P. Cherubin

Paliperidone palmitate versus oral antipsychotics in recently diagnosed schizophrenia.

OBJECTIVE Relapse and acute exacerbation are common in schizophrenia and may impact treatment response and outcome. Evidence is conflicting in respect to superiority of long-acting injectable antipsychotic therapies versus oral antipsychotics in relapse prevention. This randomized controlled study assessed the efficacy of paliperidone palmitate versus oral antipsychotics for relapse prevention. METHOD Eligible patients with a recent diagnosis of schizophrenia (within 1-5 years) were randomized 1:1 to paliperidone palmitate (n=376) or oral antipsychotic monotherapy (n=388) and entered a 2-week initial acute oral treatment phase. Patients who met predefined response criteria were eligible to enter the 24-month rater-blinded core treatment phase. Patients were evaluated for relapse, symptoms, functioning, quality of life, treatment satisfaction, and tolerability. RESULTS In the core treatment phase, time to relapse was significantly longer in the paliperidone palmitate (n=352) compared with the oral antipsychotics arm (n=363): 85% of patients were relapse-free at 469 versus 249 days (P=0.019). Significantly fewer patients receiving paliperidone palmitate met the relapse criteria (52 [14.8%] versus 76 [20.9%, oral antipsychotics]; P=0.032), representing a 29.4% relative risk reduction. For paliperidone palmitate, a significantly greater improvement in Positive and Negative Syndrome Scale total score on Day 8 (P=0.021) and a trend at endpoint (P=0.075) were observed. Functioning improvements were comparable between treatment arms. No new safety signals were identified. CONCLUSION The observed time to relapse superiority of paliperidone palmitate over oral antipsychotics provides further evidence for the value of long-acting injectable antipsychotic therapies in the treatment of schizophrenia, including during the early stages of illness.

A Prospective Flexible-Dose Study of Paliperidone Palmitate in Nonacute But Symptomatic Patients With Schizophrenia Previously Unsuccessfully Treated With Oral Antipsychotic Agents

PURPOSE The goal of this study was to explore the tolerability, safety, and treatment response of flexible doses of once-monthly paliperidone palmitate (PP) in the subset of nonacute but symptomatic adult patients with schizophrenia previously unsuccessfully treated with oral antipsychotic agents in the PALMFlexS (Paliperidone Palmitate Flexible Dosing in Schizophrenia) study. METHODS This was an interventional, single-arm, international, multicenter, unblinded, 6-month study performed in patients with schizophrenia. Patients were categorized according to reasons for switching. In patients switching because of lack of efficacy or for other reasons, primary efficacy outcomes were the proportion achieving treatment response (defined as ≥20% improvement in Positive and Negative Syndrome Scale [PANSS] total score from baseline to last-observation-carried-forward end point) and maintained efficacy (defined as noninferiority in the change in PANSS total score at end point versus baseline [Schuirmanns test]), respectively. FINDINGS A total of 593 patients (intention-to-treat population) were enrolled: 63.1% were male; their mean (SD) age was 38.4 (11.8) years; and 78.6% had paranoid schizophrenia. The main reasons for transition to PP were patients wish (n = 259 [43.7%]), lack of efficacy (n = 144 [24.3%]), lack of compliance (n = 138 [23.3%]), and lack of tolerability (n = 52 [8.8%]) with the previous oral antipsychotic medication. The recommended PP initiation regimen (150 milligram equivalents [mg eq] day 1 and 100 mg eq day 8) was administered in 93.9% of patients. Mean PANSS total score decreased from 71.5 (14.6) at baseline to 59.7 (18.1) at end point (mean change, -11.7 [15.9]; 95% CI, -13.0 to -10.5; P < 0.0001). Sixty-four percent of patients showed an improvement of ≥20% in PANSS total score, and the percentage of patients rated mildly ill or less in Clinical Global Impression-Severity increased from 31.8% to 63.2%. Mean personal and social performance total score (SD) increased (ie, improved) significantly for all patients from baseline to end point (58.1 [13.4] to 66.1 [15.7]; P < 0.0001). IMPLICATIONS The PALMFlexS study is a pragmatic interventional study compared with randomized controlled trials, conducted in a large, more representative sample of patients with schizophrenia, and designed specifically to mimic real-world clinical situations. The findings support the results from randomized controlled studies. They also demonstrate that a clinically relevant treatment response is possible in patients who are considered to be clinically stable by their physician, supporting the use of flexibly dosed PP in such patients. Clinical trials.gov number: NCT01281527.

