Search

Background: Brexpiprazole is a dopamine/serotonin receptor partial agonist (D2, 5-HT1A) and antagonist (5-HT2A) approved for treatment of schizophrenia and major depressive disorder (adjunct to antidepressants). Aims: This study aimed to investigate brexpiprazole as monotherapy in acute mania (bipolar I disorder) in two short-term (ST) studies (study 080 and study 081) and one open-label (OL) extension (study 083). Methods: ST studies were three-week randomized, double-blind, flexible dose (2–4 mg/day), placebo-controlled studies. The primary endpoint was mean change in Young Mania Rating Scale (YMRS) total score from baseline to day 21. The OL study was a 26-week flexible dose (2–4 mg/day) study for patients completing the ST studies. Results: A total of 164 and 158 (study 080) and 170 and 162 (study 081) inpatients with DSM-5 mania with/without mixed features were randomized to placebo or brexpiprazole, respectively. The primary analyses did not show a statistically significant difference between brexpiprazole and placebo: study 080: least squares mean difference (95% confidence limits): 0.14 (−1.74, 2.03), p = 0.8797; study 081: −1.62 (−3.56, 0.32), p = 0.1011. OL study patients ( n = 381) demonstrated a gradual improvement in YMRS total score. Akathisia was the only adverse event, with an incidence of ⩾5% with brexpiprazole and more than placebo in the ST studies, or ⩾5% in the OL study. Brexpiprazole was more efficacious in patients with impaired or no insight (predominantly EU patients) than in patients with excellent insight (predominantly US patients). Conclusions: Further studies are necessary to address the potential efficacy of brexpiprazole in acute mania, which should ensure that the study sample is severe enough (especially with regard to insight), and that the dose/titration schedule is not too modest.

The Distance Library Services Conference was founded in 1982 by the librarians of the Off-Campus Library Services department at Central Michigan University. From its inception through its 18th conf...

Jeffrey M Cochran,1 Hui Fang,2 Christophe Le Gallo,3 Timothy Peters-Strickland,4 Jean-Pierre Lindenmayer,5 J Corey Reuteman-Fowler6 1Medical & Real World Data Analytics, Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, USA; 2Biostatistics, Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, USA; 3Clinical Programming, Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, USA; 4PPD, Inc., Wilmington, NC, USA; 5Department of Psychiatry, New York University Grossman School of Medicine, New York, NY, USA; 6Global Clinical Development, Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, USACorrespondence: Jeffrey M Cochran, Medical & Real World Data Analytics, Otsuka Pharmaceutical Development & Commercialization, Inc., 508 Carnegie Center, Princeton, NJ, 08540, USA, Tel +1 609 535 9035, Email Jeffrey.Cochran@otsuka-us.comPurpose: A recent, phase 3b, mirror-image clinical trial of outpatients with schizophrenia found that use of aripiprazole tablets with sensor (AS; Abilify MyCite®, comprising an ingestible event-marker sensor embedded in aripiprazole tablets, wearable sensor patches, and a smartphone application) reduced the incidence of psychiatric hospitalizations relative to oral standard-of-care antipsychotics. This analysis explored the relationship between AS engagement by participants and changes in participant performance and symptom-severity measures assessed by clinical raters.Participants and Methods: This post hoc analysis used prospectively collected clinical data from a phase 3b clinical trial (NCT03892889). Outpatients had schizophrenia, were aged 18– 65 years, and had ≥ 1 psychiatric hospitalization in the previous 48 months. Participants were grouped by study completion status and a k-means clustering algorithm based on AS utilization, resulting in 3 groups: discontinued (discontinued AS before month 3 of the study); moderate engagement (completed 3 months, used AS intermittently); and high engagement (completed 3 months, used AS regularly). Baseline to end-of-study differences for the Clinical Global Impression Scale (Severity of Illness and Improvement of Illness scales), Personal and Social Performance Scale, and Positive and Negative Syndrome Scale were calculated.Results: A total of 277 outpatients were enrolled (discontinued, n = 164; moderate engagement, n = 63; high engagement, n = 50). All groups experienced symptom improvement from baseline to end-of-study, with significant changes in the more-engaged groups. Highly engaged participants showed significant improvement for all clinical scores and subscores (all P < 0.05) and demonstrated significantly more improvement in symptoms than participants with less engagement.Conclusion: Participants who completed 3 months of the study and had higher AS engagement experienced significantly greater improvement in their end-of-study clinical assessments versus participants who did not complete 3 months. Improvement may be related to more-consistent medication intake and better engagement with a digital health system.Keywords: digital medicine, medication ingestion, treatment utilization, Positive and Negative Syndrome Scale

SUMMARYDysregulated STAT3 signalling is correlated with antibody-mediated autoimmunity and B- cell neoplasia, but its effect on B cells is underexplored. Here we address this in children with STAT3 gain-of-function (GOF) syndrome and in mice with STAT3T716M, the most common STAT3 GOF syndrome human mutation, or STAT3K658N, a dimerization interface mutation responsible for STAT3 GOF syndrome in two children. The main B cell consequence of overactive STAT3 was accumulation of CD19highCD21lowatypical memory B cells in humans and of CD21lowCD23lowB cells in mice resembling age-associated B cells expressing T-bet, CD11c and plasma cell differentiation genes. Overactive STAT3 within B cells increased expression of many genes in the B cell receptor and T cell help pathways, increased the tolerogenic receptor CD22, but opposed B cell tolerance checkpoints and increased formation of T-bet+ B cells upon BCR and CD40 stimulation. These results reveal overactive STAT3 as a central driver of a key class of disease- associated B-lymphocytes in humans and mice.

