Background Clozapine is the most effective treatment for people with treatment-resistant schizophrenia (TRS). However, clozapine is underutilized, and there are stark racial disparities: Black people with psychosis are less likely to receive clozapine than White people with psychosis. Because of the lack of data on the effectiveness of clozapine in Black people, we sought to determine the clinical response to clozapine in this population. Objectives To evaluate clinical response to clozapine in Black people with psychosis to provide evidence that may help reduce disparities in clozapine access. Design Secondary analysis of a six-month, prospective, open-label clinical trial examining the safety of clozapine use in Black people. Methods We analyzed data from Black people with schizophrenia spectrum disorders ( n = 184) from sites in Maryland, USA (n = 97) and Lagos, Nigeria (n = 87). The primary outcome was reduction in symptom severity as measured by the Brief Psychiatric Rating Scale (BPRS) total score over time on clozapine. Additional outcomes included changes in BPRS subscales over time, predictors of 30% improvement in BPRS, clozapine level most predictive of clinical improvement, and the burden of side effects. Results BPRS total scores decreased significantly with time on clozapine, with a mean reduction of 8.1 points across sites. BPRS positive and resistance subscale scores also improved significantly. Nigerian participants had higher odds of 30% BPRS improvement and showed a faster response to clozapine compared with USA participants. CGI-S improved significantly from baseline to 24 weeks, and weight increased significantly. Conclusions Black participants experienced significant symptomatic benefit over 24 weeks on clozapine. These findings suggest that Black individuals eligible for clozapine may experience meaningful clinical improvement, supporting efforts to reduce disparities in clozapine access.

Background and Hypothesis To determine whether a tele-mentoring program increases clozapine utilization by improving prescriber knowledge and perceived competence in clozapine management. Study Design In a cluster-randomized controlled design, we tested the effectiveness of an Extension for Community Healthcare Outcomes (ECHO) model-based intervention, consisting of 26 biweekly didactic and case-based tele-mentoring sessions, vs enhanced treatment as usual (eTAU), in which both conditions received access to a consultation phone line and a point of care device for on-site hematologic monitoring. Prescribers completed baseline and 12-month assessments of clozapine knowledge and competence, and prescription records were used to evaluate the effects of ECHO on prescribing and treatment persistence. Study Results 266 prescribers from 43 mental health treatment settings throughout Maryland were enrolled. Prescribers randomized to ECHO demonstrated a significant increase in clozapine knowledge compared to eTAU (P < .001), and competence increased significantly in those who attended 14 or more tele-mentoring sessions (P = .017). ECHO did not increase the likelihood of clozapine prescribing during follow-up (P = .70). While there was a 17% lower hazard of clozapine discontinuation among patients of prescribers randomized to ECHO, this did not reach statistical significance (P = .72). Conclusions A statewide tele-mentoring program increased prescriber knowledge and competence in clozapine prescribing among those attending most ECHO sessions. Median time to clozapine discontinuation was double in the ECHO group, however, neither this nor rates of prescribing were statistically significantly different from control. Additional support is needed to motivate clozapine prescribing beyond providing education and increasing confidence in clozapine management.

Background: Antipsychotic medication (APM) can cause weight gain, insulin resistance, dyslipidemias, and an increased risk of developing type-2 diabetes and cardiovascular disease among youth. The study sought to increase water consumption, reduce sugar-sweetened beverage (SSB) intake, and prevent unhealthy weight gain via a healthy lifestyle intervention among youth newly started on a second-generation APM for psychiatric treatment. Methods: This randomized controlled trial enrolled 148 Medicaid-insured youth (ages 8-17) recently starting APM. The treatment group received both a biweekly home-delivery of bottled water and parental phone support from a family navigator. In-home visits conducted at baseline, three months, and six months assessed the participants' height/weight and dietary intake. All participants received basic healthy lifestyle education emphasizing increased water intake and decreased SSB consumption. Longitudinal linear mixed models were conducted to examine between-group and within-group changes in BMI z-scores, and water/SSB intake. Results: No significant between-group differences in BMI z-score were found at three (p = 0.908) and six months (p = 0.919). However, the within-group increase in BMI z-score in the control group was significant from baseline to three months (p = 0.029). A between-group comparison found the treatment group significantly increased their water intake at three (p = 0.006) and six months (p = 0.002). No between-group differences were identified at three and six months for the reduction in SSB, although the treatment group did demonstrate a decrease from baseline to three months (p = 0.004). Conclusions: Neither group experienced unhealthy increases (>0.5%) in BMI z-score over the six months. Providing a safe/free water supply showed a superior improvement in water consumption in the treatment group, and an initial decrease in SSB. Further studies are needed to identify feasible, effective, and sustainable lifestyle interventions tailored to this at-risk population.

