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Christoph U Correll,1– 4,* Jose M Rubio,1– 3,* Leslie Citrome,5,* Marko A Mychaskiw,6 Stephen Thompson,6 Kelli R Franzenburg,7 Mark Suett,8 Sameer Kotak,9 John M Kane1– 3,* 1Department of Psychiatry, The Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY, USA; 2Department of Psychiatry, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA; 3Institute of Behavioral Science, Feinstein Institutes for Medical Research, Manhasset, NY, USA; 4Department of Child and Adolescent Psychiatry, Charité – Universitätsmedizin Berlin, Berlin, Germany; 5Department of Psychiatry and Behavioral Sciences, New York Medical College, Valhalla, NY, USA; 6Global Health Economics and Outcomes Research, Teva Branded Pharmaceutical Products R&D, Inc., West Chester, PA, USA; 7Global Medical Affairs, Teva Branded Pharmaceutical Products R&D, Inc., West Chester, PA, USA; 8Global Medical Affairs, Teva UK Limited, Harlow, United Kingdom; 9Yorker Health Corp., Glen Rock, NJ, USA*These authors contributed equally to this workCorrespondence: Christoph U Correll, Email ccorrell@northwell.eduAbstract: Despite evidence of benefits beyond those of oral antipsychotics, long-acting injectable antipsychotics (LAIs) are underused in schizophrenia treatment. Underuse may be partially a result of misconceptions held by some healthcare professionals (HCPs) pertaining to LAIs. A panel of four experts convened between January 2022 and May 2022 to identify these misconceptions, and example cases or scenarios were created to illustrate common clinical situations relevant to these beliefs. Ultimately, an online platform and heuristic tool, Schizophrenia Clinical Outcome Scenarios and Patient-Provider Engagement (S.C.O.P.E.™), was developed to help prescribing clinicians and other HCPs better understand common clinical dilemmas, as well as the place for LAIs in schizophrenia treatment. Three main misconceptions related to the use of LAIs to treat schizophrenia were identified and included “physicians/providers know when patients are nonadherent”, “patients do not accept/want LAI treatment”, and “LAIs are only appropriate for patients who have demonstrated nonadherence”. All misconceptions are refuted by current evidence and were used to develop clinical scenarios with questions to consider when patients present to various sites of care for treatment. These cases are presented on the S.C.O.P.E. educational platform. The platform also includes videos designed to help non-prescribing HCPs and mental health professionals address patient/caregiver concerns and to communicate LAI benefits. In addition, S.C.O.P.E. provides a section with information about each LAI that is currently FDA approved in the United States for the treatment of schizophrenia, to help familiarize HCPs with characteristics of LAIs. S.C.O.P.E. is an educational tool designed for HCPs to help improve their understanding of how to manage common clinical dilemmas in the treatment of people with schizophrenia, to clarify the role of LAIs in medication management, and to increase understanding of the characteristics of available LAIs. S.C.O.P.E. also aims to improve care in schizophrenia by facilitating increased awareness to patients and caregivers.Plain Language Summary: Schizophrenia is a serious, lifelong mental health disorder that affects about 2.8 million adults in the United States and many more worldwide. Symptoms can include hallucinations (ie, hearing “voices”), delusions (ie, convinced something is true when it is not), poor attention, lack of motivation and interest, and cognitive problems. Schizophrenia can have considerable impact on people with the disorder as well as their families, friends, and communities. There are several treatment options available for healthcare professionals (HCPs), patients, and caregivers to consider, with antipsychotic medicines being the cornerstone of the treatment for schizophrenia. Long-acting injectable antipsychotics (LAIs) have shown benefits over antipsychotics taken orally (by mouth), but are underused, and this is likely due to some common misconceptions.Four experts in schizophrenia treatment met repeatedly online to identify some of these misconceptions and created a tool to help HCPs learn about misconceptions, using example cases of patients with schizophrenia who have different types of clinical situations and concerns. On the Schizophrenia Clinical Outcome Scenarios and Patient-Provider Engagement (S.C.O.P.E.™) interactive digital platform, HCPs can choose in which type of case they are interested in and see details of the case, information they should obtain about the case, and appropriate considerations for LAI use. The tool also provides videos about communicating with patients and their families about LAIs, and information about the different LAIs currently available.The goal of providing this tool to HCPs is to improve understanding of how to treat patients with schizophrenia and the role that LAIs can play.Keywords: long-acting injectable antipsychotic, schizophrenia, treatment, education, patient outcomes

Leslie Citrome,1 Mark Suett,2 Kelli R Franzenburg,3 Roy Eshet,4 Anna Elgart,4 Glen L Davis 3rd,5 Eran Harary,4 Orna Tohami,4 Marko A Mychaskiw,6 John M Kane7– 9 1Department of Psychiatry and Behavioral Sciences, New York Medical College, Valhalla, NY, USA; 2Global Medical Affairs, Teva UK Limited, Harlow, UK; 3Global Medical Affairs, Teva Branded Pharmaceutical Products R&D, Inc., West Chester, PA, USA; 4Innovative Medicines, Global Clinical Development, Teva Pharmaceutical Industries Ltd, Netanya, Israel; 5Global Clinical Operations, Teva Branded Pharmaceutical Products R&D, Inc., West Chester, PA, USA; 6Global Health Economics and Outcomes Research, Teva Branded Pharmaceutical Products R&D, Inc, West Chester, PA, USA; 7Department of Psychiatry, The Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY, USA; 8Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA; 9Institute of Behavioral Science, Feinstein Institutes for Medical Research, Manhasset, NY, USACorrespondence: Leslie Citrome, Department of Psychiatry and Behavioral Sciences, New York Medical College, 40 Sunshine Cottage Road, Valhalla, NY, 10595, USA, Email nntman@gmail.comBackground: TV46000 is a long-acting subcutaneous antipsychotic (LASCA) formulation of risperidone approved for the treatment of schizophrenia in adults.Methods: The RISE study (NCT03503318) compared TV-46000 once monthly (q1m) and once every 2 months (q2m) with placebo (1:1:1) in patients with schizophrenia who underwent stabilization on oral risperidone. The SHINE study (NCT03893825) evaluated the long-term safety, tolerability, and effectiveness of TV-46000 in patients who completed RISE without relapse (rollover; placebo rollover randomized [1:1] to q1m or q2m; TV-46000 rollover continued assigned treatment) or who were newly recruited (de novo; randomized [1:1] to q1m or q2m after oral stabilization). Patient-centered outcomes included the Schizophrenia Quality of Life Scale (SQLS), the 5-Level EuroQoL 5-Dimensions Questionnaire (EQ-5D-5L), the Personal and Social Performance Scale (PSP), and the Drug Attitudes Inventory 10-item version (DAI-10).Results: In RISE, SQLS least-squares mean changes (SE) improved to last assessment (LA) for TV-46000 q1m (– 4.15 [1.03]) and q2m (– 3.28 [1.06]) but worsened for placebo (1.75 [1.07]; P< 0.001 for both). PSP, EQ5D-5L, and DAI-10 showed similar trends. In SHINE, SQLS decreased (improved) at LA for both TV-46000 q1m (− 0.43 [0.98]) and q2m (− 2.16 [0.98]); reductions were observed in the de novo (q2m only) and placebo rollover (q1m and q2m) cohorts, but not for the TV46000 rollover cohort. Results for PSP, EQ5D-5L, and DAI-10 were consistent with those reported in the RISE study.Conclusion: Improvements in patient-centered outcomes were observed across cohorts, with the largest improvements observed for patients who began TV-46000 during SHINE (ie, de novo and placebo rollover cohorts), while gains made during RISE were minimally improved or maintained in the TV-46000 rollover cohort, indicating the benefit of uninterrupted TV-46000 treatment. These data support the effectiveness of TV-46000 to improve patient-centered outcomes in patients with schizophrenia.Plain Language Summary: RISE and SHINE were clinical studies where patients with schizophrenia received TV-46000. TV-46000 is injected under the skin once monthly or once every 2 months to treat schizophrenia in adults. In RISE, patients took pills for the first 3 months, and then received injections under the skin. Some patients received inactive (placebo) injections. Comparing results among groups showed the effectiveness and side effects of TV-46000. Patients who completed RISE could continue into SHINE. SHINE included patients who had not been part of RISE as well. All patients received TV-46000 in SHINE to see if results were the same long term. This report summarizes the results of patient-centered outcomes. These included measures of quality of life and attitudes toward the medicine. In RISE, quality of life and attitudes toward the medicine improved with TV-46000, but worsened with placebo. In SHINE, the patient-centered outcomes also improved. The largest improvements were for patients who began taking TV-46000 during SHINE. This analysis showed that there is a benefit in taking TV-46000 for longer times without breaks. It also showed that TV-46000 improves quality of life and attitudes toward the medicine.Keywords: schizophrenia, long-acting injectable, risperidone, patient-centered outcomes

