Aripiprazole Lauroxil Dosing Regimens: Understanding Dosage Strengths and Injection Intervals.

Aripiprazole lauroxil (AL) is a long-acting atypical antipsychotic approved for the treatment of schizophrenia in adults. AL has five regimen options that offer three different injection intervals using four different dosage strengths. The relationship between dosage strength (milligram injected), injection interval (time between injection visits), and expected steady-state plasma aripiprazole concentrations may not be readily apparent. This article illustrates the relationship by providing visual scenarios of steady-state plasma aripiprazole concentrations for the five AL regimens. The efficacy of AL was originally demonstrated in a pivotal study of two AL regimens (approved as 441 mg monthly and 882 mg monthly). The three additional regimens (662 mg monthly, 882 mg every 6 weeks, and 1064 mg every 2 months) were approved based on pharmacokinetic bridging studies and population pharmacokinetic models. For this paper, expected steady-state concentrations for each AL regimen were derived from the published population pharmacokinetic models and compared using median values and ranges. The five labeled AL regimens differ in dosage strength and injection interval; however, model-simulated concentrations illustrate that each regimen produces steady-state plasma aripiprazole concentrations within the upper and lower bounds associated with known efficacy for AL 441 mg and 882 mg administered monthly. This visual presentation of the relationship between dosage strength of the AL injection, the interval between successive injections, and steady-state aripiprazole plasma concentrations may demonstrate for clinicians how dosage strength and injection interval can be considered in selecting the AL regimen option that best fits the clinical circumstances of the individual patient.

Impaired insight in schizophrenia: impact on patient-reported and physician-reported outcome measures in a randomized controlled trial.

BACKGROUND: Impaired insight poses a challenge in the treatment of patients with schizophrenia because of its potential to jeopardize therapeutic engagement and medication adherence. This study explored how insight impairment, graded from none to extreme, is related to patient-reported mental health status, depression, and neurocognition in schizophrenia. METHODS: In a post hoc analysis of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study (NCT00014001), insight was measured using the Positive and Negative Syndrome Scale (PANSS) Item G12 (lack of insight). Additional assessments for this analysis included the 12-Item Short-Form Health Survey (SF-12) Mental Component Summary (MCS), physician- and patient-reported Clinical Global Impression-Severity (CGI-S), MATRICS Consensus Cognitive Battery, and Calgary Depression Scale for Schizophrenia. Relationships between patient-reported outcomes and PANSS total and Item G12 ratings were evaluated. RESULTS: Among 1431 CATIE study participants in this analysis, increasingly impaired insight at baseline was significantly associated with better patient-reported quality of life (QoL), lower baseline depression, and greater divergence between physician- and patient-reported illness severity. Patients with more severely impaired insight reported milder illness compared with physician reports, particularly those with moderate-severe to extreme impairment (PANSS Item G12 rating ≥ 5), approximately 10% (138/1431) of CATIE participants. For the 90% of patients with PANSS Item G12 ratings < 5, patient-reported QoL decreased with increasing symptoms. SF-12 MCS scores were linearly related to baseline PANSS total score only in patients with PANSS total score < 90 (moderately ill or better), and better symptom scores were associated with higher QoL. No significant relationship between insight and neurocognition was observed. CONCLUSIONS: In the small subgroup (10%) of CATIE study patients with schizophrenia and PANSS Item G12 ratings ≥5, moderate-severe-severe/extreme insight impairment was associated with significantly more positive perception of QoL and illness severity by the patient versus the treating physician. This was not observed in the remaining 90% of patients with normal to moderately impaired insight, suggesting that poor insight as a threat to the validity of self-report is uncommon.

Long-term effect of aripiprazole lauroxil on health-related quality of life in patients with schizophrenia.

BACKGROUND: This post hoc analysis of clinical trial data evaluated long-term, self-reported mental and physical health-related quality of life (HRQoL) scores in schizophrenia patients receiving aripiprazole lauroxil (AL), an atypical long-acting injectable (LAI) antipsychotic approved for the treatment of schizophrenia in adults. METHODS: The study population included 291 stable schizophrenia outpatients enrolled in 2 consecutive long-term safety studies of AL given every 4 weeks for up to 124 weeks. HRQoL was measured using the SF-36v2® Health Survey (SF-36v2) over the course of the follow-up. The primary outcome was change in SF-36v2 mental component summary (MCS) and physical component summary (PCS) scores from baseline to 124 weeks. To contextualize these scores, descriptive analyses were conducted to compare the scores with available scores for the general population as well as for other populations with chronic medical (ie, hypertension and type 2 diabetes) or psychiatric (ie, depression) conditions. RESULTS: Results from this post hoc analysis indicated that the mean MCS score for patients continuing AL improved significantly from baseline over 124 weeks (P < .05, all timepoints), while mean PCS score showed little change over 124 weeks. At baseline, patients had lower (worse) MCS scores than the normed general population, but by week 124, patients had MCS scores comparable to those in the general population. This pattern of change was not observed with PCS scores. Comparison of study MCS scores with those associated with other diseases showed that this schizophrenia cohort had lower scores than those with chronic medical conditions but higher scores than those with depression. PCS scores were higher in the study population than published scores for all reference populations at baseline and week 124. CONCLUSIONS: In this post hoc analysis, outpatients with schizophrenia who continued the LAI antipsychotic AL showed gradual and sustained improvement in self-reported mental HRQoL over several years of follow-up, whereas self-reported physical HRQoL did not change. By the end of follow-up, mental health scores of study patients with schizophrenia were comparable to those of the general population and better than those of patients with depression. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01626456 [trial registration date: June 15, 2012] and NCT01895452 [trial registration date: July 5, 2013]).