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/BACKGROUND:This is the second part of a 2-part article that proposes improving the United States (US) clozapine package insert. Part II focuses on fatal outcomes and the 5 boxed warnings, 4 specifically for clozapine: severe neutropenia, seizure, orthostatic hypotension and myocarditis, and 1 for all antipsychotics (elderly with dementia). METHODS:US reports to the World Health Organization's global pharmacovigilance database were analyzed from clozapine's introduction to January 15, 2023. FINDINGS/RESULTS:The US was the top reporter worldwide for clozapine with 56,003 reports and 9587 associated fatal outcomes. The 4 clozapine boxed warnings were associated with 534 fatal outcomes (218 with severe neutropenia, 131 with seizures, 125 with orthostasis, 36 with myocarditis, 24 with cardiomyopathy, and 0 with mitral valve prolapse). With no boxed warnings, pneumonia was associated with 674 fatal outcomes and increased white blood cell count (a sign of infection) with 596 fatal outcomes. After considering overlaps, pneumonia and increases in white blood cell count explained 900 fatalities, or 9.4% of 9587 fatal outcomes. The Food and Drug Administration continues to focus on severe neutropenia which was associated with only 218 or 2.3% of fatal outcomes, whereas 97.7% of fatal outcomes reported in US clozapine-treated patients had another cause. IMPLICATIONS/CONCLUSIONS:To help prevent future deaths in clozapine-treated patients, the clozapine package insert should focus on fatal outcomes during infections. Part II offers detailed solutions regarding current boxed warnings and lack of a warning for pneumonia and other infections. The Supplementary Material includes letters of support from 124 non-US clozapine experts from 44 countries/regions who support Parts I and II.

This Viewpoint provides suggestions to address challenges after elimination of the Clozapine Risk Evaluation and Mitigation Strategies (REMS) system by the US Food and Drug Administration (FDA).

Injury from medication use, known as an adverse drug event (ADE) accounts for millions of emergency department visits globally and thousands of hospitalizations annually within the United States. Efforts to prevent and detect ADEs within healthcare systems are complicated by data quality, lack of data standardization, and actionable clinical decision support systems. United States Pharmacopeia (USP) proposes the use of an ADE value set, a standardized grouping of medical terms, to improve the identification, documentation, and use of ADE information in EHRs. Artificial Intelligence and Machine Learning capabilities would be further strengthened through the standardization of ADE data and information.

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.

Introduction: Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia, but it is markedly underutilized, particularly in the US Black population, partly because of concern over clozapine-associated low absolute neutrophil count (ANC). People of African descent have a lower normative ANC range than the White population, which is associated with a specific "ACKR1-null" ("Duffy null") CC genotype (SNP rs2814778) on the ACKR1 gene, termed benign ethnic neutropenia (BEN). The range of ANC variability and safety of clozapine have not been established in people with BEN or examined prospectively in people of African descent. Methods: We completed a multisite, 6-month, prospective, open-label clinical trial of clozapine treatment in people of African descent with schizophrenia spectrum disorders for whom clozapine was clinically indicated, with or without the ACKR1-null genotype. We examined clozapine safety and weekly ANC during clozapine treatment and evaluated ANC variability by ACKR1-null genotype, sex, study site, and clozapine dosing using repeated measures analysis of covariance. Genotype was assayed using TaqMan (R) technology. Results: We enrolled 274 participants, of whom 227 (82.8 %) completed 6 months of clozapine treatment. There was one case of severe neutropenia (<500 cells/mm(3)) (0.36 %) over 1467.6 person-months of clozapine exposure. This participant recovered without sequelae after discontinuation of clozapine. Of the 249 participants with known genotypes, 199 (79.9 %) had the ACKR1-null genotype. Neutropenia (<1500 cells/mm(3)) occurred significantly more often in the ACKR1-null group (33 % [65/199]) than in those with the T allele (6 % (3/50); p < 0.001). Fourteen (5 %) patients discontinued due to adverse events. Rates of infection and fever were low and sialorrhea was the commonest side effect (N = 187, 68 %). Conclusion: To our knowledge, this is the largest prospective clozapine trial in people of African descent. Severe neutropenia was rare, despite the high prevalence (80 %) of the ACKR1-null genotype. Our findings suggest that clozapine can be used safely in Black patients including those with BEN.