Sanghyuk Seo,1 Bridget E Healey,2 Ronae McLin,2 Naomi C Sacks,2 Carmela J Benson,1 Leslie Citrome3 1Medical Affairs Neuroscience, Janssen Scientific Affairs, LLC, a Johnson & Johnson company, Titusville, NJ, USA; 2PRECISIONheor, Boston, MA, USA; 3Department of Psychiatry and Behavioral Sciences, New York Medical College, Valhalla, NY, USACorrespondence: Carmela J Benson, Medical Affairs Neuroscience, Johnson & Johnson Innovative Medicine, 1125 Trenton Harbourton Road, Titusville, NJ, 08560, USA, Email Cbenson5@its.jnj.comPurpose: Little is known about the impact of health disparities on antipsychotic treatment and healthcare resource utilization (HRU) among patients with schizophrenia. The objective of this analysis is to examine treatment patterns and HRU by age, race/ethnicity, and insurance coverage among patients with schizophrenia in an integrated delivery network (IDN).Patients and Methods: This cross-sectional study used electronic health record data from MedStar Health, an IDN in the Baltimore-Washington, DC, area. Patients were aged ≥ 18 years and had ≥ 2 outpatient encounters or ≥ 1 hospitalization with a diagnosis of schizophrenia between January 1, 2017 and March 31, 2021. Outcomes assessed included oral antipsychotic prescriptions, long-acting injectable antipsychotic (LAI) utilization, hospitalizations, emergency department (ED) visits, and outpatient visits. Analyses compared subgroups based on age, race/ethnicity (non-Hispanic Black, non-Hispanic White, and other), and type of insurance coverage at index (Medicare, Medicaid, and other) during 12 months of follow-up.Results: A total of 78.1% of patients had ≥ 1 prescription for an antipsychotic and 69.1% received ≥ 1 second-generation antipsychotic. Second-generation long-acting injectables (SGA LAI) were utilized by 9.0% of patients, with the elderly and Medicaid beneficiaries having the lowest SGA LAI utilization. Overall, 61.7% of patients had ≥ 1 hospitalization, 56.4% had ≥ 1 outpatient visit, and 50.5% had ≥ 1 ED visit. Hospitalizations and ED visits were most common in those 18 to 24 years of age and in Medicaid beneficiaries, whereas outpatient visits were more common for the elderly and Medicare beneficiaries.Conclusion: At the population level, the results indicate widespread underprescription/underutilization of antipsychotics that have been shown to improve clinical and economic outcomes in patients with schizophrenia, particularly SGA LAI. Within specific subpopulations, disparities in treatment selection and HRU were observed, suggesting the need for increased attention to at-risk groups to ensure consistent quality of care regardless of age, race/ethnicity, or insurance coverage.Keywords: health disparities, race/ethnicity, antipsychotic prescription, long-acting injectable antipsychotics, second-generation antipsychotic, clinical outcomes

Leslie Citrome,1 Mariacristina Castelli,2 Masami Hasebe,3 Takaaki Terahara,3 Justin Faden,4 Marina Komaroff2 1Department of Psychiatry and Behavioral Sciences, New York Medical College, Valhalla, NY, USA; 2Product Development, Noven Pharmaceuticals, Inc, Jersey City, NJ, USA; 3Hisamitsu Pharmaceutical Co., Inc, Tokyo, Japan; 4Department of Psychiatry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USACorrespondence: Leslie Citrome, Department of Psychiatry and Behavioral Sciences, New York Medical College, 40 Sunshine Cottage Road, Valhalla, NY, 10595, USA, Tel +1 845-362-2081, Email nntman@gmail.comIntroduction: HP-3070, a once-daily asenapine transdermal system, is the first antipsychotic “patch” formulation FDA approved for adults with schizophrenia. Positive and Negative Syndrome Scale (PANSS) score items can be grouped into a five-factor structure to describe specific schizophrenia symptom domains. This post hoc analysis of data from a pivotal study evaluated HP-3070’s efficacy by examining these factors.Methods: In a phase 3 study, adults with an acute exacerbation of schizophrenia were randomized to six weeks of treatment with HP-3070 3.8mg/24h, 7.6mg/24h, or placebo. An analysis was performed using the five PANSS factor domains (negative symptoms, positive symptoms, disorganized thought, uncontrolled hostility/excitement, anxiety/depression). Mixed-model repeated-measures (MMRM) analysis included change from baseline (CFB) in PANSS factor score as the repeated dependent variable, with country, treatment, visit, treatment by visit interaction, and baseline PANSS score as covariates.Results: The analysis included 607 patients. Treatment with HP-3070 3.8mg/24h resulted in a statistically significant LS mean CFB (improvement) vs placebo at Weeks 4– 6 for all domains except for anxiety/depression, where a numerical difference was observed in favor of active treatments. Among the domains, the positive symptom factor demonstrated the numerically greatest LS mean (SE) difference from placebo in CFB, which for HP-3070 7.6mg/24h was − 2.0 [0.57] and for HP-3070 3.8mg/24h was − 2.3 [0.57]; P< 0.001 for both. Treatment effect size for the positive symptom factor using Cohen’s d (95% confidence intervals) was 0.39 (0.17, 0.61) for HP-3070 7.6mg/24h and 0.45 (0.20, 0.64) for HP-3070 3.8mg/24h.Discussion: Post hoc analysis using a PANSS five-factor model suggests that HP-3070 may address a broad range of symptoms in people with schizophrenia.Keywords: asenapine, transdermal, patch, schizophrenia, positive and negative syndrome scale, five-factor

