Overview of global real-world data sources for pediatric pharmacoepidemiologic research.

PURPOSE: Given limited information available on real-world data (RWD) sources with pediatric populations, this study describes features of globally available RWD sources for pediatric pharmacoepidemiologic research. METHODS: An online questionnaire about pediatric RWD sources and their attributes and capabilities was completed by members and affiliates of the International Society for Pharmacoepidemiology and representatives of nominated databases. All responses were verified by database representatives and summarized. RESULTS: Of 93 RWD sources identified, 55 unique pediatric RWD sources were verified, including data from Europe (47%), United States (38%), multiregion (7%), Asia-Pacific (5%), and South America (2%). Most databases had nationwide coverage (82%), contained electronic health/medical records (47%) and/or administrative claims data (42%) and were linkable to other databases (65%). Most (71%) had limited outside access (e.g., by approval or through local collaborators); only 10 (18%) databases were publicly available. Six databases (11%) reported having >20 million pediatric observations. Most (91%) included children of all ages (birth until 18th birthday) and contained outpatient medication data (93%), while half (49%) contained inpatient medication data. Many databases captured vaccine information for children (71%), and one-third had regularly updated data on pediatric height (31%) and weight (33%). Other pediatric data attributes captured include diagnoses and comorbidities (89%), lab results (58%), vital signs (55%), devices (55%), imaging results (42%), narrative patient histories (35%), and genetic/biomarker data (22%). CONCLUSIONS: This study provides an overview with key details about diverse databases that allow researchers to identify fit-for-purpose RWD sources suitable for pediatric pharmacoepidemiologic research.

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.

Trajectories of childhood anxiety disorders in two generations at high risk.

BACKGROUND: The course of anxiety disorders during childhood is heterogeneous. In two generations at high or low risk, we described the course of childhood anxiety disorders and evaluated whether parent or grandparent major depressive disorder (MDD) predicted a persistent anxiety course. METHODS: We utilized a multigenerational study (1982-2015), following children (second generation, G2) and grandchildren (third generation, G3) of generation 1 (G1) with either moderate/severe MDD or no psychiatric illness. Psychiatric diagnoses were based on diagnostic interviews. Using group-based trajectory models, we identified clusters of children with similar anxiety disorder trajectories (age 0-17). RESULTS: We identified three primary trajectories in G2 (N = 275) and G3 (N = 118) cohorts: "no/low anxiety disorder" during childhood (G2 = 66%; G3 = 53%), "nonpersistent" with anxiety during part of childhood (G2 = 16%; G3 = 21%), and "persistent" (G2 = 18%; G3 = 25%). Childhood mood disorders and substance use disorders tended to be more prevalent in children in the persistent anxiety trajectory. In G2 children, parent MDD was associated with an increased likelihood of being in the persistent (84%) or nonpersistent trajectory (82%) versus no/low anxiety trajectory (62%). In G3 children, grandparent MDD, but not parent, was associated with an increased likelihood of being in the persistent (83%) versus nonpersistent (48%) and no/low anxiety (51%) trajectories. CONCLUSION: Anxiety trajectories move beyond what is captured under binary, single time-point measures. Parent or grandparent history of moderate/severe MDD may offer value in predicting child anxiety disorder course, which could help clinicians and caregivers identify children needing increased attention and screening for other psychiatric conditions.

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.

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.

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.

Matching HIV, tuberculosis, viral hepatitis, and sexually transmitted diseases surveillance data, 2000-2010: identification of infectious disease syndemics in New York City.

CONTEXT: In 2012, the New York City Department of Health and Mental Hygiene matched HIV, tuberculosis, viral hepatitis, and sexually transmitted disease surveillance data to identify the burden of infection with multiple diseases. METHODS: HIV, tuberculosis, hepatitis B, hepatitis C, chlamydia, gonorrhea, and syphilis surveillance data from 2000 to 2010 were matched using a deterministic method. Data on deaths from the Department of Health and Mental Hygiene's Office of Vital Statistics were also matched. RESULTS: The final data set contained 840,248 people; 13% had 2 or more diseases. People with a report of syphilis had the highest proportion of matches with other diseases (64%), followed by gonorrhea (52%), HIV (31%), tuberculosis (23%), hepatitis C (20%), chlamydia (16%), and hepatitis B (11%). CONCLUSIONS: The findings indicate several possible infectious disease syndemics in New York City and highlight the need to integrate surveillance data from different infectious disease programs. Conducting the match brought surveillance programs together to work collaboratively and has resulted in ongoing partnerships on programmatic activities that address multiple diseases.

