Optimizing therapeutic decision-making for off-label medicines use: A scoping review and consensus recommendations for improving practice and research.

PURPOSE: Off-label medicines use is a common and sometimes necessary practice in many populations, with important clinical, ethical and financial consequences, including potential unintended harm or lack of effectiveness. No internationally recognized guidelines exist to aid decision-makers in applying research evidence to inform off-label medicines use. We aimed to critically evaluate current evidence informing decision-making for off-label use and to develop consensus recommendations to improve future practice and research. METHODS: We conducted a scoping review to summarize the literature on available off-label use guidance, including types, extent and scientific rigor of evidence incorporated. Findings informed the development of consensus recommendations by an international multidisciplinary Expert Panel using a modified Delphi process. Our target audience includes clinicians, patients and caregivers, researchers, regulators, sponsors, health technology assessment bodies, payers and policy makers. RESULTS: We found 31 published guidance documents on therapeutic decision-making for off-label use. Of 20 guidances with general recommendations, only 35% detailed the types and quality of evidence needed and the processes for its evaluation to reach sound, ethical decisions about appropriate use. There was no globally recognized guidance. To optimize future therapeutic decision-making, we recommend: (1) seeking rigorous scientific evidence; (2) utilizing diverse expertise in evidence evaluation and synthesis; (3) using rigorous processes to formulate recommendations for appropriate use; (4) linking off-label use with timely conduct of clinically meaningful research (including real-world evidence) to address knowledge gaps quickly; and (5) fostering partnerships between clinical decision-makers, researchers, regulators, policy makers, and sponsors to facilitate cohesive implementation and evaluation of these recommendations. CONCLUSIONS: We provide comprehensive consensus recommendations to optimize therapeutic decision-making for off-label medicines use and concurrently drive clinically relevant research. Successful implementation requires appropriate funding and infrastructure support to engage necessary stakeholders and foster relevant partnerships, representing significant challenges that policy makers must urgently address.

The American Public Health Association Endorses Single-Payer Health System Reform.

Health care is a human right. Achieving universal health insurance coverage for all US residents requires significant system-wide reform. The most equitable and cost-effective health care system is a public, single-payer (SP) system. The rapid growth in national health expenditures can be addressed through a system that yields net savings over projected trends by eliminating profit and waste. With universal health insurance coverage through SP financing, providers can focus on optimizing delivery of services, rather than working within a system covered by payers who have incentives to limit costs regardless of benefit. Rather, with a SP, the people act as their own insurer through a partnership with provider organizations where tax dollars work for everyone. Consumer choice is then based on the best care to meet need with no out-of-pocket payments. SP financing is the best option to ensure equity, fairness, and public health priorities align with medical needs, providing incentives for wellness. Consumer choice will drive market forces, not provider network profits or insurer restrictions. This approach benefits public health, as everyone will have universal access to needed care, with treatment plans developed by providers based on what works best for the patient. In 2021, the American Public Health Association adopted a policy statement calling for comprehensive reforms to implement a SP system. The proposed action steps in this policy will help build a healthier nation, saving lives and reducing wasted health care expenditures while addressing inequities rooted in social, demographic, mental health, economic, and political determinants.

Continuity of Care and Mental Health Service Use Among Medicaid-enrolled Youths.

