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.

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.

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.

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.

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.

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].

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.

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]).

Antipsychotic Treatment Experiences of People with Schizophrenia: Patient Perspectives from an Online Survey.

BACKGROUND: This survey examined the experiences of people living with schizophrenia who have used oral antipsychotics (APs). METHODS: Adults with self-reported physician-diagnosed schizophrenia (N=200), who were members of an online research participation panel and reported taking one or more oral APs within the last year, completed a cross-sectional online survey that focused on direct report of their experiences regarding APs (eg, symptoms, side effects, adherence). Descriptive analyses were conducted for the total survey sample and for subgroups defined a priori by experience with specific, prevalent side effects. RESULTS: The mean age of the sample was 41.9 (SD=11.0) years, 50% of participants were female, and 32% were nonwhite. Overall ratings were positive for medication effectiveness and convenience but negative for side effects. While most participants reported that APs improved schizophrenia symptoms (92%), 27% reported APs as having done "more harm than good." Almost all participants (98%) reported experiencing side effects of APs, with the most common being anxiety (88%), feeling drowsy/tired (86%), and trouble concentrating (85%). Side effects frequently cited as either "extremely" or "very" bothersome were weight gain (56%), sexual dysfunction (55%), and trouble concentrating (54%). Over 80% reported that side effects had negatively impacted their work and social functioning (eg, social activities or family/romantic relationships). Since initiating treatment, 56% of respondents had stopped taking APs at some point (65% of these due to side effects). Side effects commonly reported as having led to stopping AP treatment were "feeling like a 'zombie'" (22%), feeling drowsy/tired (21%), and weight gain (20%). CONCLUSION: Most participants reported improvements in schizophrenia symptoms associated with the use of APs. However, most participants also reported experiencing numerous bothersome side effects that negatively impacted their work, social functioning, and treatment adherence. Results highlight the unmet need for new APs with favorable benefit-risk profiles.

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.

Pharmacokinetics, Safety, and Tolerability of a 2-Month Dose Interval Regimen of the Long-Acting Injectable Antipsychotic Aripiprazole Lauroxil: Results From a 44-Week Phase I Study.

BACKGROUND: Aripiprazole lauroxil (AL) is a long-acting injectable antipsychotic approved for treatment of schizophrenia in adults. Approved AL doses and dosing regimens include 441 mg monthly, 662 mg monthly, and 882 mg monthly or every 6 weeks (q6wk), as well as the most recently approved dose, 1064 mg, administered every 2 months. OBJECTIVE: Pharmacokinetics, safety, and tolerability of an AL regimen with a dose interval of every 2 months (1064 mg) were compared with two other regimens available as monthly and q6wk options. METHODS: This study evaluated pharmacokinetics of AL given at a higher dosage strength (1064 mg) and at a longer dose interval (every 8 weeks [q8wk]) than previously studied. Patients with schizophrenia or schizoaffective disorder entering this 44-week, phase I, open-label, multicenter study had no recent exposure to aripiprazole and were maintained on other oral antipsychotics throughout the study. Patients were randomized to one of three AL dose regimens for 24 weeks (four 1064-mg injections [q8wk], five 882-mg injections [q6wk], or seven 441-mg injections [q4wk], with the last AL exposure at week 24). Oral aripiprazole was prohibited. Patients were followed for an additional 20 weeks to assess terminal aripiprazole plasma concentrations and ongoing safety. Plasma concentration samples were obtained at regular intervals to provide pharmacokinetic data for the duration of AL exposure and to measure persistence of plasma aripiprazole concentrations after AL discontinuation. RESULTS: Eligible patients received AL 1064 mg q8wk (n = 35), 882 mg q6wk (n = 34), or 441 mg q4wk (n = 35). Overall, 103/104 (99.0%) patients were taking concomitant non-aripiprazole oral antipsychotic medications during the study. All three AL dose regimens provided continuous exposure to aripiprazole. Mean aripiprazole concentrations from the 1064-mg q8wk regimen were comparable to the 882-mg q6wk regimen and higher than the 441-mg q4wk regimen. Overall incidence by group of any adverse events (AEs) throughout the study was 68.6% (1064 mg q8wk), 50.0% (882 mg q6wk), and 65.7% (441 mg q4wk). The most common AE across regimens was injection-site pain (range 8.6%-11.4%). Serious AEs were reported by eight patients (all but one [increased psychosis in one patient, 441-mg q4wk group] considered unrelated to study drug). Discontinuations due to AEs were reported for 2.9%, 11.8%, and 5.7% of patients receiving the 8-, 6-, and 4-week regimens, respectively. AEs of akathisia, dyskinesia, and dystonia occurred in 2.9%, 8.6%, and 5.7% of patients in the 1064-mg q8wk group, 8.8%, 0%, and 2.9% in the 882-mg q6wk group, and 8.6%, 0%, and 0% in the 441-mg q4wk group, respectively. CONCLUSIONS: AL 1064 mg q8wk provided continuous exposure to aripiprazole throughout the 8-week dosing interval and had a safety profile consistent with the 4- and 6-week regimens. These findings were used to support FDA approval of the 1064-mg dose administered every 2 months. REGISTRATION: Clinicaltrials.gov: NCT02320032.