Aripiprazole lauroxil 2-month formulation with 1-day initiation in patients hospitalized for an acute exacerbation of schizophrenia: exploratory efficacy and patient-reported outcomes in the randomized controlled ALPINE study.

BACKGROUND: A randomized, controlled, phase 3b study (ALPINE) evaluated efficacy and safety of a 2-month formulation of aripiprazole lauroxil (AL) using a 1-day initiation regimen in patients hospitalized for an acute exacerbation of schizophrenia. Paliperidone palmitate (PP) was used as an active control. Exploratory endpoint assessments included severity of illness, positive and negative symptoms, quality of life, caregiver burden, and satisfaction with medication. METHODS: Adults were randomly assigned to AL 1064 mg q8wk or PP 156 mg q4wk as inpatients, discharged after 2 weeks, and followed through week 25. Exploratory efficacy measures included the 3 original PANSS subscales, Clinical Global Impression-Severity (CGI-S) subscale, and caregiver Burden Assessment Scale. Exploratory patient-reported outcomes (PROs) included the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) and the Medication Satisfaction Questionnaire. Within-group changes from baseline through week 25 were analyzed for AL and PP separately. PROs were summarized based on observed data. RESULTS: Of 200 patients randomized (AL, n = 99; PP, n = 101), 99 completed the study (AL, n = 56; PP, n = 43). For AL, PANSS subscale and CGI-S scores improved from baseline through week 25 (mean [SE] change from baseline at week 25: Positive, -7.5 [0.70]; Negative, -3.9 [0.46]; General, -11.8 [0.83]; CGI-S, -1.3 [0.12]). Caregiver burden also improved (mean [SD] changes from baseline at week 9: -8.4 [10.15]; week 25: -8.9 [12.36]). Most AL patients were somewhat/very satisfied with treatment at each timepoint (70.8%-74.7%); mean Q-LES-Q-SF total scores were stable in the outpatient period. For PP, results were similar: PANSS Positive, -7.3 (0.67); Negative, -3.6 (0.69); General, -10.9 (1.22); CGI-S, -1.4 (0.16); caregiver burden, week 9: -8.8 (11.89) and week 25: -9.2 (14.55); satisfaction with treatment, 64.7%-69.3%; and stable Q-LES-Q-SF scores. CONCLUSIONS: ALPINE patients initiating the 2-month AL formulation using the 1-day initiation regimen as inpatients and continuing outpatient care experienced schizophrenia symptom improvement, sustained patient satisfaction with medication, stable quality of life, and reduced caregiver burden. A similar benefit pattern was observed for PP. These results support the feasibility of starting either long-acting injectable in the hospital and transitioning to outpatient treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03345979 [trial registration date: 15/11/2017].

Size matters: the importance of particle size in a newly developed injectable formulation for the treatment of schizophrenia.

One of the challenges with initiating long-acting injectable (LAI) antipsychotic regimens is achieving relevant drug levels quickly. After first injection of the LAI antipsychotic aripiprazole lauroxil (AL), the lag to reaching relevant plasma aripiprazole levels was initially addressed using supplemental oral aripiprazole for 21 days. A 1-day AL initiation regimen using a NanoCrystal® Dispersion formulation of AL (ALNCD; Aristada Initio®) combined with a single 30 mg dose of oral aripiprazole has been developed as an alternative approach. We compared the 1-day AL initiation regimen (ALNCD + 30 mg oral aripiprazole for 1 day) with the 21-day AL initiation regimen (AL + 15 mg/day of oral aripiprazole for 21 days) using kinetic modeling. Observed and modeled data demonstrate that the 1-day AL initiation regimen provides continuous aripiprazole exposure comparable to the 21-day AL initiation regimen. Each component of the 1-day AL initiation regimen (30 mg oral aripiprazole, ALNCD, and AL) contributes to aripiprazole plasma levels at different times, with oral aripiprazole predominating in the first week, then ALNCD and AL over time. In a double-blind, placebo-controlled, phase 1 study in patients with schizophrenia, the 1-day initiation regimen resulted in rapid achievement of relevant plasma aripiprazole levels comparable to those from the 21-day initiation regimen. Safety and tolerability of the 1-day regimen were consistent with the known profile of aripiprazole. Each part of the 1-day initiation regimen, together with AL, is necessary for continuous aripiprazole exposure from treatment initiation until the next regularly scheduled AL injection is administered.

