Attitudes of European physicians towards the use of long-acting injectable antipsychotics.

BACKGROUND: Prescription rates for long-acting injectable (LAI) antipsychotic formulations remain relatively low in Europe despite improved adherence over alternative oral antipsychotic treatments. This apparent under-prescription of LAI antipsychotics may have multiple contributing factors, including negative mental health practitioner attitudes towards the use of LAIs. METHODS: The Antipsychotic Long acTing injection in schizOphrenia (ALTO) non-interventional study (NIS), conducted across several European countries, utilised a questionnaire that was specifically designed to address physicians' attitudes and beliefs towards the treatment of schizophrenia with LAI antipsychotics. Exploratory principal component analysis (PCA) of feedback from the questionnaire aimed to identify and characterize the factors that best explained the physicians' attitudes towards prescription of LAIs. RESULTS: Overall, 136/234 solicited physicians returned fully completed questionnaires. Physicians' mean age was 48.5 years, with mean psychiatric experience of 20.0 years; 69.9% were male, 84.6% held a consultant position, and 91.9% had a clinical specialty in general adult care. Most physicians considered themselves to have a high level of clinical experience with LAI antipsychotics (77.2%), with an increased rate of LAI antipsychotics prescription over the last 5 years (59.6%). Although the majority of physicians (69.9%) declared feeling no difference in stress levels when offering LAI compared to oral antipsychotics, feelings of 'no/more stress' versus 'less stress' was found to influence prescription patterns. PCA identified six factors which collectively explained 66.1% of the variance in physician feedback. Multivariate analysis identified a positive correlation between physicians willing to accept usage of LAI antipsychotics and the positive attitude of colleagues (co-efficient 3.67; p = 0.016). CONCLUSIONS: The physician questionnaire in the ALTO study is the first to evaluate the attitudes around LAI antipsychotics across several European countries, on a larger scale. Findings from this study offer an important insight into how physician attitudes can influence the acceptance and usage of LAI antipsychotics to treat patients with schizophrenia.

Aripiprazole Once-Monthly 400 mg: Comparison of Pharmacokinetics, Tolerability, and Safety of Deltoid Versus Gluteal Administration.

Background: Two open-label, randomized, parallel-arm studies compared pharmacokinetics, safety, and tolerability of aripiprazole once-monthly 400 mg following deltoid vs gluteal injection in patients with schizophrenia. Methods: In the single-dose study, 1 injection of aripiprazole once-monthly 400 mg in the deltoid (n=17) or gluteal (n=18) muscle (NCT01646827) was administered. In the multiple-dose study, the first aripiprazole once-monthly 400 mg injection was administered in either the deltoid (n=71) or gluteal (n=67) muscle followed by 4 once-monthly deltoid injections (NCT01909466). Results: After single-dose administration, aripiprazole exposure (area under the concentration-time curve) was similar between deltoid and gluteal administrations, whereas median time to maximum plasma concentration was shorter (7.1 [deltoid] vs 24.1 days [gluteal]) and maximum concentration was 31% higher after deltoid administration. In the multiple-dose study, median time to maximum plasma concentration for deltoid administration was shorter (3.95 vs 7.1 days), whereas aripiprazole mean trough concentrations, maximum concentration, and area under the concentration-time curve were comparable between deltoid and gluteal muscles (historical data comparison). Multiple-dose pharmacokinetic results for the major metabolite, dehydro-aripiprazole, followed a similar pattern to that of the parent drug for both deltoid and gluteal injection sites. Safety and tolerability profiles were similar after gluteal or deltoid injections. Based on observed data, minimum aripiprazole concentrations achieved by aripiprazole once-monthly 400 mg are comparable with those of oral aripiprazole 15 to 20 mg/d. Conclusions: The deltoid muscle is a safe alternative injection site for aripiprazole once-monthly 400 mg in patients with schizophrenia.

Multidimensional Assessment of Functional Outcomes in Schizophrenia: Results From QUALIFY, a Head-to-Head Trial of Aripiprazole Once-Monthly and Paliperidone Palmitate.

