PURPOSE/BACKGROUND:Clozapine was approved in the United States (US) using 1989 regulations and knowledge. After 30 years, many sections of the US package insert (PI) are outdated. METHODS:We comprehensively reviewed the literature to propose PI updates. We present the information in 2 articles. In Part I, we focus on basic pharmacology based on 407 relevant articles. Part II focuses on clinical aspects and pharmacovigilance. FINDINGS/RESULTS:Based on more recent expectations of Food and Drug Administration regulations, we reviewed clozapine basic pharmacology including the following: 1) clearance, 2) pharmacokinetics and pharmacodynamics, and 3) monitoring tools. We identified 9 major problems in the basic pharmacological sections of the PI including the following: 1) in vivo studies indicate that clozapine is dependent on CYP1A2 for its metabolism, 2) the minor role of CYP2D6 in clozapine metabolism requires removing the PI recommendation to lower clozapine doses in CYP2D6 poor metabolizers, 3) in nontoxic concentrations CYP3A4 has a minor role in clozapine metabolism and potent CYP3A4 inhibitors lack clinically relevant effects, 4) several drug-drug interactions need to be updated based on recent literature, 5) systemic inflammation may decrease clozapine metabolism and increase the risk of clozapine intoxication, 6) obesity may decrease clozapine metabolism, 7) patients of Asian and Indigenous American ancestry need lower clozapine doses, 8) personalized titration and c-reactive protein monitoring should be considered until prospective studies are available, and 9) the half-life section needs to be modified to acknowledge that single dosing at night is frequent in the US. IMPLICATIONS/CONCLUSIONS:An improvement in the US clozapine PI may lead to improvement in PIs worldwide.

Purpose/BackgroundClozapine was approved in the United States (US) using 1989 regulations and knowledge. After 30 years, many sections of the US package insert (PI) are outdated.MethodsWe comprehensively reviewed the literature to propose PI updates. We present the information in 2 articles. In Part I, we focus on basic pharmacology based on 407 relevant articles. Part II focuses on clinical aspects and pharmacovigilance.Findings/ResultsBased on more recent expectations of Food and Drug Administration regulations, we reviewed clozapine basic pharmacology including the following: 1) clearance, 2) pharmacokinetics and pharmacodynamics, and 3) monitoring tools. We identified 9 major problems in the basic pharmacological sections of the PI including the following: 1) in vivo studies indicate that clozapine is dependent on CYP1A2 for its metabolism, 2) the minor role of CYP2D6 in clozapine metabolism requires removing the PI recommendation to lower clozapine doses in CYP2D6 poor metabolizers, 3) in nontoxic concentrations CYP3A4 has a minor role in clozapine metabolism and potent CYP3A4 inhibitors lack clinically relevant effects, 4) several drug-drug interactions need to be updated based on recent literature, 5) systemic inflammation may decrease clozapine metabolism and increase the risk of clozapine intoxication, 6) obesity may decrease clozapine metabolism, 7) patients of Asian and Indigenous American ancestry need lower clozapine doses, 8) personalized titration and c-reactive protein monitoring should be considered until prospective studies are available, and 9) the half-life section needs to be modified to acknowledge that single dosing at night is frequent in the US.Implications/ConclusionsAn improvement in the US clozapine PI may lead to improvement in PIs worldwide.