Ivo Abraham,1 Mickael Hiligsmann,2 Kenneth KC Lee,3 Leslie Citrome,4 Giorgio Lorenzo Colombo,5 Mike Gregg6 1University of Arizona, Tucson, AZ, USA; 2Maastricht University, Maastricht, the Netherlands; 3Taylor’s University, Selangor, Malaysia; 4New York Medical College, Valhalla, New York, NY, USA; 5University of Pavia, Pavia, Italy; 6Taylor & Francis, London, SE1 8BF, UKCorrespondence: Mike Gregg, Email mike.gregg@tandf.co.uk

John FP Bridges,1,&ast; Joseph F Goldberg,2,&ast; Heather M Fitzgerald,3,&ast; Sanjeda R Chumki,4,&ast; Kathleen Beusterien,5,&ast; Oliver Will,5,&ast; Leslie Citrome6,&ast; 1Department of Biomedical Informatics, the Ohio State University College of Medicine, Columbus, OH, USA; 2Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 3Medical Affairs, Lundbeck LLC, Deerfield, IL, USA; 4Medical Affairs, Otsuka Pharmaceutical Development & Commercialization Inc, Princeton, NJ, USA; 5Cerner Enviza, North Kansas City, MO, USA; 6Department of Psychiatry & Behavioral Sciences, New York Medical College, Valhalla, NY, USA&ast;These authors contributed equally to this workCorrespondence: Sanjeda R Chumki, Otsuka Pharmaceutical Development & Commercialization Inc, 508 Carnegie Center Dr, Princeton, NJ, 08540, USA, Tel +1-609-524-6788, Email Sanjeda.Chumki@otsuka-us.comPurpose: Bipolar I disorder (BP-I) is associated with significant disease burden, but evidence on treatment goals in people diagnosed with BP-I is scarce. This study sought to quantify treatment goals related to the pharmacological management of BP-I in adults in the US and to identify if subgroups of people with similar treatment goals exist.Patients and Methods: A best–worst scaling (BWS) of treatment goals was developed based on available literature and input from experts and patients and was distributed as part of a survey between August and September 2021. Survey participants were adults with a self-reported diagnosis of BP-I who were recruited via an online panel in the US. Participants were asked to prioritize the importance of 16 treatment goals using BWS. BWS scores were computed using multinomial logistic regression, with the scores across all goals summing to 100 for each participant. Subgroups of people with similar preferences were identified using latent class analysis.Results: The most important treatment goals for people diagnosed with BP-I (N=255) were “being less impulsive, angry, or irritable” (score: 9.73), or being “able to feel pleasure or happiness” (score: 9.54). Goals related to reducing the incidence of various potential adverse events of medication (scores: ≤ 4.51) or “reducing dependence on others” (score: 3.04) were less important. Two subgroups were identified. One subgroup (n=111) prioritized symptom-focused goals, considering “reducing frequency of mania, depression, and mixed episodes” and “being less impulsive, angry or irritable” the most important (scores: 12.46 and 11.85, respectively). The other subgroup (n=144) placed significantly more importance on social functioning-focused goals, including beginning or maintaining a relationship with a partner/significant other, and with family and/or friends (scores: 8.45 and 7.70, respectively).Conclusion: People diagnosed with BP-I prioritized emotional improvements. Subgroups of people with BP-I prioritized either symptom-focused or social functioning-focused treatment goals.Keywords: patient preference, healthcare questionnaire, treatment individualization, social functioning

Leslie Citrome,1 Emily Belcher,2 Sylvie Stacy,2 Mark Suett,3 Marko Mychaskiw,4 Gregory D Salinas2 1Department of Psychiatry and Behavioral Sciences, New York Medical College, Valhalla, NY, USA; 2Department of Research and Assessment, CE Outcomes, LLC, Birmingham, AL, USA; 3Teva UK Limited, Global Medical Affairs, Harlow, UK; 4Teva Branded Pharmaceutical Products R&D, Inc., Global Health Economics and Outcomes Research, West Chester, PA, USACorrespondence: Leslie Citrome 11 Medical Park Drive, Suite 102, Pomona, NY, 10970, USATel +1 845 362 2081Email citrome@cnsconsultant.comPurpose: Schizophrenia is a chronic, serious, and disabling mental disorder that affects how an individual thinks, feels, and behaves. With the availability of effective antipsychotic medications, the care of people with schizophrenia has shifted from psychiatric hospitals to outpatient treatment and caregivers, including family members. Caregivers are an often-overlooked target for education but may be a key resource to enhance patient education and foster greater adherence to treatment. This study sought to examine the burdens faced by caregivers and determine their specific educational needs.Methods: A survey instrument was developed and fielded to 96 caregivers of patients with schizophrenia in the United States (September–October 2019) via online communities and caregiver newsletters. Survey responses were organized into specific topics: symptoms exhibited when diagnosed, current treatment options and use of long-acting injectable (LAI) antipsychotic medications, treatment adherence attitudes, barriers for caregivers and patients, informational resources utilized, and caregiver information and educational topics.Results: Caregivers identified hallucinations, delusions, disorganized behavior, thought disorder, and aggression as the most worrisome symptoms of schizophrenia. Most caregivers felt that they act as a mediator between the medical team and the patient and that they are responsible for the patient’s adherence to treatment. Caregivers report that a schizophrenia diagnosis has strained their own emotional health, reduced their ability to have a satisfying personal life, and disrupted their family life. Caregivers generally had fewer barriers caring for patients receiving LAI antipsychotic treatments than caring for patients not receiving such treatments. Caregivers were interested in learning more about new treatments, coping strategies, and understanding specific symptoms.Conclusion: Caregivers need help recognizing, understanding, and managing specific and common symptoms of schizophrenia. Information about strategies to handle these symptoms would be beneficial. Caregivers also want information on new and emerging therapies, which may help facilitate discussions with clinicians about different treatment options.Keywords: long-acting injectable antipsychotic medications, symptom management, emotional health, treatment adherence, families