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.

Efficacy and Safety of a 2-Month Formulation of Aripiprazole Lauroxil With 1-Day Initiation in Patients Hospitalized for Acute Schizophrenia Transitioned to Outpatient Care: Phase 3, Randomized, Double-Blind, Active-Control ALPINE Study.

OBJECTIVE: Evaluate efficacy and safety of a 2-month formulation of aripiprazole lauroxil (AL) with 1-day initiation during hospitalization for acute exacerbation of schizophrenia followed by transition to outpatient care. METHODS: The phase 3b double-blind Aripiprazole Lauroxil and Paliperidone palmitate: INitiation Effectiveness (ALPINE) study was conducted from November 2017 to March 2019. Adults with acute schizophrenia according to DSM-5 criteria were randomized (1:1) to AL (AL NanoCrystal Dispersion + oral aripiprazole 30 mg, day 1; AL 1,064 mg, day 8 and every 8 weeks [q8wk]) or paliperidone palmitate (PP 234 mg, day 1; PP 156 mg, day 8 and then q4wk) for 25 weeks. Patients remained hospitalized ≥ 2 weeks after randomization per protocol. Primary endpoint was within-group change in Positive and Negative Syndrome Scale total score (PANSST) from baseline to week 4. Secondary analyses included within- and between-group changes from baseline at various time points. Adverse events (AEs) and laboratory data were monitored. RESULTS: A total of 200 patients were randomized (AL, n = 99; PP, n = 101); 56.6% and 42.6%, respectively, completed the study. For AL, the mean baseline PANSST was 94.1; scores were significantly reduced from baseline at week 4 (-17.4; P < .001) and were also reduced at weeks 9 (-19.8) and 25 (-23.3). With PP, PANSST also improved significantly from baseline (94.6) at week 4 (-20.1; P < .001) and also improved at weeks 9 (-22.5) and 25 (-21.7). The 3 most common AEs over 25 weeks in the AL group were injection site pain (17.2%), increased weight (9.1%), and akathisia (9.1%). The same AEs were the most common in the PP group (injection site pain [24.8%], increased weight [16.8%], and akathisia [10.9%]). CONCLUSIONS: AL and PP were efficacious and well-tolerated for initiating treatment of schizophrenia in the hospital and continuing outpatient treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03345979.

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.

Assessing effectiveness of aripiprazole lauroxil vs placebo for the treatment of schizophrenia using number needed to treat and number needed to harm.

OBJECTIVE: Schizophrenia clinical trials commonly measure observed changes in Positive and Negative Syndrome Scale (PANSS) total score. However, it is more intuitive to think of response vs nonresponse, a binary outcome. Assessing binary outcomes enables calculation of number needed to treat (NNT) for therapeutic outcomes, number needed to harm (NNH) for adverse outcomes, and likelihood to be helped or harmed (LHH) to demonstrate benefit/risk tradeoffs. Here, NNT, NNH, and LHH were used to evaluate the clinical usefulness of aripiprazole lauroxil in patients with an acute schizophrenia exacerbation. METHODS: Categorical efficacy and tolerability data were taken from the pivotal Phase 3 trial evaluating aripiprazole lauroxil for treatment of an acute exacerbation of schizophrenia. NNT and NNH values, with 95% CIs, were calculated in this post hoc analysis. RESULTS: Using the intent-to-treat population for the pooled doses of aripiprazole lauroxil (441 mg [n=196] and 882 mg [n=204] q4w), responder rates (≥30% improvement from baseline PANSS total score) were 35.3% for aripiprazole lauroxil arms vs 18.4% for placebo (n=196), yielding a NNT of 6 (95% CI: 5-11). Discontinuation rates due to adverse events (AEs) were higher among patients randomized to placebo than to either aripiprazole lauroxil dose. Akathisia was the only AE with an incidence ≥5% in each aripiprazole lauroxil group and at least twice that of placebo (11.6%, 11.5%, and 4.3% of the patients receiving aripiprazole lauroxil 441 mg, 882 mg, and placebo, respectively), producing a NNH of 14 (95% CI: 9-33) for pooled aripiprazole lauroxil doses vs placebo. Calculating LHH for therapeutic response vs akathisia, aripiprazole lauroxil was 2.3 times more likely to result in a therapeutic response than an incident of akathisia. CONCLUSION: Using metrics of NNT, NNH, and LHH, aripiprazole lauroxil was an efficacious and well-tolerated intervention in a pivotal study in patients with an acute schizophrenia exacerbation.

A commentary on the efficacy of olanzapine for the treatment of schizophrenia: the past, present, and future.

