Escaping the Long Shadow Cast by Agranulocytosis: Reflections on Clozapine Pharmacovigilance Focused on the United Kingdom.

PURPOSE/BACKGROUND: A recent article in this journal presented a US perspective regarding the modernization of clozapine prescription and proposed an escape from the long shadow cast by agranulocytosis. METHODS: Here, an international group of collaborators discusses a point of view complementary to the US view by focusing on worldwide outcomes of clozapine usage that may be uneven in terms of frequency of clozapine adverse drug reactions. FINDINGS/RESULTS: Studies from the Scandinavian national registries (Finland and Denmark) did not find increased mortality in clozapine patients or any clear evidence of the alleged toxicity of clozapine. Data on clozapine-associated fatal outcomes were obtained from 2 recently published pharmacovigilance studies and from the UK pharmacovigilance database. A pharmacovigilance study focused on physician reports to assess worldwide lethality of drugs from 2010 to 2019 found 968 clozapine-associated fatal outcomes in the United Kingdom. Moreover, the United Kingdom accounted for 55% (968 of 1761) of worldwide and 90% (968 of 1073) of European fatal clozapine-associated outcomes. In a pharmacovigilance study from the UK database (from 2008 to 2017), clozapine was associated with 383 fatal outcomes/year including all reports from physicians and nonphysicians. From 2018 to 2021, UK clozapine-associated fatal outcomes increased to 440/year. IMPLICATIONS/CONCLUSIONS: The interpretation of fatal outcomes in each country using pharmacovigilance databases is limited and only allows gross comparisons; even with those limitations, the UK data seem concerning. Pneumonia and myocarditis may be more important than agranulocytosis in explaining the uneven distribution of fatal outcomes in clozapine patients across countries.

Feasibility of an Open Dialogue-Inspired Approach for Young Adults with Psychosis in a Public Hospital System.

The objective was to determine the feasibility of an Open Dialogue-inspired approach in a metropolitan, public hospital setting with predominately African American participants. Participants were ages 18-35, experienced psychosis within the past month, and involved at least one support person in their care. We evaluated domains of feasibility including implementation, adaptation, practicality, acceptability, and limited-efficacy. An organizational change model (Addressing Problems Through Organizational Change) facilitated implementation. Clinicians received three trainings and ongoing supervision. Network meetings were successfully implemented with good self-reported fidelity to principles of dialogic practice. Some adaptations (less frequent meetings and no home visits) were necessary. A subset of individuals completed research assessments over 12 months. Qualitative interviews with participants suggested the intervention was acceptable. Symptom and functional outcomes were preliminary but trended toward improvement. Implementation was feasible with relatively brief training, organizational change processes, and context-specific adaptations. Lessons learned can assist in planning a larger research study.

The Modernization of Clozapine: A Recapitulation of the Past in the United States and the View Forward.

PURPOSE: Although clozapine was Food and Drug Administration (FDA) approved more than 3 decades ago, major barriers and gaps in knowledge continue to prevent its effective and safe use. We review modern-day problems encountered with clozapine in the United States (US). METHODS: Information surrounding current administrative, clinical, research, and technological gaps or barriers related to clozapine use in the US was reviewed. FINDINGS: The history of how clozapine became FDA approved likely contributes to gaps in knowledge. The frequency of safety warnings added to the FDA prescribing information may add to fears about clozapine, as evidence by numerous published survey studies. The clozapine Risk Evaluation and Mitigation Strategy (REMS) program has been modified several times in the last decade, causing access and safety issues for patients, which are discussed. Evidence may suggest that the FDA REMS requirements for hematologic monitoring are too cumbersome, and there may be ability to safely loosen requirements. The COVID-19 pandemic brought forth the ability for extended interval monitoring but also greater awareness of the clozapine-inflammation interaction. Newer guidelines published describe considerations in personalizing clozapine titration based on principles of ethnopsychopharmacology. Emerging technologies to support the use of clozapine are not widely available. IMPLICATIONS: Clozapine is a unique life-saving drug but it is underused in the US, despite its established efficacy. The 2021 REMS changes led to significant difficulties for providers and patients. We highlight the importance of the clozapine-inflammation interaction, therapeutic drug monitoring, and the ability for individual care based on patient-specific factors. There is an urgent need for advancing technology used for clozapine monitoring, evaluating barriers created by REMS, and establishing consistent practices throughout the US.

An International Adult Guideline for Making Clozapine Titration Safer by Using Six Ancestry-Based Personalized Dosing Titrations, CRP, and Clozapine Levels.

This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas' original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300-600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75-150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175-300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100-200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250-400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150-300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300-600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration.

A Comparison of Attitudes, Comfort, and Knowledge of Clozapine Among Two Diverse Samples of US Psychiatrists.

