Medicaid data on youth from a mid-Atlantic state were organized in eight annual data extracts across 28 years from calendar year 1987 through 2014. In that time, the eligible youth population (0–19 years old) increased from 138,018 in 1987 to 538,901 in 2014. (The expansion in the insured population is partly explained by the 1997 legislation on the Children’s Health Insurance Program.) Datasets were assembled from enrollment files and administrative claims data (dispensed medications and, in 2007 and 2014, physicians’ files). The study years were selected from the authors’ prior published studies of psychotropic medication use and an unpublished dissertation study (10): 1987, 1991, 1996, 2001, 2006, 2007, 2010, and 2014. Collectively, the data points pinpoint antidepressant patterns across the years in a single system for state-wide Medicaid youth enrollees who were continuously enrolled for 10 to 12 months per year and appraised annually in each study year.

Retrospective analysis of eight separate datasets was undertaken; several analyses with enriched variables, e.g., diagnosis and AD polypharmacy, were available in 2007 and 2014. To examine changes in utilization, we constructed time trends based on cross-sectional annual prevalence data for the selected study years. The study received expedited status by the university review board.

Measurements and analyses fall into three broad categories and were operationalized as follows.

Annual cross-sectional analyses were used to create population-based percentage prevalence for AD total (1987–2014) for time trends across 28-years, by subclass, and age-, gender-, race- and eligibility-specific AD use were calculated by year for the most recent period (2007–2014). Prevalence ratios according to gender (M:F) and for white: African American youth were calculated for selected years. For 2014 compared to 2007, a multivariate logistic regression model was used to estimate the odds of AD use with adjustment for age group, gender, race/ethnicity, Medicaid-eligibility category, and clinician-reported diagnosis. Finally, polypharmacy among AD users was assessed in terms of the number (and percent) AD regimens with 1 or more classes of other psychotropic medications. SAS v. 9.4 was used to conduct the analyses.

Figure 1 shows the change in total AD use across 8 timepoints in 28 years. From a low of 0.2% in 1987, use rose in the 1990s to a high of 3.2% in 2001. However, rates began to decline following regulatory news in 2003 from the United Kingdom and then in 2004 from the FDA report on pediatric suicidality from clinical trial data showing an association with ADs (principally SSRI/SNRIs) (4). Antidepressant prevalence data from 2006 (2.71%) and 2010 (2.66%) are consistent with studies (1) showing fairly stable levels of AD use (compared with other psychotropic classes) after the FDA boxed warning in 2004. Across the 28 years, AD use grew from very low use to expand to many thousands more youth annually in this state Medicaid population—approximately 14-fold by 2014.

Of the total 2014 AD use (2.74%), subclass analysis showed that the vast majority of AD use was for SSRI/SNRIs (2.14%). While SSRI/SNRI use was prominent, TCA use remained unchanged and other AD use dropped substantially. Other ADs included mirtazapine and trazadone. The subclasses sum to more than 100% because more than one subclass was dispensed to an individual ( Table 1 ).

Table 1 also shows the adjusted odds ratio for any antidepressant of 1.04 (95% CI, 1.01–1.07) in 2014 which was slightly greater than in 2007. More robust is the increase in second generation ADs (SSRI/SNRI) (AOR = 1.15 95% CI = 1.11–1.19). Moreover, SSRI/SNRI users were the great majority of users, representing 78% of users.

Table 2 features AD dispensing changes specifically within subpopulations across 8 years. Focusing on 2014 compared with 2007, age-specific AD patterns show a shift to older youth. Use in 0- to 9-year olds decreased since 2007 and nearly 8% of 15- to 19-year olds had an AD dispensing in 2014. Gender-specific ratios indicate that males were the predominant users in 2007 (M:F 1.13:1) but the ratio switched in 2014 to a slight predominance of females (M:F 0.9:1). Age and gender patterns before 1987 to 2006 are consistent with 2007. Race-specific data were measured as White/Black ratios showing more than twice as much use in White as in Black youth (2.76:1) in 2014. Compared with 2007, the ratio indicates an increase in 2014 for Black youth with AD dispensings. Substantial AD growth from 2007 to 2014 occurred in foster care youth exceeding even youth with disability (SSI covered youth). In 2014, foster care youth were 6 times more likely to receive an AD dispensing compared with their income eligible counterparts, i.e. those with poverty or near poverty family income.

