Simulated Electroconvulsive Therapy: A Novel Approach to a Control Group in Clinical Trials.

OBJECTIVES: Agitation is the most common behavioral symptom of Alzheimer disease (AD) affecting approximately 40% to 60% of the AD population, yet there are no Food and Drug Administration-approved therapies for the myriad of behavioral or psychological symptoms of dementia. There is growing evidence from naturalistic studies that electroconvulsive therapy (ECT) is a safe and effective treatment for agitation in AD patients who are refractory to pharmacotherapy and behavioral interventions. Despite the existing evidence, ECT remains underused because of stigma, lack of education, and concerns regarding adverse cognitive effects. Randomized controlled clinical trials of ECT are an opportunity to provide high-quality evidence of ECT as a safe and efficacious treatment for agitation in the AD population. We describe the methods for the Electroconvulsive Therapy in Alzheimer's Dementia study, which uses a novel, simulated ECT (S-ECT) control group to conduct a single-blind efficacy study of ECT for the treatment of agitation and aggression in individuals with moderate to severe AD. METHODS: We discuss the rationale, study design, methodology, ethical and practical challenges, and management strategies in using an S-ECT group as the comparator arm in this randomized controlled trial of ECT in AD-related treatment refractory agitation and aggression. CONCLUSIONS: Validation of the safety and efficacy of ECT in patients with advanced AD with refractory agitation and aggression is necessary. This can be accomplished through creative formulation of S-ECT groups that effectively maintain the blind while providing scientific integrity.

Hospital utilization rates for influenza and RSV: a novel approach and critical assessment.

BACKGROUND: Influenza and respiratory syncytial virus (RSV) contribute significantly to the burden of acute lower respiratory infection (ALRI) inpatient care, but heterogeneous coding practices and availability of inpatient data make it difficult to estimate global hospital utilization for either disease based on coded diagnoses alone. METHODS: This study estimates rates of influenza and RSV hospitalization by calculating the proportion of ALRI due to influenza and RSV and applying this proportion to inpatient admissions with ALRI coded as primary diagnosis. Proportions of ALRI attributed to influenza and RSV were extracted from a meta-analysis of 360 total sources describing inpatient hospital admissions which were input to a Bayesian mixed effects model over age with random effects over location. Results of this model were applied to inpatient admission datasets for 44 countries to produce rates of hospital utilization for influenza and RSV respectively, and rates were compared to raw coded admissions for each disease. RESULTS: For most age groups, these methods estimated a higher national admission rate than the rate of directly coded influenza or RSV admissions in the same inpatient sources. In many inpatient sources, International Classification of Disease (ICD) coding detail was insufficient to estimate RSV burden directly. The influenza inpatient burden estimates in older adults appear to be substantially underestimated using this method on primary diagnoses alone. Application of the mixed effects model reduced heterogeneity between countries in influenza and RSV which was biased by coding practices and between-country variation. CONCLUSIONS: This new method presents the opportunity of estimating hospital utilization rates for influenza and RSV using a wide range of clinical databases. Estimates generally seem promising for influenza and RSV associated hospitalization, but influenza estimates from primary diagnosis seem highly underestimated among older adults. Considerable heterogeneity remains between countries in ALRI coding (i.e., primary vs non-primary cause), and in the age profile of proportion positive for influenza and RSV across studies. While this analysis is interesting because of its wide data utilization and applicability in locations without laboratory-confirmed admission data, understanding the sources of variability and data quality will be essential in future applications of these methods.

Improvement of Inpatient Psychiatric Facility Quality Reporting program measure: Screening for metabolic disorders through pharmacy collaborative practice agreement.