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.

Psychiatric comorbidities and prescribing tendencies of sleep medications and related medications in young people with insomnia: a United States commercial claims-based analysis.

STUDY OBJECTIVES: To characterize children and youth newly diagnosed with insomnia and to describe their use of sleep and other related prescription medications. METHODS: Within a commercial claims database (January 1, 2016-December 31, 2021), we identified children and youth (2-24 years) with a newly recorded insomnia diagnosis (G47.0x; F51.0x) and examined psychiatric diagnoses in the prior 6 months. We evaluated sleep and related prescription medications dispensed in the week after new insomnia diagnoses (i.e. trazodone, other antidepressants, hydroxyzine, alpha-agonists, benzodiazepines, non-benzodiazepine hypnotics "z-drugs," antipsychotics, and others). Analyses were stratified by age and psychiatric comorbidities. RESULTS: Among 68 698 children and 108 118 older youth (18-24 years) with a new insomnia diagnosis, three-quarters had a diagnosed comorbid psychiatric condition; anxiety disorders, depression, and ADHD were the most common. Among those without comorbid psychiatric diagnoses, 20.2% of children and 37.4% of older youth had a sleep or related medication dispensed in the following week. In children without a comorbid psychiatric diagnosis, alpha-agonists, hydroxyzine, and trazodone were the most common medications; in older youth, trazodone was the most common medication followed by hydroxyzine, z-drugs, and SSRIs. Sleep and related prescription medications were more commonly dispensed to those with psychiatric comorbidities. From 2017 to 2021, there was an increase in hydroxyzine prescriptions following a new insomnia diagnosis and decline in z-drug and benzodiazepine prescriptions. CONCLUSIONS: Our findings from a nationwide sample of young people with insomnia highlight the high prevalence of psychiatric comorbidities and variety of sleep and related medications they receive. Characterizing prescribing tendencies informs guideline development and future research.

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.

Initiation Patterns of Disease-Modifying Therapies for Multiple Sclerosis Among US Adults and Children, 2001 Through 2020.

Importance: Many disease-modifying therapies (DMTs) have been approved for multiple sclerosis (MS) in the past 2 decades. Research evaluating how these approvals have changed real-world prescribing patterns is scarce. Objective: To evaluate patterns in DMT initiations between 2001 and 2020 among commercially insured US adults and children with MS. Design, Setting, and Participants: This serial cross-sectional study was conducted from 2001 through 2020 (mean patient enrollment duration, 4.8 years) and used US commercial claims data (MarketScan). Analysis took place between January 2022 and March 2023. Of 287 084 patients with MS identified, 113 583 patients (113 095 adults and 488 children) with MS newly initiated at least 1 DMT. Exposure: New initiation episode of a DMT, defined as no claim for the same DMT in the previous year. Main Outcome Measure: The proportion of total DMT initiations per year attributable to each DMT. Trends in initiations were evaluated annually. Results: The study team identified 153 846 DMT initiation episodes among adults (median age, 46 [IQR, 38-53) years]; 86 133 female [76.2%]) and 583 among children (median age, 16 (IQR, 14-17) years; 346 female [70.9%]). Among adults, use of platform injectables showed an absolute decline of 73.8% over the study period, driven by a 61.2% reduction in interferon ß initiations (P < .001 for trend). In contrast, the 2010 introduction of oral DMTs led to a rise in their use from 1.1% (2010) to 62.3% (2020) of all DMT initiations (P = .002 for trend). Infusion therapy initiations remained relatively low, accounting for 3.2% of all initiations since their introduction in 2004 but increased modestly annually after ocrelizumab was introduced (2017), reaching 8.2% of all initiations in 2020 (P < .001 for trend). Children showed similar initiation patterns, except for preferred oral therapy. Between 2019 and 2020, dimethyl fumarate was the most commonly initiated DMT in adults (23.3% to 27.2% of all initiations), while in children fingolimod was the most commonly initiated (34.8% to 68.8%). Conclusions and Relevance: Current MS treatment guidelines emphasize shared decision-making between patients and clinicians to balance treatment efficacy, safety, cost, and convenience. This study found that oral DMTs were the predominant DMT type initiated by 2020. The cause of this shift cannot be determined from this study, but may reflect several factors, including convenience of administration, direct-to-consumer advertising, or insurance restrictions.