BACKGROUND: Recent reports of increased national estimates of pediatric psychiatric emergency department (ED) visits and psychiatric hospitalizations emphasize the need to research these utilization patterns. OBJECTIVES: To assess the patient-provider continuity of care (CoC) and compare the risk of psychiatric ED visits or hospitalization according to the CoC level. RESEARCH DESIGN: A cohort design was applied to Medicaid administrative claims data (2007-2014) for 3-16-year olds with a first psychiatric diagnosis between 2009 and 2013 (n=38,825). SUBJECTS: Continuously enrolled youths with (1) ≥1 outpatient psychiatric visits and (2) ≥4 pediatric outpatient visits in the prior 24 months. MEASURES: The authors assessed CoC in the 24 months before the first psychiatric outpatient visit and quantified CoC using the Alpha Index. The authors assessed patient-provider CoC before first psychiatric diagnosis and the odds of psychiatric ED visits or psychiatric hospitalizations in the year after diagnosis. RESULTS: Of the 38,825 youths, 88.9% received a first psychiatric diagnosis by age 14. The odds of ED visits were significantly higher among youths with low CoC [6.63%, adjusted odds ratio (AOR), 1.27; 95% confidence interval (CI), 1.13-1.41] or moderate CoC (5.76%; AOR, 1.14; 95% CI, 1.02-1.27) compared with those with high CoC (4.96%). Greater odds of psychiatric hospitalization related to low (7.53%; AOR, 1.17; 95% CI, 1.06-1.29) or moderate CoC (7.01%; AOR, 1.15; 95% CI, 1.03-1.27) compared with high CoC (6.06%). CONCLUSIONS: The odds of potentially disruptive clinical management and costly psychiatric ED visits or hospitalizations were lower for youths with high CoC. The findings support the need to research the impact of CoC on long-term pediatric mental health service use.

Impact of Coordinated Behavioral Health Management on Quality Measures of Antipsychotic Use.

A state Care Management Entity (CME) using the wraparound practice model provided intensive care coordination for youth with severe mental illness, those most likely to receive antipsychotics. The model has led to improved clinical/functional outcomes, but little is known about the impact on antipsychotic prescribing and safety monitoring. A pre-post study was conducted to evaluate antipsychotic dosing, concomitant antipsychotic use, and metabolic monitoring among CME-enrolled and non-CME-enrolled comparison groups. CME-enrolled youth had greater decrease in concomitant antipsychotic use than non-CME-enrolled youth, but no difference in dosing or metabolic monitoring. More education of prescribing antipsychotics and team-based engagement in care coordination are needed.

Hispanic Residential Isolation, ADHD Diagnosis and Stimulant Treatment among Medicaid-Insured Youth.

OBJECTIVE: This study aimed to evaluate a conceptual framework that assessed the effect of Hispanic residential isolation on Attention Deficit Hyperactivity Disorder (ADHD) health service utilization among 2.2 million publicly insured youth. DESIGN: Cross-sectional. SETTING: Medicaid administrative claims data for ambulatory care services from a US Pacific state linked with US census data. PARTICIPANTS: Youth, aged 2-17 years, continuously enrolled in 2009. MAIN OUTCOME MEASURES: The percent annual prevalence and odds of ADHD diagnosis and stimulant use according to two measures of racial/ethnic residential isolation: 1) the county-level Hispanic isolation index (HI) defined as the population density of Hispanic residents in relation to other racial/ethnic groups in a county (<.5; .5-.64; ≥.65); and 2) the proportion of Hispanic residents in a ZIP code tabulation area (<25%; 25%-50%; >50%). RESULTS: Among the 47,364 youth with a clinician-reported ADHD diagnosis, 60% received a stimulant treatment (N = 28,334). As the county level HI increased, Hispanic residents of ethnically isolated locales were significantly less likely to receive an ADHD diagnosis (adjusted odds ratio [AOR]=.92 [95% CI=.88-.96]) and stimulant use (AOR=.61 [95% CI=.59-.64]) compared with Hispanic youth in less isolated areas. At the ZIP code level, a similar pattern of reduced ADHD diagnosis (AOR=.81 [95% CI=.77-.86]) and reduced stimulant use (AOR=.65 [95% CI=.61-.69]) was observed as Hispanic residential isolation increased from the least isolated to the most isolated ZIP code areas. CONCLUSIONS: These findings highlight the opportunity for Big Data to advance mental health research on strategies to reduce racial/ethnic health disparities, particularly for poor and vulnerable youth. Further exploration of racial/ethnic residential isolation in other large data sources is needed to guide future policy development and to target culturally sensitive interventions.

