in PANSS total score between asenapine 5 mg bid and placebo was -5.5 points (unadjusted 95% CI: -10.1, -1.0; multiplicity adjusted P=0.0356). Neither asenapine 2.5 mg bid nor olanzapine 15mg were superior to placebo. Both asenapine groups demonstrated significantly less weight gain than olanzapine at day 42. Significantly higher incidences of oral hypoesthesia and dysgeusia (combined) for asenapine 2.5 mg bid (5.2% vs 0.0%; P=0.0217) and 5 mg bid (7.1% vs 0.0%; P=0.0033) were observed versus placebo. There were no significant differences between asenapine and placebo for insomnia, extrapyramidal symptoms, akathisia, dizziness, or combination of somnolence/sedation/hypersomnia. CONCLUSION: This study supports previous efficacy and safety findings of asenapine; asenapine 5 mg bid is the lowest effective dose in adults with schizophrenia. Asenapine was associated with significantly less weight gain than olanzapine at day 42.

A double-blind, randomized, placebo-controlled, fixed-dose phase III study of vilazodone in patients with generalized anxiety disorder.

BACKGROUND: Vilazodone, a selective serotonin reuptake inhibitor and 5-HT1A receptor partial agonist, is approved for treating major depressive disorder in adults. This study (NCT01629966 ClinicalTrials.gov) evaluated the efficacy and safety of vilazodone in adults with generalized anxiety disorder (GAD). METHODS: A multicenter, double-blind, parallel-group, placebo-controlled, fixed-dose study in patients with GAD randomized (1:1:1) to placebo (n = 223), or vilazodone 20 mg/day (n = 230) or 40 mg/day (n = 227). Primary and secondary efficacy parameters were total score change from baseline to week 8 on the Hamilton Rating Scale for Anxiety (HAMA) and Sheehan Disability Scale (SDS), respectively, analyzed using a predefined mixed-effect model for repeated measures (MMRM). Safety outcomes were presented by descriptive statistics. RESULTS: The least squares mean difference (95% confidence interval) in HAMA total score change from baseline (MMRM) was statistically significant for vilazodone 40 mg/day versus placebo (-1.80 [-3.26, -0.34]; P = .0312 [adjusted for multiple comparisons]), but not for vilazodone 20 mg/day versus placebo. Mean change from baseline in SDS total score was not significantly different for either dose of vilazodone versus placebo when adjusted for multiplicity; significant improvement versus placebo was noted for vilazodone 40 mg/day without adjustment for multiplicity (P = .0349). The incidence of adverse events was similar for vilazodone 20 and 40 mg/day (∼71%) and slightly lower for placebo (62%). Nausea, diarrhea, dizziness, vomiting, and fatigue were reported in ≥5% of patients in either vilazodone group and at least twice the rate of placebo. CONCLUSIONS: Vilazodone was effective in treating anxiety symptoms of GAD. No new safety concerns were identified.

Commentary on Cochrane review: "Ketamine and other glutamate receptor modulators for depression in adults with unipolar major depressive disorder".