Background: QUALIFY was a 28-week, randomized, open-label, head-to-head trial that assessed improvements across multiple measures in stable patients with schizophrenia with aripiprazole once-monthly 400 mg vs paliperidone palmitate. Methods: Secondary effectiveness assessments included physician-rated readiness for work using the Work Readiness Questionnaire, the Clinical Global Impression-Severity and Clinical Global Impression-Improvement scales, and quality of life with the rater-blinded Heinrichs-Carpenter Quality of Life Scale. Patients assessed their treatment satisfaction and quality of life with Subjective Well-Being under Neuroleptic Treatment-short version and Tolerability and Quality of Life questionnaires. Results: Odds of being ready for work at week 28 were significantly higher with aripiprazole once-monthly 400 mg vs paliperidone palmitate (adjusted odds ratio, 2.67; 95% CI, 1.39-5.14; P=.003). Aripiprazole once-monthly 400 mg produced numerically or significantly greater improvements from baseline vs paliperidone palmitate in all Quality of Life Scale items. With aripiprazole once-monthly 400 mg vs paliperidone palmitate at week 28, there were significantly more Clinical Global Impression-Severity and Clinical Global Impression-Improvement responders (adjusted odds ratio, 2.26; P=.010, and 2.51; P=.0032) and significantly better Clinical Global Impression-Improvement scores (least squares mean treatment difference, -0.326; 95% CI, -0.60 to -0.05; P=.020). Numerically larger improvements with aripiprazole once-monthly 400 mg vs paliperidone palmitate were observed for patient-rated scales Subjective Well-Being under Neuroleptic Treatment-short version and Tolerability and Quality of Life. Partial correlations were strongest among clinician-rated and among patient-rated scales but poorest between clinician and patient-rated scales. Conclusions: Consistently greater improvements were observed with aripiprazole once-monthly 400 mg vs paliperidone palmitate across all measures. Partial correlations between scales demonstrate the multidimensionality of various measures of improvement. More patients on aripiprazole once-monthly 400 mg were deemed ready to work by the study end. Trial registry: National Institutes of Health registry, NCT01795547, https://clinicaltrials.gov/ct2/results?id=NCT01795547).

The burden of disease in early schizophrenia - a systematic literature review.

BACKGROUND: Schizophrenia is a heterogeneous disorder with a burden that can vary greatly depending on the severity and the duration. Previous research has suggested that patients in the earlier stages of schizophrenia (typically first-episode schizophrenia) benefit from effective early treatment, however, a comprehensive review of the burden specifically in this population has not been undertaken. A systematic literature review was therefore conducted to characterize the clinical, economic, and humanistic burden, as reported in naturalistic studies of schizophrenia populations specifically at an early stage of disease in comparison with healthy controls, patients with chronic schizophrenia, and patients with other psychiatric disorders. METHODS AND MATERIALS: Searches were conducted in MEDLINE, MEDLINE In-Process, Embase, PsycINFO, and EconLit databases for records published between January 2005 and April 2019, and of relevant conference abstracts published between January 2014 and May 2019. Data were extracted from relevant publications and subjected to qualitative evaluation. RESULTS: Fifty-two publications were identified for inclusion and revealed a considerable burden for early schizophrenia with regards to mortality, psychiatric comorbidities such as substance abuse and depression, poor social functioning, and unemployment. Comparisons with chronic schizophrenia suggested a greater burden with longer disease duration, while comparisons with other psychiatric disorders were inconclusive. This review uncovered various gaps in the available literature, including limited or no data on incarcerations, caregiver burden, and costs associated with early schizophrenia. CONCLUSIONS: Overall, the burden of schizophrenia is apparent even in the early stages of the disease, although further research is required to quantify the burden with chronic schizophrenia and other psychiatric disorders.

Diverse definitions of the early course of schizophrenia-a targeted literature review.

Schizophrenia is a debilitating psychiatric disorder and patients experience significant comorbidity, especially cognitive and psychosocial deficits, already at the onset of disease. Previous research suggests that treatment during the earlier stages of disease reduces disease burden, and that a longer time of untreated psychosis has a negative impact on treatment outcomes. A targeted literature review was conducted to gain insight into the definitions currently used to describe patients with a recent diagnosis of schizophrenia in the early course of disease ('early' schizophrenia). A total of 483 relevant English-language publications of clinical guidelines and studies were identified for inclusion after searches of MEDLINE, MEDLINE In-Process, relevant clinical trial databases and Google for records published between January 2005 and October 2015. The extracted data revealed a wide variety of terminology and definitions used to describe patients with 'early' or 'recent-onset' schizophrenia, with no apparent consensus. The most commonly used criteria to define patients with early schizophrenia included experience of their first episode of schizophrenia or disease duration of less than 1, 2 or 5 years. These varied definitions likely result in substantial disparities of patient populations between studies and variable population heterogeneity. Better agreement on the definition of early schizophrenia could aid interpretation and comparison of studies in this patient population and consensus on definitions should allow for better identification and management of schizophrenia patients in the early course of their disease.