BACKGROUND: Second-generation antipsychotics are associated with lower risks of extrapyramidal symptoms, including tardive dyskinesia. However, many second-generation antipsychotics are associated with metabolic adverse effects, including weight gain, impaired blood glucose control, and hyperlipidemia. Metabolic monitoring for patients prescribed antipsychotic medication is 1 of several measures of the Centers for Medicare & Medicaid Services' Inpatient Psychiatric Facility Quality Reporting program. Screening for metabolic disorders (SMD) must be obtained within the previous 365 days before the hospital discharge date. National data suggest that compliance with this measure is low. OBJECTIVE: To improve compliance of metabolic monitoring by 20% while ensuring that the quality improvement interventions did not cause any unintended adverse effects on other aspects of our system. PRACTICE DESCRIPTION: This quality initiative was conducted at a large, 2000-bed academic medical center with approximately 80 inpatient psychiatric beds. PRACTICE INNOVATION: To improve the metabolic screening rates, a pharmacist collaborative practice agreement (CPA) was established as part of a quality improvement project. Previously, there were no formal processes at the institution to ensure that appropriate laboratory tests were conducted. EVALUATION METHODS: Using an uncontrolled before-and-after design, SMD data were gathered from 6 months before and 6 months after CPA implementation. Pearson chi-square test or Fisher exact test were used to compare the pre- and postintervention groups in this quasi-experimental design. RESULTS: Compared with the preintervention period, compliance of SMD monitoring increased by 21.2% in the postintervention phase-from 69.2% to 90.4% (P < 0.001). CONCLUSION: The empowerment of clinical pharmacists with a CPA significantly improved guideline-concordant metabolic monitoring of antipsychotics. These findings may have significant impact on the approach to the safe use of these essential psychotropic medications and provide a framework for other inpatient mental health facilities to optimally use the skills of their interdisciplinary team.

State Laws and Nonprofit Hospital Community Benefit Spending.

OBJECTIVE: To determine the association of state laws on nonprofit hospital community benefit spending. DESIGN: We used multivariate models to estimate the association between different types of state-level community benefit laws and nonprofit hospital community benefit spending from tax filings. SETTING: All 50 US states. PARTICIPANTS: A total of 2421 nonprofit short-term acute care hospital organizations that filled an internal revenue service Form 990 and Schedule H for calendar during years 2009-2015. RESULTS: Between 2009 and 2015, short-term acute care hospitals spent an average of $46 billion per year in total, or $20 million per hospital on community benefit activities. Exposure to a state-level community benefit law of any type was associated with an $8.42 (95% confidence interval: 1.20-15.64) per $1000 of total operating expense greater community benefit spending. Spending amounts and patterns varied on the basis of the type of community benefit law and hospital urbanicity. CONCLUSIONS: State laws are associated with nonprofit hospital community benefit spending. Policy makers can use community benefit laws to increase nonprofit hospital engagement with public health.

Establishing a Baseline: Community Benefit Spending by Not-for-Profit Hospitals Prior to Implementation of the Affordable Care Act.

CONTEXT: Community Benefit spending by not-for-profit hospitals has served as a critical, formalized part of the nation's safety net for almost 50 years. This has occurred mostly through charity care. This article examines how not-for-profit hospitals spent Community Benefit dollars prior to full implementation of the Affordable Care Act (ACA). METHODS: Using data from 2009 to 2012 hospital tax and other governmental filings, we constructed national, hospital-referral-region, and facility-level estimates of Community Benefit spending. Data were collected in 2015 and analyzed in 2015 and 2016. Data were matched at the facility level for a non-profit hospital's IRS tax filings (Form 990, Schedule H) and CMS Hospital Cost Report Information System and Provider of Service data sets. RESULTS: During 2009, hospitals spent about 8% of total operating expenses on Community Benefit. This increased to between 8.3% and 8.5% in 2012. The majority of spending (>80%) went toward charity care, unreimbursed Medicaid, and subsidized health services, with approximately 6% going toward both community health improvement and health professionals' education. By 2012, national spending on Community Benefit likely exceeded $60 billion. The largest hospital systems spent the vast majority of the nation's Community Benefit; the top 25% of systems spent more than 80 cents of every Community Benefit dollar. DISCUSSION: Community Benefit spending has remained relatively steady as a proportion of total operating expenses and so has increased over time-although charity care remains the major focus of Community Benefit spending overall. IMPLICATIONS: More than $60 billion was spent on Community Benefit prior to implementation of the ACA. New reporting and spending requirements from the IRS, alongside changes by the ACA, are changing incentives for hospitals in how they spend Community Benefit dollars. In the short term, and especially the long term, hospital systems would do well to partner with public health, other social services, and even competing hospitals to invest in population-based activities. The mandated community health needs assessment process is a logical home for these sorts of collaborations. Relatively modest investments can improve the baseline level of health in their communities and make it easier to improve population health. Aside from a population health justification for a partnership model, a business case is necessary for widespread adoption of this approach. Because of their authorities, responsibilities, and centuries of expertise in community health, public health agencies are in a position to help hospitals form concrete, sustainable collaborations for the improvement of population health. CONCLUSION: The ACA will likely change the delivery of uncompensated and charity care in the United States in the years to come. How hospitals choose to spend those dollars may be influenced greatly by the financial and political environments, as well as the strength of community partnerships.

