Relationship between clinical outcomes measures and personal and social performance functioning in a prospective, interventional study in schizophrenia.

OBJECTIVES: To explore clinical and demographic characteristics impacting patient functioning by determining extent of overlap in factors driving change in Personal and Social Performance (PSP) and other clinical outcomes. METHODS: Post-hoc analysis from a single-arm trial of paliperidone extended release in adult patients with nonacute symptomatic schizophrenia. Psychosocial functioning measures: PSP, Clinical Global Impression-Severity (CGI-S), Positive and Negative Syndrome Scale (PANSS), Short-Form 36 (SF-36), treatment satisfaction, sleep quality/daytime drowsiness, and Extrapyramidal Symptoms Rating Scale. RESULTS: Highest correlations with PSP total score change included PANSS total score change (Spearman's r = 0.607), PANSS general psychopathology change (r = 0.579), and CGI-S change (r = 0.569). A PSP score change of -32 predicted 90% probability of deterioration in CGI-S (score change of ≥1). The power of PSP change to predict PANSS total score change was lower. Linear stepwise regression demonstrated independent relationships for PSP change and: PANSS total change; CGI-S change; SF-36 Mental Component change; treatment satisfaction at endpoint; PSP at baseline; previous psychiatric hospitalizations. R 2 = 0.55 meant that 45% of PSP variation could not be explained by other clinical outcome measures. CONCLUSIONS: Psychosocial functioning improvement is important in schizophrenia. PSP may be valuable for assessing functioning; it encompasses psychosocial and clinical factors not measured by other established assessments.

Preventing Cross-Contamination during Lyophilization: GMP and Occupational Cleaning Requirements for Nonproduct and Indirect Product-Contact Parts.

A detailed overview is provided for the possible patient exposure to highly potent active pharmaceutical ingredients (HPAPIs) from potential cross-contamination through the lyophilization process. The intent of this paper is to raise awareness of the risk(s) to patients and stimulate the implementation of adequate risk-based controls, such as containment process(es), use of adequate surrogates in cleaning validation/verification, and test method-sensitivity-based cleaning validation acceptance conditions. Although lyophilizers are considered to be nonproduct-contact surfaces because their surfaces and fixtures do not usually come into direct contact with the product, product contamination can occur at critical locations within a lyophilizer and/or during the unloading process. Contamination of the air because of released product particles can also create a risk. Therefore, special attention should be paid to HPAPIs, as the permitted daily exposures (PDEs) for patients are particularly low. During a lyophilizer cycle, areas of concern are spreading of the lyophilizer HPAPI powder because of air turbulence, contaminated plates, mechanical transfer systems, and spreading because of damaged vials or contaminated stainless steel or plastic surfaces. Specific considerations for contamination containment for the lyophilizer unloading process are presented. Suggestions are provided for the prevention of patient exposure through cross-contamination via direct-contact areas and prevention of manufacturing personnel exposure via non-direct-contact areas. A surface limit(s) of 1 PDE per square decimeter for nonproduct-contact surfaces inside a lyophilizer is proposed. Risk-based cleaning validation/verification strategies are discussed, with specific consideration of the quality control test method sensitivity expectations and use of suitable surrogates for lyophilized products in the cleaning verification studies.LAY ABSTRACT: This paper provides an overview of important points to consider during the manufacture of highly potent active pharmaceutical ingredients (HPAPI) with the intention to limit patient exposure and/or manufacturing personnel exposure to these highly toxic HPAPIs. HPAPI can potentially be spread during the freeze-drying process (lyophilization) and may cross-contaminate products. Manufacturing personnel and patients taking other freeze-dried products made in the same lyophilizer could be contaminated. It is therefore necessary to implement rigorous contamination controls. Within the lyophilizer, areas of concern are spreading of the lyophilizer HPAPI powder because of air turbulence, contaminated plates, mechanical transfer systems, and spreading because of damaged vials or contaminated stainless steel or plastic surfaces. Cleaning validation/verification studies, intended to demonstrate sufficient cleanability of the freeze-drying process as well as the recommended test method sensitivity to detect these highly toxic HPAPIs, are reviewed. Limits for the relevant production surface areas where cross-contamination and/or personnel exposure (through direct contact) could occur are proposed in this paper.

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

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.

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.

Switching from oral atypical antipsychotic monotherapy to paliperidone palmitate once-monthly in non-acute patients with schizophrenia: A prospective, open-label, interventional study.