Long-term effectiveness of aripiprazole once-monthly for schizophrenia is maintained in the QUALIFY extension study.

OBJECTIVE: To evaluate long-term safety and effectiveness of continued treatment with aripiprazole once-monthly 400mg (AOM 400) in patients with schizophrenia. METHODS: Patients who completed the QUALIFY study (NCT01795547) in the AOM 400 arm were eligible for 6 additional once-monthly injections of AOM 400 during an open-label, 24-week extension (NCT01959035). Safety data were collected at each visit. Effectiveness measures included change from baseline in health-related qualify of life and functioning on the Heinrichs-Carpenter Quality of Life scale (QLS) and Clinical Global Impression - Severity (CGI-S) scale. RESULTS: Of the 88 patients enrolled, 77 (88%) completed the extension study. Most common treatment-emergent adverse events (incidence ≥2%) were weight increased (6/88, 7%), toothache (3/88, 3%) and headache (3/88, 3%). Effectiveness was maintained during the extension study, with small but continued improvements from baseline: the least squares mean (LSM) change (95% CI) from baseline to week 24 was 2.32 (-1.21 to 5.85) for the QLS total score and -0.10 (-0.26 to 0.06) for the CGI-S score. The aggregated LSM change (95% CI) from baseline of the lead-in study to week 24 of the extension study was 11.54 (7.45 to 15.64) for the QLS total score and -0.98 (-1.18 to -0.79) for the CGI-S score. CONCLUSIONS: AOM 400 was well tolerated in patients continuing AOM treatment during the extension phase of the QUALIFY study. Robust and clinically meaningful improvements in health-related quality of life and functioning were maintained, further supporting the long-term clinical benefits of AOM 400 for the treatment of patients with schizophrenia.

Baseline results from the European non-interventional Antipsychotic Long acTing injection in schizOphrenia (ALTO) study.

BACKGROUND: The Antipsychotic Long-acTing injection in schizOphrenia (ALTO) study was a non-interventional study across several European countries examining prescription of long-acting injectable (LAI) antipsychotics to identify sociodemographic and clinical characteristics of patients receiving and physicians prescribing LAIs. ALTO was also the first large-scale study in Europe to report on the use of both first- or second-generation antipsychotic (FGA- or SGA-) LAIs. METHODS: Patients with schizophrenia receiving a FGA- or SGA-LAI were enrolled between June 2013 and July 2014 and categorized as incident or prevalent users. Assessments included measures of disease severity, functioning, insight, well-being, attitudes towards antipsychotics, and quality of life. RESULTS: For the 572 patients, disease severity was generally mild-to-moderate and the majority were unemployed and/or socially withdrawn. 331/572 were prevalent LAI antipsychotic users; of whom 209 were prescribed FGA-LAI. Paliperidone was the most commonly prescribed SGA-LAI (56% of incident users, 21% of prevalent users). 337/572 (58.9%) were considered at risk of non-adherence. Prevalent LAI users had a tendency towards better insight levels (PANSS G12 item). Incident FGA-LAI users had more severe disease, poorer global functioning, lower quality of life, higher rates of non-adherence, and were more likely to have physician-reported lack of insight. CONCLUSIONS: These results indicate a lower pattern of FGA-LAI usage, reserved by prescribers for seemingly more difficult-to-treat patients and those least likely to adhere to oral medication.

Quantifying the treatment goals of people recently diagnosed with schizophrenia using best-worst scaling.

