Implementation of academic detailing for pharmacists on opioid use disorder and harm reduction.

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.

Effects of Cigarette Smoking and Clozapine Treatment on 20-Year All-Cause & Cardiovascular Mortality in Schizophrenia.

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.

Clozapine in Reducing Aggression and Violence in Forensic Populations.

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.

Urine testing for antipsychotics: a pilot trial for a method to determine detection levels.

OBJECTIVE: The goal of the present study was to demonstrate that the analytical assay of interest can detect antipsychotics in human urine specimens. METHOD: Forty inpatients treated with haloperidol, quetiapine, risperidone, or olanzapine were recruited to participate in a one visit study. During the study visit, demographic and clinical information was collected as well as one urine sample that was forwarded to the Ameritox Laboratory and assayed for the presence of antipsychotic medications and/or metabolites. Urine samples were analyzed to determine detection sensitivity for four antipsychotic medications and their metabolites (risperidone, quetiapine, olanzapine, and/or haloperidol) using Ultra Performance Liquid Chromatography-Tandem Mass Spectrometry. RESULTS: All urine samples produced positive results for the antipsychotic(s) the participants were known to be taking. Urine concentrations (level of quantification) for parent drugs ranged from <25-417 ng/mL for haloperidol, <25-4017 ng/mL for quetiapine, 0-997 ng/mL for risperidone, and 57-700 ng/mL for olanzapine. CONCLUSION: The analytical assay produced by Ameritox, Ltd using Ultra Performance Liquid Chromatography-Tandem Mass Spectrometry can qualitatively detect antipsychotics in human urine specimens. The present study highlights the potential utility of the urine assay to help monitor adherence to antipsychotic medications.

The Family Value of Information, Community Support, and Experience Study: Rationale, Design, and Methods of a "Family-Centered" Research Study.

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.

Training student pharmacists to administer long-acting injectable medications.

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.

Clozapine and neutrophil response in patients of African descent: A six-month, multinational, prospective, open-label clinical trial.

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® 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/mm3) (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/mm3) 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.

Anti-aggressive effects of clozapine in involuntarily committed black patients with severe mental illness.

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 clozapine 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 (χ2 = 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 involuntarily 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. GOV IDENTIFIER: NCT02404155.

Cardiac-related findings at autopsy in people with severe mental illness treated with clozapine or risperidone.

Clozapine is a superior agent for treatment-refractory patients with schizophrenia, but is underutilized in the US, likely due to the risk of side effects. This study examined all available autopsy data on cardiac disease and risk factors in people with schizophrenia in a sample of deceased persons with severe mental illness who had received clozapine (N=62) or risperidone (N=42). The mean body mass index (BMI) at the time of death was 31.4+/-8.8 kg/m2 and 27.1+/-8.2 kg/m2 in the clozapine and risperidone groups respectively (t=1.98, df=60, p=0.052). Cardiac related measures examined included: abdominal wall thickness, heart weight, left ventricle thickness, right ventricle thickness, presence of notable cardiac involvement (atherosclerosis, fibrosis and hypertrophy) and number of cardiac arteries occluded. No significant differences in any of the cardiac findings were noted between patients in the clozapine and risperidone groups. Independent of treatment, cardiomyopathy deaths were associated with a higher abdominal wall thickness (p=0.042) and a tendency towards higher BMI (p=0.051) as compared to the other causes of death. The results of this study suggest that while clozapine is associated with weight gain and metabolic abnormalities, there does not appear to be an increased occurrence of cardiac abnormalities in deceased persons who were treated with clozapine as compared to risperidone.

Psychiatric pharmacist's role in overcoming barriers to clozapine use and improving management.

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.

Metabolic risk with second-generation antipsychotic treatment: a double-blind randomized 8-week trial of risperidone and olanzapine.

BACKGROUND: The second-generation antipsychotics are effective for treating psychotic disorders and incur fewer motor side effects than are commonly experienced with the use of first-generation antipsychotics. However, their use is commonly associated with weight gain and metabolic disturbances. This study examined weight and metabolic changes with two widely used antipsychotics, risperidone and olanzapine; addressing the issue of early monitoring for metabolic side effects. METHODS: This 8-week double blind randomized trial included patients with schizophrenia or schizoaffective disorder (N = 377) randomly assigned to risperidone (2-6 mg/day) or olanzapine (5-20 mg/day). Weight, BMI, HbA1C, total cholesterol (TC), LDL-C, HDL-C and triglycerides (TG) were monitored. RESULTS: Mean BMI increases were higher in the olanzapine group as compared to risperidone (1.3 kg/m(2)(SD = 0.13) vs. 0.7 kg/m(2) (SD = 0.13)(p < 0.001). Increases in mean TC (13.5 mg/dl (SD 2.4), LDL-C (11.0 mg/dl (SD 2.2)) and TG (14.8 mg/dl (SD = 7.6)) occurred in the olanzapine group while significant changes in TC (-3.9 mg/dl (SD = 2.5)) and TG (-32.8 mg/dl (SD = 7.8)) were noted in the risperidone group. Men (not women) on olanzapine had higher than expected increases in lipids given the amount of weight gain. Baseline values and prior therapy did not contribute to the significant differences, however BMI increases (p = 0.0002) were linked to study discontinuation in both drug groups. CONCLUSIONS: The fact that significant metabolic changes occurred (both positive and negative) in eight weeks is important to clinical care. Monitoring for metabolic changes may be important within the first eight weeks of treatment, as changes can be determined very early in antipsychotic treatment.