Objective To evaluate the effect of aripiprazole once-monthly 400 mg (AOM 400; Abilify Maintena®) on personal and social functioning in patients with schizophrenia in both the acute treatment and maintenance therapy settings. Methods Post hoc analyses were conducted on data from Study 291 (NCT01663532), a 12-week, randomized, double-blind, placebo-controlled trial conducted in patients who were experiencing an acute psychotic episode, and Study 248 (NCT00731549), a 52-week open-label extension of two randomized, controlled trials of AOM 400 as maintenance therapy. Assessment of functioning was made using the Personal and Social Performance (PSP) scale. In Study 291, results were stratified by age (≤35 years or >35 years). Results In Study 291, 340 patients were included in the analysis (n=168 randomized to AOM 400 [n=49 aged ≤35 years, n=119 aged >35 years]; n=172 randomized to placebo [n=54 aged ≤35 years, n=118 aged >35 years]). In Study 248, 1,081 patients entered the open-label maintenance phase and 858 completed the study. In Study 291, AOM 400, compared with placebo, resulted in a significant increase (improvement) in PSP scores based on LSM (SE) changes from baseline to Week 12 in patients aged ≤35 years (20.6 [1.9] for AOM 400 vs 9.5 [2.4] for placebo; P=0.001) and a numerically (but not significantly) larger increase in PSP scores in patients aged >35 years (16.1 [1.7] for AOM 400 vs 12.5 [1.9] for placebo; P=0.093). Improvements in both age groups met criteria for a minimally important clinical difference (7-10 points). In Study 248, AOM 400 resulted in either numerical improvements (increases) from baseline in PSP total score or maintenance of stable baseline values throughout the study. Conclusion AOM 400 was effective in improving personal and social functioning during acute treatment and maintaining function during long-term treatment.

J Corey Fowler,1 Nathan Cope,2 Jonathan Knights,3 Hui Fang,4 Taisa Skubiak,5 Sukhi S Shergill,6 Peter Phiri,7 Shanaya Rathod,7 Timothy Peters-Strickland1 1Global Clinical Development, CNS and Digital Medicine, Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, 08540, USA; 2Program Management, Otsuka Pharmaceutical Europe Ltd., Wexham, SL3 6PJ, UK; 3Data Insights and Analytics, Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, 08540, USA; 4Biostatistics, Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, 08540, USA; 5Clinical Management, Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, 08540, USA; 6Institute of Psychiatry, Psychology and Neuroscience, King’s College London and South London and Maudsley NHS Foundation Trust, London, SE5 8AF, UK; 7Southern Health NHS Foundation Trust, Moorgreen Hospital, Clinical Trials Facility, Research Department, Southampton, SO30 3JB, UKCorrespondence: J Corey FowlerOtsuka Pharmaceutical Development & Commercialization, Inc., 508 Carnegie Center, Princeton, NJ, 08540, USATel +1 919 475 4823Email corey.fowler@otsuka-us.comPurpose: Symptoms of psychotic disorders can complicate efforts to accurately evaluate patients’ medication ingestion. The digital medicine system (DMS), composed of antipsychotic medication co-encapsulated with an ingestible sensor, wearable sensor patches, and a smartphone application, was developed to objectively measure medication ingestion. We assessed performance and acceptance of the DMS in subjects with psychotic disorders.Methods: This was an 8-week open-label, single-arm, multicenter, Phase 4 pragmatic study (NCT 03568500; EudraCT #2017-004602-17). Eligible adults were diagnosed with schizophrenia, schizoaffective disorder, or first-episode psychosis; were receiving aripiprazole, quetiapine, olanzapine, or risperidone; and could use the DMS with the application downloaded on a personal smartphone. The primary endpoint was good patch coverage, defined as the proportion of days over the assessment period where ≥ 80.0% of patch data was available, or an ingestion was detected. Exploratory endpoints included a survey on user satisfaction, used to assess acceptance of the DMS. Safety analyses included the incidence of treatment-emergent adverse events (TEAEs).Results: From May 25, 2018 to March 22, 2019, 55 subjects were screened and 44 were enrolled. Good patch coverage was achieved on 63.4% of days assessed and the DMS generated an adherence metric of ≥ 80.0%, reflecting the percentage of ingestion events expected when good patch coverage was reported. Most subjects (53.5%) were satisfied with the DMS. Medical device skin irritations were the only TEAEs reported.Conclusion: The DMS had sufficient performance in, and acceptance from, subjects with psychotic disorders and was generally well tolerated.Keywords: digital medicine, antipsychotic, digital health, medication adherence