BACKGROUND: Cochrane recently published a review of esketamine and other glutamate receptor modulators in depression. AIM: To address the limitations of the review, analyses of esketamine data were conducted to provide additional perspective to the reviewers' interpretation of their findings. METHODS: Response rate, remission rate, and change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score were determined using data from all esketamine phase 2/3 registration studies of treatment-resistant depression (TRD) and, separately, all esketamine phase 2/3 registration studies of major depressive disorder (MDD) and active suicidal ideation with intent. Outcomes were assessed at all timepoints (i.e., 24 h, 72 h (MDD with active suicidal intent only), and 1, 2, and 4 weeks). Enrollment criteria of the TRD studies were different than those of the studies of MDD and active suicidal ideation with intent, resulting in differences in patients' clinical characteristics and depression severity between the cohorts. Thus, we did not compare results between these cohorts (as was done in the Cochrane review). RESULTS/OUTCOMES: In the combined TRD studies, a statistically significant between-group difference favored esketamine plus antidepressant over antidepressant plus placebo at 24 h (based on response, remission, and change in MADRS score), 1 week (change in MADRS score), 2 weeks (response and change in MADRS score), and 4 weeks (response, remission, and change in MADRS score). In the combined studies of MDD and active suicidal ideation with intent, the between-group difference was statistically different, favoring esketamine plus standard-of-care over placebo plus standard-of-care, at 24 h (response, remission, and change in MADRS score), 72 h and 1 week (change in MADRS score), 2 weeks (response), and 4 weeks (response, remission, and change in MADRS score). For both study types, the between-group difference in outcomes was not statistically significant at the other timepoints. CONCLUSIONS/INTERPRETATION: Esketamine improves response, remission, and depressive symptoms as early as 24 h post-first dose among patients with TRD and among patients with MDD and active suicidal ideation with intent.

Use of Clinical Global Impressions-Severity (CGI-S) to Assess Response to Antidepressant Treatment in Patients with Treatment-Resistant Depression.

Background: This post-hoc analysis evaluated the agreement between Clinical Global Impressions-Severity (CGI-S) score- and Montgomery-Åsberg Depression Rating Scale (MADRS) total score-based assessment of response in patients with treatment-resistant depression (TRD) treated with esketamine nasal spray plus a newly initiated oral antidepressant (ESK-NS + AD). Methods: Data were analyzed from a phase 3, randomized, double-blind study (TRANSFORM-2) of flexibly dosed esketamine or placebo nasal spray plus a newly initiated oral-AD in adults with moderate-to-severe TRD. Patients with ≥50% reduction in MADRS from baseline at the end of the 4-week acute treatment phase were defined as responders. For the CGI-S-based assessment of response, patients with ≥2 points decrease from baseline or a CGI-S score of ≤3 (mildly depressed to normal) were considered responders. Cohen's kappa coefficient was calculated to assess level of agreement between MADRS and CGI-S-based assessments. Results: At the end of 4-week treatment, the proportion of responders among all study patients (n=201) was similar when assessed using the MADRS (61%) and CGI-S (62%) methods, with substantial agreement (Cohen's kappa=0.76; sensitivity=92%; specificity=84%) between both methods. When restricting analysis to ESK-NS + AD-treated patients (n=101) who had a higher response rate (on MADRS: 69%; on CGI-S: 68%), the agreement remained substantial (Cohen's kappa=0.75; sensitivity=91%; specificity=84%). Conclusion: The CGI-S may be a practical and reliable alternative to the MADRS to assess response to ESK-NS + AD in patients with TRD and can be used in real-world practice to support informed treatment decisions.

Patient profiles, initial hospital encounter characteristics, and hospital re-encounters of patients with a hospital emergency department visit or inpatient admission for major depressive disorder.

OBJECTIVES: To gain a better understanding of the characteristics of patients with a hospital encounter for major depressive disorder (MDD) and evaluate associated hospital resource utilization, hospital charges and costs, and hospital re-encounters. METHODS: Adult patients with a hospital encounter (i.e. emergency department [ED] visit only or inpatient admission) with MDD as the primary discharge diagnosis (index event) during July 2018‒March 2019 were selected from the Premier Healthcare Database. Patient characteristics, hospital resource utilization, and hospital charges and costs were evaluated during index events. During a 12-month follow-up, hospital re-encounters (MDD-related and all-cause ED visit only or inpatient readmissions) were examined. RESULTS: The study population included 77,178 patients with an index hospital encounter (ED visit only: 49.9%; inpatient admission: 50.1%) for MDD. The most common secondary mental health-related diagnosis was suicidal ideation/behavior, which was recorded in 51.8% of patients. The mean age was 38.2 years, 53.0% were female, and 72.1% were Caucasian. Among patients with an ED visit only, the mean index hospital charges and costs were $3,608 and $639, respectively. Among those with inpatient admissions, the mean length of stay was 4.9 days, and the mean index hospital charges and costs were $17,107 and $6,095, respectively. During the 12-month follow-up, 13.3% of patients in the overall study population had an MDD-related hospital re-encounter (primary or secondary discharge diagnosis code indicating MDD); nearly one-third (31.3%) occurred within 30 days post-discharge. During the follow-up, 28.1% had an all-cause hospital re-encounter with 29.7% having occurred within 30 days post-discharge. LIMITATIONS: Due to constraints of the Premier Healthcare Database, healthcare resource utilization and costs outside of the hospital could not be evaluated. CONCLUSIONS: Patients with a hospital encounter for MDD are relatively young, commonly have suicidal ideation/behavior, utilize substantial hospital resources, and have a high risk for a hospital re-encounter in the 30 days post-discharge.

