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.

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.

Benzodiazepine receipt in adults with psychogenic non-epileptic seizures in the USA.

Background: Characterising benzodiazepine (BZD) prescribing to individuals with psychogenic non-epileptic seizures (PNES) is important for optimising PNES outcomes, but existing data is lacking. Methods: Using a nationwide administrative claims database (2016-2022), incident PNES was defined as an International classification of diseases, tenth revision, clinical modification (ICD-10-CM) diagnosis in an inpatient or outpatient healthcare encounter after a 1-year period with no documented diagnosis. We described clinical characteristics of adults with incident PNES and estimated the prevalence of outpatient BZD treatment in the baseline year and 30-day follow-up period, with secondary analyses stratifying by baseline ES, anxiety and/or insomnia diagnoses, representing common indications for BZD receipt. We used logistic regression to evaluate predictors of post-PNES BZD receipt. Results: Among 20 848 adults with incident PNES diagnosis, 33.1% and 15.1% received BZDs in the year and month prior to PNES diagnosis, respectively, and 18.1% received BZDs in the month following a PNES diagnosis; 5.4% of those without prior BZD prescriptions received BZDs after diagnosis. The median days' supply was 30 days, with clonazepam, alprazolam and lorazepam representing the most common BZDs prescribed after PNES. Most people who received BZDs in the month prior to PNES diagnosis remained on BZDs in the month after PNES diagnosis (62.9%), with similar findings in the subcohorts without ES, anxiety and/or insomnia. Baseline BZD receipt and anxiety disorders, but not baseline ES diagnoses, were strong independent predictors of post-PNES BZD receipt. Conclusions: While new BZD initiation is rare after PNES, most individuals with BZD scripts 1 month before PNES continue scripts after diagnosis.

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.

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.

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.

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.

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.

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.

Psychotherapy Claims Surrounding Pharmacotherapy Initiation in Children and Adolescents with Anxiety Disorders.

OBJECTIVES: Psychotherapy is an effective, recommended treatment for pediatric anxiety disorders. Nevertheless, individuals with mental health conditions often do not receive psychotherapy, with variation across provider types. This study sought to examine psychotherapy claims surrounding medication initiation in U.S. children with diagnosed anxiety disorders. METHODS: The study cohort included privately insured children (3-17 years) with a diagnosed anxiety disorder initiating a medication to treat anxiety from 2004 to 2014. We examined psychotherapy claims in the 3 months before and 3 months after medication initiation and described children with multiple (2+) psychotherapy claims per 3-month period. RESULTS: Of the 75,024 children initiating a medication for anxiety (median age = 14 years, 58% female), 35% had multiple psychotherapy claims before medication initiation, with variation by age, anxiety disorder, and psychiatric comorbidity and with little change across time. Psychotherapy claims after medication initiation varied by whether the child had prior psychotherapy: 80% in children with prior psychotherapy and 30% in children without prior psychotherapy claims (44% of children diagnosed by a psychiatrist, 21% of children diagnosed by a pediatrician). CONCLUSION: Many privately insured children do not have claims for psychotherapy before or after pharmacotherapy initiation for anxiety. Findings can inform future research and efforts to ultimately increase appropriate psychotherapy utilization in children with anxiety disorders.

Treating Pediatric Anxiety: Initial Use of SSRIs and Other Antianxiety Prescription Medications.

OBJECTIVE: Multiple pharmacotherapies for treating anxiety disorders exist, including selective serotonin reuptake inhibitors (SSRIs), the recommended first-line pharmacotherapy for pediatric anxiety. We sought to describe initial antianxiety medication use in children and estimate how long antianxiety medications were continued. METHODS: In a large commercial claims database, we identified children (3-17 years) initiating prescription antianxiety medication from 2004 to 2014 with a recent anxiety diagnosis (ICD-9-CM = 293.84, 300.0x, 300.2x, 300.3x, 309.21, 309.81, 313.23). We estimated the proportion of children initiating each medication class across the study period and used multivariable regression to evaluate factors associated with initiation with an SSRI. We evaluated treatment length for each initial medication class. RESULTS: Of 84,500 children initiating antianxiety medication, 70% initiated with an SSRI (63% [95% CI, 62%-63%] SSRI alone, 7% [95% CI, 7%-7%] SSRI + another antianxiety medication). Non-SSRI medications initiated included benzodiazepines (8%), non-SSRI antidepressants (7%), hydroxyzine (4%), and atypical antipsychotics (3%). Anxiety disorder, age, provider type, and comorbid diagnoses were associated with initial medication class. The proportion of children refilling their initial medication ranged from 19% (95% CI, 18%-20%) of hydroxyzine initiators and 25% (95% CI, 24%-26%) of benzodiazepine initiators to 81% (95% CI, 80%-81%) of SSRI initiators. Over half (55%, 95% CI, 55%-56%) of SSRI initiators continued SSRI treatment for 6 months. CONCLUSIONS: SSRIs are the most commonly used first-line medication for pediatric anxiety disorders, with about half of SSRI initiators continuing treatment for 6 months. Still, a third began therapy on a non-SSRI medication, for which there is limited evidence of effectiveness for pediatric anxiety, and a notable proportion of children initiated with 2 antianxiety medication classes.