Blockade of the immune checkpoint protein Programmed Cell Death Protein-1 or its ligand (PD-1 and PD-L1, respectively) allows durable cancer control in a proportion of patients with non-small cell lung cancer (NSCLC). However, a substantial proportion of patients have suboptimal outcomes and variability in response remains incompletely understood. Immune-related adverse events (irAEs) correlate with survival for single agent anti-PD1/PD-L1 therapy in NSCLC, suggesting benefits of systemic immune activation. Similarly, combined pharmacological blockade of a second checkpoint, such as Cytotoxic T-lymphocyte Antigen-4 (CTLA-4), with PD-1 gives heightened immune activation, resulting in both improved cancer outcomes and more irAEs. Inherited heterozygosity for single nucleotide polymorphisms (SNPs) within and surrounding CTLA-4 is associated with autoimmune disease, including autoimmune thyroid disease, rheumatoid arthritis (RA) and Type 1 diabetes (T1D). Many of these autoimmune diseases are clinically and pathologically indistinguishable from anti-CTLA4-induced irAEs, suggesting equivalence of pharmacological and genetic blockade of the gene. We hypothesised that SNPs impacting CTLA-4 function would be enriched in a cohort of NSCLC patients exhibiting exceptional response to single-agent anti-PD1. For the purposes of this analysis, exceptional response was defined as progression free survival of at least 2 years and one or more irAE of CTCAE grade 2 or higher. We performed whole genome sequencing (Illumina HiSeq X Ten) on germline DNA from 35 prospectively recruited patients meeting these criteria from a treatment pool of over 700 patients. In these individuals, frequency of a curated list of SNPs located within a 200 kilobase region encompassing CTLA-4 was analysed and compared to patients with lung cancer within the Pan-Cancer Analysis of Whole Genomes (PCAWG) and to cancer- and dementia-free elderly individuals in the Medical Genome Reference Bank (MGRB). Using linear regression analysis, we identified several non-coding SNPs enriched within the exceptional responders compared with control populations. One SNP was present in 15.7% of exceptional responders; twice the frequency of comparable cases within PCAWG and almost four times more than MGRB, remaining statistically significant following rigorous adjustment. This non-coding SNP is reported to exhibit differential enhancer activity and has been associated with RA and T1D. Its enrichment within the exceptional responders suggests that the altered CTLA-4 function may cooperate with blockade of PD-1 to confer higher immune response. This common variant may provide a biomarker for single agent anti-PD1 treatment or a potential therapeutic target. Pre-clinical analyses and validation within an independent cohort are underway. Citation Format: India A. Allen, Amanda Russell, Katherine J. Jackson, Timothy Peters, Greg Gibson, Anthony M. Joshua, Christopher C. Goodnow, Deborah L. Burnett, Megan B. Barnet. Correlation between a CTLA-4 single nucleotide polymorphism and high response to anti-PD1/PDL1 immunotherapy in advanced non small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 665.

This book sets a new trajectory for considering the intertwined relationship between theology and law. Through close readings of a range of popular Hollywood speculative fiction films—Shyamalan’s Unbreakable, Snyder’s Man of Steel, Lucas’s and Disney’s Star Wars, Nolan’s The Dark Knight & The Dark Knight Rises, Proyas’ I, Robot, Nolfi’s The Adjustment Bureau and Jackson’s The Hobbit—Timothy Peters explores how fictional worlds, particularly those that ‘make strange’ the world of the viewer, can render visible and make explicit the otherwise opaque theologies of modern law. The book offers a key contribution to the fields of cultural legal studies, law and film and law and theology by considering speculative fiction (superheroes, science fiction, fantasy) as a way of revealing the theologies of modern law and legal theory. The overall narrative of the work marks a course from antagonism to reconciliation, from autonomy to reciprocity and from law to love. Throughout the work, the book draws on resources within the Christian theological tradition’s critical engagement with law, as a means for rethinking and reimagining our post-secular legal modernity—enabling both a deactivating and fulfilling of the law. In exploring speculative film’s estranged accounts of the mythos of modernity and modern law, it articulates an alternative theological jurisprudence based on a love that takes us beyond the law.

Common causes of death in COVID-19 due to SARS-CoV-2 include thromboembolic disease, cytokine storm and adult respiratory distress syndrome (ARDS). Our aim was to develop a system for early detection of disease pattern in the emergency department (ED) that would enhance opportunities for personalised accelerated care to prevent disease progression. A single Trust’s COVID-19 response control command was established, and a reporting team with bioinformaticians was deployed to develop a real-time traffic light system to support clinical and operational teams. An attempt was made to identify predictive elements for thromboembolism, cytokine storm and ARDS based on physiological measurements and blood tests, and to communicate to clinicians managing the patient, initially via single consultants. The input variables were age, sex, and first recorded blood pressure, respiratory rate, temperature, heart rate, indices of oxygenation and C-reactive protein. Early admissions were used to refine the predictors used in the traffic lights. Of 923 consecutive patients who tested COVID-19 positive, 592 (64%) flagged at risk for thromboembolism, 241/923 (26%) for cytokine storm and 361/923 (39%) for ARDS. Thromboembolism and cytokine storm flags were met in the ED for 342 (37.1%) patients. Of the 318 (34.5%) patients receiving thromboembolism flags, 49 (5.3% of all patients) were for suspected thromboembolism, 103 (11.1%) were high-risk and 166 (18.0%) were medium-risk. Of the 89 (9.6%) who received a cytokine storm flag from the ED, 18 (2.0% of all patients) were for suspected cytokine storm, 13 (1.4%) were high-risk and 58 (6.3%) were medium-risk. Males were more likely to receive a specific traffic light flag. In conclusion, ED predictors were used to identify high proportions of COVID-19 admissions at risk of clinical deterioration due to severity of disease, enabling accelerated care targeted to those more likely to benefit. Larger prospective studies are encouraged.

Is it possible to “enjoy” the law? And, if so, how does one engage in such practices of enjoyment? Such are the questions that one might pose and engage with having read Daniel Hourigan’s bookLaw and Enjoyment. However, to understand enjoy- ment here is to recognize, as the subtitle indicates, not simply a hedonistic desire but rather the technical framing of the discourse of psychoanalysis. 1 Hourigan’s work, situated within the field of cultural legal studies, takes up specifically the challenge of the field of law and psychoanalysis through a series of engaging inter- ventions in both popular texts (from China Mieville’s speculative fiction to the online gaming communityEve Online) as well as discussions in continental and legal philosophy (from the debate over necessity and contingency in speculative realism to the question of legal knowledge and jurisprudence as a science). This is an exciting and engaging contribution to the fields of both cultural legal studies, and psychoanalysis and law. In addition, one of its key claims intersects with those two fields arguing that any engagement orreadingof “law psychoanalytically [...] will eventually arrive at the other side of the discourse: a legal reading of psycho- analysis” (12). This insight of the reversal of analysis is one that also applies to cul- tural legal studies that undertake not only legal readings of popular culture texts but also pop culture readings of law and legal theory. This doubling, which Houri- gan performs throughout the book, also goes to the way in which he situates law within the realm of fantasy and the fantasmatic – a fantasy that is essential to the operation and efficacy of the law, be it in the courtroom, legal office, negotiating room, trial film, police procedural, or law school.