Antipsychotic treatment experiences of people with bipolar I disorder: patient perspectives from an online survey.

BACKGROUND: Oral antipsychotic (AP) medications are frequently prescribed to people with bipolar I disorder (BD-I). A cross-sectional online survey examined the experiences of people living with BD-I with a history of recent AP use. METHODS: Adults with self-reported physician-diagnosed BD-I (N = 200) who received oral APs during the prior year completed a survey on AP-related experiences, including side effects and their perceived burden on social functioning, adherence, and work. Items also assessed preferences for trade-offs (balancing symptom management and side effects) when considering a hypothetical new AP. The perceived impact of specific, prevalent side effects on adherence, work, and preferences for a hypothetical AP were also examined. Analyses were descriptive. RESULTS: The survey sample had a mean age of 43.2 (SD = 12.4) years, was 60% female, and 31% nonwhite. Almost all participants (98%) had experienced AP side effects. Common self-reported side effects were feeling drowsy or tired (83%), lack of emotion (79%), anxiety (79%), dry mouth (76%), and weight gain (76%). Weight gain was cited as the most bothersome side effect, rated by most participants (68%) as "very" or "extremely bothersome." Nearly half of participants (49%) reported that AP side effects negatively impacted their job performance; almost all (92%) reported that side effects - most commonly anxiety and lack of emotion - negatively impacted social relationships (e.g., family or romantic partners). The most commonly-reported reason for stopping AP use was dislike of side effects (48%). Side effects most likely to lead to stopping or taking less of AP treatment included "feeling like a 'zombie'" (29%), feeling drowsy or tired (25%), and weight gain (24%). When considering a hypothetical new AP, the most common side effects participants wanted to avoid included AP-induced anxiety (50%), weight gain (48%), and "feeling like a 'zombie'" (47%). CONCLUSIONS: Side effects of APs were both common and bothersome, and impacted social functioning, adherence, and work. Findings highlight the prevailing unmet need for new APs with more favorable benefit-risk profiles.

Switching stable patients with schizophrenia from their oral antipsychotics to aripiprazole lauroxil: a post hoc safety analysis of the initial 12-week crossover period.

OBJECTIVE: Switching antipsychotic medications is common in patients with schizophrenia who are experiencing persistent symptoms or tolerability issues associated with their current drug regimen. This analysis assessed the safety of switching from an oral antipsychotic to the long-acting injectable antipsychotic aripiprazole lauroxil (AL). METHODS: This was a post hoc analysis of outpatients with schizophrenia who were prescribed an oral antipsychotic and who enrolled in an international, open-label, long-term (52-week) safety study of AL. The analysis focused on the first 3 injections of AL 882 mg over 12 weeks, divided into the immediate 4-week crossover period between the first and second AL injections (initiation phase) and the subsequent 8 weeks (stabilization phase). Patients were grouped by preswitch oral antipsychotic medication, and safety and clinical symptoms were assessed. RESULTS: In total, 190 patients had switched from one of the following oral antipsychotic medications: aripiprazole, conventional antipsychotics, risperidone/paliperidone, olanzapine, or quetiapine. The 12-week completion rate was high (92.1%) and similar across the different preswitch oral antipsychotic groups. Overall, adverse event (AE) rates experienced over 12 weeks were modest; no AEs were considered serious. The most common AEs in the initiation phase were injection site pain (5.8%), insomnia (5.8%), and akathisia (3.2%). No apparent relationship was observed between preswitch medication and early-onset AEs. Mean Positive and Negative Syndrome Scale total scores remained stable during this period across preswitch antipsychotic groups. CONCLUSION: Switching from an oral antipsychotic to AL was feasible in an outpatient setting for patients with schizophrenia, and the 12-week retention rate was favorable.

Long-term safety and tolerability of aripiprazole lauroxil in patients with schizophrenia.

OBJECTIVE: Safety and tolerability of long-term treatment with the long-acting antipsychotic aripiprazole lauroxil (AL) were evaluated in patients with schizophrenia. METHODS: This was an international, multicenter, phase 3, 52-week safety study of 2 fixed doses of AL (441 mg or 882 mg intramuscular every 4 weeks). Safety endpoints included adverse events (AEs) and extrapyramidal symptoms (EPS) including akathisia, injection-site reactions (ISRs), and clinically relevant changes in metabolic and endocrine values. RESULTS: Of 478 patients entering this study, 236 (49%) continued from a previous 12-week, phase 3 efficacy study of AL, and 242 (51%) were newly enrolled. Overall, 77% and 23% of patients received AL 882 mg (N = 368) and 441 mg (N = 110), respectively. AEs occurred in 50.4% of patients; most were mild (28.7%) or moderate (18.2%). The most common AEs were insomnia (8.4%) and increased weight (5.0%). Akathisia was reported as an AE in 3.8% of the overall population, with higher rates in patients initiating AL on study entry than those continuing on AL. EPS-related AEs occurred in 9.4% of patients, and AEs related to metabolic parameters were reported in 4.6% of patients. Weight gain was minimal (0.8 kg), and no clinically relevant changes were observed for metabolic parameters. The overall incidence of ISRs was 3.8%; most were associated with the initial injections in patients receiving their first injection in this study. CONCLUSION: Long-term treatment with AL is generally well tolerated, with a safety profile consistent with that of oral aripiprazole. It is a suitable option for patients with schizophrenia.