Antipsychotic prescribing for behavioral disorders in US youth: physician specialty, insurance coverage, and complex regimens.

PURPOSE: To assess antipsychotic prescribing patterns according to insurance coverage type and physician specialty in the outpatient treatment of behavioral disorders (BD) in US youth. METHODS: We used 2003-2010 National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey data to compare antipsychotic prescribing in the outpatient treatment of BD in youth (6-19 years) according to insurance coverage (public vs. private) and physician specialty (psychiatrist vs. non-psychiatrist) using population-weighted Chi-square and multivariable analyses. Also, we examined co-prescribing of antipsychotics with other psychotropic medication classes. Subgroup analyses were conducted in BD visits with no other clinician-reported psychiatric diagnosis (non-comorbid BD visits). RESULTS: A large majority (71.0%) of BD visits were provided by non-psychiatrists. However, psychiatrists prescribed antipsychotics far more frequently than non-psychiatrists (24.2% vs. 4.6%; adjusted odds ratio (AOR) = 5.1 [95% confidence interval (CI), 2.8-9.2]) in total BD visits as well as in non-comorbid BD visits (18.6% vs. 3.6%; AOR = 5.8 [95% CI, 3.2-10.5]). Antipsychotic prescribing was nearly two-fold greater in visits by publicly insured 6-12 year olds (11.3% vs. 5.8%; AOR = 1.9 [95% CI, 1.1-3.5]) and 13-19 year olds (16.2% vs. 8.9%; AOR = 2.0 [95% CI, 1.1-3.6]) compared with their privately insured counterparts. In more than one-third of antipsychotic-prescribed BD visits, antipsychotics were prescribed concomitantly with ≥2 psychotropic medication classes regardless of age group, insurance coverage, or even in the absence of psychiatric comorbidities. CONCLUSION: In outpatient visits by youth for BD, antipsychotics were primarily prescribed by psychiatrists, concomitantly, and for the publicly insured. These treatment patterns merit further investigation.

Stimulant Patterns, Alone or with Other Psychotropic Classes, in Medicaid-Insured Youth Continuously Enrolled for 3-8 Years.

Objective: Little U.S. pharmacoepidemiologic study is based on treatment during continuous enrollment for periods more than a year. This study aims to show pediatric patterns of stimulant use (alone or with other psychotropic classes) from Medicaid administrative claims data for stimulant patterns of 3- to 8-year continuous enrollees. Methods: A retrospective cohort study was derived from Medicaid enrollment, pharmacy, and diagnosis claims data (2007-2014) in a mid-Atlantic state. Youth aged 2-17 years with 3-8 years of continuous enrollment treated with stimulants were compared with a date-matched comparison group treated without stimulants. Major outcomes include prevalence and duration of stimulant use and patterns of stimulant polypharmacy across relatively long enrollments (3-8 years). Results: Among 264,518 unique 2- to 17-year olds with 3-8 years of continuous enrollment, 16.5% had stimulant prescription dispensings, doubling the annual national prevalence of 8.1%. Subgroup analysis showed that the highest prevalence of stimulant use was for 6- to 11-year olds (20.4%), foster care eligible youth (42.3%), and those with 7-8 years of continuous enrollment (20.1%). Externalizing psychiatric disorders were far more common in those treated with stimulants than in those treated without stimulants. The duration of stimulant exposure overall was a median of 487 days, half that of foster care stimulant users. Stimulant polypharmacy with two or more psychotropic classes concomitantly characterized 29.8% of stimulant users. Among those with three or four or more class polypharmacy, 85% and 88%, respectively, had concomitant stimulant and antipsychotic use. The adjusted odds ratio (AOR) of three or more class polypharmacy significantly increased in 12- to 17-year-old age group (AOR = 1.8), foster care eligibility (AOR = 4.5), and among those with the longest enrollment (AOR = 1.7). Conclusions and Relevance: Stimulant prevalence in Medicaid-insured youth with continuous enrollment of 3-8 years was twice as common as in annual data sets. Future research should investigate three to five interclass stimulant polypharmacy effectiveness in reliably diagnosed community populations.