Introduction Two risk minimization (RM) tools—a healthcare professional frequently asked questions (HCP-FAQs) brochure and a patient/caregiver information brochure (PCIB)—were developed for HCPs and for adolescents (aged ≥ 13 years) receiving aripiprazole for bipolar I mania and their caregivers. Objectives This study evaluated the effectiveness of these RM tools in improving the awareness and education of HCPs and patients/caregivers. Method The RM tools were distributed to HCPs (identified in agreement with the marketing authorization holder [MAH] and local regulatory authorities), who in turn distributed the PCIBs to patients/caregivers. A web-based survey was then conducted targeting HCPs and patients/caregivers. Results The response rate was low: 118 of 23,282 invited HCPs and 16 patients/caregivers completed the survey. Overall, 42% (49/118) of HCP respondents were aware of aripiprazole RM tools; of these, 59% (29/49) of HCPs read them at least once and 66% (19/29) of these used the RM tools while discussing the benefit–risk profile of aripiprazole with patients/caregivers. In total, 30 of the 118 HCPs (25%) were aware of the PCIB, and 26 distributed it to their patients/caregivers, whereas seven HCPs advised them to read the brochure. Overall, 15 of the 16 patients/caregivers were aware of the PCIB, and 13 read/referred to it. Of these, 12 found the PCIB useful, and five monitored their weight while receiving aripiprazole and reported potential risks immediately to their HCP. Conclusion The response rate to the survey was low, and the tools displayed limited utility and effectiveness in improving awareness and education in a small number of responders. Therefore, the aripiprazole risk management plan was amended, and the tools were discontinued. Electronic supplementary material The online version of this article (10.1007/s40264-018-0662-2) contains supplementary material, which is available to authorized users.

Central Michigan University (CMU) provides a unique opportunity to study the impact of the move from face-to-face to online classes on student use of virtual reference services. As enrollments in f...

Alex Kopelowicz,1 Ross A Baker,2 Cathy Zhao,2 Claudette Brewer,3 Erica Lawson,3 Timothy Peters-Strickland2 1David Geffen School of Medicine, University of California, Los Angeles, CA, 2Otsuka Pharmaceutical Development and Commercialization Inc., Princeton, NJ, 3Otsuka Pharmaceutical Development and Commercialization Inc., Rockville, MD, USA Background: Medication nonadherence is common in the treatment of serious mental illness (SMI) and leads to poor outcomes. The digital medicine system (DMS) objectively measures adherence with oral aripiprazole in near-real time, allowing recognition of adherence issues. This pilot study evaluated the functionality of an integrated call center in optimizing the use of the DMS. Materials and methods: An 8-week, open-label, single-arm trial at four US sites enrolled adults with bipolar I disorder, major depressive disorder, and schizophrenia on stable oral aripiprazole doses and willing to use the DMS (oral aripiprazole + ingestible event marker [IEM], IEM-detecting skin patch, and software application). Integrated call-center functionality was assessed based on numbers and types of calls. Ingestion adherence with prescribed treatment (aripiprazole + IEM) during good patch wear and proportion of time with good patch wear (days with ≥80% patch data or detected IEM) were also assessed. Results: All enrolled patients (n=49) used the DMS and were included in analyses; disease duration overall approached 10 years. For a duration of 8 weeks, 136 calls were made by patients, and a comparable 160 calls were made to patients, demonstrating interactive communication. The mean (SD) number of calls made by patients was 2.8 (3.5). Approximately half of the inbound calls made by patients occurred during the first 2 weeks and were software application- or patch-related. Mean ingestion adherence was 88.6%, and corresponding good patch wear occurred on 80.1% of study days. Conclusion: In this pilot study, the integrated call center facilitated DMS implementation in patients with SMI on stable doses of oral aripiprazole. In clinical practice, the call center and the DMS will facilitate objective measurement of adherence and potentially improve rates of adherence in patients with SMI. Keywords: schizophrenia, bipolar I disorder, major depressive disorder, digital medicine, adherence&nbsp

Background As the capabilities and reach of technology have expanded, there is an accompanying proliferation of digital technologies developed for use in the care of patients with mental illness. The objective of this review was to systematically search published literature to identify currently available health technologies and their intended uses for patients with serious mental illness. Materials and methods The Medline, Embase, and BIOSIS Previews electronic databases were searched to identify peer-reviewed English language articles that reported the use of digital, mobile, and other advanced technology in patients with schizophrenia/schizoaffective disorder, bipolar disorder, and major depressive disorder. Eligible studies were systematically reviewed based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results Eighteen studies that met the inclusion criteria were identified. Digital health technologies (DHTs) assessed in the selected studies included mobile applications (apps), digital medicine, digital personal health records, and an electronic pill container. Smartphone apps accounted for the largest share of DHTs. The intended uses of DHTs could be broadly classified as monitoring to gain a better understanding of illness, clinical assessment, and intervention. Overall, studies indicated high usability/feasibility and efficacy/effectiveness, with several reporting validity against established clinical scales. Users were generally engaged with the DHT, and mobile assessments were deemed helpful in monitoring disease symptoms. Conclusion Rapidly proliferating digital technologies seem to be feasible for short-term use in patients with serious mental illness; nevertheless, long-term effectiveness data from naturalistic studies will help demonstrate their usefulness and facilitate their adoption and integration into the mental health-care system.