Geographic Trends in Pediatric Psychotropic Medication Dispensing Before and After the Start of the COVID-19 Pandemic.

OBJECTIVE: This study examined trends and geographic variability in dispensing of prescription psychotropic medications to U.S. youths before and after the start of the COVID-19 pandemic. METHODS: Using national data on prescription medication dispensing, the authors performed a cross-sectional study examining the monthly percent change in psychotropic medications dispensed (total N=95,639,975) to youths (ages 5-18 years) in 2020 versus 2019, across medication classes and geographic regions. RESULTS: For many medications, more were dispensed in March 2020 than in March 2019 and fewer in April-May 2020 versus April-May 2019. Stimulants had the largest decline: -26.4% in May 2020 versus May 2019. The magnitude of the monthly percent change varied by region. CONCLUSIONS: Fewer psychotropic medications were dispensed to U.S. youths after the start of the COVID-19 pandemic compared with 2019. Although some medication classes rebounded to prepandemic dispensing levels by September 2020, dispensing varied by class and region.

Endometrial receptivity defects during IVF cycles with and without letrozole.

BACKGROUND: Our aim was to study ways to improve IVF success rates in women with suspected endometrial receptivity defects. METHODS: We conducted a retrospective cohort study examining the effect of letrozole (aromatase inhibitor) on integrin expression as a marker of endometrial receptivity. We compared IVF outcomes in 97 infertile women who had undergone ανß3 integrin assessment by immunohistochemistry in mid-luteal endometrial biopsies. Of 79 women undergoing standard IVF, 29 (36.7%) lacked normal integrin expression. Eighteen other women with low integrin were studied after receiving letrozole during early IVF stimulation. An independent set of ανß3 integrin-negative patients (n = 15) who had undergone repeat endometrial biopsy for integrin testing while taking letrozole were re-evaluated. RESULTS: Clinical pregnancy and delivery rates were higher in women with normal ανß3 integrin expression compared with those who were integrin negative [20/50 (40%) versus 4/29 (13.8%); P = 0.02 and 19/50 (38%) versus 2/29 (7%); P < 0.01, respectively]. In 18 women who received letrozole early in IVF, 11 conceived (61.1%; P < 0.001) compared with integrin-negative patients who did not receive letrozole. In integrin-negative women who were rebiopsied on letrozole, 66.7% reverted to normal integrin expression. Positive endometrial aromatase immunostaining using a polyclonal antibody was a common finding in infertile patients compared with controls. CONCLUSIONS: Lack of endometrial ανß3 integrin expression is associated with a poor prognosis for IVF that might be improved with letrozole co-treatment. Prospective studies are needed to confirm and extend these findings but the data suggest that aromatase expression may contribute to implantation failure in some women.

Association of Benzodiazepine Treatment for Sleep Disorders With Drug Overdose Risk Among Young People.

