Drug overdose risk with benzodiazepine treatment in young adults: Comparative analysis in privately and publicly insured individuals.

BACKGROUND AND AIMS: Benzodiazepines (BZDs) carry a risk for drug overdose and are prescribed alone or simultaneously with selective-serotonin reuptake inhibitors (SSRIs) for the treatment of anxiety and depression in young adults. We aimed to measure risks of drug overdose following BZD treatment initiation, and simultaneous BZD and SSRI initiation, compared with SSRI treatment alone in young adults with depression or anxiety. DESIGN, SETTING, PARTICIPANTS: The cohort study used administrative databases covering privately (MarketScan, 1/1/2009-12/31/2018) and publicly (Medicaid, 1/1/2015-12/31/2016) insured young adults (18-29 years) in the United States. Those with depression or anxiety diagnoses newly initiating BZD or SSRI treatment (without BZD or SSRI prescriptions in prior year) were included. Simultaneous "BZD + SSRI" initiation was defined as starting BZD and SSRI treatment on the same day. The cohorts included 604 664 privately insured young adults (BZD = 22%, BZD + SSRI = 10%, SSRI = 68%) and 110 493 publicly insured young adults (BZD = 23%, BZD + SSRI = 5%, SSRI = 72%). MEASUREMENTS: Incident medically treated drug overdose events were identified from emergency department and inpatient encounters (ICD poisoning codes) within 6 months of treatment initiation. Crude and propensity-score adjusted cumulative incidence and hazard ratios (HR) were estimated. Sub-analyses evaluated drug overdose intent. FINDINGS: Adjusted HRs of drug overdose for BZD vs. SSRI treatment was 1.36 (95% confidence interval [CI]:1.23-1.51) in privately and 1.59 (95%CI:1.37-1.83) in publicly insured young adults. The adjusted HRs of drug overdose for BZD + SSRI treatment vs. SSRI treatment were 1.99 (95%CI:1.77-2.25) in privately and 1.98 (95%CI:1.47-2.68) in publicly insured young adults. CONCLUSIONS: Among young adults in the United States, initiating benzodiazepine treatment for anxiety and depression, alone or simultaneously with selective-serotonin reuptake inhibitors (SSRI), appears to have an increased risk of medically treated drug overdose compared with SSRI treatment alone. These associations were observed in publicly and privately insured individuals.

Antipsychotic Medication Use In Medicaid-Insured Children Decreased Substantially Between 2008 And 2016.

After the rapid growth of pediatric antipsychotic prescribing in the early 2000s, especially in the Medicaid population, concerns regarding the safety and appropriateness of such prescribing increased. Many states implemented policy and educational initiatives aimed at safer and more judicious antipsychotic use. Antipsychotic use leveled off in the late 2000s, but there have been no recent national estimates of trends in antipsychotic use in children enrolled in Medicaid, and it is unclear how use varied by race and ethnicity. This study observed a sizable decline in antipsychotic use among children ages 2-17 between 2008 and 2016. Although the magnitude of change varied, declines were observed across foster care status, age, sex, and racial and ethnic groups studied. The proportion of children with an antipsychotic prescription who received any diagnosis associated with a pediatric indication that was approved by the Food and Drug Administration increased from 38 percent in 2008 to 45 percent in 2016, which may indicate a trend toward more judicious prescribing.

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.

Trends in Antipsychotic Medication Use in Young Privately Insured Children.