OBJECTIVE: This study seeks to quantify the treatment goals of people recently diagnosed with schizophrenia and explore their impact on treatment plan. METHODS: People aged 18-35 years with a confirmed diagnosis of schizophrenia within the past 5 years were surveyed in the UK, Germany, and Italy. Treatment goals were assessed via a validated best-worst scaling instrument, where participants evaluated subsets of 13 possible treatment goals identified using a balanced incomplete block design. Participants identified the most and least important goals within each task. Data were also collected on current treatment and preference for daily oral versus long-acting injectable (LAI) treatment. Hierarchical Bayes was used to identify preference weights for the goals, and latent class analysis was used to identify segments of people with similar goals. The segments were compared with the current treatment and preference for oral versus LAI treatment. RESULTS: Across 100 participants, the average age was 26 years, 75% were male and 50% were diagnosed within 2 years ago. Overall, preferences were most favorable for reduced disease symptoms, think clearly, reduced hospitalizations, reduced anxiety, and take care of self. A total of 61% preferred oral medication and 39% LAI. Two groups were identified with different treatment goals; 50% of participants emphasized clinical goals, including reduced disease symptoms (preference weight =19.7%), reduced hospitalizations (15.5%), and reduced anxiety (10.5%). The other 50% emphasized functional goals, including improved relationships with family/friends (11.4%), increased interest in work (10.6%), experiencing a fuller range of emotions (8.4%), and ability to socialize (7.5%). Those emphasizing functional goals were more likely to be on LAI (44% versus 26%; p=0.059) and preferred LAI (46% versus 32%; p=0.151). CONCLUSIONS: People with recent-onset schizophrenia may focus more on clinical goals or functional goals, a discussion of which may help facilitate patient engagement.

Development of a stated-preference instrument to prioritize treatment goals in recent onset schizophrenia.

OBJECTIVE: This study sought to evaluate a new stated-preference instrument to prioritize multiple treatment goals among people with recent onset schizophrenia. METHODS: A draft survey instrument was developed to assess preferences for 13 key treatment goals that were identified based on the literature. The survey incorporates best-worst scaling (BWS), which shows repeated subsets comprising 4 of the 13 goals, and respondents identify which is most important and which is least important to them. Pre-test interviews were conducted in the UK, Italy, and Germany among people aged 18 to 35 diagnosed with schizophrenia within the past 5 years. Specifically, participants completed the instrument online in their native language, followed by a telephone interview to provide feedback on the clarity, relevance, and comprehensiveness of the survey. The interview data were analyzed to assess interpretation and content validity of the survey. RESULTS: Fifteen participants (five per country) provided feedback (mean age = 31; 60% male). Feedback was comparable across countries and confirmed that the key treatment goals assessed were relevant and meaningful. Probing by interviewers ascertained that respondents interpreted the questions appropriately and identified the treatment goals that were most and least important to them. Based on the characterization of the goals, a conceptual model was developed illustrating hypothesized associations among them. CONCLUSION: The results confirm that the BWS methodology and key treatment goals in this new instrument are appropriate for use in recent onset schizophrenia. These results will help guide measurement of patient-relevant endpoints in future studies.

Relationship between response to aripiprazole once-monthly and paliperidone palmitate on work readiness and functioning in schizophrenia: A post-hoc analysis of the QUALIFY study.

Schizophrenia is a chronic disease with negative impact on patients' employment status and quality of life. This post-hoc analysis uses data from the QUALIFY study to elucidate the relationship between work readiness and health-related quality of life and functioning. QUALIFY was a 28-week, randomized study (NCT01795547) comparing the treatment effectiveness of aripiprazole once-monthly 400 mg and paliperidone palmitate once-monthly using the Heinrichs-Carpenter Quality-of-Life Scale as the primary endpoint. Also, patients' capacity to work and work readiness (Yes/No) was assessed with the Work Readiness Questionnaire. We categorized patients, irrespective of treatment, by work readiness at baseline and week 28: No to Yes (n = 41), Yes to Yes (n = 49), or No at week 28 (n = 118). Quality-of-Life Scale total, domains, and item scores were assessed with a mixed model of repeated measures. Patients who shifted from No to Yes in work readiness showed robust improvements on Quality-of-Life Scale total scores, significantly greater than patients not ready to work at week 28 (least squares mean difference: 11.6±2.6, p<0.0001). Scores on Quality-of-Life Scale instrumental role domain and items therein-occupational role, work functioning, work levels, work satisfaction-significantly improved in patients shifting from No to Yes in work readiness (vs patients No at Week 28). Quality-of-Life Scale total scores also significantly predicted work readiness at week 28. Overall, these results highlight a strong association between improvements in health-related quality of life and work readiness, and suggest that increasing patients' capacity to work is an achievable and meaningful goal in the treatment of impaired functioning in schizophrenia.