Importance: Benzodiazepines are prescribed for the treatment of adolescent sleep disorders; however, benzodiazepine overdoses occur, often in combination with opioids. Objective: To evaluate whether benzodiazepine treatment for sleep disorders, compared with alternative pharmacologic treatments (trazodone, hydroxyzine, zolpidem, zaleplon, and eszopiclone), is associated with increased risk of drug overdose for young people. Design, Setting, and Participants: This cohort study included privately insured people 10 to 29 years of age identified from a US commercial claims database (MarketScan), from January 1, 2009, to December 31, 2018. Young people with a sleep disorder diagnosis initiating benzodiazepine (n = 23 084) or comparator pharmacologic treatments (n = 66 706) were included in the study. Statistical analysis was performed from November 1, 2021, to May 16, 2022. Exposures: New use of benzodiazepine treatment or comparator pharmacologic treatments (defined as ≥1 year without a prescription for benzodiazepine or comparator medications). Main Outcomes and Measures: Incident diagnosed drug overdoses were identified from inpatient and emergency department records within 6 months of treatment initiation. The propensity score-adjusted cumulative incidence of overdose and hazard ratios (HRs) were estimated with intention-to-treat (analyzed based on initial treatment) and as-treated analyses (added censoring at treatment discontinuation). Results were stratified by prior prescription opioid fill. Results: The cohort included 23 084 young people initiating benzodiazepine treatment (14 444 female participants [62.6%]; mean [SD] age, 23 [4.1] years) and 66 706 initiating a comparator treatment (38 446 female participants [57.6%]; mean [SD] age, 22 [4.4] years). Six months after treatment initiation, 9.7% (95% CI, 9.3%-10.1%) of benzodiazepine users and 12.3% (95% CI, 12.1%-12.6%) of the comparator group were still receiving treatment. The crude incidence of drug overdose at 6 months was 0.9% for benzodiazepine initiators and 0.8% for comparator treatment initiators. In adjusted analyses, an increased risk of drug overdose was associated with benzodiazepines vs comparator treatments (intention-to-treat analysis: HR, 1.25 [95% CI, 1.03-1.51]; as-treated analysis: HR, 1.44 [95% CI, 1.14-1.80]). This association was stronger among young people with a recent prescription opioid fill vs those without a recent prescription opioid fill (as-treated analysis: adjusted HR, 2.01 [95% CI, 1.24-3.25] vs adjusted HR, 1.31 [95% CI, 1.00-1.70]). Conclusions and Relevance: The findings of this study suggest that benzodiazepines, compared with alternative pharmacologic treatments for common sleep disorders, were associated with an increased risk of drug overdose among young people during the following 6-month period, especially among those with a recent opioid prescription. Drug overdose is an important safety consideration when treating young people with benzodiazepines.

Sex differences in US emergency department non-fatal visits for benzodiazepine poisonings in adolescents and young adults.

BACKGROUND: Benzodiazepine (BZD)-related overdose deaths have risen in the past decade and BZD misuse contributes to thousands of emergency department (ED) visits annually, with the highest rates in adolescents and young adults. Because there are gaps in understanding BZD poisoning in youth and whether differences occur by sex, we aimed to characterize BZD poisoning ED visits in young people by sex. METHODS: BZD poisoning visits were identified in the Nationwide Emergency Department Sample, among adolescents (12-17 years) and young adults (18-29 years). Stratified by sex and age, we described ED visits for BZD poisonings in 2016, including poisoning intent, concurrent substances involved, and co-occurring mental health disorder diagnoses. With logistic regression we examined the association between intent and concurrent substance. RESULTS: There were approximately 38,000 BZD poisoning ED visits by young people nationwide with annual population rates per 10,000 of 2.9=adolescents and 5.8=young adults. Depression was diagnosed in 40 % of female and 23 % of male BZD visits (p < 0.01). Over half of BZD poisonings in females and a third in males were intentional (p < 0.01). Male BZD visits were more likely to involve opioids or cannabis and less likely to involve antidepressants than females (p-values<0.01). In males and females, BZD poisonings concurrent with antidepressants and other psychotropic medications were more likely to be intentional than unintentional (OR range:2.1-6.3). CONCLUSIONS: The high proportion of BZD poisonings that are intentional and include mental health disorder diagnoses, especially among young females, underscore the importance of ED mental health and suicide risk assessment with appropriate follow-up referral.

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.

Simultaneous Benzodiazepine and SSRI Initiation in Young People With Anxiety Disorders.

Objective: There are potential risks and benefits of combining benzodiazepine (BZD) and selective serotonin reuptake inhibitor (SSRI) therapy at anxiety disorder treatment onset. We investigated how often adolescents and young adults with anxiety disorders simultaneously initiate BZD treatment with SSRI treatment and examined whether SSRI treatment duration varies by simultaneous BZD initiation.Methods: In a United States commercial claims database (January 2008-December 2016), we identified adolescents (10-17 years) and young adults (18-24 years) with ICD-9-CM/ICD-10-CM anxiety disorder diagnoses initiating SSRI treatment, without past-year SSRI and BZD treatment. We defined simultaneous initiation as filling a new BZD prescription on the date of SSRI initiation. We estimated time to SSRI treatment discontinuation and used stabilized inverse probability of treatment weighting for adjusted estimates.Results: The study included 94,399 adolescents and 130,971 young adults initiating SSRI treatment with an anxiety disorder. Four percent of adolescents and 17% of young adults simultaneously initiated BZD treatment, varying by age, anxiety disorder, comorbidities, health care utilization, and provider type. Simultaneous BZD initiation among SSRI initiators declined from 2008 to 2016. SSRI treatment duration was similar in initiators of simultaneous therapy vs SSRI monotherapy: ≥ 6 months in adolescents (55% vs 56%, respectively) and in young adults (39% vs 40%). Nine percent of simultaneous initiators continued BZDs for ≥ 6 months.Conclusions: Simultaneous initiation of BZD and SSRI treatment is relatively common in young adults with anxiety disorders and was not associated with longer SSRI persistence. Given risks of BZD treatment, potential benefits and risks of adding a BZD at SSRI treatment initiation must be carefully weighed.