This analysis used pharmacokinetic (PK) modeling to characterize dosing conversions and switching strategies from R064766, a once-every-2-weeks, intramuscular long-acting injectable antipsychotic (LAI) formulation of risperidone microspheres, and RBP-7000, a subcutaneous (sc) LAI formulation of risperidone administered in the abdomen once monthly (q1m), to TV-46000, a q1m or once-every-2-months (q2m) sc LAI formulation of risperidone. Total active moiety (TAM; risperidone + 9-OH risperidone) concentration–time profiles were simulated on the basis of published population PK models with virtual populations of 5000 patients. Simulations were performed to predict TAM exposures when switching to TV-46000 q1m and q2m 2–6 weeks after the last steady-state R064766 injection and 4 weeks after the last dose of RBP-7000. Comparable doses of oral risperidone, TV-46000, R064766, and RBP-7000 were identified. Initiating TV-46000 4–6 weeks after the last dose of R064766 resulted in similar trends for maximal (Cmax) and minimal (Cmin) plasma concentration ratios after the first injection for all TV-46000 doses and durations (q1m, q2m) compared with R064766 at steady state. Initiating TV-46000 q1m 4 weeks after the last dose of RBP-7000 resulted in slightly higher, but generally comparable, average plasma concentrations, Cmax, and Cmin at first dose and at steady state for TV-46000 compared with RBP-7000; Cmin of TV-46000 q2m and RBP-7000 were also comparable. Similar trends in plasma concentrations were observed for both back-of-the-upper-arm and abdominal administration when switching from R064766 and RBP-7000 to TV-46000. These simulations revealed switching to TV-46000 4–6 weeks after the last dose of R064766 and 4 weeks after the last dose of RBP-7000 provided generally comparable PK exposures at first dose and steady state of TV-46000. Clinician discretion will determine which switching strategy is most appropriate in context based on factors such as patient preference, scheduling convenience, and concerns about tolerability. Injected drugs that last in the body for weeks or months can be used to treat people living with schizophrenia. There are differences in the amount of drug in the blood over time between different brands of drugs, which can make it difficult for clinicians to figure out how much of a new drug to use and how long to wait between injections when switching patients from one injectable drug to another. The aim of this study was to use computer models to test different options when switching from one drug to another. The options studied included how much time to wait between the last dose of one drug and the first dose of another. The different dose amounts were also studied. In this work, the drugs being switched from are given either once every 2 weeks (R064766) or once per month (RBP-7000). The drug that is being switched to (TV-46000) is given once per month or once every 2 months. The predictions showed that TV-46000 injected 4–6 weeks after the last dose of R064766 and 4 weeks after the last dose of RBP-7000 did not significantly affect the amount of active drug in the blood over time. This study gives clinicians more information about how they can switch patients from one injectable drug to another. The decision to switch from one drug to another will be based on many factors, such as the patient’s preferences, convenience, and any concerns about safety or symptoms returning.

Abstract Objective A combination of olanzapine and the opioid receptor antagonist samidorphan (OLZ/SAM) has been approved in the United States for the treatment of adults with schizophrenia or adults with bipolar I disorder. In a phase 3 study in adults with schizophrenia (ENLIGHTEN-2), OLZ/SAM treatment was associated with significantly less weight gain compared with olanzapine. Prespecified subgroup analyses explored the consistency of the weight mitigation effect of OLZ/SAM vs olanzapine across demographic subgroups in ENLIGHTEN-2. Methods The multicenter, randomized, double-blind ENLIGHTEN-2 study (NCT02694328) included outpatients aged 18–55 years with a diagnosis of schizophrenia based on DSM-5 criteria, a body mass index (BMI) of 18 to 30 kg/m2, and stable body weight (self-reported change ≤5% for ≥3 months before study entry). Patients were randomized 1:1 to receive OLZ/SAM or olanzapine for 24 weeks. Co-primary endpoints (previously reported) were percent change in body weight and proportion of patients with at least 10% weight gain from baseline at week 24. Prespecified exploratory subgroup analyses by sex, age, self-reported race, and baseline BMI were conducted. Results At week 24, treatment with OLZ/SAM resulted in numerically less percent weight gain than with olanzapine across all subgroups evaluated. The proportion of patients with at least 10% weight gain was smaller in each subgroup treated with OLZ/SAM vs olanzapine. Conclusion In these exploratory subgroup analyses from the ENLIGHTEN-2 study, weight-mitigating effects of OLZ/SAM vs olanzapine were observed consistently across patient subgroups and were in line with results from the overall study population.

Introduction:Two vesicular monoamine transporter 2 (VMAT2) inhibitors are approved in the United States (US) for the treatment of tardive dyskinesia (TD). There is a paucity of information on the impact of VMAT2 inhibitor treatment on patient social and physical well-being. The study objective was to elucidate clinician-reported improvement in symptoms and any noticeable changes in social or physical well-being in patients receiving VMAT2 inhibitors.Methods:A web-based survey was offered to physicians, nurse practitioners, and physician assistants based in the US who prescribed valbenazine for TD within the past 24 months. Clinicians reported data from the charts of patients who met the inclusion criteria and were allowed to recall missing information.Results:Respondents included 163 clinicians who reviewed charts of 601 VMAT2-treated patients with TD: 47% had TD symptoms in ≥2 body regions, with the most common being in the head or face and upper extremities. Prior to treatment, 93% of patients showed impairment in ≥1 social domain, and 88% were impaired in ≥1 physical domain. Following treatment, among those with improvement in TD symptoms (n = 540), 80% to 95% showed improvement in social domains, 90% to 95% showed improvement in physical domains, and 73% showed improvement in their primary psychiatric condition.Discussion:In VMAT2-treated patients with TD symptom improvement, clinicians reported concomitant improvement in psychiatric disorder symptoms and in social and physical well-being. Regular assessment of TD impact on these types of domains should occur simultaneously with movement disorder ratings when evaluating the value of VMAT2 inhibitor therapy.