Considerable variation in clozapine utilization exists across the United States, and little is known about the perspective of psychiatrists in states with low clozapine use. To better understand clozapine practices, attitudes, and barriers, a survey was administered to a group of southeastern state conference attendees (SSCA; N = 86). The same survey was administered to psychiatrists belonging to a national community psychiatry organization (AACP; N = 57), and differences were analyzed across the two samples. In comparison to the AACP, the SSCA group felt less comfortable, perceived clozapine as less safe and effective, had fewer patients on clozapine, and were more likely to prefer antipsychotic polypharmacy to clozapine use. Across the sample, use of a myocarditis screening protocol was rare (N = 14/76; 18%) and less than half used plasma antipsychotic levels to guide dosage (N = 60/129; 47%). Continuing professional education on clozapine are needed for psychiatrists who see individuals with psychotic disorders.

Should we routinely add CRP to clozapine titrations? - Learning from three cases.

Objectives: An international guideline recently provided certain personalized schedules for titrating clozapine in adult inpatients by considering: 1) DNA ancestry group, 2) sexsmoking subgroup, and 3) presence/absence of clozapine poor metabolizer (PM) status. Measuring CRP levels at baseline and during the first 4 weeks is recommended. Titrations too fast for the metabolism of specific patients can lead to clozapine-induced inflammations and CRP elevations. Methods: Three published cases are reinterpreted. Better outcomes might have been obtained by using the guideline. Results: Case 1 was a Chinese male non-smoker, a clozapine PM due to an underlying inflammation. Case 2 was a Turkish female non-smoker who developed clozapine-induced myocarditis in the context of 4 risk factors (undiagnosed infl ammation, obesity, valproate and olanzapine co-prescription). Case 3 was a United States patient of European ancestry with no known risk factors who developed myocarditis after a routine titration and had an unsuccessful rechallenge with 12.5 mg/day. Application of the international clozapine titration guideline may have prevented: 1) Case 1 by recommending against clozapine titration for a patient with an abnormal CRP level, 2) Case 2 by considering 4 risk factors and using a slow titration for clozapine PMs, and 3) Case 3 by using CRP elevations for early identification of a possible genetic PM. Conclusions: When baseline or prior CRPs are normal and then become abnormal during a clozapine titration, this indicates: 1) clozapine-induced inflammation associated with too-rapid titration for that specific patient, and/or 2) co-occurrence of an infection. Prospective studies need to verify this hypothesis.

Four cases of myocarditis in US hospitals possibly associated with clozapine poor metabolism and a comparison with prior published cases.

Objectives: Clozapine-induced myocarditis may be a hypersensitivity reaction due to titration that was too rapid for a patient's clozapine metabolism. Obesity, infections, and inhibitors (e.g., valproate) may lead to clozapine poor metabolizer (PM) status. The hypothesis that 4 patients with clozapine-induced myocarditis from two United States hospitals were clozapine PMs was tested by studying their minimum therapeutic clozapine doses and titrations. Methods: Using methodology from a prior myocarditis case series of 9 Turkish patients, we studied: 1) the concentration-to-dose (C/D) ratio; 2) minimum therapeutic dose required to reach 350 ng/ml (a marker for PM status); and 3) titration speed. Results: All 4 patients were possible clozapine PMs (their respective minimum therapeutic doses were: 134, 84, 119 and 107 mg/day). The identified possible contributors to clozapine PM status were: 1) valproate in Cases 1, 2 and 4; 2) obesity and a urinary tract infection in Case 2; and 3) obesity and very rapid titration in Case 4. Case 3, who was given a normal US titration, appeared to be a genetic clozapine PM. He developed clozapineinduced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome after rechallenge using 12.5 mg/day > 3 months later. The results were similar to 9 Turkish cases, all of which were PMs (6 on valproate, 4 with obesity, 1 with infection and 1 possibly genetic). Conclusions: Future studies using clozapine levels and considering the role of clozapine PM status should explore whether or not all cases of clozapine-induced myocarditis could be explained by lack of individualized titration. (Neuropsychopharmacol Hung 2022; 24(1): 29-41).

A survey of personnel and services offered in 32 outpatient US clozapine clinics.

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.

Off-label use of antipsychotic medications in psychiatric inpatients in China: a national real-world survey.

BACKGROUND: The off-label use of antipsychotic medications is common in many countries, and the extent of such use in psychiatric inpatients in China has not been sufficiently studied. The purpose of this study was to survey the incidence and examine the correlates of off-label antipsychotic use in a large, nationally-representative sample in China. METHODS: This study included discharged psychiatric patients between March 19 and 31, 2019 from 41 tertiary psychiatric hospitals across 29 provinces in China. Their socio-demographic and clinical data were collected and analyzed. RESULTS: After excluding patients with schizophrenia spectrum disorder or bipolar disorder, 981 patients were included in the analysis. Overall, antipsychotics were prescribed to 63.2% (95%CI 60.2-66.2%) of the sample. Antipsychotics were used in a wide spectrum of psychiatric disorders, with the rate being the highest among patients with dissociative (conversion) disorders (89.9, 95%CI 83.0-94.8%), organic mental disorders (81.7, 95%CI 73.1-88.7%), dementia (79.0,95%CI 67.8-87.9%), obsessive-compulsive disorder (77.8, 95%CI 55.7-92.5%), mental disorders due to psychoactive substances (75.3,95%CI 64.7-84.2%), behavioural and emotional disorders with onset usually occurring in childhood and adolescence (71.4, 95%CI 45.5-90.1%), somatoform disorders (63.2, 95%CI 40.8%-82..2%), major depression disorder (53.7,95%CI 48.8-58.6%), anxiety disorder (38.8,95%CI 30.5-47.7%), and insomnia (25.0, 95%CI 8.5-28.9%). The top three most commonly used antipsychotics were olanzapine (29.1%), quetiapine (20.3%) and risperidone (6.8%), and their corresponding average doses were 9.04 ± 5.80 mg/day, 185.13 ± 174.72 mg/day, and 2.98 ± 1.71 mg/day, respectively. A binary logistic regression showed that younger age, having the Employee Health Insurance or Residents Health Insurance, having psychotic symptoms and requiring restraint during hospitalization were significantly associated with off-label use of antipsychotics. CONCLUSION: Off-label use of antipsychotics is very common in psychiatric inpatients in China, mainly with moderate-dose use of single agents. However, the efficacy and safety of this practice is uncertain for many diagnoses and for the elderly. Clinicians should be cautious about this practice while waiting for more research data.