Mental Disorders, Substance Use Disorders, and Psychotropic Medication Use Among Sudden-Death Victims.

OBJECTIVE: The authors sought to estimate the prevalence of mental and substance use disorders and psychotropic medication prescriptions among working-age sudden-death victims. METHODS: Using a written protocol, the authors screened for sudden deaths attended by emergency medical services (EMS) in a large metropolitan county in North Carolina from March 1, 2013, to February 28, 2015. Sudden-death cases were adjudicated by three cardiologists. Mental health and chronic disease diagnoses and treatments were abstracted from EMS, medical examiner, toxicology, and autopsy reports and from clinical records for the past 5 years before death. RESULTS: Sudden death was identified for 399 adults ages 18-64 years, 270 of whom had available medical records. Most sudden-death victims were White (63%) and male (65%), had a comorbid condition such as hypertension or respiratory disease, and had a mean±SD age of death of 53.6±8.8 years. Most victims (59%) had at least one mental health or substance use disorder documented in a recent medical record; 76%-78% of victims with a mental disorder had a documented psychotropic medication prescription. However, fewer than one-half (41%) had a documented referral to a mental health professional. The most common diagnostic categories were depressive, anxiety, and alcohol-related disorders. Almost one-half (46%) of the victims had a recent psychotropic prescription, most commonly antidepressants (29%) and benzodiazepines (19%). CONCLUSIONS: Mental illness, substance use disorders, and psychotropic medication prescriptions were prevalent among sudden-death victims. The health care needs of these individuals may be better addressed by collaborative care for general medical and mental disorders.

Benzodiazepine Treatment and Fracture Risk in Young Persons With Anxiety Disorders.

BACKGROUND: Benzodiazepines are commonly prescribed to treat anxiety disorders and have been associated with falls and fractures in older adults. It is unknown whether benzodiazepines increase fracture risk in youth. We examined whether youth with anxiety disorders initiating benzodiazepine treatment have an increased risk of fractures compared with youth initiating selective serotonin reuptake inhibitors (SSRIs). METHODS: We used claims from commercially insured children (6-17 years) and young adults (18-24) with a recent anxiety disorder diagnosis, initiating benzodiazepines or SSRIs (2008-2016). Youth were followed until fracture, treatment discontinuation or switching, disenrollment, 3 months, or December 31, 2016. The primary end point was diagnostic codes for upper and lower limb fractures. Incident fracture rates, incident rate ratios (IRRs), and incident rate differences (IRDs) were estimated with propensity score inverse probability of treatment weighting. RESULTS: The cohort included 120 715 children and 179 768 young adults. In children, crude fracture rates during treatment were 33.1 per 1000 person-years (PYs) for benzodiazepine initiators and 25.1 per 1000 PYs for SSRI initiators. Adjusted IRR and IRD were 1.53 (95% confidence interval [CI]: 0.94-2.50) and 13.4 per 1000 PYs. Risk was heightened in children initiating long-acting benzodiazepines versus SSRIs (adjusted IRR = 2.30 [95% CI: 1.08-4.91]). Fracture rates were lower in young adults, with minimal differences between treatments (adjusted IRR = 0.85 [95% CI: 0.57-1.27]; adjusted IRD = -1.3 per 1000 PYs). CONCLUSIONS: An increased rate of fractures in children, but not young adults, with anxiety disorders initiating benzodiazepine treatment compared to SSRI treatment suggests a need for increased caution in the weeks after benzodiazepine initiation in children.

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.