Short- and Long-Term Antidepressant Clinical Trials for Major Depressive Disorder in Youth: Findings and Concerns.

The diagnosis of major depressive disorder (MDD) in U.S. youth is increasing as is the rate of antidepressant medication (ADM) treatment for the disorder. Fluoxetine and escitalopram are FDA approved for the short term and maintenance treatment of MDD in youth. Placebo-controlled short-term ADM trials represent the basis for Food and Drug Administration (FDA) approval. Meta-analyses in 2007 and 2016 revealed that short-term ADM treatment of youth diagnosed with MDD resulted in no meaningful benefit for children and only marginal benefit for adolescents. Placebo substitution trials of ADM short-term responders represent the basis for FDA approval of ADM maintenance treatment. These ADM placebo substitution maintenance trials for youth with MDD are characterized by high dropout rates, a rapid withdrawal that often can follow the switch to placebo, and relapse rates that are not dissimilar from those in the natural course of the disorder. Without the evidence from problematic ADM placebo substitution trials, there is no acceptable support for the inclusion of ADM in maintenance treatment for MDD in youth.

Getting to Long-Term Effectiveness and Safety of Attention-deficit Hyperactivity Disorder Medications.

Attention-deficit hyperactivity disorder (ADHD) medication use has dramatically increased in youth worldwide. Recent prevalence data in some European countries show expanded use with one country now matching US usage. Still, substantial geographic differences by country remain regarding the extent to which children receive ADHD medications. These geographic differences by country raise research questions about which country's prevalence data represents appropriate medication use. We urgently need country level studies to contribute to our understanding of an appropriate prevalence of ADHD medication use.

The Impact of a State Medicaid Peer-Review Authorization Program on Pediatric Use of Antipsychotic Medications.

OBJECTIVE: This cross-sectional study assessed the impact of a peer-review program on the prevalence of pediatric antipsychotic use among Medicaid-insured youths in a Mid-Atlantic state. METHODS: Medicaid claims (2010-2014) were assessed among continuously enrolled youths in the 12 months before and after implementation of peer review. The study identified children ages zero to four preimplementation (N=118,815) and postimplementation (N=121,431), ages five to nine preimplementation (N=98,681) and postimplementation (N=107,872), and ages 10 to 17 preimplementation (N=154,696) and postimplementation (N=161,370). (Age ranges are inclusive of the final number). In each age group, multivariable logistic regression models with generalized estimating equations assessed the change in annual prevalence of antipsychotic use pre- to postimplementation. Use of other leading psychotropic classes and antipsychotic prescribing by medical specialty were also examined. RESULTS: The annual pre- to postimplementation prevalence of antipsychotic use decreased significantly, from .07% to .03% (adjusted odds ratio [AOR]=.41) among children ages zero to four, from 1.57% to .86% (AOR=.54) among those ages five to nine, and from 3.28% to 2.40% (AOR=.72) among those ages 10 to 17. With the exception of alpha-agonist use, which increased postimplementation (AOR=1.30) among those ages zero to four, no clinically significant pre-post change was noted in other leading psychotropic classes among children ages zero to four and 10 to 17. By contrast, postimplementation use of other psychotropic medications decreased among those ages five to nine (AOR=.73). CONCLUSIONS: A state Medicaid peer-review program resulted in decreased antipsychotic use across all age groups, particularly among children younger than ten. No notable substitution of other psychotropic classes for antipsychotics was observed.

Nurse Practitioner Independent Practice Authority and Mental Health Service Delivery in U.S. Community Health Centers.

OBJECTIVE: Little is known about how nurse practitioner independent practice authority (NP-IPA) influences patient care. This study examined the effect of NP-IPA on patterns of mental health-related visits provided by NPs in U.S. community health centers (CHCs). METHODS: State NP regulatory information was linked to National Ambulatory Medical Care Survey data on NP- and physician-provided visits (N=61,457) in CHCs from 2006 through 2011. The proportion of NP-provided versus physician-provided mental health-related visits in states with NP-IPA was compared with the proportion in states without NP-IPA. The adjusted odds of mental health-related visits in CHCs provided by NPs in states with and without NP-IPA were compared by using multiple logistic regression models while accounting for the complex survey design. RESULTS: Between 2006 and 2011, the odds of NP- versus physician-provided mental health-related visits in CHCs were more than two times greater in states with NP-IPA than in states with no NP-IPA (adjusted odds ratio [OR]= 2.43, 95% confidence interval [CI]=1.12-4.60). In contrast, no significant difference between states with and without NP-IPA was noted in non-mental health-related CHC visits provided by NPs. Among all mental health-related visits, the odds of visits in which psychotropic medications were prescribed by an NP were more than three times higher in states with NP-IPA than in those without NP-IPA (adjusted OR=3.14, CI=1.50-6.54). CONCLUSIONS: Compared with physicians, NPs provided proportionally more CHC mental health-related visits in states with NP-IPA than in states without NP-IPA.