International Medical Graduate Resident Physicians in Psychiatry: Decreasing Numbers, Geographic Variation, Community Correlations, and Implications.

OBJECTIVES: The number of International Medical Graduate (IMG) physicians matching into categorical psychiatry decreased steadily over the past decade. The authors sought to understand if this trend was occurring in other specialties, if US IMG physicians and non-US IMG physicians were equally affected, and if certain regions of the USA were more affected by this decrease than others. Finally, the authors compared the proportion of foreign-born individuals within a US census region to the proportion of non-US IMG physicians within that region. METHODS: The authors analyzed data from the National Resident Matching Program from the years 2014-2020. Statewide data was aggregated into nine geographic regions, as per the US Census Bureau. The number of foreign-born individuals within each US census region was calculated from the 2018 American Community Survey data. RESULTS: In comparison to eight other specialties, psychiatry saw the greatest decrease (46.3%) in IMG physicians matching into PGY-1 positions. Both US IMG physicians and non-US IMG physicians were equally affected. The percentage of IMG physicians decreased in each of the nine US census regions. In six out of nine geographic regions, non-US IMG physicians were under-represented when comparing their proportion to the number of foreign-born people that lived within that region. CONCLUSIONS: Decreasing numbers of IMG physicians in psychiatry training may have long-term implications for cultural competency, serving underserved populations, and fellowship recruitment. We advocate for program directors to recognize IMG physicians as an important source of diversity and to recruit residents that reflect the communities they serve.

Characteristics of Medicaid Recipients Receiving Persistent Antipsychotic Polypharmacy.

Antipsychotic polypharmacy (APP) is a common strategy despite guidelines advising against this practice. This article seeks to quantify the prevalence and correlates of APP using Medicaid Analytic eXtract files from 2003 to 2004. Nineteen percent of Medicaid recipients who received an antipsychotic were treated with APP. Individuals who received APP were more likely to be white, male, disabled, between the ages of 18-29, diagnosed with a psychotic disorder, and diagnosed with a higher number of psychiatric conditions. Geographic variation in APP rates was also observed. Quality improvement initiatives may help reduce APP for medically vulnerable patients.

Antipsychotic Cardiometabolic Side Effect Monitoring in a State Community Mental Health System.

Antipsychotic medications can cause serious cardiometabolic side effects. No recent research has broadly evaluated monitoring and strategies to improve monitoring in U.S. public mental health systems. To address this knowledge gap, we evaluated education with audit and feedback to leaders to improve cardiometabolic monitoring in a state mental health system. We used Chi square statistics and logistic regressions to explore changes in monitoring recorded in randomly sampled records over 2 years. In 2009, assessment of patients on antipsychotics was 29.6 % for cholesterol, 40.4 % for glucose, 29.1 % for triglycerides, 54.3 % for weight, 33.6 % for blood pressure, and 5.7 % for abdominal girth. In 2010, four of ten mental health centers improved their rate of adult laboratory monitoring. Overall monitoring in the state did not increase. Education for prescribers with audit and feedback to leaders can improve monitoring in some settings, but more intensive and/or prolonged interventions may be required.

Cocaine-induced psychotic disorders: presentation, mechanism, and management.

Cocaine, the third mostly commonly used illicit drug in the United States, has a wide range of neuropsychiatric effects, including transient psychotic symptoms. When psychotic symptoms occur within a month of cocaine intoxication or withdrawal, the diagnosis is cocaine-induced psychotic disorder (CIPD). Current evidence suggests those with CIPD are likely to be male, have longer severity and duration of cocaine use, use intravenous cocaine, and have a lower body mass index. Differentiating CIPD from a primary psychotic disorder requires a detailed history of psychotic symptoms in relation to substance use and often a longitudinal assessment. Treatment includes providing a safe environment, managing agitation and psychosis, and addressing the underlying substance use disorder. This review begins with a clinical case and summarizes the literature on CIPD, including clinical presentation, differential diagnosis, mechanism and predictors of illness, and treatment.