Paliperidone palmitate in non-acute patients with schizophrenia previously unsuccessfully treated with risperidone long-acting therapy or frequently used conventional depot antipsychotics.

PALMFlexS, a prospective multicentre, open-label, 6-month, phase IIIb interventional study, explored tolerability, safety and treatment response in adults (n = 231) with non-acute but symptomatic schizophrenia switching to flexibly dosed paliperidone palmitate (PP) after unsuccessful treatment with risperidone long-acting injectable therapy (RLAT) or conventional depot antipsychotics (APs). Treatment response was measured by change in Positive and Negative Syndrome Scale (PANSS) total score from baseline (BL) to last-observation-carried-forward (LOCF) endpoint (EP). Safety and tolerability assessments included Extrapyramidal Symptom Rating Scale (ESRS) total score and treatment-emergent adverse events. Significant reductions in mean PANSS total score were observed for all groups (−7.5 to −10.6; p ⩽ 0.01 [BL to LOCF EP]). After switching to PP, more than 50% of all patients achieved ⩾20% and one-third of RLAT-treated patients even achieved ⩾50% improvement in PANSS total score. Across groups, there were significant improvements (p < 0.05) in symptom severity as measured by Clinical Global Impression-Severity (CGI-S; trend for improvement with RLAT; p = 0.0568), subjective well-being, medication satisfaction, and patient functioning with PP. PP was generally well tolerated. Clinically relevant benefits were observed in non-acute patients with schizophrenia switched from RLAT or conventional depot APs to PP.

Long-acting injectable risperidone and oral antipsychotics in patients with schizophrenia: results from a prospective, 1-year, non-interventional study (InORS)

Abstract Objective. To explore differences in outcomes for patients with schizophrenia treated with risperidone long-acting treatment (RLAT) or oral antipsychotics (oAP). Methods. The International Observational Registry on Schizophrenia (InORS) explored flexible doses of newly initiated RLAT and oAPs for adults with schizophrenia, exploring 6-month retrospective hospitalization data and 12-month prospective medication use, outcomes, and tolerability. Efficacy outcomes included hospitalizations, the Clinical Global Impression of Schizophrenia (CGI-SCH), and the Global Assessment of Functioning (GAF). Medication switch patterns were also analysed. Results. Data were analysed from 1083 patients (561 RLAT, 522 oAP). At baseline, RLAT patients had higher symptom severity, greater functional impairment, and poorer compliance. Percentages of patients hospitalized were similar between groups, and median duration per hospitalization decreased after RLAT initiation and with oAP. The difference in duration of hospitalization between the retrospective and prospective period was significantly better with RLAT (P = 0.002). Mean CGI-SCH change from baseline was significantly better for RLAT vs. oAP patients for overall, positive, and negative symptom scores (P < 0.05). Mean functional improvement from baseline was significantly higher with RLAT vs. oAP (P < 0.001). Conclusions. Hospitalizations and symptomatic and functional outcomes were better with RLAT vs. oAP; frequent medication switches were associated with less favourable outcomes.

Once-monthly paliperidone palmitate in recently diagnosed and chronic non-acute patients with schizophrenia.

ABSTRACT Objective: To explore the treatment response, tolerability and safety of once-monthly paliperidone palmitate (PP1M) in non-acute patients switched from oral antipsychotics, stratified by time since diagnosis as recently diagnosed (≤3 years) or chronic patients (>3 years). Research design and methods: Post hoc analysis of a prospective, interventional, single-arm, multicentre, open-label, 6-month study performed in 233 recently diagnosed and 360 chronic patients. Main outcome measures: The proportion achieving treatment response (defined as ≥20% improvement in Positive and Negative Syndrome Scale [PANSS] total score from baseline to endpoint) and maintained efficacy (defined as non-inferiority in the change in PANSS total score at endpoint [Schuirmann’s test]). Results: 71.4% of recently diagnosed and 59.2% of chronic patients showed a ≥20% decrease in PANSS total score (p = 0.0028 between groups). Changes in PANSS Marder factors, PANSS subscales, and the proportion of patients with a Personal and Social Performance scale (PSP) total score of 71–100 were significantly greater in recently diagnosed compared with chronic patients. PP1M was well tolerated, presenting no unexpected safety findings. Conclusion: These data show that recently diagnosed patients treated with PP1M had a significantly higher treatment response and improved functioning, as assessed by the PSP total score, than chronic patients.