Additionally, Table 2 presents row percent data and shows AD use grew from 2007 to 2014 in foster care such that 12.7% of foster care youth had AD dispensings, an increase of 17.9%. By contrast, the analysis of column percent data ( Supplemental Table 4 ) shows that foster care use of ADs dropped from 2007 to 2014. The drop, however, resulted from fewer foster care youth in total (denominator) rather than a drop in youth with dispensed ADs (numerator). Thus, analyses by row percent ( Table 2 ) and column percent ( Supplemental Table, S.4 ) were useful to clarify the patterns of AD users in foster care youth across the most recent 8-year period (available in terms of both subpopulations and time period). Furthermore, foster care prevalence exceeds the income-eligible prevalence by six-fold, a substantial difference.

Figure 2 illustrates the ICD-9 clinician-reported diagnostic patterns according to the hierarchical assignment. Only half the diagnosed youth with AD dispensings had a diagnosis of a depressive disorder (DD). Behavior disorders were prominent for more than one quarter of youth and other mental health diagnoses accounted for the remaining 14%. Notably, 12.2% (2007) and 9.17% (2014) had no diagnosis associated with AD use.

Table 3 reveals that monotherapy is the exception rather than the rule. Only 20% of AD use was for monotherapy in 2007 rising to 27% in 2014 using a ≥60 day overlap rule. Thus, concomitant psychotropic class use is widespread in this state Medicaid program. It is worthwhile to note greater proportions are defined as concomitant use when the window is only 30-days of overlap: the proportions are greater but switching cannot be ruled out.

Up to 88% of SSRI users received a dispensing for sertraline, fluoxetine or escitalopram in 2007 which grew again in 2014 ( Table 4 ). However, there were notable proportional decreases in venlafaxine, paroxetine, fluvoxamine, and duloxetine.

The prevalent use of ADs in the foster care population deserves attention. For the past decade, major federal agencies (12, 13) have conducted oversight medication studies of psychotropic use in foster care youth, calling attention to the extensive use of polypharmacy and the lack of monitoring that these high-risk medication regimens require. In the current study, there was a six-fold (5.98) greater AD use in foster care youth than in their family income-eligible counterparts. The deep disparity raises several questions: 1) Is it really illness severity that explains the disparity or unmet social needs? 2) Are state child welfare and judicial oversight programs responsible for requiring frequent physician visits which inadvertently increase multiple prescribers over time and could result in overtreatment with polypharmacy? Unfortunately, these questions cannot be addressed without new research to assess outcomes of treatment in community-treated youth. In particular, scientific approaches to safe reduction of dose and drug discontinuation in youngsters when complex multidrug regimens are ineffective would be most critical.

Olfson et al. (1) traced the national growth in major psychotropic classes across 3 critical time periods from 1996 to 2012. Whereas a large increase in stimulant users and moderate growth in antipsychotic users were observed, antidepressant prevalence growth was more modest. AD prevalence was 2.5% in 2010–2012 among youth (6–17 years old) according to (parent-reported) data from the Medical Expenditure Panel Survey (1). Our Medicaid data for the closest matching age group (5–19 years old) was 2.64%. Narrowing the age range to adolescents, Mojtabai et al. (2) observed a prevalence of clinician-reported depression of 8.8% in 12- to 17-year olds with an increase in psychotropic medication for its treatment from 11.2% in 2005 to 13.6% in 2014 (2).

On the international level, Bachmann et al. compared pediatric AD use in a US-insured cohort with western European youth cohorts from four countries. In 2010, US percent prevalence was 1.3 to 3.2 times greater than that of Denmark, Germany, Netherlands, and United Kingdom in all age groups, (0–19 years), particularly among those less than 10 years of age (14).