RATIONALE: Long-acting injectable antipsychotic therapies may offer benefits over oral antipsychotics in patients with schizophrenia. OBJECTIVE: This study aimed to explore the safety, tolerability, and treatment response of paliperidone palmitate once-monthly in non-acute but symptomatic adult patients switched from previously unsuccessful monotherapy with frequently used oral atypical antipsychotics. METHODS: This was a post hoc analysis of a prospective, interventional, single-arm, international, multicenter, open-label, 6-month study. RESULTS: The patients (N = 472) were switched to paliperidone palmitate once-monthly (PP1M) from daily oral treatment with either aripiprazole (n = 46), olanzapine (n = 87), paliperidone extended-release (n = 104), quetiapine (n = 44), or risperidone (n = 191). In all groups, mean Positive and Negative Syndrome Scale total (p < 0.0001) and Clinical Global Impression-Severity scores improved significantly (p = 0.0004 to p < 0.0001). An improvement of ≥50 % in the Positive and Negative Syndrome Scale total score was observed in 21.7 % (aripiprazole), 29.9 % (olanzapine), 29.8 % (paliperidone extended-release), 27.3 % (quetiapine), and 37.2 % (risperidone) of patients. The patients showed significant improvements in the Personal and Social Performance score (aripiprazole p = 0.0409, all others p ≤ 0.0015); Mini International Classification of Functionality, Disability and Health Rating for Activity and Participation Disorders in Psychological Illnesses total scores (all p < 0.01); and Treatment Satisfaction Questionnaire for Medication Global Satisfaction score (olanzapine and risperidone p < 0.0001, quetiapine p = 0.0465, paliperidone extended-release p = 0.0571, aripiprazole p = NS). Paliperidone palmitate once-monthly was well tolerated, presenting no new safety signals. CONCLUSIONS: These data illustrate that stable, non-acute but symptomatic patients on oral antipsychotic monotherapy may show clinically meaningful improvement of symptoms, functioning, and treatment satisfaction after direct transition to PP1M. The findings are limited by the naturalistic study design; thus, further studies are required to confirm the current findings.

A Flexible-Dose Study of Paliperidone ER in Patients With Nonacute Schizophrenia Previously Treated Unsuccessfully With Oral Olanzapine.

OBJECTIVE: The goal of this study was to explore the tolerability, safety, and treatment response of switching from oral olanzapine to paliperidone extended release (ER). METHODS: Adult patients with nonacute schizophrenia who had been treated unsuccessfully with oral olanzapine were switched to flexible doses of paliperidone ER (3 to 12 mg/d). The primary efficacy outcome was a ≥ 20% improvement in Positive and Negative Syndrome Scale (PANSS) total scores from baseline to endpoint for patients who switched medications because of lack of efficacy with olanzapine and noninferiority versus previous olanzapine treatment (mean endpoint change in PANSS total scores vs. baseline of ≤ 5 points) for patients who switched for reasons other than lack of efficacy. Safety and tolerability were assessed by monitoring adverse events, extrapyramidal symptoms, and weight change. RESULTS: Of 396 patients, 65.2% were men, mean age was 40.0 ± 12.0 years, and 75.5% had paranoid schizophrenia. Among the patients whose main reason for switching was lack of efficacy, an improvement in the PANSS total score of ≥ 20% occurred in 57.4% of patients. Noninferiority was confirmed for each subgroup of patients whose main reason for switching was something other than lack of efficacy. Paliperidone ER was generally well tolerated. Extrapyramidal symptoms as measured by total Extrapyramidal Symptom Rating Scale scores showed statistically significant and clinically relevant improvements at endpoint, the average weight decreased by 0.8 ± 5.2 kg at endpoint, and a clinically relevant weight gain of ≥ 7% occurred in 8.0% of patients. CONCLUSION: Paliperidone ER flexibly-dosed over 6 months was well tolerated and associated with a meaningful clinical response in patients with nonacute schizophrenia who had previously been unsuccessfully treated with oral olanzapine.

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.

Treatment response, safety, and tolerability of paliperidone extended release treatment in patients recently diagnosed with schizophrenia.