Simultaneous Antidepressant and Benzodiazepine New Use and Subsequent Long-term Benzodiazepine Use in Adults With Depression, United States, 2001-2014.

Importance: Benzodiazepines have been prescribed for short periods to patients with depression who are beginning antidepressant therapy to improve depressive symptoms more quickly, mitigate concomitant anxiety, and improve antidepressant treatment continuation. However, benzodiazepine therapy is associated with risks, including dependency, which may take only a few weeks to develop. Objectives: To examine trends in simultaneous benzodiazepine and antidepressant new use among adults with depression initiating an antidepressant, assess antidepressant treatment length by simultaneous new use status, estimate subsequent long-term benzodiazepine use in those with simultaneous antidepressant and benzodiazepine new use, and identify determinants of simultaneous new use and long-term benzodiazepine use. Design, Setting, and Participants: This cohort study using a US commercial claims database included commercially insured adults (aged 18-64 years) from January 1, 2001, through December 31, 2014, with a recent depression diagnosis who began antidepressant therapy but had not used antidepressants or benzodiazepines in the prior year. Exposures: Simultaneous new use, defined as a new benzodiazepine prescription dispensed on the same day as a new antidepressant prescription. Main Outcomes and Measures: The proportion of antidepressant initiators with simultaneous new use and continuing antidepressant treatment for 6 months and the proportion of simultaneous new users receiving long-term (6-months) benzodiazepine therapy. Results: Of the 765 130 adults (median age, 39 years; interquartile range, 29-49 years; 507 451 women [66.3%]) who initiated antidepressant treatment, 81 020 (10.6%) also initiated benzodiazepine treatment. The mean annual increase in the proportion simultaneously starting use of both agents from 2001 to 2014 was 0.49% (95% CI, 0.47%-0.51%), increasing from 6.1% (95% CI, 5.5%-6.6%) in 2001 to 12.5% (95% CI, 12.3%-12.7%) in 2012 and stabilizing through 2014 (11.3%; 95% CI, 11.1%-11.5%). Similar findings were apparent by age group and physician type. Antidepressant treatment length was similar in simultaneous new users and non-simultaneous new users. Among simultaneous new users, 12.3% (95% CI, 12.0%-12.5%) exhibited long-term benzodiazepine use (64.0% discontinued taking benzodiazepines after the initial fill). Determinants of long-term benzodiazepine use after simultaneous new use were longer initial benzodiazepine days' supply, first prescription for a long-acting benzodiazepine, and recent prescription opioid fills. Conclusions and Relevance: One-tenth of antidepressant initiators with depression simultaneously initiated benzodiazepine therapy. No meaningful difference in antidepressant treatment at 6 months was observed by simultaneous new use status. Because of the risks associated with benzodiazepines, simultaneous new use at antidepressant initiation and the benzodiazepine regimen itself require careful consideration.

Dosing of Selective Serotonin Reuptake Inhibitors Among Children and Adults Before and After the FDA Black-Box Warning.

OBJECTIVE: Prior research evaluated various effects of the 2004 black-box warning by the U.S. Food and Drug Administration (FDA) on the risk of suicidality among children associated with use of antidepressants, but the warning's effect on dosing of antidepressants has not been evaluated. This study estimated whether the initial antidepressant dose prescribed decreased and the proportion of patients who augmented the dose on the second fill increased following the 2004 warning and its 2007 expansion to young adults. METHODS: The study utilized the LifeLink Health Plan Claims Database. The study cohort consisted of commercially insured children (ages 5-17), young adults (18-24), and adults (25-64) who initiated a selective serotonin reuptake inhibitor (SSRI) (citalopram, fluoxetine, paroxetine, or sertraline) from January 1, 2000, to December 31, 2009. Dose per day was determined by days' supply, strength, and quantity dispensed. Initiation with a low dose and augmentation of >1 mg/day on the second prescription before and after the 2004 warning were considered. RESULTS: Of 51,948 children who initiated an SSRI, 15% initiated with a low dose before the 2004 warning compared with 31% after the warning; there was a smaller change among young adults (6 percentage points) and adults (3 percentage points). The overall increase in dose augmentations among children and young adults was driven by the increase in patients initiating with a low dose. CONCLUSIONS: The proportion of commercially insured children initiating an SSRI with a low dose was higher after the 2004 FDA warning on the risk of suicidality among children, suggesting improved prescribing practices surrounding SSRI dosing among children.