Objective/Process In June of 2022, the State of Maryland Board of Pharmacy issued regulations permitting pharmacist administration of maintenance injectable medications. Subsequently, the University of Maryland School of Pharmacy created a laboratory to train student pharmacists based on these regulations on administering long-acting maintenance injections. This training included a review of regulations, reconstitution and administration of medications, and education for patients and caregivers on long-acting injectable medications. This is the first training the authors are aware of incorporating both reconstitution and administration of these medications. The objective of this paper is to describe the laboratory details and future directions of the training course. Results/Conclusions The first training laboratory trained 94 student pharmacists in the administration technique of long-acting injectable medications. The program has been adapted for practicing pharmacists and other healthcare providers. Thus far, more than 300 practitioners have participated in the learning lab.

Significant research and clinical efforts have improved the safety of clozapine since FDA approval. This includes work resulting in strategies to prevent, detect, and manage clozapine-related adverse drug reactions (ADRs) such as gastrointestinal hypomotility and inflammatory reactions [1–4]. Tools and guidelines to screen for clozapine-related ADRs and awareness of how clozapine clinics help support the use of clozapine have also advanced care [5–7]. Continued efforts to improve clozapine prescribing are critical as clozapine is the only FDA approved medication indicated for treatment-resistant schizophrenia and reduction of suicidality in schizophrenia or schizoaffective disorder. Unfortunately, literature suggests clozapine use remains suboptimal in the US and throughout parts of the world [8,9]. In the US, the Clozapine Risk Evaluation and Mitigation Strategy (REMS), implemented to ensure completion of hematologic monitoring, remains a major barrier to clozapine use. Prior to the turbulent rollout of the 2021 REMS, the REMS website displayed the trademarked phrase, ‘No blood, no drug,’ which may still be engrained in the minds of healthcare professionals, caretakers, and patients. Not only is this phrase not true, as exceptions existed, it could be interpreted that hematologic risks remain constant throughout the duration of clozapine exposure. This is also not true [10]. Unfortunately, the ‘No blood, no drug’ slogan continues to have real-world negative impacts through the refusal to dispense clozapine from community pharmacists unaware of REMS flexibilities. This was highlighted by situations encountered during the COVID-19 pandemic (e.g. patient in quarantine without access to a laboratory) and the 2021 REMS rollout (e.g. inaccessible call center, preventing enrollment). During these times, some pharmacies denied clozapine prescriptions despite clear guidance from the FDA and international expert consensus to allow and justify monitoring variance in certain patients (e.g. every 3-month monitoring for patients on clozapine at least 1 year without prior hematologic abnormalities) [11]. Yet, given perceived liabilities, prescribers in many countries likely grappled with how to adopt variance from the usual hematologic monitoring requirements. With some REMS parameters still suspended by the FDA, now may be a time for major reformation. 2. How did we get here?

Introduction: Patients with severe mental illness are falsely characterized as aggressive by the media, perpetuating stigma. While exaggerated, some patients with severe mental illness are more aggressive without treatment. Clozapine may have a unique anti-aggressive effect in patients with schizophrenia-related disorders, independent of antipsychotic or sedative effects. Limited data in forensic and involuntary committed patients is currently available. Purpose: This study evaluates clozapine's effects on hostility and aggression in court-ordered Black patients. Methods: This study analyzes a subgroup of Black patients from a larger prospective 24-week open-label cloza-pine study. All patients were involuntarily committed and enrolled from two participating state psychiatric hospitals. The primary outcome measured was total use of 'as needed' (PRN) or 'immediate need' (STAT) medications for aggression/hostility. Secondary outcomes included number and duration of seclusion and restraint (S/R) episodes, and changes in Brief Psychiatric Rating Scale (BPRS) hostility factor score. Results: Sixty-nine patients were included in our analysis. Significant reductions were noted in PRN/STAT medication use over time (chi(2) = 6.90; p = 0.008) and the BPRS hostility factor score was reduced by 30% over the 24 weeks (F = 4.34, df = 62, p = 0.002). Conclusions: Treatment with clozapine effectively reduced hostility and aggression within this cohort of invol-untarily committed Black patients with mental illness compared to baseline. Specifically, it helped lower the total number of PRN/STAT medication administrations and improved clinician-rated hostility factor scores on the BPRS. Our findings are pertinent as data in forensic settings is lacking and Black patients have been infrequently included in large prospective clinical trials with clozapine.