OBJECTIVE: To estimate trends of annual antipsychotic medication use by privately insured young children (aged 2-7 years) in the United States, and to describe the clinical and treatment characteristics of these children. METHOD: The study population included young children from a nationwide commercial claims database (2007-2017). We estimated annual antipsychotic use by age and sex, defined as the number of children dispensed an antipsychotic per year divided by the number enrolled. We described clinical diagnoses and mental health service use in those with prescription antipsychotic use in 2009 and 2017. RESULTS: Annual antipsychotic use in young children was 0.27% in 2007, peaked at 0.29% in 2009, and statistically significantly declined to 0.17% by 2017 (linear trend: -0.017% per year, 95% CI: -0.018 to -0.016). Antipsychotic use was higher in boys than in girls. A greater proportion of antipsychotic users received a mental disorder diagnosis in 2017 (89%) than in 2009 (86%, p < .01). The most common clinical diagnoses in antipsychotic users, under a hierarchical classification, were pervasive developmental disorder (2009 = 27%, 2017 = 38%, p < .01), conduct or disruptive behavior disorder (2009 = 15%, 2017 = 21%, p < .01), and attention-deficit/hyperactivity disorder (2009 = 24%, 2017 = 18%, p < .01). Among 2017 antipsychotic users, 32% had 4+ psychotherapy claims, 43% had a psychiatrist visit, and the majority used another psychotropic medication, most commonly a stimulant (boys = 57%, girls = 50%). CONCLUSION: In privately insured young children, antipsychotic use declined from 2009 to 2017, with shifts toward indications with some supporting evidence. Nevertheless, a majority of use remains off label and for conditions lacking effectiveness and safety data. Improving antipsychotic prescribing in young children remains a challenge.

Prescription Benzodiazepine Use in Privately Insured U.S. Children and Adolescents.

INTRODUCTION: Benzodiazepines are commonly prescribed in the U.S. but entail safety concerns, including dependency. In pediatrics, many indications lack trial data. Authors aimed to describe youth initiating prescription benzodiazepine treatment, identify potential indications and prescribing concerns, estimate the duration of treatment by potential indication, and identify factors that predict long-term use. METHODS: The study cohort included children (aged 3-12 years) and adolescents (aged 13-17 years) initiating prescription benzodiazepine treatment (≥3 days' supply) from January 2010 to September 2015 in a U.S. commercial claims database. Potential indications included selected ICD-9-CM diagnoses (≤30 days prior). Long-term (≥6 months) benzodiazepine treatment was estimated with Kaplan-Meier estimation and modified Poisson regression identified independent predictors of long-term benzodiazepine treatment (analysis completed in 2018). RESULTS: Of 24,504 children and 61,046 adolescents initiating benzodiazepines, 62% of the children and 68% of the adolescents had a potential indication. Anxiety disorders were the most common indication, with mental health indications more common among adolescents (45%) than children (23%) and epilepsy and movement disorders higher in children. Recent opioid prescriptions were common before benzodiazepine initiation (children, 22%; adolescents, 21%). Six percent of the initiators became long-term benzodiazepine users. Potential indication, provider contact, psychotropic medication, and chronic conditions independently predicted long-term benzodiazepine treatment in adolescents and children. CONCLUSIONS: U.S. children and adolescents are prescribed benzodiazepines for various mental health and other medical conditions, many lacking evidence of pediatric efficacy. Long-term benzodiazepine treatment, concurrent opioid prescriptions, psychotropic use, and prior substance use disorder diagnoses suggest safety risks among some youth prescribed benzodiazepines.

Incident Substance Use Disorder Following Anxiety Disorder in Privately Insured Youth.