In the most recent psychotropic polypharmacy study in children with Medicaid insurance (fee for service type), multiclass polypharmacy applied to one-quarter of medicated youth less than 18 years of age (15). However, the operational definition of more than 1 psychotropic class from overlapping dispensings for 45 or more days was less restrictive than in previous studies and the current study (16). In a one-month extract of dispensings among Texas foster care youths, 41% of medicated youth experienced 3 or more concomitant classes (17). Antidepressants comprised 56% of these complex regimens. Comer and colleagues (18) operationalized psychotropic polypharmacy as 2 or more concurrent prescription orders in a national survey of physician office visits by 6- to 17-year olds. Their analysis revealed that among psychiatrically diagnosed youth, 2 or more classes grew from 22.2% (96–99) to 32.2%. (2004–2007). Our 2014 data for antidepressant polypharmacy for ≥60 days show substantial growth in polypharmacy compared with the Comer data. Comer measured any prescribed psychotropic combinations at one time whereas we assessed dispensed antidepressant combinations with 60 or more overlapping days. Methodologic variations limit precise comparisons, although the trends generally suggest increasingly complex regimens (2 out of 5 AD users) despite a dearth of evidence that polypharmacy benefits exceed risks.

In 2014, our analysis revealed that 40% of AD users had 1 or more other psychotropic classes in a 60-day window ( Table 3 ) and many had a non-depression diagnosis. The combinations reflect a fundamental change in the theory of psychiatric treatment regarding medication use. Concomitant class use presents a non-specificity of psychopharmacologic class use regardless of diagnosis that is generally accepted as standard. In effect, theories of mental illness based on selection of specific classes of medication in relation to diagnosis are moot. Whereas the mechanism of action of a drug, e.g., fluoxetine was used in marketing campaigns tied to serotonin and norepinephrine brain receptor theory and promoted the concept that depression was a serotonin deficiency disorder (19), the theory does not explain the frequent use of ADs for behavioral disorders. Even less evidence exists for a 4-drug concomitant regimen of AD with stimulant, alpha-agonist, and antipsychotic, the most common 4-drug combination in the current data set. The drug-specific theory has been offered as an alternative to the diagnosis-specific theory (20). But, in our view, much stronger evidence is needed to accept multi-drug regimens in a drug-specific (i.e. symptom-specific) theory as the standard of care. The impact of polydrug interactions on the physical and mental health of youngsters is unknown and rarely the subject of clinical research.

Like second generation antipsychotics, second generation ADs, specifically SSRI/SNRIs, have been the subject of serious adverse drug events, e.g., activation and recommendations for its clinical management (21). Earlier analysis of clinical trials has shown that SSRI adverse drug events (ADEs), e.g., activation and vomiting in children are two to three times more prevalent than in adolescents and least common in adults (22). As knowledge in adults has produced concerns about bone density changes and delayed sexual response, expanded, long-term use in adolescents demands a robust research agenda. Large simple trials would provide the population-based data that are needed while continuous monitoring of individual patients by the prescribing doctor who initiated the medication would aid in recognizing medication treatment-emergent symptoms. Risk assessment by Burcu et al. found the addition of ADs to an antipsychotic regimen increased the risk of type 2 diabetes two-fold among Medicaid enrollees from 5 large US states (23). The results were consistent when ADs were examined in a separate analysis (6). Risk increased with longer duration and higher dose in both studies (6, 23).

Meta analyses have cast doubt on the role of ADs alone for the treatment of pediatric depressive disorders. Cipriani et al. (24) conducted a network analysis of pediatric clinical trials to document benefits and risks from randomized double-blind clinical trials involving 5,260 youth and 14 ADs in terms of effectiveness and discontinuations due to adverse drug events (24). Only fluoxetine was significantly greater than placebo. Discontinuations due to ADEs were more likely for imipramine, venlafaxine, and duloxetine than placebo. The authors concluded that a clear AD advantage for children and adolescents was not shown. While we wait for clinical research to corroborate such big data analyses based on administrative claims data, we might consider revising medication authorization consent forms to include a statement that concomitant medication treatment has very weak research support.