Among patients with schizophrenia (SZ) and bipolar I disorder (BD-I) treated with second-generation antipsychotics (SGAs), clinically-significant weight gain (CSWG) and treatment interruptions (TIs) are challenges that may result in morbidity/mortality.CSWG and TIs were assessed among patients who initiated oral SGAs of moderate-to-high weight gain risk (no exposure to index SGAs/first-generation antipsychotics for =12 months) using medical records/claims (OM1 Data Cloud; January 2013-February 2020). Outcomes included CSWG (=7% increase in baseline weight) and TIs (switches [to SGAs of low weight gain risk/long-acting injectables] or discontinuations [no SGAs for >30 days]). Descriptive analyses included proportions of patients with CSWG and TIs, and median time to these outcomes.Approximately three-quarters of patients were overweight/obese at baseline (SZ: N=8,174; BD-I: N=9,142). Within 3 months of SGA initiation, 12% of all patients experienced CSWG. For patients on treatment with index SGAs for >6 months (SZ: 29%; BD-I: 27%), 28% (SZ) and 30% (BD-I) experienced CSWG during follow-up. Median time to CSWG was 14 weeks. CSWG results were numerically similar among patients with SZ and BD-I.Over 96% of patients had TIs during follow-up (median time of 12 [SZ] and 13 [BD-I] weeks). Among patients with CSWG and subsequent TIs and weight measurements, 74% did not return to baseline weight after interrupting treatment; the remainder returned to baseline weight with median times of 38 (SZ) and 39 (BD-I) weeks. Results suggest that most patients with CSWG do not return to baseline weight after stopping treatment with oral SGAs of moderate-to-high weight gain risk.Funding. Alkermes, Inc.

The proposed pathophysiologicalmechanisms of neuroleptic-associated dysphagia include dopamine blockade and/or anticholinergic effects. Bradykinetic dysphagia can affect any stage of swallowing, and the symptom onset can vary from a few days to months after initiating antipsychotics. Management is based on previously published case reports and included drug cessation, dosage reduction, or switching to a different medication. Drugs like benztropine (anticholinergic) can be used to combat the involuntary movements caused as a side effect of antipsychotics. However, elderly individuals like our patient are at increased risk of developing adverse effects from benztropine, making it less ideal for controlling neuroleptic adverse reactions. A high index of clinical suspicion can help early diagnosis and further management preventing undesirable complications, including weight loss, airway obstruction, and aspiration. Neuroleptic use has shown to be an independent risk factor for the development of pneumonia. A systematic review andmeta-analysis have shown that the risk of pneumonia was increased by firstgeneration, second-generation, and all antipsychotics compared with no antipsychotic use. Therefore, neuroleptics can increase the risk of developing pneumonia directly or indirectly as a complication of dysphagia, indicating the importance of identifying the problem and instituting prompt management. The presented case describes a patient with well-controlled psychotic depression, treated with olanzapine for 15 years. He had a history of being treated with multiple drugs in the past and reported good control of psychotic symptoms only with his current dose of olanzapine. Studies have shown that the DaT scan has an increased sensitivity and specificity to diagnose Parkinson disease. A systematic review has shown that pooled accuracy measures in differentiating between Parkinson disease and vascular or drug-induced parkinsonism were relatively high, with sensitivity and specificity values greater than 85% and 80%, respectively. Hence, he was diagnosed with drug-associated parkinsonism, and an extensive workup also indicated the likely bradykinetic dysphagia associated with long-term use of olanzapine. Even after explaining the complications that may occur with dysphagia, he declined to switch to another drug or even decrease the dose of olanzapine. The possibility of olanzapine-associated dysphagia had never been explained to our patient previously

The psychopharmacology field is moving toward a mechanism-based nomenclature to replace outmoded descriptors of molecules with multiple pharmacological properties. In addition to publications covering these efforts [15–17], a Neuroscience-Based Nomenclature website was created (https://nbn2r.com) where one can download a free smartphone app, and which posts twice-yearly glossary updates in May and September. For the sake of simplicity, the term second-generation antipsychotic (SGA) will be used in this chapter, but the antipsychotics described herein have a range of pharmacologic properties, and a wide variety of kinetic profiles. Moreover, with the exception of transdermal asenapine and cariprazine, the SGAs presented in this chapter represent a group that are generally available worldwide.