National Trends in ADHD Diagnosis and Treatment: Comparison of Youth and Adult Office-Based Visits.

OBJECTIVES: The study objective was to assess national trends in the diagnosis of attention-deficit hyperactivity disorder (ADHD) in outpatient visits by comparing adults and youths. Also examined were recent stimulant prescribing patterns for ADHD visits by youths and adults. METHODS: Databases from the 1999-2010 National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey were used in this cross-sectional study to analyze outpatient visit data of youths (ages two to 17 years; unweighted N=112,404) and adults (ages 18-64; unweighted N=426,209). The 12-year trends in ADHD visits were assessed as a proportion of youth and adult visits. The interaction of time period and age group was added to multivariable and weighted logistic regression models to assess whether trends in ADHD diagnosis differed by age group. RESULTS: As a percentage of total visits, those involving an ADHD diagnosis were more common among youths than adults. However, from 1999 through 2010, the percentage of total visits involving a diagnosis of ADHD increased proportionally more among adult visits (from .3%, unweighted N=363 of 132,065, to .7%, unweighted N=1,015 of 154,764; adjusted odds ratio [AOR]=2.7, 95% confidence interval [CI]=2.1-3.7) than among youth visits (from 3.9%, unweighted N=2,033 of 36,263, to 5.2%, unweighted N=2,609 of 37,906; AOR=1.3, CI=1.1-1.6; p<.001). ADHD visits by adults compared with those by youths represented significantly greater proportions of females, Caucasians, patients with private insurance, and visits with a psychiatrist. Stimulant prescribing was common in ADHD visits regardless of age group (>70%). CONCLUSIONS: As a percentage of total office-based visits, those at which ADHD was diagnosed increased more among adults than among youths from 1999 to 2010. Further research is warranted on the appropriateness, benefit-risk, and policy implications of stimulant use among adults with ADHD.

National Trends in Psychiatric Not Otherwise Specified (NOS) Diagnosis and Medication Use Among Adults in Outpatient Treatment.

OBJECTIVE: This study examined national trends between 1999 and 2010 in not otherwise specified (NOS) DSM-IV psychiatric diagnoses and in related medication treatment patterns reported for adults during outpatient physician office visits. METHODS: Data on physician office visits by adults (ages 18-64) with a psychiatric diagnosis were from the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey (1999-2010) (N=52,026). Trends for visits with full-criteria diagnoses compared with visits with NOS diagnoses were analyzed for major psychiatric diagnostic groups, physician specialty, and prescribed medications. Population weighted chi square and logistic regression analyses were utilized. RESULTS: Between 1999-2002 and 2007-2010, the proportion of all mental health visits by adults to office-based physicians that involved an NOS diagnosis increased significantly, from 42% to 50% (p<.001). Significant proportional increases in NOS diagnoses included bipolar disorders NOS (5% to 55%), anxiety disorders NOS (50% to 62%), and mood disorders NOS (.4% to 1.8%). In 2007-2010, NOS visits accounted for a greater proportion of visits to nonpsychiatrists than to psychiatrists (61% and 35%, respectively). Psychotropic medications prescribed during visits increased over time for both full-criteria and NOS diagnoses, but the increase was greater for NOS visits, specifically for antipsychotics, anticonvulsants-mood stabilizers, and lithium. By 2007-2010, psychotropic monotherapy and multidrug regimens were comparable for full-criteria and NOS diagnoses. CONCLUSIONS: The proportion of U.S. physician visits with an NOS psychiatric diagnosis increased to nearly 50% in 2007-2010. The increase raises concerns about the precision of psychiatric diagnoses in community care and about the impact on concomitant medication regimens.

Atypical antipsychotic use among Medicaid-insured children and adolescents: duration, safety, and monitoring implications.