The effect of long-acting paliperidone palmitate once-monthly on negative and depressive symptoms in patients with schizophrenia switched from previous unsuccessful treatment with oral aripiprazole

Background: The negative symptoms of schizophrenia are generally harder to recognize, more difficult to treat than positive symptoms, and have a significant impact on patient functioning and overall outcomes. Treatment with aripiprazole may be associated with benefits on negative symptoms and functioning given its partial agonism to the dopamine D2 receptor. The aim of this subanalysis was to explore the impact of flexibly dosed, long-acting paliperidone palmitate once monthly (PP1M) on negative and depressive symptoms, disorganized thoughts, anxiety, extrapyramidal symptoms, and patient functioning in nonacute adult patients with schizophrenia previously unsuccessfully treated with oral aripiprazole monotherapy. Methods: Post-hoc subanalysis of 46 nonacute but symptomatic patients enrolled in a prospective, interventional, single-arm, multicenter, open-label 6-month study. Results: At endpoint, improvements of ⩾ 20% and ⩾ 50% in the Positive and Negative Syndrome Scale (PANSS) total score were observed in 52.2% and 21.7% of patients, respectively. Significant and clinically relevant improvements were observed at endpoint in mean (standard deviation [SD]) PANSS negative subscale score (−3.0 (5.0); p < 0.0001) and in the PANSS Marder factor scores for negative symptoms (−2.9 (5.4); p = 0.0006), disorganized thoughts (−2.8 (4.3); p < 0.0001) and anxiety/depression (−1.8 (3.9); p = 0.0031). Patient functioning assessed by mean (SD) Personal and Social Performance scale score (3.9 (13.2); p = 0.0409), Mini International Classification of Functioning rating for Activity and Participation Disorders in Psychological Illnesses total scores (−2.9 (7.1); p = 0.0079), and Extrapyramidal Symptom Rating Scale scores (−0.6 (3.4); p = 0.0456) improved significantly at endpoint. PP1M was well tolerated with no new safety signals. Conclusions: Six-month treatment with flexibly dosed PP1M was associated with significant and clinically relevant improvements in negative and depressive symptoms, disorganized thoughts, functioning, and extrapyramidal symptoms in nonacute but symptomatic patients with schizophrenia previously unsuccessfully treated with oral aripiprazole.

Treatment response and tolerability with once-monthly paliperidone palmitate initiated shortly after hospital admission in patients with schizophrenia

Abstract Objectives: Partial or non-adherence in patients with schizophrenia is common and increases the risk of relapse. This study explored safety, tolerability and treatment outcomes in patients hospitalised for an exacerbation of schizophrenia initiated on maintenance treatment of once-monthly paliperidone palmitate (PP1M). Methods: A 6-week, observational cohort study of patients initiated on PP1M within 3 weeks after hospital admission. Results: Overall, 367 patients were documented, 85.8% with paranoid schizophrenia subtype. Mean time from hospital admission to PP1M initiation was 9.4 ± 7.7 days. Treatment-emergent adverse events were reported by 22.9% of patients. From baseline to endpoint, significant improvements were observed in psychotic symptoms (Brief Psychiatric Rating Scale total score mean change –19.3 ± 12.6, P < .0001) and functioning (Personal and Social Performance scale total score mean change 14.3 ± 12.4, P < .0001). Overall, 6.0% of patients were very or extremely satisfied with their prior antipsychotic medication at baseline compared with 47.2% very or extremely satisfied with PP1M treatment at endpoint. Conclusions: Initiating PP1M in patients with exacerbated schizophrenia shortly after hospital admission was well tolerated and resulted in statistically significant and clinically relevant improvements in symptoms and patient functioning, suggesting that patients may benefit from early initiation of PP1M during their hospital stay.