Pharmacokinetic Evaluation of a 1-Day Treatment Initiation Option for Starting Long-Acting Aripiprazole Lauroxil for Schizophrenia.

BACKGROUND: Aripiprazole lauroxil (AL), a long-acting injectable antipsychotic for the treatment of schizophrenia, requires 21 days of oral aripiprazole supplementation upon initiation. We report findings from a phase 1 study investigating a nanocrystalline milled dispersion of AL (ALNCD) as a potential 1-day initiation regimen. The 1-day initiation regimen is designed to enable rapid achievement of plasma aripiprazole concentrations that are comparable with the 21-day oral initiation regimen. Here, a 6-month pharmacokinetic study compared 2 different initiation regimens for starting AL. METHODS: Patients were randomized 1:1:1:1 to receive 1 of 4 treatments consisting of the 1-day (single ALNCD injection + one 30-mg dose of oral aripiprazole on day 1 only) or the 21-day (15-mg daily dose of oral aripiprazole for 21 days) initiation regimen, each combined with a starting AL dose of either 441 mg or 882 mg. RESULTS: In total, 133/161 patients completed the study. The pharmacokinetic profile of the 1-day initiation regimen was comparable to the 21-day initiation regimen; both achieved aripiprazole concentrations in the therapeutic range within 4 days and remained in a comparable concentration range during treatment initiation. Common adverse events (≥5.0%) were injection-site pain, headache, increased weight, insomnia, dyspepsia, and anxiety. Nine akathisia events occurred (4 events in 4 patients and 5 events in 2 patients in the 1-day and 21-day initiation regimen groups, respectively). CONCLUSIONS: The 1-day initiation regimen resulted in plasma aripiprazole concentrations consistent with the 21-day initiation regimen. Therefore, a single dose of ALNCD with a single 30-mg oral dose of aripiprazole provides an alternative initiation regimen for starting AL.

Patient preferences concerning the efficacy and side-effect profile of schizophrenia medications: a survey of patients living with schizophrenia.

BACKGROUND: Despite the availability of numerous antipsychotic medications, many patients with schizophrenia continue to experience side effects that contribute to the overall burden of the illness. The present survey of patients with schizophrenia and schizoaffective disorder aimed to assess patient attitudes toward antipsychotic treatment, and understand key factors about willingness to try a new medication. METHODS: A cross-sectional survey was administered to 250 patients with a primary clinical diagnosis of a schizophrenia spectrum disorder across five outpatient clinics in the United States. The survey included self-reported gender, age, weight, and height, and questions about the importance of efficacy and side effects on the decision to take a prescribed antipsychotic medication. RESULTS: Patients rated efficacy and side effects as important attributes of antipsychotic treatment, with 93.6% and 83.6% of patients listing these as "very" or the "most" important factors in taking prescribed medication. A total of 87.6% of respondents identified the ability to think more clearly as an important property of their medication. Patients identified weight gain, physical restlessness, and somnolence as important side effects of current treatments ("very" or "most" important by 61.6%, 60.8%, and 58.8%, respectively). When asked about willingness to change antipsychotic medication, anticipated weight gain had a negative influence on willingness to try the new treatment, with 22.0% declining to try a medication that would lead to weight gain of 2.7-4.5 kg (6-10 lb), 34.0% declining for anticipated weight gain of 5.0-9.1 kg (11-20 lb), and 52.4% declining for anticipated weight gain greater than 9 kg (20 lbs). CONCLUSION: Patients living with schizophrenia spectrum disorders are influenced by many factors when considering whether to take their medication, including efficacy and side effects. It is important for clinicians to assess specific patient concerns to develop a comprehensive treatment plan that maximizes adherence to the prescribed therapy.

Aripiprazole Lauroxil Compared with Paliperidone Palmitate in Patients with Schizophrenia: An Indirect Treatment Comparison.