Effect of Sleep Disturbance on Efficacy of Esketamine in Treatment-Resistant Depression: Findings from Randomized Controlled Trials.

PURPOSE: To evaluate the relationship of sleep disturbance to the antidepressant effects of esketamine. MATERIALS AND METHODS: Two double-blind, 4-week studies randomized adults with treatment-resistant depression (TRD) to placebo or esketamine nasal spray, each with newly initiated antidepressant. Sleep was assessed using Montgomery-Åsberg Depression Rating Scale (MADRS) item 4. Change in response (≥50% decrease in MADRS total score) and remission (total MADRS score ≤12) at day 28 was examined by presence/absence of baseline sleep disturbance using logistic regression models. Impact on reported sleep disturbance (MADRS item 4 score) was examined using ANCOVA models. RESULTS: At baseline, most patients reported disturbed sleep - moderate/severe (65.3%, 369/565), mild (25.3%, 143/565), or none/slightly (9.4%, 53/565) - with similar distribution between treatment groups. A higher proportion of esketamine-treated patients achieved response (OR = 2.05; 95% CI: 1.40-3.02; P < 0.001) and remission (OR = 1.81; 95% CI: 1.23-2.66; P = 0.003) at day 28 compared to antidepressant plus placebo, regardless of presence/severity of sleep disturbance. Consistent with this, sleep (MADRS item 4 score) improved in both groups after the first dose, more so with esketamine by day 8 (between-group difference: P ≤ 0.02 at all time points). Across both treatment groups, 1-point improvement in sleep at day 8 increased the probability of antidepressant response on day 28 by 26% (OR = 1.26, 95% CI: 1.12-1.42; P < 0.001), and remission by 28% (OR = 1.28, 95% CI: 1.14-1.43; P < 0.001). CONCLUSION: Antidepressant efficacy of esketamine was demonstrated in patients with TRD, regardless of the presence of sleep disturbance. After 8 days of treatment and thereafter, significantly more esketamine-treated patients reported improvement in sleep versus antidepressant plus placebo.

Pharmacokinetic Characteristics of Long-Acting Injectable Antipsychotics for Schizophrenia: An Overview.

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

Relapse and Treatment Adherence in Patients with Schizophrenia Switching from Paliperidone Palmitate Once-Monthly to Three-Monthly Formulation: A Retrospective Health Claims Database Analysis.

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

Effect of Concomitant Benzodiazepine Use on Efficacy and Safety of Esketamine Nasal Spray in Patients with Major Depressive Disorder and Acute Suicidal Ideation or Behavior: Pooled Randomized, Controlled Trials.