An Open-Label, Pilot Study of Daily Right Unilateral Ultrabrief Pulse Electroconvulsive Therapy.

Right unilateral ultrabrief (RUL-UB) pulse width electroconvulsive therapy (ECT) has attracted much research attention recently due to its smaller effect on memory than is associated with other forms of ECT, such as bitemporal placement or unilateral standard pulse width. However, RUL-UB has demonstrated slower antidepressant efficacy in comparison to the other techniques. One method to enhance the speed of response to RUL-UB ECT is administration of 5 times a week (termed "daily") treatments as opposed to the more standard twice or thrice weekly schedule. In this open label study, we treated 20 depressed patients with daily RUL-UB treatments for up to 2 weeks (ie, 10 treatments) using standardized assessments of depression and retrograde amnesia. Response and remission rates were commensurate with those reported in other recent studies using this technique with twice or thrice weekly treatment frequencies, and there was no clinically significant effect on retrograde memory function. We conclude that daily administration of RUL-UB ECT may shorten the duration of the course of ECT treatments without compromising cognition. A randomized trial comparing this technique to a thrice weekly schedule of RUL-UB treatments is indicated.

Electroconvulsive therapy for the acute management of severe agitation in dementia (ECT-AD): A modified study protocol.

OBJECTIVE: This study began as a single-blind randomized controlled trial (RCT) to investigate the efficacy and safety of electroconvulsive therapy (ECT) for severe treatment-refractory agitation in advanced dementia. The aims are to assess agitation reduction using the Cohen-Mansfield Agitation Inventory (CMAI), evaluate tolerability and safety outcomes, and explore the long-term stability of agitation reduction and global functioning. Due to challenges encountered during implementation, including recruitment obstacles and operational difficulties, the study design was modified to an open-label format and other protocol amendments were implemented. METHODS: Initially, the RCT randomized participants 1:1 to either ECT plus usual care or simulated ECT plus usual care (S-ECT) groups. As patients were enrolled, data were collected from both ECT and simulated ECT (S-ECT) patients. The study now continues in an open-label study design where all patients receive actual ECT, reducing the targeted sample size from 200 to 50 participants. RESULTS: Study is ongoing and open to enrollment. CONCLUSION: The transition of the ECT-AD study design from an RCT to open-label design exemplifies adaptive research methodologies in response to real-world challenges. Data from both the RCT and open-label phases of the study will provide a unique perspective on the role of ECT in managing severe treatment-refractory agitation in dementia, potentially influencing future clinical practices and research approaches.

Efficacy of Ketamine with and without Lamotrigine in Treatment-Resistant Depression: A Preliminary Report.

Intravenous (IV) ketamine and FDA-approved intranasal (IN) esketamine are increasingly used for treatment-resistant depression (TRD). Preliminary studies have suggested a synergistic effect of ketamine and lamotrigine, although the data are inconclusive. Herein, we report the response to serial ketamine/esketamine treatment among patients with TRD with or without lamotrigine therapy. In this historical cohort study, we included adult patients with TRD who received serial IV racemic ketamine (0.5 mg/kg over 40-100 min) or IN esketamine (56/84 mg) treatments. A change in depressive symptoms was assessed using the 16-item Quick Inventory of Depressive Symptomatology self-report (QIDS-SR) scale. There were no significant differences in response or remission rates among the patients on or not on lamotrigine during the ketamine/esketamine treatments. For a percent change in the QIDS-SR from baseline, no interaction was found between the lamotrigine groups and treatment number (p = 0.70), nor the overall effect of the group (p = 0.38). There was a trend towards lower dissociation (based on the CADSS score) among current lamotrigine users, especially in patients who received IV ketamine. A major limitation is the limited number of patients taking lamotrigine (n = 13). This preliminary study provides insufficient evidence that continuing lamotrigine therapy attenuates the antidepressant effect of repeated ketamine/esketamine; however, there seems to be a signal toward attenuating dissociation with lamotrigine in patients receiving serial ketamine treatments. Further observational studies or randomized controlled trials are needed to replicate these findings.