Once-monthly paliperidone palmitate in early stage schizophrenia – a retrospective, non-interventional 1-year study of patients with newly diagnosed schizophrenia

Background Long-acting antipsychotic therapy may be best suited for patients in the early stage of schizophrenia, when the most can be done before disease progression associated with poor adherence occurs. We explored the patterns of use of once-monthly paliperidone palmitate (PP1M), concomitant medication use, hospitalization, and clinical outcomes of adult, newly diagnosed patients with schizophrenia receiving continuous treatment with PP1M for at least 12 months. Methods This was an international, multicenter, exploratory, retrospective chart review of medical records of adult patients who were newly diagnosed (not more than 1 year before initiation of PP1M treatment) with schizophrenia and who had received continuous treatment with PP1M for ≥12 months in naturalistic clinical settings. Results A total of 84 (93.3%) patients were included in the analysis. All but one patient (98.8%, n=83) had received oral antipsychotic medication at least during the last month before the first PP1M administration. Three patients (3.6%) were newly hospitalized during the 12-month documentation period. The reason for hospitalization for all three was management of episode/relapse. A total of 79.2% of patients had a ≥20% improvement and 47.2% had a ≥50% improvement in Positive and Negative Syndrome Scale total score from baseline to endpoint. Half of patients (53.3%) showed a significant improvement, as reflected by an increase in Personal and Social Performance (PSP) total score of at least 7 points from baseline to endpoint (mean [SD] 11.9 [15.0] points; P<0.001). One quarter of patients (24.4%, n=11) moved from a PSP score of 31–70 (ie, moderate to marked functional impairment) at baseline to a PSP score of mild to no functional impairment (PSP score ≥71) at endpoint. Most adverse drug reactions were mild or moderate in severity. Conclusion Continuous treatment with PP1M over 12 months was associated with statistically significant and clinically meaningful improvements in psychotic symptoms, disease severity, and functional outcomes in patients with schizophrenia.

Tolerability, Safety and Treatment Response of Flexibly-dosed Paliperidone Palmitate in Patients Hospitalized for an Exacerbation of Schizophrenia

Objective To explore tolerability, safety and treatment response of flexibly-dosed paliperidone palmitate (PP) in adult patients hospitalized for an exacerbation of schizophrenia. Methods International 6-week prospective open-label non-interventional study. Outcome parameters were changes in Brief Psychiatric Rating Scale (BPRS) total score, Clinical Global Impression-Severity Scale (CGI-S), Personal and Social Performance Scale (PSP), treatment satisfaction (Medication Satisfaction Questionnaire (MSQ)), Extrapyramidal Symptom Rating Scale (ESRS) scores and treatment-emergent adverse events (TEAEs) from baseline to last-observation-carried-forward endpoint. Results 367 patients (65.9% male, mean age (±SD) 39.8±12.1 years, 85.8% paranoid schizophrenia) were documented. 91.6% completed the 6-week observation period. Mean time from hospital admission to initiation of PP was 9.4±7.7 days. Mean baseline BPRS total score of 50.2±13.6 improved by -6.5±8.6 at day 8 and by -19.3±12.6 at endpoint; 95% confidence interval [CI]-20.7;-18.0; both p Conclusions These data support results from previous randomized controlled and pragmatic studies that flexibly dosed paliperidone palmitate is well tolerated and associated with an early and clinically meaningful treatment response and functional improvement in patients hospitalized for an exacerbation of schizophrenia.

Paliperidone Palmitate – Effect On Negative, Depression/anxiety, Patient Functioning and Extrapyramidal Symptoms in Non-acute Schizophrenia Patients Previously Unsuccessfully Treated with Oral Aripiprazole

Introduction To explore the effect of flexibly dosed paliperidone palmitate (PP) on negative, depression/anxiety, patient functioning and extrapyramidal symptoms in adult non-acute schizophrenia patients previously unsuccessfully treated with oral aripiprazole. Methods International, prospective 6-month open-label study. Outcomes analyzed were changes from baseline (BL) to last-observation-carried-forward endpoint (EP) in Positive and Negative Syndrome Scale (PANSS) negative subscale, PANSS negative and anxiety/depression Marder factors, patient functioning (Personal and Social Performance Scale (PSP) and Mini International Classification of Functioning (Mini-ICF)) and Extrapyramidal Symptom Rating Scale (ESRS). Results : 46 patients were analyzed: 73.9% male, mean age 34.4±9.4 years, 78.3% paranoid schizophrenia, 67.4% completed the study. Mean prior oral aripiprazole dose was 22.7±10.7 mg/day. PANSS negative subscale score decreased from 20.3±5.0 at BL to 17.3±6.1 at EP (mean change -3.0±5.0; 95% confidence interval (CI) of change -4.4;–1.5; p Conclusions Transition from unsuccessful treatment with oral aripiprazole to flexibly dosed paliperidone palmitate in non-acute schizophrenia patients was well tolerated and associated with significant improvements in negative, depressive, anxiety and extrapyramidal symptoms as well as patient functioning.