PURPOSE: The impact of benzodiazepines on the efficacy and safety of esketamine as a rapid-acting antidepressant remains unclear. MATERIALS AND METHODS: Data from two identically designed, randomized double-blind studies were pooled and analyzed on a post-hoc basis. In both studies, adults with major depressive disorder with acute suicidal ideation or behavior were randomized to placebo or esketamine 84 mg nasal spray twice-weekly for 4 weeks, each with comprehensive standard-of-care (initial hospitalization and newly initiated or optimized oral antidepressant[s]). Efficacy and safety were analyzed in two groups based on whether patients used concomitant benzodiazepines, which were prohibited within 8 hours before and 4 hours after the first dose of esketamine and within 8 hours of the primary efficacy assessment at 24 hours. The primary efficacy endpoint - change from baseline to 24 hours post-first dose in Montgomery-Asberg Depression Rating Scale (MADRS) total score - was analyzed using ANCOVA. RESULTS: Most patients (309/451, 68.5%) used concomitant benzodiazepines. Greater decrease in MADRS total score was observed with esketamine (mean [SD]: -16.1 [11.73]) versus placebo (-12.6 [10.56]) at 24 hours (least-squares mean difference: -3.7, 95% CI: -5.76, -1.59). The differences between the esketamine and placebo groups were clinically meaningful, irrespective of benzodiazepine use (benzodiazepine: -4.3 [-6.63, -1.89]; no benzodiazepine: -3.1 [-6.62, 0.45]). Among patients taking esketamine, change in MADRS total score was not significantly different between patients taking benzodiazepines (-15.8 [11.27]) versus those not taking benzodiazepines (-16.8 [12.82]) (least-squares mean difference: 1.1, [-2.24, 4.45]). Among esketamine-treated patients, the incidence of sedation was higher with benzodiazepine use, whereas dissociation was similar. CONCLUSION: Benzodiazepines do not meaningfully affect the rapid-acting antidepressant effect of esketamine at 24 hours post-first dose among patients with MDD and acute suicidal ideation or behavior.

Comments to Drs. Bahji, Vazquez, and Zarate.

In the absence of head-to-head studies directly comparing the efficacy of intranasal esketamine to that of intravenous ketamine, valid conclusions regarding comparative efficacy cannot be made based on the existing data from trials using markedly differing study designs and patient populations.

Evaluation of paliperidone palmitate long-acting injectable antipsychotic therapy as an early treatment option in patients with schizophrenia.

AIM: This exploratory post hoc analysis of a randomized, double-blind (DB), multicentre, non-inferiority study (NCT01515423) evaluated the effects of the long-acting injectable antipsychotic therapies once-monthly paliperidone palmitate (PP1M) and once-every-3-months paliperidone palmitate (PP3M) on symptom severity and functional remission in patients with schizophrenia with differing durations of illness (≤5, 6-10 and >10 years). METHODS: Endpoints included Personal and Social Performance (PSP) scale and Positive and Negative Syndrome Scale (PANSS) total scores during the DB phase (DB baseline and DB endpoint) and the proportion of patients meeting PSP or PANSS remission criteria at any time during the open-label (OL) or DB phases that were maintained for ≥3, ≥6, ≥9 or ≥12 months. RESULTS: In both the OL and DB phases, significant improvements in PSP scale and PANSS scores were observed from baseline in all duration-of-illness groups, with significantly greater improvements observed in the ≤5-year and 6-10-year groups compared with the >10-year group. The proportion of patients who maintained PSP or PANSS remission criteria for ≥3, ≥6, ≥9 and ≥12 months was higher in the ≤5-year and 6-10-year groups than in the >10-year group. Safety profiles were similar across duration-of-illness groups in the DB phase. CONCLUSIONS: Symptomatic and functional improvements were observed with PP1M/PP3M in patients with differing durations of schizophrenia, but the magnitude of the effects was greater in those with early illness vs chronic illness. These findings advocate implementation of PP1M and PP3M in all stages of schizophrenia, including early illness.

Patients' Preference for Long-Acting Injectable versus Oral Antipsychotics in Schizophrenia: Results from the Patient-Reported Medication Preference Questionnaire.