Leslie Citrome,1 Emily Belcher,2 Sylvie Stacy,2 Mark Suett,3 Marko Mychaskiw,4 Gregory D Salinas2 1Department of Psychiatry and Behavioral Sciences, New York Medical College, Valhalla, NY, USA; 2Department of Research and Assessment, CE Outcomes, LLC, Birmingham, AL, USA; 3Teva UK Limited, Global Medical Affairs, Harlow, UK; 4Teva Branded Pharmaceutical Products R&D, Inc., Global Health Economics and Outcomes Research, West Chester, PA, USACorrespondence: Leslie Citrome 11 Medical Park Drive, Suite 102, Pomona, NY, 10970, USATel +1 845 362 2081Email citrome@cnsconsultant.comPurpose: Schizophrenia is a chronic and serious mental disorder characterized by disturbances in thought, perception, and behavior that impair daily functioning and quality of life. Long-acting injectable (LAI) antipsychotic medications may improve long-term outcomes over oral medications; however, LAI antipsychotic medications are often only considered as a last resort late in the disease course. This study sought to assess current clinical practice patterns, clinicians’ attitudes, and barriers to the use of LAI antipsychotic medications as well as identify unmet educational needs of psychiatric clinicians in managing patients with schizophrenia.Methods: A survey was distributed via email to 2330 United States-based clinicians who manage patients with schizophrenia; 379 completed the survey and were included for analysis. The survey included five patient case-based scenarios, with seven decision points. Data were analyzed with qualitative and quantitative methodologies.Results: Clinicians were most confident in determining when to initiate treatment and least confident in transitioning to injectable therapy or administering injectable therapy. Clinicians cited nonadherence, and not wanting to take daily medicine or the “hassle” of frequent treatment, as key factors for which patients were most suitable for an LAI antipsychotic medication. Patient nonadherence was considered the most important barrier to optimal management of patients with schizophrenia. A clinician’s perception of relapse was a strong driver of whether or not the clinician would discuss/recommend an LAI antipsychotic medication.Conclusion: This study suggests that clinicians may be reluctant to discuss or recommend switching patients to an LAI antipsychotic medication if they are perceived as doing well on current therapy. These results will inform future research and continuing education that aims to improve the confidence, knowledge, and competence of clinicians who provide care for patients with schizophrenia who may benefit from treatment with an LAI antipsychotic medication and clinicians who may be more likely to routinely offer an LAI antipsychotic medication to their patients.Keywords: long-acting antipsychotic medication, depot, injectable, long-acting, barriers, unmet needs

Leslie Citrome,1 Stuart H Isaacson,2 Danielle Larson,3 Daniel Kremens4 1New York Medical College, Valhalla, NY, USA; 2Parkinson’s Disease and Movement Disorders Center of Boca Raton, Boca Raton, FL, USA; 3Parkinson’s Disease and Movement Disorders Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; 4Department of Neurology, Jefferson Comprehensive Parkinson’s Disease and Movement Disorders Center, Thomas Jefferson University, Philadelphia, PA, USACorrespondence: Leslie CitromeNew York Medical College, 40 Sunshine Cottage Road, Valhalla, NY, 10595, USATel +1 845 362-2081Email citrome@cnsconsultant.comAbstract: Tardive dyskinesia (TD) is a hyperkinetic movement disorder caused by the use of dopamine receptor-blocking agents (DRBAs), a category of medications that includes first- and second-generation antipsychotics (APs) and agents such as metoclopramide that are used for the treatment of nausea and gastrointestinal dysmotility. While TD can affect people of all ages, older age is associated with increased risk of TD and also with the emergence of TD occurring after shorter treatment durations and lower dosages of DRBAs. TD is characterized by involuntary movements that include the face, limbs, and trunk, and is associated with increased comorbidities, social stigmatization, and impaired physical and mental health. Once present, TD tends to persist despite AP dose adjustment or discontinuation. Even with the use of US Food and Drug Administration (FDA)-approved medications for TD, symptoms may persist. Because the leading hypothesis for the pathophysiology of TD has been dysregulation of dopamine transmission due to treatment with DRBAs, APs that avoid postsynaptic dopamine receptor blockade may provide an alternative therapeutic approach for patients who require an AP. In this review, we discuss the risks, burdens, prevention, and management of TD, with a focus on older people.Keywords: tardive dyskinesia, antipsychotic medications, age

Leslie Citrome,1 Christine Graham,2 Adam Simmons,2 Ying Jiang,2 Mark S Todtenkopf,2 Bernard Silverman,2 Lauren DiPetrillo,2 Hannah Cummings,2 Lei Sun,2 David McDonnell3 1Department of Psychiatry and Behavioral Sciences, New York Medical College, Valhalla, NY, USA; 2Alkermes, Inc., Waltham, MA, USA; 3Alkermes Pharma Ireland Limited, Dublin, IrelandCorrespondence: Leslie Citrome 11 Medical Park Drive, Suite 102, Pomona, NY, 10970, USATel +1-845-362-2081Email citrome@cnsconsultant.comAbstract: Olanzapine effectively treats schizophrenia and bipolar I disorder (BD-I); however, its use is limited by the risk of significant weight gain and metabolic effects. OLZ/SAM, a combination of olanzapine and samidorphan, was recently approved in the United States for the treatment of adults with schizophrenia or BD-I. OLZ/SAM provides the efficacy of olanzapine while mitigating olanzapine-associated weight gain through opioid-receptor blockade. Here, we summarize OLZ/SAM clinical data characterizing pharmacokinetics, antipsychotic efficacy, weight mitigation efficacy, safety, and long-term treatment effects. In an acute exacerbation of schizophrenia, OLZ/SAM and olanzapine provided similar symptom improvements versus placebo at week 4. In stable outpatients with schizophrenia, OLZ/SAM treatment resulted in significantly less weight gain, reducing the risk for clinically significant weight gain and waist circumference increases of ≥ 5 cm by half, compared with olanzapine at week 24. Based on open-label extension studies, OLZ/SAM is safe and well tolerated for up to 3.5 years of treatment, while maintaining schizophrenia symptom control and stabilizing weight. The olanzapine component of OLZ/SAM was bioequivalent to branded olanzapine (Zyprexa); adjunctive OLZ/SAM had no clinically significant effects on lithium or valproate pharmacokinetics. Additionally, OLZ/SAM had no clinically relevant effect on electrocardiogram parameters in a dedicated thorough QT study. Overall, safety and tolerability findings from clinical studies with OLZ/SAM indicate a similar safety profile to that of olanzapine, with the exception of less weight gain. As OLZ/SAM contains the opioid antagonist samidorphan, it is contraindicated in patients using opioids and in those undergoing acute opioid withdrawal. Clinical trial results from more than 1600 subjects support the use of OLZ/SAM as a new treatment option for patients with schizophrenia or BD-I.Keywords: antipsychotic agents, clinical efficacy, olanzapine, opioid antagonists, safety, weight gain