Global and national influenza-associated hospitalisation rates: Estimates for 40 countries and administrative regions.

Background: WHO estimates that seasonal influenza epidemics result in three to five million cases of severe illness (hospitalisations) every year. We aimed to improve the understanding of influenza-associated hospitalisation estimates at a national and global level. Methods: We performed a systematic literature review of English- and Chinese-language studies published between 1995 and 2020 estimating influenza-associated hospitalisation. We included a total of 127 studies (seven in Chinese) in the meta-analysis and analyzed their data using a logit-logistic regression model to understand the influence of five study factors and produce national and global estimates by age groups. The five study factors assessed were: 1) the method used to calculate the influenza-associated hospitalisation estimates (rate- or time series regression-based), 2) the outcome measure (divided into three envelopes: narrow, medium, or wide), 3) whether every case was laboratory-confirmed or not, 4) whether the estimates were national or sub-national, 5) whether the rates were based on a single year or multiple years. Results: The overall pooled influenza-associated hospitalisation rate was 40.5 (95% confidence interval (CI) = 24.3-67.4) per 100 000 persons, with rates varying substantially by age: 224.0 (95% CI = 118.8-420.0) in children aged 0-4 years and 96.8 (95% CI = 57.0-164.3) in the elderly aged >65 years. The overall pooled hospitalisation rates varied by calculation method; for all ages, the rates were significantly higher when they were based on rate-based methods or calculated on a single season and significantly lower when cases were laboratory-confirmed. The national hospitalisation rates (all ages) varied considerably, ranging from 11.7 (95% CI = 3.8-36.3) per 100 000 in New Zealand to 122.1 (95% CI = 41.5-358.4) per 100 000 in India (all age estimates). Conclusions: Using the pooled global influenza-associated hospitalisation rate, we estimate that seasonal influenza epidemics result in 3.2 million cases of severe illness (hospitalisations) per annum. More extensive analyses are required to assess the influence of other factors on the estimates (e.g. vaccination and dominant virus (sub)types) and efforts to harmonize the methods should be encouraged. Our study highlights the high rates of influenza-associated hospitalisations in children aged 0-4 years and the elderly aged 65+ years.

Correction: Joseph et al. Efficacy of Ketamine with and without Lamotrigine in Treatment-Resistant Depression: A Preliminary Report. Pharmaceuticals 2023, 16, 1164.

In the original publication [...].

Varied Health Spending Growth Across US States Was Associated With Incomes, Price Levels, And Medicaid Expansion, 2000-19.

Little is known about health care spending variation across the US for recent years. To estimate health spending by state and payer, we combined data from the government's State Health Expenditure Accounts, which have estimates through 2014, with other primary data on spending. In 2019 state-specific per person spending ranged from $7,250 to $14,500. After adjustment for inflation, annualized per person spending growth for each state ranged from 1.0 percent in Washington, D.C., to 4.2 percent in South Dakota between 2013 and 2019. The factors that explained the most variation across states were incomes (25.3 percent) and consumer prices (21.7 percent). Medicaid expansion was associated with increases in total spending per person, although the median of spending in expansion states showed slower growth in out-of-pocket spending than the median in nonexpansion states. Contemporary estimates of state health spending are valuable for tracking divergent expenditure trajectories in the US and assessing the associated factors.

National burden estimates of hospitalisations for acute lower respiratory infections due to respiratory syncytial virus in young children in 2019 among 58 countries: a modelling study.