OBJECTIVE: This study was designed to explore the efficacy and tolerability of oral paliperidone extended release (ER) in a sample of patients who were switched to flexible doses within the crucial first 5 years after receiving a diagnosis of schizophrenia. METHODS: Patients were recruited from 23 countries. Adults with nonacute but symptomatic schizophrenia, previously unsuccessfully treated with other oral antipsychotics, were transitioned to paliperidone ER (3-12 mg/day) and prospectively treated for up to 6 months. The primary efficacy outcome for patients switching for the main reason of lack of efficacy with their previous antipsychotic was at least 20% improvement in Positive and Negative Syndrome Scale (PANSS) total scores. For patients switching for other main reasons, such as lack of tolerability, compliance or 'other', the primary outcome was non-inferiority in efficacy compared with the previous oral antipsychotic. RESULTS: For patients switching for the main reason of lack of efficacy, 63.1% achieved an improvement of at least 20% in PANSS total scores from baseline to endpoint. For each reason for switching other than lack of efficacy, efficacy maintenance after switching to paliperidone ER was confirmed. Statistically significant improvement in patient functioning from baseline to endpoint, as assessed by the Personal and Social Performance scale, was observed (p < 0.0001). Treatment satisfaction with prior antipsychotic treatment at baseline was rated 'good' to 'very good' by 16.8% of patients, and at endpoint by 66.0% of patients treated with paliperidone ER. Paliperidone ER was generally well tolerated, with frequently reported treatment-emergent adverse events being insomnia, anxiety and somnolence. CONCLUSIONS: Flexibly dosed paliperidone ER was associated with clinically relevant symptomatic and functional improvement in recently diagnosed patients with non-acute schizophrenia previously unsuccessfully treated with other oral antipsychotics.

Intramuscular long-acting paliperidone palmitate in acute patients with schizophrenia unsuccessfully treated with oral antipsychotics.

In this prospective multicentre, open-label, 6-month study (Paliperidone Palmitate Flexible Dosing in Schizophrenia [PALMFlexS]), tolerability, safety and treatment response with paliperidone palmitate (PP) were explored in patients with acute symptoms of schizophrenia following switching from previously unsuccessful treatment with oral antipsychotics. This pragmatic study was conducted in a large, more representative sample of the general schizophrenia population compared to randomized controlled pivotal trials, to specifically mimic real-world clinical situations. After initiation on Day 1 and Day 8, patients received PP once monthly at flexible doses (50-150mgeq.) intramuscularly. The primary efficacy outcome was defined as the percentage of patients achieving ≥30% improvement in 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 (TEAEs). Overall, 212 patients received PP at least once after switching from oral antipsychotics, primarily due to lack of efficacy (45.8%). Significant improvements from BL in mean (SD) PANSS total score were observed from Day 8 onwards (BL to LOCF EP: -31.0 [29.0]; p<0.0001). At endpoint, two-thirds (66.7%) and 43.5% of patients achieved a ≥30% and ≥50% improvement in mean PANSS total score, respectively. PP was associated with significant improvements across secondary measures of symptom severity, subjective well-being, medication satisfaction, illness-related disorders of activity and participation, and patient functioning (p<0.0001; BL to LOCF EP). PP was generally well tolerated, with significant reductions in ESRS total score (p<0.0001) and mainly mild-to-moderate TEAEs. TEAEs reported in ≥5% of patients were injection-site pain (13.7%), insomnia (10.8%), psychotic disorder (10.4%), headache and anxiety (both 6.1%). The PALMFlexS study findings provide valuable pragmatic clinical data on PP treatment in patients with acute schizophrenia previously unsuccessfully treated with oral antipsychotics.

Nurses' perceptions of medication adherence in schizophrenia: results of the ADHES cross-sectional questionnaire survey.

OBJECTIVES: Poor adherence to antipsychotic treatment is a widespread problem within schizophrenia therapy with serious consequences including increased risks of relapse and rehospitalization. Mounting evidence supports the key roles that nurses play in monitoring patient progress and facilitating long-term treatment adherence. The Adherencia Terapéutica en la Esquizofrenia (ADHES) nurses' survey was designed to assess the opinions of nurses on the causes and management of partial/nonadherence to antipsychotic medication. METHODS: A questionnaire-based cross-sectional survey of 4120 nurses from Europe, the Middle East and Africa. Interpretation of results was based on a descriptive comparison of responses. RESULTS: Nurses perceived 54% of patients seen in the preceding month to be partially/nonadherent to treatment. Most nurses (90%) reported some level of experience with administration of long-acting injectable (LAI) antipsychotics, with 24% of nurses administering >10 injections per month. The majority (85%) of nurses surveyed believed that improving adherence would improve patient outcomes. Nearly half (49%) reported that most of their patients depend on a family member or other nonprofessional carer to remind them to take their medication as prescribed. A similar proportion of nurses (43%) reported that most of their patients relied on a professional to remind them to take medication. Most nurses (92%) felt that ensuring continuous medication with LAI antipsychotics would yield long-term benefits for patients, but their opinion was that over a third of patients were unaware of LAI antipsychotic treatments. In a series of forced options, the strategy used most often by respondents (89%) to promote medication adherence was to build trusting relationships with patients while listening to and interpreting their needs and concerns. Respondents also rated this as the most effective strategy that they used (48%). CONCLUSION: Nurses are highly aware of adherence issues faced by their patients; further patient education on treatment options is needed.