Background Long-acting injectable antipsychotics are treatment options for acute and long-term treatment of patients with schizophrenia. In a previously published 12-week randomized, double-blind, placebo-controlled clinical trial of patients with schizophrenia experiencing an acute psychotic episode, aripiprazole once-monthly 400 mg (AOM 400) produced significantly greater improvement than placebo on the primary endpoint, Positive and Negative Syndrome Scale (PANSS) total score at week 10. Methods To examine the efficacy of AOM 400 across a broader representation of schizophrenia symptoms, including agitation, a post hoc analysis of this trial was carried out to assess the change in PANSS Marder factor domains (positive symptoms, negative symptoms, disorganized thought, uncontrolled hostility/excitement, and anxiety/depression) and the PANSS excited component (equivalent to Marder factor domain uncontrolled hostility/excitement plus the tension item) by comparing differences in change from baseline between AOM 400 and placebo using a mixed model for repeated measures. Results The differences between treatment and placebo for all factors were statistically significant, with improvements seen as early as week 1 or 2, and maintained through week 12. Thus, AOM 400, supplemented with oral aripiprazole in the first 2 weeks, showed significantly greater efficacy versus placebo in acutely ill patients with schizophrenia in all 5 Marder illness domains, as well as in agitation as conceptualized by the PANSS excited component score. Conclusions These findings indicate that AOM 400 is efficacious across the spectrum of schizophrenia symptoms in acutely ill patients, with implications for both short-term and, by extension, long-term patient outcomes.

Supplemental Digital Content is available in the text., 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 (

Background This was a multicentre, 8-week, single-arm, open-label, pragmatic trial to explore the acceptance and performance of using the Digital Medicine System (DMS) with health care professionals (HCPs) and adult subjects with schizophrenia, schizoaffective disorder (SAD), or first episode psychosis (FEP) on an oral atypical antipsychotic (aripiprazole, olanzapine, quetiapine, or risperidone). Methods Subjects received an initial introduction to the DMS, and had HCP visits at screening/baseline, Week 4, Week 8/early termination (ET), and as directed by the HCP for the duration of the subject’s participation in the trial. Safety and tolerability data was collected and evaluated on an ongoing basis, as assessed by the frequency and severity of serious adverse events (SAEs), and device-related non-serious adverse events (AEs). Subjects were monitored on the DMS technology by the HCPs through review of the HCP dashboard data at a minimum of every 2 weeks and to make changes to the current treatment plan and therapy at their discretion. The study initiated in May 2018 and concluded in September 2019. NCT03568500 Results Fifty-five (55) subjects were screened, and forty-three (43) subjects were treated and included in the sample analysis. Subjects enrolled were on average 34.4 years old. There were twenty-eight (28) male and fifteen (15) female subjects in the study. The most common reasons for discontinuation was subject withdrawal of consent (5 subjects, 11.6%), loss to follow-up (4 subjects, 9.3%), and adverse events (4 subjects, 9.3%). The primary endpoint was the proportion of days with good patch coverage during the trial, calculated by the number of days with good patch coverage divided by the total number of trial days for each subject. Over the duration of the study, subjects had 63.4 % (SD = 26.6%) of days with good patch coverage during the trial time. No notable differences were observed across the disease types, with schizophrenic subject 64.3% (SD=20.2%), FEP subject 62.5% (SD = 27.5%), and SAD subject 63.0% (SD = 37.7%). The secondary endpoint was subject adherence, defined as the proportion of detected ingestible events markers (IEM) over the expected during the trial days with good patch coverage. Overall, subjects had a mean of 86.6% (SD = 14.5%) IEMs detected during the good patch coverage days. The proportion of IEM detected by disease type were: FEP 91.0% (SD = 7.4%), schizophrenic 88.9% (SD = 8.1%), and SAD 72.3% (SD=25.7%). There were nine (9) subjects (20.9%) who had eleven (11) AEs during the study, all were non-serious. Out of all the AEs, nine (9) subjects had nine (9) treatment emergent adverse events (TEAE) that were all reported as medical device site irritation, and four (4) subjects discontinued the study due to AEs. Discussion In conclusion, during the 8-week treatment with the DMS, subjects reported good patch coverage 63.4% of the time on average for this pragmatic study. Using the DMS, subjects’ medication adherence reached 86.6% on average when subjects were having good patch coverage. The acceptance and performance of DMS is considered safe and there were no SAEs associated with its use. Funding This study was supported by Otsuka Pharmaceutical Development & Commercialization, Inc.

Background Adherence to medication regimens and patient rest are two important factors in the well-being of patients with serious mental illness. Both of these behaviors are traditionally difficult to record objectively in unsupervised populations. Objective A digital medicine system that provides objective time-stamped medication ingestion records was used by patients with serious mental illness. Accelerometer data from the digital medicine system was used to assess rest quality and thus allow for investigation into correlations between rest and medication ingestion. Methods Longest daily rest periods were identified and then evaluated using a k-means clustering algorithm and distance metric to quantify the relative quality of patient rest during these periods. This accelerometer-derived quality-of-rest metric, along with other accepted metrics of rest quality, such as duration and start time of the longest rest periods, was compared to the objective medication ingestion records. Overall medication adherence classification based on rest features was not performed due to a lack of patients with poor adherence in the sample population. Results Explorations of the relationship between these rest metrics and ingestion did seem to indicate that patients with poor adherence experienced relatively low quality of rest; however, patients with better adherence did not necessarily exhibit consistent rest quality. This sample did not contain sufficient patients with poor adherence to draw more robust correlations between rest quality and ingestion behavior. The correlation of temporal outliers in these rest metrics with daily outliers in ingestion time was also explored. Conclusions This result demonstrates the ability of digital medicine systems to quantify patient rest quality, providing a framework for further work to expand the participant population, compare these rest metrics to gold-standard sleep measurements, and correlate these digital medicine biomarkers with objective medication ingestion data.