BACKGROUND: Respiratory syncytial virus (RSV) is the predominant viral pathogen associated with acute lower respiratory infection (ALRI) in children who are younger than 5 years. Little is reported on the national estimates of RSV-associated ALRI hospitalisations in these children on the basis of robust epidemiological data. We aimed to generate national level estimates for RSV-associated ALRI hospitalisations in children aged younger than 5 years. METHODS: We included data for RSV and ALRI hospitalisation in children who were younger than 5 years from systematic literature reviews (including unpublished data) and from inpatient databases, representing 58 countries. We used two different methods, the rate-based method and the proportion-based method, to estimate national RSV-associated ALRI hospitalisations in children younger than 5 years in 2019. The rate-based method synthesised data for laboratory-confirmed RSV-associated ALRI hospitalisation rates using a spatiotemporal Gaussian process meta-regression (ST-GPR). The proportion-based method applied data for RSV positive proportions among ALRI to all-cause ALRI hospitalisation envelopes (ie, total disease burden of ALRI hospitalisations of any cause) using a Bayesian regularised trimmed meta-regression (MR-BRT). Where applicable, we reported estimates by both methods to provide a plausible range for each country. FINDINGS: A total of 334 studies and 1985 data points (defined as an individual estimate for one age group and 1 year for each study) were included in our analysis, accounting for 398 million (59%) of the 677 million children aged younger than 5 years worldwide representing 58 countries. We reported the number of annual national RSV-associated ALRI hospitalisations for 29 countries using the rate-based method, and for 42 countries using the proportion-based method. The median number of RSV-associated ALRI hospitalisations in children younger than 5 years was 8·25 thousand (IQR 1·97-48·01), and the median rate of RSV-associated ALRI hospitalisations was 514 (339-866) hospitalisations per thousand children younger than 5 years. Despite large variation among countries, a high proportion of the RSV-associated ALRI hospitalisations were in infants aged younger than 1 year in all countries (median proportion 45%, IQR 32-56). In 272 (76%) of the 358 years included in the analysis, the RSV-associated ALRI hospitalisation rate fluctuated between 0·8 and 1·2 times the country's median yearly rate. General agreement was observed between estimates by the rate-based method and proportion-based method, with the exceptions of India, Kenya, Norway, and Philippines. INTERPRETATION: By incorporating data from various sources, our study provides robust estimates on national level burden of RSV-associated ALRI hospitalisation in children aged younger than 5 years. These estimates are important for informing policy for the introduction of RSV immunisations and also serve as baseline data for the RSV disease burden in young children. FUNDING: The Foundation for Influenza Epidemiology.

Perinatal Mood and Anxiety Disorder Management in Multicenter Community Practices: Clinicians' Training, Current Practices and Perceived Strategies to Improve Future Implementation.

BACKGROUND: This study aimed to explore clinicians' perspectives on the current practice of perinatal mood and anxiety disorder (PMAD) management and strategies to improve future implementation. METHODS: This study had a cross-sectional, descriptive design. A 35-item electronic survey was sent to clinicians (N = 118) who treated perinatal women and practiced at several community clinics at an academic medical center in the United States. RESULTS: Among clinicians who provided care for perinatal women, 34.7% reported never receiving PMAD management training and 66.3% had less than 10 years of experience. Out of 10 patients who reported psychiatric symptoms, 47.8% of clinicians on average reported providing PMAD management to 1 to 3 patients and 40.7% noted that they conducted screening only when patient expresses PMAD symptoms. Suggested future improvements were providing training, developing a referral list, and establishing integrated behavioral health services. CONCLUSIONS: Results from this study indicated that while PMAD screening and management was implemented, improvements are warranted to meet established guidelines. Additionally, clinicians endorsed providing PMAD management to a small percentage of perinatal patients. Suggested strategies to increase adoption and implementation of PMAD management should be explored to improve access to behavioral health services for perinatal women.

Pharmacogenetic testing in psychiatric inpatients with polypharmacy is associated with decreased medication side effects but not via medication changes.