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 [Schuirmann's 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 patient's 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.

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

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.

Dosing and switching of paliperidone ER in patients with schizophrenia: recommendations for clinical practice.

Many patients with schizophrenia receive long-term treatment with antipsychotic medication. Switching of antipsychotic medication due to lack of efficacy, tolerability issues, and partial/non-adherence is common. Despite this, consensus strategies for switching between antipsychotics are lacking. This manuscript provides practical recommendations for switching antipsychotic medication to ensure optimal management of patients with schizophrenia, with a particular focus on paliperidone extended release (ER). The authors drew on their clinical experience supported by detailed discussion of literature describing antipsychotic switching techniques and strategies and findings from paliperidone ER clinical trials. Antipsychotic switching strategies should be individualized and take into consideration the pharmacokinetic (PK) and pharmacodynamic (PD) properties of the pre- and post-switch medication. The use of temporary concomitant medications may be appropriate in some scenarios. Abrupt withdrawal of pre-switch medication may be appropriate in some instances but carries a greater risk of rebound and withdrawal symptoms than other strategies. Cross-tapering is the method most widely used in clinical practice. Paliperidone ER can be initiated without dose titration. The EU SmPC recommended dose of paliperidone ER is 6 mg/day; but doses should be individualized within the approved range of 3-12 mg/day. Higher doses may be required due to insufficient efficacy of the previous antipsychotic or in patients with acute symptoms. Recently diagnosed patients, those with renal impairment, or patients who have previously experienced tolerability issues with other antipsychotics may require lower doses. When switching from risperidone, higher doses of paliperidone ER may be required compared with risperidone. When switching from antipsychotics that have sedative and/or significant anticholinergic activity, the pre-switch antipsychotic should be tapered off gradually. Antipsychotics with less sedating and little anticholinergic activity can be tapered off over a shorter period. Temporary concomitant sedative medication may be beneficial when switching from antipsychotics with relatively higher sedative propensities. Switching from another antipsychotic to paliperidone ER requires individualized switching strategies and dosing, dependent on the characteristics of the patient and the PK and PD properties of the pre-switch medication. Cross-tapering strategies should be considered as a means of reducing the risk of rebound and withdrawal symptoms.

Paliperidone extended-release in patients with non-acute schizophrenia previously unsuccessfully treated with other oral antipsychotics.

OBJECTIVE: This study explores relevant outcomes with flexibly dosed paliperidone extended-release (ER) in a real-world design. RESEARCH DESIGN AND METHODS: Patients were recruited from 23 countries. Adults with non-acute schizophrenia (n = 1812), previously unsuccessfully treated with other oral antipsychotics, were transitioned to paliperidone ER and prospectively treated for 6 months. MAIN OUTCOME MEASURES: Primary efficacy outcome for patients switching for the main reason of lack of efficacy was ≥ 20% improvement in Positive and Negative Syndrome Scale (PANSS) total scores. For patients switching for main reasons other than lack of efficacy, primary outcome was non-inferiority in efficacy compared with the previous medication. RESULTS: Among the lack-of-efficacy group, 61% achieved a ≥ 20% improvement in PANSS total scores from baseline to endpoint. For switchers from other than the lack-of-efficacy group, efficacy maintenance after switching to paliperidone ER was confirmed. Clinically relevant and statistically significant symptomatic improvements occurred for each patient group based on main reason for switching. CONCLUSION: Paliperidone ER was well tolerated and associated with a meaningful clinical response in patients who switched from other oral antipsychotics, with insomnia and anxiety as most frequent side-effects.

Treatment of acute schizophrenia with paliperidone ER: predictors for treatment response and benzodiazepine use.