OBJECTIVE: Over the last two decades, the increased use of atypical antipsychotic medications, often for unlabeled indications including attention-deficit/hyperactivity disorder (ADHD), has been profound. This study aims to characterize duration of atypical antipsychotic use by age group and Medicaid eligibility category, and among youth with noncomorbid ADHD. METHODS: Administrative data on 266,590 youth 2-17 years of age, and continuously enrolled in a mid-Atlantic state Medicaid program in 2006, were assessed in terms of median days of atypical antipsychotic use using bivariate analyses and multivariable quantile regression. Also, in a subanalysis of youth diagnosed with ADHD without any reported psychiatric comorbidities (i.e., noncomorbid ADHD), age-specific adjusted odds and adjusted median days of atypical antipsychotic use by Medicaid eligibility category were assessed. Additionally, patterns of use of single atypical antipsychotic regimens and two concomitant atypical antipsychotic regimens were described. RESULTS: Overall, the median annual duration of atypical antipsychotic use was 180 days (interquartile range: 69-298 days). Children (2-12-year-olds) had longer durations of use than did adolescents (13-17-year-olds) (median 192 vs. 179 days), respectively. In the absence of any comorbid psychiatric diagnosis, ADHD-diagnosed foster care youth had more than threefold greater adjusted odds of atypical antipsychotic use than did youth enrolled in income-eligible Medicaid categories. Nearly one third of such ADHD-diagnosed foster care youth received atypical antipsychotics regardless of age group, with annual duration of use >250 median days in 2-12-year-olds. In concomitant atypical antipsychotic regimens, risperidone, aripiprazole, and quetiapine were the most common. CONCLUSIONS: Exposure to atypical antipsychotics in Medicaid-insured youth, in particular for children in foster care and those diagnosed with ADHD, was substantial, warranting outcomes research for long-term effectiveness, safety, and oversight for appropriate cardiometabolic monitoring.

Antipsychotic use by medicaid-insured youths: impact of eligibility and psychiatric diagnosis across a decade.

OBJECTIVE: This cross-sectional study evaluated the impact of Medicaid-eligibility category on the increased use of antipsychotic medication by Medicaid-insured youths across a decade. METHODS: The authors analyzed computerized administrative claims data for 456,315 youths aged two to 17 years who were continuously enrolled in Medicaid in a mid-Atlantic state in 1997 (N=159,171) and 2006 (N=297,144). Bivariate and multivariable analyses quantified changes in antipsychotic use in relation to the youths' psychiatric diagnosis and eligibility category (Temporary Assistance for Needy Families [TANF], state Children's Health Insurance Program [SCHIP], Supplemental Security Income [SSI], and foster care). A second multivariable regression model examined changes in demographic and clinical characteristics of antipsychotic users with a psychiatric diagnosis. RESULTS: The prevalence of antipsychotic use increased from 1.2% in 1997 to 3.2% in 2006. The increase in odds of antipsychotic use in 2006 was greatest among youths enrolled in SCHIP (adjusted odds ratio [AOR]=5.9), followed by youths enrolled in foster care (AOR=4.1), TANF (AOR=3.6), and SSI (AOR=2.8). Among users of antipsychotics who had a psychiatric diagnosis, youths with externalizing behavior disorders and bipolar disorder had 2.4- to 3.8-fold greater odds of using antipsychotics in 2006 versus 1997 compared with youths with schizophrenia or other psychoses and pervasive developmental disorders. The proportion of youths using antipsychotics between 1997 and 2006 increased significantly more among African Americans and Hispanics than among whites. CONCLUSIONS: The expansion of antipsychotic use was most prominent among youths who were Medicaid eligible because of low family income (SCHIP) and reflects increased medication use for behavioral problems.

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

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

Anticonvulsant treatment for psychiatric and seizure indications among youths.

OBJECTIVE: This study compared the prevalence of anticonvulsant treatment for youths with a diagnosis of a psychiatric disorder to youths with a diagnosis of a seizure disorder. METHODS: Administrative claims from outpatient visits and prescriptions were organized for a data set of 258,472 youths who were younger than 18 years of age in a mid-Atlantic state Medicaid program and were continuously enrolled in 2000. Youths dispensed an anticonvulsant were grouped into the following ICD-9 diagnostic categories: a diagnosis of a psychiatric disorder without a seizure disorder, a diagnosis of a seizure disorder without a psychiatric disorder, and a diagnosis of both a psychiatric and a seizure disorder. Anticonvulsant use was analyzed for specific diagnostic classes by age, gender, race or ethnicity, and Medicaid eligibility categories. RESULTS: A total of 4,522 youths in the one-year data set received an anticonvulsant (1.75 percent): 3,061 had a psychiatric disorder only, 251 had a seizure disorder only, and 611 had both psychiatric and seizure disorders. Among anticonvulsant-treated youths with diagnosis information in their records (3,923 of 4,522 youths), 81 percent had a psychiatric diagnosis and 19 percent had a seizure disorder; 71 percent of those with a seizure disorder also had a psychiatric disorder. Anticonvulsant use for seizure control was proportionally greater for those younger than five years. By contrast, a vast majority of anticonvulsant users with a psychiatric diagnosis were between five and 17 years. Among anticonvulsant-treated youths with a psychiatric diagnosis, males were approximately twice as common as females. For youths with a seizure disorder, no difference was found for gender. Mood disorders and attention-deficit hyperactivity disorder were the major psychiatric diagnoses associated with anticonvulsant use. Valproic acid products were the most commonly dispensed type of anticonvulsant. CONCLUSIONS: Recent state Medicaid data reveal that youths who use anticonvulsants are far more likely to have a psychiatric diagnosis than a seizure diagnosis. Widespread off-label use of anticonvulsants for psychiatric disorders among youths warrants attention to ensure benefits and minimize risks.