Olanzapine is a second-generation atypical antipsychotic with proven efficacy for the treatment of schizophrenia. Approved in 1996, olanzapine is one of the most studied antipsychotics, resulting in a considerable amount of clinical data across diverse patient populations. Despite the fact that olanzapine is associated with a known risk of metabolic side effects, including weight gain, many clinicians continue to prescribe olanzapine for the treatment of schizophrenia with the expectation of additional therapeutic antipsychotic efficacy relative to other first-line atypical antipsychotics. The goal of this narrative is to revisit the role of oral olanzapine in the management of patients with schizophrenia, including those with recently diagnosed schizophrenia ("first-episode"), those with an established schizophrenia diagnosis who experience acute exacerbations, those receiving long-term antipsychotic treatment as a maintenance intervention, and those with suboptimal response to antipsychotic treatment, including treatment resistance. Collectively, data from published literature support the favorable efficacy of olanzapine compared with other first- and second-generation antipsychotics, including lower rates of treatment discontinuation and clinically meaningful improvements in the symptoms of schizophrenia. The development of antipsychotic medications with the favorable efficacy of olanzapine, but with reduced weight gain, could address a major unmet need in the treatment of schizophrenia.

Best Practices for Aripiprazole Lauroxil Administration: From Formulation Development to Injection Technique.

Long-acting injectable (LAI) antipsychotics are an important treatment option for patients with schizophrenia. Advances and variability in formulation technology have provided several LAI antipsychotic treatment options for schizophrenia, with a wide range of doses and dose intervals. However, clinical reviews of LAIs have not focused on formulation development despite its clinical relevance to injection safety and technique. This article reviews the relationship between formulation technology and clinical practices for LAIs, with a focus on aripiprazole lauroxil, a long-acting atypical antipsychotic indicated for the treatment of schizophrenia. The formulation developed for aripiprazole lauroxil is an aqueous-based suspension suitable for use as a prefilled syringe that, after injection, will release aripiprazole slowly into the plasma. The clinical relationship between the aripiprazole lauroxil formulation and proper injection techniques is explained, including why tapping and shaking the syringe to resuspend the drug particles and rapid injection speed are key steps for best injection practices for this formulation.

Mitigation of Olanzapine-Induced Weight Gain With Samidorphan, an Opioid Antagonist: A Randomized Double-Blind Phase 2 Study in Patients With Schizophrenia.

OBJECTIVE: Preclinical evidence and data from a proof-of-concept study in healthy volunteers suggest that samidorphan, an opioid antagonist, mitigates weight gain associated with olanzapine. This study prospectively compared combination therapy of olanzapine plus either samidorphan or placebo for the treatment of schizophrenia. METHODS: This was an international, multicenter, randomized phase 2 study of olanzapine plus samidorphan in patients with schizophrenia. The study had a 1-week open-label olanzapine lead-in period followed by a 12-week double-blind treatment phase in which patients were randomly assigned in a 1:1:1:1 ratio to receive olanzapine plus placebo (N=75) or olanzapine plus 5 mg (N=80), 10 mg (N=86), or 20 mg (N=68) of samidorphan. The primary aims were to confirm that the antipsychotic efficacy of olanzapine plus samidorphan was comparable to olanzapine plus placebo, to assess the effect of combining olanzapine with samidorphan on olanzapine-induced weight gain, and to assess the overall safety and tolerability of olanzapine plus samidorphan. RESULTS: Antipsychotic efficacy, as assessed by total score on the Positive and Negative Syndrome Scale (PANSS), was equivalent across all treatment groups. Treatment with olanzapine plus samidorphan resulted in a statistically significant lower weight gain (37% lower weight gain compared with olanzapine plus placebo). The least square mean percent change from baseline in body weight was 4.1% (2.9 kg) for the olanzapine plus placebo group and 2.6% (1.9 kg) for the olanzapine plus samidorphan group (2.8% [2.1 kg] for the 5 mg group, 2.1% [1.5 kg] for the 10 mg group, and 2.9% [2.2 kg] for the 20 mg group). Adverse events reported at a frequency ≥5% in any of the olanzapine plus samidorphan groups and occurring at a rate ≥2 times greater than in the olanzapine plus placebo group were somnolence, sedation, dizziness, and constipation. Other safety measures were comparable between the olanzapine plus samidorphan groups and the olanzapine plus placebo group. CONCLUSIONS: The antipsychotic efficacy of olanzapine plus samidorphan was equivalent to that of olanzapine plus placebo, and olanzapine plus samidorphan was associated with clinically meaningful and statistically significant mitigation of weight gain compared with olanzapine plus placebo. Olanzapine plus samidorphan was generally well tolerated, with a safety profile similar to olanzapine plus placebo.

Switching patients with schizophrenia from paliperidone palmitate to aripiprazole lauroxil: A 6-month, prospective, open-label study.

We assessed the effectiveness of switching from paliperidone palmitate (PP) or risperidone long-acting injection (RLAI) to aripiprazole lauroxil (AL). Prospective, 6-month study in patients with schizophrenia with residual symptoms or intolerance with PP/RLAI. Effectiveness assessed via all-cause and medication-related discontinuation; CGI-S/BPRS and adverse event monitoring assessed efficacy/tolerability, respectively. Fifty-one patients (n = 50 PP; n = 1 RLAI) enrolled; 35 completed the study. All-cause and medication-related discontinuation was 30% and 9% over 6 months, respectively. CGI-S/BPRS improved significantly in those continuing treatment. Adverse events were generally mild to moderate. Patients with efficacy or tolerability concerns with PP/RLAI can be switched to AL.