The Paliperidone ER Treatment in Acute Intervention (PERTAIN) study was designed to explore treatment response, tolerability, and safety of flexible doses of paliperidone ER in patients with schizophrenia admitted for an acute exacerbation. This paper addresses a secondary analysis of PERTAIN data designed to explore predictors for treatment response, flexible dosing, and concomitant benzodiazepine use. This prospective, multicenter, phase 3b, open-label, single-arm, 6-week study used flexible doses of paliperidone ER (3 to 12mg once daily) to treat patients hospitalized for an acute exacerbation of schizophrenia, reflecting more closely daily clinical practice. Predictive models were evaluated for paliperidone ER flexible dosing, treatment response, and concomitant treatment with benzodiazepines as distinct independent variables. For the analysis of explanatory variables, a stepwise logistic regression was used, taking into account patient age, gender, body mass index, diagnosis and duration of schizophrenia, number of prior hospitalizations, psychotic symptoms (PANSS), disease severity (CGI-S), and patient functioning (PSP) at baseline. Early response (defined as response within 2weeks of treatment initiation) was also used as a predictor. Clinical response (defined as ≥30% decrease in PANSS total score and ≥1 point decrease in CGI-S from baseline to endpoint) was predicted by early clinical response (p<0.001) and there was a trend for the diagnosis of paranoid schizophrenia vs. other types of schizophrenia to predict clinical response (p=0.0525). High response (defined as ≥50% decrease in PANSS total score and ≥2 points decrease in CGI-S from baseline to endpoint) was predicted by early high response, higher baseline CGI-S, or female gender. More severely ill patients with a higher baseline CGI-S were twice likely to be treated concomitantly with a benzodiazepine.

Definitions and drivers of relapse in patients with schizophrenia: a systematic literature review.

Relapse in patients with schizophrenia has devastating repercussions, including worsening symptoms, impaired functioning, cognitive deterioration and reduced quality of life. This progressive decline exacerbates the burden of illness on patients and their families. Relapse prevention is identified as a key therapeutic aim; however, the absence of widely accepted relapse definition criteria considerably hampers achieving this goal. We conducted a literature review in order to investigate the reporting of relapses and the validity of hospitalization as a proxy for relapse in patients with schizophrenia. The primary aim was to assess the range and validity of methods used to define relapse in observational or naturalistic settings. The secondary aim was to capture information on factors that predicted or influenced the risk of relapse. A structured search of the PubMed database identified articles that discussed relapse, and hospitalization as a proxy of relapse, in patients with schizophrenia. National and international guidelines were also reviewed. Of the 150 publications and guidelines identified, 87 defined relapse and 62% of these discussed hospitalization. Where hospitalization was discussed, this was as a proxy for, or a component of, relapse in the majority of cases. However, hospitalization duration and type varied and were not always well defined. Scales were used to define relapse in 53 instances; 10 different scales were used and multiple scales often appeared within the same definition. There were 95 references to factors that may drive relapse, including non-adherence to antipsychotic medication (21/95), stress/depression (11/95) and substance abuse (9/95). Twenty-five publications discussed the potential of antipsychotic therapy to reduce relapse rates-continuous antipsychotic therapy was associated with reduced frequency and duration of hospitalization. Non-pharmacological interventions, such as psychoeducation and cognitive behavioural therapy, were also commonly reported as factors that may reduce relapse. In conclusion, this review identified numerous factors used to define relapse. Hospitalization was the factor most frequently used and represents a useful proxy for relapse when reporting in a naturalistic setting. Several factors were reported to increase the risk of relapse, and observation of these may aid the identification of at-risk patients.

Long-term remission in schizophrenia and schizoaffective disorder: results from the risperidone long-acting injectable versus quetiapine relapse prevention trial (ConstaTRE).

OBJECTIVE: The objective of this study was to report the long-term remission results from the ConstaTRE relapse prevention trial, in which clinically stable adults with schizophrenia or schizoaffective disorder treated with oral risperidone, olanzapine, or oral conventional antipsychotics were randomized to risperidone long-acting injectable (RLAI) or oral quetiapine, dosed according to package-insert recommendations. METHODS: In the ConstaTRE trial, efficacy and tolerability were recorded for up to 24 months. This post hoc analysis presents remission data, defined, according to the Schizophrenia Working Group criteria, as achieving and maintaining eight core symptoms of schizophrenia that are mild or less over 6 months. Additional secondary outcome measures are also presented. RESULTS: A total of 710 patients were randomized to RLAI (n = 355) or quetiapine (n = 355). Mean mode ± standard deviation (SD) drug doses were RLAI 33 ± 10 mg every 2 weeks and quetiapine 413 ± 159 mg daily. Full remission was achieved by 51.1% of patients with RLAI and 39.3% with quetiapine (p = 0.003). Mean ± SD of full remission durations were not significantly different with RLAI (540 ± 181 days) and quetiapine (508 ± 188 days). Overall tolerability was similar between treatment groups. CONCLUSIONS: Among stable patients with schizophrenia or schizoaffective disorder, remission was more likely after switching to RLAI than quetiapine.