Russell Rosenberg,1 Leslie Citrome,2 Christopher L Drake3 1Neurotrials Research, Atlanta, GA, USA; 2Department of Psychiatry and Behavioral Sciences, New York Medical College, Valhalla, NY, USA; 3Thomas Roth Sleep Disorders and Research Center, Henry Ford Health System, Detroit, MI, USACorrespondence: Russell RosenbergNeurotrials Research, 5887 Glenridge Drive, Suite 400, Atlanta, GA, 30328, USATel +1 404 851 9934Email rrosenberg@neurotrials.comAbstract: Chronic insomnia disorder, which affects 6– 10% of the population, is diagnostically characterized by ongoing difficulties with initiating or maintaining sleep occurring at least three times per week, persisting for at least 3 months, and associated with daytime impairment. While chronic insomnia is often considered a condition primarily related to impaired sleep, the disorder can also adversely affect domains of physical and mental health, quality of life, and daytime function, which highlights the importance of treating the multidimensional sleep disorder. Owing to misperceptions about the safety and effectiveness of treatment options, many individuals with insomnia may not seek professional treatment, and alternatively use ineffective home remedies or over-the-counter medications to improve sleep. Some physicians may even believe that insomnia is remediated by simply having the patient “get more sleep”. Unfortunately, treatment of insomnia is not always that simple. The disorder’s complex underlying pathophysiology warrants consideration of different nonpharmacologic and pharmacologic treatment options. Indeed, recent insights gained from research into the pathophysiology of insomnia have facilitated development of newer treatment approaches with more efficacious outcomes. This narrative review provides a summary of the diagnostic criteria and pathophysiology of insomnia and its subtypes. Further, this review emphasizes new and emerging nonpharmacologic and pharmacologic treatments for chronic insomnia, including recent enhancements in approaches to cognitive behavioral therapy for insomnia (CBT-I) and the new dual orexin receptor antagonist (DORA) pharmacologics. These advances in treatment have expanded the treatment options and are likely to result in improved outcomes in patients with chronic insomnia.Keywords: dual orexin receptor antagonists, cognitive behavioral therapy-insomnia, insomnia subtype, hypnotic

Richard Jackson,1 Matthew N Brams,2 Leslie Citrome,3 Amber R Hoberg,4 Stuart H Isaacson,5 John M Kane,6 Rajeev Kumar7 1University of Michigan School of Medicine, Ann Arbor, MI, USA; 2Baylor College of Medicine, Houston, TX, USA; 3New York Medical College, Valhalla, NY, USA; 4GeroPsych Associates of Central Texas, Austin, TX, USA; 5Parkinson’s Disease and Movement Disorders Center of Boca Raton, Boca Raton, FL, USA; 6Feinstein Institution for Medical Research, Lynbrook, NY, USA; 7Rocky Mountain Movement Disorders Center, Englewood, CO, USACorrespondence: Richard JacksonUniversity of Michigan School of Medicine, 4111 Andover Road, Suite W100, Bloomfield Hills, MI, 48302, USATel +1 248 290 5400Fax +1 248 290 5401Email richardjackson2000@yahoo.comPurpose: Tardive dyskinesia (TD) is a hyperkinetic movement disorder in which patients experience abnormal involuntary movements that can have profound negative impacts on physical, cognitive, and psychosocial functioning. Use of measures to assess the functional impact of TD in routine clinical practice is lacking. To address this gap, an advisory panel of experts in psychiatry and movement disorder neurology was convened to develop consensus recommendations on assessment of the impact of TD on patients’ functioning that can be used in clinical practice.Methods: An advisory panel provided recommendations using an iterative process, beginning with a narrative literature review regarding current practices for assessing the impact of TD in clinical settings. A detailed summary was generated, and the advisory panel provided comments about the content and answered questions about assessing TD impact in clinical practice. The panelists’ responses were discussed during a virtual meeting held on August 28, 2020. A second meeting on September 25, 2020, focused on developing and refining recommendations for assessment of the impact of TD in clinical practice. At the conclusion of the second meeting, general consensus was reached on all recommendation statements.Results: As part of routine clinical practice, it is imperative to assess the impact of TD on the patient’s life to help guide treatment decisions. Key domains for assessing the overall impact of TD include social, physical, vocational, and psychological functioning and the impact of TD on the underlying psychiatric disorder. Assessment of TD impact should be performed at every patient visit. Impact assessments should include consultation with patients, caregivers, and family members. Shared decision-making to initiate TD treatment should consider impact.Conclusion: The impact of TD should be assessed routinely, including the key domains of social, physical, vocational, and psychological functioning and the impact of TD on the underlying psychiatric disorder.Keywords: hyperkinetic movement, functional domains, diagnosis, treatment

Leslie Citrome,1 Yangchun Du,2 Peter J Weiden3 1Psychiatry and Behavioral Sciences, New York Medical College, Valhalla, NY, USA; 2Biostatistics, Alkermes, Inc., Waltham, MA, USA; 3Medical Affairs, Alkermes, Inc., Waltham, MA, USACorrespondence: Leslie Citrome 11 Medical Park Drive, Suite 106, Pomona, NY 10970, USATel +1 845 362 2081Email citrome@cnsconsultant.comObjective: 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.Keywords: aripiprazole lauroxil, long-acting injectable, psychotic disorders, antipsychotic agents, number needed to treat, effect size

Leslie Citrome1, Joseph P McEvoy2, Mark S Todtenkopf3, David McDonnell4, Peter J Weiden3 1Department of Psychiatry and Behavioral Sciences, New York Medical College, Valhalla, NY, USA; 2Department of Psychiatry and Health Behavior, Medical College of Georgia, Augusta University, Augusta, GA, USA; 3Alkermes, Inc., Waltham, MA, USA; 4Alkermes Pharma Ireland Ltd., Dublin, IrelandCorrespondence: Leslie Citrome 11 Medical Park Drive, Suite 106, Pomona, NY 10970, USATel +1 845 362 2081Email citrome@cnsconsultant.comAbstract: 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.Keywords: antipsychotic, efficacy, metabolic dysregulation, weight gain