Treatment-emergent adverse events from selective serotonin reuptake inhibitors by age group: children versus adolescents.

OBJECTIVE: The aim of this study was to report the frequency of common treatment-emergent adverse events (AEs) from selective serotonin reuptake inhibitors (SSRIs) in children, adolescents, and adults. METHOD: AE data were obtained from all published double-blind, placebo-controlled SSRI studies of children and adolescents that separated AE findings by age group. The AE findings were pooled for purposes of age-group comparisons. Double-blind, placebo-controlled SSRI studies of adolescents (n = 2) and of adults identified in systematically identified trials (n = 22) were assessed to compare patterns and rates across the age span. Other reports, primarily from the published SSRI literature, were added to clarify the findings presented. RESULTS: Activation and vomiting SSRI AEs were 2- to 3-fold more prevalent in children than in adolescents, and their rate was lowest in adults. Somnolence as a SSRI AE was uncommon in children; its rate increased with advancing age. Insomnia and nausea were common SSRI AEs across the age span. Activation AEs were a frequent reason for discontinuation from SSRI clinical trials in preadolescents, whereas somnolence, nausea, and insomnia AEs were the most common reasons for trial discontinuations in adults. CONCLUSIONS: Children are particularly vulnerable to specific AEs from certain medications, such as SSRIs. It is likely that the level of children's biological immaturity explains part of this phenomenon.

Antidepressant use in children and adolescents in Germany.

OBJECTIVE: The expanded use of antidepressants in youth has been the subject of numerous studies and some concerns in recent years. This study describes prescription patterns of antidepressants (ATD) for youths in Germany for the years 2000-2003 and includes prescription use of St. John's Wort. METHODS: Prescription data from a health insurance organization with 1.4 million members per year across Germany, of whom approximately 280,000 were under 20 years of age, were accessed. Total age- and gender-specific ATD yearly utilization rates were computed. Prevalence was defined as the dispensing of 1 or more prescriptions for an ATD per calendar year per 1000 continuously enrolled youth. RESULTS: ATD prevalence was 3.43 per 1000 (95% Confidence Interval [CI], 3.21-3.65) in 2000 and 3.74 per 1000 (3.25-3.97) in 2003. St John's Wort products, which are approved for antidepressant use by the German drug agency, and tricyclic antidepressants (TCAs), accounted for more than 80% of antidepressant use. Although selective serotonin reuptake inhibitors (SSRIs) represented only 15% of antidepressant use, there was a doubling of its use over the 4-year period. Adolescent girls (age, 15-19 years) had utilization rates ranging from 11.44 to 13.82 per 1000, and accounted for most ATD use. Overall, females were twice as likely as males to get an antidepressant. Among users, there were low rates of multiple medication use (5.6% used more than one class of ATD, and 6.7% more than one drug). CONCLUSIONS: Prescription patterns in Germany reveal predominate use of St. John's Wort and TCAs, which contrasts sharply with U.S. patterns, wherein SSRIs predominate. Also, in the United States, unlike Germany, 5-9- and 10-14 year olds receive sizable proportions of ATDs. Labeling status (only herbal hypericum preparations and TCAs are labeled for the treatment of depression in children and adolescents in Germany) and cost restrictions appear to influence the prescribing pattern of doctors in Germany. Recent treatment recommendations of national and international regulatory agencies need to take into account the different national situations.

Effect of initial ziprasidone dose on treatment persistence in schizophrenia.