Number needed to harm: its limitations in psychotropic drug safety research.

Commonly used statistical measures to quantify the likelihood of an adverse drug event (ADE) from clinical trials include risk ratio; odds ratio; and number needed to harm (NNH), the reciprocal of absolute risk. This critical review focused on NNH, specifically on its limitations in controlled trials with psychotropic medication. Data for this evaluation were obtained primarily from articles in MEDLINE from 1988 to 2012. Limitations of NNH were found to include the following: a) arbitrary binary cutoffs for continuous measures, b) limited use of confidence intervals, c) limited adjustments for potential baseline confounders, d) limited adjustments for differences in dose and treatment duration, e) rare consideration of high attrition rates, f) variable use of the term harm, g) oversimplified single harm comparisons, h) frequent biased design and reporting, i) undue emphasis on less severe ADEs, j) application primarily to short-term clinical trials, and k) little or no generalizability in community practice. In sum, the NNH metric supplies very limited information on the risks of psychotropic medication. Postmarketing surveillance of community treatment populations using case-control methodology provides far more useful data on serious ADEs.

Age-grouped differences in bipolar mania.

OBJECTIVE: This review of published studies compares scores on individual items of mania rating scales that systematically recorded symptom severity in persons diagnosed with bipolar disorder to identify age-grouped differences. METHODS: An extensive literature search identified item scores from mania rating scales, with a particular emphasis on baseline Young Mania Rating Scale (YMRS) item scores in published double-blind, placebo-controlled studies of bipolar I manic disorder. These baseline YMRS item scores were assessed as a proportion of the total YMRS score and compared by age group. Additional YMRS item/total scores in subjects with bipolar spectrum disorders were added to expand the analysis. RESULTS: Preadolescents with bipolar disorder had significantly higher YMRS item scores than adolescents on aggression, irritability, and motor activity. Young Mania Rating Scale baseline item scores relative to the YMRS total score revealed that adolescents diagnosed with bipolar I mania scored comparatively higher than did adults on YMRS aggression and irritability items, whereas adults with bipolar I manic disorder scored comparatively higher on the grandiosity and sexual interest items. Age-grouped findings from subjects diagnosed with bipolar I, II, and Not Otherwise Specified (NOS) disorders yielded similar age-grouped results. CONCLUSION: In age-grouped YMRS item assessments of bipolar mania, anger dyscontrol was most prominent for youth, whereas disordered thought content was paramount for adults.

Psychotropic Polypharmacy in the US Pediatric Population: A Methodologic Critique and Commentary.

Background: Psychotropic concomitant medication use for the treatment of youth with emotional and behavioral disorders has grown significantly in the U.S. over the past 25 years. The use of pharmacy claims to analyze these trends requires the following: age of the selected population, overlapping days of use, and precision of the outcome itself. This review will also address the gaps in reporting of pediatric psychotropic polypharmacy. Methods: An electronic literature search was undertaken for the period 2000 through 2020 using keywords such as "pediatric," "concomitant," "polypharmacy," "multiple medications," and "concurrent psychotropic"; Relevant references in textbooks were also used. Only English language and U.S. studies were included, resulting in 35 inter-class studies. Results: Studies were organized into seven groups according to data sources and clinical topics: (1) population surveys; (2a) multi-state publicly insured populations; (2b) single/two state studies; (3) privately insured populations; (4) diagnosed populations; (5) foster care populations; (6) special settings. Across 20 years it is apparent that pediatric psychotropic polypharmacy affects substantially more children and adolescents today than had been the case. As many as 300,000 youth now receive 3 or more classes concomitantly. The duration of concomitant use is relatively long, e.g., 69-89% of annual medicated days. Finally, more adverse event reports were associated with 3-class compared with 2-class drug regimens. Discussion: Factors that contribute to the growth of pediatric psychotropic polypharmacy include: (1) predominance of the biological model in psychiatric practice; (2) invalid assumptions on efficacy of combinations, (3) limited professional awareness of metabolic and neurological adverse drug events, and (4) infrequent use of appropriate deprescribing. Conclusion: A review of publications documenting U.S. pediatric psychotropic polypharmacy written over the last 20 years supports the need to standardize the methodologies used. The design of population-based studies should maximize information on the number of youth receiving regimens of 3-, 4-, and 5 or more concomitant classes and the duration of such use. Next, far more post-marketing research is needed to address the effectiveness, safety and tolerability of complex drug regimens prescribed for youngsters.