Addressing Barriers to Clozapine Underutilization: A National Effort.

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.

Blood Draw Barriers for Treatment with Clozapine and Development of a Point-of-Care Monitoring Device.

BACKGROUND: While clozapine (CLZ) is the most effective antipsychotic drug for schizophrenia treatment, it remains underused. In order to understand the barriers of frequent blood draws for white blood cell counts (WBCs) and clozapine levels, we developed a psychiatrist survey and began an integrative approach of designing a point-of-care device that could eventually have real-time monitoring with immediate results. METHODS: We ascertained barriers related to CLZ management and the acceptance of possible solutions by sending an anonymous survey to physicians in psychiatric practice (n=860). In parallel, we tested CLZ sensing using a prototype point-of-care monitoring device. RESULTS: 255 responses were included in the survey results. The two barriers receiving mean scores with the highest agreement as being a significant barrier were patient nonadherence to blood work and blood work's burden on the patient (out of 28). Among nine solutions, the ability to obtain lab results in the physician's office or pharmacy was top ranked (mean±sd Likert scale [4.0±1.0]). Physicians responded that a point-of-care device to measure blood levels and WBCs would improve care and increase CLZ use. Residents ranked point-of-care devices higher than older physicians (4.07±0.87 vs. 3.47±1.08, p<0.0001). Also, the prototype device was able to detect CLZ reliably in 1.6, 8.2, and 16.3 µg/mL buffered solutions. DISCUSSION: Survey results demonstrate physicians' desire for point-of-care monitoring technology, particularly among younger prescribers. Prototype sensor results identify that CLZ can be detected and integrated for future device development. Future development will also include integration of WBCs for a complete detection device.

Clozapine underutilization and discontinuation in African Americans due to leucopenia.

Clozapine use has been notably lower in African American patients than in Caucasians. It has been suggested that lower normal ranges for white blood cell (WBC) counts in African Americans, known as benign ethnic neutropenia, may account partially for the disparity. We examined the rates of leucopenia and agranulocytosis as reasons for discontinuation of clozapine in a sample of 1875 patients with schizophrenia treated in the State of Maryland. Between 1989 and 1999, 5.3% (31/588) of African Americans and 2.4% (31/1287) of Caucasians discontinued clozapine treatment due to leucopenia (chi square = 10.35, df = 1, P = 0.001). No African American patients developed agranulocytosis while 8 Caucasian patients (0.62%) developed this blood dyscrasia. Discontinuations due to leucopenia occurred throughout treatment. Discontinuations due to agranulocytosis occurred primarily in the first 18 weeks (7/8; 87.5% patients with agranulocytosis). It is likely that African Americans had clozapine discontinued unnecessarily due to benign ethnic neutropenia. We concur with recent recommendations to acknowledge differences in WBC values in African Americans and to modify prescribing guidelines or formally acknowledge benign ethnic leucopenia like in other countries in order to facilitate greater use of clozapine in these patients.

Clozapine utilization and outcomes by race in a public mental health system: 1994-2000.

OBJECTIVE: This study aimed to assess racial differences in clozapine prescribing, dosing, symptom presentation and response, and hospitalization status. This study extends previous studies of clozapine by examining patient- and treatment-related factors that may help explain or eliminate reasons for differential prescribing. METHOD: Clozapine records for 373 white and African American patients with schizophrenia or schizoaffective disorder treated between March 1, 1994, and December 31, 2000, in inpatient mental health facilities in the state of Maryland were examined. Records for this study were derived from 3 state of Maryland databases: the Clozapine Authorization and Monitoring Program, the State of Maryland Antipsychotic Database, and the Health Maintenance Information System Database. RESULTS: A total of 10.3% of African Americans (150/1458) with schizophrenia received clozapine treatment compared with 15.3% of whites (223/1453) (chi2 = 16.74, df = 1, p < .001) during inpatient treatment in the public mental health system in Maryland. Clozapine doses were lower in African Americans relative to whites (385.3 +/- 200.6 vs. 447.3 +/- 230.3 mg/day) (t = -2.66, df = 366, p = .008). At the time of clozapine initiation, whites had more activating symptoms as measured by the Brief Psychiatric Rating Scale (BPRS) (t = -3.98, df = 301, p < .0001); however, African Americans had significantly greater improvements in BPRS total symptoms (F = 4.80, df = 301, p = .03) and in anxiety/ depressive symptoms during 1 year of treatment with clozapine (F = 10.04, df = 303, p = .002). The estimated rate of hospital discharge was not significantly different for African Americans compared to whites prescribed clozapine (log-rank chi2 = 0.523, df = 1, p = .470); however, African Americans were more likely than whites to discontinue clozapine during hospitalization (log-rank chi2 = 4.19, df = 1, p = .041). CONCLUSION: Our data suggest underutilization of clozapine in African American populations. This racial disparity in clozapine treatment is of special concern because of the favorable outcomes associated with clozapine in treatment-resistant schizophrenia and in the specific benefits observed in African American patients. More research is needed to determine why disparities with clozapine treatment occur and why African Americans may be discontinued from clozapine at a higher rate, despite potential indicators of equal or greater effectiveness among African Americans compared with whites.