BACKGROUND:The United States is experiencing an opioid crisis, substantially worsened by the pandemic. Pharmacists play a critical role in expanding access to care through harm reduction efforts and medications to treat opioid use disorder (mOUD), yet lack necessary education and resources. Academic detailing is a one-on-one technique, which can effectively address educational gaps. OBJECTIVE:The purpose was to assess needs and equip pharmacy staff to address the health of people with substance use disorders (SUD). PRACTICE DESCRIPTION:Community pharmacists provide ongoing care for patients with SUD. PRACTICE INNOVATION:Based on needs' assessment findings, an academic detailing program was designed to provide education and resources for community pharmacies. The project sought to assess current practice and needs and address pharmacists' skills in managing patients with opioid use disorder (OUD) and/or at risk for overdose (OD). Visits were scheduled in high-risk regions. Coaching and materials were provided. EVALUATION METHODS:Detailers completed visits reports. Discrete variables were reported using descriptive statistics. Associations between discrete variables were detected with Chi-square or Fisher's exact test. RESULTS:Detailers visited 136 pharmacies. Most stocked naloxone (86.8%), mOUD (94.9%) and would sell syringes (64%) per state law. Fifty-seven percent of pharmacies provided all of these services. However, additional education and resources were needed. Only 27.9% had naloxone signage and/or handouts; 22.1% had supplemental materials; and 25% had referral information. When asked to explain barriers, frequently cited themes included providing resources/help, financial issues, stigma, and transportation. CONCLUSION:Pharmacists routinely care for patients at risk for OD and diagnosed with OUD. Academic detailing is a well-received strategy to disseminate education and materials, while gathering information about pharmacist needs and barriers. However, there remains room for expansion of services and opportunities for improved care. Further efforts should incorporate ongoing training and access to materials with visual cues, as well as referral and cost savings information.

Clozapine is an antipsychotic that exhibits superior efficacy and effectiveness for those with schizophrenia and other serious mental illness. However, its side-effect profile and administrative burdens present challenges to its use. In the United States, the medication is grossly underused even though it may improve outcomes and reduce costs. Current barriers to use include lack of prescriber knowledge and confidence, negative prescriber attitudes, special monitoring requirements, administrative factors, lack of clozapine on formularies, lack of support and infrastructure to use the medication within many health systems, and inadequate understanding or acknowledgement of clozapine prescribing and risks by policy makers and payers. Approaches using interprofessional models of care, which include pharmacists specializing in psychiatric care, can help meet the needs of patients receiving clozapine. This article lays out the big picture of barriers to clozapine and how psychiatric pharmacists could play a role in improving access.

To estimate 20-year mortality risk in people with schizophrenia treated with second-generation antipsychotics (SGA) and examine the effects of cigarette smoking on mortality. Of the 1199 individuals with schizophrenia in the study, estimated 20-year all-cause mortality risk by Kaplan Meier Curve was 30% and leading causes of death included 27% cardiovascular disease, 13% cancer, 12% non-HIV infection, 5% respiratory causes, 20% other causes and 18% had unknown cause of death. For all-cause mortality, we found that white race and male sex were significant risk factors (HR=1.5, p=0.002 and HR=1.33, p=0.033, respectively). For cardiovascular mortality risk, we showed that cigarette smokers and white race were at higher risk (HR=1.86, p=0.017 and HR=1.71, p=0.045, respectively). Cardiovascular mortality risk at 20-years is 11%. Kaplan-Meier Survival Curve showed a statistical difference for smokers and non-smokers in cardiovascular mortality over the 20-year follow-up (Log rank chi-square=5.35, df=1, p=0.02). 20-year all-cause mortality risk for individuals with schizophrenia was found to be 30% with cardiovascular disease as a leading cause. Cigarette smokers and white race were associated with an increased risk of death. Regarding cardiovascular mortality specifically, cigarette smoking increased risk by 86% over a 20-year period. Clozapine was neither a risk factor for all-neither cause nor cardiovascular mortality. This data suggests that long-term cardiovascular mortality continues to be increased in schizophrenia for those who are or have been cigarette smokers.