Abstract Background Clozapine clinics can facilitate greater access to clozapine, but there is a paucity of data on their structure in the US. Methods A 23-item survey was administered to participants recruited from the SMI Adviser Clozapine Center of Excellence listserv to understand characteristics of clozapine clinics. Results Clozapine clinics (N = 32) had a median caseload of 45 (IQR = 21–88) patients and utilized a median of 5 (IQR = 4–6) interdisciplinary roles. The most common roles included psychiatrists (100%), pharmacists (65.6%), nurses (65.6%), psychiatric nurse practitioners (53.1%), and case managers (53.1%). The majority of clinics outreached to patients who were overdue for labs (78.1%) and had access to on-site phlebotomy (62.5%). Less than half had on call services (46.9%). Conclusions In this first systematic description of clozapine clinics in the US, there was variation in the size, staffing, and services offered. These findings may serve as a window into configurations of clozapine teams.

As with many first-generation antipsychotics (FGAs), perphenazine has no unique therapeutic benefit compared to other D2 antagonists, but does have a long-acting injectable (LAI) preparation available in certain parts of the world (Belgium, Denmark, Finland, Iceland, The Netherlands, Norway, Portugal, Sweden) and a large database of plasma level information. As the FGA arm of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia study, many clinicians came to appreciate that modest perphenazine dosages are effective, that perphenazine is associated with lower metabolic risk than many second-generation antipsychotics, and that perphenazine treatment is associated with less prolactin elevation than risperidone therapy [2, 3].

As with many first-generation antipsychotics (FGAs), zuclopenthixol and flupenthixol have no unique therapeutic benefit compared to other D2 antagonists, but have long-acting injectable (LAI) preparations available in certain parts of the world and a modest database of plasma level information. In addition to an LAI formulation, zuclopenthixol also has an injectable formulation (zuclopenthixol acetate) that provides therapeutic levels over several days, with a time to peak plasma levels (Tmax) of 24–48 hours [1].

AbstractObjectiveVesicular monoamine transporter 2 (VMAT2) inhibitors including valbenazine are first-line therapies for tardive dyskinesia (TD), a persistent movement disorder associated with antipsychotic exposure. This real-world study was performed to assess the association between patient awareness of TD symptoms and clinician-assessed symptom severity.MethodsClinicians who treated antipsychotic-induced TD with a VMAT2 inhibitor within the past 24 months were asked to extract demographic/clinical data from patients charts and complete a survey for additional data, including patient awareness of TD (yes/no) and TD symptom severity (mild/moderate/severe).ResultsData for 601 patients were provided by 163 clinicians (113 psychiatrists; 46 neurologists; 4 primary care physicians). Patient demographics: 50% male; mean age 50.6 years; 55% schizophrenia/schizoaffective disorder; 29% bipolar disorder; 16% other psychiatric diagnoses. Positive relationships were seen between patient awareness and clinician-assessed symptom severity. Awareness was highest in patients with severe symptoms in specific body regions: face (88% vs 78%/69% [awareness by severe vs moderate/mild symptoms]); jaw (90% vs 80%/67%); wrists (90% vs 69%/63%). In other regions, awareness was similar in patients with severe or moderate symptoms: lips (85%/86% vs 68% [severe/moderate vs mild]); tongue (81%/80% vs 73%); neck (80%/78% vs 68%); arms (67%/66% vs 62%); knees (67%/67% vs 53%).ConclusionsIn patients prescribed a VMAT2 inhibitor for TD, patient awareness was generally higher in those determined to have moderate-to-severe symptom severity as assessed by the clinician. More research is needed to understand how awareness and severity contribute to TD burden, and whether different treatment strategies are needed based on these factors.FundingNeurocrine Biosciences, Inc.

OBJECTIVE A nominal group process followed by a modified Delphi method was used to survey expert opinions on best practices for tardive dyskinesia (TD) screening, diagnosis, and treatment and to identify areas lacking in clinical evidence. PARTICIPANTS A steering committee of 11 TD experts met in nominal group format to prioritize questions to be addressed and identify core bibliographic materials and criteria for survey panelists. Of 60 invited experts, 29 (23 psychiatrists and 6 neurologists) agreed to participate. EVIDENCE A targeted literature search of PubMed (search term: tardive dyskinesia) and recommendations of the steering committee were used to generate core bibliographic material. Inclusion criteria were as follows: (1) review articles, meta-analyses, guidelines, or clinical trials; (2) publication in English between 2007 and 2017; (3) > 3 pages in length; and (4) publication in key clinical journals with impact factors ≥ 2.0. Of 29 references that met these criteria, 18 achieved a score ≥ 5 (calculated as the number of steering committee votes multiplied by journal impact factor and number of citations divided by years since publication) and were included. CONSENSUS PROCESS Two survey rounds were conducted anonymously through electronic media from November 2017 to January 2018; responses were collected, collated, and analyzed. Respondent agreement was defined a priori as unanimous (100%), consensus (75%-99%), or majority (50%-74%). For questions using a 5-point Likert scale, agreement was based on percentage of respondents choosing ≥ 4 ("agree completely" or "agree"). Round 1 survey included questions on TD screening, diagnosis, and treatment. Round 2 questions were refined per panelist feedback and excluded Round 1 questions with < 25% agreement and > 75% agreement (unless feedback suggested further investigation). CONCLUSIONS Consensus was reached that (1) a brief, clinical assessment for TD should be performed at every clinical encounter in patients taking antipsychotics; (2) even mild movements in 1 body area may represent possible TD; (3) management requires an overall evaluation of treatment, including reassessment of antipsychotics and anticholinergics as well as consideration of vesicular monoamine transporter 2 (VMAT2) inhibitors; and (4) informed discussions with patients/caregivers are essential.