In the current findings, it is encouraging to see reduced use of venlafaxine, paroxetine, fluvoxamine, and duloxetine as these shorter-acting products have been associated with more severe withdrawal (7), an important concern in balancing benefits and risks (24). Nevertheless, fluoxetine, the best evidenced SSRI represented only one-third of the leading SSRI usage.

Our findings support the call for rigorous research on long-term benefit risk assessment in community populations including Medicaid-insured youth. These findings include: 1) The frequent use of ADs, particularly SSRI/SNRIs, has increased over the past 28 years even among less severely ill youths, i.e. those not meeting full criteria for major depressive disorder (25). 2) The relatively high off-label use has occurred despite growing concerns of weak AD effectiveness for major depressive disorder from meta-analyses. Equivocal effectiveness heightens concerns about unnecessary exposure to adverse drug events, e.g., weight gain and risk of type 2 diabetes mellitus (6, 23). In addition, the growth of polypharmacy (15) calls for scientific studies to safely reduce dosage and discontinue ADs safely. AD polypharmacy increases the risk of misdiagnosis of withdrawal symptoms upon discontinuation (26). 3) AD polypharmacy in the face of inadequate evidence of benefit increases the risk of unnecessary and costly adverse events (27).

More broadly, polypharmacy is a challenge in psychiatric practice because of the risk of not recognizing behavioral symptoms emerging from complex medication regimens and mistaking them for new underlying symptoms of illness—called behavioral toxicity (28). Behavioral toxicity is a relatively poorly recognized problem in psychiatry. Multiple prescribers increase the risk that patients will not be well known to each subsequent prescriber. Then, medications previously prescribed and responsible for new adverse symptoms will be viewed as new symptoms of illness to the prescriber who inherited a child on a complex concomitant regimen. Furthermore, a poorly designed health care delivery system makes continuity of care the exception rather than the rule for many Medicaid-insured youth (29). Moreover, failure to assure continuity of treatment puts patients at risk for unnecessary, costly services. Low continuity of care in the pediatric Medicaid population was shown to increase emergency department visits and psychiatric hospitalizations (29).

A critical priority for future research is post-marketing surveillance to ensure a long-term public health perspective on medication use. Such phase 4 research studies would go beyond the occasional FDA-mandated Risk Evaluation and Management Study (REMS) study conducted by manufacturers. REMS study results often have weak designs, delayed, or never completed and are rarely published in the clinical practice literature (30). If federal agencies (FDA, SAMHSA, and NIMH) prioritized funding for Phase 4 (post-marketing) studies, independent investigators could use advanced epidemiologic methods to follow cohorts over time so that ‘real world population’ use of medications would be comprehensively evaluated. Essentially, the expanded use of ADs, particularly SSRI/SNRIs, is a call for large national prospective cohort studies, possibly through electronic medical record studies at regionally diverse major academic centers. Protocols would be designed to assess functional improvement and safety outcomes in addition to assessing duration of treatment, monitoring for drug-induced risks, reasons for discontinuation, and following prescribed discontinuation regimens to minimize withdrawal syndrome.

Administrative claims data though far from ideal provide inexpensive profiles of medication use in ‘usual care’ settings with ‘real world’ populations. This Medicaid study describes AD treatment in a single state Medicaid population over nearly 3 decades. Thus, the impact of geography and physician training are minimized as extraneous factors that might impact AD patterns over time. However, to our knowledge, the reach across 28 years in a single system is unique among pharmacoepidemiology studies. Furthermore, the medication patterns reflect dispensed medications so that unfilled prescription data do not inflate the prevalence. Nonetheless, the limitations of single state Medicaid prescription practice patterns include exclusion of US regional practices, limited ethnic subgroups, and coverage differences which may vary across state Medicaid programs. Selection of a Medicaid population may show greater prevalence of monotherapy and concomitant use if one uses federal oversight reports as a gauge of Medicaid drug utilization (12, 13). Privately insured patterns are much less available for comparison. Diagnostic data were not available before 2007. Furthermore, clinician-reported diagnoses are questionable as they do not rise to the level of research-assessed diagnoses, although learning how clinicians are linking drugs with diagnoses is useful. The study lacks information on the number and specialty of prescribers which did not permit continuity of care to be assessed.