Justin Faden,1 Leslie Citrome21Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19125, USA; 2Psychiatry & Behavioral Sciences, New York Medical College, Valhalla, NY 10595, USAAbstract: Agitation is a common and serious symptom of bipolar mania and schizophrenia, and can be defined as excessive motor and verbal activity. If left unrecognized and untreated, agitation can evolve into aggression, resulting in potential patient and staff injury. An ideal treatment for agitation would have a rapid onset, cause calmness without sedation, and be tolerable, efficacious, and non-coercive, while managing the underlying condition. A novel approach for the treatment of agitation is inhaled loxapine. Inhaled loxapine is rapidly absorbed into the systemic circulation through the alveoli, resulting in a near immediate onset of action. The efficacy of inhaled loxapine was established in an extensive clinical development program that included persons with schizophrenia and bipolar mania. Additionally, inhaled loxapine has comparable efficacy to intramuscular ziprasidone, olanzapine, haloperidol, aripiprazole, and lorazepam, with the added benefit of being non-painful and non-traumatizing. Inhaled loxapine carries a bolded black box warning for bronchospasm, and as a result, in the US, requires enrollment in a Risk Evaluation and Mitigation Strategy program, and is contraindicated in those with pulmonary disease. Additionally, the use of inhaled loxapine can be associated with dysgeusia and throat irritation. Inhaled loxapine requires some degree of patient cooperation, and therefore may not be appropriate for all agitated patients.Keywords: inhaled loxapine, agitation, schizophrenia, bipolar disorder, mania, antipsychotic

Kristen Ward,1 Leslie Citrome2 1Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI, USA; 2Department of Psychiatry and Behavioral Science, New York Medical College, Valhalla, NY, USA Abstract: The purpose of this review is to describe the available data for brexpiprazole in the maintenance treatment of schizophrenia. This objective was completed by searching the databases PubMed, Embase, and ClinicalTrials.gov to identify relevant study results presented as papers or abstracts. In summary, brexpiprazole is a new agent in the D2 partial agonist class that has a unique receptor-binding profile, based in part on high affinity for serotonin 5HT1A and 5HT2A receptors, paired with lower intrinsic activity at dopamine D2 receptors. The average dose used in efficacy and safety studies for the maintenance treatment of schizophrenia ranged from 3.0 and 3.1 mg in the open-label safety studies to 3.6 mg in the double-blind randomized relapse-prevention study. Highlights from the 52-week double-blind placebo-controlled relapse-prevention trial evidenced rates of relapse in the brexpiprazole group of 13.5% vs 38.5% in the placebo group (number needed to treat 4, 95% CI 3–8; P

Leslie Citrome Department of Psychiatry and Behavioral Sciences, New York Medical College, Valhalla, NY, USA Abstract: Cariprazine is an oral antipsychotic approved in the US and EU for the treatment of schizophrenia. Cariprazine differs from other antipsychotics in that it is a dopamine D3- and D2-receptor partial agonist, with tenfold higher affinity for D3 receptors than for D2 receptors. Cariprazine is metabolized in two steps by CYP3A4 to didesmethyl-cariprazine (DDCAR). DDCAR has a long half-life of 1–3 weeks and is the predominant circulating active moiety. Efficacy and safety in persons with acute schizophrenia were assessed in four similarly designed, short-term, randomized, placebo-controlled clinical trials in nonelderly adults, with three studies considered positive and yielding a number needed to treat vs placebo for response (change from baseline ≥30% in Positive and Negative Syndrome Scale total score) of ten for the approved dose range of cariprazine 1.5–6 mg/day. The most common adverse reactions were extrapyramidal symptoms (15% and 19% for 1.5–3 and 4.5–6 mg/day, respectively, vs 8% for placebo) and akathisia (9% and 12.5% for 1.5–3 and 4.5–6 mg/day, respectively, vs 4% for placebo). For the approved dose range, rates of discontinuation because of an adverse event were lower overall for patients receiving cariprazine vs placebo (9% vs 12%). Weight and metabolic profile appear favorable. Cariprazine does not increase prolactin levels or prolong the electrocardiographic QT interval. Cariprazine has also been found to be effective for the maintenance treatment of schizophrenia by delaying time to relapse when compared with placebo (HR 0.45). A 26-week randomized clinical trial evidenced superiority of cariprazine over risperidone for the treatment of predominantly negative symptoms in patients with schizophrenia. Cariprazine is also approved in the US for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults and is being studied for the treatment of bipolar I depression and major depressive disorder. Keywords: cariprazine, didesmethyl-cariprazine, dopamine-receptor partial agonist, schizophrenia, dopamine D3 receptor

Myrlene S Aigbogun,1 Sizhu Liu,2 Siddhesh A Kamat,1 Christophe Sapin,3 Amy M Duhig,2 Leslie Citrome4 1Health Economics and Outcomes Research, Otsuka Pharmaceutical Development and Commercialization, Inc, Princeton, NJ, USA; 2Global Health Economics and Outcomes Research, Xcenda, Palm Harbor, FL, USA; 3Global Analytics, Lundbeck, Paris, France; 4Psychiatry and Behavioral Sciences, New York Medical College, Valhalla, NY, USA Objective: This study used a decision-analytic framework to assess the cost-effectiveness of brexpiprazole vs comparator branded therapies for reducing relapses and hospitalizations among adults with schizophrenia from a US payer perspective.Methods: An economic model was developed to assess patients with stable schizophrenia initiating treatment with brexpiprazole (1–4 mg), cariprazine (1–6 mg), or lurasidone (40–80 mg) over a 1-year period. After 6 months, patients remained on treatment or discontinued due to relapse, adverse events, or other reasons. Patients who discontinued due to relapse or adverse events were assumed to have switched to other therapy, and those who discontinued due to other reasons were assumed to have received no therapy. Primary outcomes were incremental cost per relapse avoided and hospitalization avoided, and the secondary outcome was cost per quality-adjusted life-year (QALY) gained. Sensitivity and scenario analyses were also conducted.Results: Brexpiprazole was associated with the highest per-patient clinical effectiveness (avoided relapses 0.637, avoided hospitalizations 0.719, QALYs 0.707) among comparators, followed by cariprazine (avoided relapses 0.590, avoided hospitalizations 0.683, QALYs 0.683) and lurasidone (avoided relapses 0.400, avoided hospitalizations 0.536, QALYs 0.623). Annual per-patient health-care costs were lowest for brexpiprazole ($20,510), followed by cariprazine ($22,282) and lurasidone ($25,510). Brexpiprazole was the least costly and most effective treatment strategy for all outcomes. Results were sensitive to relapse rates and daily cost of brexpiprazole. Limitations include data principally obtained from drug-specific randomized withdrawal studies and lack of direct-comparison trials.Conclusion: This analysis evaluated brexpiprazole treatment for the reduction of schizophrenia relapses and hospitalizations over a 1-year period compared to other recently available branded antipsychotics, and excluded generic antipsychotic treatments. Brexpiprazole treatment may lead to clinical benefits and medical cost savings, and provides a cost-effective treatment option for patients relatively to other branded second-generation antipsychotics. Keywords: schizophrenia, cost-effectiveness, relapse prevention, cost-benefit, indirect analysis, event avoided, hospitalization avoided, brexpiprazole