BACKGROUND: Aripiprazole lauroxil (AL) is a long-acting injectable atypical antipsychotic recently approved for treatment of schizophrenia on the basis of a large-scale trial of two doses of AL versus placebo. There are no direct-comparison studies with paliperidone palmitate (PP; long-acting antipsychotic used most often in acute settings) for the acute psychotic episode. OBJECTIVES: To indirectly compare efficacy and safety of the pivotal AL study with all PP studies meeting indirect comparison criteria. METHODS: Systematic searches of MEDLINE, Embase, Cochrane CENTRAL, PsycINFO, ClinicalTrials.gov, International Clinical Trials Registry Platform, and gray literature were performed to identify randomized controlled trials of PP with similar designs to the AL trial. Bayesian network meta-analysis compared treatments with respect to symptom response and tolerability issues including weight gain, akathisia, parkinsonism, and likelihood of treatment-emergent adverse events. RESULTS: Three appropriate PP studies were identified for indirect comparison. Both doses of AL (441 mg and 882 mg monthly) were used and compared with two efficacious doses of PP (156 mg and 234 mg monthly). All four active-treatment conditions were associated with comparable reductions in acute symptoms (Positive and Negative Syndrome Scale) versus placebo and were of similar magnitude (range of mean difference -8.12 to -12.01, with overlapping 95% credible intervals). Between-group comparisons of active-treatment arms were associated with summary estimates of magnitude near 0. No clinically meaningful differences in selected safety or tolerability parameter incidence were found between active treatments. CONCLUSIONS: These results suggest that both AL and PP are effective for treatment of adults experiencing acute exacerbation of schizophrenia.

Comparison of olanzapine long-acting injection and oral olanzapine: a 2-year, randomized, open-label study in outpatients with schizophrenia.

We compared long-term treatment effectiveness of monthly olanzapine long-acting injection (LAI) with that of oral olanzapine. Outpatients with 2 or more episodes of psychotic worsening in the past 24 months with Positive and Negative Syndrome Scale total score of lower than 70 were randomized to 405 mg/4 weeks of olanzapine LAI (n = 264) or 10 mg/d of oral olanzapine (n = 260) for 2 years of open-label treatment. Dosing thereafter was flexible (150-405 mg/4 weeks of LAI vs 5-20 mg/d of oral). Primary outcome was time to all-cause discontinuation. At baseline, patients were clinically stable (mean Positive and Negative Syndrome Scale total score of 57). Seventeen percent of patients had been psychiatrically hospitalized in the previous 6 months, and 4.6% were rated nonadherent in the month before study entry. The groups did not differ significantly in median time to all-cause discontinuation (645 days for LAI, 678 days for oral; P = 0.61), discontinuation rate (53.8% for LAI, 51.2% for oral; P = 0.60), or relapse rate (20.1% for LAI, 18.5% for oral; P = 0.66). Postbaseline psychiatric hospitalization rate was low for both groups (7.6% for LAI, 9.2% for oral), but mean hospitalization duration was significantly longer for oral patients (1.80 days [20 for those hospitalized] vs 0.43 days [6 for those hospitalized], P = 0.02). There were no clinically significant group differences in adverse events or safety measures. No post-injection delirium/sedation syndrome events occurred. In conclusion, olanzapine LAI and oral olanzapine were similarly effective and well tolerated for up to 2 years of treatment in patients with schizophrenia. Treatment discontinuation for olanzapine LAI was similar to that of oral olanzapine, despite the 3-hour post-injection observation period and other precautionary procedures related to risk of post-injection delirium/sedation syndrome.

Effectiveness of lurasidone in schizophrenia or schizoaffective patients switched from other antipsychotics: a 6-month, open-label, extension study.

OBJECTIVE: To evaluate the long-term safety and tolerability of lurasidone in schizophrenia and schizoaffective disorder patients switched to lurasidone. METHOD: Patients in this multicenter, 6-month open-label, flexible-dose, extension study had completed a core 6-week randomized trial in which clinically stable, but symptomatic, outpatients with schizophrenia or schizoaffective disorder were switched to lurasidone. Patients started the extension study on treatment with the same dose of lurasidone taken at study endpoint of the 6-week core study; following this, lurasidone was flexibly dosed (40-120 mg/day), if clinically indicated, starting on Day 7 of the extension study. The primary safety endpoints were the proportion of patients with treatment emergent adverse events (AEs), serious AEs, or who discontinued due to AEs. Secondary endpoints included metabolic variables and measures of extrapyramidal symptoms and akathisia, as well as the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impressions-Severity (CGI-S), and the Calgary Depression Scale for Schizophrenia (CDSS). The study was conducted from August 2010 to November 2011. RESULTS: Of the 198 patients who completed the 6-week core study, 149 (75.3%) entered the extension study and 148 received study medication. A total of 98 patients (65.8%) completed the 6-month extension study. Lurasidone 40, 80, and 120 mg were the modal daily doses for 19 (12.8%), 65 (43.9%), and 64 (43.2%) of patients, respectively. Overall mean (SD) daily lurasidone dose was 102.0 mg (77.1). The most commonly reported AEs were insomnia (13 patients [8.8%]), nausea (13 patients [8.8%]), akathisia (12 patients [8.1%]), and anxiety (9 patients [6.1%]). A total of 16 patients (10.8%) had at least one AE leading to discontinuation from the study. Consistent with prior studies of lurasidone, there was no signal for clinically relevant adverse changes in body weight, lipids, glucose, insulin, or prolactin. Movement disorder rating scales did not demonstrate meaningful changes. Treatment failure (defined as any occurrence of discontinuation due to insufficient clinical response, exacerbation of underlying disease, or AE) was observed for 19 patients (12.8% of patients entering) and median time to treatment failure was 58 days (95% CI 22-86). The discontinuation rate due to any cause was 50/148 (33.8%), and median time to discontinuation was 62 days (95% CI 30-75). The mean PANSS total score, mean CGI-S score, and mean CDSS score decreased consistently from core study baseline across extension visits, indicating an improvement in overall condition. CONCLUSIONS: In this 6-month, open-label extension study, treatment with lurasidone was generally well-tolerated with sustained improvement in efficacy measures observed in outpatients with schizophrenia or schizoaffective disorder who had switched to lurasidone from a broad range of antipsychotic agents.