Psychiatrists' perceptions of the clinical importance, assessment and management of patient functioning in schizophrenia in Europe, the Middle East and Africa.

BACKGROUND: It has been estimated that as many as two thirds of patients with schizophrenia are unable to perform basic personal and social roles or activities. Occupational functioning and social functioning, as well as independent living, are considered as core domains of patient functioning. Improvement in patient functioning has also been recognized as an important treatment goal in guidelines and an important outcome by regulatory agencies. Nevertheless, information is lacking on how these aspects are being considered by psychiatrists across the world and how they are being assessed and managed. METHODS: The 'Europe, the Middle East and Africa functioning survey' was designed to canvas opinions of psychiatrists across these regions to ascertain their perceptions of the clinical importance, assessment and management of functioning amongst their patients with schizophrenia. The survey comprised 17 questions and was conducted from March to April 2011 in 42 countries. Data collected included the demographics of respondents and their opinions regarding personal and social functioning in patients with schizophrenia. RESULTS: Results were obtained from 4,163 clinicians. Psychiatrists estimated that more than two thirds (70%) of their patients with schizophrenia showed impaired or very poor levels of functioning. The majority of psychiatrists (92%) believed that personal and social functioning was an important treatment goal for patients with schizophrenia, and 91% believed it was an important goal for patients' families. The majority of psychiatrists (55%) assess the personal and social functioning of their patient at each visit; however, 81% reported that they determine the level of functioning through clinical interview and not by using a specific assessment scale. To manage personal and social functioning in their patients, 26% of psychiatrists prefer pharmacological interventions, whereas 46% prefer psychosocial interventions. CONCLUSION: Psychiatrists recognize that functioning is impaired/very poor in patients with schizophrenia, and there is still an important need to address functioning as a main treatment goal for patients with schizophrenia.

Psychiatrists' awareness of adherence to antipsychotic medication in patients with schizophrenia: results from a survey conducted across Europe, the Middle East, and Africa.

BACKGROUND: Nonadherence is common among patients with schizophrenia, although the rates vary according to means of assessment and patient population. Failure to adhere to medication can have a major impact on the course of illness and treatment outcomes, including increasing the risk of relapse and rehospitalization. Understanding psychiatrists' perception of the causes and consequences of nonadherence is crucial to addressing adherence problems effectively. METHODS: The Europe, the Middle East, and Africa (EMEA) Spanish Adherencia Terapéutica en la Esquizofrenia (ADHES) survey was conducted by questionnaire during January-March 2010 among psychiatrists treating patients with schizophrenia in 36 countries. The survey comprised 20 questions. In addition to recording the demographic details of the 4722 respondents (~12% response rate), it canvassed their preferred methods of assessing adherence, their perceptions of adherence rates, reasons for nonadherence, and strategies to improve adherence. RESULTS: Psychiatrists estimated that 53% of their patients with schizophrenia were partially/nonadherent during the previous month. They estimated only one-third of patients who deteriorated after stopping medication were able to attribute this to nonadherence. Psychiatrists assessed adherence most often by patient interview. Lack of insight was viewed as the most important cause of medication discontinuation, followed by patients feeling better and thinking their medication unnecessary, and experiencing undesirable side effects. Considerably fewer psychiatrists viewed insufficient efficacy, cognitive impairment, or drug/alcohol abuse as the most important reasons for their patients stopping medication. CONCLUSION: Psychiatrists throughout EMEA recognize the impact of partial/nonadherence to medication, with patient enquiry being the most commonly used means of assessment. There remains a need for more proactive management of patients with schizophrenia, particularly in increasing patient insight of their illness in order to improve adherence and minimize the consequences of relapse. Strategies focused on raising awareness of the importance of adherence are also warranted, with the aim of improving patient outcomes in schizophrenia.