PURPOSE: Anxiety disorders in childhood might be associated with an increased risk of substance use disorders. Incident substance use-related diagnoses were quantified in the 2 years after youth were newly diagnosed with an anxiety disorder and in a similar cohort of youth without diagnosed anxiety. METHODS: Privately insured youth (10-17 years) were identified in a commercial claims database who were newly diagnosed with an anxiety disorder (2005-2014), treatment naïve, and without baseline substance-related disorder diagnoses. The comparison cohort included age, sex, region, and date matched youth with equivalent baseline exclusions. We used Kaplan-Meier estimator to calculate 2-year cumulative incidence of substance use disorder diagnosis following a new office-based anxiety disorder diagnosis (or match date for comparison cohort). RESULTS: In 131,271 youth with a new anxiety disorder diagnosis (male = 41%, median age = 14 years), 1.5% (95% confidence interval = 1.5-1.6) had an incident substance use disorder diagnosis 1 year after their anxiety diagnosis, 2.9% (95% confidence interval = 2.8-3.0) by 2 years. Over the same period, .5% and 1.1% of the comparison cohort had incident substance use disorder diagnoses (n = 1,321,701). In the anxiety cohort, 2-year incidence was higher in youth aged 14-17 years (4.6%) versus 10-13 years (.7%). Incidence of substance use diagnosis varied by anxiety disorder (e.g., 2-year incidence: 4.3% for post-traumatic stress disorder, 3.0% for generalized anxiety disorder). CONCLUSION: Approximately 3% of youth newly diagnosed with anxiety received an incident substance use disorder diagnosis within 2 years, almost threefold the incidence in youth without an anxiety diagnosis, emphasizing the need for increased awareness and prevention of substance-related disorders in pediatric anxiety.

Incidence of mental health hospitalizations, treated self-harm, and emergency room visits following new anxiety disorder diagnoses in privately insured U.S. children.

BACKGROUND: Anxiety disorders are one of the most common mental illnesses in children and associated with high healthcare utilization. We aimed to estimate 2-year cumulative incidence of mental health-related hospitalizations, treated self-harm, and emergency room (ER) visits in children newly diagnosed with anxiety disorders and, for context, in children without anxiety disorders. METHODS: We identified commercially insured treatment naïve children (3-17 years) with a new office-based anxiety disorder diagnosis (ICD-9-CM) from 2005-2014 in the MarketScan claims database. We followed children for up to 2 years after diagnosis for the first of each event: mental health-related hospitalization, inpatient, treated self-harm, and ER visits (any, anxiety-related, injury-related). Children without anxiety diagnoses were included as comparators, matched on age, sex, date, and region. We estimated cumulative incidence of each event using Kaplan-Meier analysis. RESULTS: From 2005-2014, we identified 198,450 children with a new anxiety diagnosis. One-year after anxiety diagnosis, 2.0% of children had a mental health-related hospitalization, 0.08% inpatient, treated self-harm, 1.4% anxiety-related ER visit, and 20% any ER visit; incidence was highest in older children with baseline comorbid depression. One-year cumulative incidence of each event was lower in the comparison cohort without anxiety (e.g., mental health-related hospitalizations = 0.5%, treated self-harm = 0.01%, and ER visits = 13%). CONCLUSIONS: Given the prevalence of anxiety disorders, 2-year incidence estimates translate to a significant number of children experiencing each event. Our findings offer caregivers, providers, and patients information to better understand the burden of anxiety disorders and can help anticipate healthcare utilization and inform efforts to prevent these serious events.

Who diagnosed and prescribed what? Using provider details to inform observational research.

PURPOSE: To describe how often patients with depression initiating antidepressants receive their depression diagnosis and prescriptions from the same provider and, when simultaneously initiating benzodiazepines, how often both prescriptions come from the same provider. METHODS: Using a US healthcare claims database, we created a cohort of adults (18-64 years) with a depression diagnosis who initiated antidepressants. We examined concordance by provider specialty and provider identifier between (a) the first antidepressant prescription fill and most proximal depression diagnosis, and (b) the initial antidepressant and benzodiazepine prescription fills among simultaneous benzodiazepine and antidepressant initiators. RESULTS: Among 245 166 antidepressant initiators with a recent depression diagnosis (female = 67%; median age = 39), the specialty of the provider assigning the depression diagnosis matched the antidepressant prescriber's specialty in 94% of cases with known provider details (provider identifier concordance = 93%). Concordance was higher for adults diagnosed by a general practitioner (98%) or psychiatrist (92%) than for those diagnosed by a psychologist (74%). In simultaneous new users of antidepressants and benzodiazepines (n = 19 371), both prescriptions were issued by the same provider specialty and provider identifier 94% and 93% of the time, respectively. CONCLUSIONS: The vast majority of patients who received antidepressant prescriptions and depression diagnoses appear to have received both diagnosis and antidepressants from the same provider, suggesting that when antidepressants are issued around the time a patient is diagnosed with depression, the antidepressant was likely prescribed for depression. In addition, the great majority of patients who simultaneously initiate benzodiazepines appear to do so under the direction of one provider.