BACKGROUND Adherence to medication regimens and patient rest are two important factors in the well-being of patients with serious mental illness. Both of these behaviors are traditionally difficult to record objectively in unsupervised populations. OBJECTIVE A digital medicine system that provides objective time-stamped medication ingestion records was used by patients with serious mental illness. Accelerometer data from the digital medicine system was used to assess rest quality and thus allow for investigation into correlations between rest and medication ingestion. METHODS Longest daily rest periods were identified and then evaluated using a k-means clustering algorithm and distance metric to quantify the relative quality of patient rest during these periods. This accelerometer-derived quality-of-rest metric, along with other accepted metrics of rest quality, such as duration and start time of the longest rest periods, was compared to the objective medication ingestion records. Overall medication adherence classification based on rest features was not performed due to a lack of patients with poor adherence in the sample population. RESULTS Explorations of the relationship between these rest metrics and ingestion did seem to indicate that patients with poor adherence experienced relatively low quality of rest; however, patients with better adherence did not necessarily exhibit consistent rest quality. This sample did not contain sufficient patients with poor adherence to draw more robust correlations between rest quality and ingestion behavior. The correlation of temporal outliers in these rest metrics with daily outliers in ingestion time was also explored. CONCLUSIONS This result demonstrates the ability of digital medicine systems to quantify patient rest quality, providing a framework for further work to expand the participant population, compare these rest metrics to gold-standard sleep measurements, and correlate these digital medicine biomarkers with objective medication ingestion data.

Currently, with the legalization of cannabis and the opening of recreational dispensaries in states across the country, the question of whether or not proximity to recreational cannabis dispensaries affects high school students in terms of their cannabis use, their perceptions of the accessibility of cannabis and their perceptions on the harmfulness and wrongfulness of using cannabis is particularly relevant and timely. In 2014 in Colorado, Amendment 64 went into effect and communities were allowed to legally permit recreational cannabis dispensaries; some communities agreed to permit the opening of recreational dispensaries while other communities did not. Using data from the cross-sectional Healthy Kids Colorado Survey collected from students in randomly selected high schools in both 2013 and 2015, data on student use and perceptions towards cannabis use was analyzed comparing communities that permitted recreational cannabis dispensaries and communities that did not. The random cross-sectional design used a 2X2 factorial ANOVA for each of the dependent factors: use, access, wrongfulness, and harm. There were a total of three communities that permitted recreational dispensaries, and within those three communities, data was collected from seven high schools. There were four communities that did permit recreational dispensaries, and within those four communities, data was collected from five high schools. The data were aggregated into two groups: ‘yes’ allows dispensaries, and ‘no’ does not allow dispensaries. These two groups were used as comparisons in the factorial ANOVA along with the two collection event years of 2013 and 2015. The analysis indicates differences between students in communities that have never permitted recreational cannabis dispensaries and students in communities that opened recreational dispensaries in 2014. Students in communities that permitted recreational dispensaries used more cannabis, thought cannabis was less harmful, less wrong, and was more difficult to access than high school students in communities that did not permit recreational cannabis dispensaries, however these differences existed before and after recreational dispensaries were introduced in 2014. Looking at each type of community to see if there was a change between 2013 and 2015, there were no statistically significant differences between students in 2013 and 2015 in each type of community with one exception; students in communities that did not permit recreational cannabis dispensaries felt even more strongly in 2015 that cannabis use is wrong compared to 2013. Based on the 2013 and 2015 Healthy Kids Colorado Survey data, permitting or not permitting recreational cannabis dispensaries in a community does not appear to change student cannabis use or perceptions towards cannabis.

Egr2 and Egr3 genes encode early growth response (EGR) transcription factors, act as immediate early genes following B cell receptor (BCR) signalling and are highly up-regulated in anergic mouse B cells. Anergy preserves microbial epitope responsiveness from a finite pool of pre-immune B cells, but is also reversible – creating a risk of autoimmune disease. Pathological proliferation of self-reactive B cells can also cause chronic lymphocytic leukemia (CLL), 3.8% of which harbour somatic missense EGR2 mutations resulting in loss- or change-of-function and correlated with poor prognosis. We analysed B cells in mice lacking one or both alleles of Egr2 and/or Egr3 and show that Egr2 and Egr3 deletion cause the cell-intrinsic accumulation in spleen, blood and bone marrow of populations enriched for self-reactive BCRs: B1a and CD21low CD23low age-associated B cells. Global single-cell RNA profiling of these expanded populations in vivo demonstrated their differential expression of genes involved in their survival and maintenance. We used chromatin immunoprecipitation sequencing (ChIP-Seq) to show that several of these genes are direct EGR2 transcriptional targets in human CLL. This is the first report on the roles of Egr2/3 in B cells and we demonstrate herein that Egr2 and Egr3 transcription factors are crucial in suppressing the accumulation of B1a and age-associated or atypical memory B cells.