Impact of the 2004 Food and Drug Administration pediatric suicidality warning on antidepressant and psychotherapy treatment for new-onset depression.

OBJECTIVE: To assess the national impact of the March 2004 Food and Drug Administration (FDA) antidepressant suicidality warning on the outpatient treatment of new-onset depression in youth. METHOD: A repeated measures, longitudinal design in a cohort of youth diagnosed with new-onset depression was used to assess pre- and post-FDA warning effects. US commercial insurance enrollees in the i3 INNOVUS database from January 2003 through December 2006 were examined. The study population included youth 2- to 17-years old with a new-onset depression diagnosis from July 2003 through June 2006 (N = 40,309). The main independent variables were the warning period (post- vs. pre-FDA warning) and age group (children vs. adolescents). The main outcome measures were youth with antidepressant dispensings and psychotherapy visits measured in 30-day intervals across 36 months following a new-onset diagnosis of any depressive disorder (N = 40,309) and specifically major depressive disorder (MDD) (N = 11,532). RESULTS: Compared to youth with a new-onset diagnosis of depression in the pre-FDA warning period, youth with new-onset diagnosis of depression during the postwarning period had (1) A significantly lower likelihood of antidepressant use: (odds ratio [OR] = 0.85 [0.81-0.89]); When youth with the diagnosis of depression were separated into those with MDD and those with less severe depression diagnoses, only the latter had a significant postwarning antidepressant decline. (2) A significant increase in the odds of a psychotherapy visit (children, OR = 1.31 [1.23-1.40]; adolescents OR = 1.19 [1.15-1.24]). CONCLUSIONS: The FDA suicidality warning was associated with an overall decrease in antidepressant treatment for youth with a clinician-reported diagnosis of depression, but not for those with MDD. Also, following the warning, psychotherapy without medication increased.

Patterns of antidepressant use in Quebec children and adolescents: trends and predictors.

Antidepressants are highly prescribed in youth although most products have not been approved for use in this population. Furthermore, regulatory warnings have led to changes in antidepressant use that might have differed across various countries. Our study aimed at determining factors associated with antidepressant prescribing practices and at assessing trends in use from 1997 to 2005 in Quebec youth.A retrospective cohort study was conducted through claims databases of the Quebec public health care program (RAMQ). The study included 5094 children (age 2-14) and 11,121 adolescents (age 15-19) who were incident users of antidepressant between 1997 and 2005. The characteristics of users and prescribers were the main independent variables.Tricyclics were the most frequently dispensed products among children (50.9%) and selective serotonin reuptake inhibitors among adolescents (58.8%). Selection of an antidepressant class was associated with patient characteristics and with prescriber specialty. The number of antidepressant users increased from 1997 until 2001 then decreased thereafter.The selection of an antidepressant class was associated with clinical and non-clinical characteristics. Although antidepressant use decreased after regulatory warnings, there appears to be a care gap between the evidence generated by efficacy studies and the products prescribed in a real-life setting.