Examining Parental Medication Adherence as a Predictor of Child Medication Adherence in Pediatric Anxiety Disorders.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are the recommended first-line pharmacotherapy for pediatric anxiety disorders but adherence remains difficult to predict. OBJECTIVES: To estimate SSRI adherence in children with anxiety disorders and determine if prior parental medication adherence is predictive of child high SSRI adherence. METHODS: We identified children (3-17 y) initiating SSRI treatment after an anxiety disorder diagnosis in a commercial claims database (2005-2014). We evaluated parent SSRI, statin, and antihypertensive adherence [6-mo proportion days covered (PDC), high adherence=PDC≥0.80] in the year before child SSRI initiation. We estimated risk differences (RD) of child high SSRI adherence (6-mo PDC) stratified by parent adherence and multivariable risk ratios using modified Poisson regression. We estimated change in c-statistic and risk reclassification when adding parent-level covariates with child-level covariates to predict child adherence. RESULTS: In 70,979 children with an anxiety disorder (59%=female, 14=median age), the mean 6-month SSRI PDC was 0.72, with variation by anxiety disorder. Overall 64% of children had high adherence if their parent had high SSRI adherence versus 53% of children with parents with low SSRI adherence (RD, 12%; multivariable risk ratios, 1.17; 95% confidence interval, 1.14-1.20). Findings were similar for parent statin (RD=10%) and antihypertensive adherence (RD=8%) and when stratified by child age and parent sex. There was minor improvement in risk reclassification and the c-statistic after adding parent adherence and parent-level covariates. CONCLUSIONS: Parental medication adherence could help providers identify children at risk of nonadherence to inform the treatment decision, reduce unnecessary medication switches, and lead to broader effective interventions.

Predicting persistence to antidepressant treatment in administrative claims data: Considering the influence of refill delays and prior persistence on other medications.

BACKGROUND: Many patients with major depressive disorder (MDD) who begin antidepressant treatment discontinue use before for six months, the recommended minimum treatment length. This study sought to identify predictors of six-month antidepressant persistence including predictors utilizing patients' electronic prescription records. METHODS: Commercially insured children (3-17 years) and adults (18-64 years) with MDD who initiated antidepressant treatment, 1/1/2003-2/28/2010, were assessed for six-month persistence (based on prescriptions' days supply, allowing a 30-day grace period). Antidepressant persistence prediction models were developed separately for children and adults. Two additional measures, days without medication between the first and second antidepressant fill (children and adults) and prior persistence on other medications (adults only), were added to the models, concordance (c) statistics were compared and risk reclassification evaluated. RESULTS: Among children (n=8837 children) and adults (n=47,495) with MDD, six-month antidepressant persistence was low and varied by age (37%, 18-24 years to 52%, 3-12 and 50-64 years). Independent baseline predictors of persistence were identified, with model c-statistics: children=0.582, adults=0.584. Patients with more days without medication between fills were less likely to be persistent (10-30 vs. 0 days, children: RR=0.72, adults: RR=0.74), as were adults not previously persistent to other medications (RR=0.73). LIMITATIONS: The definition of six-month persistence is dependent on correct days supply values and the grace period utilized; potential predictors were limited to measures available in claims data. CONCLUSIONS: Six-month antidepressant persistence was low and overall prediction of persistence was poor; however, days without medication between fills and prior persistence on other medications marginally improved the ability to predict antidepressant persistence.