In psychiatric patients, medication adverse effects are regularly attributed to psychosomatic causes. However, many psychotropic medications are metabolized by cytochrome P450 (CYP450) enzymes. In the setting of polypharmacy, the activity of these enzymes may produce unfavorable drug-drug interactions (DDI) and drug-genotype interactions (DGI) that contribute to morbidity and mortality. This study sought to estimate the risk of adverse DDI and DGI in psychiatric inpatients with polypharmacy. We assessed whether medication changes made after pharmacogenetics (PGx) testing correlated with changes in side effects and overall improvement. Adult psychiatry inpatients with polypharmacy, defined as 5 or more scheduled prescription medications, completed the 24-item Antidepressant Side Effect Checklist (ASEC) questionnaire on enrollment and underwent PGx testing. Analysis of PGx results focused on whether the CYP2D6 and CYP2C19 phenotypes were "extreme," defined as poor, poor to intermediate, or ultrarapid. Approximately 30 days after PGx results were sent to outpatient providers, patients were contacted to obtain their current medication list and ASEC and Clinical Global Impression Improvement (CGI-I) scores. A total of 80 patients were enrolled, and 52 (65%) completed follow-up. ASEC scores improved from 11.5 (±8.1) to 7.2 (±6.0) (p = 0.0009). Mean CGI-I score was 2.7 (±1.4), between "minimal" to "much improved." However, linear regression revealed that these improvements were not correlated with whether medications were changed. We concluded that the impact of drug-genotype interactions in this small sample of inpatients with polypharmacy was low, and that patient improvement was related not to PGx-guided medication changes but to other treatments during hospitalization.

Addressing clozapine under-prescribing and barriers to initiation: a psychiatrist, advanced practice provider, and trainee survey.

Clozapine use has declined, despite its superior antipsychotic efficacy in treatment-resistant schizophrenia. Implications for clozapine underutilization include suboptimal treatment outcomes and increased hospitalizations. Many barriers preventing the use of clozapine have been described in the literature, including suboptimal knowledge and poor perceptions. The aim of this study was to assess psychiatry prescribers' perception and knowledge of clozapine. A survey was distributed to advanced practice providers, psychiatrists, and trainees (i.e. residents and fellows) at 10 medical centers within the US and Canada. The survey asked respondents about their perception of clozapine use and assessed their pharmacotherapeutic knowledge of clozapine. Two hundred eleven individual submitted completed surveys of a possible 1152; a response rate of 18.3%. There were no statistically significant differences between the advanced practice provider plus psychiatrist groups and the trainee group for most perception (eight of nine) and knowledge (eight of nine) questions. The knowledge questions with the lowest scores pertained to clozapine reinitiation and myocarditis. The majority of all respondents (144, 68.2%) felt that clozapine prescribing was a burden. Findings of this study support the need for continued clozapine education regardless of a prescriber's age/experience. Future studies to assess barriers to clozapine prescribing should extend beyond academic centers.

Decreasing Treatment Duration of Electroconvulsive Therapy (ECT) Using Daily Right Unilateral Ultrabrief Instead of Bitemporal ECT.

OBJECTIVE: Electroconvulsive therapy (ECT) is an effective treatment for depression, but the standard 2 to 3 times weekly treatment course results in a total treatment duration of >2 weeks. We explored the viability of decreasing treatment duration by using daily right unilateral ultrabrief (RULUB) ECT instead of standard bitemporal (BT) ECT. METHODS: This study involved a retrospective review of records of inpatients 18 to 64 years of age who were treated between 2012 and 2017 at a large tertiary ECT center. Lead placement/technique, treatment duration (days from first to last ECT), number of ECT treatments, and scores on the Patient Health Questionnaire-9 (PHQ-9), and the Hamilton Depression Rating Scale (HamD-24) were collected. Statistical analysis was performed using 1-way analysis of variance and t tests. RESULTS: Of 214 patients, 112 started daily RULUB ECT (86 were completers and 26 were eventually switched to BT), and 83 started and completed BT ECT. Daily RULUB completers finished their course of ECT 6.5 days faster than those who received BT ECT (11.7 vs. 18.2 d, P<0.0001), while the number of ECT treatments did not significantly differ between the 2 groups (daily RULUB 8.6 treatments vs. BT 8.3 treatments, P=0.4402). There were no significant differences in the final PHQ-9 or HamD-24 depression scores between the 2 groups. One case of significant cognitive impairment was observed in the daily RULUB group. CONCLUSIONS: Daily RULUB ECT compared with BT ECT allowed depression to be treated faster and with similar efficacy. Randomized controlled trials, which include the use of formal cognitive and physical side effect measures, are needed to further explore the viability of daily RULUB ECT.