Antipsychotic Efficacy of KarXT (Xanomeline-Trospium): Post Hoc Analysis of Positive and Negative Syndrome Scale Categorical Response Rates, Time Course of Response, and Symptom Domains of Response in a Phase 2 Study.

Objective: To evaluate Positive and Negative Syndrome Scale (PANSS) categorical response rates, time course of response, and symptom subdomains of response with the combination oral agent KarXT (xanomeline-trospium) in the treatment of schizophrenia.Methods: Post hoc analysis was conducted for EMERGENT-1 (NCT03697252), a 5-week, inpatient, placebo-controlled, phase 2 study of acute psychosis in patients who met DSM-5 criteria for schizophrenia. The EMERGENT-1 study was conducted between September 2018 and August 2019. Categorical thresholds of response used were PANSS total score reductions of ≥ 20%, ≥ 30%, ≥ 40%, and ≥ 50% between baseline and study end. Number needed to treat (NNT) for each categorical threshold was calculated. The proportion of KarXT- and placebo-treated patients achieving each response threshold at weeks 2, 4, and 5 was assessed. Marder 5-factor analysis of PANSS assessed response with KarXT across symptom domains.Results: A total of 83 patients in the KarXT group and 87 patients in the placebo group were included in the modified intent-to-treat analysis. Response rates with KarXT ranged from 59.0% for a ≥ 20% threshold to 15.7% for a ≥ 50% threshold. All response rates with KarXT were significantly higher than in the placebo arm (P < .05), with NNTs ranging from 3 (≥ 20% improvement) to 11 (≥ 50% improvement). KarXT was associated with a significantly higher response rate relative to placebo as early as 2 weeks for ≥ 20% (P = .0001) and ≥ 30% (P = .0022) thresholds and at 4 weeks for the ≥ 40% (P = .0049) and ≥ 50% (P = .0041) thresholds. Each of the Marder 5 factors showed significant differences favoring KarXT over placebo (P < .05) by 2 weeks and continuing through week 5 (endpoint Cohen d effect sizes, 0.48-0.66).Conclusions: KarXT provided clinically meaningful responder rates on PANSS total score compared with placebo at each response threshold, providing further support of the successful primary and secondary endpoints. Response was demonstrated as early as 2 weeks relative to placebo. KarXT demonstrated improvements vs placebo in all 5 factors (positive symptoms, negative symptoms, disorganized thought, uncontrolled hostility, and anxiety/depression).Trial Registration: ClinicalTrials.gov identifier: NCT03697252.

Safety and tolerability of KarXT (xanomeline-trospium) in a phase 2, randomized, double-blind, placebo-controlled study in patients with schizophrenia.

KarXT combines xanomeline, an M1/M4 preferring muscarinic agonist with no direct D2 receptor antagonism, with the peripherally restricted anticholinergic trospium. In EMERGENT-1 (NCT03697252), a 5-week, randomized, double-blind, placebo-controlled, phase 2 study in inpatients with schizophrenia, KarXT met the primary efficacy endpoint, numerous secondary endpoints, and was generally well tolerated. Here, we conducted additional post hoc analyses of safety and tolerability data of KarXT from EMERGENT-1 with a particular focus on adverse events (AEs) that may be associated with muscarinic receptor agonism (nausea or vomiting) or antagonism (dry mouth or constipation). A total of 179 patients received at least one dose of either KarXT (n = 89) or placebo (n = 90) and were included in the analyses. KarXT was associated with a low overall AE burden. The majority of procholinergic and anticholinergic AEs with KarXT were mild, occurred in the first 1-2 weeks of treatment, and were transient with a median duration ranging from 1 day for vomiting to 13 days for dry mouth. No patients in either treatment group discontinued the study due to any procholinergic or anticholinergic AEs. Incidence of somnolence/sedation AEs with KarXT were low and similar to those in the placebo group. KarXT was associated with no significant or clinically relevant changes in body weight, metabolic parameters, or vital signs. KarXT was generally well tolerated with an AE profile consistent with the activity of xanomeline-trospium at muscarinic receptors.

Muscarinic acetylcholine receptors for psychotic disorders: bench-side to clinic.