Leslie Citrome,1 Judith C Kando,2 Caleb Bliss3 1Department of Psychiatry and Behavioral Sciences, New York Medical College, Valhalla, NY, USA; 2Shire, Global Medical Affairs, Lexington, MA, USA; 3Shire, Biostatistics, Lexington, MA, USA Objectives: In two Phase III studies, lisdexamfetamine dimesylate (LDX) reduced binge eating (BE) days/week in adults with moderate to severe binge eating disorder (BED) and was associated with improvement based on the Clinical Global Impressions–Improvement (CGI-I) scale. In this study, post hoc analyses examined the relationships between clinical observations and clinical rating scales in individuals with BED. Clinical trial registration: NCT01718483 (ClinicalTrials.gov/ct2/show/NCT01718483); NCT01718509 (ClinicalTrials.gov/ct2/show/NCT01718509). Methods: Two 12-week, double-blind, placebo-controlled studies randomized (1:1) adults meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, BED criteria and with protocol-defined moderate to severe BED (study 1, N=383; study 2, N=390) to placebo or dose-optimized LDX (50 or 70 mg). Assessments included the number of BE days/week, CGI–Severity (CGI-S) and CGI-I scores, and Yale-Brown Obsessive Compulsive Scale modified for Binge Eating (Y-BOCS-BE) total scores. For these post hoc analyses, data were pooled across studies and treatment arms. Statistical assessments included Spearman correlations and equipercentile linking analyses (ELA). Reported P-values are nominal (descriptive and not adjusted for multiplicity). Results: At baseline, nominally significant correlations with CGI-S scores were reported for BE days/week (r=0.374; P

Leslie Citrome,1 Ronald Landbloom,2 Cheng-Tao Chang,3 Willie Earley4 1Department of Psychiatry and Behavioral Sciences, New York Medical College, Valhalla, NY, USA; 2Department of Neuroscience, Merck, Whitehouse Station, NJ, USA; 3Biostatistics, Allergan, Jersey City, NJ, USA; 4Clinical Development, Allergan, Jersey City, NJ, USA Background: Bipolar disorder is associated with an increased risk of aggression. However, effective management of hostility and/or agitation symptoms may prevent patients from becoming violent. This analysis investigated the efficacy of the antipsychotic asenapine on hostility and agitation in patients with bipolar I disorder.Methods: Data were pooled from three randomized, double-blind, placebo-controlled, Phase III trials of asenapine in adults with manic or mixed episodes of bipolar I disorder (NCT00159744, NCT00159796, and NCT00764478). Post hoc analyses assessed the changes from baseline to day 21 on the Young Mania Rating Scale (YMRS) and the Positive and Negative Syndrome Scale (PANSS) hostility-related item scores in asenapine- or placebo-treated patients with at least minimal or mild symptom severity and on the PANSS-excited component (PANSS-EC) total score in agitated patients. Changes were adjusted for improvements in overall mania symptoms to investigate direct effects on hostility.Results: Significantly greater changes in favor of asenapine versus placebo were observed in YMRS hostility-related item scores (irritability: least squares mean difference [95% confidence interval] =–0.5 [–0.87, –0.22], P=0.001; disruptive–aggressive behavior: –0.7 [–0.99, –0.37], P

Suresh Durgam,1 Changzheng Chen,1 Carl P Gommoll,1 John Edwards,1 Leslie Citrome2 1Allergan, Jersey City, NJ, USA; 2Department of Psychiatry and Behavioral Sciences, New York Medical College, Valhalla, NY, USA Background: In three 8-week studies of vilazodone 40 mg/d (NCT00285376, NCT00683592, and NCT01473394) and a 10-week study of vilazodone 20 or 40 mg/d (NCT01473381), adults with major depressive disorder (MDD) showed significantly greater improvement with vilazodone versus placebo in global disease severity as measured by mean change from baseline in Clinical Global Impression of Severity (CGI-S) score. To assess the proportion of patients achieving clinically meaningful improvement, a post hoc pooled analysis was conducted using categorical shifts in disease severity based on CGI-S scores at baseline and end of treatment (EOT). Methods: Analyses were conducted in the pooled intent-to-treat population (N=2,218). Definitions of categorical shifts included CGI-S ≥4 (moderately ill or worse) at baseline to CGI-S ≤2 (normal or borderline ill) at EOT; CGI-S ≥5 (markedly ill or worse) at baseline to CGI-S ≤2 at EOT; and CGI-S ≥6 (severely ill or worse) at baseline to CGI-S ≤3 (mildly ill or better) at EOT. Results: At baseline, 2,217 patients were moderately ill or worse. The percentage who improved to normal or borderline ill was significantly higher with vilazodone than with placebo (40.0% versus 27.8%; odds ratio [OR] =1.7, P

Denise E Wilfley,1 Leslie Citrome,2 Barry K Herman3 1Department of Psychiatry, Washington University School of Medicine, St Louis, MO, 2Department of Psychiatry & Behavioral Sciences, New York Medical College, Valhalla, NY, 3Global Medical Affairs, Shire, Lexington, MA, USA Abstract: The objective of this review was to examine the evidentiary basis for binge eating disorder (BED) with reference to the Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition (DSM-5) diagnostic criteria for BED. A PubMed search restricted to titles and abstracts of English-language reviews, meta-analyses, clinical trials, randomized controlled trials, journal articles, and letters using human participants was conducted on August 7, 2015, using keywords that included “binge eating disorder,” DSM-5, DSM-IV, guilt, shame, embarrassment, quantity, psychological, behavior, and “shape and weight concerns.” Of the 257 retrieved publications, 60 publications were considered relevant to discussions related to DSM-5 diagnostic criteria and were included in the current review, and 20 additional references were also included on the basis of the authors’ knowledge and/or on a review of the reference lists from relevant articles obtained through the literature search. Evidence supports the duration/frequency criterion for BED and the primary importance of loss of control and marked distress in identifying individuals with BED. Although overvaluation of shape/weight is not a diagnostic criterion, its relationship to the severity of BED psychopathology may identify a unique subset of individuals with BED. Additionally, individuals with BED often exhibit a clinical profile consisting of psychiatric (eg, mood, obsessive–compulsive, and impulsive disorders) and medical (eg, gastrointestinal symptoms, metabolic syndrome, and type 2 diabetes) comorbidities and behavioral profiles (eg, overconsumption of calories outside of a binge eating episode and emotional eating). Future revisions of the BED diagnostic criteria should consider the inclusion of BED subtypes, perhaps based on the overvaluation of shape/weight, and an evidence-based reassessment of severity criteria. Keywords: binge eating disorder, diagnosis, obesity, psychotherapy, pharmacotherapy, psychopathology