Author(s): Potkin, Steven G; Loze, Jean-Yves; Forray, Carlos; Baker, Ross A; Sapin, Christophe; Peters-Strickland, Timothy; Beillat, Maud; Nylander, Anna-Greta; Hertel, Peter; Nitschky Schmidt, Simon; Eramo, Anna; Hansen, Karina; Naber, Dieter | Abstract: BackgroundQUALIFY 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.MethodsSecondary 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.ResultsOdds 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.ConclusionsConsistently 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 registryNational Institutes of Health registry, NCT01795547, https://clinicaltrials.gov/ct2/results?id=NCT01795547).

Timothy Peters-Strickland,1 Linda Pestreich,1 Ainslie Hatch,2 Shashank Rohatagi,1 Ross A Baker,1 John P Docherty,2 Lada Markovtsova,1 Praveen Raja,3 Peter J Weiden,4 David P Walling5 1Otsuka Pharmaceutical Development & Commercialization, Inc., 2ODH, Inc., Princeton, NJ, 3Proteus Digital Health, Inc., Redwood City, CA, 4Department of Psychiatry, University of Illinois, Chicago, IL, 5CNS Network, LLC, Long Beach, CA, USA Objective: Digital medicine system (DMS) is a novel drug–device combination that objectively measures and reports medication ingestion. The DMS consists of medication embedded with an ingestible sensor (digital medicine), a wearable sensor, and software applications. This study evaluated usability of the DMS in adults with schizophrenia rated by both patients and their health care providers (HCPs) during 8-week treatment with prescribed doses of digital aripiprazole.Methods: Six US sites enrolled outpatients into this Phase IIa, open-label study (NCT02219009). The study comprised a screening phase, a training phase (three weekly site visits), and a 5-week independent phase. Patients and HCPs independently rated usability of and satisfaction with the DMS.Results: Sixty-seven patients were enrolled, and 49 (73.1%) patients completed the study. The mean age (SD) of the patients was 46.6years (9.7years); the majority of them were male (74.6%), black (76.1%), and rated mildly ill on the Clinical Global Impression – Severity scale (70.1%). By the end of week 8 or early termination, 82.1% (55/67) of patients had replaced the wearable sensor independently or with minimal assistance, based on HCP rating. The patients used the wearable sensor for a mean (SD) of 70.7% (24.7%) and a median of 77.8% of their time in the trial. The patients contacted a call center most frequently at week 1. At the last visit, 78% (47/60) of patients were somewhat satisfied/satisfied/extremely satisfied with the DMS.Conclusion: A high proportion of patients with schizophrenia were able to use the DMS and reported satisfaction with the DMS. These data support the potential utility of the DMS in clinical practice. Keywords: adherence, antipsychotics, aripiprazole, digital medicine, schizophrenia, usability

Background Nonadherence to medication compromises the effectiveness of psychiatric treatments in patients with serious mental illness (SMI). A newly developed digital medicine system (DMS) offers an opportunity to objectively assess and report patient medication adherence. DMS includes a wearable sensor that receives a data signal from a medication tablet with an embedded ingestible sensor after ingestion of the medication and transmits that data to the patient's mobile device to display health care information for the patient and treatment team. Methods/results Development of a DMS requires a program that investigates safety, tolerability, and usability of the system in patients with SMI. It necessitates rapid design adaptation of the individual components and the integrated system and human factors studies with the intended users. This article describes the program's methodology and shows results from 3 early studies, conducted in 2013 and 2014, to illustrate diversity of the programs' methodology. First, a standard 28-day study showed minimal skin irritation and demonstrated acceptable wearability of the wearable sensor. Second, a 16-week study provided usability feedback from patients with SMI and caregivers to improve the mobile application. Third, end-to-end bench-level integrated system testing led to multiple substudies of a master protocol (ClinicalTrials.gov identifier: NCT02091882) to investigate various aspects of the system (eg, ingestible sensor detection and latency). Conclusions To develop a DMS in psychiatry, the system's multiple components must be considered simultaneously using various methodologies. A focus on usability, along with agile evaluation and feedback across studies, provides an optimal strategy for ensuring patient acceptance and successful regulatory review.

BACKGROUND A digital medicine system (DMS) has been developed to measure and report adherence to an atypical antipsychotic, aripiprazole, in psychiatric patients. The DMS consists of 3 components: ingestible sensor embedded in a medication tablet, wearable sensor, and secure mobile and cloud-based applications. An umbrella study protocol was designed to rapidly assess the technical performance and safety of the DMS in multiple substudies to guide the technology development. METHODS Two sequential substudies enrolled 30 and 29 healthy volunteers between March-April 2014 and February-March 2015, respectively, to assess detection accuracy of the ingestible sensor by the DMS and the latency period between ingestion and detection of the ingestion by the wearable sensor or the cloud-based server. RESULTS The first substudy identified areas for improvement using early versions of the wearable sensor and the mobile application. The second substudy tested updated versions of the components and showed an overall ingestion detection rate of 96.6%. Mean latency times for the signal transmission were 1.1-1.3 minutes (from ingestion to the wearable sensor detection) and 6.2-10.3 minutes (from the wearable sensor detection to the server detection). Half of transmissions were completed in < 2 minutes, and ~90% of ingestions were registered by the smartphone within 30 minutes of ingestion. No serious adverse events, discontinuations, or clinically significant laboratory/vital signs findings were reported. CONCLUSIONS The DMS implementing modified versions of the smartphone application and the wearable sensor has the technical capability to detect and report tablet ingestion with high accuracy and acceptable latency time. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02091882.

Following the landmark regulatory approval of digital aripiprazole (Abilify Mycite™) late in 2017 [1], digital medicines have begun the transition from clinical trials and early clinical success to...