Modern interest in muscarinic acetylcholine receptor (mAChR) activators for schizophrenia began in the 1990s when xanomeline, an M1/M4-preferring mAChR agonist developed for cognitive symptoms of Alzheimer's disease (AD), had unexpected antipsychotic activity. However, strategies to address tolerability concerns associated with activation of peripheral mAChRs were not available at that time. The discovery of specific targeted ligands and combination treatments to reduce peripheral mAChR engagement have advanced the potential of mAChR activators as effective treatments for psychotic disorders. This review provides perspectives on the background of the identification of mAChRs as potential antipsychotics, advances in the preclinical understanding of mAChRs as targets, and the current state of mAChR activators under active clinical development for schizophrenia.

Systematic Review of Real-World Treatment Patterns of Oral Antipsychotics and Associated Economic Burden in Patients with Schizophrenia in the United States.

BACKGROUND: Schizophrenia is a chronic mental disorder associated with substantial morbidity and mortality affecting 0.25-1.6% of adults in the USA. Antipsychotic treatment is the standard of care for schizophrenia, but real-world treatment patterns and associated costs have not been systematically reviewed. OBJECTIVE: We conducted a systematic review to summarize treatment patterns and associated costs related to oral antipsychotic treatment of patients with schizophrenia in the USA. DATA SOURCES: We searched Medline (via PubMed) and Embase to identify relevant observational studies published from January 1, 2008, to June 1, 2018; costs were converted to 2018 US dollars. STUDY ELIGIBILITY: Observational, real-world studies reporting on patterns of treatment and/or associated costs for adult patients with schizophrenia treated with oral antipsychotics in the USA were included. RESULTS: Eighty-one studies were identified. Frequently prescribed oral second-generation antipsychotics were olanzapine (up to 50.9%), risperidone (up to 40.0%), and quetiapine (up to 30.7%). Suboptimal adherence was common across studies. Antipsychotic switching occurred in about half of patients, while antipsychotic combination therapy occurred in nearly 30%; all were associated with increased medication-related costs. Mean annual direct medical costs differed by treatment, with reported costs of $17,115 to $26,138 for patients treated with olanzapine, $18,395 for risperidone, and $17,656 to $28,101 for quetiapine. LIMITATIONS: This systematic review is limited by the variations in definitions of schizophrenia-related clinical terms used between studies and by the inclusion of studies focused on only the US health care system. CONCLUSIONS: In the treatment of schizophrenia, suboptimal adherence, antipsychotic switching, and antipsychotic augmentation were all associated with high costs of care in comparison to patients who were adherent and did not require antipsychotic switching or augmentation. These findings illustrate the need for the development of new treatments that address efficacy and adherence challenges of currently available therapies.

Schizophrenia is a debilitating mental disorder that affects up to 1.6% of adults in the USA. Antipsychotic medications reduce symptoms of the disease, but many patients with schizophrenia are not fully adherent or choose to discontinue treatment entirely, increasing their risk of hospitalization. In others, efforts to achieve better symptom control or to avoid intolerable side effects may result in switching antipsychotic medications or adding additional medications, leading to higher medical treatment costs. The magnitude of these cost increases is unclear. This study sought to assess medical costs associated with antipsychotic treatment adherence, switching, and adding additional antipsychotics. We reviewed 81 studies published from January 2008 through June 2018 examining treatment adherence in patients with schizophrenia. We calculated rates of adherence, switching, and adding antipsychotics, as well as associated medical costs. Overall adherence to antipsychotic treatment was less than 50%, with up to 50% of patients switching medications and up to 29% adding an additional antipsychotic medication to their current treatment. Patients who were not treatment adherent incurred annual medical costs of $10,316 compared with $5723 in patients who were adherent. The costs of immediate or delayed switching of antipsychotic medications ranged from $21,922 to $28,232, while costs of adding an additional antipsychotic ranged from $24,045 to $29,344. These data suggest that suboptimal medication adherence, along with high rates of patient discontinuation and medication switching, lead to higher treatment costs in the management of patients with schizophrenia.

Real-World Outcomes and Costs Following 6 Months of Treatment with the Long-Acting Injectable (LAI) Aripiprazole Lauroxil for the Treatment of Schizophrenia.