Although clozapine has demonstrated unique efficacy for the treatment of seriously ill patients with refractory psychosis, its real-world use presents challenges to clinicians in a variety of settings, leading to its underutilization in the United States. The barriers include a lack of prescriber knowledge and confidence, negative prescriber attitudes, special monitoring requirements, administrative burden, unprepared health systems, and inadequate appreciation of clozapine's unique nature by policy makers and payers. In 2016, the National Association of State Mental Health Program Directors (NASMHPD) gathered a national team of expert clinicians and researchers to identify and address barriers to clozapine use. NASMHPD has since expanded the work group, which convenes monthly to continue addressing specific recommendations. This Open Forum describes the deliberations of the work group and urges practitioners, administrators, local and state governments, researchers, families, and patients to join similar efforts to promote better access to clozapine and improve the treatment management for patients receiving clozapine.

Popular media often portray people with a mental illness as being aggressive, violent, and incarcerated as a result of their behavior. Despite exaggeration in the media, risks for some aggressive behaviors are in fact higher in individuals with schizophrenia. This is often the case with influence of comorbid substance use disorders. It is essential that mental health professionals are aware of treatments that may help with attenuating and treating behaviors that contribute to violence, aggression and incarceration. This paper reviews violence and incarceration in individuals with schizophrenia as well as recommendations, guidelines and benefits for the use of clozapine in this population. Clozapine remains one of the most underutilized evidence-based medications available in the psychiatric arena in the United States. It is a viable and recommended option in the forensic population and it may be helpful on the path to recovery as well as bring substantial savings to the criminal justice system.

Background: Despite its proven efficacy for the treatment of psychosis, clozapine remains underutilized due to many barriers associated with its use. To date no large scale efforts have been undertaken to tackle and improve these barriers. Methods: Two anonymous surveys were distributed to Maryland prescribers to identify and rank the importance of potential barriers to clozapine use (first survey) and possible solutions (second survey sent only to current clozapine prescribers). Subsequently, a work group assembled by the National Association of State Mental Health Program Directors (NASMHPD) of researchers and clinicians, funded by SAMHSA, used the survey findings to generate recommendations on how to address major barriers and implement desired solutions. Results: Thirty-two percent of prescribers (n = 255/860) responded to the first survey. Closer monitoring, regular blood work, and potential for non adherence to blood work (highest overall) were reported as the greatest clinical barriers while lack of a centralized system (prior to ClozapineREMS), time spent on administration tasks, and lack of administration structure were the most significant nonclinical barriers. The most significant side effect barriers were cardiomyopathy, metabolic syndrome and agranulocytosis. Prescribers who did not use clozapine also ranked “not feeling competent” and “limited experience in residency training.” The solutions survey (22.3%; n = 21/94) found that current clozapine prescribers ranked point of care fingerstick, Benign Ethnic Neutropenia support, education for families, centralized clinic, and physician education program as the most helpful solutions. As for the workgoup, 35 recommendations were developed and the White Paper was accessible following national feedback. Conclusion: Our work proffers new national recommendations to help varied systems of care address barriers to the use of clozapine. Improved access to clozapine could benefit millions of patients and, in turn, could result in substantial cost savings to the entire health care system.

The Patient Protection and Affordable Care Act focuses on improving consumer engagement and patient-centered care. This article describes the design and rationale of a study targeting family engagement in pediatric mental health services. The study is a 90-day randomized trial of a telephone-delivered Family Navigator services versus usual care for parents of Medicaid-insured youth younger than 13 years with serious mental illness. Youth are identified through a pediatric antipsychotic medication preauthorization program. Family Navigators offer peer support to empower and engage parents in their child's recovery. Outcomes include parent report of empowerment, social support, satisfaction with child mental health services, and child functioning as well as claims-based measures of psychotherapy service utilization and antipsychotic medication dosage. The focus on "family-centered" care in this study is strongly supported by the active role of consumers in study design and implementation.