Reduced sexual dysfunction with aripiprazole once-monthly versus paliperidone palmitate: results from QUALIFY.

Sexual dysfunction, a common side effect of antipsychotic medications, may be partly caused by dopamine antagonism and elevation of prolactin. In QUALIFY, a randomized study, aripiprazole once-monthly 400 mg (AOM 400), a dopamine D2 receptor partial agonist, showed noninferiority and subsequent superiority versus paliperidone palmitate (PP), a dopamine D2 receptor antagonist, on the Heinrichs-Carpenter Quality-of-Life Scale (QLS) in patients with schizophrenia aged 18-60 years. Sexual dysfunction (Arizona Sexual Experience Scale) and serum prolactin levels were also assessed. Odds for sexual dysfunction were lower with AOM 400 versus PP [week 28 adjusted odds ratio (95% confidence interval), 0.29 (0.14-0.61); P=0.0012] in men [0.33 (0.13-0.86); P=0.023], women [0.14 (0.03-0.62); P=0.0099], and patients aged 18-35 years [0.04 (<0.01-0.34); P=0.003]. Among patients shifting from sexual dysfunction at baseline to none at week 28, there was a trend toward greater improvement in the QLS total score. The mean (SD) prolactin concentrations decreased with AOM 400 [-150.6 (274.4) mIU/l] and increased with PP [464.7 (867.5) mIU/l] in both men and women. Six PP-treated patients experienced prolactin-related adverse events. In addition to greater improvement on QLS, patients had a lower risk for sexual dysfunction and prolactin elevation with AOM 400 versus PP in QUALIFY.

Long-term outcomes of antipsychotic treatment in patients with first-episode schizophrenia: a systematic review.

BACKGROUND: Treatment during first-episode psychosis (FEP) or early schizophrenia may affect the rates of relapse and remission, as well as cognitive functioning, over time. Prolonged duration of psychosis is associated with a poor prognosis, but the effects of treatment in patients with FEP or early schizophrenia on the long-term outcomes are not well defined. OBJECTIVE: To understand the long-term effects of treatment with antipsychotic agents on remission, relapse, and cognition in patients with FEP or early schizophrenia. METHODS: Using PubMed and Scopus databases, a systematic review was undertaken of articles published between January 1, 2000, and May 20, 2015, that reported randomized and nonrandomized prospective clinical trials on the long-term effects of oral or long-acting injectable antipsychotics on measures of relapse, remission, or cognition in patients with FEP or early schizophrenia. For comparative purposes, trials reporting the effects of later intervention with antipsychotics in patients with longer disease history were also evaluated. Titles, abstracts, and full-text articles were independently screened for eligibility by all the authors based on the predefined criteria. RESULTS: Nineteen studies met inclusion criteria: 13 reported long-term outcomes of relapse, remission, or cognition following antipsychotic treatment in patients with FEP and six reported on patients with a longer disease history. Antipsychotic treatment in patients with FEP produced high rates of remission in the year following treatment initiation, and untreated FEP reduced the odds of later achieving remission. Maintenance therapy was more effective than treatment discontinuation or intermittent/guided discontinuation in preventing relapse. Initiating antipsychotic treatment in patients with FEP also produced sustained cognitive improvement for up to 2 years. Antipsychotic therapy also reduced the risk or rate of relapse in patients with a longer disease history, with outcomes in one study favoring a long-acting injectable formulation over an oral antipsychotic. CONCLUSION: Treatment of patients with FEP is associated with benefits in the long-term outcomes of remission, relapse, and cognition. More long-term studies of treatment in patients with FEP are needed to confirm these findings.

Initiation of aripiprazole once-monthly in patients with schizophrenia.