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

Accurate diagnosis and appropriate treatment of tardive dyskinesia (TD) are imperative, as its symptoms can be highly disruptive to both patients and their caregivers. Misdiagnosis can lead to incorrect interventions with suboptimal or even deleterious results. To aid in the identification and differentiation of TD in the psychiatric practice setting, we review its clinical features and movement phenomenology, as well as those of other antipsychotic-induced movement disorders, with accompanying links to illustrative videos. Exposure to dopamine receptor blocking agents (DRBAs) such as antipsychotics or antiemetics is associated with a spectrum of movement disorders including TD. The differential diagnosis of TD is based on history of DRBA exposure, recent discontinuation or dose reduction of a DRBA, and movement phenomenology. Common diagnostic challenges are the abnormal behaviors and dyskinesias associated with advanced age or chronic mental illness, and other movement disorders associated with DRBA therapy, such as akathisia, parkinsonian tremor, and tremor related to use of mood stabilizing agents (eg, lithium, divalproex). Duration of exposure may help rule out acute drug-induced syndromes such as acute dystonia or acute/subacute akathisia. Another important consideration is the potential for TD to present together with other drug-induced movement disorders (eg, parkinsonism, parkinsonian tremor, and postural tremor from mood stabilizers) in the same patient, which can complicate both diagnosis and management. After documentation of the phenomenology, severity, and distribution of TD movements, treatment options should be reviewed with the patient and caregivers.

Real-world and clinical trial data support that clozapine is the only effective antipsychotic for treatment resistant schizophrenia and other severe mental illnesses. Clozapine also reduces rates of suicidality, psychiatric hospitalization and all-cause mortality. However, clozapine is underutilized for two reasons: misunderstandings of its efficacy benefits and misapprehension of, limited knowledge or misinformation about the management of treatment related risks and adverse effects. In response to worldwide efforts to promote clozapine use, this user-friendly Handbook provides clinicians with evidence-based approaches for patient management, as well as logical approaches to the management of clinical situations and adverse effects. It outlines clearly the rationale for specific management decisions and prioritises the options based on this logic. This Handbook is designed for use by clinicians worldwide and is essential reading for all mental health care professionals.

Objective: To explore the timing of relapse following drug discontinuation and its relationship to estimated plasma levels and elimination half-life by comparing data from a randomized, placebo-controlled discontinuation study of cariprazine with those from similarly designed and conducted randomized control trials of other oral atypical antipsychotics (AAPs). Methods: Data from a long-term, randomized, double-blind, placebo-controlled relapse prevention study in participants with schizophrenia (NCT01412060) were analyzed. Similarly designed, published studies of other AAPs were used for comparison. Time to drug-placebo relapse separation and relapse rates were estimated from Kaplan-Meier curves and evaluated descriptively. Separation was defined as a sustained difference of >= 5% incidence of relapse between the AAP and placebo curves. Results: The Kaplan-Meier curve for cariprazine showed a time to drug-placebo relapse separation at 6-7 weeks after randomization, compared to the Kaplan-Meier curves for the other AAPs, which showed earlier separation at 1-4 weeks. The placebo relapse rates at 4 weeks after randomization were 5% for cariprazine and 8-34% for other AAPs. Geometric mean values of model-predicted plasma concentrations for total active cariprazine moieties (sum of cariprazine, desmethyl-cariprazine, and didesmethyl-cariprazine) were 20.0 and 6.1 nM at 2 and 4 weeks after discontinuation, respectively. Elimination half-lives of other AAPs and their active metabolites (<4 days) suggest that plasma concentrations would be low or negligible at 2-4 weeks after last dose. Conclusion: Discontinuation of cariprazine treatment appeared to be associated with a delayed incidence of relapse compared with other AAPs, which may be due to the longer half-life of cariprazine and its active metabolites.