Risperidone, quetiapine, and fluphenazine in the treatment of patients with therapy-refractory schizophrenia.

This 12-week, double-blind study evaluated the effectiveness of risperidone (4 mg/day), quetiapine (400 mg/day), or fluphenazine (12.5 mg/day) in a stringently defined treatment-resistant population of people with schizophrenia. No differences were noted in total Brief Psychiatric Rating Scale (BPRS) or Clinical Global Impression scores among the drug groups (n = 38). More subjects tended to complete the study on risperidone (69%) or quetiapine (58%) than those treated with fluphenazine (31%; P value not significant). Eighty-nine percent of those who discontinued on fluphenazine (8 of 9) were due to lack of efficacy. Discontinuation due to adverse effects was low, with only 2 subjects (both on quetiapine) stopping due to side effects. Three of 13 risperidone-treated subjects (23%) and 3 of 12 quetiapine-treated subjects (25%) met response criteria (decrease of 20% of total BPRS score), whereas 2 of 13 subjects (15%) responded to fluphenazine. Side effect occurrence was similar among drug groups and EPS ratings on the Simpson Angus Scale improved in all drug groups (quetiapine, 1.64; risperidone, 1.30; fluphenazine, 0.69; P value not significant). Despite the newer class of second-generation antipsychotic medications, this treatment-resistant population remains difficult to treat. Many people have only minimal to modest improvements with antipsychotic treatment and most continue to have residual psychotic symptoms. Treatment with first- and second-generation antipsychotics may demonstrate similar efficacy; however, patients treated with second-generation antipsychotics may be more likely to adhere to treatment.

Comparison of clozapine use in Maryland and in Victoria, Australia.

OBJECTIVE: Studies of how differences in systems of care, including cultural differences, affect prescribing practice and patient outcomes are important and can help answer questions such as the effectiveness of clozapine in routine practice. This study examined the use of clozapine in Maryland and in Victoria, Australia. METHODS: This study used medical record data to examine the use of clozapine in January 2000 for people with schizophrenia in two different countries. Data were gathered from all six public inpatient facilities in Maryland and from the two main community outpatient centers in Victoria. Outpatients were studied in Victoria because Australia's inpatient mental health facilities have closed and people with treatment-resistant schizophrenia are managed exclusively as outpatients. RESULTS: In Maryland 591 inpatients with schizophrenia were given a prescription for second-generation antipsychotics; in Victoria 356 outpatients with schizophrenia were given such a prescription. Among second-generation antipsychotics, clozapine was used significantly more frequently in Australia than in Maryland for the treatment of schizophrenia (173 prescriptions, or 49 percent, compared with 144 prescriptions, or 19 percent). Both systems used clozapine mostly for the treatment of schizophrenia (94 percent in Victoria compared with 88 percent in Maryland). The mean clozapine dosages that were used for the treatment of schizophrenia were significantly higher in Maryland than in Australia (522 mg per day compared with 431 mg per day). CONCLUSIONS: Significant differences in use and dosages of clozapine were found in two populations that were similar in diagnoses and demographic characteristics.

Novel factor-based symptom scores in treatment resistant schizophrenia: implications for clinical trials.

To study the factor structure of symptoms in patients with treatment resistant schizophrenia and whether it is altered by treatment, we analyzed ratings on the Brief Psychiatric Rating Scale (BPRS) from two independent groups of patients with treatment resistant schizophrenia. With confirmatory factor analysis of pre-clozapine BPRS scores in 1074 patients in an administrative data base, the Clozapine Authorization and Monitoring Program (CAMP), we assessed the fit of published factor models and developed a better-fitting model. Model fit was validated in an independent group of 197 research unit participants. Stability of model fit six months post-clozapine was assessed in 834 CAMP patients. A new 4-factor model (negative symptoms, reality distortion, disorganization, and anxiety/depression) had better fit in both data sets than two commonly used factor models, and also fit better post-clozapine. We recommend these four factor scores as clinical trial outcomes in patients with treatment resistant schizophrenia.