Objective To directly compare aripiprazole once-monthly 400 mg (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 4 weeks. 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 28 weeks 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 ≤ 35 years. 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 .

Purpose – This paper is a case study of the decision at Central Michigan University to take librarians off the reference desk. Departmental data on reference desk traffic and other ancillary functions of the reference department was used to make the case for removing the librarians from the desk. Data collected since the decision was made has supported the decision to move to an on-call reference desk staffing model. The paper aims to discuss these issues. Design/methodology/approach – The department reviewed and analyzed data on reference desk transactions of all types from previous years to inform its decision making. Data trends and an analysis of the nature of the questions asked at the reference desk were instrumental in the analysis. Findings – The department determined that the statistical data justified the removal of the librarians from the reference desk. Data collected since moving to the on-call model supports the earlier decision. Originality/value – This paper provides libraries considering their own desk staffing models with a discussion of another library’s decision-making process and evidence of a successful migration to a new reference service model.

The retrospective diagnosis of illnesses by medical historians can often be difficult and prone to bias, although knowledge of the medical disorders of historical figures is key to the understanding of their behavior and reactions. The recent application of computer diagnostics to historical figures allows an objective differential diagnosis to be accomplished. Taking an example from clinical neurology, we analyzed the earliest reported cases of Devic’s disease (neuromyelitis optica) that commonly affects the optic nerve and spinal cord and was previously often confused with multiple sclerosis. We conclude that in most identified cases the software concurred with the contemporary physicians’ interpretation, but some claimed cases either had insufficient data to provide a diagnosis or other possible diagnoses were suggested that had not been considered. Computational methods may, therefore, help historians to diagnose the ailments of historical figures with greater objectivity.

Objective: To compare hospitalization rates in patients with schizophrenia treated prospectively with aripiprazole once-monthly 400 mg (AOM 400; an extended-release injectable suspension) vs the same patients’ retrospective rates with their prior oral anti-psychotic therapy. Research design and methods: Multi-center, open-label, mirror-image, naturalistic study in a community setting in North America. Patients who required a change in treatment and/or would benefit from long-acting injectable anti-psychotic therapy were treated prospectively for 6 months with AOM 400. Retrospective data on hospitalization rates were obtained. Clinical trial registration: ClinicalTrials.gov: NCT01432444. Main outcome measures: The proportion of patients with ≥1 psychiatric inpatient hospitalization with oral anti-psychotic therapy examined retrospectively (months –4 to –1 before oral conversion) and after switching to AOM 400 (months 4–6 after initiating AOM 400). Results: Psychiatric hospitalization rates were significantly lower when patients were treated with AOM 400 compared with oral anti-psychotic therapy both in the 3-month primary efficacy sample (2.7% [n = 9/336] vs 27.1% [n = 91/336], respectively; p 1 and

BackgroundLong-acting injectable formulations of antipsychotics are treatment alternatives to oral agents.AimsTo assess the efficacy of aripiprazole once-monthly compared with oral aripiprazole for maintenance treatment of schizophrenia.MethodA 38-week, double-blind, active-controlled, non-inferiority study; randomisation (2:2:1) to aripiprazole once-monthly 400 mg, oral aripiprazole (10–30 mg/day) or aripiprazole once-monthly 50mg (a dose below the therapeutic threshold for assay sensitivity). (Trial registration: clinicaltrials.gov, NCT00706654.)ResultsA total of 1118 patients were screened, and 662 responders to oral aripiprazole were randomised. Kaplan–Meier estimated impending relapse rates at week 26 were 7.12% for aripiprazole once-monthly 400mg and 7.76% for oral aripiprazole. This difference (−0.64%, 95% CI −5.26 to 3.99) excluded the predefined non-inferiority margin of 11.5%. Treatments were superior to aripiprazole once-monthly 50mg (21.80%, P⩽0.001).ConclusionsAripiprazole once-monthly 400mg was non-inferior to oral aripiprazole, and the reduction in Kaplan–Meier estimated impending relapse rate at week 26 was statistically significant v. aripiprazole once-monthly 50 mg.

Contemporary accounts credit Dr Francis Willis (1718–1807) with facilitating the recovery of King George III from his major episode of acute mania in 1788–9. Subsequently Willis was summoned to Lisbon to advise on the mental health problems of Queen Maria I. This article reports the nature of the illnesses of Maria and her two similarly affected sisters, and uses the program OPCRIT to propose diagnoses of major depressive disorders. The high prevalence of consanguinity and insanity among the Portuguese monarchy and their antecedents probably contributed to their mental health problems. The successive contributions of the Willis family from Thomas Willis (1621–75) to his grand-nephew, Francis Willis (1792–1859), are reviewed; the popular image is somewhat inaccurate and does not highlight their part in the development of psychiatry.

Objective: To report the design and preliminary results of a mirror-image study comparing total psychiatric hospitalisation rates pre- and post-switch to aripiprazole once-monthly, an extended release injectable solution. Methods: A multi-center, open-label mirror-image study of patients (18–65 years) with schizophrenia to compare total psychiatric hospitalisation rates between retrospective treatment with oral standard-of-care (SOC) anti-psychotics and prospective treatment with aripiprazole once-monthly in a naturalistic community setting in North America. Total psychiatric hospitalisation rates were assessed between retrospective (Months −4 to −1) and prospective treatment periods (Months 4–6) for patients who completed ≥3 months aripiprazole once-monthly. Results: One hundred and eighty-three patients entered the prospective phase. After switching to aripiprazole once-monthly, total psychiatric hospitalisation rates for the 3-month prospective period were significantly lower (p

Objective To evaluate long-term safety and effectiveness of continued treatment with aripiprazole once-monthly 400 mg (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.