OBJECTIVE: To determine the relationship between ziprasidone initial dose and treatment persistence among patients diagnosed with schizophrenia. METHOD: Adult Medicaid recipients (N=1096) diagnosed with schizophrenia who had ziprasidone prescription claims between July 1, 2001 and September 30, 2003, were categorized by initial dose: low (20-60 mg per day, n=464), medium (61-119 mg per day, n=320) and high dose (120-160 mg per day, n=312). Treatment persistence up to 365 days was measured using refill patterns, allowing 15-day gaps between expected refill dates. Multivariate survival analysis explored the simultaneous impact of age, gender, race, previous hospitalization, and concomitant medication usage, in addition to initial dose of ziprasidone. Sensitivity analysis tested the robustness of results with different definitions for persistence and allowable gaps between refills. RESULTS: Discontinuation rates across the observation period (maximum, 12 months per individual) were lower for patients initiated with high-dose than low-dose ziprasidone (P=0.001). Other factors significantly associated with greater discontinuation of medication were monotherapy (versus combination therapy) and hospitalization within the 6 months prior to the index date of therapy. Black race was associated with greater discontinuation, although this was not consistent across sensitivity analyses. CONCLUSIONS: Patients with schizophrenia started on high doses of ziprasidone have lower discontinuation rates in a retrospective Medicaid database than patients started on low doses. These results were robust across various sensitivity analyses.

Effect of Medicaid eligibility category on racial disparities in the use of psychotropic medications among youths.

OBJECTIVE: This study sought to determine the degree to which Medicaid eligibility categories modify disparities between black and white youths in the prevalence of psychotropic medication. METHODS: Computerized claims for 189,486 youths aged two to 19 years who were continuously enrolled in a mid-Atlantic state Medicaid program for the year 2000 were analyzed to determine population-based annual prevalence of psychotropic medication by race or ethnicity and by whether the youths were eligible for Medicaid for reasons of family income, disability, or foster care placement. Logistic regression was used to assess the interaction of eligibility category and race. RESULTS: The mean annual prevalence of psychotropic medication for the population was 9.9 percent. The prevalence was 2.17 times higher for white youths than for black youths (16.5 percent compared with 7.6 percent). However, within eligibility categories, the white-to-black disparity was 3.8 among youths who were eligible for Medicaid because their family income was below the federal poverty level and 3.2 for youths enrolled in the State Children's Health Insurance Program. CONCLUSIONS: Medicaid eligibility categories had a profound impact on the racial disparity associated with the prevalence of psychotropic medications for youths. Eligibility category should be taken into account when ascertaining the role of access, undertreatment, and culture in disparities in mental health treatment.

Comparative prevalence of psychotropic medications among youths enrolled in the SCHIP and privately insured youths.

The one-year prevalence of use of psychotropic medications among youths enrolled in a Mid-Atlantic State Children's Insurance Program (SCHIP) in 1999 or 2000 was compared with the 1998-2000 prevalence findings for youths enrolled in four large multistate private medical insurance programs. Prevalence was significantly higher among youths enrolled in the SCHIP than among those with private insurance in all eight medication group comparisons. Unlike private insurance, the surveyed state SCHIP program did not require a copayment or have a restrictive formulary. These administrative differences may partly explain the comparatively higher rate of psychotropic use under the SCHIP.

The ethical use of placebo in clinical trials involving children.

The authors reviewed various statements describing the ethical use of placebo-controls in clinical trials involving minors. Attention was focused upon the Guidelines for the Ethical Conduct of Studies to Evaluate Drugs in Pediatric Populations, published by the American Academy of Pediatrics (AAP) (Kaufman et al. 1995). A brief review of certain key documents and a possible expansion of the guidelines are presented. Specifically, it is recommended that a review and update of guidelines for the use of placebo-controlled trials in children be undertaken by a working group comprised of stakeholders, including academic clinical and research professionals, bioethicists, consumers, members of key government agencies, and the pharmaceutical industry.

Parental perceptions and satisfaction with stimulant medication for attention-deficit hyperactivity disorder.

Few reports have documented parental perceptions of stimulants for attention-deficit hyperactivity disorder (ADHD), despite the recent increased use of stimulants among youths. Of 302 parents recruited from six pediatric primary care clinics, 84% completed a survey of their knowledge, attitudes, and satisfaction with the medication their child was taking for ADHD. Two thirds of the parents believed that sugar and diet affect hyperactivity. Although few parents believed that stimulants could lead to drug abuse, 55% initially were hesitant to use medication on the basis of information in the lay press, and 38% believed that too many children receive medication for ADHD. Parents were more satisfied with the behavioral and academic improvement relative to improvement in their child's self-esteem. Attitudes were positively correlated with satisfaction and were more positive among white than nonwhite parents. The findings highlight parental misconceptions and reservations about ADHD medication treatment that require clarification as to whether race/ethnicity, income, and social status influence their views and use of treatments.