INTRODUCTION: Understanding patients' preferences for long-acting injectable (LAI) or oral antipsychotics (pills) could help reduce potential barriers to LAI use in schizophrenia. METHODS: Post hoc analyses were conducted from a double-blind, randomized, non-inferiority study (NCT01515423) of 3-monthly vs 1-monthly paliperidone palmitate in patients with schizophrenia. Data from the Medication Preference Questionnaire, administered on day 1 (baseline; open-label stabilization phase), were analyzed. The questionnaire includes four sets of items: 1) reasons for general treatment preference based on goals/outcomes and preference for LAI vs pills based on 2) personal experience, 3) injection-site (deltoid vs gluteal), 4) dosing frequency (3-monthly vs 1-monthly). A logistic regression analysis was performed to assess the effect of baseline variables on preference (LAIs or pills). RESULTS: Data from 1402 patients were available for analysis. Patients who preferred LAIs recognized these outcomes as important: "I feel more healthy" (57%), "I can get back to my favorite activities" (56%), "I don't have to think about taking my medicines" (54%). Most common reasons for medication preference (LAI vs pills) were: "LAIs/pills are easier for me" (67% vs 18%), "more in control/don't have to think about taking medicine" (64% vs 14%), "less pain/sudden symptoms" (38% vs 18%) and "less embarrassed" (0% vs 46%). Majority of patients (59%) preferred deltoid over gluteal injections (reasons: faster administration [63%], easier [51%], less embarrassing [44%]). In total, 50% of patients preferred 3-monthly over 1-monthly (38%) or every day (3%) dosing citing reasons: fewer injections [96%], fewer injections are less painful [84%], and fewer doctor visits [80%]. From logistic regression analysis, 77% of patients preferred LAI over pills; culture and race appeared to play a role in this preference. CONCLUSION: Patients who preferred LAI antipsychotics prioritized self-empowerment and quality-of-life-related goals. When given the option, patients preferred less-frequent, quarterly injections over monthly injections and daily oral medications.

Effect of Paliperidone Palmitate 3-Month Formulation on Goal Attainment and Disability After 52 Weeks' Treatment in Patients with Clinically Stable Schizophrenia.

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

Improvement of Negative Symptoms in Schizophrenia with Paliperidone Palmitate 1-Month and 3-Month Long-Acting Injectables: Results from a Phase 3 Non-Inferiority Study.

BACKGROUND: Negative symptoms in schizophrenia are associated with impairments in social and cognitive functioning leading to substantial long-term disability. Available antipsychotic treatments have demonstrated only modest benefit in the improvement of negative symptoms. OBJECTIVE: To compare improvements in negative symptoms among patients treated with paliperidone palmitate 3-month (PP3M) or paliperidone palmitate 1-month (PP1M) long-acting injectable (LAI) formulations. METHODS: Data from a randomized double-blind (DB), phase-3, non-inferiority study in patients with schizophrenia were analyzed. Following screening, patients entered a 17-week open-label (OL) phase to receive flexibly dosed PP1M followed by a 48-week DB phase where patients were randomized (1:1) to receive either PP1M or PP3M. Positive and Negative Syndrome Scale (PANSS) total scores with emphasis on 7-item negative subscale scores for PP1M vs PP3M were assessed. RESULTS: Of 1429 patients enrolled, 1016 were randomized to receive PP3M (n=504) or PP1M (n=512). At baseline, mean (SD) PANSS negative subscale was 23.2 (4.60) and negative symptom factor score was 22.3 (4.87), indicating moderate-to-severe negative symptoms. Negative subscale and symptoms factor scores showed continuous improvements throughout OL (15.9 [4.99]) and DB (14.9 [4.81]) phases. Mean (SD) changes from DB baseline in the PANSS negative subscale score were comparable between PP1M (-1.4 [3.67]) and PP3M (-1.4 [3.63]) treatment groups. CONCLUSION: Treatment with PP3M or PP1M demonstrated comparable improvement in negative symptoms in patients with moderate-to-severe negative symptoms and in patients with prominent negative symptoms. Long-term treatment with PP3M demonstrated benefit, suggesting that continuous antipsychotic medication treatment for >1 year is needed to achieve greater benefit for negative symptoms. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01515423.