Leslie Citrome Department of Psychiatry and Behavioral Sciences, New York Medical College, Valhalla, NY, USA Abstract: When treating persons with schizophrenia, delaying time to relapse is a main goal. Antipsychotic medication has been the primary treatment approach, and there are a variety of different choices available. Lurasidone is a second-generation (atypical) antipsychotic agent that is approved for the treatment of schizophrenia and bipolar depression. Three long-term studies of lurasidone have examined time to relapse in persons with schizophrenia, including a classic placebo-controlled randomized withdrawal study and two 12-month active comparator studies (vs risperidone and vs quetiapine extended-release). Lurasidone 40–80 mg/d evidenced superiority over placebo (number needed to treat [NNT] vs placebo for relapse, 9). Lurasidone 40–160 mg/d was noninferior to quetiapine extended-release 200–800 mg/d on the outcome of relapse, and was superior on the outcome of avoidance of hospitalization (NNT 8) and the outcome of remission (NNT 7). Lurasidone demonstrated a lower risk for long-term weight gain than the active comparators. Demonstrated differences in tolerability profiles among the different choices of antipsychotics make it possible to attempt to match up an individual patient to the best choice for such patient based on past history of tolerability, comorbidities, and personal preferences, potentially improving adherence. Keywords: antipsychotic, lurasidone, relapse, tolerability, schizophrenia, weight gain

Leslie Citrome,1 Anna Eramo,2 Clement Francois,2 Ruth Duffy,3 Susan N Legacy,3 Steve J Offord,3 Holly B Krasa,3 Stephen S Johnston,4 Alice Guiraud-Diawara,5 Siddhesh A Kamat,3 Patricia Rohman3 1Department of Psychiatry and Behavioral Sciences, New York Medical College, Valhalla, NY, 2Lundbeck, Deerfield, IL, 3Otsuka America Pharmaceuticals, Princeton, NJ, 4Truven Health Analytics, Bethesda, MD, USA; 5Lundbeck SAS, Issy-les-Moulineaux, France Purpose: Atypical antipsychotics (AAs), an effective treatment for schizophrenia, have a range of pharmacologic properties leading to differences in tolerability as well as heterogeneity in treatment response. Individual patient characteristics must be considered when making treatment choices, especially from an adverse event (AE) or tolerability perspective. Despite the availability of numerous AAs, after appraising patient characteristics at the time of treatment selection, physicians may quickly run out of tolerable treatment options. Patients and methods: AE risk factors, defined as having either a prior history of an AE or a risk factor for that AE, were determined for Medicaid-insured and Commercially insured patients using database analysis. Patients receiving AA treatment between January 1, 2010 and December 31, 2012 defined the index date of first observed AA prescription during this period. Nine AAs were evaluated for association with AE risk factors as informed by drug prescribing information from the different manufacturers and published meta-analyses. The proportion of patients with pre-index AE risk factors prescribed an AA associated with that risk factor was then determined. Results: A high proportion of patients (>80%) were prescribed an AA associated with extrapyramidal symptoms or akathisia despite experiencing extrapyramidal symptoms or akathisia prior to AA treatment initiation. Similar trends were observed among patients with diabetes (>60%) and obesity (>40%). From the nine treatment options available, the number of optimal choices for individual patient segments were limited based on their prior history, including those with cardiometabolic and cardiovascular comorbidities (four); experiencing prolactin elevation-related problems (seven); needing to avoid excessive sedation (four); or at risk of extrapyramidal symptoms or akathisia (two). Options were then further restricted among patients in more than one segment when multiple pre-index AE risk factors were combined. Conclusion: When combining patient risk profile with antipsychotic AE profile, physicians may quickly run out of tolerable treatment options for individual patients, despite the availability of many AAs, suggesting a need for additional treatment options with better tolerability and without compromising efficacy. Keywords: schizophrenia, atypical antipsychotics, tolerability, comorbidities, treatment

Leslie CitromeDepartment of Psychiatry and Behavioral Sciences, New York Medical College, Valhalla, NY, USAAbstract: Agitation (excessive motor or verbal activity) can be associated with schizophrenia or bipolar mania, and can further escalate into aggressive behavior and potentially lead to injuries in patients and staff. Medications used to treat agitation include antipsychotics and benzodiazepines, usually administered intramuscularly when rapid action is desired. Loxapine, a first-generation antipsychotic, has recently been reformulated into an inhaled powder that allows for direct administration to the lungs, resulting in rapid absorption into the systemic circulation. Administered via a single-use device, inhaled loxapine was tested in randomized controlled trials in agitation associated with schizophrenia or bipolar mania; doses of 5 mg and 10 mg were found to be efficacious, with an apparent dose response. In the Phase III studies, number needed to treat versus placebo for a ≥40% reduction from baseline on the Positive and Negative Syndrome Scale – Excited Component (PANSS-EC) at 2 hours was three for patients with bipolar disorder, and five for 5 mg and four for 10 mg for patients with schizophrenia, with effect sizes comparable to what has been observed in analogous studies of intramuscular injection of antipsychotics or lorazepam. Separation from placebo on the PANSS-EC was as early as 10 minutes postinhalation, the first time point where this was measured. Dysgeusia was the most commonly encountered spontaneously reported adverse event. Adverse events related to extrapyramidal symptoms and akathisia were relatively rare. Spirometry studies identified the potential for bronchospasm particularly in persons with asthma. Because of concerns over pulmonary safety, inhaled loxapine is restricted to use in hospitals and patients need to be prescreened for the presence of pulmonary disease, as well as monitored for signs and symptoms of bronchospasm for 1 hour postdose administration, as per a Food and Drug Administration-mandated Risk Evaluation and Mitigation Strategy.Keywords: agitation, antipsychotic, bipolar disorder, inhaled loxapine, mania, schizophrenia

Leslie CitromeNew York University School of Medicine, Department of Psychiatry, New York, NY, USAAbstract: Asenapine tablets are a new option for the treatment of schizophrenia. Sublingual administration is essential because bioavailability if ingested is less than 2%. Efficacy is supported by acute and long-term randomized controlled studies conducted by the manufacturer, with asenapine 5 mg twice daily evidencing superiority over placebo in six-week studies of acute schizophrenia, and flexibly-dosed asenapine (modal dose 10 mg twice daily) superior to placebo in a 26-week maintenance of response study. Tolerability advantages over some second-generation antipsychotics, such as olanzapine, include a relatively favorable weight and metabolic profile, as demonstrated in a 52-week randomized, head-to-head, double-blind clinical trial. Although dose-related extrapyramidal symptoms and akathisia can be present, the frequency of these effects is lower than that for haloperidol and risperidone. Somnolence may also occur, and appears to be somewhat dose-dependent when examining rates of this among patients receiving asenapine for schizophrenia and bipolar disorder. Prolactin elevation can occur, but at a rate lower than that observed for haloperidol or risperidone. Unique to asenapine is the possibility of oral hypoesthesia, occurring in about 5% of participants in the clinical trials. Obstacles to the use of asenapine are the recommendations for twice-daily dosing and the need to avoid food or liquids for 10 minutes after administration, although the bioavailability is only minimally reduced if food or liquids are avoided for only two minutes.Keywords: antipsychotic, asenapine, clinical trials, schizophrenia