BACKGROUND: Continuous antipsychotic therapy is recommended as part of long-term maintenance treatment of schizophrenia, and gaps in antipsychotic treatment have been associated with increased risks of relapse and rehospitalization. Because the use of long-acting injectable (LAI) antipsychotics may reduce the likelihood of undetected medication gaps, initiating an LAI medication may affect resource utilization and costs. The LAI aripiprazole lauroxil (AL) was approved in the United States (US) in 2015 for the treatment of schizophrenia in adults. OBJECTIVE: The objective of this retrospective observational cohort study was to examine treatment patterns, resource utilization, and costs following initiation of AL for the treatment of schizophrenia in adults. METHODS: A retrospective analysis of Medicaid claims data identified a cohort of patients (N = 485) starting AL shortly after Food and Drug Administration approval in October 2015. Treatment patterns, resource utilization, and costs were compared 6 months before and after treatment initiation. Subgroup analyses were conducted based on the type of antipsychotic (LAI, oral, or none) received before initiation of AL. RESULTS: Over 6 months of follow-up, patients received an average of 4.6 injections out of a maximum of six (77%). After initiating AL, all-cause inpatient admissions decreased by 22.4%; other significant reductions were observed in mental health-related admissions and emergency room (ER) visits. All-cause inpatient costs decreased by an average of US$2836 per patient (p < 0.05) in the 6-month post-AL period, whereas outpatient pharmacy costs increased by US$4121 (p < 0.05), resulting in no significant difference in overall costs between the pre- and post-AL periods. The subgroup of patients who had been prescribed an oral antipsychotic before starting AL had significant reductions in proportion of patients with inpatient and ER visits and costs, but also reported a significant increase in pharmacy costs. CONCLUSIONS: AL was associated with a significant reduction in inpatient costs and an increase in outpatient pharmacy costs, resulting in no changes in total healthcare costs over 6 months. The adherence rate and reductions in inpatient use may indicate the potential for greater clinical stability among patients initiated on AL compared with their previous treatment.

A post hoc analysis of negative symptoms and psychosocial function in patients with schizophrenia: a 40-week randomized, double-blind study of ziprasidone versus haloperidol followed by a 3-year double-blind extension trial.

Schizophrenia is a persistent, lifelong illness such that enduring functional improvements may only occur over the course of years [corrected].This post hoc analysis in stable outpatients with schizophrenia investigated the negative symptom efficacy and treatment outcomes of ziprasidone (80-160 mg/d given twice a day, mean modal dose of 112 mg/d; and 80-120 mg/d given every day, mean modal dose of 96 mg/d) versus haloperidol (5-20 mg/d, mean modal dose of 12 mg/d) in a randomized, 40-week, double-blind study, followed by a double-blind continuation trial that extended up to 156 additional weeks. Symptomatic and functional recovery criteria were met when subjects attained both negative symptom remission and adequate psychosocial functioning based on the 4 Quality-of-Life subscales (instrumental role, interpersonal relations, participation in community, and intrapsychic foundations). Negative symptom remission (P = 0.005), as well as sustained adequate functioning (6 months) in instrumental role (P = 0.04) and participation in community (P = 0.02), was associated with significantly shorter time to remission in the ziprasidone 80 to 160 mg group than in the haloperidol group, as was the combination of symptomatic and functional recovery during the 196-week double-blind study period. A similar pattern was observed for the ziprasidone 80 to 120 mg group, which showed significant differences versus haloperidol in negative symptom remission and instrumental role functioning (but not other Quality-of-Life subscale measures). The clinically relevant outcome differences detected in this post hoc exploratory analysis support the potential for both enhanced remission in negative symptoms and psychosocial recovery during long-term treatment with an atypical agent and add to our understanding regarding the degree to which negative symptom remission can be attained in the maintenance phase.

Beyond 52-Week Long-Term Safety: Long-Term Outcomes of Aripiprazole Lauroxil for Patients With Schizophrenia Continuing in an Extension Study.

OBJECTIVE: To describe the long-term safety, tolerability, and symptom trajectory with the long-acting injectable antipsychotic aripiprazole lauroxil (AL) in patients with DSM-5-diagnosed schizophrenia followed for up to 180 weeks (3.5 years). METHODS: Long-term safety of 2 fixed doses of AL (441 or 882 mg every 4 weeks) was assessed during up to 180 weeks (3.5 years) of continuous AL exposure using data from 2 sequential long-term safety studies. Safety metrics included adverse events (AEs), AEs leading to study discontinuations, physical examinations, laboratory parameters, and extrapyramidal symptom (EPS) rating scales. Symptom trajectory was assessed in post hoc analyses using Positive and Negative Syndrome Scale total (PANSST) and Clinical Global Impressions-Severity of Illness scale (CGI-S) scores. RESULTS: A total of 478 patients entered the 52-week study and were included in the safety analysis. After the first 52 weeks, safety assessments revealed no new safety concerns and were consistent with the known safety profile of aripiprazole. AEs were reported by 57.5% of patients (441 mg, 52.7%; 882 mg, 59.0%). EPS-related AEs occurred in 12.8% of patients (441 mg, 9.1%; 882 mg, 13.9%). In the post hoc analysis (n = 432), least-squares mean (SE) PANSST scores improved significantly from weeks 12 to 124 with AL 441 mg (-5.5 [0.9]) and 882 mg (-5.0 [0.5]; both P < .0001). CGI-S scores followed a similar pattern of improvement. CONCLUSIONS: The AL safety profile over 180 weeks (3.5 years) of follow-up was consistent with prior 52-week results. Continued therapeutic efficacy, based on PANSST and CGI-S scores, was observed throughout the post hoc analysis period. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01626456; ClinicalTrials.gov identifier: NCT01895452.