OBJECTIVE: This article provides rationale for recommendations on how to initiate aripiprazole once-monthly 400 mg (AOM 400), an injectable suspension, in patients with schizophrenia, supported by pharmacokinetic (PK) data and based on clinical studies. METHODS: An overview of data from a PK study, PK simulations, controlled clinical trials, and a naturalistic study is presented. RESULTS: Pharmacokinetic data support 400 mg as the starting and maintenance dose of AOM; the plasma concentration profile of aripiprazole after initiating AOM 400 was consistent with therapeutic concentrations observed with oral aripiprazole 10 to 30 mg/d. PK simulations and observed data from a single-dose clinical trial indicate that median aripiprazole plasma concentrations reach therapeutic levels within 7 days of initiating AOM 400. Because of interpatient variability, a 14-day overlap with oral aripiprazole or another antipsychotic medication is considered sufficient to ensure therapeutic concentrations. In clinical studies, when patients initiated AOM 400 with concomitant oral aripiprazole (10-15 mg/d based on stabilized dose) or continued their previous antipsychotic for ≤14 days, mean aripiprazole plasma concentration after 4 weeks (93 to 112 ng/mL) was in range of the therapeutic window established for aripiprazole (94.0-534.0 ng/mL). In clinical studies, the 400-mg starting dose of AOM was efficacious and well tolerated. Across studies of variable duration and design, 1296/1439 (90.1%) patients initiated AOM 400 and required no dose change. Overall rates of discontinuation due to lack of efficacy across clinical studies were low in patients treated with AOM 400 (range, 2.3%-10.0%). In a post hoc analysis from a naturalistic study, cross-titration from other oral antipsychotic therapies to oral aripiprazole before initiating AOM 400 was better tolerated with a >1- to 4-week cross-titration period versus a ≤1-week period, as evidenced by lower rates of discontinuation due to adverse events during cross-titration (2.7% [7/239] vs 10.4% [5/48]). The efficacy and safety of AOM 400 in the month after initiation in the pivotal maintenance studies were comparable between subpopulations of patients previously stabilized on 10- or 30-mg doses of oral aripiprazole. CONCLUSIONS: Findings from PK data, PK simulations, and clinical studies all support that 400 mg is the appropriate initiation dose of AOM for patients with schizophrenia. When switching to oral aripiprazole before initiating AOM 400, tapering the prior oral antipsychotic while titrating up the oral aripiprazole dose (target dose 10-30 mg/d) over >1 to 4 weeks may be an effective strategy. The efficacy, safety, and tolerability of AOM 400 were comparable regardless of whether patients were previously stabilized on oral aripiprazole 10 or 30 mg/d or other antipsychotic therapy and continued to receive the same oral antipsychotic for the first 14 days after initiating AOM 400.

Qualify: a randomized head-to-head study of aripiprazole once-monthly and paliperidone palmitate in the treatment of schizophrenia.

OBJECTIVE: To directly compare aripiprazole once-monthly 400mg (AOM 400) and paliperidone palmitate once-monthly (PP) on the Heinrichs-Carpenter Quality-of-Life Scale (QLS), a validated health-related quality of life and functioning measure in schizophrenia. METHOD: This 28-week, randomized, non-inferiority, open-label, rater-blinded, head-to-head study (QUALIFY) of AOM 400 and PP in adult patients (18-60 years) comprised oral conversion, initiation of AOM 400 or PP treatment, and continuation with intramuscular injections every 4weeks. The primary endpoint assessed non-inferiority and superiority on QLS total score analyzed using a mixed model for repeated measurements. RESULTS: Of 295 randomized patients, 100/148 (67.6%) of AOM 400 and 83/147 (56.5%) of PP patients completed 28weeks of treatment. A statistically significant least squares mean difference in change from baseline to week 28 on QLS total score (4.67 [95%CI: 0.32;9.02], p=0.036) confirmed non-inferiority and established superiority of AOM 400 vs PP. There were also significant improvements in Clinical Global Impression - Severity scale and the Investigator's Assessment Questionnaire for AOM 400 vs PP, and pre-defined sub-group analyses revealed a consistent pattern of significance favoring AOM 400 in patients ≤35years. Common treatment-emergent adverse events in the treatment continuation phase were more frequent with PP vs AOM 400, and adverse events were the most frequent reason for discontinuation (27/137 [19.7%] for PP and 16/144 [11.1%] for AOM 400). All-cause discontinuation was numerically lower with AOM 400. CONCLUSION: Superior improvements on clinician-rated health-related quality of life and a favorable tolerability profile suggest greater overall effectiveness for aripiprazole once-monthly vs paliperidone palmitate. ClinicalTrials.gov identifier:NCT01795547.